HPN 2022 February

HOSPITAL PROFESSIONAL NEWS IRELAND

HPN February 2022 Issue 93 HOSPITALPROFESSIONALNEWS.IE

Ireland’s Dedicated Hospital Professional Publication

IN THIS ISSUE:

CONFRONT R/R CLL

NEWS: Hospital Pharmacy Position Paper Page 4 REPORT: New Medicines Supply Agreement Reached Page 10 DIGITAL: HospitalBuddy offers New Solutions Page 13

VENCLYXTO® in combination with rituximab is NOW AVAILABLE for the treatment of adult patients with CLL who have received at least one prior therapy1

INDICATIONS1: VENCLYXTO® in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) (see section 5.1) †. VENCLYXTO® in combination with rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy*. VENCLYXTO® monotherapy is indicated for the treatment of CLL in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B cell receptor pathway inhibitor or in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B cell receptor pathway inhibitor*. VENCLYXTO® in combination with a hypomethylating agent is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy †.

Full Summary of Product Characteristics is available at www.medicines.ie. ▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance; Website: www.hpra.ie. Suspected adverse events should also be reported to AbbVie Limited on 01-4287900.

LEGAL CATEGORY: POM (S1A). MARKETING AUTHORISATION NUMBERS/PRESENTATIONS: 10mg film-coated tablet, 14 tablets, EU/1/16/1138/002; 50mg filmcoated tablet, 7 tablets, EU/1/16/1138/004; 100mg film-coated tablet, 7 tablets, EU/1/16/1138/005;100mg film-coated tablet, 14 tablets, EU/1/16/1138/006; 100mg film-coated tablet, 112 tablets, EU/1/16/1138/007. MARKETING AUTHORISATION HOLDER: AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany. Further information is available from AbbVie Limited, 14 Riverwalk, Citywest Business Campus, Dublin 24, Ireland. † Indications are not reimbursed. * Indications are reimbursed. R/R, Relapsed/Refractory.

References: 1. VENCLYXTO® Summary of Product Characteristics, available at www.medicines.ie.

IE-VNCLY-210025 Date of Preparation: July 2021

This Publication is for Healthcare Professionals Only

FEATURE: Cardiac Rehabilitation Page 18 CPD: Updates in Rheumatoid Arthritis Page 31 ONCOLOGY FOCUS: Management of Colorectal Cancer Page 39 ONCOLOGY FOCUS: Transforming Cancer in Ireland Page 77

Scan QR Code to learn more about ZIRABEV®

BUILDING ONTO THE CLINICAL EXPERIENCE OF BEVACIZUMAB WITH PFIZER1 2

ZIRABEV® is a biosimilar of bevacizumab ZIRABEV®▼ (bevacizumab) 25 mg/ml concentrate for solution for infusion PRESCRIBING INFORMATION - IE Please refer to the full Summary of Product Characteristics (SmPC) before prescribing Zirabev.

Presentation: Each 4 ml and 16 ml vial containing 100 mg or 400 mg respectively of bevacizumab concentrate for solution for infusion (bevacizumab is a recombinant humanised monoclonal antibody produced by DNA technology in Chinese Hamster Ovary cells). Administration: Intravenous (IV) infusion only under the supervision of a physician experienced in the use of antineoplastic medicinal products. If first (over 90 mins) and second (over 60 mins) infusions are well tolerated, all subsequent infusions may be administered over 30 mins. Dose reductions not recommended. If indicated, therapy should be stopped or temporarily suspended. Indications and dosage: 1) Zirabev (5 or 10 mg/kg every 2 weeks or 7.5 or 15 mg/kg every 3 weeks) in combination with fluoropyrimidine-based chemotherapy is indicated for treatment of adult patients with metastatic carcinoma of the colon or rectum. 2) Zirabev (10mg/kg every 2 weeks or 15mg/kg every 3 weeks) in combination with paclitaxel is indicated for first-line treatment of adult patients with metastatic breast cancer. 3) Zirabev in combination with capecitabine is indicated for first-line treatment of adult patients with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate. Patients who have received taxane and anthracycline-containing regimens in the adjuvant setting within the last 12 months should be excluded from treatment with Zirabev in combination with capecitabine. 4) Zirabev (7.5 or 15 mg/kg every 3 weeks), in addition to platinumbased chemotherapy (for up to 6 cycles, then Zirabev monotherapy), is indicated for first-line treatment of adult patients with unresectable advanced, metastatic or recurrent non-small cell lung cancer other than predominantly squamous cell histology. 5) Zirabev (15 mg/kg every 3 weeks) in combination with erlotinib is indicated for first-line treatment of adult patients with unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer with Epidermal Growth Factor Receptor (EGFR) activating mutations. 6) Zirabev (10 mg/kg every 2 weeks) in combination with interferon alfa-2a is indicated for first line treatment of adult patients with advanced and/or metastatic renal cell cancer. 7) Zirabev (15 mg/kg every 3 weeks), in combination with carboplatin and paclitaxel (for up to 6 cycles followed by Zirabev monotherapy until disease progression, a maximum of 15 months or until unacceptable toxicity, whichever occurs earlier) is indicated for the front-line treatment of adult patients with advanced (International Federation of Gynecology and Obstetrics (FIGO) stages III B, III C and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer. 8) Zirabev (15 mg/kg every 3 weeks), in combination with carboplatin and gemcitabine (6 to 10 cycles, followed by Zirabev monotherapy) or in combination with carboplatin and paclitaxel (6 to 8 cycles, followed by Zirabev monotherapy), is indicated for treatment of adult patients with first recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor–targeted agents. 9) Zirabev (10 mg/kg every 2 weeks) in combination with paclitaxel, topotecan (given weekly), or pegylated liposomal doxorubicin is indicated for the treatment of adult patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than two prior chemotherapy regimens and who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor–targeted agents. If topotecan is administered every 3 weeks, the Zirabev dose is 15 mg/kg every 3 weeks. 10) Zirabev (15 mg/kg every 3 weeks), in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot receive platinum therapy, is indicated for the treatment of adult patients with persistent, recurrent, or metastatic carcinoma of the cervix. Elderly patients (≥ 65 years of age): Dosage adjustments are not required in elderly patients. Hepatic impairment & renal impairment: The safety and efficacy have not been studied in patients with hepatic or renal impairment. Paediatric patients (< 18 years): Not indicated. Contra-indications: Hypersensitivity to the active substance or to any of the excipients. Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies. Pregnancy. Pregnancy and lactation: Women of childbearing potential have to use effective contraception during (and up to 6 months after) treatment. Bevacizumab is contraindicated in pregnancy. Women must discontinue breast-feeding during therapy and not breast-feed for at least six months following the last dose of bevacizumab. Warnings and precautions: Traceability: Zirabev is a biological medicine; clearly record the name and batch number. There is an increased risk of developing the following serious conditions (see

SmPC for full guidance on patient risk factors and when to discontinue or withhold Zirabev): Gastrointestinal (GI) perforations and fistulae, GI-vaginal fistulae, Non-GI fistulae, wound healing complications, hypertension, aneurysms and artery dissections, posterior reversible encephalopathy syndrome (PRES), proteinuria, arterial thromboembolism, venous thromboembolism, haemorrhage, pulmonary haemorrhage/haemoptysis, congestive heart failure, neutropenia and infections, hypersensitivity reactions/infusion reactions, osteonecrosis of the jaw. Zirabev is not formulated for intravitreal use. Unapproved intravitreal use has led to serious ocular adverse reactions including permanent blindness as well as systemic adverse effects including non-ocular haemorrhages and arterial thromboembolic reactions. As bevacizumab may cause ovarian failure, discuss fertility preservation strategies with women of child-bearing potential prior to starting treatment. Consideration should be given to patients who are on a controlled sodium diet. Sodium content: 3 mg sodium per 4 ml vial and 12.1 mg sodium per 16 ml vial.

Side-effects: The overall safety profile of bevacizumab is based on data from over 5,700 patients with various malignancies, predominantly treated with bevacizumab in combination with chemotherapy in clinical trials. The most serious adverse reactions were: gastrointestinal perforations; haemorrhage, including pulmonary haemorrhage/haemoptysis, which is more common in non-small cell lung cancer patients: arterial thromboembolism. The most frequently observed adverse reactions across clinical trials in patients receiving bevacizumab were hypertension, fatigue or asthenia, diarrhoea and abdominal pain. Very common (> 1/10) side effects were: febrile neutropenia, leucopenia, neutropenia, thrombocytopenia, anorexia, hypomagnesaemia, hyponatraemia, peripheral sensory neuropathy, dysarthria, headache, dysgeusia, eye disorder, lacrimation increased, hypertension, thrombo-embolism (venous), dyspnoea, rhinitis, epistaxis, cough, rectal haemorrhage, stomatitis, constipation, diarrhoea, nausea, vomiting, abdominal pain, wound healing complications, exfoliative dermatitis, dry skin, skin discoloration, arthralgia, myalgia, proteinuria, ovarian failure, asthenia, fatigue, pyrexia, pain, mucosal inflammation, weight decreased.

Common (≥1/100 to <1/10) reported side-effects were: sepsis, abscess, cellulitis, infection, urinary tract infection, anaemia, lymphopenia, hypersensitivity, infusion reactions, dehydration, cerebrovascular accident, syncope, somnolence, congestive heart failure, supraventricular tachycardia, thrombo-embolism (arterial), haemorrhage, deep vein thrombosis, pulmonary haemorrhage/haemoptysis, pulmonary embolism, hypoxia, dysphonia, gastrointestinal perforation, intestinal perforation, ileus, intestinal obstruction, recto-vaginal fistulae, gastrointestinal disorder, proctalgia, palmar-plantar erythro-dysaesthesia syndrome, fistula, muscular weakness, back pain, pelvic pain and lethargy. The following severe side effects (frequency not known) have also been reported: necrotising fasciitis, hypersensitivity, infusion reactions, posterior reversible encephalopathy syndrome, hypertensive encephalopathy, aneurysms and artery dissections, renal thrombotic microangiopathy, pulmonary hypertension, nasal septum perforation, GI ulcer and perforation, rectal haemorrhage, gallbladder perforation, osteonecrosis of the jaw, non-mandibular osteonecrosis, ovarian failure, foetal abnormalities. See SmPC for full details on all other side effects. Driving and operating machinery: If patients are experiencing symptoms that affect their vision or concentration, or their ability to react, they should be advised not to drive and use machines until symptoms abate. Legal category: POM, S1A Marketing Authorisation Number: EU/1/18/1344/001, EU/1/18/1344/002 Marketing Authorisation Holder: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium.

Last revised: 05/2021 Ref: bZR 6_0 For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at medical.information@pfizer.com. For queries regarding product availability please contact: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 + 353 1 4676500.

References: 1. ZIRABEV® (bevacizumab) Summary of Product Characteristics. 2. European Medicines Agency. ZIRABEV® EPAR summary for the public. https://www.ema.europa.eu/en/medicines/human/EPAR/zirabev .

Accessed August 2021.

PP-BVC-IRL-0046 | Date of Preparation: August 2021

▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. Refer to section 4.8 of the SPC for how to report adverse reactions.

February Issue Issue 93

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Contents

Foreword

New Board appointments at Medicines for Ireland P5

Editor A new report from the Irish Medical Council, ‘‘Your Training Counts Report for 2019 - 2020’ shows that that 44% of trainees intend to go abroad to practise medicine, at a huge loss to Ireland’s acute hospital services.

Children’s Hospital Care a ‘ticking time bomb’ P6 Innovative weight management clinic launched in Ireland P8

The Irish health system is losing its future Hospital Consultants at an alarming rate despite the huge need for them here, the Irish Hospital Consultants Association has warned on the back of this report. The IHCA said that this report was further evidence of the recruitment and retention crisis of doctors and consultants in the Irish health system. It added that the poor working conditions and other factors highlighted in the Medical Council’s report was feeding the cycle of poor retention and impacting on recruitment at Consultant level.

5

New Medicines Supply Agreement reached P10 Irish Research Council Researcher of the Year Awards P14 Focus on International Epilepsy Day P22

8

The impact of transitioning on juvenile arthritis patients P26 REGULARS Feature: Pelvic Floor Training P38 CPD: Rheumatoid Arthritis P31 Oncology Focus: Surgical Care of Colorectal Cancer P39

10

Oncology Focus: Soft Tissue Sarcoma P56

You can read his comments and more on page 10.

Clinical R&D: P82

All rights reserved by Hospital Professional News. All material published in Hospital Professional News is copyright and no part of this magazine may be reproduced, stored in a retrieval system of transmitted in any form without written permission. IPN Communications Ltd have taken every care in compiling the magazine to ensure that it is correct at the time of going to press, however the publishers assume no responsibility for any effects from omissions or errors.

PUBLISHER IPN Communications Ireland Ltd Clifton House, Lower Fitzwilliam Street, Dublin 2 (01) 669 0562 GROUP DIRECTOR Natalie Maginnis n-maginnis@btconnect.com EDITORIAL editorial@hospitalprofessionalnews.ie

In our special report, we look in more detail at the recently approved new Medicines Supply Agreement. The multiannual agreements with the Irish Pharmaceutical Healthcare Association (IPHA) and Medicines for Ireland (MFI) represent an important step in reducing the cost of medicines and improving access to innovative new medicines for patients.

It is estimated that this will result in the State paying between ¤600 million and ¤700 million less for medicines than it would otherwise. Director of Medicines for Ireland, David Delaney says “This is a transformational agreement that will ensure even greater access to generic and biosimilar medicines in Ireland. The Minister, the HSE, the Department of Health and our member companies have worked tirelessly to make this new Agreement a reality, ensuring the focus remained on patient access to medicines.”

Oncology Focus: Non Muscle Invasive Bladder Cancer P47

Hospital Professional News is a publication for Hospital Professionals and Professional educational bodies only. Subscription rate for Hospital Professional News ¤60 plus vat per year.

Turn to page 5 for the full story.

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ACCOUNTS Rachel Wilson cs.ipn@btconnect.com DIGITAL MARKETING & EDITORIAL EXECUTIVE Danielle Norton danielle@hospitalprofessionalnews.ie MARKETING & ADVERTISING EXECUTIVE Ashling Goodall ashling@hospitalprofessionalnews.ie CPD Lead Sibongile Swan Mude swan@ipn.ie CONTRIBUTORS

Dr Oisin O'Connell | Louise Brent Padraig Denn | Paddy McGeoghegan Dr Fahd Adeeb | Aoife Ni Eochaidh Professor Ronan Cahill | Dr Padraic Ridge Dr David Breen | Charles O’Connor Mohammed Hegazy | David Galvin Gregory Nason | Dr Luke Jones Dr Oleksii Rukhlenko | Matthew G. Davey Professor Aoife J. Lowery | Dr Ronan Joyce Dr Charles Gillham | Dr Ananya Gupta Dr Dearbhaile Collins | Niall J O’Sullivan Rowan G Casey | Dr Neil Barrett Professor Owen Patrick Smith

HOSPITALPROFESSIONALNEWS.IE

@HospitalProNews HospitalProfessionalNews

Dr Oisin O’Connell give HPN readers an exclusive overview of the digital solutions offered by HospitalBuddy on page 13. HospitalBuddy is a free mobile phone app and website developed by a team of hospital doctors working throughout Ireland. At the start of the Covid pandemic, a team of doctors around Ireland recognised that there was a clinical need for increased digital solutions for Irish based hospital doctors.

Our Oncology Special Focus, starting on page 39 carries a wide range of clinically authored articles covering everything from colorectal cancer and breast cancer to Non-Muscle Invasive Bladder Cancer and Cancer Treatment Related Cardiac Dysfunction.

I hope you enjoy the issue.

HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication

HOSPITALPROFESSIONALNEWS.IE | HPN • FEBRUARY 2022

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News

Breakthrough Approach in Nerve Damage Professor Fergal O’Brien, Principal Investigator application of additional cells or growth factors. In these pre-clinical trials, the team's novel ECMloaded medical device known as a 'nerve guidance conduit', was shown to support improved recovery responses at eight weeks following the repair of traumatic nerve lacerations with substantial loss of tissue.

The research team found that by fine-tuning the combination and ratio of ECM proteins and loading them into the nerve guidance conduit, it was possible to support increased pro-repair inflammation, increased blood vessel density, and increased density of regenerating nerves, all as compared to standard of care. By mimicking the body’s nerve repair processes, this new approach may eliminate the need for additional stem cells and drug therapies.

Researchers from the RCSI University of Medicine and Health Sciences, AMBER, the SFI Research Centre for Advanced Materials and BioEngineering Research along with leading global medical technology company Integra LifeSciences, have announced a new breakthrough

for nerve repair therapies based on body’s own processes in the journal Matrix Biology.

The pre-clinical study showed that use of extracellular matrix (ECM) supports improved nerve fibre regeneration across large nerve defects without the need for

Commenting on the results, lead authors Drs Alan Hibbitts and Zuzana Kočí from the Tissue Engineering Research Group based at Department of Anatomy and Regenerative Medicine at RCSI, and AMBER, said, "In our lab-based trials, we discovered that at eight weeks post implantation our nerve guidance conduit had successfully improved the prognosis for nerve regeneration and repair over the current clinical gold standard.

Our conduit supported clear improvements in nerve repair and blood vessel formation and most importantly, we saw that we could scale this up to approach very large nerve defects in our preclinical studies."

Regarding the success of this study, Professor Fergal O’Brien, Principal Investigator on the project and Professor of Bioengineering and Regenerative Medicine, Head of Tissue Engineering Research Group at RCSI and Deputy Director of AMBER, said the partnership between RCSI, AMBER and Integra LifeSciences was critical to ensure clinical relevance and a pathway from lab to patient.

"Working with Integra Chief Scientist, Dr Simon Archibald, the research had a clear focus – to create a device based on scientific excellence with improved outcomes that would translate well through regulatory assessment, into the clinical setting, and ultimately, patients. This provides a more direct route to market and therefore the potential for faster real-world impact in improving patient quality of life."

Detailing his team's plans, Professor O'Brien said, "The outputs from this project will address increasingly challenging nerve defect distances with the ambition to relieve the current clinical reliance on grafted nerves and move into the next phase of pre-clinical trials.”

Position Paper on Hospital Pharmacy Specialisation Hospital pharmacists are the key stakeholders responsible for medication management and safety in the hospital environment, covering both in- and outpatient services and supporting the seamless transition of care for patients moving within the healthcare system.

To provide the best treatment for all patients, hospital pharmacists must be able to operate in a complex hospital setting and work collaboratively within multidisciplinary healthcare teams.

To prepare the hospital pharmacy profession for the future, the European Association of Hospital Pharmacists (EAHP) adopted the European Statements of Hospital Pharmacy in 2014. They express

commonly agreed objectives that every European health system should aim for in the delivery of hospital pharmacy services.

To further enhance the quality, safety and equity of access to patient care in every European country, EAHP additionally created the Common Training Framework (CTF) project for hospital pharmacy education in Europe. This project not only fosters the further development of hospital pharmacy practice but also seeks to guarantee the access of European citizens to the highest available standard of care and the freedom of movement of the hospital pharmacy profession which is currently not accessible to all.

FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

In June 2021, EAHP's General Assembly adopted a Position Paper on Hospital Pharmacy Specialisation. The position centres around advancing the profession by harmonising the recognition of hospital pharmacy education, enhancing the role of the hospital pharmacist and preparing the profession for future challenges.

To make a difference in medication by advancing the hospital pharmacy profession, EAHP • calls on the European Commission and the Member States to assist the Association in setting up a CTF through the adoption of a delegated act; • touches on the need for Member States to recognise the

changing role of the hospital pharmacists and further foster their implementation; and, • underlines the importance of further promoting the uptake of such cross-sector tools inter-sector communication, coordination and multidisciplinary collaboration in all healthcare facilities should be strengthened.

To adequately address future challenges linked to the ageing society, changing healthcare needs and other unknown factors, like future pandemics, EAHP urges that Member States invest in better workforce planning for the hospital pharmacy profession, including the availability of hospital pharmacy services for all patients of each hospital.

News

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Alarming Rate in Consultant Losses The Irish health system is losing its future Hospital Consultants at an alarming rate despite the huge need for them here, the Irish Hospital Consultants Association has warned.

The IHCA was commenting following the publication by the Medical Council of its ‘Your Training Counts Report for 2019 - 2020’* which shows that 44% of trainees intend to go abroad to practise medicine, at a huge loss to our acute hospital services.

The IHCA said that this report

was further evidence of the recruitment and retention crisis of doctors and consultants in the Irish health system. It added that the poor working conditions and other factors highlighted in the Medical Council’s report was feeding the cycle of poor retention and impacting on recruitment at Consultant level.

The report worryingly found that 86% of trainee specialist doctors were working more than 40 hours per week with 46% regularly working over 48 hours.

The Medical Council report highlights the critical need for a considerable increase in the numbers of medical specialists and trainees across the entire health system to meet the projected demand for additional Hospital Consultants and match the increasing need for acute hospital services.

Ireland has the lowest number of medical specialists per 1,000 population in Europe at 1.48, 42% below the EU average of 2.54. In addition, around one in five permanent Consultant posts in

Ireland are either vacant or filled on a temporary or agency basis, some of which are not specialist registered.

The Council’s recommendations on the supply and demand of medical specialists echoes the recently released strategic framework report on medical training from the Forum of Irish Postgraduate Medical Training Bodies, which has also called for greater alignment between postgraduate medical training and the workforce planning needs of our health service.

Hospital Pharmacists Annual Congress The European Association of Hospital Pharmacists (EAHP) will soon be hosting the largest European gathering of hospital pharmacists in Vienna, Austria. The 26th Congress of EAHP, which will take place from 23 to 25 March, will bring together healthcare professionals from all over the globe that are seeking to improve their level of training. If you are planning to attend, don’t forget to register and benefit from the special rate which will expire on 1st February.

EAHP’s Scientific Committee, under the lead of Thomas De Rijdt, has prepared an interesting and innovative Congress programme that caters to the educational needs of the profession and takes into account the latest developments in hospital pharmacy. The 26th edition of EAHP’s Congress – which will also celebrate our association’s 50th anniversary – centres around theme " Hospital pharmacists – changing roles in a changing world".

The Student Programme will explore contemporary ethical challenges in hospital pharmacy practice, while the Pharmacotherapy Session will be looking at advances in heart failure pharmacotherapy. Different seminars will be hosted that will provide attendees with up-to-date information on for example working with limited resources, the role of the hospital pharmacist in disaster management, waste reduction, gene and cell therapies, compounding for paediatrics and medication safety. Hands-on workshops will focus on teamwork in the hospital, pharmacoeconomics, quality improvement and quality assurance, the prescribing cascade and patient-centred medication reviews.

New Appointments at MFI Medicines for Ireland has announced the appointment of Managing Director of Accord Healthcare Ireland, Padraic O’Brien as new Chairperson of the organisation, with Paul Neill, Director of Generic Products for Teva Pharmaceuticals Ireland, taking over the role of Vice Chairperson.

Since its foundation in 2016, Medicines for Ireland has been promoting the benefits of the increased use of generic and biosimilar medicines in Ireland.

The organisation’s core objective is to improve the way Ireland procures and supplies medicines, in order to expand the patient access to affordable, lifesaving and life-enhancing treatment.

Chairperson, Padraic O’Brien previously served as MFI Vice

Chairperson in 2020 and 2021.

Through MFI, he has been actively engaging with policy makers on both a national and European level with respect to increasing access of affordable medicines for patients, as well as highlighting the need for safeguarding measures to be putting place to help mitigate threats to the supply of medicines to Ireland brought about by Brexit and Covid-19.

Newly appointed Vice Chairperson, Paul Neill is Director of Generic Medicines for Teva Pharmaceuticals, the largest supplier of prescription medicines to the State and has experience working in the pharmaceutical sector for almost twenty years.

“As we look to the future, Medicines for Ireland will continue

Paul Neill, Vice-Chairperson, Medicines for Ireland

to engage with the Minister for Health, the Department of Health, the HSE and Government on key issues, especially on expanding access and usage of generic and biosimilar medicines. In Ireland,

we continue to remain well below what is the norm in most other European States, and while much progress has been made, much more can be done in this area,” said Mr Neill.

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News

‘Ticking Time Bomb’ in Children’s Care Ms Mary Bresnihan, Consultant ENT Surgeon

and potentially their future healthcare outcomes.

However, many children’s conditions are straightforward to treat and could be managed quickly, often without requiring any stay in hospital.

The Irish Hospital Consultants Association (IHCA) has called on health service leaders to address the severe consultant shortages in paediatric care, warning of a ‘ticking time bomb’ in children’s hospital care.

The call comes after successive weeks of cancelled and postponed operations across the three Dublin paediatric hospitals that make up Children’s Health Ireland (CHI) - Crumlin, Temple Street and Tallaght - due to an earlier than expected winter surge in Emergency Department (ED) presentations of children with seasonal respiratory illness. The number of ED presentations at the hospitals is at its highest level in four years.

Latest analysis* shows that there are now 97,400 children waiting to see a hospital consultant or receive treatment (1 in 12 children in Ireland), with some 38,600

waiting longer than 12 months for hospital care. Of these, 29,193 have been waiting longer than 18 months.

More than four in 10 (42%) children waiting to be assessed or treated by a hospital consultant are waiting longer than one year, with almost one third (32%) of those awaiting inpatient or day case treatment across the country left on a waiting list for longer than 12 months.

The three Dublin paediatric hospitals have seen a five-fold increase since 2015 in the number of children waiting longer than a year for an outpatient appointment.

Waiting for care has the biggest impact on the youngest patients Consultants say that the adverse impact of waiting this long for care can mean some children’s conditions may significantly deteriorate, hampering their development and quality of life

The IHCA projects that without empathetic health service management leadership that engages constructively with frontline hospital staff, current rates of growth could mean it will take healthcare staff and hospitals as long as 14 years (to 2035) to reduce waiting lists to manageable levels and clear the backlog of care built up over the past two years of the pandemic.

Ms Mary Bresnihan, a Consultant ENT surgeon at Sligo University Hospital, said, “In ENT, some of the longest lists are for procedures like tonsillectomies, where surgery could be managed through day-case procedures.

But we face challenges even getting to see and assess the patient in the first place. When we do, and we schedule treatment, patients can unfortunately be at the mercy of emergency or other priorities taking theatre slots at the last minute.

“In the meantime, children of all ages are missing a lot of school due to being off sick regularly with tonsillitis or other infections meaning their education is set back. Some children are not able to hear properly and this can his affect their overall development and yet these are problems that are quick and straightforward to

resolve given adequate resources.

This is a tragedy for those patients and should not happen.”

Consultant crisis According to an HSE report**, an additional 207 consultants are needed across the specialties of paediatrics, neonatology and paediatric surgery by 2028 to address current shortfalls and meet increased patient demand. That would mean recruiting some 30 consultants every year over the next 7 years.

Ireland has just 9.38 paediatric specialists per 100,000 population compared with and EU-27 average of 18.65 – in other words just 50% of the EU average.*** As at 1 February 2021, 39 of the 232 approved consultant posts in Paediatrics were either vacant (20) or filled on a temporary basis (19). This is 17% of the total approved posts.

Around 1 in 5 approved permanent hospital consultant posts across all specialties are either vacant or filled on a temporary or agency basis, with around 720 posts not filled as needed across our acute public hospitals and mental health services.

The IHCA says that ongoing talks between the Department of Health, HSE and Consultant representatives are pivotal and must result in the implementation of unambiguous commitments from the Minister for Health to resolve the root causes of recruitment and retention issues, including reversing the pay discrimination imposed on Consultants contracted since 2012.

Reducing Medications in the Elderly A study by researchers at RCSI University of Medicine and Health Sciences of GP-delivered medication for older people led to an overall reduction in the number of medicines prescribed.

The research was led by Professor Susan Smith and Dr Caroline McCarthy of the Department of General Practice at RCSI. There is an increasing number of older people living with multiple medical conditions, known as multimorbidity, who are prescribed several medicines. This creates significant challenges for the healthcare system at large in terms of costs, as well as for

the individual (and their carers) in coping with taking so many medicines, and for the clinicians who decide what should be taken. The SPPiRE (Supporting prescribing in older people with multimorbidity and significant polypharmacy in primary care) research project aimed to address these challenges.

This study consisted of a randomised controlled trial involving 51 GP practices and 404 patients throughout the Republic of Ireland. Older patients with multimorbidity taking at least 15 regular medicines were invited to attend a medication review with their GP. The review included

FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

screening their prescription for potentially inappropriate combinations of medicines, considering opportunities for stopping medicines and assessing the patient’s priorities for treatment.

It then assessed whether this once-off GP-delivered medication review reduced the number of medicines and improved the quality of prescribing.

There was a significant reduction in the number of medicines in the intervention group compared to the control group, with over 800 medicines being stopped in 208 intervention patients. Of the 800+ medicines ceased, 15 possible adverse events were

reported, almost all of which were mild reactions that stopped once the medicine was re-introduced, indicating that stopping certain medicines in older people is generally safe.

The quality of prescribing was also assessed, using a checklist of potentially inappropriate combinations of medicines.

While there were no significant improvements in the quality of prescribing in the intervention group compared to the control group, overall there were improvements in both groups during the study period.

Update on Falsified Medicines Directive

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News

The next two phases of the end of use and learn plan for FMD that were scheduled to take effect on 10 January have been deferred until further notice, i.e., phase 3 (wholesalers to investigate alerts on returned packs) and phase 4 (red/amber/green colours switched on in FMD software for pharmacies and hospitals).

Update on Falsified Medicines Directive

This decision has been made by the Safety Features Oversight Group due to the unprecedented situation that has arisen with Covid and the pressures this poses for pharmacies, hospitals and wholesalers, given the rapidly expanding Covid booster programme and staffing levels being impacted due to Covid.

The next two phases of the end of use and learn plan for FMD that were scheduled to take effect on 10 January have been deferred until further notice, i.e., phase 3 (wholesalers to investigate alerts on returned packs) and phase 4 (red/amber/green colours switched on in FMD software for pharmacies and hospitals).

What this means:

Phase 4 Red/amber/green changes for pharmacies and hospitals

Original Plan: Pharmacy and hospital FMD software to display colour coded responses, depending on the outcome when the pack is scanned

Updated Advice: This phase is now deferred until further notice. This means that for most FMD software, you will continue to see green responses for all scans, regardless of whether there is an alert.

Pharmacies and hospitals do not need to take any action.

IMVO will inform the FMD software providers directly.

This decision has been made by the Safety Features Oversight Group due to the unprecedented situation that has arisen with Covid and the pressures this poses for pharmacies, hospitals and wholesalers, given the rapidly expanding Covid booster programme and staffing levels being impacted due to Covid.

The advice to pharmacies and hospitals on what to do if you see alerts remains unchanged: You may continue to supply packs that generate alerts to patients in accordance with your existing procedures, unless you have overriding concerns that a falsified medicine is involved.

However, if you have reason to believe that packaging has been interfered with, based on your examination of the anti-tampering device on the pack, you must report your concern to the HPRA (as a suspected quality defect via the usual reporting

SKYRIZI Amendment In the January 2022 issue of Hospital Professional News, a Skyrizi (Risankizumab) advertisement was published which did not contain the latest abbreviated prescribing information as supplied

by AbbVie. This was rectified in our digital magazine issue with the correct information. We regret this error. The correct version is published in this (February) version on pages 24-25.

In the meantime, if you require support with any aspect of FMD, please visit the IMVO website www.imvo.ie or contact IMVO at info@imvo.ie.

Innovating Weight Management in Ireland The My Best Weight Team -Dr Andy Grannell. PhD, Clinical Exercise Physiologist, Dr Michael Crotty, GP Specialist in Bariatric Medicine and Clinical Lead and Prof Carel Le Roux, expert in bariatric and metabolic medicine therapy. My Best Weight has been recognised by the European Association for the Study of Obesity as a leading obesity management centre in Europe and becomes the first non-hospital based accredited centre in Ireland.

Research conducted by Eurostat last year showed that Ireland has the second highest rate of obesity in Europe with approximately 29% of the adult population living with overweight and a further 26% living with obesity. This data further underlines the need for a new and fresh approach to weight management services in the country.

A first of its kind in Ireland, My Best Weight is a dedicated medical weight management clinic which

has opened in Dublin. This team of internationally accredited doctors and experts provide an innovative approach using the most up to date scientific research. Employing a collaborative approach with the person being treated, they explore the underlying reasons for issues with weight and assess the impact that this may have on health. An individualised, long term treatment plan may include medication therapy, behavioural supports, medical nutrition and exercise

FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Led by Dr Michael Crotty, a GP specialist in bariatric medicine and clinical lead, My Best Weight is a non-judgemental, patient-centred service that provides a caring and supportive environment for people to discuss weight without blame or shame. Knowledge of the biology regulating weight has advanced significantly and it is clear that weight is not simply an issue of willpower or lifestyle. My Best Weight does not take this over simplistic and stigmatising view but recognises the many factors associated with weight. Obesity is a condition where excess or nontypical fat tissue impairs health. It

is not just a risk factor for disease but a medical issue in its own right.

Speaking at the launch of My Best Weight, Dr Michael Crotty said, “Our best weight is the weight we will be when living the healthiest life we can enjoy and sustain long term. Excess weight is not due to lifestyle issues or a lack of willpower. It is a complex medical issue influenced by genetics, our nervous system and hormones as well as the environment we live in. Our weight is regulated by subconscious parts of the brain that we cannot control - telling someone to simply eat less and move more does not work in the long term, most people have tried this over and over again. We now have very effective options including medications to manage weight safely. We do not blame and shame people for having other medical conditions. People living with overweight and obesity deserve the highest quality of care - that’s why our approach is different.”

Anyone interested in finding out more about the new clinic can visit www.mybestweight.ie or contact the clinic directly to make an appointment.

10 Medicine Report

New Medicines Supply Agreement Four-year Agreement reached between international researchbased biopharmaceutical industry and the State.

The Minister for Health, Stephen Donnelly TD, has announced two new Framework Agreements on Pricing and Supply of Medicines 2021-2025.

The multiannual agreements with the Irish Pharmaceutical Healthcare Association (IPHA) and Medicines for Ireland (MFI) represent an important step in reducing the cost of medicines and improving access to innovative new medicines for patients.

The new deals will deliver: • improved access for patients to new and innovative medicines • reductions in the cost of existing medicines • an easing of financial pressure on the health services into the future It is estimated that this will result in the State paying between ¤600 million and ¤700 million less for medicines than it would otherwise.

The four-year Framework Agreement on the Supply and Pricing of Medicines, agreed between the research-based industry and the State, takes effect from January 1, 2022. It means that medicines, brought forward by the research-based biopharmaceutical industry after years of research and development, will be available to patients faster through an improved funding framework.

Padraic O’Brien, Chairperson, Medicines for Ireland commented, ‘We welcome the new Supply and Pricing of Medicines Framework announced by Minister Donnelly.

We believe, as the representative of the companies who supply the

majority of medicines in Ireland daily, this agreement will bring increased patient access to generic and biosimilar medicines in Ireland, offering patients and healthcare professionals more choice, and yielding substantial savings to the State over the years ahead.”

Director David Delaney echoed these sentiments adding, “This is a transformational agreement that will ensure even greater access to generic and biosimilar medicines in Ireland. The Minister, the HSE, the Department of Health and our member companies have worked tirelessly to make this new Agreement a reality, ensuring the focus remained on patient access to medicines. The Agreement is a positive step forward, bringing patients in Ireland earlier access to best value biosimilar and generic medicines in their patient journey.”

Next year, IPHA member companies expect to propose about 35 innovative new medicines for a range of medical conditions, including arthritis, multiple sclerosis, psoriasis, spinal muscular atrophy and many forms of cancer. These medicines would treat almost 17,500 patients. The ¤30 million for new medicines, announced by the Government in Budget 2022, will help to give more patients access to new treatments in the innovation pipeline. Over the four years of the Agreement, the research-based industry expects to propose over 170 innovative new medicines. The new Agreement means there will be an improved funding framework in place to support the Health Service Executive’s reimbursement process and growth in the availability of innovative new medicines.

The research-based biopharmaceutical industry has agreed to staged increases in rebates to the State on sales of

“We believe, as the representative of the companies who supply the majority of medicines in Ireland daily, this agreement will bring increased patient access to generic and biosimilar medicines in Ireland” Padraic O’Brien, Chairperson, Medicines for Ireland

FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

“The Agreement is a positive step forward, bringing patients in Ireland earlier access to best value biosimilar and generic medicines in their patient journey” David Delaney, Director, Medicines for Ireland on-patent and off-patent unique medicines, rising from 5.5% this year to reach 9% in October 2024. The industry will deliver about ¤89 million in rebates in that period. When combined with price discounts on off-patent medicines that have market competitors and with price realignment measures, IPHA calculates the value of efficiencies over four years at between ¤700 million and ¤800 million.

The research-based industry believes the Agreement provides for adequate, sustained investment in innovative new medicines, with allocations decided annually based on horizon scanning and the budgetary process. IPHA will monitor, and contribute towards, the achievement of an improved timeline between a company’s application for reimbursement of a new medicine in the health services, with the State committing to resourcing the reimbursement system sufficiently for the timely processing of applications. Our analysis shows that it has taken more than three years to reimburse some innovative new medicines.

The State has committed to increasing the number of HSE Drugs Group reimbursement decision-making slots. These are expected to total between 50 and 60 annually. That would represent an increase in the number of slots of between 35% and 62% over 2020. The move is a capacity-building measure that should improve the flow of clinically beneficial innovative new medicines to the health services.

The most recent data, gathered annually by health analysts IQVIA for EFPIA, the research-based biopharmaceutical industry’s European representative organisation, shows that, among western European countries, only France and Portugal are slower than Ireland in making innovative new medicines available to patients. Patients in Germany get

The Agreement provides a platform for helping to raise healthcare standards through a steady, continuous flow of innovative new medicines that emerge from years of research and development. The announcement by the Government of ¤30 million for new medicines in Budget 2022 was a welcome step towards improving the funding environment” Paul Reid, President, IPHA innovative new medicines four times faster than in Ireland. Among 34 European countries surveyed, Ireland places 18th.

There will be no change in the 14 European countries used to calculate medicines prices in Ireland. This ‘reference basket’ comprises Austria, Belgium, Denmark, Finland, France, Germany, Greece, Italy, Luxembourg, the Netherlands, Portugal, Spain, Sweden and the UK.

Pemetrexed

EVER Pharma 25mg/ml Concentrate for Solution for Infusion Ready to Dilute

AVAILABLE NOW FROM UNIPHAR

Pemetrexed EVER Pharma is provided as a ready to dilute liquid formulation and is an antineoplastic chemotherapy drug. It is indicated for the treatment of malignant mesothelioma and locally advanced or metastatic nonsquamous non-small cell lung cancer.

Available as a ready to dilute liquid formulation – does not require reconstitution from powder saving time and costs.

Can be stored at room temperature.

Available in 3 presentations – providing greater flexibility and convenience when preparing patient specific doses.

All vial sizes come in CytoWrap® – for safer handling and transportation.

Refer to the full Summary of Product Characteristics (SmPC) before prescribing.

Name and active ingredients: Pemetrexed EVER Pharma 25mg/ml concentrate for solution for infusion. One ml of concentrate contains 25mg pemetrexed (as pemetrexed disodium).

One vial of 4 ml concentrate contains 100mg pemetrexed; one vial of 20ml concentrate contains 500mg pemetrexed; one vial of 40ml concentrate contains 1000mg pemetrexed.

Pharmaceutical form: Concentrate for solution for infusion. Aqueous, clear, slightly yellowish or yellow-greenish solution, pH 7.5 – 8.1. Indications: Pemetrexed in combination with cisplatin is indicated for the treatment of unresectable malignant pleural mesothelioma, and for first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. As monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy and as monotherapy for the second line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. For full details, see SmPC section 5.1. Posology and method of administration: The daily dose is determined by the indication. See SmPC section 4.2 for dosage, preparation and administration. Contraindications: Hypersensitivity to pemetrexed or to excipients listed in section 6.1 of the SmPC; breast-feeding (see section 4.6 of SmPC); concomitant yellow fever vaccine (see SmPC section 4.5). Special warnings and precautions for use: Please see SmPC section 4.4 for full details. Interactions: The list of products to avoid concomitant use of or to closely monitor the use of can be found in the SmPC section 4.5. Pregnancy and fertility: Effective contraception must be used by women of childbearing potential due to possible genetically damaging effects of Pemetrexed. Sexually mature males are advised not to father a child during the treatment and up to 6 months thereafter. Contraceptive measures or abstinence are recommended (see section 4.6 of SmPC). Adverse reactions: Very common: infection, pharyngitis, neutropenia, leukopenia, haemoglobin decreased, stomatitis, anorexia, vomiting, diarrhoea, nausea, rash, skin exfoliation, creatinine clearance decreased, blood creatinine increased, fatigue. Common: sepsis, febrile neutropenia, platelet count decreased, hypersensitivity, dehydration, taste disorder, peripheral motor neuropathy, peripheral sensory neuropathy, dizziness, conjunctivitis, dry eye, lacrimation increased, keratoconjunctivitis sicca, eyelid oedema, ocular surface, alanine aminotransferase increased, aspartate aminotransferase increased, hyperpigmentation, pruritus, erythema multiforme, alopecia, urticaria, renal failure, glomerular filtration rate decreased, pyrexia, pain, oedema, chest pain, mucosal inflammation, gamma-glutamyltransferase increased. For full information see SmPC section 4.8. Presentations: 1 x 4ml, 1 x 20ml or 1 x 40ml colourless type I glass vial, with bromobutyl rubber stopper coated in fluoropolymer, aluminium cap and plastic flip-off.

Legal Classification: POM. Marketing Authorisation Number: PA1774/005/001. Distributed by: Uniphar, on behalf of Athlone Pharmaceuticals Ltd. For a copy of the SmPC or further medical information, please contact: medical@kent-athlone.com. Date of preparation: November 2021. IE21/007/SmPC July 2021.

Adverse events should be reported. Reporting forms and information can be found on the HPRA website (www.hpra.ie) or by email medsafety@hpra.ie Adverse events should also be reported to Kent Athlone Pharma Group on (090) 666 1109 or medical@kent-athlone.com. Additional information available on request.

For further information on this product, please contact Gavin Butler, Key Account Manager, Athlone Pharmaceuticals Ltd., Ballymurray, Co. Roscommon Tel: + 353 (0) 87 3354523 | Email: Gavin.Butler@kent-athlone.com

Date of preparation: November 2021 IE2021/017/00

Prescribing information

12

Medicine Report

The research-based biopharmaceutical industry believes the new Agreement has the potential to improve the operating environment for the adoption of innovative new medicines in the health services.

That will improve health outcomes, with medicines shown to contribute to lower mortality rates and better survival rates for a range of conditions including heart disease, stroke, cancer and many more.

innovative new medicines faster, complementing the strength of the research-based biopharmaceutical manufacturing sector across the regions. We want to help to close the gap between scale and speed - that Ireland can have a significant international biopharmaceutical footprint and fast adoption of innovative new medicines in the health services.”

Paul Reid, President of IPHA, said, “The Agreement is the product of joint working with the State. We need to find ways to get innovative new medicines to patients faster while, at the same time, managing affordability challenges with the State. The Agreement provides a platform for helping to raise healthcare standards through a steady, continuous flow of innovative new medicines that emerge from years of research and development. I hope the researchbased biopharmaceutical industry and the State can continue to work in partnership in areas like horizon scanning and shorter times to reimbursement decisions so that we can adopt innovation faster in the health services. The announcement by the Government of ¤30 million for new medicines in Budget 2022 was a welcome step towards improving the funding environment.

The biopharmaceutical sector is among Ireland’s strongest industrial performers, including during the pandemic. Rising exports and strong corporate tax receipts are helping to generate Exchequer revenues and economic activity across the regions. The sector accounts for some 45,000 jobs and generates almost ¤15 billion in gross value-added for the economy annually. Advancements in medicines have helped to extend life expectancy which climbed by 25 years for men and by 29 for women between 1911 and 2011.

In cancer, five-year survival rates have improved dramatically. The mortality rate for heart attacks dropped by 51% between 2008 and 2018. Thousands of treatments are in development globally to tackle unmet medical needs across a range of therapy areas. In Invest In Our Futures, the IPHA campaign in the run-up to the new Agreement and Budget 2022, we highlighted this progress in medicines.

“We are putting in place the conditions for Ireland to adopt

Oliver O’Connor, Chief Executive of IPHA added, “The Agreement,

“As the world of medicines innovation turns, Ireland should be a strong performer across all stages of the lifecycle discovery, development, manufacturing and adoption. Let us resolve to do our best in each of them” Oliver O’Connor, Chief Executive, IPHA

and the policy behind it, supports innovation by making clear distinctions between savings measures affecting patentprotected medicines and offpatent, non-exclusive medicines.

It provides for significant price reductions for non-exclusive medicines. Our companies support robust competition on a level playing field.

“IPHA member companies discover, develop, manufacture and supply new medicines, bringing to patients the product of research and development that is enabled by a stable intellectual property framework. Over the lifetime of this Agreement, we expect to launch more than 170 innovative new medicines for serious medical

conditions. We now have the basis for making innovative new medicines available to patients faster than before.

“So, clinically, this Agreement can be a milestone in the delivery of new treatment options.

Economically, too, we know that medicines are productive investments, with more people staying active in the workforce for longer and, potentially, avoiding long-term hospitalisations. As the world of medicines innovation turns, Ireland should be a strong performer across all stages of the lifecycle - discovery, development, manufacturing and adoption. Let us resolve to do our best in each of them.”

News Second Implementation Plan for Activity Based Funding The second Implementation Plan for Activity Based Funding (ABF) in Ireland has just been published, as part of a programme of work to support the delivery of the Sláintecare Implementation Strategy.

This Plan represents an important step forward in increasing transparency in funding, encouraging efficiency, value for money and sustainability, and ultimately providing greater accountability for the way resources are allocated in the Irish healthcare system.

Since the Government committed to introducing ABF in 2012, they have worked to build the skillsets and underlying data needed to do this, and to establish an annual price development cycle to support funding decisions.

The first Implementation Plan (2015) laid the groundwork for this with the establishment of the Healthcare Pricing Office (HPO) centrally within the Health Service Executive (HSE) and the development of patientlevel costing at 19 hospitals.

39 hospitals have been funded

by ABF for 70% of their total funding, moving away from historic block funding and increasing transparency and accountability.

In 2018 the Government reconfirmed its commitment to ABF as part of the Sláintecare Implementation Strategy and included actions in the Strategy to progress ABF. This second ABF Implementation Plan provides a vehicle to continue to progress these actions including preparatory work around introduction of structured healthcare purchasing,

FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

taking foundational steps towards the necessary costing and data improvements needed to support pricing for community services, and building on the work already undertaken to further expand and enhance the costing and pricing of hospital services.

This Plan signals a shift from the necessary foundational and technical work around the costing and pricing of services towards creating a more holistic healthcare resourcing and purchasing process that links insights from key clinical, operational and patient stakeholders, with the core Sláintecare intent around integrated care, in the least complex setting appropriate, as close to home as practical.

COVID-19 has had a significant impact on the healthcare

system and has created major challenges for in accounting for new and unknown patterns of healthcare usage and costs.

Whilst emergency measures have included temporary increases to block funding, ABF and its building blocks have proved useful in providing the information needed to monitor the impact and effects of the disease and make important decisions as to where resources should be deployed, and will continue to be critical for health system insights and funding into the future.

Many aspects of the changes introduced over the last 21 months are fully consistent with the intent of Sláintecare, and will be maintained after the pandemic has ended.

Digital 13

HospitalBuddy delivers Digital Solution HospitalBuddy is a free mobile phone app and website developed by a team of hospital doctors working throughout Ireland. At the start of the Covid pandemic, a team of doctors around Ireland recognised that there was a clinical need for increased digital solutions for Irish based hospital doctors.

The group initially consisted of 15 consultants and registrars including surgeons, paediatricians, obstetricians, physicians and intensivists working throughout Ireland who amalgamated content for the HospitalBuddy platform.

We partnered with an experienced MedTech software development team who have previously designed three highly successful medical websites in Ireland – GPBuddy.ie, PharmaBuddy.ie and Medcafe.ie.

The aim of the HospitalBuddy platform was to develop an interface for doctors and frontline health workers to streamline several of their daily clinical pinch points into one app and website.

HospitalBuddy has several integrated features to help doctors working in hospitals across Ireland including: • the ability to digitally track internal hospital CPD meetings • regular updates on national medical educational meetings • medical educational flashcards & infographics • a discussion forum for each hospital and a separate national NCHD discussion forum • a database of over 200 printable patient information leaflets To date there are over 1,000 hospital doctors in Ireland using the app regularly. To achieve this milestone, we were greatly assisted by the Health Innovation Hub (HIHI) who helped us to roll out our internal CPD meeting tracking system to a number of hospitals across the country. As a result of the Covid pandemic, it has become increasingly difficult for hospital administrators to keep a record of those attending meetings in person and those attending virtually. Whether the doctor is attending in person or virtually, they can track their attendance via the HospitalBuddy app using a specific PIN password for each meeting. Hospital

Written by Dr Oisin O'Connell, MD, FRCPI, Respiratory Consultant Bon Secours Hospital Cork; Senior Medical Lecturer UCC

administrators can also track attendance of doctors to these meetings and can print out a copy of each doctor’s attendance at the end of the academic year.

The Clinical Resources section of the HospitalBuddy platform contains a large list of infographics, educational flashcards and material relevant to keeping up to date as medical information rapidly evolves.

Our Consultant team are constantly emailing new and useful information for this section of the app.

The Educational Resources section contains over 60 online medical lectures and educational podcasts given mainly by Consultants around Ireland. We have partnered with Medcafe.ie to organise live online streams of medical meetings and SpR study days. These meetings are also recorded so doctors can watch the recordings in their own time. We have had some excellent speakers both nationally and internationally on the app recently, such as Dr Mark Levy, the co-author of the GINA guidelines lecturing on Asthma.

HospitalBuddy offers users at each hospital a dedicated discussion forum that can be accessed by doctors who work at that hospital.

We are currently working with medical manpower teams to facilitate sharing of key messages from the Medical Manpower team to doctors working in their hospital via the app. On the ground, NCHDs have found the ability to let new NCHDs starting in their hospital know about everything from membership exam teaching sessions to extracurricular activities particularly helpful using the Hospital discussion forum also. We also offer a National NCHD discussion forum which is particularly helpful to NCHDs who can discuss the many issues facing NCHDs nationally– for example, discussions on contracts, medical indemnity and tips about revenue returns for NCHDs by NCHDs.

Following on from an awardwinning project by Dr Jessica McCarthy who developed a National Irish Thoracic Society endorsed Patient Information Leaflet on solitary pulmonary nodules, HospitalBuddy is developing a national database of patient information leaflets commonly used by Consultants across Ireland, with the support of the UCC Medtech Society and UCC medical student Adina Zago.

To date we have built a database of over 200 printable patient information leaflets filterable by clinical specialty. We anticipate this database to continuously grow and have made it particularly easy for doctors to print these patient information handouts by not requiring a login to print them from our website. We are seeing doctors in emergency departments and outpatient clinics printing out these patient information handouts which address the most common clinical queries and helps doctors have extra time in clinic to cover the areas these approved patient education handouts do not cover.

Recently, several hospitals have emailed us their phone directories and NCHD handbooks for the Hospital Resources section of the app. This has saved doctors hours trying to ring switchboards just to get an internal ward phone number. Our support team have also created a directory of useful

hospital switchboard numbers for doctors trying to get through to other hospitals.

The HospitalBuddy app has been recently supported by the Medical Protection Society (MPS) in Ireland who recognise that by making clinical information and medical education more readily available to doctors, HospitalBuddy will help to reduce clinical risks and help standardise care to conform to best international practices.

We are also collaborating with the NDTP, the HIHI and hospital medical administration teams to develop further solutions to address key needs facing hospital doctors and hospital admin staff in Ireland. The app can be downloaded free using the links below. Feel free to email our support team at support@hospitalbuddy.ie with any resources, internal hospital phone directories or speciality guidelines you feel we should add to the platform. We are always looking to learn and share at the HospitalBuddy team.

Android users can download the HospitalBuddy app using: https://play.google.com/ store/apps/details?id=com. cmemeetingsltd.cpdplanner Apple users can download the HospitalBuddy app using: https://apps.apple.com us/app/ cpdplanner/id1484966217

HOSPITALPROFESSIONALNEWS.IE | HPN • FEBRUARY 2022

14 News

Researcher of the Year Awards UCD Chair of Critical Care Medicine Professor Alistair Nichol with Minister for Further and Higher Education, Research, Innovation and Science

The Irish Research Council has announced its 2021 Researcher of the Year awards.

UCD Chair of Critical Care Medicine, Professor Alistair Nichol received a special commendation for his ‘exceptional contribution’ in the field of medical research, specifically in critical care clinical trials and especially in the global fight against the COVID-19 pandemic.

On receiving the accolade, Professor Nichol said, “I am honoured that the IRC has recognised my work and that of my team over the last decade and particularly during the COVID pandemic, with their special

commendation today. This represents many years’ work by a large team in Ireland and beyond. I am very grateful to my colleagues within UCD, the Irish Critical Care Community and our global network collaborators.

“Ireland’s Intensive Care Units continue to be the front line in our ongoing war against COVID. Our research collaborations have allowed us to understand the COVID waves during the pandemic – allowing us clinicians to identify patients at the highest risk of death, and the genetic factors associated with death in the ICU, so we can identify novel therapies.”

Professor Nichol is Director of the Irish Critical Care-Clinical Trials

Network (ICC-CTN), which runs, and builds capacity for running, clinical trials in Irish Intensive Care Units (ICUs). Funded by the Health Research Board, the ICC-CTN has also become a world-leading coordination centre for major global clinical trials, including REMAP-CAP. REMAP (Randomised, Embedded, Multifactorial, Adaptive Platform trial) is a global trial that determines and continuously updates the optimal set of treatments for communityacquired pneumonia. REMAPCAP has added trial domains so that the platform can respond rapidly to COVID-19, specifically (i) antiviral therapy and (ii) immune modulation therapy.

To date, REMAP-CAP has identified three safe and effective treatments that reduce death and organ failure in critically ill COVID patients, namely steroids,

IL6 receptor antagonists and anticoagulation, in ward patients.

It has also determined that Hydroxychloroquine, Keletra, Hydroxychloroquine and Keletra in combination, convalescent plasma, Anakinra and anticoagulation do not improve outcomes in critically ill patients with COVID-19.

Professor of Zoology at Trinity College Dublin, Yvonne Buckley was named Researcher of the Year for work focused on the growth, reproduction and survival of plant and animal species.

UCD’s Professor of Social Policy Michelle Norris was awarded the Impact Award for her proven record of research impact ‘beyond academia’ in the field of social housing policy.

Postdoctoral researcher in the School of Psychology and Institute of Neuroscience at Trinity College Dublin, Dr Kathy Ruddy won the ‘Early Career Researcher of the Year’ award for her work using brain-computer interfaces to improve brain function.

Postdoctoral researcher Dr Sara Delmedico, UCD School of Languages, Cultures and Linguistics, was awarded the IRC Maurice J Bric Medal of Excellence. Postdoctoral researcher Dr Marco Timpanella, UCD School of Mathematics and Statistics, was awarded the IRC Thomas Mitchell Medal of Excellence.

Osteoporosis: Keeping Safe at Home Written by Louise Brent, Irish Hip Fracture Database (IHFD) and Major Trauma Audit (MTA) Manager for NOCA

Each year many injuries are sustained in the home due to falls, a lot of which could potentially be prevented. Data from the Irish Hip Fracture Database (IHFD) and the Major Trauma Audit (MTA) two

FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

national clinical audits governed by the National Office of Clinical Audit (NOCA) show year on year that the leading cause of people sustaining a hip fracture and major trauma injuries (which result in life threatening or life changing injuries) are falls typically from standing height or less and most occur in the home.

Over the course of both audits much has been done to raise awareness about home safety for the prevention of falls, however due to the unprecedented impact of the COVID-19 pandemic this has never been more important.

Over the last two years we have all had to endure prolonged periods at home none more so effected than our older population. Indeed

it was right to tell our older people to cocoon to protect themselves from the pandemic in the early stage but little has been done to support older people regain their confidence to go back outside and resume normal activities.

This increased time at home will undoubtedly lead to a higher risk of falls at home owing to the increase in frailty associated with restricting ones mobility.

In addition the social isolation, fear of going outside, decreased bone density, sarcopenia are all valid concerns as this pandemic refusing to abate. In the most recent Irish Hip Fracture Database Report advice was included about how people can remain active at home while being safe at home too.

If it’s out there... we can source it for you

For more information please contact: Free Phone 1800 440 440 I PharmaSource@uniphar.ie I www.uniphar.ie

Strength of Balance

Indicated for the treatment of moderate to severe active rheumatoid arthritis in adults who have responded inadequately to, or are intolerant to one or more disease modifying anti-rheumatic drugs.1 May be used as monotherapy or in combination with methotrexate.1 Refer to Summary of Product Characteristics (SmPC) before prescribing, and for full prescribing information.

JYSELECA® filgotinib 100 mg or 200 mg film-coated tablets. Indication: Jyseleca is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease modifying anti rheumatic drugs (DMARDs). Jyseleca may be used as monotherapy or in combination with methotrexate (MTX). Dosage: Adults: 200 mg once daily. Taken orally with/without food. It is recommended that tablets are swallowed whole. Laboratory Monitoring: Refer to the SmPC for information regarding laboratory monitoring and dose initiation or interruption.

Elderly: A starting dose of 100 mg once daily is recommended for patients aged 75 years and older as clinical experience is limited. Renal impairment: No dose adjustment required in patients with estimated creatinine clearance (CrCl) ≥ 60 mL/min. A dose of 100 mg of filgotinib once daily is recommended for patients with moderate or severe renal impairment (CrCl 15 to < 60 mL/min).

Not recommended in patients with CrCl < 15 mL/min. Hepatic impairment: Mild/moderate hepatic impairment: no dose adjustment required. Severe hepatic impairment: not recommended. Children (< 18years): Safety and efficacy not yet established. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active tuberculosis (TB) or active serious infections. Pregnancy. Warnings/Precautions: See SmPC for full information. Immunosuppression: Combination use, with immunosuppressants e.g. azathioprine, ciclosporin, tacrolimus, or biologic DMARDs (bDMARDs) or other Janus kinase (JAK) inhibitors is not recommended as a risk of additive

immunosuppression cannot be excluded. Infections: Infections, including serious infections such as pneumonia and opportunistic infections e.g. tuberculosis (TB), oesophageal candidiasis, and cryptococcosis have been reported. Risk benefit should be assessed prior to initiating in patients with risk factors for infections (see SmPC). Patients should be closely monitored for the development of signs and symptoms of infections during and after filgotinib treatment. Treatment should be interrupted if the patient is not responding to antimicrobial therapy, until infection is controlled. There is a higher incidence of serious infections in the elderly aged 75 years and older, caution should be used when treating this population. Tuberculosis: Patients should be screened for TB before initiating filgotinib, and filgotinib should not be administered to patients with active TB. Viral reactivation: Cases of herpes virus reactivation (e.g., herpes zoster), were reported in clinical studies (see SmPC). If a patient develops herpes zoster, filgotinib treatment should be temporarily interrupted until the episode resolves. Screening for viral hepatitis and monitoring for reactivation should be performed. Malignancy: Immunomodulatory medicinal products may increase the risk of malignancies. Malignancies were observed in clinical studies (see SmPC). Fertility: In animal studies, decreased fertility, impaired spermatogenesis, and histopathological effects on male reproductive organs were observed (see SmPC). The potential effect of filgotinib on sperm production and male fertility in humans is currently unknown. Haematological abnormalities: Do not start therapy, or temporarily stop, if Absolute Neutrophil Count (ANC) <1 × 109 cells/L, ALC <0.5 × 109 cells/L or haemoglobin <8 g/dL. Temporarily stop therapy if these values are observed during routine patient

JYSELECA, GALAPAGOS and the JYSELECA and GALAPAGOS logos are registered trademarks of Galapagos NV. © 2022 Galapagos NV. All rights reserved.

JYSELECA – a preferential JAK1 inhibitor for moderate to severe RA1 JYSELECA shows more than 5x greater potency for JAK1 over JAK2/3 and TYK21* Balancing sustained efficacy2-6 with acceptable tolerability1,7

*This is based on biochemical assays, the clinical consequence of this is unknown.

Common adverse events (≥1/100 to <1/10) include: nausea, upper respiratory tract infection, urinary tract infection, dizziness.1

Visit strengthofbalance.co.uk to learn more management. Vaccinations: Use of live vaccines during, or immediately prior to, filgotinib treatment is not recommended. Lipids: Treatment with filgotinib was associated with dose dependent increases in lipid parameters, including total cholesterol, and high-density lipoprotein (HDL) levels, while low density lipoprotein (LDL) levels were slightly increased (see SmPC). Cardiovascular risk: Rheumatoid arthritis patients have an increased risk for cardiovascular disorders. Patients should have risk factors (e.g., hypertension, hyperlipidaemia) managed as part of usual standard of care. Venous thromboembolism: Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving JAK inhibitors including filgotinib. Caution should be used in patients with risk factors for DVT/PE, such as older age, obesity, a medical history of DVT/PE, or patients undergoing surgery, and prolonged immobilisation. Lactose content: Contains lactose; patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take filgotinib. Pregnancy/ Lactation: Filgotinib is contraindicated in pregnancy. Filgotinib should not be used during breast-feeding. Women of childbearing potential must use effective contraception during and for at least 1 week after cessation of treatment.

Driving/Using machinery: No or negligible influence, however dizziness has been reported. Side effects: See SmPC for full information. Common (≥1/100 to <1/10): nausea, upper respiratory tract infection, urinary tract infection and dizziness. Uncommon (≥1/1000 to <1/100): herpes zoster, pneumonia, neutropenia, hypercholesterolaemia and blood creatine phosphokinase increase.

Serious side effects: See SmPC for full information Legal category: POM Pack:

30 film-coated tablets/bottle Price: UK Basic NHS cost: £863.10; Ireland: POA Marketing authorisation number(s): Jyseleca 100mg film-coated tablets EU/1/20/1480/001 EU/1/20/1480/002 Jyseleca 200mg film-coated tablets EU/1/20/1480/003 EU/1/20/1480/004 Further information: Galapagos UK, Belmont House, 148 Belmont Road, Uxbridge UB8 1QS, United Kingdom 00800 7878 1345 medicalinfo@glpg.com Jyseleca® is a trademark. Date of Preparation: January 2022 IE-RA-FIL-202112-00003 Additional monitoring required Adverse events should be reported.

For Northern Ireland, reporting forms and information can be found at yellowcard.mhra.gov.uk or via the Yellow Card app (download from the Apple App Store or Google Play Store).

Adverse events should also be reported to Galapagos via email to Drug.safety.UK.Ireland@glpg.com or 00800 7878 1345 Adverse events should be reported.

For Ireland, reporting forms and information can be found at www.hpra.ie and can be reported to HPRA on +353 1 6764971.

Adverse events should also be reported to Galapagos via email to Drug.safety.UK.Ireland@glpg.com or 00800 7878 1345

References: 1. JYSELECA SPC. Available at: www.medicines.org.uk / www.medicines.ie. Last accessed: January 2022. 2. Combe B, et al. Ann Rheum Dis 2021;doi:10.1136/annrheumdis-2020-219214.

3. Genovese MC, et al. JAMA 2019;322 (4):315–325. 4. Westhovens R, et al. Ann Rheum Dis 2021;doi:10.1136/annrheumdis-2020-219213. 5. Combe B, et al. Poster presented virtually at ACR, November 3–10, 2021. 6. Buch MH, et al. Poster presented virtually at ACR, November 3–10, 2021. 7. Genovese MC, et al. Poster presented virtually at the European League Against Rheumatism (EULAR) 2020 E-Congress, June 3–6, 2020.

January 2022 IE-RA-JY-202201-00001

18

Cardiac Rehabilitation

Cardiac Rehabilitation: Is it important with Modern Interventional Reperfusion Techniques?

Written by Padraig Denn, Clinical Nurse Manager 3, Mater Private Network

Reperfusion techniques have their origins in the work of Alexis Carrell in the early 20th century with his initial concepts regarding coronary perfusion and subsequent intrathoracic anastomosis of aorta and myocardial tissue in dogs. This eventually lead to a technique of attaching an adjunct artery into the myocardium of the left ventricle with the theorised result that collateral perfusion would be provided to the left anterior descending (LAD) coronary artery called the Veinberg procedure.

This work was developed further when Ake Senning placed a patch over the left main stem (LMS) to improve blood flow. Modern coronary artery bypass grafting was eventually an option when Mason Sones inadvertently injected contrast dye into the right coronary artery (RCA) of a patient with rheumatic heart disease and mapped the coronary perfusion system allowing for direct identification of the coronary arteries. This discovery allowed conduit vessels to be attached directly to blocked arteries and thus “bypassing” the occlusions. This has been refined in the subsequent years to now being carried out very effectively utilising microsurgical techniques with various vascular conduits to bypass blockages in main coronary arteries as well as branch vessels. Such techniques allow for early discharge and reduced adverse events as a result.

to most recent drug eluting stents and techniques allow those appropriately trained and experienced to treat the most complex of coronary disease including chronic total occlusions.

Both Coronary Artery Bypassing Grafting (CABG) and Percutaneous Coronary

Interventions (PCI) have a Level 1A recommendation from a multitude of international bodies.

Figure 1 below identifies the type of patient that is best suited to the PCI versus CABG intervention.

However, this level of recommendation is only valid for proven ischaemic or flow limiting coronary disease. New research released initially in 2019 has proven that PCI and CABG have no additional benefit for the management of non-ischaemic coronary disease above medical therapy. Research has shown that utilisation of non-internal mammary vascular conduits for CABG have limited duration of patency especially if there is competitive flow from the native system. PCI techniques are limited to specific areas of coronary disease and care needs to be taken to prevent inadvertent occlusion of branch vessels which can cause on-going symptoms of angina after successful treatment of a significant coronary occlusion.

Similarly, percutaneous interventional reperfusion has had significant improvements since the early work of the Italian Dr Gruentzig. From the initial treatments with balloons

FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Figure 1: PCI Vs CABG

One must also consider that both CABG and PCI reperfusion techniques are limited to the three main coronary arteries and a limited number of branch vessels. Therefore, when we look at Figure 2 we can see that the coronary perfusion system is far more elaborate than the three main arteries and main branches. Therefore, we can see why pharmacological treatment after initial intervention for the management of certain risk factors of coronary artery disease (CAD)is necessary. However, an individual’s tolerance of pharmacological treatments varies significantly and in the era of an ageing population with multiple co-morbidities the risk of polypharmacy needs to be considered and can

Figure 1: PCI Vs CABG

FOR YOURSELF, WOULD YOU CONSIDER

BOTH EFFICACY AND SAFETY?

Choose both efficacy and safety with ELIQUIS®

ELIQUIS is a factor Xa inhibitor that offers superior risk reduction in stroke and systemic embolism, with significantly less major bleeding vs. warfarin in non-valvular AF patients.1,* • Superiority demonstrated on stroke / systemic embolism vs. warfarin 1 • Superiority demonstrated on major bleeding vs. warfarin 1 ELIQUIS® (apixaban) PRESCRIBING INFORMATION Ireland Consult Summary of Product Characteristics (SmPC) before prescribing PRESENTATION: Film-coated tablets; 5 mg and 2.5 mg apixaban. INDICATION (SPC section 4.1): Prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF) with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA), age ≥ 75 years, hypertension, diabetes mellitus or symptomatic heart failure (NYHA Class ≥ II). Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults (see Special warnings and precautions for information on haemodynamically unstable PE patients). Prevention of venous thromboembolic events (VTE) in adults who have undergone elective hip or knee replacement surgery (2.5 mg only). DOSAGE AND ADMINISTRATION (SPC section 4.2): Oral. Taken with water, with or without food. Prevention of stroke and systemic embolism in patients with NVAF: The recommended dose is 5 mg twice a day. In patients who meet at least two of the following criteria: serum creatinine ≥ 1.5 mg/dL (133 micromole/L), age ≥ 80 years, or body weight ≤ 60 kg the recommended dose is Eliquis, 2.5 mg twice daily. Patients with severe renal impairment (creatinine clearance 15-29 ml/min) should receive Eliquis 2.5 mg twice daily. Therapy should be continued long term. Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt): The recommended dose for the treatment of acute DVT and treatment of PE is 10 mg twice daily for the first 7 days followed by 5 mg twice daily. As per available medical guidelines, short duration of treatment (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation). The recommended dose for the prevention of recurrent DVT and PE is 2.5 mg twice daily. When prevention of recurrent DVT and PE is indicated, the 2.5 mg twice daily dose should be initiated following completion of 6 months of treatment with Eliquis 5 mg twice daily or with another anticoagulant. The duration of overall therapy should be individualised after careful assessment of the treatment benefit against the risk for bleeding. Prevention of VTE (VTEp): elective hip or knee replacement surgery: The recommended dose is 2.5 mg twice a day. The initial dose should be taken 12 to 24 hours after surgery. Hip replacement surgery, the recommended duration of treatment is 32 to 38 days. Knee replacement surgery, the recommended duration of treatment is 10 to 14 days. Missed Dose for All Indications: If a dose is missed, Eliquis should be taken immediately and then continue with twice daily dose as before. Switching: Switching treatment from parenteral anticoagulants to Eliquis (and vice versa) can be done at the next scheduled dose. These medicinal products should not be administered simultaneously. Switching treatment from VKA therapy to Eliquis: Warfarin or other VKA therapy should be discontinued and Eliquis started when the international normalized ratio (INR) is < 2. Switching treatment from Eliquis to VKA therapy: Administration of Eliquis should be continued for at least 2 days after beginning VKA therapy. After 2 days of co- administration of Eliquis with VKA therapy, an INR should be obtained prior to next scheduled dose of Eliquis. Co-administration of Eliquis and VKA therapy should be continued until the INR is ≥2. Renal Impairment - mild or moderate renal impairment: For the prevention of VTE in elective hip or knee replacement surgery (VTEp), for the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt), no dose adjustment is necessary. For the prevention of stroke and systemic embolism in patients with NVAF and serum creatinine ≥ 1.5 mg/dL (133 micromole/L) associated with age ≥ 80 years or body weight ≤ 60 kg, a dose reduction is necessary. In the absence of other criteria for dose reduction (age, body weight), no dose adjustment is necessary. Severe renal impairment (creatinine clearance 15-29 mL/min): For the prevention of VTE in elective hip or knee replacement surgery (VTEp), for the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt), Eliquis is to be used with caution. For the prevention of stroke and systemic embolism in patients with NVAF, patients should receive the lower dose of Eliquis 2.5mg twice daily. In patients with creatinine clearance < 15 mL/min, or in patients undergoing dialysis, there is no clinical experience therefore Eliquis is not recommended. See SmPC for further details. Hepatic impairment: Contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Not recommended in patients with severe hepatic impairment. Use with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B). No dose adjustment is required in patients with mild or moderate hepatic impairment. Use with caution in patients with elevated liver enzymes (ALT/AST >2 x ULN) or total bilirubin ≥ 1.5 x ULN. Prior to initiating Eliquis, liver function testing should be performed. Catheter ablation (NVAF): Patients can continue Eliquis use while undergoing catheter ablation. Cardioversion (NVAF): Eliquis can be initiated or continued in NVAF patients who may require cardioversion. See SmPC for further details. Patients with NVAF and acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI): There is limited experience of treatment with apixaban at the recommended dose for NVAF patients when used in combination with antiplatelet agents in patients with ACS and/or undergoing PCI after haemostasis is achieved. See SmPC for further details. Paediatric population: Eliquis is not recommended in children and adolescents below the age of 18. CONTRAINDICATIONS (SPC section 4.3): Hypersensitivity to active substance or to excipients, active clinically significant bleeding, hepatic disease associated with coagulopathy and clinically relevant bleeding risk, lesion or condition if considered a significant risk factor for major bleeding, see SmPC for further details. Concomitant treatment with any other anticoagulant agent except under specific circumstances of switching anticoagulant therapy or when unfractionated heparin (UFH) is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation, see SmPC for further details. WARNINGS AND PRECAUTIONS (SPC section 4.4): Haemorrhage risk: Carefully observe for signs of bleeding. Use with caution in conditions with increased risk of haemorrhage. Discontinue administration if severe haemorrhage occurs. An agent to reverse the anti-factor Xa activity of apixaban is available. For information on reversal and managing bleeding, see SmPC for further details.

Interaction with other medicinal products affecting haemostasis: Concomitant treatment with any other anticoagulant is contraindicated (see contraindications). Concomitant use of Eliquis with antiplatelet agents increases the risk of bleeding. Care with concomitant SSRIs, SNRIs or NSAIDs, including acetylsalicylic acid. Following surgery, other platelet aggregation inhibitors are not recommended concomitantly with Eliquis. In patients with atrial fibrillation and conditions that warrant mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the potential risks should be made before combining this therapy with Eliquis. A clinical trial enrolled patients with atrial fibrillation with ACS and/or undergoing PCI and a planned treatment period with a P2Y12 inhibitor, with or without ASA, and oral anticoagulant (either apixaban or VKA) for 6 months. Concomitant use of ASA increased the risk of ISTH (International Society on Thrombosis and Hemostasis) major or CRNM (Clinically Relevant Non-Major) bleeding in apixaban-treated subjects. See SmPC for further details. Use of thrombolytic agents for the treatment of acute ischemic stroke: Limited experience. Patients with prosthetic heart valves: safety and efficacy of Eliquis have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, the use of Eliquis is not recommended in this setting. Patients with antiphospholipid syndrome: Direct acting Oral Anticoagulants (DOACs), including Eliquis, are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome (see SmPC for further details). Surgery and invasive procedures: Discontinue at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of bleeding.

Discontinue at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding. If surgery or invasive procedures cannot be delayed, appropriate caution should be exercised, taking into consideration an increased risk of bleeding. Eliquis should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established. For patients undergoing catheter ablation for atrial fibrillation, Eliquis treatment does not need to be interrupted. Temporary discontinuation: Discontinuing anticoagulants, including Eliquis, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thrombosis. Lapses in therapy should be avoided and if anticoagulation with Eliquis must be temporarily discontinued for any reason, therapy should be restarted as soon as possible. Spinal/ epidural anaesthesia or puncture: Patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long- term or permanent paralysis. The risk of these events may be increased by the post- operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. Indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of Eliquis. The risk may also be increased by traumatic or repeated epidural or spinal puncture.

Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinical experience with the use of Eliquis with indwelling intrathecal or epidural catheters. See SmPC for further details. Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy: Eliquis is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy since the safety and efficacy of Eliquis have not been established. Patients with active cancer: Patients with active cancer can be at high risk of both venous thromboembolism and bleeding events. When apixaban is considered for DVT or PE treatment in cancer patients, a careful assessment of the benefits against the risks should be made. Renal impairment: see dosage and administration section. Elderly patients: Increasing age may increase haemorrhagic risk. Also, the co-administration of Eliquis with ASA in elderly patients should be used cautiously because of a potentially higher bleeding risk. Body weight: Low body weight (< 60 kg) may increase haemorrhagic risk. Hepatic impairment: see dosage and administration section. Interaction with Inhibitors of CYP3A4 and P-gp: Not recommended with strong inhibitors of both CYP3A4 and P-gp. These medicinal products may increase Eliquis exposure by 2-fold or greater in the presence of additional factors that increase Eliquis exposure (e.g. severe renal impairment) see SmPC for further details. Interaction with Inducers of CYP3A4 and P-gp: Eliquis should not be used for the treatment of DVT and PE in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp since efficacy may be compromised. Concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp, Eliquis should be used with caution for the prevention of VTE in elective hip or knee replacement surgery, for the prevention of stroke and systemic embolism in patients with NVAF and for the prevention of recurrent DVT and PE, though no dose adjustment for Eliquis is required during concomitant therapy with such medicinal products. Hip fracture surgery: Eliquis has not been studied in clinical trials in patients undergoing hip fracture surgery.

Therefore, it is not recommended in these patients. Laboratory parameters: Clotting tests (PT, INR, and aPTT) are affected by the mechanism of action of apixaban. Changes observed at the expected therapeutic dose are small and subject to a high degree of variability, see SmPC for further details. Information about excipients: Eliquis contains lactose. Patients with galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take Eliquis. DRUG INTERACTIONS (SPC Section 4.5): Eliquis should be used with caution when co-administered with SSRIs/SNRIs, NSAIDs, ASA and/or P2Y12 inhibitors because these medicinal products typically increase the bleeding risk. There is limited experience of co-administration with other platelet aggregation inhibitors (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, co-administration of these products with Eliquis is not recommended. See SmPC for further details.Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated, except under specific circumstances of switching anticoagulant therapy, when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation. Administration of activated charcoal reduces Eliquis exposure. Also see contraindications and special warnings and precautions section; Consult SmPC (contraindications, special warnings and precautions and drug interactions) for full details on interactions. PREGNANCY AND LACTATION (SPC section 4.6): Pregnancy: As a precautionary measure, it is preferable to avoid the use of apixaban during pregnancy. Breastfeeding: A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from apixaban therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. UNDESIRABLE EFFECTS (SPC section 4.8): Increased risk of occult or overt bleeding from any tissue or organ, which may result in post haemorrhagic anaemia. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding. Frequencies: common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Prevention of VTE in adult patients who have undergone elective hip or knee replacement surgery (VTEp): Common: anaemia; haemorrhage*; haematoma*; nausea; contusion. Uncommon: thrombocytopenia*; epistaxis*; haematochezia*; liver function test abnormal (including blood bilirubin increased*); haematuria*; specific haemorrhage such as gastrointestinal*, abnormal vaginal*, urogenital*, post procedural*, wound secretion*, incision site*, operative*. Rare: hypersensitivity*; anaphylaxis*; haemoptysis*; gingival bleeding*; specific haemorrhage such as eye (including conjunctival)*, rectal*, muscle*. Not known: angioedema*; specific haemorrhage such as brain (encompassing intracranial, intraspinal)*, intra-abdominal*, respiratory tract*, haemorrhoidal*, mouth*, retroperitoneal*, traumatic*, erythema multiforme*. Prevention of stroke and systemic embolism in adult patients with NVAF, with one or more risk factors (NVAF): Common: anaemia; haemorrhage*; haematoma*; hypotension (including procedural hypotension); epistaxis*; nausea; gingival bleeding*; gamma-glutamyltransferase increased; haematuria*; contusion; specific haemorrhage such as eye (including conjunctival)*, gastrointestinal*, rectal*. Uncommon: thrombocytopenia*; hypersensitivity*; anaphylaxis*; haemoptysis*; haematochezia*; liver function test abnormal (including blood bilirubin increased*); specific haemorrhage such as brain (encompassing intracranial, intraspinal)*, intra-abdominal*, haemorrhoidal*, mouth*, abnormal vaginal*, urogenital*, post procedural*, wound secretion*, incision site*, operative*, traumatic*. Rare: specific haemorrhage such as respiratory tract*, retroperitoneal*, muscle*. Very Rare: erythema multiforme*. Not known: angioedema*.

Treatment of DVT and PE, and prevention of recurrent DVT and PE (VTEt): Common: anaemia; thrombocytopenia*; haemorrhage*; haematoma*; epistaxis*; nausea; gingival bleeding*; gamma-glutamyltransferase increased; alanine aminotransferase increased; skin rash; haematuria*; contusion; specific haemorrhage such as gastrointestinal*, mouth*, rectal*, abnormal vaginal*, urogenital*. Uncommon: hypersensitivity*; anaphylaxis*; haemoptysis*; haematochezia*; liver function test abnormal (including blood bilirubin increased*); specific haemorrhage such as eye (including conjunctival)*, haemorrhoidal*, muscle*, post procedural*, wound secretion*, incision site*, operative*, traumatic*. Rare: specific haemorrhage such as brain (encompassing intracranial, intraspinal)*, respiratory tract*. Not Known: angioedema*; specific haemorrhage such as intra-abdominal* and retroperitoneal*, erythema multiforme*. *Denotes serious adverse reaction Refer to SmPC for all other adverse events LEGAL CATEGORY: POM. MARKETING AUTHORISATION NUMBER (SPC section 8): EU/1/11/691/002-3, EU/1/11/691/008, EU/1/11/691/014 PACKAGE QUANTITIES: Carton of 20 film-coated tablets 2.5 mg, 60 film-coated tablets 2.5 mg, 56 film-coated tablets 5 mg, 28 film- coated tablets 5 mg. MARKETING AUTHORISATION HOLDER (SPC section 7): Bristol-Myers Squibb/Pfizer EEIG, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland FOR FURTHER INFORMATION CONTACT: medical.information@bms.com or 1 800 749 749 (Ireland) DATE OF PREPARATION: April 2021 ADDITIONAL INFORMATION AVAILABLE ON REQUEST Approval Code: 432-IE-2100041

Adverse events should be reported. Reporting forms and information can be found at: Ireland - via HPRA Pharmacovigilance at www.hpra.ie Adverse events should also be reported to Bristol-Myers Squibb via medical.information@bms.com or 1 800 749 749 (Ireland)

*with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA); age≥ 75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥ II) AF = Atrial Fibrillation. Reference: 1. Granger CB et al. N Engl J Med 2011; 365: 981–992.

Date of approval: May 2021 Job code: PP-ELI-IRL-0497 www.eliquis.ie

20

Cardiac Rehabilitation of the COVID 19 pandemic some facilities have had their nursing allocation decimated for prolonged periods due to the acute care service needs.

It is recommended that the CR programs be multidisciplinary to ensure all specialities expert knowledge is utilised to better educate the participants on how best to manage their condition independently in the community setting. It is this that is the cornerstone of the CR programs. CR phases one and two are designed to ensure that participant takes personal change of the management of their disease.

Figure 2: Representation of Coronary Perfusion

often complicate the decisionmaking processes of effective pharmacological treatment of the risks of CAD. We must also note that CAD causes are multifactorial (See Table 1) and many of them cannot be managed either pharmacologically or with invasive interventions. Risk factors such as increased body mass index (BMI), increased alcohol consumption, poorly managed levels of stress and smoking all require more complex interventions to ensure that they are effectively managed without worsening the risk of polypharmacy.

It is for the above, and many other, research guided reasons that Cardiac Rehabilitation (CR) has a Level 1A recommendation for all those who have a confirmed diagnosis of CAD without any restrictions from the initial causes or treatment modalities utilised for the management of the disease.

A Cochrane systematic review and meta-analysis has shown that participation in a CR programme reduces cardiovascular mortality, reduces hospitalisations and improves quality of life.

International governing bodies have recommended the utilisation of CR for the management of CAD leading to CR reported to be utilised in nearly one-hundred and twenty countries worldwide.

CR in Ireland falls under the remit of the Irish Association of Cardiac Rehabilitation (IACR) and this

service is overseen by the Irish Heart Foundation (IHF).

CR in Ireland is recommended to be delivered on a phased basis.

Figure 3 identifies the four phases of CR in Ireland. According to IACR information prior to the COVID 19 pandemic CR was delivered in thirty-seven centres across Ireland, mostly in the acute care setting. The services appeared to have stagnated over the previous ten years and were often provided by the nursing profession alone in each setting, despite national and international recommendations that CR be provided by a multidisciplinary team (MDT). The guidelines recommend that the MDT is made up of physiotherapists, social workers, occupational therapists, psychologists and administrative staff. Unfortunately, for periods

In phase I, according to the IACR guidelines, patients are usually hospitalised for two to five days after a significant cardiac event.

It is at this time when the CR process should commence with the visit of a member of the CR team. The duration of stay is dependent upon the cause of the patient’s admission to hospital.

The recommendation of the IACR guidelines is that this phase of the programme should involve • Give support and information to the patient and their families about heart disease • Assist the patient to identify personal cardiovascular risk factors • Discuss lifestyle modifications of personal risk factors and help provide an individual plan to support these lifestyle changes

• Gain support from family Figure 2: Representation of Coronary Perfusion

members to assist the patient in maintaining the necessary progress

We must also note that CAD causes are multifactorial (See Table 1) and man • Plan a personal discharge cannot be managed either pharmacologically or with invasive interventions. activity programme and the patient to such as increased body mass index (BMI), increasedencourage alcohol consumption, po adhere to this and commence daily walks levels of stress and smoking all require more complex interventions to ensur effectively managed without worsening the risk of polypharmacy.

Table 1: Risk Factors for CAD

FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Table 1: Risk Factors for CAD

21 Figure 3: Phases of Cardiac Rehabilitation

Phase I: In hospital patient period

Phase lI: Post discharge pre exercise period

Cardiac Rehab Phase III: Exercise and Education Programme

• Inform patients regarding Phase II and Phase III programmes, if available, and encourage their attendance The CR member who meets with the patient in this phase is dependent upon the structure of the programme in that specific setting. Ideally education on the components of the CR programme (e.g. disease process, medication management, exercise regime) should be provided by those with that specific expertise (e.g. CNS, Pharmacist, Physiotherapist). This phase is also an opportunity for the patient to become actively involved in their own care through completion of assessments and identification of their own risk factors for CAD. This will facilitate the patient to take ownership of their condition and its future management.

The focus of this phase of the programme is to create an individualised plan of care for each patient. This involves assessments of the various components of CAD including psychological status, risk factor profile, activity level, smoking and others. Based on these assessments appropriate referrals should be made to relevant healthcare professionals.

In Phase II the aim is to reinforce the education that was provided in Phase I and to maintain lifestyle changes. It happens after discharge but prior to the commencement of Phase III. It can occur in a wide variety of settings (e.g. phone contact, clinic reviews, patient’s own home or GP’s office). The patient should commence some degree

Phase lV: Maintenance

of exercise in this phase which is often self-directed and is dependent upon the initiating event that caused the referral to the CR system.

Phase III is a structured longitudinal exercise programme that entails regular attendance (most often twice weekly for six weeks) and each session involves a warm-up, aerobic and cool down phase. Some programmes may also include heart rhythm monitoring and resistance training.

According to the IACR 2013 Guidelines Phase III comprises all the following: • Exercise prescription based on clinical status, risk stratification, previous activity and future needs • Education for patient and family regarding: • Cardiac anatomy and physiology related to the cardiac event • Recognition of cardiac pain and symptom management • Risk factor identification and management • Benefits of physical activity • Energy conservation/graded return to activities of daily living • Cardio protective healthy eating • Prescribed cardiac medication and importance of compliance with same • Resumption of sexual activity • Benefits and entitlements

• Stress management and relaxation techniques • Counselling and behaviour modification • Smoking cessation • Vocational counselling This phase is dependent upon the expertise of the MDT to ensure that all components of the programme are met.

Phase IV of CR is designed to consolidate the improvements in exercise levels and to reinforce the education provided in Phase III. The aim is to maintain lifestyle changes to best ensure long-term change. This can be facilitated in several settings if there are appropriately qualified and experienced providers of this phase of the programme.

Unfortunately, this appears to be an area that is lacking in Ireland with only ten recognised providers of Phase IV CR and only one of the thirty-seven registered CR sites providing this phase within their facility.

There is no published evidence as to what extent each of the thirty-seven sites for CR in Ireland adhere to these guidelines. The author was further unable to gain access to any official numbers of patients that attend each of the programmes. Similarly, there is no available information to the author regarding the short, medium or long-term benefits of CR programmes in Ireland as any information regarding this is generally maintained in site specific databases. The IACR have previously requested

participating sites to complete Excel spreadsheets regarding numbers and outcomes for individual patients through each CR site but this information has not yet been made public.

International research has shown that CR is inconsistently implemented not only between countries but within individual countries. Further research has shown that guideline implementation is often improved through the utilisation of Information and Communication Technologies (ICT). The use of such technologies may also assist as we migrate from previous group setting for CR to the new COVID restriction limitations on indoor group activities, allowing for remote interaction of groups.

The CR team in the Mater Private Cork have managed to utilise Skype to allow for group exercise and education sessions to be facilitated without impinging on the restrictions in effect during this international pandemic.

Further utilisation of ICT should be considered not only to assist the members of the MDT to effectively document the various components of CR programs but to subsequently assess the effectiveness of individual programs and potentially improve the effectiveness of programs.

It is clear that the utilisation of CR for those who have a confirmed diagnosis of CAD is clearly beneficial for the longterm outcomes of patients irrespective of the interventional reperfusion method utilised for confirmed occlusive CAD. CR is designed to equip the participant with the skills and knowledge to best manage all aspects of their lifestyle to reduce symptoms of and progression of their CAD. It is also designed to create a support network for on-going management of symptoms and the psychological impact of a diagnosis of CAD. Therefore, Cardiac Rehabilitation should be considered a pivotal treatment modality for any individual with a diagnosis of coronary artery disease.

HOSPITALPROFESSIONALNEWS.IE | HPN • FEBRUARY 2022

22 Epilepsy

A focus on epilepsy for International Epilepsy Day 2022!

Written by Paddy McGeoghegan, Epilepsy Ireland Advocacy & Communications Manager

know about SUDEP – whether they are deemed as being high risk or not. In the past, SUDEP was often something that was not widely discussed but attitudes are changing. In a 2020 survey we conducted, it was found that 81% of people with epilepsy wanted to know more about SUDEP and that they wanted to hear about it early in their diagnosis with the condition – preferably from their consultant.

For healthcare professionals, knowing when to talk to a patient about SUDEP can be difficult but it is a conversation that most people with epilepsy want to have. Again, we have an information resource on www.epilepsy.ie about SUDEP and if you have direct contact with patients with epilepsy, please do take the time to visit it and learn more.

In advance of International Epilepsy Day 2022 on the 14th of February, I was delighted to be contacted by the Hospital Professional News editorial team to provide an update to you about Epilepsy Ireland’s plans for the day – and to give a general update on topics which may be of interest to readers of Hospital Professional News that could assist in your professional lives.

On the behalf of everyone at Epilepsy Ireland, we would like to put on record our thanks to everyone involved in hospital services for your service over the last two years. The dedication and service of frontline workers across Ireland has been a constant throughout this pandemic and while I know that times remain challenging, we felt it wholly appropriate to outline our thanks to you all at the outset of this article.

Our team here at Epilepsy Ireland have fielded many questions about COVID-19 and epilepsy and the potential impact of vaccination on persons with epilepsy. For those of you who may have patients with epilepsy, I want to highlight that there is a direct information resource on our website www.

epilepsy.ie addressing many of the common questions which are being received. Please feel free to visit the site and use the resources in working with your patients.

One key question we have received is whether a person with epilepsy will be more susceptible to catching the virus due to their condition. The answer here is that there is no known evidence to suggest people with epilepsy are at higher risk of catching the virus.

Another key question has been around whether a person with epilepsy will be more adversely affected should they unfortunately contract COVID-19. Again, there is no evidence to suggest that people with epilepsy are more adversely affected by the virus in terms of developing severe infection which may lead to hospitalisation or death. However, we have highlighted throughout the pandemic how the virus could have an impact on their existing condition – i.e, their epilepsy. This is because in most cases the virus comes with a temperature and a temperature in a person with epilepsy could reduce the person’s seizure threshold. This could therefore lead to a breakthrough seizure which could lead to a deterioration in seizure control;

FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

social implications through the loss of a driving license; and it should not be forgotten that a seizure can be life-threatening in cases.

The life-threatening nature of epilepsy is something that can often come as a surprise to the wider public when discussing the condition. However, this is unfortunately a reality of epilepsy.

The public can be particularly surprised when we discuss Sudden Unexpected Death in Epilepsy (SUDEP). SUDEP is a rare but devastating aspect of epilepsy and approximately 21-44 people with epilepsy pass away due to SUDEP each year in Ireland.

Discussing SUDEP with people with epilepsy and their families can be a difficult conversation for healthcare professionals to have as there is so much we don’t know about this aspect of the condition.

However, at Epilepsy Ireland, we prefer to focus on what we do know. We know that the better a person’s epilepsy is controlled, the less a risk of SUDEP. We know that the better a person’s epilepsy is managed (knowing triggers, taking medication as directed etc), the less of a risk about SUDEP. Crucially, we also know that people with epilepsy in Ireland want to

With our contact with people with epilepsy and their families across Ireland, what is communicated to us daily is the importance of the public knowing what to do in the event of someone having a seizure – which brings us nicely into what the focus of our International Epilepsy Day campaign will be.

Last year, in a survey of 1,000 members of the Irish public, 9 out of 10 respondents completely underestimated the prevalence of epilepsy in Ireland – believing it to be quite rare. The reality is that there are 40,000 people living with the condition around Ireland with approximately 2,000 new diagnoses every year. The condition is far from rare and is actually one of the most common neurological condition in the country.This is why it is vitally important the public know what to do in the event of a person having a seizure as there are people within their family, friend group and workplace who may be living with epilepsy.

However, seizure first aid is often misunderstood as being quite complex and this is not helped by the fact that there are longheld myths about the seizure first aid when it comes to helping someone having a seizure. These include the belief that you must

23 of people with epilepsy living in Ireland show, this is information that the public needs to know – you never know when they might need to use it. Any support which the readers of Hospital Professional News can give us would be warmly received and appreciated.

Finally, I would like to remind readers that Epilepsy Ireland is here to assist and support people with epilepsy and their families on their journeys with the condition.

Our 11 Community Resource Officers cover the entire country and each represent different regions so if you feel a patient may benefit from their support, please do not hesitate to put them in touch with us.

Likewise, should our organisation be of assistance to you in your professional or personal life, please do get in touch. I can be contacted by emailing pmcgeoghegan@epilepsy.ie.

Thank you for reading and I hope that this provided some insight on these topics for you. Keep your eyes peeled for the launch of our campaign on International Epilepsy Day on February 14th!

put something in a person’s mouth during a seizure to prevent them from swallowing their tongue; that there is only one type of epileptic seizure; and that a person should be restrained or pinned down during a seizure. As noted, all of these are myths! Thankfully, our survey from 2021 showed that these beliefs are deteriorating but the fact that these myths have existed for so long, means there is still much work to do in terms of public education.

SAFE – keep the person having a seizure SAFE. Cushion their head if possible and remove any harmful objects from around their vicinity but never restrain them, pin them down or put anything in their mouth.

Because of these myths, we have often been in the position of talking more about what not to do rather than what to do when we’re discussing seizure first with the public.

With the key messages of TIME – SAFE – STAY that we will be delivering to the public as part of our International Epilepsy Day campaign, what we are seeking to do is create a key memorable message in an epilepsy context – taking inspiration from “Act FAST” in response to a stroke and “Staying Alive” in response to a cardiac arrest.

For this year’s International Epilepsy Day campaign, we will be reinforcing key seizure first aid messaging which we developed last year in an effort to overcome the belief that seizure first aid is complex and to dispel the myths associated with seizure first aid.

This message boils down to three key words: TIME – SAFE – STAY. TIME – if you encounter a person having a seizure, the first thing you should do is begin timing that seizure. This is because if it goes over 5 minutes, it is potentially dangerous for the person and an ambulance will need to be called.

STAY – after the seizure has ended, STAY with that person.

Often after a seizure, a person will be dazed, confused and exhausted. Talk gently and stay with them until you know they are ok.

We would appeal to readers of Hospital Professional News to please help us in advance of Epilepsy Day and on the Day itself to reinforce this key message of TIME – SAFE – STAY amongst the Irish public.

We want to make sure that everyone knows what to do in the event of a person having a seizure and as the large numbers

HOSPITALPROFESSIONALNEWS.IE | HPN • FEBRUARY 2022

PRESCRIBING INFORMATION (PI) SKYRIZI®▼ (risankizumab) 75 mg solution for injection in pre-filled syringe; Skyrizi 150 mg solution for injection in pre-filled pen and Skyrizi 150 mg solution for injection in prefilled syringe. Refer to Summary of Product Characteristics (SmPC) for full information before prescribing.

PRESENTATION: Skyrizi 150 mg solution for injection in pre-filled pen/syringe: each prefilled pen/syringe contains 150 mg risankizumab in 1 mL solution. Skyrizi 75 mg solution for injection in pre-filled syringe: each pre-filled syringe contains 75 mg risankizumab in 0.83 ml mL solution. INDICATION: For treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy. DOSAGE AND ADMINISTRATION: Intended for use under guidance and supervision of a physician experienced in diagnosis and treatment of psoriasis. Dosage: The recommended dose of Skyrizi is 150 mg by subcutaneous injection at weeks 0, 4, and every 12 weeks thereafter. Two 75mg pre-filled syringes should be injected for the full 150 mg dose. Consider discontinuation of treatment in patients showing no response after 16 weeks of treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks. Special Populations: Elderly: No dose adjustment required. Renal or hepatic impairment: No dose adjustment required. Paediatric Population: No data available. Overweight patients: No dose adjustment required.

CONTRAINDICATIONS: Hypersensitivity to any of the active substances or excipients. Clinically important active infections (e.g. active tuberculosis). SPECIAL WARNINGS AND PRECAUTIONS: See SmPC for full details. In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Skyrizi may increase the risk of infections. In patients with a chronic infection or history of recurrent infections, or known risk factors for infection, Skyrizi should be used with caution. Treatment with Skyrizi should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated. Patients should be evaluated for tuberculosis infection prior to initiating treatment. Anti-TB therapy should be considered prior to initiating Skyrizi in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Completion of all appropriate immunisations should be considered prior to initiating therapy.

If a patient has received live vaccination (viral or bacterial), it is recommended to wait at least 4 weeks prior to starting treatment with Skyrizi. Patients treated with Skyrizi should not receive live vaccines during treatment and for at least 21 weeks after treatment. If a serious hypersensivity reaction occurs, administration of Skyrizi should be discontinued immediately and appropriate therapy initiated. Excipients with known effect (75 mg solution for injection only): Skyrizi contains 68.0 mg sorbitol and less than 1 mmol sodium (23 mg) per 150 mg dose. INTERACTIONS: The safety and efficacy of Skyrizi in combination with immunosuppressants, including biologics or phototherapy have not been evaluated. PREGNANCY AND LACTATION: Women of Childbearing potential: An effective method of contraception during treatment and for at least 21 weeks after treatment should be used. Pregnancy: Limited data available. It is preferable to avoid the use of Skyrizi during pregnancy as a precautionary measure. Lactation: It is not known whether Skyrizi is excreted in breast milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which decreases to low concentrations soon afterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period. A decision should be made whether to discontinue/abstain from Skyrizi therapy, taking into account the benefit of breast-feeding to the child and the benefit of Skyrizi therapy to the woman. Fertility: The effect of Skyrizi on human fertility has not been evaluated.

ADVERSE REACTIONS: See SmPC for full details on adverse reactions. Very common adverse reactions (≥1/10): Upper respiratory infections. Common adverse reactions (≥1/100 to <1/10): Tinea infections, headache, pruritus, fatigue and injection site reactions. ▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance; Website: www.hpra.ie. Suspected adverse events should also be reported to AbbVie Limited on 01-4287900.

LEGAL CLASSIFICATION: POM (S1A). MARKETING AUTHORISATION NUMBERS/PRESENTATIONS: Skyrizi 75 mg solution for injection in pre-filled syringe (Pack of 2 prefilled syringes): EU/1/19/1361/001; Skyrizi 150 mg solution for injection in pre-filled pen: EU/1/19/1361/002; Skyrizi 150 mg solution for injection in pre-filled syringe: EU/1/19/1361/003.

Not all presentations may be marketed. Further information is available from: AbbVie Ltd., 14 Riverwalk, Citywest Business Campus, Dublin 24. DATE OF REVISION: May 2021 PI/1361/003 HRQoL, Health-Related Quality of Life; PASI, Psoriasis Area Severity Index.

REFERENCES: 1. Gordon KB, et al. Lancet 2018; 392: 650661. 2. Ryan C et al. Poster presented at the 27th European Academy of Dermatology & Venerology (EADV) Congress 2018; September 12–16; Paris, France.

Skyrizi® Summary of Product Characteristics, available on www. medicines.ie.

Date of preparation: August 2021 | IE-RISN-210074

High skin clearance matters to patients: Patients who achieve and maintain high levels of skin clearance (PASI 90-99 or PASI 100) have significantly better HRQoL than those with lower levels of skin clearance (PASI 75-89).2 Sustaining high skin clearance or complete skin clearance is associated with incremental and durable benefits in HRQoL and mental health of psoriasis patients.2

What means everything to the patient?

The potential for nothing left on their skin.* * Nothing on the skin: Defined as 75% achievement of PASI90 at Week 16 and ≥50% achievement of PASI 100 at Week 52 in UltIMMa-1 and UltIMMa-2.1

26 Juvenile Arthritis

Transitioning – Part of the JIA Journey Cal have both used our workshops and now are mentors guiding families through this process.”

Below, they share their personal journeys. For any more information contact iCAN on 0868289817 or email icanireland@gmail.com Niamh Costello My experience of life with Juvenile Idiopathic Arthritis and transitioning from paediatric care to adult services– Niamh Costello, 22

The Irish Childrens Arthritis Network, also known as iCAN, is working to get children in Ireland better access to rheumatological.

Currently, Ireland is at the bottom of the EU for paediatric rheumatological care.

Over one thousand children and teens in Ireland are diagnosed with JIA, with numbers growing daily. iCAN offers help through our online support network, family days out and information days.

Idiopathic Arthritis. As part of our support to families we run workshops on transitioning from paediatric services to adult. Our focus is to prepare families for this important move.

“Our expert speakers include clinicians, nurses, young people and parents. No one size fits all but we can work with each family individually in conjunction with their rheumatology teams. Niamh and

Wendy Costello is Chairperson of iCAN. She tells us, “Transition is a part of the JIA journey that is sometimes forgotten as the race to find remission is focused on.

“The young patient needs to be making the decisions in conjunction with their rheumatology team. Self management skills are so important and together as a family and rheumatology team these can start as early as 11yrs of age. By the time transition to your new team comes you are ready for that leap.

“We need to put more time, research and education into this vital period of a young patients life.

Leaving the paediatric setting of Crumlin or Temple St and heading to local adult services is daunting for a 16yr old. We in iCAN want to help smooth that journey. “iCAN support, advocate for and raise awareness of Juvenile

FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

My name is Niamh Costello. I am 22 years old and I was diagnosed with Juvenile Idiopathic Arthritis when I was 3. I sometimes think that being diagnosed at such a young age was a blessing in disguise, as I have grown up with JIA. It has been a part of my life for as long as I can remember and it will always be this crutch that I have to carry. Because of this, I have had to adapt my life to suit my needs and also learn to know my limits. Whereas I know lots of young people who lived a healthy, sporty and energetic lifestyle until they suddenly got diagnosed in their teenage years. This must be hard to accept as their lives have now become completely different.

I also count my blessings that I don’t remember much of my diagnosis, as I was so young. My poor parents had to take the brunt of it. They tell me that one morning I crawled into their bedroom on my hands and knees screaming that I couldn’t walk with the pain in my knee. They looked down to see my whole left leg swollen up like a

balloon. My knee was red and hot to touch and I was clearly in a lot of pain as they couldn’t stop me crying. They brought me straight to my GP who brushed it off as a virus or growing pains. I soon turned from this happy, energetic 3 year old to a whiney, tiresome one who had to be carried everywhere.

This persisted for a number of weeks until my parents brought me back up to the GP as they knew it clearly wasn’t a virus. I was admitted to hospital with a rash and a temperature and this swollen knee that was getting bigger by the day. Lots of tests and scans were done and one day, a doctor who had done some of his training under Paediatric Rheumatology, recognised my symptoms and referred me straight to Our Lady’s Children’s Hospital in Crumlin, Dublin. That is where my lifelong journey of JIA began.

I was diagnosed a couple of weeks later and was put on a high course of steroids. At the time there was no paediatric rheumatologist in Ireland so little was known about JIA and its prognosis. It was going to be a case of trial and error with my treatment. The oral steroids didn’t work so I was given a steroid injection directly into the knee joint and the fluid was drained. And believe it or not that was it for 4 years! I went into remission and I thought I would never have to see a hospital again.

Unfortunately I was wrong.

When I was 7, the trips to hospitals started again and this time I wouldn’t get a 4 year break.

27

My JIA resurfaced and soon spread to other joints which made my day to day life that bit harder. Getting up for school every morning was a struggle. I needed help with things like brushing my hair and teeth, getting in and out of bed, showering etc. I had little independence and always wanted to be near my Mum for reassurance. I had to miss out on lots of things growing up as some days I physically couldn’t get out of bed due to the pain, swelling and stiffness of my joints.

I felt like I missed out on a normal childhood. Instead of birthday parties, sleepovers, school trips and running around with my friends my childhood consisted of weekly injections, trips to hospitals, blood tests, scans, needles, fatigue, side effects and a whole lot of pain.

I was always told when I was younger that I could possibly grow out of JIA, so my family lived in hope. We did everything we could to try and keep my JIA at bay but when I was 12 I remember my consultant telling me that I will probably have this for the rest of my life. When you are 12 that is a shock to the system. All these thoughts were running through my head, how can I deal with this pain for the rest of my life, will I have to take injections forever, will I be able to have children?! I hit a slump and I was very down in myself for a couple of years after that.

I worked my way through various biologic injections until the options started to get less and less and they soon stopped working for me.

I had to start on infusions in my teenage years which meant I had to travel to hospital once a week to be hooked up to an IV drip. The infusions made me quite sick and extremely tired. I missed a lot of school throughout this time which was hard academically and socially.

When I was around 13/14, I started to go to Teen Clinics in Crumlin

children’s hospital. I would go in to clinic and see my nurse and consultant first on my own. This was daunting at first because my parents would do all the talking for me at my appointments and tell my doctors my issues and worries, I would just smile and nod. So the thoughts of having to speak to doctors on my own scared me. It turned out to be a good thing though because if I had any worries or concerns that I didn’t want to discuss in front of my parents I could discuss it with my consultant during this time. It also gave me more independence and a chance to start learning to selfmanage my illness. My parents would then come in at the end of the appointment and say anything that I might have forgotten to say.

When I hit 16 I was asked by my paediatric consultant to start thinking about what hospital I would like to transition to. I had to think about some factors such as where I live, what facilities might be available to me at this hospital – Occupational Therapy, Physio etc, where I might be going to third level education – would the hospital be far from here? All of these things had to come into consideration when I was picking an adult hospital.

I transitioned from paediatric care to adult services when I was 17. I was quite scared to go to an adult hospital as I had spent my whole life under the care of paediatric doctors.

One of the challenges that I found when I transitioned was that I had to speak up for myself a lot more and tell the doctors what I wanted for my care. This was new to me as I was used to going into teen

clinic appointments and having my consultant telling me what drug I was going onto next or saying that I needed a steroid injection straight away. I remember my adult doctor saying to me ‘do you think you need a steroid injection?’ I remember thinking well you’re the doctor! You tell me if you think I need one! It taught me that I am the only person who knows my body and illness the best. I have to start making the decisions now such as realising when I need a steroid injection or when I need to start a course of steroids/change in biologic etc.

I was also used to going into paediatric consultants and them lying me on the bed and checking my joints and then discovering that actually I had quite a few joints flaring. Sometimes I didn’t even know myself that I was flaring. In adult care they rarely do a full body check of your joints so you have to tell them which joints you feel are flaring.

I also have to now organise all my own blood tests and keep track of my own markers in my bloods.

Something that my mam and my paediatric consultant did for me when I was younger.

For me personally, at 17 I found the time of transition hard as I was in an exam year in school which was another added stress. I think transition should not be carried out until you are either finished exams or the year before you go into final year. It just gives you a chance to get settled.

I am now 22 and on a drug that is doing wonders for me. I have graduated from university and have started my first full time job as a primary school teacher. The

daily demands in my job have its own challenges but I try to balance my work and downtime as I know this balance is important to stop me from having flare ups due to stress.

I have become much more aware of my illness and know when I need something to be done with regards to my care and wellbeing.

Don’t let your illness define you, you can still lead the life you want to live just maybe with a few adaptions. I always say that I have JIA, but it doesn’t have me.

Cal’s Experience My name is Cal I am 18 years old and I have been living with Ankylosing spondylitis arthritis since I was 11 years old.

I transitioned from Crumlin children’s Hospital to St James’s Hospital when I was 16 years old.

I was in two frames of mind; not knowing what was to come but yet excited for a new beginning.

A lot of people helped through my transitioning, including my family (especially my mom and dad), the two mentors Niamh and Aine and my second family as I say - iCAN. Transitioning is different as you have to ask the questions and tell them everything where a lot of the time I would have to ask my mom.

I would prefer adult services than child services due to how well the team works. It helps when the Consultant specialises in AS. If I had to give advice on transitioning from child services to adults, it would be that it’s a new beginning. Speak up and ask question about everything around your condition.

HOSPITALPROFESSIONALNEWS.IE | HPN • FEBRUARY 2022

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PRESCRIBE AMGEVITA® BY BRAND NAME AMGEVITA® (adalimumab) Brief Prescribing Information Please refer to the Summary of Product Characteristics (SmPC) before prescribing Pharmaceutical Form: Single dose pre-filled syringe contains 20 mg adalimumab in 0.4 mL (50 mg/mL) solution, 40 mg adalimumab in 0.8 mL (50 mg/mL) solution or single dose pre-filled pen (SureClick®) contains 40 mg adalimumab in 0.8 mL (50 mg/mL) solution. Indications and Dosage: please refer to SmPC for full information. For subcutaneous injection. Treatment should be initiated and supervised by specialist physicians experienced in conditions for which AMGEVITA® is indicated. Ophthalmologists should consult with an appropriate specialist before starting treatment. Give patients a Patient Reminder Card. After training in injection technique, patients may self-inject with medical follow-up as necessary. Optimise other concomitant therapies (e.g. corticosteroids and or/immunomodulatory agents). Rheumatoid arthritis (RA), adults: In combination with methotrexate (MTX) for: 1. Moderate to severe, active RA with inadequate response to disease-modifying antirheumatic drugs (DMARDs) including MTX; 2. Severe, active and progressive RA not previously treated with MTX. Can be given as monotherapy if intolerance to or when continued treatment with MTX is inappropriate.

Dosage: 40 mg every other week (EOW). Continue concomitant MTX. In monotherapy, patients may require 40 mg every week or 80 mg EOW if there is a decrease in clinical response. Reconsider treatment beyond 12 weeks if no clinical response. Consider need for dose interruption, e.g. before surgery or if serious infection occurs. Polyarticular juvenile idiopathic arthritis (pJIA), paediatrics ≥ 2 years: In combination with MTX for active pJIA with inadequate response to one or more DMARDs. Can be given as monotherapy if intolerance to or when continued treatment with MTX is inappropriate.

Dosage: 10 kg to < 30 kg: 20 mg EOW. ≥ 30 kg: 40 mg EOW. Reconsider treatment beyond 12 weeks if no clinical response. Enthesitis-related arthritis (ERA), paediatrics, ≥ 6 years: Active ERA with inadequate response to or intolerance to conventional therapy. Dosage: 15 kg to < 30 kg: 20 mg EOW. ≥ 30 kg: 40 mg EOW. Ankylosing spondylitis (AS), adults: Severe active AS with inadequate response to conventional therapy. Axial spondyloarthritis without radiographic evidence of AS (nr-axSpA), adults: Severe nr-axSpA with objective signs of inflammation (elevated CRP and/or MRI), and an inadequate response to or intolerance to nonsteroidal anti-inflammatory drugs. Psoriatic arthritis (PsA), adults: Active and progressive PsA with inadequate response to DMARDs. Dosage (AS, nr-axSpA, PsA): 40 mg EOW. Reconsider treatment beyond 12 weeks if no clinical response. Psoriasis, adults: Moderate to severe chronic plaque psoriasis in candidates for systemic therapy. Dosage: 80 mg at Week 0, followed by 40 mg EOW from Week 1. Reconsider treatment beyond 16 weeks if no clinical response. Refer to SmPC. Paediatric Plaque Psoriasis, ≥ 4 years: Severe chronic plaque psoriasis with inadequate response to or if topical therapy and phototherapies are inappropriate. Dosage: 15 kg to < 30

kg: 20 mg followed by 20 mg EOW starting one week after initial dose. ≥ 30 kg: 40 mg then 40 mg EOW starting one week after initial dose. Reconsider treatment beyond 16 weeks if no clinical response. Safety has been assessed in paediatric patients with plaque psoriasis for a mean of 13 months.

Hidradenitis suppurativa (HS), adults and adolescents ≥ 12 years: Active moderate to severe HS (acne inversa) with inadequate response to conventional systemic therapy. Dosage, adult: 160 mg at Day 1, followed by 80 mg at Day 15. At day 29 continue with 40 mg every week or 80 mg EOW. Reintroduction after treatment interruption: 40 mg every week or 80 mg EOW. Dosage: adolescent (≥ 30 kg): 80 mg at week 0 then 40 mg EOW starting at week 1. If response is inadequate, consider increasing to 40 mg every week or 80 mg EOW. Dosage, adult and adolescent: Antibiotics may be continued if necessary. Use concomitant topical antiseptic wash on a daily basis.

Reconsider treatment beyond 12 weeks if no improvement. Periodically evaluate the benefit and risk of continued treatment. Crohn’s disease (CD), adults: Moderately to severely active CD with no response despite a full and adequate course of, intolerance to or contraindication for a corticosteroid and/ or an immunosuppressant therapy. Dosage: Induction: 80 mg at Week 0, then 40 mg at Week 2. For a more rapid response: 160 mg at Week 0, then 80 mg at Week 2; risk of adverse events higher during rapid induction. Maintenance: 40 mg dose EOW. Corticosteroids may be tapered in accordance with clinical guidelines. If decrease in clinical response, can increase to 40 mg every week or 80 mg EOW. If no response by Week 4 there may be benefit from continued therapy to week 12. Reconsider treatment beyond 12 weeks if no clinical response. Paediatric CD, ≥ 6 years: Moderately to severely active CD with inadequate response to, intolerance to or contraindication to conventional therapy including primary nutrition therapy and a corticosteroid and/or an immunomodulator. Dosage: < 40 kg: Induction: 40 mg at week 0 then 20 mg at week 2. For a more rapid response: 80 mg at week 0 then 40 mg at week 2; risk of adverse events higher during rapid induction. Maintenance starting at week 4: 20 mg dose EOW. If insufficient response, consider 20 mg every week. Dosage: ≥ 40 kg: Induction: 80 mg at Week 0 then 40 mg at Week 2. For a more rapid response: 160 mg at Week 0, then 80 mg at Week 2; risk of adverse events higher during rapid induction. Maintenance starting at week 4: 40 mg dose EOW. If insufficient response, consider 40 mg every week or 80 mg EOW. Reconsider treatment beyond 12 weeks if no clinical response.

Ulcerative colitis (UC), adults: Moderately to severely active UC with inadequate response to, intolerance to or contraindication for conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA). Dosage: Induction: 160 mg at week 0 and 80 mg at week 2.

Maintenance: 40 mg EOW. Corticosteroids may be tapered in accordance with clinical guidelines. If insufficient response, consider increasing to 40 mg every week or 80 mg EOW. Do not continue treatment beyond 8 weeks if no

clinical response. Paediatric UC, ≥6 years: Moderately to severely active UC with an inadequate response to conventional therapy including corticosteroids and/or 6-MP or AZA, or who are intolerant to or have contraindications.

Dosage: < 40 kg: Induction: 80 mg at Week 0 and 40 mg at Week 2.

Maintenance starting at week 4: 40mg EOW. Dosage: ≥ 40 kg: Induction: 160 mg Week 0 and 80 mg Week 2. Maintenance starting at week 4: 80mg EOW. Patients reaching 18 years should continue their prescribed maintenance dose. Reconsider treatment beyond 8 weeks if no clinical response. No relevant use in children <6 years. Uveitis, adults: Non-infectious intermediate, posterior and panuveitis with inadequate response to corticosteroids, in patients in need of corticosteroid-sparing, or in whom corticosteroid treatment is inappropriate. Dosage: 80 mg at Week 0 and 40 mg EOW from Week 1.

There is limited experience in initiation of treatment with adalimumab alone.

Treatment can be initiated in combination with corticosteroids and/or with other non-biologic immunomodulatory agents. Concomitant corticosteroids may be tapered starting two weeks after initiating treatment with AMGEVITA®.

Evaluate on a yearly basis the benefit and risk of continued treatment.

Paediatric uveitis, ≥ 2years: Chronic non-infectious anterior uveitis with inadequate response or intolerance to conventional therapy, or in whom conventional therapy is inappropriate. In paediatric uveitis, there is no experience in the treatment with AMGEVITA® without concomitant treatment with methotrexate. Dosage: < 30 kg: 20 mg EOW in combination with MTX. Dosage: ≥ 30 kg: 40 mg EOW in combination with MTX. A loading dose of 40 mg (< 30 kg) or 80 mg (≥ 30 kg) may be administered 1 week in advance of maintenance therapy. No clinical data on use of loading dose in patients < 6 years. Evaluate benefit and risk of continued treatment on a yearly basis.

Contraindications: Hypersensitivity to the active substance or to any excipients; Active tuberculosis (TB) or other severe infections such as sepsis and opportunistic infections; Moderate to severe heart failure (NYHA class III/ IV). Warnings and Precautions: Clearly record the name and batch number.

Infections: Patients taking TNF-antagonists are more susceptible to serious infections, especially if impaired lung function. Monitor for infections, before, during and for 4 months after treatment. Do not initiate treatment during an active infection, until infection is controlled. Consider risk/benefit prior to treatment in patients exposed to TB or who have travelled in areas of high risk of TB or endemic mycoses. Evaluate new infections and monitor closely. Stop treatment if new serious infection or sepsis and treat. Exercise caution in patients with a history of recurring infections or who are predisposed to infections, including the use of concomitant immunosuppressive medications.

Serious Infections: Consult SmPC for details. Serious infections, including those associated with hospitalisation or death, were reported in patients receiving treatment. TB: Reactivation and new onset TB, both pulmonary and extra-pulmonary (disseminated). Screen all patients before therapy initiation

MAKES THE DIFFERENCE AMGEVITA® 40mg SureClick® Pre-filled pen

AMGEVITA® 20mg Pre-filled syringe

AMGEVITA® 40mg Pre-filled syringe

Information for Healthcare Professionals The Medicine Management Programme recommends AMGEVITA® as a citrate-free formulation of adalimumab.

Prescribing AMGEVITA® has lead to significant savings for the health service, in the order of millions of euros1,2,3 for active or inactive (latent) TB. Perform detailed medical assessment and appropriate screening tests for TB in all patients and results recorded on patient reminder card. If latent TB is suspected, consult physician with appropriate expertise Despite prophylaxis, TB reactivation has occurred on adalimumab. If active TB is diagnosed, do not initiate AMGEVITA® treatment.

Other opportunistic infections: Opportunistic infections were observed in patients receiving adalimumab. Stop AMGEVITA® in patients with signs and symptoms of such infections. Consult with physician with appropriate expertise for diagnosis and administration of empiric antifungal therapy.

Hepatitis B reactivation: Reactivation of HBV has occurred in chronic carriers; some cases were fatal. Test patients for HBV infection before initiating treatment. HBV carriers should consult a specialist physician and be closely monitored for reactivation of HBV infection throughout therapy and for several months after treatment. If reactivation occurs, stop treatment and initiate appropriate antiviral and supportive treatment. Neurological events: Caution in patients with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders. Consider discontinuation if any of these develop.

Perform neurologic evaluation in patients with non-infectious intermediate uveitis prior to initiation of treatment and regularly during treatment. Allergic reactions: Reports of serious allergic reactions including anaphylaxis. For serious allergic or anaphylactic reaction, stop AMGEVITA® immediately and initiate appropriate therapy. Dry natural rubber: The needle cover of the pen (SureClick®) is made from dry natural rubber (a derivative of latex), which may cause allergic reactions. Malignancies and lymphoproliferative disorders: A possible risk of malignancy, some fatal, including lymphomas and leukaemia, cannot be excluded (see SmPC). Examine all patients, especially those with a medical history of extensive immuno-suppressant therapy or psoriasis patients with a history of PUVA treatment, for non-melanoma skin cancer prior to and during treatment. Melanoma and Merkel cell carcinoma have also been reported. Caution in COPD patients, and in patients with increased risk for malignancy due to heavy smoking. Consider the potential risk with the combination of AZA or 6-MP and AMGEVITA® (hepatosplenic T-cell lymphoma has occurred). Caution in patients with a history of malignancy. Risk of developing dysplasia or colon cancer unknown. Screen patients with UC, history of dysplasia or colon carcinoma, for dysplasia before and during treatment. Haematologic reactions: Adverse events of the haematologic system, including medically significant cytopenia, have been reported. Advise patients to seek immediate medical attention if signs and symptoms of blood dyscrasias develop. Vaccinations: Patients may receive concurrent vaccinations, except for live vaccines. Bring paediatric patients up to date with all immunisations prior to initiating treatment. Congestive heart failure: See contraindications. Caution in mild heart failure (NYHA class I/II). Discontinue treatment if new or worsening symptoms of congestive heart failure.

Autoimmune processes: Autoimmune antibodies may form. Stop treatment if development of a lupus-like syndrome with positive antibodies against doublestranded DNA. Surgery: Consider the long half-life of AMGEVITA® for planned surgical procedures. Monitor closely for infections. There is limited safety experience in patients undergoing arthroplasty or surgical procedures. Elderly patients: Serious infections were higher in patients over 65, some of which were fatal. Consider risk of infections in these patients. Interactions: Antibody formation was lower when AMGEVITA® was given together with MTX rather than as monotherapy. Combination of AMGEVITA® with other biologic DMARDs (e.g. anakinra and abatacept) or other TNF-antagonists is not recommended. Fertility, pregnancy and lactation Only use during pregnancy if clearly needed. Women of childbearing age to consider use of adequate contraception during and for at least 5 months after the last treatment. Administration of live vaccines (e.g. BCG) to infants exposed to AMGEVITA ® in utero is not recommended for 5 months following the mother’s last injection during pregnancy. AMGEVITA ® can be used during breastfeeding.

Effects on ability to drive and use machines: AMGEVITA® may have a minor influence on the ability to drive and use machines. Adverse Reactions: Very common ≥ 1/10: Respiratory tract infections, leukopenia, anaemia, lipids increased, headache, abdominal pain, nausea and vomiting, elevated liver enzymes, rash, musculoskeletal pain, injection site reaction. Common ≥ 1/100 to < 1/10: Systemic infections, intestinal infections, skin and soft tissue infections, ear infections, oral infections , reproductive tract infections , urinary tract infections, fungal infections, joint infections, skin cancer excluding melanoma, benign neoplasm, leucocytosis, thrombocytopenia, hypersensitivity, allergies, hypokalaemia, uric acid increased, blood sodium abnormal, hypocalcaemia, hyperglycaemia, hypophosphataemia, dehydration, mood alterations , anxiety, insomnia, paraesthesia, migraine, nerve root compression, visual impairment, conjunctivitis, blepharitis, eye swelling, vertigo, tachycardia, hypertension, flushing, haematoma, asthma, dyspnoea, cough, GI haemorrhage, dyspepsia, gastroesophageal reflux disease, Sicca syndrome, worsening or new onset of psoriasis , urticaria, bruising , dermatitis, onychoclasis, hyperhidrosis, alopecia, pruritus, muscle spasms , renal impairment, haematuria, chest pain, oedema, pyrexia, coagulation and bleeding disorders, autoantibody test positive , blood lactate dehydrogenase increased, impaired healing. Serious, including fatal, adverse reactions have been reported including infections/sepsis, TB, opportunistic infections, allergic reactions, HBV reactivation and malignancies.

Serious haematological, neurological and autoimmune reactions have also been reported. These include rare reports of pancytopenia, aplastic anaemia, central and peripheral demyelinating events and reports of lupus, lupusrelated conditions and Stevens-Johnson syndrome. Other less common and rarely reported adverse reactions are listed in the SmPC. Pharmaceutical

Precautions: Store in a refrigerator (2°C – 8°C). Do not freeze. Keep in the outer carton in order to protect from light. Out of the refrigerator, may be stored up to 25°C for up to 14 days. Legal Category: POM. Presentation and Marketing Authorisation Number. AMGEVITA® 20 mg solution for injection in pre-filled syringe: EU/1/16/1164/001 – 1 pack: cost AMGEVITA® 40 mg solution for injection in pre-filled syringe: EU/1/16/1164/003 – 2 pack AMGEVITA® 40 mg solution for injection in pre-filled pen: EU/1/16/1164/007 – 2 pack. Marketing Authorisation Holder: Amgen Europe B.V. Minervum 7061, 4817 ZK Breda, The Netherlands. Further information is available from Amgen Ireland Limited, 21 Northwood Court, Santry, Dublin D09 TX31.

AMGEVITA® is a registered trademark of Amgen Inc. Date of PI preparation: December 2021 (Ref:IE-AMB-1121-00005) Adverse reactions/events should be reported to the Health Products Regulatory Authority (HPRA) using the available methods via www.hpra.ie. Adverse reactions/events should also be reported to Amgen Limited on +44 (0) 1223 436441 or Freephone 1800 535 160.

1.

2.

3.

4.

BVBM Amgevita Product Information Sheet. https://www.hse. ie/eng/about/who/cspd/ncps/medicines-management/bestvalue-medicines/best-value-biological-medicines/bvb-medicineamgevita-product-information-sheet.pdf. Accessed January 2022.

Oireachtas.ie, Debates, December 2020, Written Answer by Minister for Health. https://www.oireachtas.ie/en/debates/ question/2020-12-10/373/. Accessed January 2022.

Medicines Management Programme Best-Value Biological Medicines: Adalimumab 20 mg solution for injection. https://www.hse.ie/eng/ about/who/cspd/ncps/medicines-management/best-value-medicines/ best-value-biological-medicines/mmp-report-bvb-medicineadalimumab-20mg-march-2021.pdf. January 2022.

AMGEVITA® (adalimumab) summary of product characteristics.

IE-AMB-0122-00003 Date of preparation: January 2022

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CPD 84: RHEUMATOID ARTHRITIS Continuing Professional Development

CPD 60 Second Summary Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by symmetrical inflammatory polyarthritis and is associated with extraarticular manifestations.

It is an accepted independent non-traditional risk factor for cardiovascular disease, which is related to severity and duration of inflammation; therefore, promotion of healthy lifestyle and optimal disease control with disease-modifying antirheumatic drugs (DMARDs) are important therapeutic strategies.

Early recognition, diagnosis and treatment initiation significantly improve patients’ overall outcome.

The advent of targeted therapies such as biologic and targeted synthetic DMARDs has change the whole vista regarding the treatment of RA. Biosimilar DMARDs are still relatively new to the Irish healthcare system but becoming increasingly common drug of choice for RA patients requiring DMARD escalation due to 1) cost-containment and 2) its similar efficacy and safety profiles compared to bio-originator DMARDs. Refractory or “difficult-to-treat” RA remains a challenging task among rheumatologists and will continue to drive and inspire discoveries of more novel therapies in the future.

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Written by Dr Fahd Adeeb, Consultant Rheumatologist & Physician, UL Hospitals Group Prior to his appointment to University of Limerick (UL) Hospitals Group in 2021, Fahd was a Consultant Rheumatologist & Physician at University Hospital Kerry between 2018 and 2020. He graduated from TCD, completed his dual specialty training (CSCST) in rheumatology and general internal medicine in early 2017 and holds an MSc in Sports & Exercise Medicine from UCC and PhD in Behçet’s disease from UL. His professional and research interests include Behçet’s disease and vasculitis, inflammatory arthritis, connective tissue diseases, and bone health.

1. REFLECT - Before reading this module, consider the following: Will this clinical area be relevant to my practice?

knowledge gap - will this article satisfy those needs - or will more reading be required?

2. IDENTIFY - If the answer is no, I may still be interested in the area but the article may not contribute towards my continuing professional development (CPD). If the answer is yes, I should identify any knowledge gaps in the clinical area.

4. EVALUATE - Did this article meet my learning needs - and how has my practise changed as a result?Have I identified further learning needs?

3. PLAN - If I have identified a

5. WHAT NEXT - At this time you may like to record your learning for future use or assessment. Follow the

4 previous steps, log and record your findings.

Published by HPN. Copies can be downloaded from www.irishpharmacytraining.ie Disclaimer: All material published is copyright, no part of this can be used in any other publication without permission of the publishers and author. Galapagos UK, has no editorial oversight of the CPD programmes included in these modules.

Rheumatoid Arthritis: Current Updates Introduction Rheumatoid arthritis (RA) is one of the commonest chronic, systemic autoimmune diseases characterized by symmetrical inflammatory polyarthritis (which may be asymmetrical initially at very early stage of disease).

It typically affects the small peripheral joints of the hands, wrists and feet, but may extend to larger joints, and is associated with extraarticular manifestations. Left untreated or improperly managed, it leads to irreversible erosive bone destruction and structural joint damage resulting in disability, significant morbidity and increased mortality. It is one of the leading causes of work disability with an estimated cost of ¤45.3 billion in Europe.1 The aetiology of RA is not completely understood, but is thought to be influenced by a complex interaction between genetic, epigenetic and environmental factors leading to breakdown of immune tolerance.

The shared epitope alleles of HLA-DRB1 are the most important genetic risk factor for development of RA in patients with antibodies

to citrullinated protein antigens (ACPA) while cigarette smoking is the strongest environmental risk factor associated with RA. Antibodies such as rheumatoid factor (RF; less specific for RA) and ACPA (highly specific for RA) are currently the main antibodies

associated with RA; however, other distinct anti-modified protein antibodies (AMPAs) such as anticarbamylated protein and antiacetylated protein antibodies have been recently described. Recent insight on RA pathophysiology points toward autoimmunity generation outside of the joints

Tables

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CPD 84: RHEUMATOID ARTHRITIS Table 1: Identified risk and protective factors associated with RA development in RArelated antibody individuals [6]

Table 1: Identified risk and protective factors associated with RA development in RA-related antibody individuals6

Risk factors

Protective factors

Female sex

Longer duration of breast-feeding

First-degree relatives

Higher parity

at mucosal sites such as the gut, lungs or periodontium and is related to microbiome.2, 3

High-titre RA-related antibodies or positive High-fatty fish intake and Omega-3 fatty in both RF and ACPAs acids

Window of opportunity to prevent irreversible joint damage by early treatment initiation may be impeded by delays in 1) seeking care by patients when developed symptoms 2) referral to a rheumatologist, and the long waiting-list. It is estimated that a potential savings of ¤237,547 over five-year timeframe can be achieved by the Irish Healthcare system through the reconfiguration of the diagnostic care pathway for suspected RA patients using an early referral pathway.4

Obesity or inflammatory diet

The “Pre-RA” Phase It may take months or years before a subset of susceptible individuals with RA-related antibodies to develop and manifest polyarthritis (polysynovitis). The term “Pre-RA” stage of seropositive individuals (RF and/or ACPA) with other factors (e.g., joint symptoms/ arthralgia without synovitis) was initially suggested by the European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) study group in 2012 while predicting the risks and assessing the earliest clinically apparent phases in RA.5

Tobacco exposure (especially long duration, high-intensity) Presence of shared-epitope (having genes conferring higher risk such as HLA-DR4 allele) Lung disease (airways, parenchyma) Periodontal inflammation currently limited or yet to be robustly validated especially on 1) which subset of high-risk patients would have the greatest benefit from the prevention treatment? 2) which phase of disease should the treatment commence? 3) should treatment strategy focus on once-off therapy or a more frequent regime? 4) is the benefit-to-risk ratio of treatment prevention favourable?

The criteria is grouped into four classifications and weighted in favour of more small joints involvement (up to 5 points), high The 2010 American College of Table 2: ACR/EULAR criteria for RA (up Rheumatology (ACR)/EULAR classification titres of RA-related antibodies

to 3 points), and to a lesser extent for larger joints, symptom duration, and acute-phase reactants; classification is satisfied if the total score reaches 6 points (Table 2). As mentioned earlier, the clinical “diagnosis” has to be established by the rheumatologist based upon many other aspects and may be guided by the classification criteria.

Extraarticular manifestations & comorbidities RA does not exclusively affect the joints. Extraarticular manifestations usually occur in RA patients with more active and severe disease and

Joint distribution (0-5)

Points

*

0

Negative RF and ACPA

0

2-10 large joints

1

Low positive RF or ACPA

2

1-3 small joints ** (large joints not counted 4-10 small joints (large joints not counted >10 joints (at least 1 small joint) ***

2

High positive RF or ACPA

3

3

Symptom Duration (0-1)

5

<6 weeks

0

≥ 6 weeks

1

1 large joint

Acute phase reactants (0-1) Normal CRP and ESR

0

Abnormal CRP or ESR

1

Serology (0-3)

Points

7

≥ 6= definite RA. If very short duration of symptoms, other differentials should be considered *

Table 2: ACR/EULAR classification criteria for RA

classification criteria for RA was not intended to be diagnostic, but has helped to identify early RA and is utilized for conducting clinical trials involving early disease. This relatively new criteria emphasizes on RA characteristics that emerge early in disease and contrasts the older 1987 revised ACR criteria, which relied on chronic disease features such as radiographic erosions and rheumatoid nodules.

Current Classification Criteria: The 2010 ACR/EULAR Criteria for RA

Current data suggest early reactivity to limited number of self-antigens with limited systemic inflammation followed by evolution over time of expanding innate and adaptive responses until certain threshold is crossed where clinically-apparent RA develops.6 The concept has since evolved and many clinical prevention trials are either ongoing or have been completed including a single-dose of Rituximab to delay disease onset.7 Several risk and protective factors have been identified so far to be associated with RA development in individuals with RA-related antibodies (Table 1).

The evidence across many aspects of the concept is however

OCP

Large joints=shoulder, elbow, hip, knee, ankle

** does not include 1st CMC, 1st MTP and DIP joints ***additional joints include TMJ, SC, AC and other joints that are reasonably expected in RA

Table 3: Biologic and targeted synthetic DMARD therapy in RA Biologic DMARD therapy

bDMARD

TNF inhibitors

Adalimumab, Infliximab, Etanercept, Certolizumab, Golimumab Tocilizumab, Sarilumab

IL-6 receptor inhibitors

** does not include 1st CMC, 1st MTP and DIP joints ***additional joints include TMJ, SC, AC and other joints that are reasonably expected in RA

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Table 3: Biologic and targeted synthetic DMARD therapy in RA Biologic DMARD therapy

bDMARD

TNF inhibitors

Adalimumab, Infliximab, Etanercept, Certolizumab, Golimumab IL-6 receptor inhibitors Tocilizumab, Sarilumab CD80 and CD86 inhibitor (T cell co- Abatacept stimulator blockade) CD20/B-cell inhibitor Rituximab Targeted synthetic DMARD therapy tsDMARD JAK1/JAK3 inhibitor Tofacitinib JAK1/JAK2 inhibitor Baricitinib Selective JAK1 inhibitors Upadacitinib, Filgotinib TNF: tumour necrosis factor; IL: interleukin; JAK: Janus kinase; DMARD: disease-modifying antirheumatic drugs

is associated with higher morbidity and mortality. This includes rheumatoid nodules, vasculitis, ocular manifestations (e.g., scleritis, keratitis, keratoconjunctivitis sicca), cardiovascular involvement (such as heart failure, pericarditis, myocarditis, myocardial infarction), pulmonary features (including interstitial lung disease/ILD, pleural disease, brionchiolitis), secondary amyloidosis and Sjogren’s syndrome.

Osteoporosis is one of the common comorbidities of RA, with 60100% increased of fracture risk compared to general population.8 Accumulating evidence points toward RA negatively impacting mental health, not just due to distress and disability but also from immunological alterations.9 Patients with RA also have increased risk of malignancy, mainly of lymphoma and lung cancer, which does not appear to be related to diseasemodifying antirheumatic drugs (DMARD) therapy. The most common cause of premature death among RA patients is CVD, followed by ILD. Cardiovascular risk RA is an independent, non-traditional risk factor for cardiovascular disease (CVD).

Patients with RA have up to two-times higher risk of developing atherosclerotic CVD compared to general population (similar to diabetes), and almost twice the risk of developing congestive heart failure, with the risk already increased during early disease or disease onset.10 The risk can

be reduced by healthy lifestyle (healthy diet, regular exercise, smoking cessation) and use of DMARDs for optimal disease control; however, caution is required in patients taking NSAIDs or higher doses of Tofacitinib (10mg twice daily), based on recent postmarketing trial results.

It is recommended that CVD risk assessment should be performed at least once in every 5 years in low-to moderate risk RA patients but more often in intermediate or higher risk and following major changes in DMARD therapy.11 Management The treatment strategies in RA have evolved significantly over the past several decades. Early diagnosis, prompt DMARD initiation and regular assessment to achieve remission or low disease state have been shown to improve patients’ outcome.

Current therapeutic strategies focus on treat-to-target approach for better disease control, which involves close, frequent monitoring during active disease and prompt DMARD escalation when target is not achieved. The main goal is for early sustained complete remission to prevent irreversible joint damage.

Patients should ideally be seen by a rheumatologist within 6 weeks of symptom(s) onset. Treatment is based on recommended guidelines and upon a shared decision between patient and the rheumatologist. Multidisciplinary team approach is key, and should ideally involve primarily

the rheumatologist, advanced nurse practitioner/clinical nurse specialist, physiotherapist and occupational therapist, but may extend to other specialties depending on patients’ comorbidities such as ILD, CVD or chronic hepatitis.

Methotrexate (MTX) monotherapy is recommended as first line; however, if unresponsive, intolerant, or contraindicated, leflunomide or sulfasalazine should be considered. Short term glucocorticoid as bridging therapy during DMARD initiation or switch should be considered but tapered as soon as clinically reasonable.

Additional therapy with either a biological (bDMARD) or targeted synthetic DMARD (tsDMARD) should be considered if disease is not controlled (Table 3).

Majority of these targeted therapies are broadly similar in efficacy but differ in terms of mode and frequency of administration, safety and adverse events (AEs). Most are recommended as adjunct to MTX, and so far, only Tocilizumab and Janus Kinase (JAK) inhibitors have shown efficacy as monotherapy compared to MTX monotherapy.12, 13 Low-dose MTX at 7.5 to 10mg weekly provides added efficacy to anti-TNFs and reduces the incidence of antidrug antibodies (immunogenicity). In case of failure of bDMARD or tsDMARD, another bDMARD (from the same group or a different group), or tsDMARD can be used.14

Table 3: Biologic and targeted synthetic DMARD therapy in RA

Assessment of vaccination status and cardiovascular risk, smoking cessation, dental care, and weight control should be part of patients’ care. Periodic osteoporosis screening should be considered, initially by fracture risk assessment and dual-energy x-ray absorptiometry (DXA), with repeat DXA every 2-3 years in patients 40 years and above and those under 40 years but with high risk for developing osteoporosis.15 The need for orthopaedic intervention has declined with early treat-to-target therapy and the incidence for joint replacements closely resembles those with non-inflammatory disease.

Biosimilars and the small molecules Following the expiration of patent protections for some native biologic originator (bio-originator; boDMARDs), there have been increasing amount of relatively lowcost biosimilars (bsDMARDs) in the market. These bsDMARDs are deemed highly similar in structure without any clinical meaningful difference to the reference boDMARDs including in its’ safety and efficacy profile. It is costeffective and as part of the solution to reduce national 8 healthcare expenditure, the Irish Government initiated price competition between biosimilar manufacturers (bestvalue biological) and gainshare prescribing incentive initiatives (which can be reinvested back for service development and patients’ care).

Currently there are several bsDMARDs approved for the Irish market including Benepali (Etanercept; others include Erelzi, Lifmior, Nepexto), Idacio, Amgevita, Imraldi, Hulio and Yuflyma (Adalimumab; others include Amsparity, Hefiya, Hyrimoz), Inflectra, Flixabi, Remsima, Zessly (Infliximab; given intravenously however CT-P13 biosimilar which is not yet approved may be given subcutaenously) and for antiCD20 Rituxan (Rituximab; others include Blitzima, Ritemvia, Rixathon, Riximyo, Ruxience, Truxima). The patent for the pegylated monoclonal antibody

34

5 Questions

CPD 84: RHEUMATOID ARTHRITIS

(certolizumab) which prolongs renal clearance, and stops it from crossing the placenta, making it safer in pregnancy is expected to expire in 2024.

JAK inhibitors (Jakinibs) represents the latest targeted therapies approved for treatment of RA. Currently there are four approved for RA in Ireland; Tofacitinib, Baricitinib, Upadacitinib and Filgotinib. Many phase 3 clinical trials, real-world and long-term data uniformly demonstrated rapid efficacy over time of Jakinibs in RA patients as monotherapy, or in combination to conventional DMARDs, and in anti-TNF partial responders. Recent studies suggested that Jakinibs may also have additional independent effect on non-inflammatory pain.16 Being orally administered, it may offer convenience especially for those frequently air-travel, or have needle-phobia. More compellingly is that its’ shorter half-lives that range in hours means that the AEs are short-lived when it is held or discontinued.

There is higher incidence of herpes zoster compared to other mode of actions DMARDs, and emerging postapproval safety data of slight increased risk for 1) major adverse cardiovascular events among patients above 65 years or those who ever smoke and 2) venous thromboembolic events on Tofacitinib.17, 18 Currently there is no definitive data on switching Jakinibs in non or partial responders albeit promising results in several observational studies on switching to another Jakinib.

Refractory or “difficult-to-treat” RA A proportion of RA patients are non-responsive to multiple advanced targeted DMARD therapies. They are known as refractory or “difficult-to-treat” RA patients, and encompasses patients who likely to have cycled through and exhausted all available DMARD therapies due to either 1) persistent joint or systemic inflammation with high disease activity resistant to multiple DMARDs, or requiring moderately high doses of glucocorticoids alongside DMARD therapy to achieve disease control i.e. “Persistent inflammatory refractory RA”, or 2) poor patient adherence to therapies, or 3) persistent measured disease activity mediated predominantly by pain and patient reported outcomes

(PROMs) but without joint and/ or systemic inflammation i.e. “Noninflammatory refractory RA”.19 EULAR task-force recommends a threshold of a failure of ≥2 bDMARDs or tsDMARDs (with different mechanisms of action) as “difficult-to-treat” RA.20 Suboptimal or delayed treatment, having high composite disease activity scores, development of anti-drug antibodies, obesity and unhealthy lifestyle may all favour the development of refractory RA. The disease process of these patients may involve different pathogenetic pathways, which require further research and additional interventions or therapies.

Conclusion Early diagnosis and treatment advancement have revolutionised the landscape of RA management.

Several aspects in disease understanding remain less well studied and currently not supported by robust evidence, mainly in RA prevention for those at risk and those with refractory RA. These unmet needs will continue to serve as a challenge among global scientific community to drive further research and inspire discoveries.

References 1. Lundkvist J, Kastäng F, Kobelt G. The burden of rheumatoid arthritis and access to treatment: health burden and costs. Eur J Health Econ 2008;8 Suppl 2: S49-60 2. Holers VM, Demoruelle MK, Kuhn KA, et al. Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction. Nat Rev Rheumatol 2018; 14: 542-557 3. Zaiss MM, Joyce Wu HJ, Mauro D, et al. The gut-joint axis in rheumatoid arthritis. Nat Rev Rheumatol 2021; 17: 224-237 4. Kelleher D, Barry L, McGowan B, et al. Budget impact analysis of an early identification and referral model for diagnosing patients with suspected rheumatoid arthritis in Ireland.

Rheumatol Adv Pract. 2020; 4: rkaa059 5. Gerlag DM, Raza K, van Baarsen LG, et al. EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis. Ann Rheum Dis 2012; 71: 638-41 6. Deane KD, Holers VM. Rheumatoid Arthritis Pathogenesis, Prediction, and Prevention: An Emerging Paradigm Shift. Arthritis Rheumatol 2021 Feb; 73: 181-193 7. Greenblatt HK, Kim HA, Bettner LF, et al. Preclinical rheumatoid arthritis and rheumatoid arthritis prevention. Curr Opin Rheumatol 2020; 32: 289-296 8. Jin S, Hsieh E, Peng L, et al. Incidence

1. Which of the following is false? of fractures among patients with rheumatoid arthritis: a systematic review and meta-analysis. Osteoporos Int 2018; 29: 1263-1275 9. Nerurkar L, Siebert S, McInnes IB, et al. Rheumatoid arthritis and depression: an inflammatory perspective. Lancet Psychiatry.

2019; 6: 164-173 10. Hansildaar R, Vedder D, Baniaamam M, et al. Cardiovascular risk in inflammatory arthritis: rheumatoid arthritis and gout. Lancet Rheumatol.

2021; 3: e58-e70 11. Agca R, Heslinga SC, Rollefstad S, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis 2017; 76: 17-28 12. Nam JL, Takase-Minegishi K, Ramiro S, et al. Efficacy of biological diseasemodifying antirheumatic drugs: a systematic literature review informing the 2016 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis 2017; 76: 1113-1136 13. Chatzidionysiou K, Emamikia S, Nam J, et al. Efficacy of glucocorticoids, conventional and targeted synthetic disease-modifying antirheumatic drugs: a systematic literature review informing the 2016 update of the EULAR recommendations for the management of rheumatoid arthritis.

Ann Rheum Dis 2017; 76: 1102-1107 14. Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020; 79: 685-699 15. Adami G, Saag KG. Osteoporosis Pathophysiology, Epidemiology, and Screening in Rheumatoid Arthritis. Curr Rheumatol Rep 2019; 21: 34 16. Simon LS, Taylor PC, Choy EH, et al.

The Jak/STAT pathway: A focus on pain in rheumatoid arthritis. Semin Arthritis Rheum 2021; 51: 278-284 17. Ytterberg S, Bhatt D, Mikuls T, et al.

Safety and Efficacy of Tofacitinib vs TNF Inhibitors in RA Patients Aged 50 Years or Older with One or More Cardiovascular Risks: Results from a Phase 3b/4 Randomized Safety Trial [abstract]. Arthritis Rheumatol 2021; 73 (suppl 10) 18. Charles-Schoeman C, Fleischmann R, Mysler E, et al. The Risk of Venous Thromboembolic Events in Patients with RA Aged ≥ 50 Years with ≥ 1 Cardiovascular Risk Factor: Results from a Phase 3b/4 Randomized Safety Study of Tofacitinib vs TNF Inhibitors [abstract]. Arthritis Rheumatol 2021; 73 (suppl 10) 19. Buch MH, Eyre S, McGonagle D. Persistent inflammatory and noninflammatory mechanisms in refractory rheumatoid arthritis. Nat Rev Rheumatol 2021; 17: 17-33 20. Nagy G, Roodenrijs NMT, Welsing PM, et al. EULAR definition of difficult-totreat rheumatoid arthritis. Ann Rheum Dis. 2021; 80: 31-35

a. Biosimilar DMARDs are more cost effective than biooriginator DMARDs b. Osteoporosis and fragility fractures are associated with RA c. RA typically affects the small joint of the hands and wrists d. Suspected RA patients should ideally be seen within 6 months of symptom onset e. The two commonest causes of premature deaths in RA are CVD and ILD 2. Cardiovascular disease risk assessment in RA patients should be performed: a. After minor changes in antirheumatic therapy b. Annually for all patients c. Biannually in moderate CVD risk patients d. Once every 3 years in all patients e. Once every 5 years in low CVD risk patients 3. Which of the following is a treatment option for rheumatoid arthritis? a. Abatacept b. Apremilast c. Guselkumab d. Secukinumab e. Ustekinumab 4. Which of the following is not a risk factor for developing RA in individuals with RA-related antibodies? a. Cigarette smoking b. High-fatty fish intake c. High-titre RA-related antibodies d. Periodontal inflammation e. Presence of shared-epitope alleles 5. Which of the following is true about JAK inhibitors? a. Currently licenced treatment for RA includes Baricitinib and Upadacitinib b. Has a lower risk of herpes zoster compared to other mode of action DMARDs c. Has a slower efficacy onset compared to anti-TNFs d. Is considered as one of the first-line therapies for newly diagnosed RA patients e. Is extremely safe in heavy smoker elderly patients

Vitamin D 35 _________________________________________________________________ 72: Vitamin D Levels and Supplementation in Frail Older Adults Presenting to an Irish Level 5 Emergency Department (ED) C. Pender, L. Dillon, C. Byrne, S. Magner, A. Ryan, A. Murphy, N. Carribine, R. Laguna, K. Malomo Mater Misericordiae University Hospital (MMUH), Dublin, Ireland ciarapender@mater.ie

Background •

• •

The Department of Health published new guidance in November 2020 “Vitamin D advice for people aged 65 and older” which states that all adults > 65 years should be supplemented with 15 micrograms of Vitamin D daily. Adequate vitamin D is essential for bone and muscle health in adults > 65 years.

TILDA research states that 55.5 % of adults >65 years have either insufficient or deficient vitamin D levels in winter (TILDA 2020).

The MMUH Frailty Intervention Team (FIT) assess frail adults > 65 years in the ED using medication review and Comprehensive Geriatric Assessment (CGA) to identify vitamin D supplementation.

Aim

Results

Methods

70% (n=42) were prescribed vitamin D. • Of those 92% (n=39) were prescribed a supplement containing at least 15 micrograms of vitamin D. • The most common supplementation (45%, n=27) was 800 international units (20 micrograms) of vitamin D.

To determine if the new guideline “Vitamin D advice for people aged 65 and older” is being implemented in frail older adults presenting to an Irish Level 5 ED.

• •

• • •

The audit was approved by the MMUH Clinical Audit & Effectiveness Committee All patients who had a medicine reconciliation (MR) completed by the FIT Pharmacist in January 2021 were included in a retrospective audit.

Patients were identified from the pharmacists worklist.

Data was collected from the Hospital Clinical System using an excel data collection sheet.

The data recorded included: Variable Indicative of Placement risk (VIP), Age, Sex, Rockwood Clinical Frailty Score (CFS), serum vitamin D level, date of last serum vitamin D level and vitamin D supplementation.

Comprehensive Geriatric Assessment by FIT

>65 years, ED presentation and VIP competed

Medication reconciliation

The FIT Pharmacist completed 60 MRs in January 2021; • Mean age (+/-SD) was 81.9 (+/- 7.9) years • Male to female ratio was 1:2.3 • Median CFS was 5 (mildly/moderately frail) with an IQR of 2

85% (n=51) had a vitamin D level reported in the preceding 6 years: • 19 in 2021, 13 in 2020, 8 in 2019, 2 in 2018, 6 in 2017 and 3 in 2016.

• Of those 76% (n=39) had sufficient vitamin D levels (>50nmol/L), 21% (n=11) had insufficient or deficient vitamin D levels (<50nmol/L).

Of those with insufficient or deficient serum vitamin D levels 81% (n=9) were prescribed vitamin D supplementation.

Patients prescribed Vitamin D

Patients not prescribed Vitamin D

Figure 1: Process of frail patients presenting to ED •

All data was obtained from the Hospital Clinical System biochemistry results, medication reconciliation and CGA documentation as routinely collected data.

8%

Vitamin D Levels and Supplementation 100%

Figure 3: Frail patients receiving at last 15mcg of vitamin D

18%

20%

17%

80%

80%

60% 40%

82%

80%

83%

20% 0%

92%

Prescribed at least 15mcg of vitamin D Low Dose

20% >50nmol/L

30-50nmol/L

Vitamin D Supplement

<30nmol/L

no result on No Vitamin D Supplement system

Figure 2: Vitamin D levels and supplementation

Conclusion • • • • •

The new guideline was implemented in 65% (n=39) of frail patients > 65 years. The rate of vitamin D insufficiency in this cohort was lower than TILDA research suggests.

The audit results were presented at MMUH Journal Clubs.

The MMUH Vitamin D Policy was updated following the audit to include the new recommendation.

The MMUH menus were analysed to determine provision of vitamin D in food with strategies to increase proposed.

While it is important that adults > 65 years are prescribed a supplement containing at least 15 micrograms of vitamin D it is essential to ensure only one form of vitamin D is in use to prevent the adverse effects of vitamin D toxicity.

References: TILDA (2020) Vitamin D deficiency in Ireland implications for COVID 19. Results from the Irish Longitudinal Study on Ageing. Available at: https://tilda.tcd.ie/publications/reports/pdf/Report_Covid19VitaminD.pdf Department of Health (2021). New advice on Vitamin D supplement for people aged 65 years and older. Available at: https://www.gov.ie/en/pressrelease/7d595-new-advice-on-vitamin-d-supplement-for-people-aged-65-years-and-older/

HOSPITALPROFESSIONALNEWS.IE | HPN • FEBRUARY 2022

WITH ITS RAPID RESPONSES AND PROVE SEE THE DIFFERENCE XELJANZ®• CAN M XELJANZ®• (tofacitinib) Prescribing Information: Please refer to the Summary of Product Characteristics (SmPC) before prescribing XELJANZ 5 mg or 10 mg film-coated tablets, XELJANZ 11 mg prolonged release tablets or XELJANZ 1 mg/mL oral solution.

Presentation: Film-coated tablet containing tofacitinib citrate, equivalent to 5 mg or 10 mg tofacitinib. Prolonged-release tablets containing tofacitinib citrate, equivalent to 11 mg tofacitinib. Oral solution containing tofacitinib citrate, equivalent to 1 mg/mL tofacitinib.

Indications: Please note not all presentations are licensed for all indications, please see dosage section for details: In combination with methotrexate (MTX) for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs. Can be given as monotherapy in case of intolerance to MTX or when treatment with MTX is inappropriate. In combination with MTX for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or who have been intolerant to a prior disease modifying antirheumatic drug (DMARD) therapy. For the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent. For the treatment of active polyarticular juvenile idiopathic arthritis (rheumatoid factor positive [RF+] or negative [RF-] polyarthritis, and extended oligoarthritis), and juvenile psoriatic arthritis (PsA) in patients 2 years of age and older, who have responded inadequately to previous therapy with DMARDs. Can be given in combination with methotrexate (MTX) or as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.

Dosage: Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of the condition for which tofacitinib is indicated. Tofacitinib is given with or without food.

RA and PsA: The recommended dose is 5 mg orally twice daily or 11 mg once daily which should not be exceeded. Treatment with tofacitinib 5 mg film coated tablets twice daily and tofacitinib 11 mg prolonged release tablet once daily may be switched between each other on the day following the last dose of either tablet.

UC: The recommended dose is 10 mg given orally twice daily for induction for 8 weeks. For patients who do not achieve adequate therapeutic benefit by week 8, the induction dose of 10 mg twice daily can be extended for an additional 8 weeks (16 weeks total), followed by 5 mg twice daily for maintenance. Tofacitinib induction therapy should be discontinued in any patient who shows no evidence of therapeutic benefit by week 16. The recommended dose for maintenance treatment is tofacitinib 5 mg given orally twice daily. Tofacitinib 10 mg twice daily for maintenance treatment is not recommended in patients with UC who have known venous thromboembolism (VTE) risk factors, unless there is no suitable alternative treatment available. For patients with UC who are not at increased risk for VTE, tofacitinib 10 mg orally twice daily may be considered if the patient experiences a decrease in response on tofacitinib 5 mg twice daily and failed to respond to alternative treatment options for ulcerative colitis such as tumour necrosis factor inhibitor (TNF inhibitor) treatment. Tofacitinib 10 mg twice daily for maintenance treatment should be used for the shortest duration possible. The lowest effective dose needed to maintain response should be used.

Polyarticular JIA and juvenile PsA: The recommended dose in patients 2 years of age and older: 10 kg - < 20 kg: 3.2 mg (3.2 mL of oral solution) twice daily, 20 kg - < 40 kg: 4 mg (4 mL of oral solution) twice daily, and ≥ 40 kg 5 mg (5 mL of oral solution or 5 mg film-coated tablet) twice daily. Patients ≥ 40 kg treated with tofacitinib 5 mL oral solution twice daily may be switched to tofacitinib 5 mg film-coated tablets twice daily. Patients < 40 kg cannot be switched from tofacitinib oral solution.

Dose interruption in adults and paediatric patients: Tofacitinib treatment should be interrupted if a patient develops a serious infection until the infection is controlled. Interruption of dosing may be needed for management of dose-related laboratory

abnormalities including lymphopenia, neutropenia, and anaemia. It is recommended not to initiate dosing in patients with an absolute lymphocyte count (ALC) less than 0.75 x 10 9/L, an absolute neutrophil count (ANC) less than 1x10 9 /L or with haemoglobin less than 9 g/dL. It is recommended not to initiate dosing in paediatric patients with an absolute neutrophil count (ANC) less than 1.2 x 10 9/L or with haemoglobin less than 10 g/dL. Renal impairment: No dose adjustment is required in patients with mild or moderate renal impairment. Patients with severe renal impairment the dose should be reduced to 5 mg once daily when the indicated dose in the presence of normal renal function is 5 mg twice daily or 11 mg prolonged-release tablet once daily. Dose should be reduced to 5 mg twice daily when the indicated dose in the presence of normal renal function is 10 mg twice daily. Patients with severe renal impairment should remain on a reduced dose even after haemodialysis. Hepatic impairment: No dose adjustment is required in patients with mild hepatic impairment. Patients with moderate hepatic impairment dose should be reduced to 5 mg once daily when the indicated dose in the presence of normal hepatic function is 5 mg twice daily or 11 mg prolonged-release tablet once daily. Dose should be reduced to 5 mg twice daily when the indicated dose in the presence of normal hepatic function is 10 mg twice daily. Tofacitinib should not be used in patients with severe hepatic impairment. Elderly: No dose adjustment is required in patients aged 65 years and older. Use with caution as increased risk and severity of adverse events. See also Warnings & Precautions for use in patients over 65 years of age. Interactions: Tofacitinib total daily dose should be reduced by half in adult and paediatric patients receiving potent inhibitors of cytochrome P450 (CYP) 3A4 (e.g. ketoconazole) and in patients receiving 1 or more concomitant medicinal products that result in both moderate inhibition of CYP3A4 as well as potent inhibition of CYP2C19 (e.g. fluconazole). Coadministration of tofacitinib with potent CYP inducers (e.g. rifampicin) may result in a loss of or reduced clinical response. Coadministration of potent inducers of CYP3A4 with tofacitinib is not recommended. Only in paediatric patients: available data suggest that clinical improvement is observed within 18 weeks of initiation of treatment with tofacitinib.

Continued therapy should be carefully reconsidered in a patient exhibiting no clinical improvement within this timeframe. The safety and efficacy of tofacitinib in children less than 2 years of age with polyarticular JIA and juvenile PsA has not been established. The safety and efficacy of tofacitinib in children less than 18 years of age with other indications (e.g. ulcerative colitis) has not been established. The safety and efficacy of tofacitinib prolonged-release formulation in children aged less than 18 years have not been established.

Contraindications: Hypersensitivity to any of the ingredients, active tuberculosis (TB), serious infections such as sepsis, or opportunistic infections, severe hepatic impairment, pregnancy and lactation.

Warnings and Precautions: Patients treated with tofacitinib should be given a patient alert card. Use in patients over 65 years of age: Considering the increased risk of serious infections, myocardial infarction, and malignancies with tofacitinib in patients over 65 years of age, tofacitinib should only be used in patients over 65 years of age if no suitable treatment alternatives are available. Combination with other therapies: There was a higher incidence of adverse events for the combination of tofacitinib with MTX versus tofacitinib as monotherapy in RA clinical studies. Tofacitinib should be avoided in combination with biologics and potent immunosuppressants such as azathioprine, 6-mercaptopurine, ciclosporine and tacrolimus. Venous thromboembolism (VTE): Serious VTE events including pulmonary embolism (PE), some of which were fatal, and deep vein thrombosis (DVT), have been observed in patients taking tofacitinib. In a randomised post authorisation safety study in patients with rheumatoid arthritis who were 50 years of age or older with at least one additional cardiovascular risk factor,

a From the start of treatment with XELJANZ in patients with moderately to severely active UC who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent. 3 XELJANZ 10 mg BID achieved higher rates of remission (primary endpoint) at week 8 vs placebo in OCTAVE Induction 1 (19% [88/476] vs 8% [10/122]; P=0.007) and OCTAVE Induction 2 (17% [71/429] vs 4% [4/112]; P<0.001)1 XELJANZ 10 mg BID achieved higher rates of clinical response at week 8 vs placebo in OCTAVE Induction 1 (60% [285/476] vs 33% [40/122]; P<0.001) and OCTAVE Induction 2 (55% [236/429] vs 29% [32/112]; P<0.001)1 In OCTAVE Sustain, for patients showing remission or clinical response following induction, XELJANZ 5 mg BID achieved higher rates of remission at week 52 (primary endpoint) vs placebo (34% [68/198] vs 11% [22/198]; P<0.001).1 Decreases in rectal bleeding and stool frequency Mayo subscores were observed as early as day 3 in patients treated with XELJANZ 10 mg BID2

PP-XEL-IRL-0686

© 2021 Pfizer Inc.

All rights reserved.

November 2021

EN MAINTENANCE OF EFFICACY, AKE FROM THE START1,2,a a dose dependent increased risk for VTE was observed with tofacitinib compared to TNF inhibitors. In a post hoc exploratory analysis within this study, in patients with known VTE risk factors, occurrences of subsequent VTEs were observed more frequently in tofacitinib-treated patients that, at 12 months treatment, had D-dimer level greater than or equal to twice the upper limit of normal (2× ULN) versus those with D-dimer level <2×ULN. For patients with RA with known risk factors for VTE, consider testing D-dimer levels after approximately 12 months of treatment. If D-dimer test result is ≥ 2× ULN, confirm that clinical benefits outweigh risks prior to a decision on treatment continuation with tofacitinib. Tofacitinib should be used with caution in patients with known risk factors for VTE, regardless of indication and dosage. Tofacitinib 10 mg twice daily for maintenance treatment is not recommended in patients with UC who have known VTE risk factors, unless there is no suitable alternative treatment available. Promptly evaluate patients with signs and symptoms of VTE and discontinue tofacitinib in patients with suspected VTE, regardless of dose or indication. Infections: Serious and sometimes fatal infections have been reported in patients administered tofacitinib. Rheumatoid arthritis patients taking corticosteroids may be predisposed to infection. Patients should be closely monitored for infections, with prompt diagnosis and treatment. Treatment should be interrupted if a serious infection develops. As there is a higher incidence of infections in the elderly and in the diabetic populations in general, caution should be used when treating the elderly and patients with diabetes. Tuberculosis: Patients should be evaluated for both active and latent TB prior to being treated with tofacitinib. Patients who test positive for latent TB should be treated with standard antimycobacterial therapy before administering tofacitinib. Viral Reactivation: In clinical studies viral reactivation and cases of herpes zoster have been observed. Screening for viral hepatitis should be performed in accordance with clinical guidelines prior to starting therapy with tofacitinib. The impact on chronic viral hepatitis is not known. Major adverse cardiovascular events (MACE): MACE have been observed in patients taking tofacitinib. In a randomised post authorisation safety study in patients with RA who were 50 years of age or older with at least one additional cardiovascular risk factor, an increased incidence of myocardial infarctions was observed with tofacitinib compared to TNF inhibitors. In patients over 65 years of age, patients who are current or past smokers, and patients with other cardiovascular risk factors, tofacitinib should only be used if no suitable treatment alternatives are available. Vaccinations: Prior to initiating tofacitinib, it is recommended that all patients, particularly pJIA and jPsA patients, be brought up to date with all immunisations in agreement with current immunisation guidelines. Live vaccines should not be given concurrently with tofacitinib. Malignancy and lymphoproliferative disorder: Tofacitinib may affect host defences against malignancies. In a randomised post authorisation safety study in patients with RA who were 50 years of age or older with at least one additional cardiovascular risk factor, an increased incidence of malignancies excluding non-melanoma skin cancer (NMSC), particularly lung cancer and lymphoma, was observed with tofacitinib compared to TNF inhibitors. Lung cancers and lymphoma in patients treated with tofacitinib have also been observed in other clinical studies and in the post marketing setting. Other malignancies in patients treated with tofacitinib were observed in clinical studies and the post marketing setting, including, but not limited to, breast cancer, melanoma, prostate cancer, and pancreatic cancer. In patients over 65 years of age, patients who are current or past smokers, and patients with other malignancy risk factors (e.g. current malignancy or history of malignancy other than a successfully treated non-melanoma skin cancer) tofacitinib should only be used if no suitable treatment alternatives are available. NMSCs have been reported in patients treated with tofacitinib; the risk of NMSC may be higher in patients treated with tofacitinib 10 mg twice daily than in patients treated with 5 mg twice daily. Periodic skin examination is recommended in patients at increased risk for skin cancer. Interstitial lung disease: Caution is

recommended in patients with a history of chronic lung disease as they may be more prone to infection. Asian patients are known to be at higher risk of ILD, caution should be exercised with these patients. Gastrointestinal perforations: Tofacitinib should be used with caution in patients who may be at increased risk, e.g. history of diverticulitis or concomitant use of corticosteroids or NSAIDs. Hypersensitivity: Cases of drug hypersensitivity associated with tofacitinib administration have been reported. Allergic reactions included angioedema and urticaria; serious reactions have occurred. If any serious allergic or anaphylactic reaction occurs, tofacitinib should be discontinued immediately. Laboratory Parameters: Increased incidence of lymphopenia and neutropenia have been reported, and decreases in haemoglobin, which should be monitored in accordance with the SmPC. Monitor ANC and haemoglobin at baseline, 4-8 weeks and 3 monthly, ALC at baseline and 3 monthly. Tofacitinib has been associated with increases in lipid parameters, maximal effects were observed within 6 weeks. Monitoring should be performed 8 weeks after initiation and managed according to hyperlipidaemia guidelines. Increases in liver enzymes greater than 3x ULN were uncommonly reported; use caution when initiating with potential hepatotoxic medicinal products. Gastrointestinal obstruction with a non-deformable prolonged-release formulation: Caution should be used when administering tofacitinib 11 mg prolonged release tablets to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic).

Pregnancy & Lactation: Use of tofacitinib during pregnancy and breast-feeding is contraindicated.

Side Effects: RA: The most common serious adverse reactions were serious infections; pneumonia, cellulitis, herpes zoster, UTIs, diverticulitis, appendicitis and opportunistic infections. The most commonly reported adverse reactions during the first 3 months in controlled clinical trials were headache, upper respiratory tract infections, nasopharyngitis, diarrhoea, nausea and hypertension.

UC: The most commonly reported adverse reactions in patients receiving tofacitinib 10 mg twice daily in the induction studies were headache, nasopharyngitis, nausea, and arthralgia. Commonly reported adverse reactions (>1/100 to <1/10) across all indications were pneumonia, influenza, herpes zoster, urinary tract infection, sinusitis, bronchitis, viral upper respiratory tract infection, pharyngitis, anaemia, headache, hypertension, cough, abdominal pain, vomiting, diarrhoea, nausea, gastritis, dyspepsia, rash, arthralgia, pyrexia, oedema peripheral, fatigue, blood creatine phosphokinase increased. Refer to section 4.8 of the SmPC for further information on side effects, including description of selected adverse reactions.

Legal Category: S1A. Marketing Authorisation Number: EU/1/17/1178/003 – 5 mg (56 film-coated tablets); EU/1/17/1178/007 – 10 mg (56 film-coated tablets); EU/1/17/1178/012 – 11 mg (28 prolonged-release tablets); EU/1/17/1178/015 1mg/mL oral solution.

Marketing Authorisation Holder: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium.

For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at medical.information@pfizer.com.

For queries regarding product availability please contact: Pfizer Healthcare Ireland, 9 Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24, + 353 1 467 6500. ˸ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information.

Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the SmPC for how to report adverse reactions.

Last revised: 10/2021.

Ref: XJ 13_0.

References: 1. Sandborn WJ, Su C, Sands BE, et al; for the OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain Investigators. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376(18):1723-1736.

2. Hanauer S et al. Tofacitinib Induction Therapy Reduces Symptoms Within 3 Days for Patients With Ulcerative Colitis. Clin Gastroenterol Hepatol. 2019;17(1):139-147.

3. XELJANZ Summary of Product Characteristics.

38 Pelvic Training

Digital Therapeutic Core & Pelvic Floor Training – Using technology, Affordable & Discrete

Written by Aoife Ni Eochaidh Chartered Physiotherapist, Clinical Specialist Pelvic, Women's & Men's Health Physiotherapist, Bon Secours Consultant Clinic

We all know the dreadful feeling of needing the bathroom suddenly to empty the bladder while having coffee with friends or while out shopping and how humiliating and embarrassing it is to be caught short and leak urine. Imagine the awful feeling with an over whelming urge to empty your bladder or needing to cough or sneeze and not making it to the bathroom in time and leaking urine. Worse still is the fear of not being able to control stool or gas.

New mothers (and some not so new mothers!) up and down the country are dealing with these awful problems. Help is available to give yourself back your freedom without fear of bladder leaks.

Progressive pelvic floor muscle training is recommended as a first line treatment for incontinence (CG171 NICE Guideline 2016). Two thirds of women with any type of incontinence who have pelvic floor muscle training see improvements or cure with 75% of women reporting resolution of symptoms such as episodes of incontinence (National Institute of Research

doi:10.33310/signal-000702. That is 2 out of 3 women will be cured of incontinence with pelvic floor muscle training!

Pregnancy & childbirth and menopause are leading causes of incontinence for women. Many hide the problem and are too embarrassed to deal with the issues. Women wear incontinence pads, reduce their sexual activity, their exercise levels, and their social life too. As a woman trains her pelvic floor muscles, she will find that her core (or tummy) muscles also improve!

It is important to know where the pelvic floor muscles are in the body. Firstly, think of the area of your body between your waist and the top of your legs. This is where your Pelvis is located, think of it as a basin shaped region. Your tummy area is where your core muscles are located. The pelvic floor muscles form the base of the pelvic basin and are really the underneath part of your core.

We need to train our muscles to be in the normal range or

FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

function. This involves a series of exercises and training routines.

Home Pelvic Routine for Women, is a type of digital therapeutics, using an e learning platform, it takes what was once done one on one, in a clinical room, to the masses, using technology, discretely, at an affordable price.

It is an on-line pelvic floor training product. It is affordable and allows for discrete training in private at home, using a smart phone, tablet, or laptop. Home Pelvic Routine for Women is a type of digital therapeutics, people fill out an on-line pre-screening form, to ensure suitability. The online product consists of 3 videos and 3 e-booklets, it includes a program and problem tracker, it is designed by an expert, experienced, multi award winning pelvic floor physiotherapist, women’s health specialist, Aoife Ni Eochaidh. Home Routine is based on Aoife’s 25 years of experience treating thousands of women with incontinence, it is evidence based, it uses tried and tested methods of training, in the right order, and at the right pace of training to

optimal results. We also have a Home Pelvic Routine for Men too, suitable for men with the following pelvic floor muscle issues, pre and post prostate cancer surgery, bladder and bowel incontinence and erectile dysfunction.

Pelvic Floor Muscle Training with the Home Pelvic Routine is not a quick fix, it takes time, but it works, and it is so worth it! Home Pelvic Routine for Women and Men costs ¤70 and is available to purchase on our digital therapeutic platform, courses.homepelvicroutines.com or see Aoife’s website for further information www.ippm.ie One to one, in person appointments, and online one on one appointments are also available, one on one, in person is the gold standard of pelvic floor care, but Home Pelvic Routine gives an affordable alternative using the latest technology. Please visit www.ippm.ie and contact us for further information. Follow Aoife Ni Eochaidh on social media via @pelvicexpert

COLORECTAL CANCER

Evolving Surgical Care of Colorectal Cancer into the 21st Century “It’s crucial for better patient outcomes that surgery is not seen as a steadystate treatment, not just a baseline therapy for other approaches and therapies to be compared to but one that can and needs to transform positively onwards” Different to the other commonest solid cancers (i.e. breast, prostate, lung), surgery is the predominant treatment for colorectal cancer, forming all or part of the therapy for the majority of patients with this disease. It remains the only curative modality either as sole treatment in those with localised disease, as majority treatment in those with regional disease or final definitive treatment in those responding to chemo/immunotherapeutics (most especially those with liver metastases but also increasingly those with nonhepatic oligometastatic disease).

Furthermore, it has a major role in best palliative therapy to relieve symptoms either by debulking disease in those with peritoneal carcinomatosis or alleviating critical secondary problems such as obstruction or haemorrhage.

Indeed along with endoscopic resection of earliest stage cancers at colonoscopy, the majority of colorectal cancer patients are fully cared for completely outside of medical oncology. However surgery is considerably underrecognised in terms of clinical trial and specialty development funding, certainly relative to medical oncology in general and specifically with respect to this disease. For further broad advancement in care of patients with this disease, this clearly needs to be addressed nationally most especially because of the increasing numbers of people being diagnosed (due to both increased incidence especially in younger patients as well as higher rates of detection of earlier stage disease due to population and at risk group screening). To acuminate outcomes in face of

this pressure, surgery needs to be better both in terms of even greater efficiency as well as effectiveness everywhere patients undergo operative care.

Surgery is a major undertaking focussed around a single point in time intervention which can often be planned electively (many emergency presentations can too be converted to elective cancer care by managing the acute component separately from the primary cancer resection, e.g. by proximal defunctioning of bowel obstruction etc). However it risks major consequences and complications. While enhanced recovery programmes and prehabilitation exercise optimisation can reduce hospital stay after uncomplicated operations, surgical complications such as anastomotic breakdown undermine greatly the good intentions and expectations of surgery causing considerable misery, risking mortality and consuming high amounts of hospital and community care resources. Anastomotic leak rates have not been significantly affected by specialisation, centralisation or evolution of operative access (from open to minimally invasive) and the continuance of this problem justifies consideration of nonoperative or compromised operative care of certain patients, especially the elderly and comorbid (perhaps the groups who have the most to gain from single modality surgical treatment).

New methods to impact this risk and indeed many other surgical complications thankfully are entering practice.

Written by Professor Ronan Cahill, Consultant General and Colorectal Surgeon, Mater Misericordiae University Hospital (MMUH), Dublin and Professor of Surgery, University College Dublin (UCD). Director of Centre for Precision Surgery, UCD, and Digital Surgery Unit, MMUH

Anastomoses heal best when healthy tissue is opposed without tension. While the potential influence of local microbiomes being better understood through ongoing research efforts, local blood supply is of course a major factor in ensuring successful healing after technically competent anastomotic construction. While, previously, adequacy of perfusion has been judged empirically by subjective assessment intraoperative, near-infrared perfusion assessment is now possible with the addition of a safe fluorescent agent, indocyanine green, with synchronous visualisation using one of the many, widely available nearinfrared laproscopes commonly used in key-hole operations. This enables greater appreciation of the presence and dynamics of tissue microperfusion and has

been shown in many studies to be associated with significant reductions in anastomotic complication. Additional tissueresponsive fluorphores are also emerging to allow more precise appreciation of anatomy, physiology and pathology within the operative view. The usefulness of computer-assisted video display to provide meaningful additional data to the surgeon is being taken further too with the application of computer vision and artificial intelligence (AI) to the surgical imagery. For near-infrared techniques this can mean specific quantification of blood perfusion among other parameters providing greater sensitivity in appreciation of inter-individual differences at both patient and surgeon level.

More broadly, AI methods are beginning to prove capable at automatic step-sequencing of

HOSPITALPROFESSIONALNEWS.IE | HPN • FEBRUARY 2022 | 39

COLORECTAL CANCER operative video feeds, recognising instruments and anomalies in anatomy based on appearance and, potentially, revealing insights that prompt reaction during and after surgery on a personalised basis. Furthermore, reformatting of standard preoperative staging imagery such as CT scans can be used to display individual patient anatomical maps to support intraoperative decision making alongside their existing role in delineating disease presence and stage.

All these modalities are showing promise in selected centres internationally and indeed nationally and definitive studies are in process to now determine their exact place among current standards of care. As softwarebased technological innovations, they have the potential to be deployed at scale without major capital investment and so can be capably deployed widely soon after practitioner recommendation

and acceptance. Much of these too can be integrated into existing laparoscopic and robotic platforms and, importantly, there are increasingly alternate vendors and visions of differing hardware technology systems entering into the market needing application development work.

All these evolving technological capabilities, and others, require appropriate development and research frameworks and all successful outcomes will evolve additional areas for investigation and application. Alongside the traditionally strong surgical research areas of basic science in tumour biology and perioperative care, there is both room and a need for practical and conceptual development of existing and new surgical techniques and technologies for best near-term application into patient care. It’s for this purpose that we opened an Academic Centre for Precision Surgery in University College

Dublin and a Digital Surgery Unit at the Mater Misericordiae University Hospital that have already been successful in initiating, leading and collaborating in major national and internationally consortium projects for such better surgery.

While the fact that the majority of patients undergoing surgery for colorectal cancer cease to be cancer patients on completion of their surveillance thanks to its high rates of successful cure likely plays a role in its underappreciation as an evolving entity in need of further developmental investment in terms of time, energy and funding.

It’s crucial for better patient outcomes that surgery is not seen as a steady-state treatment, not just a baseline therapy for other approaches and therapies to be compared to but one that can and needs to transform positively onwards. Alongside the colorectal cancer community itself having a role in facilitating broad ongoing development (and

News OncoMark Acquired by Cepheid Inc. University College Dublin (UCD) has formally announced the acquisition of OncoMark Ltd, a UCD spin-out company, by Cepheid Inc., a US molecular diagnostics company. The transaction was completed in March for an undisclosed sum.

OncoMark was co-founded by Professor William Gallagher and Steve Penney as a spin-out from the UCD School of Biomolecular and Biomedical Science and the UCD Conway Institute, and was based at NovaUCD, the University’s Centre for New Ventures and Entrepreneurs.

The company developed a novel test for early-stage Breast Cancer (OncoMasTR) that has the potential to reduce the number of breast cancer patients receiving unnecessary chemotherapy. The test was CE Marked in preparation for launch in EU markets. With the acquisition of OncoMark by Cepheid, the test will now be launched on Cepheid’s worldleading GeneXpert Platform in global markets.

The OncoMasTR test is based on a panel of genetic 'drivers' of breast cancer. The original research that resulted in the identification of the panel was led by Professor Adrian Bracken, Smurfit Institute of Genetics, Trinity College Dublin and involved researchers at the

UCD Conway Institute, led by Professor William Gallagher. The OncoMasTR technology was subsequently exclusively licenced by both universities to OncoMark.

Subsequent to the sale of OncoMark, a new company, OncoAssure, was established with all former OncoMark staff moving across to OncoAssure to continue the development of biomarkers in other cancers, outside of breast cancer. OncoAssure is headquartered at NovaUCD. Professor William Gallagher, Professor of Cancer Biology, UCD School of Biomolecular and Biomedical Science, former Chief Scientific Officer (CSO) at OncoMark and currently OncoAssure CSO said, “I am delighted to see the ongoing translation of OncoMasTR towards the clinic via Cepheid’s innovative GeneXpert platform.

The underpinning OncoMasTR technology originated from a fantastic collaboration between Professor Adrian Bracken’s team based at Trinity College Dublin whose focus on fundamental aspects of cancer cell biology dovetailed very nicely with our interests in translational cancer research at UCD.” Tom Flanagan, UCD Director of Enterprise and Commercialisation,

40 | FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Pictured at University College Dublin is Professor William Gallagher, UCD School of Biomolecular and Biomedical Science, co-founder, OncoMark and CSO, OncoAssure.

(Mac Innes Photography)

NovaUCD said, "I would like to congratulate OncoMark's founders, senior management team and indeed the entire OncoMark team, following today's announcement that Cepheid Inc. has acquired the UCD spinout company. OncoMark is an excellent example of the quality of the spin-outs which have emerged from UCD and we have been delighted to support the company to develop and grow over the last number of years."

He added, "I would especially like to commend the entrepreneurial spirit and mindset of OncoMark's founders and management team in immediately establishing a new company, OncoAssure. The company, based at NovaUCD, is focused on developing a new panel of biomarkers for a prostate cancer test and we look forward to working with the team in the years ahead to support them to reach their global ambitions."

Pictured at NovaUCD is Des O’Leary, former CEO, OncoMark and CEO, OncoAssure (Nick Bradshaw, Fotonic)

move on now from the recent and rather superficial focus on simply acquiring robotic systems in isolation which has been the main feature of surgical investment at both institutional and national level over the last five years) so too do the major funding bodies and research centres and organisations in Ireland. Correction of the historical deficit in supporting surgical clinical research and networks alongside the already well established pharmaceutical trial groups will give great opportunity to the strong medtech environment that exists throughout the country (both small/ medium enterprises as well as multinationals and both incumbent device and smart technologies creatives) in addition to many well distributed, capable surgical units.

Through such investment, Ireland will deliver great advantages for its patients, healthcare system and general economy.

MAKE TIME for more moments that matter Extend overall survival for patients in 3rd line mCRC1

trifluridine/tipiracil Lonsurf® (Trifluridine/ tipiracil): Abbreviated Prescribing Information: Please refer to the Summary of Product Characteristics before prescribing. COMPOSITION*: Lonsurf 15 mg/6.14 mg: film-coated tablet containing 15 mg trifluridine and 6.14 mg tipiracil (as hydrochloride).

Lonsurf 20 mg/8.19 mg: film-coated tablet containing 20 mg trifluridine and 8.19 mg tipiracil (as hydrochloride). INDICATION*: As monotherapy for the treatment of adult patients with metastatic colorectal cancer who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents. As monotherapy for the treatment of adult patients with metastatic gastric cancer including adenocarcinoma of the gastroesophageal junction, who have been previously treated with at least two prior systemic treatment regimens for advanced disease. DOSAGE AND ADMINISTRATION*: Recommended starting dose: 35 mg/m2/dose taken orally twice daily on Days 1 to 5 and Days 8 to 12 of each 28-day cycle, within 1 hour after completion of the morning and evening meals (20mg/m2/dose for patients with severe renal impairment). Dosage calculated according to body surface area, not exceeding 80 mg/dose. Possible dosing adjustments based on individual safety and tolerability: permitted dose reductions to a minimum dose of 20 mg/m2 twice daily (15mg/m2/dose for patients with severe renal impairment), dose escalation not permitted after a dose reduction. CONTRAINDICATIONS*: Hypersensitivity to the active substances or to any of the excipients. WARNINGS *: Bone marrow suppression: Complete blood cell counts must be obtained prior to initiation of therapy, prior to each cycle and as needed. Treatment must not be started if absolute neutrophil count < 1.5 x 109/L, if platelet counts < 75 x 109/L, or if unresolved Grade 3 or 4 non-haematological clinically relevant toxicity. Patient should be monitored closely for infections, appropriate measures should be administered as clinically indicated. Gastrointestinal toxicity: anti-emetic, anti-diarrhoeal and other measures should be administered as clinically indicated, dose modifications should be applied as necessary. Renal impairment: not recommended if end-stage renal disease. Patients with renal impairment should be monitored closely; patients with moderate or severe renal impairment should be more frequently monitored for haematological toxicities. Hepatic impairment: not recommended if baseline moderate or severe hepatic impairment. Proteinuria: monitoring by dipstick urinalysis recommended prior to starting and during therapy. Excipients: contain lactose. INTERACTIONS*: Precautions: medicinal products that interact with nucleoside transporters CNT1, ENT1 and ENT2, inhibitors of OCT2 or MATE1, human thymidine kinase substrates (e.g. zidovudine), hormonal contraceptives. FERTILITY*. PREGNANCY AND BREASTFEEDING*: Not recommended. CONTRACEPTION*: For women and men, highly effective contraceptive measures must be used during treatment and for 6 months after stopping treatment. DRIVE & USE MACHINES*: Fatigue, dizziness or malaise may occur. UNDESIRABLE EFFECTS*: Very common: Neutropenia, leukopenia, anaemia, thrombocytopenia, decreased appetite, diarrhoea, nausea, vomiting, fatigue. Common: Lower respiratory tract infection, febrile neutropenia, lymphopenia, hypoalbuminaemia, dysgeusia, neuropathy peripheral, dyspnoea, abdominal pain, constipation, stomatitis, oral disorder, hyperbilirubinaemia, Palmar-plantarerythrodysaesthesia syndrome, rash, alopecia, pruritus, dry skin, proteinuria, pyrexia, oedema, mucosal inflammation, malaise, hepatic enzyme increased, blood alkaline phosphatase increased, weight decreased. Uncommon: Septic shock, enteritis infectious, lung infection, biliary tract infection, influenza, urinary tract infection, gingivitis, herpes zoster, tinea pedis, candida infection, bacterial infection, infection, neutropenic sepsis, upper respiratory tract infection, conjunctivitis, cancer pain, pancytopenia, granulocytopenia, monocytopenia, erythropenia, leukocytosis, monocytosis, dehydration, hyperglycaemia, hyperkalaemia, hypokalaemia, hypophosphataemia, hypernatraemia, hyponatraemia, hypocalcaemia, gout, anxiety, insomnia, neurotoxicity, dysaesthesia, hyperaesthesia, hypoaesthesia, syncope, paraesthesia, burning sensation, lethargy, dizziness, headache, visual acuity reduced, vision blurred, diplopia, cataract, dry eye, vertigo, ear discomfort, angina pectoris, arrhythmia, palpitations, embolism, hypertension, hypotension, flushing, pulmonary embolism, pleural effusion, rhinorrhoea, dysphonia, oropharyngeal pain, epistaxis, cough, enterocolitis haemorrhagic, gastrointestinal haemorrhage, pancreatitis acute, ascites, ileus, subileus, colitis, gastritis, reflux gastritis, oesophagitis, impaired gastric emptying, abdominal distension, anal inflammation, mouth ulceration, dyspepsia, gastrooesophageal reflux disease, proctalgia, buccal polyp, gingival bleeding, glossitis, periodontal disease, tooth disorder, retching, flatulence, breath odour, hepatotoxicity, biliary dilatation, skin exfoliation, urticaria, photosensitivity reaction, erythema, acne, hyperhidrosis, blister, nail disorder, joint swelling, arthralgia, bone pain, myalgia, musculoskeletal pain, muscular weakness, muscle spasms, pain in extremity, renal failure, cystitis noninfective, micturition disorder, haematuria, leukocyturia, menstrual disorder, general physical health deterioration, pain, feeling of body temperature change, xerosis, discomfort, blood creatinine increased, electrocardiogram QT prolonged, international normalised ratio increased, activated partial thromboplastin time prolonged, blood urea increased, blood lactate dehydrogenase increased, protein total decreased, C-reactive protein increased, haematocrit decreased. Post-marketing experience: interstitial lung disease. OVERDOSE*. PROPERTIES*: Trifluridine is an antineoplastic thymidine-based nucleoside analogue and tipiracil hydrochloride is a thymidine phosphorylase (TPase) inhibitor. Following uptake into cancer cells, trifluridine, is phosphorylated by thymidine kinase, further metabolised in cells to a deoxyribonucleic acid DNA substrate, and incorporated directly into DNA, preventing cell proliferation. However, trifluridine is rapidly degraded by TPase and readily metabolised by a first-pass effect following oral administration, hence the inclusion of the TPase inhibitor, tipiracil hydrochloride.PRESENTATION* Pack of 20 or 60 film-coated tablets. Marketing Authorisation Holder LES LABORATOIRES SERVIER, 50 rue Carnot, 92284 Suresnes cedex France. www.servier.com. Marketing Authorisation: EU/1/16/1096/001-006. Legal Classification for Supply: POM. Further information available from: Servier Laboratories (Ireland) Ltd., Second Floor, 19 Lr. George’s Street, Dun Laoghaire, Co. Dublin A96 ER84, Ireland, Tel (01) 6638110, www.servier.ie. *For complete information, please refer to the Summary of Product Characteristics available on medicines.ie. Date of last revision of text: January 2021 (Date of last approved SmPC: December 2020) Reference: 1. Lonsurf SmPC December 2020 Date of preparation of item September 2021. 2122c1LNPressAd A4

LUNG CANCER

Lung cancer: The importance of the mediastinum and role of EBUS combined with EUS-B Written by PC Ridge, D Breen - Interventional Respiratory Unit, Department of Respiratory Medicine, Galway University Hospitals, Galway, Ireland.

Correspondence: Dr Padraic Ridge, Interventional Respiratory Unit, Galway University Hospitals, Galway, Ireland E mail: p.macaniomaire1@gmail.com Abstract: Lung cancer is a leading cause of morbidity and mortality across Europe. Prompt identification, diagnosis and staging and onward referral to management, is key to improving outcomes.

We present an overview of: General principles of staging lung cancer, the importance of accurately staging the mediastinum and hilum in lung cancer and the current and evolving role of a combined EBUS and EUS-B in lung cancer intervention.

Introduction

Figure 1 Dr David Breen

Dr Padraig Ridge

42 | FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Lung cancer is the 2nd most prevalent cancer in men after prostate cancer and the 3rd most prevalent after breast and colorectal in women within the European Union. However lung cancer is associated with the highest mortality in men and is predicted to overtake breast in women in 2021. The World Health Organisation predict the worldwide incidence of lung cancer to increase by 58% from 2.2 million in 2020 to 3.5 million in 2040.1,2,27 The aim of this review is to discuss lung cancer staging; overall principles, the importance of establishing nodal status, the rationale and role of

EBUS and EUS-B. We will also address evolving roles of EBUS in the diagnostic work up of lung malignancy.

Definitions EBUS (Endobronchial Ultrasound): A flexible bronchoscope with an Ultrasound attached at the distal end. It allows the Interventional pulmonologist to visualise and sample structures adjacent to the airway not visible with standard bronchoscopy.

Figure 1

Lead your patients to stronger bones with Prolia®

1-4

10 YEAR DATA 5S

Osteoporosis is a serious ongoing condition and ongoing treatment is required.6,7,8,9*

* Prolia® should not be stopped without considering alternative treatment in order to prevent rapid bone mineral density loss and a potential rebound in vertebral fracture risk.6 PROLIA® (denosumab) Brief Prescribing Information

Please refer to the Summary of Product Characteristics (SmPC) before prescribing Prolia. Pharmaceutical Form: Pre-filled syringe with automatic needle guard containing 60 mg of denosumab in 1 ml solution for injection for single use only. Contains sorbitol (E420). Indication: Treatment of osteoporosis in postmenopausal women at increased risk of fractures. Dosage and Administration: 60 mg Prolia administered as a subcutaneous injection once every 6 months. Patients must be supplemented with calcium and vitamin D. No dosage adjustment required in patients with renal impairment. Not recommended in paediatric patients under 18 years of age. Give Prolia patients the package leaflet and patient reminder card. Re-evaluate the need for continued treatment periodically based on the benefits and potential risks of denosumab on an individual patient basis, particularly after 5 or more years of use. Contraindications: Hypocalcaemia or hypersensitivity to the active substance or to any of the product excipients. Special Warnings and Precautions: Traceability: Clearly record the name and batch number of administered product to improve traceability of biological products. Hypocalcaemia: Identify patients at risk for hypocalcaemia. Hypocalcaemia must be corrected by adequate intake of calcium and vitamin D before initiation of therapy. Clinical monitoring of calcium levels is recommended before each dose and, in patients predisposed to hypocalcaemia, within 2 weeks after the initial dose. Measure calcium levels if suspected symptoms of hypocalcaemia occur. Renal Impairment: Patients with severe renal impairment (creatinine clearance < 30 ml/ min) or receiving dialysis are at greater risk of developing hypocalcaemia. Skin infections: Patients receiving Prolia may develop skin infections (predominantly cellulitis) requiring hospitalisation and if symptoms develop then they should contact a health care professional immediately. Osteonecrosis of the jaw (ONJ): ONJ has been reported rarely with Prolia 60 mg every 6 months. Delay treatment in patients with unhealed open soft tissue lesions in the mouth.

A dental examination with preventative dentistry and an individual benefit:risk assessment is recommended prior to treatment with Prolia in patients with concomitant risk factors. Refer to the SmPC for risk factors for ONJ. Patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups and immediately report oral symptoms during treatment with Prolia. While on treatment, invasive dental procedures should be performed only after careful consideration and avoided in close proximity to Prolia administration. The management plan of patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Osteonecrosis of the external auditory canal: Osteonecrosis of the external auditory canal has been reported with Prolia. Refer to the SmPC for risk factors. Atypical femoral fracture (AFF): AFF has been reported in patients receiving Prolia. Discontinuation of Prolia therapy in patients suspected to have AFF should be considered pending evaluation of the patient based on an individual benefit risk assessment. Longterm antiresorptive treatment: Long-term antiresorptive treatment may contribute to an increased risk for adverse outcomes such as ONJ and AFF due to significant suppression of bone remodelling. Concomitant medication: Patients being treated with Prolia should not be treated concomitantly with other denosumab containing medicinal products. Warnings for Excipients: Patients with rare hereditary problems of fructose intolerance should not use Prolia. Interactions: Prolia did not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4). There are no clinical data on the co-administration of denosumab and hormone replacement

Amgen Ireland 21 Northwood Court, Santry, Dublin 9, Ireland.

therapy (HRT), however the potential for pharmacodynamic interactions would be considered low. Pharmacokinetics and pharmacodynamics of Prolia were not altered by previous alendronate therapy. Fertility, pregnancy and lactation: There are no adequate data on the use of Prolia in pregnant women and it is not recommended for use in these patients. It is unknown whether denosumab is excreted in human milk. A risk/benefit decision should be made in patients who are breast feeding. Animal studies have indicated that the absence of RANKL during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation post-partum. No data are available on the effect of Prolia on human fertility. Undesirable Effects: The following adverse reactions have been reported: Very common (≥ 1/10) pain in extremity, musculoskeletal pain (including severe cases). Common (≥ 1/100 to < 1/10) urinary tract infection, upper respiratory tract infection, sciatica, constipation, abdominal discomfort, rash, alopecia and eczema. Uncommon (≥ 1/1000 to < 1/100): Cellulitis, ear infection and lichenoid drug eruptions. Rare (≥ 1/10,000 to < 1/1,000): Osteonecrosis of the jaw, hypocalcaemia (including severe symptomatic hypocalcaemia and fatal cases), atypical femoral fractures, and hypersensitivity (including rash, urticaria, facial swelling, erythema and anaphylactic reactions). Very rare (< 1/10,000): Hypersensitivity vasculitis. Please consult the Summary of Product Characteristics for a full description of undesirable effects. Pharmaceutical Precautions: Prolia must not be mixed with other medicinal products. Store at 2°C to 8°C (in a refrigerator). Prolia may be exposed to room temperature (up to 25°C) for a maximum single period of up to 30 days in its original container.

Once removed from the refrigerator Prolia must be used within this 30 day period. Do not freeze. Keep in outer carton to protect from light. Legal Category: POM. Presentation and Marketing Authorisation Number: Prolia 60 mg: Pack of 1 pre-filled syringe with automatic needle guard; EU/1/10/618/003. Price in Republic of Ireland is available on request. Marketing Authorisation Holder: Amgen Europe B.V., Minervum 7061, NL-4817 ZK Breda, The Netherlands. Further information is available from Amgen Ireland Limited, 21 Northwood Court, Santry, Dublin DO9 TX31. Prolia is a registered trademark of Amgen Inc. Date of PI preparation: July 2021 (Ref: IE-PRO-0721-00001) Adverse reactions/events should be reported to the Health Products Regulatory Authority (HPRA) using the available methods via www.hpra.ie. Adverse reactions/events should also be reported to Amgen Limited on +44 (0)1223 436441 or Freephone 1800 535 160.

References: 1. Prolia® [denosumab], Summary of Product Characteristics.

2. Cummings SR et al, N. Eng. J Med 2009;361:756-765.

3. Holzer G et al, J Bone Miner Res 2009;24(3):468-74.

4. Poole K et al; J Bone Miner Res 012; 27 (suppl1):S44 abstract 1122.

5. Bone HG, et al; Lancet Diabetes Endocrinol. 2017;5:513-23;3-23.

6. Tsourdi E, et al. Bone. 2017;105:11–7.

7. Hernlund E, et al. Arch Osteoporos. 2013;8:136; 8. Kanis JA, et al. Osteoporos Int. 2019;30:3–44; 9. Brown JBMR 2013 Vol28 pp746-752.

© 2021 Amgen Inc. All rights reserved.

IE-PRO-0821-00003. Date of preparation: August 2021

LUNG CANCER EUS (Endoscopic Ultrasound): A gastroscope with an ultrasound at the distal end.

Allows the gastroenterologist to sample lesions adjacent to the gastrointestinal tract under ultrasound guidance. The gastroscope is larger and longer than an EBUS scope so can be passed beyond the stomach.

EUS-B (Endoscopic Ultrasound using EBUS scope): When an interventional pulmonologist passes the EBUS scope down the oesophagus to sample and visualise structures adjacent to the oesophagus and upper stomach such as stations, 8, 9 left lobe of liver and left adrenal gland. This additional accessibility is particularly important in lung cancer staging.

Staging and Principles Treatment options depend on the stage of disease at presentation particularly for non-small cell lung carcinoma.3,4 For the management of intra-thoracic, locally confined NSCLC the nodal status of the disease is of utmost importance. Radical, or curative, treatments are options for those with N0 and N1 (ipsilateral hilar nodes). However, N2 (ipsilateral mediastinal nodes), for the most part, will exclude upfront radical surgical or radiotherapy options.

For those with N3 disease such as contralateral nodes to the primary cancer or supraclavicular nodal involvement then initial curative surgery is not an option.4 Figure

1. Therefore timely, accurate staging prior to the initiation of treatment is vital to allow a tailored management approach and to avoid unnecessary futile surgical procedures with their associated morbidity and mortality while still identifying those suitable for radical treatment options.4,5 A key principle in the staging process is to perform the least invasive and most timely investigation that provides the most clinical information with respect to stage and diagnosis in the least number of steps and with the least risk to the patient.

This principle is enshrined in all international guidelines.3,5 For example in a radiological T4N2M0 presumed bronchogenic carcinoma all efforts should be made to sample the thoracic node with the highest stage as this will provide the histological diagnosis and stage the patient in one procedure. Likewise, if the patient is presumed M1 disease, then first attempts should be made at sampling the site of metastatic disease, if feasible and acceptable to the patient and clinical team from a risk perspective.3,5 Establishing nodal status Radiologically, computed tomography with contrast enhancement and PET are key in the staging process for bronchogenic carcinoma both for identifying metastatic disease but also for mediastinal staging.3,6 CT has a sensitivity and specificity of 51% and 85% respectively, while PET has a sensitivity and

specificity of 84% and 85%.

Both modalities are non-invasive techniques and do not provide tissue confirmation. In addition, the high false positive rates of both techniques mandate that tissue confirmation of findings is required and of the utmost importance.6,7 Therefore except for Stage 1A disease, CT and PET cannot be relied upon to stage the mediastinum accurately prior to initiation of treatment due to lack of sensitivity and specificity.8,9 This means in practice the majority of patients with suspected bronchogenic carcinoma will need to undergo histological staging of the mediastinum.5,6 Mediastinoscopy is the historic “gold standard” for mediastinal staging. Mediastinoscopy is an invasive procedure performed in theater under general anesthesia.

It involves an incision above the sternal notch, blunt dissection of the fascial planes followed by insertion of the mediastinoscopy alongside the trachea to sample the mediastinal nodes.28 Due to the invasive nature of this procedure, repeat investigations; if required, can be fraught with difficulty due to fibrosis. While mediastinoscopy has been traditionally considered the “gold standard” mediastinal staging procedure this was based mostly on single center studies.29 A more recent multicenter survey in the United states revealed only 47% of procedures obtained lymph node tissue and the majority only sampled one station suggesting few centers were actually achieving the “gold standard”.9,30

Real time Endobronchial Ultrasound transbronchial needle aspiration (EBUS-TBNA) which is performed under conscious sedation has surpassed this modality due to less morbidity, better diagnostic yield and allows access to lymph nodes not amenable to mediastinoscopy in particular when combined with endoscopic ultrasound (EUS-B).10,11 Figure 2 A meta-analysis revealed combined EBUS-TBNA and EUS-B has a mean sensitivity of 86% and a mean negative predictive value of 92%.12 EBUS-TBNA has also been shown to be superior to standard bronchoscopy and traditional TBNA due to the better direct visualization of lymph nodes and centrally located tumors alongside the central bronchi.26 EBUS and EUS-B EBUS, over the last twenty years, has occupied a central role in lung cancer staging; particularly in establishing the N status.

Unfortunately, no single mediastinal tissue sampling method can sample all stations. However as mentioned EBUS allows access to a greater number of lymph nodes than mediastinoscopy.10 In addition the combination of both EBUS and EUS, and more recently EUS-B provides a greater reach than any technique alone and potentially offers the most accurate staging of the mediastinum.

EBUS can sample the mediastinal stations 2R, 2L, 4R, 4L, 7 and the hilar and intrapulmonary stations 10, 11, 12 with varying degrees of difficulty.10 These hilar and intrapulmonary nodes were not traditionally accessible by mediastinoscopy.10 EUS-B, as previously described, utilizes the EBUS scope via the esophagus to the level of the stomach. This is different from EUS as it is the smaller EBUS scope that is used rather than the larger gastroscope.12 This can be done as part of the EBUS procedure and is normally done after the endobronchial mediastinal staging process.12,13 With EUS-B stations 2L, 4L and 7 can again be sampled but via the oesophagus.14 The right sided nodes are not usually accessible due to the interposition of the trachea. In addition, above the diaphragm EUS-B allows sampling of para-oesaphageal

Figure 2

44 | FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Figure 3

A Enlarged lymph node at EBUS, heterogeneous

A Enlarged lymph node at EBUS, heterogeneous

BSampling Sampling enlarged lymph node under realLympn timenode USoverlying guidance.

B enlarged lymph node under real time US guidance. vessel Lymph node

Figure 3

overlying vessel

masses and lymph node stations 8 and 9. Below the diaphragm it allows sampling of retroperitoneal nodes, the celiac trunk, left lobe of liver and left adrenal gland, thus further increasing the reach of the EBUS scope.14 Figure 2 When the two techniques are combined all thoracic nodal stations can be sampled except for stations 5 and 6. These stations are usually only accessible by an anterior mediastinotomy (chamberlain); via an incision through the second or third intercostal space on the left or Video assisted thoracoscopy (VATS).14 However a case series of 14 patients described the sampling of station 6 safely via a transaortic route using the EBUS probe. This saved all 14 individuals a more invasive staging procedure. Only 2 small para-aortic hematomas were reported which were of no clinical concern.31 EBUS can now be described as a diagnostic procedure or a staging procedure. For the benefit of this article we are concentrating on EBUS as a staging endoscopic examination when it should provide sufficient information to make the final treatment decision.

A Staging EBUS procedure should be performed in a systematic way. Sampling is often guided by the morphological appearance of the nodes identified during the initial nodal mapping phase at the beginning of the procedure.14 Sonographic characteristics such as size, shape, border definition, vascularity and necrosis help predict malignant involvement and guide which nodes need to be sampled to increase diagnostic

yield.15 Figure 3 When sampling nodal stations, samples furthest away from the primary should be sampled first to avoid falsely upstaging the patient from tumor cells remaining within the needle.14 As per ESTS guidelines; 3 lymph node stations should be sampled 4L, 4R and 7 at a minimum when practical. As is the practice in our unit these should be sampled sequentially in a stepwise manner from highest to lowest stage (N3->N2->N1).14 Two randomized control trials have been pivotal for the establishment of combined EBUS and EUS-B (EBUS/EUS-B) as the standard in staging for intra thoracic lung cancer as well as some oligometastatic lung cancer.16,17 The ASTER study showed that upfront combination of EBUS and EUS-B followed by surgical staging (mediastinoscopy if indicated) for those with radiologic suspicion for nodal disease is superior to upfront surgical mediastinal staging or EUS or EBUS alone with a sensitivity of 94% for nodal metastatic disease and a negative predictive value of 93% (ASTER).

Upfront combination EBUS and EUS-B reduced the number of unnecessary mediastinoscopies by 47% and futile thoracotomies from 18% to 7%. From the EBUS/EUS-B group, of the 11 who subsequently underwent mediastinoscopy only 1 person had malignant mediastinal involvement.16 The lung-BOOST trial explored the upfront use of EBUS/EUS-B compared to conventional diagnosis and staging (CDS)

in those with suspected stage I-IIIA lung carcinoma on CT. CDS consisted of bronchoscopy +/- CT guided biopsy. The sensitivity of EBUS/EUS in this trial was 92% (95% CI 78–98).

The negative predictive value of EBUS-TBNA was 90% (72–97).

Upfront EBUS +/- EUS B (when indicated) shortened the median time to treatment decision from index CT from 29 days to 14 days compared to CDS (p<0.0001). A post hoc analysis revealed the median survival was longer in the EBUS/EUS group compared to the CDS group 503 days vs 312 days (P = .0382). Postulated reasons for the increased survival in this cohort include the shorter time to treatment initiation and the possible better selection of surgical candidates in the EBUS/ EUS group. The lung BOOST trial also showed a reduction in futile thoracotomies in the EBUS/ EUS group vs CDS 29% vs 76% and resulted in less overall investigations to stage and diagnose lung cancer.17 It is important to note that these trials did not completely obviate the need for mediastinoscopy. If there was ongoing high clinical concern for malignant nodal involvement post EBUS/EUS-B subjects proceeded to mediastinoscopy prior to surgery.16,17 EBUS T status While defining the nodal status of lung cancer is the most established role of EBUS it also has a critical role in defining T status of intra-thoracic tumors.

In the past, for those with central tumors abutting airways but without macroscopic endobronchial invasion detectable on CT or standard bronchoscopy decision regarding T stage was quite difficult. Prior to EBUS this would have to be clarified with thoracotomy or VATS with associated increased morbidity.18,19 However with the use of EBUS, primary cancer adjacent to the airway can be identified using the ultrasound probe and sampling can be obtained under real time ultrasound guidance. This institution has previously reported a case where this principle was used in a patient who presented with severe airflow obstruction, meaning that a percutaneous approach or surgical diagnostic approach was associated with significant increase risk of morbidity. CT scan demonstrated a small but spiculated lesion located posterior to the Bronchus intermedius causing mild compression but no invasion.

This was confirmed at EBUS and TBNA confirmed adenocarcinoma.

The patient underwent lobectomy which was well tolerated with final pathology pT1aN0.20 This role of EBUS has also been reported as viable in studies by Tourney et al and Nakajima et al.21, 22 EBUS also has a complimentary role with CT in assessing T4 status elsewhere in the thoracic cavity.

T4 is defined based on the size of the tumor or on invasion of certain structures including the mediastinum, great vessels and heart. Invasion of these structures can often be difficult to ascertain on CT, however invasion can often be directly visualized using

HOSPITALPROFESSIONALNEWS.IE | HPN • FEBRUARY 2022 | 45

LUNG CANCER Figure 4 Figure 4

Figure 4

the EBUS probe. Figure 4 is an example from our unit of a patient with tumor invasion into the left atrium confirmed with EBUS. Invasion of the mediastinum confirmed on EBUS equates to a T4 status regardless of size of the primary tumor and in most cases, obviates the need for futile surgery.

Our institution has shown as part of a multi-centre retrospective study that EUS-B in combination with CT has a high specificity and positive predictive value for establishing theT4 status of intra-thoracic lung tumors but in particular those located para-esophageal.23, 24, 32 EBUS M status As part of the mediastinal assessment procedure metastatic disease to the left adrenal, celiac nodes and left lower lobe of the liver can be assessed using EUS-B.14, 25 The same scope that is used for EBUS can be passed down the esophagus to the stomach (after mediastinal staging) and if suspicious lesions are identified in these sites they can be sampled.14, 25

A Lung with strial mediastinal windows on CT A lungmass mass withinvasion atrialoninvasion on mediastinal windows on CT B FDG avid primary mass with extension into left atrium B FDG avid primary mass with extension into left atrium C Ultrasound confirmation of tumour into left atrium via pulmonary vein

C Ultrasound confirmation of tumor into left atrium via pulmonary vein The most recent addition of Figure 5

the TNM staging highlights the important role of radical management of oligometastatic disease as these patients often have a longer survival than patients with more widespread metastasis if treated radically.33, 34, 35 The ability to sample the adrenal gland in this manner is particularly important as it is a common site for oligometastatic disease. Radiological studies and post mortem studies have confirmed isolated adrenal metastases in 1.6 to 3.5% and 3 to 7% of patients with NSCLC.36 Standard CT thorax or PETCT will often identify adrenal abnormalities due to the loss of the normal “seagull” shape of the gland or increased uptake. Normal adrenal gland will also appear like a seagull during EUS-B.

Pathological glands will appear enlarged and heterogeneous. Fig 5 However, malignant involvement must never be presumed based on radiological findings and must always be confirmed histologically as false positives are common in the form of benign adenomas.26 If presumed involved on imaging criteria alone many individuals could be excluded from undergoing curative treatment due to a false assumption of oligometastatic disease.14

and diagnosis in the least number of steps and with the least risk to the patient.

Initial imaging should consist of CT and subsequent PET for those without evidence of metastatic disease.

Despite a significant and growing body of evidence supporting the primary role for EBUS many centres still rely on investigations such as bronchoscopy and CT guided biopsy prior to staging the mediastinum thus increasing the time to a treatment plan and overall number of investigations which can negatively affect patient outcomes.

A lung mass with atrial invasion on mediastinal windows on CT Conclusion B FDG avid primary mass with extension into left atrium with suspected intrathoracic In summary, when staging those

lung cancer we must focus on performing the least invasive and most timely investigation that provides the most clinical information with respect to stage

References available C Ultrasound confirmation of tumor into left atrium via pulmonary vein on request

Figure 5

46 | FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Figure 5

BLADDER CANCER

An Overview of the Management of NonMuscle Invasive Bladder Cancer (NMIBC) Written by Charles O’Connor, Mohammed Hegazy, David Galvin, Gregory Nason Department of Urology, Mater Misericordiae University Hospital, Dublin

Charles O’Connor

Mohammed Hegazy

David Galvin

Gregory Nason

Bladder cancer is the 10th most common cancer globally and carries the 13th highest cancer related mortality.1 Bladder cancer is the 4th most commonly diagnosed cancer in men and the 10th most commonly diagnosed cancer in women in the US.2 Bladder cancer is four times more common in men than women. The risk factors for bladder cancer can be separated into unavoidable and avoidable. Unavoidable risk factors include aforementioned gender, age and genetics. Bladder cancer is predominantly a disease of older adults, with 90% of cases diagnosed over 55 and 80% over 65 in the United States (US). Cancer syndromes like Lynch syndrome and Cowden’s syndrome can predispose to bladder cancer. Mutations in growth factor receptor FGFR and p53 are also implicated in bladder cancer carcinogenesis.1

avoidable risk factor for bladder cancer is occupational exposure, which accounts for about 18% of bladder cancer cases. One meta-analysis found red meat and processed meat to increase bladder cancer risk by 17% and 10%, respectively, while another meta-analysis found a 22% increase for processed meats and no statistically significant increase for red meat.6, 7 Pre-obesity and obesity increased the risk of bladder cancer in one meta-analysis by 7% and 10%, respectively.8

The Model of Care for Urology document recommended haematuria should have a direct access pathway through onestop haematuria clinics.11 These clinics could potentially be led by advanced nurse practitioners.12

being the most and grade 2 being somewhere in the middle.

The patient’s risk of disease progression can be calculated as low, intermediate, high or very high using the EAU non-muscle invasive bladder cancer (NMIBC) Risk calculator https://www. nmibc.net/. This calculator also gives the patient’s probability of progression and 95% confidence interval at 1, 5 and 10 years. This risk is calculated based upon tumor size, grade, multifocality, presence of carcinoma in situ (CIS), age of patient and whether it is a primary or recurrent tumor.

Smoking is the most significant and avoidable risk factor for bladder cancer accounting for 50-65% of new cases each year.3 One study found that smoking cessation reduced the risk of bladder cancer by approximately 40% within 1-4 years, with a complete return to baseline by 20 years.4 The importance of smoking cessation is highlighted in an Irish review on the incidence of bladder cancer.

This retrospective review found the cases per 100,000 drop from approximately 24 and 9 to 13 and 4 in men and women respectively, from the year 1996-2015, in line with trends in smoking cessation.5 The second most common

With regards to survival rates from bladder cancer, according to the American cancer society, there is a 96% 5-year survival for in situ disease, 69% for localised disease (confined to the bladder), 37% for regional disease (spread to nearby structures or lymph nodes) and 6% for metastatic disease.9 These figures highlight the importance of early detection and management.

The main presentation of bladder cancer is haematuria (blood in the urine). Haematuria is classified as visible (VH) or non-visible (NVH), while NVH is further classified as symptomatic NVH and asymptomatic NVH. The investigation of haematuria is risk stratified- patients with VH >45 years or patients with persistent NVH >60 years being deemed high risk. Haematuria investigation includes flexible cystoscopy for direct bladder visualisation, upper tract imaging with renal ultrasound or CT and urine for cytology. 10

At flexible cystoscopy, any abnormality within the bladder can be pictured, and if this abnormality looks suspicious for urothelial cancer, the patient is booked for an urgent transurethral resection of bladder tumour (TURBT). The principle of this procedure is to get a tissue sample that gives an accurate representation of the layers of the bladder, including the urothelium, lamina propria and muscularis propria (muscle). TURBT can be diagnostic but also therapeutic.

Getting a good tissue sample ensures the histopathologist can demarcate whether the sample of tissue is in situ – stage pTis (confined to urothelium- but flat), pTa: non-invasive (confined to urothelium but often papillary growing in finger-like projections toward the hollow centre of the bladder), pT1 (invading lamina propria), pT2 (invading muscle), pT3 (invading peri-vesical fat) or pT4 (invading surrounding structures like prostate, uterus or vagina). The majority (95%) of the specimens will be transitional cell carcinomas (TCC).2 Bladder cancer is then categorised as non-muscle invasive (up to 80%) and muscle invasive based on depth of invasion. These should also be reported with grades 1-3, with grade 1 being the least anaplastic, grade 3

Management of low-risk bladder cancer If a bladder cancer is suspected or known to be low or intermediate risk, a patient should receive a single postoperative instillation of intravesical chemotherapy, e.g., mitomycin C, within 24 hours of TURBT. The patient should then be enrolled in standard low-grade flexible cystoscopy follow-up, including a check flexible cystoscopy at 3 & 12 months postoperatively and annually thereafter until five years. Urine for cytology is not recommended for low-risk bladder cancer follow-up. At the 5-year mark, recurrence is unlikely and follow up can be decided between clinician and patient, but some patients like to continue surveillance for peace of mind.

If the patient has a recurrence during follow-up, a repeat TURBT should be carried out and their risk of progression re-calculated.

If there is a low volume, low-grade

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BLADDER CANCER recurrence, this patient should maintain in the low-risk category, provided recurrence was not in less than one year; however, if there is a high-volume, low-grade recurrence, this patient would be switched to the intermediaterisk group.

Management of Intermediate risk bladder cancer One option for these patients is intravesical chemotherapy which has fewer side effects than BCG therapy. The optimal dosing schedule and duration for intravesical chemotherapy is still unknown.13 These patients can also be offered an induction course of Bacillus CalmetteGuerin (BCG). Induction BCG is a six successive weekly course of 1 hour BCG instillations. If patients do not respond to this, they can be offered a re-induction.

If the patient responds to either of these inductions, they can be enrolled in maintenance BCG for one year, which comprises BCG given once a week for three successive weeks at 3-, 6- and 12-months post-induction.

After this, they can continue surveillance according to the high-grade, flexible cystoscopy follow up schedule, which is every three months for two years, then every six months for three years and annually thereafter. As these patients are intermediate risk there may be more leniency with this schedule. Urine for cytology should be checked

at each flexible cystoscopy, similar to high-risk patients. If an intermediate-risk bladder cancer does not respond to 2 inductions of BCG or maintenance BCG, they should be offered a radical cystectomy, if fit. If patients are unfit, they should be enrolled in a clinical trial; if no trial is available, they should have intravesical chemotherapy if none has already been given. If an intermediate-risk patient recurs in less than a year after one-year maintenance BCG, they are deemed BCG refractory and they should be offered cystectomy; if they recur over a year after one-year maintenance BCG, they may be offered a re-induction of BCG. If a patient recurs after chemotherapy, they may still be offered BCG therapy as intravesical chemotherapy has no effect on BCG instillations.14 Management of high-risk bladder cancer Patients with pT1 and highgrade pTa tumours should have a re-resection within six weeks of initial TURBT. Patients with pT1 tumours, any high-grade tumour or CIS are deemed high risk for progression. If a patient is pT1, high risk according to the EAU risk calculator and do not respond to induction BCG; they should be offered radical cystectomy. If they are unfit, they should be enrolled in a clinical trial and intravesical chemotherapy if unavailable. Other high-risk patients at a lower stage than pT1 may be offered a trial of re-induction before progressing

in the same manner. If high-risk patients respond to induction or re-induction BCG, they may be enrolled in maintenance BCG for three years.15 Management of very high risk bladder cancer A subset of patients with NMIBC are deemed very high risk- These patients include very high-risk pT1 disease, lymphovascular invasion & variant histology, e.g., plasmacytoid. These patients should be considered for up front radical cystectomy.

Intravesical immunotherapy with BCG BCG is the gold standard bladder instillation for reducing the risk of recurrence and progression in bladder cancer. Simply put, BCG works by three steps: 1. Infection of the urothelium, 2. Induction of an immune response and 3. Inducing an anti-neoplastic effect. Infection of the urothelium promotes immune response by both TH1-cytokines (cell-mediated acquired immune response) and TH2-cytokines (humoral immune response) which synergistically provide antineoplastic activity.16 A systematic review and metaanalysis by Chou et al. from 2017 concluded that while several forms of intravesical therapy decreased the risk of recurrence versus TURBT alone, BCG was the only therapy to decrease the risk of progression versus TURBT alone. This review also found that BCG maintenance

regimens were associated with a decreased risk of recurrence vs intravesical chemotherapy; the strength of evidence was low.

The rate of adverse events was higher with BCG vs intravesical chemotherapy, including haematuria, granulomatous cystitis, dysuria and fever; strength of evidence was low.17 Intravesical chemotherapy The most common form of intravesical chemotherapy used in Ireland is Mitomycin C (MMC). Other examples of intravesical chemotherapy include gemcitabine, epirubicin, valrubicin, doxorubicin, thiotepa, interferon, apaziquone, paclitaxel and docetaxel.

Different chemotherapy agents have different mechanisms of action, benefits and risks. For example, an alkylating agent, MMC, has a low molecular weight, meaning better bladder wall penetration with increased risk of allergic skin reaction and possible systemic absorption.

In contrast, the anthracyclines, e.g., epirubicin and doxorubicin, have high molecular weight and lower systemic absorption.18 All chemotherapy agents have the general risks of haematuria, dysuria and frequency, but to a lesser extent than BCG. The role of these, as mentioned previously,

Figure 1. Flow diagram of NMIBC with most common interventions in each risk group Figure 1. Flow diagram of NMIBC with most common interventions in each risk group

NMIBC

low-risk

post-op MMC

intermediate -risk

post-op MMC BCG/Chemo

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high-risk

BCG

very high-risk

Cystectomy

(DARATUMUMAB)

Unlocking hope

≥5x

Meaningful response

increase in rate of MRD negativity2

3x

Remarkable PFS benefit

DVd complete response (CR) or better vs Vd2

>79%

RRR* in disease progression or death vs Vd of patients with 1PL of therapy2

Transform the treatment of multiple myeloma

DARZALEX® in combination with Velcade® (bortezomib) + dexamethasone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. See DARZALEX® SmPC for full indication, including its use as a monotherapy.1 * Recorded Response Rates DARZALEX® 20 mg/ml Concentrate for Solution for Infusion and 1 800 mg Solution for Injection PRESCRIBING INFORMATION. ACTIVE INGREDIENT(S): Daratumumab. Please refer to Summary of Product Characteristics (SmPC) before prescribing. INDICATION(S): Newly diagnosed multiple myeloma: in combination with lenalidomide/dexamethasone or bortezomib/melphalan/prednisone in adults, ineligible for autologous stem cell transplant; in combination with bortezomib, thalidomide and dexamethasone in adults, eligible for autologous stem cell transplant. Relapsed/Refractory multiple myeloma: Monotherapy for adults whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on last therapy. In combination with lenalidomide/dexamethasone or bortezomib/dexamethasone in adults who have received ≥ one prior therapy. Darzalex SC: in combination with pomalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received one prior therapy containing a proteasome inhibitor and lenalidomide and were lenalidomide refractory, or who have received at least two prior therapies that included lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or after the last therapy. AL Amyloidosis: Darzalex SC in combination with cyclophosphamide, bortezomib and dexamethasone for the treatment of adult patients with newly diagnosed systemic light chain (AL) amyloidosis. DOSAGE & ADMINISTRATION: Administration by healthcare professional where resuscitation facilities are available, intravenous (IV) infusion or subcutaneous (SC) injection. For SC injection, resuscitation facilities required only for first dose. Adults: Recommended IV dose: 16 mg/kg body weight. Dilute with sodium chloride 0.9% solution for injection and administer by IV infusion using incremental escalation of infusion rate, only if previous infusion well-tolerated. SC dose: inject 15 mL (1 800 mg) Darzalex solution for SC injection into the subcutaneous tissue of the abdomen approximately 7.5 cm to the right or left of the navel over approximately 3-5 minutes according to dosing schedule. Patients > 120 kg, flat-dose 1 800 mg SC, efficacy not established. SC injection: no dose adjustments based on body weight recommended. Darzalex solution for SC injection should never be injected into areas where the skin is red, bruised, tender, hard or areas where there are scars, rotate injection site. During treatment with Darzalex SC injection, do not administer other medicinal products for subcutaneous use at the same site as Darzalex. Check the vial labels to ensure that the appropriate formulation (IV or SC formulation) and dose is being given as prescribed. For dose and schedule of medicinal products administered with DARZALEX, refer to SmPC 4.2 and the corresponding SmPC for other products.

Administer pre- and post -injection medicinal products to reduce the risk of infusion related reactions (IRRs). Recommended concomitant medications for management of infusion/injection-related reactions (IRRs): administer pre-IV infusion/SC Injection medicinal products to all patients 1-3 hours prior to every infusion (corticosteroid, antipyretics and antihistamine). For SC injections, premedications can be given orally from the first dose. When dexamethasone is background regimen specific corticosteroid, this dose will serve as pre medication on infusion days. If dexamethasone given on infusion day, do not take additional background regimen specific corticosteroids (e.g. prednisone). Post-IV infusion/SC injection medicinal products should be administered to reduce the risk of delayed IRRs: administer oral corticosteroid. SC injections: if the patient experiences no major IRRs after the first three SC injections, post-injection corticosteroids (excluding any background regimen corticosteroids) may be discontinued. Consider short/long acting bronchodilators and inhaled corticosteroids in patients with history of chronic obstructive pulmonary disorder. IV Infusion: Any grade/severity IRRs, interrupt Darzalex immediately and manage symptoms. Re-starting Darzalex IV infusion: reduce infusion rate (refer to SmPC); Grade 4 IRRs (or third occurrence of Grade 3) – permanently discontinue. For haematological toxicity dose delay may be required to allow recovery of blood cell counts. No dose reductions of Darzalex recommended. Consider anti viral prophylaxis for prevention of herpes zoster virus reactivation. Children: No data available. Elderly/ Renal impairment/Hepatic impairment: No dose adjustments. CONTRAINDICATIONS: Hypersensitivity to active substance or excipients. SPECIAL WARNINGS & PRECAUTIONS: IRRs: can cause serious IRRs including anaphylactic reactions. Majority occurred following first IV infusion/SC injection.

Fatal outcomes have been reported with IV infusion. IV infusion: monitor for IRRs throughout the IV infusion, continue monitoring post-IV infusion until symptoms resolve. For SC injection, median time to onset of IRRs was 3.7 hours following injection, monitor IRRs especially in the first and second

SC injection. IV infusion: interrupt Darzalex for any severity IRRs. Institute medical management/ supportive treatment as needed. For both IV and SC Darzalex if an anaphylactic reaction or life threatening (Grade 4) IRR occurs, initiate appropriate emergency resuscitation immediately and discontinue Darzalex immediately and permanently. Neutropenia/Thrombocytopenia: Darzalex may increase neutropenia and thrombocytopenia induced by background therapy; monitor for infections & periodic complete blood cell counts (refer to relevant SmPCs); consider supportive care.

Indirect Antiglobulin Test (Indirect Coombs Test): Daratumumab binds to CD38; may mask detection of antibodies to minor antigens; ABO and Rh blood typing not impacted. Interference may occur up to 6 months post-treatment. Type and screen patients prior to starting daratumumab; consider phenotyping; red blood cell genotyping not affected by daratumumab. Inform blood transfusion centres when appropriate. If emergency transfusion required, give non-cross-matched ABO/RhDcompatible RBCs. Hepatitis B virus (HBV) reactivation: Fatal cases reported in patients treated with Darzalex. Perform HBV screening before initiation of treatment. Suspend treatment in patients who develop reactivation of HBV while on Darzalex. Patient’s with body weight >120 kg receiving SC injection, potential for reduced efficacy. IV infusion contains sodium. SC injection contains sorbitol.

SIDE EFFECTS: Very common: IRRs, pneumonia, bronchitis, upper respiratory tract infection, anaemia, neutropenia, thrombocytopenia, lymphopenia, leukopenia, decreased appetite, peripheral sensory neuropathy, paraesthesia, headache, hypertension, cough, dyspnoea, nausea, diarrhoea, constipation, vomiting, back pain, muscle spasms, fatigue, pyrexia, oedema peripheral, asthenia. SC only: insomnia, arthralgia, rash. Common: urinary tract infection, influenza, sepsis, cytomegalovirus infection, hypogammaglobulinemia, hyperglycaemia, hypocalcaemia, dehydration, fainting, atrial fibrillation, pulmonary oedema, pancreatitis, chills. SC only: dizziness, musculoskeletal chest pain, pruritus, injection site reactions. Other side effects: HBV reactivation (uncommon), anaphylactic reaction (rare). Refer to SmPC for other side effects. LEGAL CATEGORY: Prescription only medicine. PRESENTATIONS, PACK SIZES, MARKETING AUTHORISATION NUMBER(S): 5 ml vial (100mg daratumumab), X 1, EU/1/16/1101/001; 20 ml vial (400mg daratumumab), X 1, EU/1/16/1101/002; 15 ml vial (1 800 mg daratumumab), X 1, EU/1/16/1101/004. MARKETING AUTHORISATION HOLDER: Janssen-Cilag International NV Turnhoutseweg 30, B-2340 Beerse, Belgium. FURTHER INFORMATION IS AVAILABLE FROM: Janssen Sciences Ireland UC, Barnahely, Ringaskiddy, IRL – Co. Cork P43 FA46.

Prescribing information last revised: October 2021 Adverse events should be reported.  This medicinal product is subject to additional monitoring and it is therefore important to report any suspected adverse events related to this medicinal product. Healthcare professionals are asked to report any suspected adverse events via: HPRA Pharmacovigilance, Website: www.hpra.ie. Adverse events should also be reported to, Janssen Sciences Ireland UC on 1800 709 122 or at dsafety@its.jnj.com.

References: 1. Darzalex® SmPC. Available at www.medicines.ie/medicines/darzalex-1-800-mg-solution-forinjection-34971/patient-info. 2. Weisel K et al, Castor Four Year Update. Ash 2019, Poster 3192.

Date of Preparation: November 2021 | CP-273392 | Janssen Sciences Ireland UC 2021

BLADDER CANCER STAGES OF BLADDER CANCER

is to be used either as a single dose postoperatively in low and intermediate-risk bladder cancer, as possible adjuvant treatment in intermediate-risk bladder cancer and when BCG fails.

Patients with BCG unresponsive tumours who are not radical cystectomy candidates This subgroup of patients should be enrolled in a clinical trial if available. If no trial is available, they may be offered intra-vesical chemotherapy. A Recent randomised controlled trial looked at the effect of MMC with radiofrequency-induced thermo-chemotherapy effect (RITE). Patients who recurred after at least one induction course of BCG patients were randomised to MMC with RITE vs control second line therapy- BCG, MMC & MMC and electromotive drug administration. This study found higher disease-free survival for MMC with RITE in non-CIS papillary tumours (53% vs 24%), suggesting patients with papillary tumours may benefit from this.19 A 2021 phase 2 clinical trial in the Lancet examined the effect of pembrolizumab monotherapy (200mg intravenously every 3 weeks for up to 24 months) in high risk NMIBC patients unresponsive to BCG. This initially showed promising results with

39 (41%) of 96 patients showing complete response at 3 months.

However, only 11% of the initial cohort remained in remission.

This means pembrolizumab monotherapy delayed cystectomy in a small number of patients.

Given 95% of this patient population were eligible for, but declined cystectomy, it was not considered a sensible treatment option, but may be beneficial for patients who are unfit for cystectomy.20 The financial cost of bladder cancer Bladder cancer is the most expensive cancer from a health economic perspective given the frequent surveillance schedules, the intravesical treatments and the reoperation rates due to risk of recurrence and progression. As a result, it is key to establish the risk category of the patient accurately at diagnosis and ensure they receive optimal treatment.21 Challenges in the management of bladder cancer One of the biggest challenges faced with the management of bladder cancer is the lack of supply of BCG and the lack of resources to enrol patients in maintenance BCG. This problem started in 2017 when one of the

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two suppliers of BCG, Sanofi Pasteur, shut down production.

Merck Millipore remains the sole producer of BCG for the US, Canada and 70 countries worldwide. This underproduction means that supply cannot keep up with demand despite production being increased by 100%. This BCG shortage encouraged the use of alternative treatments like intravesical chemotherapy, particularly in intermediate-risk bladder cancer, where there may be less of a distinction regarding inferiority vs BCG. The advice was also given during BCG shortage to curtail maintenance BCG if patients had already received it for a year or two. The priority for usage of BCG was to get high risk, first diagnosis patients, through their induction and 3-month doses of BCG.22 It was also suggested that patients could be considered for early radical cystectomy which is a significant undertaking. While this shortage is not felt as strongly now, there were occasions over the preceding year or two where BCG was unavailable. This hold on the delivery of maintenance and sometimes induction BCG meant that the resources of staffing, hospital beds or outpatient rooms were redirected elsewhere in some hospitals. In a situation where BCG is now becoming again more accessible,

this reorganisation to put in place effective BCG induction delivery is a challenge, with the delivery of maintenance BCG being a more significant challenge.

Nonetheless, these efforts to reestablish BCG delivery are rightly well supported.

Conclusion NMIBC is common. Patients often present with VH. Diagnosis is made by means of a cystoscopy and TURBT. From a urologist’s perspective, the crucial part of NMIBC management is the risk stratification of patients. Once the risk is calculated, the next part of management is following the correct treatment algorithm for a patient based on risk category and to engage in multi-disciplinary decision making if necessary.

The wider hospital team can also help manage patients with bladder cancer; this may include aiding with resources for effective and timely BCG delivery.

Smoking is the key risk factor for bladder cancer that cannot be overlooked or disregarded, and in this regard, there is a duty on patients to manage NMIBC- to help prevent it from occurring or recurring.

References available on request

BLOOD CANCER

Targeting the ‘Achilles heel’ of childhood AML using Systems Biology Written by Dr. Luke Jones, Irish Cancer Society Research Fellow at Systems Biology Ireland, University College Dublin Dr. Oleksii Rukhlenko, Research Scientist at Systems Biology Ireland, University College Dublin Acute myeloid leukaemia (AML) is the leading cause of blood cancer-related mortality in children. While outcomes for patients have certainly improved in recent decades, survival rates have reached a plateau at approximately 60%. Efforts to improve survival rates have been hampered by a lack of knowledge about the nature of paediatric AML and limited development of new treatments. In fact, treatments for childhood AML have remained essentially unchanged for nearly 50 years, comprising highly toxic drugs which carry significant short- and long-term side effects.

It is therefore a priority to identify safer, more effective treatments for these patients.

Biology can be used to predict kinase inhibitor combinations able to shut down overactive kinases.

Many blood cancers, including AML, are aggressive because mutations in a cells’ DNA cause overactivity in proteins called kinases. Kinases are enzymes that act like traffic lights within a cell, dynamically switching from ‘go’ to ‘stop’ to allow cells to make decisions, such as whether to grow or divide. These decision processes are normally tightly regulated, however when a kinase is mutated it often results in a constant ‘green light’, causing the cells to grow uncontrolled.

Coming back to the traffic analogy, computational biology allows us to obtain maps of all the ‘traffic systems’ within a cell. This allows us to gain a holistic understanding of the main signalling routes activated in cancer cells, and what bypasses can potentially exist.

Understanding these bypasses can prove vital in understanding why cancers develop resistance to some targeted drugs, such as kinase inhibitors. Establishing these maps largely simplifies the task of effectively blocking oncogenic routes and allows identifying optimal combinations of drugs to cut all possible alternative routes of oncogenic signalling.

Recent decades have seen the development of drugs called kinase inhibitors, with many already used clinically across a range of cancers. These drugs interact with overactive kinases to halt the uncontrolled growth of cancer cells. Unfortunately, these drugs are commonly ineffective when used on their own as they are unable to completely shut down kinase activity. In keeping with the traffic analogy, cancer cells can divert traffic away from the targeted kinase and use an alternate route. These drugs are more effective when used in combination, however the challenge lies in identifying which combinations will work best for which patient.

In order to address this challenge, we are using an approach called Systems Biology which combines in vitro experimental data with computer modelling. Systems

Systems Biology provides a holistic understanding of cancers Systems Biology stands on two pillars, computational (“dry”) biology and experimental (“wet”) biology, which work in tandem.

Results obtained in the lab provide data to feed into computational models, and these models allow refinement of our experimental approach. At Systems Biology Ireland we are utilising this strategy to identify potential vulnerabilities in cancers and discover novel therapeutic options.

Targeting oncogenic signalling using Systems Biology Previously we have focused on studying oncogenic signalling resulting from mutations which activate members of the RAS family of genes, particularly N-RAS, K-RAS and H-RAS. Mutations in these genes occur in approximately 30% of all cancers and are commonly found in leukaemias. These mutations cause overactivity of kinases leading to uncontrolled growth and survival of cancer cells.

Using a Systems Biology approach, our research has identified a potential, non-obvious vulnerability in the signalling that occurs as a result of mutations in RAS genes. This vulnerability

takes advantage of two key facts, one being that kinase inhibitors of different shapes (structures) exist and the second being that kinases commonly form pairs (known as dimers) when activated. When a kinase inhibitor binds to one kinase in the pair it can cause the other to undergo a subtle change in shape. This change in shape makes it susceptible to being bound by a kinase inhibitor with a different structure from that of the first inhibitor.

As a result, our studies identified new, non-obvious drug combinations which consist of previously approved drugs and effectively block RAS oncogenic signalling. Based on our findings a new Phase II clinical trial has recently started in the USA (https://clinicaltrials.gov/ct2/ show/NCT05068752), which is sponsored by the HonorHealth Research and Innovation Institute of Scottsdale, Arizona, with support from Bayer and Genentech. This study will assess the potential for our computational model to predict effective drug combinations in patients with pancreatic cancer.

Dr. Luke Jones, Irish Cancer Society Research Fellow at Systems Biology Ireland, University College Dublin

Applying this model to paediatric acute leukaemia patients Thanks to funding from the Irish Cancer Society, we are currently applying our modelling approach to kinase mutations frequently observed in childhood AML patients. Our current model is readily applicable to childhood AML, as mutations in RAS genes occur in 15-20% of patients and are commonly associated with poor clinical outcome. As such, we are currently working to identify novel kinase inhibitor combinations for these patients.

One of the key benefits of our modelling strategy is that it can theoretically be applied to other types of kinases. As mutations in kinases are common in childhood AML, we are currently developing similar models to focus on kinase mutations which are commonly associated with resistance to standard therapies and poor clinical outcomes.

Dr. Oleksii Rukhlenko, Research Scientist at Systems Biology Ireland, University College Dublin

These predicted combinations will require rigorous lab testing before reaching the clinical setting. As part of this testing, we are currently developing experimental platforms which will help to ensure that our combinations are both safe and effective for patients. While there is still a lot of work to do, this approach has significant potential to allow rapid identification of kinase inhibitor combinations that will provide safe and effective treatment strategies for high-risk childhood AML patients.

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BREAST CANCER Cancer Treatment Related Cardiac Dysfunction Unravelling the Mechanisms to Improve Breast Cancer Patient Care and Detailing the Need for a National Cardio-Oncology Network Written by Matthew G. Davey, Aoife J. Lowery - On behalf of the Precision Cardio-Oncology Research Enterprise (P-CORE) Group, National University of Ireland, Galway CTRCD (defined as left ventricular dysfunction on echocardiogram or clinical manifestation of heart failure decompensation following treatment) to Trastuzumab (Herceptin©). Trastuzumabmediated cardiotoxicity occurs due to TOP2B binding by Trastuzumab, highlighting the danger of Trastuzumab and anthracyclines synergistically inducing CTRCD.

Breast Cancer Epidemiology and Current Treatment Paradigms Currently one in eight Irish women are diagnosed with breast cancer during their lifetime. Breast cancer treatment has evolved to include personalised therapeutic approaches, with refined locoregional strategies including conservative surgical techniques, more patient and tumour specific radiotherapy regimens and the development of targeted systemic therapies informed by an improved understanding of tumour biology.

The contemporary approach to breast cancer treatment aims to optimise oncologic outcomes, while minimising the negative sequelae of cancer treatment.

This approach has been validated through the enhancement of oncological and survival outcomes, with National Cancer Registry data confirming five and ten year breast cancer survival of 90.3% and 83.8% respectively.

As breast cancer-survival continues to improve survivorship issues are becoming increasingly important. There is emerging evidence to suggest that female breast cancer survivors are more likely to die of cardiovascular disease (CVD) than their agematched counterparts. This relates not only to a higher prevalence

of risk factors for CVD in this population, but is increased exponentially by Cancer Treatment Related Cardiac Dysfunction (CTRCD). CTRCD refers to the cardiotoxic effects of cancer treatment which can occur acutely during cancer treatment, disrupting the treatment course, or later, negatively impacting the quality of life and survival of these patients (Figure 1). The combination of chemotherapy, radiotherapy and targeted therapy (anti-oestrogen and anti-human epidermal growth factor receptor-2 (HER2)) poses a significant cardiotoxic risk.

These risks are even higher in an aging breast cancer population in whom pre-existing CVD is increasingly common. Therefore, in order to maximise anticipated clinical outcomes, it is critical that cardiovascular assessment and monitoring are considered for patients being treated for breast cancer. This article focuses on the need for clinical and translational research programme to inform care pathways dedicated to improving cardiac and oncological outcomes for breast cancer patients. It contextualises the national and international evidence and sets the scene for a necessary new national network being piloted at the National University of Ireland, Galway (NUIG).

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Cancer Treatment Related Cardiac Dysfunction & Risk Factors Contemporary breast cancer management is multimodal, involving surgical resection and the use of combined chemotherapy, radiotherapy and targeted therapies to maximise oncological outcomes. In the era of personalised therapy each of these therapeutic strategies carries their own risk of CTRCD, which highlights the requirement for care pathways to individualise and stratify according to the competing risks. Anthracyclinebased chemotherapy leads to CTRCD in between 3 - 48% of patients. Cellular targeting of DNA topoisomerase IIB (TOP2B) is hypothesized to cause anthracycline-induced CTRCD, but the mechanism of myocardial cell injury remains unclear. Recently, Sandamali et al. outlined that 33.2% of patients being treated for invasive breast cancer developed subclinical CTRCD in the 6-months following treatment with anthracycline chemotherapies.

Similarly, anti-HER2 therapies are known to be cardiotoxic: In their analysis of 931 patients being treated for HER2+ disease, Battisti et al. recently outlined that 16.6% of patients experienced

The majority of patients are diagnosed with oestrogen receptor positive breast cancer, necessitating treatment with anti-oestrogen endocrine agents.

There is some evidence that Tamoxifen may be cardioprotective compared to aromatase inhibition. A clinical study of 9,350 patients from Abdul-Qadir et al. previously illustrated an increased risk of myocardial infarction in postmenopausal women treated with aromatase inhibitors (AIs) versus tamoxifen (a selective estrogen receptor modulator) (hazard ratio: 2.02, 95% confidence interval (CI): 1.16 – 3.53). Interestingly, Khosrow-Khavar et al. performed a systematic review and meta-analysis of randomized controlled trials illustrating the cardioprotective value of Tamoxifen relative to placebo (rate ratio (RR): 0.67, 95% CI: 0.45 – 0.98) and increased risk of cardiac events with AI use (RR: 1.18, 95% CI: 1.07 – 1.34) relative to tamoxifen use. Similarly, a large study from the Surveillance Epidemiology and End Results (SEER) database observed radiotherapy-induced heart disease (RIHD) in 2% and 1% of those in receipt of left- and right- sided chest wall radiotherapy respectively. Consequently, there remains a current need to establish an algorithmic approach to identify those at risk of developing CTRCD from multimodal breast cancer treatment and delineate a risk benefit ratio for therapeutic effectiveness for the various interventions.

▼ The Next Line Is Clear¹

LORVIQUA as monotherapy is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) whose disease has progressed after: •

lectinib or ceritinib as the first ALK tyrosine kinase a inhibitor (TKI) therapy; or

•

crizotinib and at least one other ALK TKI.1

References: 1. Lorviqua® Summary of Product Characteristics.

PRESCRIBING INFORMATION ▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. Refer to section 4.8 of the SPC for how to report adverse reactions.

Lorviqua®▼ 25 mg and 100 mg film-coated tablets IE Prescribing Information: Before prescribing Lorviqua (lorlatinib) please refer to the full Summary of Product Characteristics (SmPC). Presentation: Each 25 mg film-coated tablet contains 25 mg lorlatinib; Each 100 mg film-coated tablet contains 100 mg lorlatinib. Indications: Lorviqua as monotherapy is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK) positive advanced non small cell lung cancer (NSCLC) whose disease has progressed after alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy, or crizotinib and at least one other ALK TKI. Dosage and Administration: Treatment should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. The recommended dose is 100 mg lorlatinib taken orally once daily. Treatment is recommended as long as the patient is deriving clinical benefit from therapy without unacceptable toxicity. If a dose is missed, then it should be taken as soon as the patient remembers unless it is less than 4 hours before the next dose. Patients should not take 2 doses at the same time to make up for a missed dose. To manage adverse reaction, dose interruption or dose reduction see SmPC section 4.2. Concurrent use of lorlatinib with medicinal products that are strong CYP3A4/5 inhibitors and grapefruit juice products may increase lorlatinib plasma concentrations, see SmPC section 4.2 for further information. Special populations: Elderly (≥ 65 years): There are limited data on this population, no dose recommendation can be made for patients aged 65 years and older (see section 5.2). Renal impairment: See SmPC section 4.2. No dose adjustment is required for patients with mild or moderate renal impairment. A reduced dose of lorlatinib is recommended in patients with severe renal impairment (absolute eGFR < 30 mL/min), e.g. a once daily starting dose of 75 mg taken orally (see SmPC section 5.2). No information is available for patients on renal dialysis. Hepatic impairment: See SmPC section 4.2. No dose adjustment is required for patients with mild hepatic impairment. No information is available for lorlatinib in patients with moderate or severe hepatic impairment. Therefore, lorlatinib is not recommended in patients with moderate to severe hepatic impairment (see section 5.2). Paediatric population: The safety and efficacy of lorlatinib in children and adolescents < 18 years of age have not been established. Method of administration: Lorlatinib is for oral use. Patients should be encouraged to take their dose of lorlatinib at approximately the same time each day with or without food (see SmPC section 5.2). The tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact.

Contra-indications: Hypersensitivity to the active substance or to any of the excipients. Concomitant use of strong CYP3A4/5 inducers (see SmPC sections 4.4 and 4.5). Special Warnings and Precautions: Hyperlipidaemia: The use of lorlatinib has been associated with increases in serum cholesterol and triglycerides (see SmPC section 4.8). Serum cholesterol and triglycerides should be monitored before initiation of lorlatinib; 2, 4 and 8 weeks after initiating lorlatinib and regularly thereafter. Initiate or increase the dose of lipid lowering medicinal products, if indicated (see SmPC section 4.2). Central nervous system (CNS) effects: CNS effects have been observed in patients receiving lorlatinib, including psychotic effects and changes in cognitive function, mood, mental status or speech (see SmPC section 4.8). Dose modification or discontinuation may be required for those patients who develop CNS effects (see SmPC section 4.2).

Atrioventricular block: Lorlatinib was studied in a population of patients that excluded those with second degree or third degree AV block (unless paced) or any AV block with PR interval > 220 msec. PR interval

prolongation and AV block have been reported in patients receiving lorlatinib (see SmpC section 5.2). Monitor electrocardiogram (ECG) prior to initiating lorlatinib and monthly thereafter, particularly in patients with predisposing conditions to the occurrence of clinically significant cardiac events. Dose modification may be required for those patients who develop AV block (see SmPC section 4.2). Left ventricular ejection fraction decrease: Left ventricular ejection fraction (LVEF) decrease has been reported in patients receiving lorlatinib who had baseline and at least one follow-up LVEF assessment. In patients with cardiac risk factors and those with conditions that can affect LVEF, cardiac monitoring, including LVEF assessment at baseline and during treatment, should be considered. In patients who develop relevant cardiac signs/symptoms during treatment, cardiac monitoring, including LVEF assessment, should be considered.

Lipase and amylase increase: Elevations of lipase and/or amylase have occurred in patients receiving lorlatinib (see SmPC section 4.8). Risk of pancreatitis should be considered in patients receiving lorlatinib due to concomitant hypertriglyceridemia and/or a potential intrinsic mechanism.

Patients should be monitored for lipase and amylase elevations prior to the start of lorlatinib treatment and regularly thereafter as clinically indicated (see SmPC section 4.2). Interstitial lung disease/Pneumonitis: Severe or life threatening pulmonary adverse reactions consistent with ILD/pneumonitis have occurred with lorlatinib (see SmPC section 4.8). Any patient who presents with worsening of respiratory symptoms indicative of ILD/ pneumonitis (e.g. dyspnoea, cough and fever) should be promptly evaluated for ILD/pneumonitis. Lorlatinib should be withheld and/or permanently discontinued based on severity (see SmPC section 4.2).

Hypertension: Hypertension has been reported in patients receiving lorlatinib (see SmPC section 4.8). Blood pressure should be controlled prior to initiation of lorlatinib. Blood pressure should be monitored after 2 weeks and at least monthly thereafter during treatment with lorlatinib.

Lorlatinib should be withheld and resumed at a reduced dose or permanently discontinued based on severity (see SmPC section 4.2).

Hyperglycaemia: Hyperglycaemia has occurred in patients receiving lorlatinib (see SmPC section 4.8). Fasting serum glucose should be assessed prior to initiation of lorlatinib and monitored periodically thereafter according to national guidelines. Lorlatinib should be withheld and resumed at a reduced dose or permanently discontinued based on severity (see SmPC section 4.2). Interactions: Concomitant use of a strong CYP3A4/5 inducer is contraindicated (see SmPC sections 4.3 and 4.5). No clinically meaningful changes in liver function tests were seen in healthy subjects after receiving a combination of lorlatinib with the moderate CYP3A4/5 inducer modafinil (see section 4.5). Concurrent administration of lorlatinib with CYP3A4/5 substrates with narrow therapeutic indices, including but not limited to alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, hormonal contraceptives, pimozide, quinidine, sirolimus and tacrolimus, should be avoided since the concentration of these medicinal products may be reduced by lorlatinib (see SmPC section 4.5). Lorlatinib is a weak inducer of CYP2B6, no dose adjustment is necessary when lorlatinib is used in combination with medicinal products that are mainly metabolised by CYP2B6 (see SmPC section 4.5). Lorlatinib is a weak inducer of CYP2C9, no dose adjustment is required for medicinal products that are mainly metabolised by CYP2C9. Patients should be monitored in case of concomitant treatment with medicinal products with narrow therapeutic indices metabolised by CYP2C9 (e.g. coumarin anticoagulants) (see SmPC section 4.5). Lorlatinib is a weak inducer of UGT, no dose adjustment is required for medicinal products that are mainly metabolised by UGT. Patients should be monitored in case of concomitant treatment with medicinal products with narrow therapeutic indices metabolised by UGT (see SmPC Section 4.5). Lorlatinib is a moderate inducer of P gp. Medicinal products that are P gp substrates with narrow therapeutic indices (e.g. digoxin, dabigatran etexilate) should be used with caution in combination with lorlatinib due to the likelihood of reduced

PP-LQA-IRL-0068

Preparation Date: September 2021

plasma concentrations of these substrates. Lorlatinib should be used with caution in combination with substrates of BCRP, OATP1B1, OATP1B3, OCT1, MATE1 and OAT3 as clinically relevant changes in the plasma exposure of these substrates cannot be ruled out (see SmPC section 4.5).

Fertility, pregnancy and Breast-feeding: Fertility: Male fertility may be compromised during treatment with lorlatinib (see SmPC section 5.3). Men should seek advice on effective fertility preservation before treatment. It is not known whether lorlatinib affects female fertility. Pregnancy: Lorlatinib is not recommended during pregnancy or for women of childbearing potential not using contraception. Women of childbearing potential should be advised to avoid becoming pregnant while receiving lorlatinib. A highly effective non hormonal method of contraception is required for female patients during treatment because lorlatinib can render hormonal contraceptives ineffective (see SmPC sections 4.5 and 4.6). If a hormonal method of contraception is unavoidable, then a condom must be used in combination with the hormonal method. Effective contraception must be continued for at least 35 days after completing therapy (see SmPC section 4.6). During treatment and for at least 14 weeks after the final dose, male patients with female partners of childbearing potential must use effective contraception, including a condom, and male patients with pregnant partners must use condoms (see SmPC section 4.6).

Breast-feeding: Lorlatinib should not be used during breast feeding. Breast feeding should be discontinued during treatment and for 7 days after the final dose. Lactose intolerance: This medicinal product contains lactose as an excipient. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose galactose malabsorption should not take this medicinal product. Effects on ability to drive and use machines: Lorlatinib has moderate influence on the ability to drive and use machines. Caution should be exercised when driving or operating machines as patients may experience CNS effects (see SmPC section 4.8).

Undesirable Effects: See SmPC section 4.8. The overall safety profile of lorlatinib is presented from data from 295 adults treated with lorlatinib 100 mg once daily with advanced NSCLC from Study A (Phase II 1001 (n=275), Phase I (n=17), Japanese Cohort (n=3)). The most common (≥2%) Grade ≥3 adverse reactions of lorlatinib were Anaemia, Hypercholesterolaemia, Hypertriglyceridaemia, Cognitive effects, Peripheral neuropathy, Oedema, Weight increased, Lipase increased, Amylase increased. Commonly reported adverse events (≥ 1/100 to < 1/10) were Hyperglycaemia, Psychotic effects, Mental status changes, Speech effects, Pneumonitis. Dose reductions due to adverse reactions occurred in 23.4% of patients receiving lorlatinib. Very common (≥ 1/10) adverse reactions in patients receiving lorlatinib in this study were Anaemia, Hypertension, Hypercholesterolaemia, Hypertriglyceridaemia, Mood effects, Cognitive effects, Peripheral neuropathy, Headache, Vision disorder, Diarrhoea, Nausea, Constipation, rash, Arthralgia, Myalgia, Oedema, Fatigue, Weight increased, Lipase increased, Amylase increased.

Common (≥ 1/100 to < 1/10) adverse effects were Speech effects, Pneumonitis. Legal Category: S1A. Package quantities and Marketing Authorisation Numbers: Lorviqua 25 mg film-coated tablets EU/1/19/1355/003, 90 tablets. Lorviqua 100 mg film-coated tablets EU/1/19/1355/002, 30 tablets. For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at EUMEDINFO@pfizer.com For queries regarding product availability please contact: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 + 353 1 4676500. Marketing Authorisation Holder: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium.

Date of Preparation: 07/2021 Ref: LQ 5_0

BREAST CANCER Predicting Tumour and Host Response to Treatment The establishment of biomarker discovery programs is the cornerstone of improved personalised treatment strategies. These biomarkers can be present in the circulation or represented in clinical data such as available imaging. An enhanced understanding of the biological and genomic properties of cancers, factors which may leverage anticancer effects and produce less host toxicity is key to better survivorship.

Measurement of circulating biomarkers from venous sampling before, during, or after treatment have proven useful in deciphering those likely to respond favourably to the treatment as well as those at risk of CTRCD. For example, mi(cro)RNAs are small (19–25 nucleotides in length), endogenous, non-coding RNA understood to play important regulatory roles in governing gene expression and cellular activity.

Aberrant miRNA expression profiles have been correlated with and provide valuable information in predicting patients likely to

achieve favourable responses to (neo)adjuvant treatment for breast cancer. Interestingly, there is emerging in-vivo clinical trial data illustrating the predictive value of expression profiles of circulating miRNA such as miR-21 and miR-195 in predicting patients who will successfully achieve a pathological complete response to neoadjuvant chemotherapy in breast cancer. While these efforts have focused on tumour response to treatment, efforts to decipher patients at risk of CTRCD are also being explored: Silencing of miR-34a has been reported as key modulatory step in reducing

doxorubicin-induced CTRCD while miR-215 has been identified as an informative biomarker of RIHD. Furthermore, there are several genetic biomarkers which have been associated with predicting treatment response and host toxicity to treatment: The seminal work of Zhang et al. first illustrated that cardiomyocyte-specific deletion of TOP2B protects cardiomyocytes from Doxorubicininduced DNA double-strand breaks and transcriptome changes responsible for CTRCD. A recent systematic review outlined 88 genes and 154 single nucleotide polymorphisms (SNPs) perceived to be causative for chemotherapy-induced CTRCD and highlighted the importance of 6 key variants which were obviously associated with chemotherapy-induced CTRCD. Interestingly, radiogenomics (or radiomics) is an emerging field in medical imaging with potential to interrogate data from grey scale images from medical imaging to outline quantitative diagnostic and prognostic genomic information through high-throughput extraction of primary tumour features.

Radiomics seems promising in deciphering host and tumour outcomes and the hypothesis has evolved to indicate that treatment naïve imaging may be practical in identifying those at risk of CTRCD. In the context of breast cancer treatment, Meshman et al. recently outlined the value of doseweighted computed tomography radiomics for predicting patients likely to succumb to RIHD among those being treated for early breast cancer. While this concept remains in its infancy, refinement of artificial intelligence models looks promising in facilitating earlier detection rates of CTRCD in patients diagnosed with breast cancer.

Survivorship Needs Quality of life is defined by the World Health Organization as “an individual’s perception of their position in life in the context of the culture and value system in which they live and in relation to their goals, expectations, and standards and concerns”. Quality of life QoL comprises, among other elements, the sense of mental and physical well-being, opportunities for personal development, material status, social relationships, and functioning in the immediate environment. Health related

Figure 1. The potential impact of Cancer Treatment Related Cardiac Dysfunction (CTRCD) on patients being treated for cancer

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QoL, defined as the functional effect of physical, mental and social response to the disease and treatment, as perceived subjectively by the patient as well as the patient’s assessment of their life situation during the treatment period. The determinants of Health Related QoL may include the disease itself, the resulting disability and the type of intervention performed. For patients undergoing multimodal treatment for breast cancer, there are multiple factors that may impact HRQoL including the effects of the disease itself but also the toxic sequelae of cancer treatment, including CRTCD. QoL assessment is an important consideration when optimising a care pathway or intervention.

There is very little data reported on the impact that CTRCD has on HRQoL, with only qualitative data in small patient series, therefore there remains an unmet need to establish the current survivorship issues within patients who have developed CTRCD following treatment for breast cancer using current multimodal strategies.

Cardio-Oncology: The Irish Context Breast cancer management requires a careful balance of adequate and appropriate cancer treatment while minimising cardiac risk and other toxicities. Despite over 3,000 new patients being diagnosed and treated for breast cancer in the Republic of Ireland each year, the relationship between breast cancer treatment and cardiovascular health has never been extensively investigated.

Additionally, the scientific evidence upon which clinical decisions can be made is currently limited, with documented knowledge gaps in the area of Cardio-Oncology.

Consequently, there is a lack of data regarding cardio-oncological incidence, causative factors, and clinical and survivorship outcomes, which further highlights the necessity for a multidisciplinary approach to both research and clinical management of breast cancer patients. Therefore, the involvement of both Cardiology and Oncology specialists is essential in the delivery of care and long-term surveillance of breast cancer patients.

In Ireland, there is currently no established Cardio-Oncology clinical pathway or network which may enhance detection.

Moreover, there is limited data outlining the cardiovascular and survival outcomes in those being treated for breast cancer. Prior et al. recently described the competing risks of cardiovascular and oncological 10-year mortality in their recent analysis of 102 patients diagnosed and treated for stage I-III breast cancer who underwent resection with curative intent. Interestingly, the authors

report a decrease in CVD-related risk of mortality at 10-years from 26.5% to 9.9% in highrisk patients through risk factor optimisation. While these authors report predictive CVD outcomes in a small Irish cohort, there remains a paucity of data in relation to the risk of, biomarker prediction, and survivorship outcomes associated with CTRCD in Irish patients.

Furthermore, there remains a lack of established services dedicated to enhancing Cardio-Oncology patient care in the Republic of Ireland.

Informing the development of a Cardio-Oncology Clinical Network - European and International Guidelines The primary aim of establishing a Cardio-Oncology Clinical Network is to manage and optimise CVD in the cancer treatment-naïve patient, to minimise the risk of CTRCD, and to treat those who succumb to CTRCD as a sequalae of their cancer treatment. To achieve this, a multi-faceted, multi-disciplinary, and collaborative approach from several specialists is required and the preliminary data from the United Kingdom is overwhelmingly positive: Overall, 94% of the total number of cancer patients referred with left ventricular CTRCD observed an improved ejection fraction with appropriate therapies and 88% were fit to continue their treatment following intervention

by Cardio-Oncology services.

Therefore, it seems imperative that efforts are made in the Republic of Ireland to provide these services to our prospective cancer patients: Guidelines from the European Society of Cardiologists (ESC) recently outlined several template structures which Cardio-Oncology programs can be run, which encompass several local and regional circumstances. Interestingly, the ESC emphasize the importance of a tight-knit multi-disciplinary approach in developing and ensuring the provision of CardioOncology services to a region, irrespective of local infrastructure and resources. Ghosh et al. provide a concise review of their experience in establishing the Bart’s Heart Centre and University College London Hospital cardiooncology services in the United Kingdom. Similarly to the ESC, these authors highlight the value of the multi-disciplinary team in ensuring benchmark care, while emphasizing the clinical importance of research, clinical audit, education and training in ensuring the provision of the service to their population. These principles echo the fundamental philosophy outlined by the British Cardio-Oncology Society, which was established to enhance

cardio-oncological patient services in 2012. Finally, the American College of Cardiologists (ACC) provide an extensive review and guideline outlining the key stakeholders expected to partake in providing Cardio-Oncology services. The ACC demonstrate the necessity of Cardio-Oncologyspecific cardiologists, other cardiologists, oncologists, specialist nurses, research nurses, cardiac physiologists, secretarial support, and cardio-oncology management staff to ensure adequate provision of cardiooncology services in a centre of excellence. Of note, the ACC uses the Bart’s Heart Centre to exemplify the key requirements needed to establish CardioOncology clinic in a new centre.

Precision Cardio-Oncology Research Enterprise (P-CORE) The Precision Cardio-Oncology Research Enterprise (P-CORE) at NUIG is a multidisciplinary collaboration of cardiologists with specific expertise in advanced cardiac imaging which has the potential to identify early signs of CTRCD, working closely with surgical and medical oncologists responsible for biomarker discovery programmes to individualise breast cancer treatment delivery

and surveillance. The P-CORE principle investigators are as follows (Figure 2): Professor Aoife Lowery (Professor in Translational Research & Consultant Breast Surgeon), Professor Osama Soliman (Professor of Cardiovascular Research & Consultant Cardiologist), Professor William Wijns (Professor of Interventional Cardiology) and Professor Michael Kerin (Chair of Surgery and Managed Clinical and Academic Network Director).

References made available upon request from the Corresponding Author

Figure 2: Principle investigators from the Precision Cardio-Oncology Research Enterprise (P-CORE) at the National University of Ireland, Galway (NUIG). Clockwise from top: Professor Michael Kerin, Chair and Professor of Surgery at NUIG; Professor Aoife Lowery, Associate Professor of Surgery at NUIG; Professor William Wijns, Professor of Interventional Cardiology at NUIG; and Professor Osama Soliman, Professor of Cardiovascular Research at NUIG.

Figure 2. Principle investigators from the Precision Cardio-Oncology Research Enterprise (P HOSPITALPROFESSIONALNEWS.IE | HPN • FEBRUARY 2022 | 55

CORE) at the National University of Ireland, Galway (NUIG). Clockwise from top: Professo

weeks. Early results of a phase II trial using extreme hypofractionation in the for ablative radiotherapy (8x 5Gy) has given promising results for pathological respo control, but longer term follow up is required to assess the impact on late toxici introduction into routine clinical practice.

SARCOMA

Treatment De-escalation- Reports for myxoid liposarcoma have consistently sho radiation sensitivity characterised by marked tumour volume reduction during r excellent local control rates. A dose reduction of (18x2Gy) is now being investiga liposarcoma in a multi-centre prospective phase II clinical trial. This deviation fro Written by Dr Ronan Joyce, Radiation Oncology Specialist Registrar, St Luke’s Radiation Oncology Network, Dublin & dose escalation and hypofractionation Dr Charles Gillham, Consultant common Radiation Oncologist, St Luke’s Radiation Oncology Network,studies Dublin in STS highlights the diff significant heterogeneity of STS subtypes.

Modern Management of Soft Tissue Sarcoma

Dr Ronan Joyce Introduction Soft tissue sarcomas (STS) are mesenchymally derived malignant tumours that can arise almost anywhere in the body. In Ireland, approximately 200 patients are diagnosed with (STS) each year. The prognosis of these rare tumours in Ireland is approximately 50-60% at 5 years. This is comparable to other major European and North American centres and is not dissimilar, for example, to more common cancers such as those of the colorectum.

STS consists of a group of diseases which includes many histological subtypes with specific characteristics reflective of underlying differences in biology, genetics, clinical behaviour and/or sensitivity to treatment. This large heterogenous group of tumours with over 50 distinct subtypes can be broadly classified under the morphological headings of leiomyosarcoma, liposarcoma, fibrosarcoma, synovial sarcoma, rhabdomyosarcoma, angiosarcoma, nerve sheath tumours and malignant phyllodes tumours.

to warrant further investigation

tumours in whom wide margins

Patient’s suspected of having a STS should be investigated first with MRI and/or ultrasound and discussed with a specialist multidisciplinary team. If a sarcoma is suspected a diagnostic core biopsy should be performed by someone experienced in investigating these tumours. Incomplete excision of a STS carries a greater risk of local and distant recurrence.

local control and overall survival do not differ for pre and post operative radiotherapy. Due to the higher radiotherapy dose and generally larger treatment fields required post-operatively there is a significant difference in rates of late toxicities such as fibrosis, arthrosis and oedema and an overall diminished functional outcome compared to pre-operative RT. It is generally accepted that pre-operative RT results in an increased risk of wound complications postoperatively and this fact has led to some reticence in the widespread adoption of pre-operative RT. However, the acute post-operative complications are generally temporary whereas the potential decreased functional morbidity which is more prevalent following

Retroperitoneal Sarcoma- ifInit measures contrast tothan STS of the extremities the efficacy of rad more 5cm, are easily achievable. is deep to the fascia and is (RT) - abdominal Absolute retroperitoneal sarcoma isenlarging. not established.

Rates ofRadiotherapy locoregional rec Symptoms are often risk of local recurrence following misdiagnosed as musculoskeletal surgical excision varies and the heterogeneity of retroperitoneal with different biological beh injuries or benign lumpssarcomas and as significantly between patients a result the time from symptoms and histological but treatment and oncologicaltorisks according to subtypes renderssubtypes a homogenous th diagnosis is typically 4-6 in most cases, radiotherapy is months. It is not unusual for given to reduce the risk of local difficult and explains the great variability outcome that has been observed.

Ra a general practitioner toin see relapse. Traditionally radiotherapy only or two new patients with a retroperitoneal tumours issarcoma sometimes difficult andasmaximal is given either a 5-week tumour d in their entire career. to achieve course pre-operatively (25 x Common tumour sites in order of operatively is optimal but decreasing at present this include isn’t being satisfactorily by co 2Gy) to the tumour orachieved a 6-6.5frequency the week course post-operatively extremities (45%), trunk (30%), radiotherapy techniques. The international STRASS (30-33 II trial plans tosurgical investigate th x 2Gy) to the visceral (19%), retroperitoneal bed. Published randomised data (15%) and head and neck (8%). operative chemotherapy for retroperitoneal STS. suggests that endpoints for Dr Charles Gillham

predominance. In most cases the cause of STS is unclear but known environmental risk factors include exposure to ionizing radiation, herbicides, thorotrast, chlorophenols, vinyl chloride and arsenic. Cancer predisposition syndromes like NF-1, familial retinoblastoma, Li-Fraumeni syndrome and Gardner’s syndrome confer an increased risk of STS but these are extremely rare.

Conclusion

Soft tissue sarcomas are a rare group of tumours characterised by enormous va presentation, pathology, treatment response and prognosis. The one size fits all sarcoma management is becoming antiquated in the modern era of personalise Management many cancer sites. Rare tumours in general Surgery- Localised STS is asuffer from a lack of high-quality lev potentially curable disease and as such there has been relatively little change to the standard practices in sarcom surgical resection is the mainstay Presentation of treatment. Limb sparing surgery the past 2 decades in comparison to the more common cancer sites. Increasing in expert hands has largely Patient’s typically present with a replaced the need for amputation. painless mass.

This, of course, surgical expertise, advanced radiotherapy techniques, improved systemic option Surgical resection alone is is dependent on the site in which they develop.

A lump should be adequate patients of two multidisciplinary units (St for Vincent’s Hospital, Dublin and University Colleg regarded as suspicious enough with superficial and/or small helping to optimise the standard of care for patients with sarcoma in Ireland.

Epidemiology The median age at presentation is 40-60 years with a slight male

Figure 1a/b: Axial and Coronal MRI T1 Contrast images highlight a large pleiomorphic sarcoma of the distal left thigh

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In treating a broad range of women with HR+/HER2- mBC:1

CONFIDENCE

BUILT ON STRENGTH STRENGTH FROM… Powerful clinical efficacy1 Real-world experience2 Patient-reported outcomes3 Established safety profile1 One scheduled monitoring provision1 One capsule, Once daily1 Indications: IBRANCE® is indicated for the treatment of HR+/HER2- locally advanced or mBC:1 • In combination with an AI • In combination with fulvestrant in women who have received prior ET • In pre- or peri-menopausal women, the ET should be combined with an LHRH agonist For more information visit www.pfizerpro.ie/product/ibrance IBRANCE® (PALBOCICLIB) PRESCRIBING INFORMATION: Please refer to the Summary of Product Characteristics (SmPC) before prescribing IBRANCE 75 mg, 100 mg or 125 mg hard capsules.

Presentation: Hard capsules containing 75 mg, 100 mg or 125 mg palbociclib. Indications: Treatment of hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced or metastatic breast cancer: in combination with an aromatase inhibitor; or in combination with fulvestrant in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinizing hormone releasing hormone (LHRH) agonist. Dosage: Therapy should be initiated and supervised by a physician experienced in the administration of anti-cancer medicinal products. The recommended dose is 125 mg of palbociclib once daily for 21 consecutive days followed by 7 days off treatment (Schedule 3/1) to comprise a complete cycle of 28 days.

When coadministered with palbociclib, the aromatase inhibitor should be administered according to the dose schedule reported in the SmPC. Treatment of pre/perimenopausal women with the combination of palbociclib plus letrozole should always be combined with an LHRH agonist (see SmPC section 4.4). Capsules should be swallowed (should not be chewed, crushed, or opened prior to swallowing). They should be taken with food, preferably a meal to ensure consistent palbociclib exposure (see SmPC section 5.2). Palbociclib should not be taken with grapefruit or grapefruit juice (see SmPC section 4.5). Dose modification of IBRANCE is recommended based on individual safety and tolerability.

Management of some adverse reactions may require temporary dose interruptions/delays, and/or dose reductions, or permanent discontinuation. For dose reduction guidelines for management of adverse reactions, haematologic and non-haematologic toxicities, refer to SmPC section 4.2. IBRANCE should be permanently discontinued in patients with severe interstitial lung disease (ILD)/pneumonitis.

For patients who experience a maximum of Grade 1 or 2 neutropenia in the first 6 cycles, complete blood counts for subsequent cycles should be monitored every 3 months, prior to the beginning of a cycle and as clinically indicated. No dose adjustments of IBRANCE are required for patients with mild or moderate hepatic impairment (Child-Pugh classes A and B). For patients with severe hepatic impairment (Child-Pugh class C), the recommended dose of IBRANCE is 75 mg once daily on Schedule 3/1 (see SmPC section 5.2). No dose adjustments of IBRANCE are required for patients with mild, moderate or severe renal impairment (creatinine clearance [CrCl] ≥15 mL/min) (see SmPC section 5.2). No dose adjustment of IBRANCE is necessary in patients ≥65 years of age (see section 5.2). Contraindications: Hypersensitivity to the active substance or to any of the excipients (see SmPC section 6.1), use of preparations containing St. John’s Wort

(see SmPC section 4.5). Warnings and Precautions: Ovarian ablation or suppression with an LHRH agonist is mandatory when pre/ perimenopausal women are administered IBRANCE in combination with an aromatase inhibitor, due to the mechanism of action of aromatase inhibitors. Palbociclib in combination with fulvestrant in pre/perimenopausal women has only been studied in combination with an LHRH agonist. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia. Appropriate monitoring should be performed (see SmPC sections 4.2 and 4.8). Severe, life-threatening, or fatal ILD and/or pneumonitis can occur in patients treated with cyclin dependent kinase 4/6 (CDK4/6) inhibitors, including IBRANCE when taken in combination with endocrine therapy. Across clinical studies (PALOMA-1, PALOMA-2, PALOMA-3), 1.4% of IBRANCE-treated patients had ILD/ pneumonitis of any grade, 0.1% had Grade 3, and no Grade 4 or fatal cases were reported. Additional cases of ILD/pneumonitis have been observed in the post-marketing setting, with fatalities reported.

Patients should be monitored for pulmonary symptoms and IBRANCE treatment should be immediately interrupted in patients suspected to have developed ILD/pneumonitis, see SmPC section 4.2, 4.4 and 4.8. Since IBRANCE has myelosuppressive properties, it may predispose patients to infections. Infections have been reported at a higher rate in patients treated with IBRANCE in randomised clinical studies compared to patients treated in the respective comparator arm. Grade 3 and Grade 4 infections occurred respectively in 5.6% and 0.9% of patients treated with IBRANCE in any combination (see SmPC section 4.8). Patients should be monitored for signs and symptoms of infection and treated as medically appropriate (see SmPC section 4.2). Physicians should inform patients to promptly report any episodes of fever.

Strong inhibitors of CYP3A4 may lead to increased toxicity (see SmPC section 4.5). Avoid concomitant use of strong CYP3A inhibitors during treatment with palbociclib. Coadministration should only be considered after careful evaluation of the potential benefits and risks. If coadministration with a strong CYP3A inhibitor is unavoidable, reduce the IBRANCE dose to 75 mg once daily. When the strong inhibitor is discontinued, the dose of IBRANCE should be increased (after 3–5 halflives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor (see SmPC section 4.5). Coadministration of CYP3A inducers may lead to decreased palbociclib exposure and consequently a risk for lack of efficacy. Therefore, concomitant use of palbociclib with strong CYP3A4 inducers should be avoided. No dose adjustments are required for coadministration of palbociclib with moderate CYP3A inducers (see SmPC section 4.5). Women of childbearing potential or their male partners must use a highly effective method

of contraception while taking IBRANCE (see SmPC section 4.6). IBRANCE contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product. Drug Interactions: The concomitant use of strong CYP3A inhibitors including, but not limited to: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice, should be avoided (see sections 4.2 and 4.4). No dose adjustments are needed for mild and moderate CYP3A inhibitors. The concomitant use of strong CYP3A inducers including, but not limited to: carbamazepine, enzalutamide, phenytoin, rifampin, and St. John’s Wort should be avoided (see SmPC sections 4.3 and 4.4). No dose adjustments are required for moderate CYP3A inducers. The dose of sensitive CYP3A substrates with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) may need to be reduced when coadministered with IBRANCE as IBRANCE may increase their exposure. Based on in vitro data, palbociclib is predicted to inhibit intestinal P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) mediated transport. Therefore, administration of palbociclib with medicinal products that are substrates of P-gp (e.g., digoxin, dabigatran, colchicine, pravastatin) or BCRP (e.g., rosuvastatin, sulfasalazine) may increase their therapeutic effect and adverse reactions. Based on in vitro data, palbociclib may inhibit the uptake transporter organic cationic transporter OCT1 and then may increase the exposure of medical product substrates of this transporter (e.g., metformin). Pregnancy & Lactation: Females of childbearing potential who are receiving this medicinal product, or their male partners should use adequate contraceptive methods (e.g., doublebarrier contraception) during therapy and for at least 3 weeks or 14 weeks after completing therapy for females and males, respectively (see SmPC section 4.5). There are no or limited amount of data from the use of palbociclib in pregnant women. Studies in animals have shown reproductive toxicity (see SmPC section 5.3). IBRANCE is not recommended during pregnancy and in women of childbearing potential not using contraception. Based on male reproductive organ findings (seminiferous tubule degeneration in testis, epididymal hypospermia, lower sperm motility and density, and decreased prostate secretion) in nonclinical safety studies, male fertility may be compromised by treatment with palbociclib (see SmPC section 5.3). Thus, men may consider sperm preservation prior to beginning therapy with IBRANCE. Driving and Operating Machinery: IBRANCE may cause fatigue and patients should exercise caution when driving

PP-IBR-IRL-0429 | Date of preparation: July 2021

or using machines. Side Effects: The most common (≥20%) adverse reactions of any grade reported in patients receiving palbociclib in randomised clinical studies were neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anaemia, diarrhoea, alopecia, and thrombocytopenia. The most common (≥2%) Grade ≥3 adverse reactions of palbociclib were neutropenia, leukopenia, anaemia, fatigue, infections, alanine aminotransferase (ALT) increased and aspartate aminotransferase (AST) increased. Dose reductions or dose modifications due to any adverse reaction occurred in 38.4% of patients receiving IBRANCE in randomised clinical studies regardless of the combination. Very common adverse events (>1/10) are neutropenia, infections, leukopenia, fatigue, anaemia, asthenia, pyrexia, nausea, stomatitis, alopecia, diarrhoea, thrombocytopenia, vomiting, rash, decreased appetite, dry skin, AST increased, ALT increased and aspartate aminotransferase (AST) increased. Commonly reported adverse events (>1/100 to <1/10), are, dysgeusia, epistaxis, ILD/pneumonitis, lacrimation increased, vision blurred, dry eye, febrile neutropenia.

Refer to SmPC for further information on side effects. Refer to section 4.8 of the SmPC for further information on side effects, including description of selected adverse reactions. Legal Category: S1A. Marketing Authorisation Numbers: EU/1/16/1147/001 – 75 mg (21 capsules); EU/1/16/1147/003 – 100 mg (21 capsules); EU/1/16/1147/005 – 125 mg (21 capsules). Marketing Authorisation Holder: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium. For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at EUMEDINFO@pfizer. com. For queries regarding product availability please contact: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 + 353 1 4676500.

Last revised: 07/2021 Ref: IB 9_0 References: 1. IBRANCE® Summary of Product Characteristics.

2. Taylor-Stokes G, et al. Breast. 2019;43:22-27. 3. Rugo HS,et al. Ann Oncol. 2018;29(4):888-894.

AI = aromatase inhibitor; ET = endocrine therapy; HR+/HER2- = hormone receptor-positive, human epidermal growth factor receptor 2-negative; LHRH = luteinising hormone releasing hormone; mBC = metastatic breast cancer; SmPC = summary of product characteristics.

SARCOMA post-op RT is typically permanent and can significantly impact a patient’s quality of life.

Systemic Therapy: There is a more limited role for systemic treatment in localised STS at present. Historical randomised trials that included chemotherapy pre-operatively, concurrently with RT or post-operatively have shown modest improvements in oncological outcomes but some increased toxicity risks.

Chemotherapy trials are restricted by the relative paucity of eligible patients and histology dependent chemo-sensitivity of individual tumours. As such chemotherapy is generally reserved for patients with metastatic disease. However, it may be considered as induction therapy if tumour downsizing is necessary to facilitate radiotherapy or surgical resection for unfavourably located tumours and for those histologies that are known to be more chemosensitive.

Recent Advances and Future Developments Image Guided Intensity Modulated Radiotherapy (IGIMRT) - Increasingly more cancer subsites are benefiting from highly conformal image-guided radiotherapy techniques that can more precisely deliver high-dose radiation to the tumour while better avoiding normal tissue.

Historically radiotherapy planning for STS employs large expansions on the tumour to account for subclinical microscopic disease

and patient and limb movement.

There is promising recent prospective data suggesting more favourable acute and late toxicity in patients with STS treated with pre-operative IGIMRT using more conservative target volumes. Importantly there doesn’t seem to be any negative impact on oncological outcomes but larger scale randomised data are necessary before widespread changes to target volume delineation in STS are to be adopted.

Targeted Systemic Therapy The management of many cancers has changed significantly over the last 15 years with the increasing use of highly targeted anti-cancer therapies. In STS the VEGF receptor and c-Kit pathways are commonly dysregulated. The multitargeted tyrosine kinase inhibitor pazopanib has been shown to improve outcomes in patients with advanced/metastatic STS. The introduction of pazopanib earlier in the treatment paradigm for localized STS is currently under investigation.

There is promising phase 2 data supporting its addition to neo-adjuvant chemotherapy to improve pathological response rates and potentially local control rates. STS prognosis however is dictated by distant failure risk and larger patient numbers are often necessary for clinical trials to detect significant differences in overall survival and other significant oncological endpoints.

Stereotactic Radiotherapy Globally, across cancer sites there is a trend to shorten radiotherapy schedules by hypofractionating treatments. The introduction of these highly conformal techniques has facilitated this but there have also been radiobiological developments supporting the move towards shorter treatments particularly in breast and prostate cancer. As such some of these cancers are inherently more susceptible to radiotherapy regimes that employ a higher dose per fraction delivered over a shorter time. Emerging data suggests that certain STS subtypes may potentially benefit from hypofractionated regimes.

This would obviously be more convenient for patients who would otherwise need to attend a radiotherapy department for five consecutive weeks. Early results of a phase II trial using extreme hypofractionation in the form of stereotactic ablative radiotherapy (8x 5Gy) has given promising results for pathological response rates and local control, but longer term follow up is required to assess the impact on late toxicity before introduction into routine clinical practice.

prospective phase II clinical trial.

This deviation from the more common dose escalation and hypofractionation studies in STS highlights the difficulties posed by the significant heterogeneity of STS subtypes.

Treatment De-escalation Reports for myxoid liposarcoma have consistently shown exquisite radiation sensitivity characterised by marked tumour volume reduction during radiotherapy and excellent local control rates.

A dose reduction of (18x2Gy) is now being investigated for myxoid liposarcoma in a multi-centre

Conclusion

Retroperitoneal Sarcoma - In contrast to STS of the extremities the efficacy of radiotherapy for retroperitoneal sarcoma is not established. Rates of locoregional abdominal recurrences can be high and the heterogeneity of retroperitoneal sarcomas with different biological behaviour, response to treatment and oncological risks according to subtypes renders a homogenous therapeutic approach difficult and explains the great variability in outcome that has been observed. Radical resection of retroperitoneal tumours is sometimes difficult to achieve and maximal tumour downstaging pre-operatively is optimal but at present this isn’t being satisfactorily achieved by conventional radiotherapy techniques. The international STRASS II trial plans to investigate the role of pre-operative chemotherapy for retroperitoneal STS.

Soft tissue sarcomas are a rare group of tumours characterised by enormous variation in presentation, pathology, treatment response and prognosis. The one size fits all approach to sarcoma management is becoming antiquated in the modern era of personalised medicine for so many cancer sites. Rare tumours in general suffer from a lack of high-quality level one evidence and as such there has been relatively little change to the standard practices in sarcoma management in the past 2 decades in comparison to the more common cancer sites.

Increasing site specialisation, surgical expertise, advanced radiotherapy techniques, improved systemic options and the evolution of two multidisciplinary units (St Vincent’s Hospital, Dublin and University College Hospital, Cork) are helping to optimise the standard of care for patients with sarcoma in Ireland.

Figure 2: Highly conformal dose distribution for VMAT plan for lower limb soft tissue sarcoma

| HOSPITALPROFESSIONALNEWS.IE 58 | FEBRUARY 2022 • HPN Figure 2: Highly conformal dose distribution for VMAT plan for lower limb soft tissue sarcoma.

▼

CAR-T Cell Therapy

I AM KYMRIAH Kymriah is indicated for the treatment of: 1 – Paediatric and young adult patients up to and including 25 years of age with B-cell acute lymphoblastic leukaemia (ALL) that is refractory, in relapse post-transplant or in second or later relapse.

– Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy.

Further information is available upon request by contacting Novartis Ireland Ltd. on 01 260 1255 Full prescribing information available via the Kymriah SmPC at www.medicines.ie Reference: 1. Kymriah [summary of product characteristics] https://www.medicines.ie/medicines/kymriah-1-2-x-106-6-x-108-cells-dispersion-for-infusion-34945/spc ▼This medicinal product is subject to additional monitoring. Reporting suspected adverse reactions of the medicinal product is important to Novartis and the HPRA. It allows continued monitoring of the benefit/risk profile of the medicinal product. All suspected adverse reactions should be reported via HPRA Pharmacovigilance, website www.hpra.ie. Adverse events could also be reported to Novartis preferably via www.report.novartis.com or by email: drugsafety.dublin@novartis.com or by calling 01 2080 612.

Novartis Ireland Ltd., The Vista Building, Elm Park Business Pk., Merrion Road, Dublin 4, D04 A9N6

POM

7 April 2021 | 115416

REHABILITATION

Can-React: A personalised at-home exercise programme, supporting long-term survivorship and rehabilitation needs of cancer patients Dr Ananya Gupta, Director of Exercise Physiology, NUI Galway

Cancer treatments have many adverse effects on patients’ health leading to reduced healthrelated quality of life (HRQoL).

The National-Cancer-Strategy (2017-2026) emphasises the need for effective management of post-treatment health issues for improvement in HRQoL. Improved treatment and supportive cancer care has led to increased life expectancy for cancer survivors.

Cancer is a chronic disease as

survivors experience long-term adverse physical/psychological side-effects. Exercise therapy can significantly contribute to restoration by increasing functional capacity. An exercise programme that combines aerobic, resistance and flexibility exercises and is tailored to individual needs, can have a significant positive impact on patients’ health and HRQoL. The NUI Galway team, led by Dr Ananya Gupta (Director of Exercise Physiology, NUI Galway), have developed and implemented a ’personalised‘ patient-centred cancer exercise programme [Can-React] based on international guidelines. This programme was launched in 2019 and the first cohort consisting of 36 post-treatment breast

cancer patients participated in it. All the participants reported significant improvements in physical function and reduction in fatigue. All participants showed significant improvements in outcome measures, including cardiorespiratory fitness and muscle strength, balance, flexibility, mobility, reduced fatigue, and anxiety. All participants reported improved HRQoL, evaluated using a standard HRQoL questionnaire and scoring system.

In 2020 the ongoing coronavirusdisease pandemic (COVID-19) led to restrictions being imposed to prevent the spread of the SARSCov2 virus. These significantly disrupted cancer support services including the delivery of the Can-React exercise programme on NUI Galway campus. Cancer patients receiving or recovering from treatment are at high risk of COVID-19 infection-related

Figure 1: The Can-React Pathway: Diagrammatic representation of the Can-React patient care pathway.

The programme includes an online assessment followed by a personalised exercise prescription.

The programme aims to deliver the exercise programme via video chat and online instructions so that patients can attend from the safety of their home. The exercise programme includes a personalised exercise programme based on individual’s current exercise capacity and symptoms. This consists of appropriate combination of aerobic, resistance and flexibility training and is supported by nutritional advice and motivational support aimed to increase functional capacity and health-related quality of life (HRQoL).

The diagram shows the progress made by participants after signing up for the programme: baseline assessment, exercise prescription, exercise monitoring, exercise progression and adaption.

Can-React an “at-home” Personalised Exercise-Rehabilitation Programme for Cancer Survivors Recruitment of Study Participants Cancer Patients (all cancer types and treatment)

Qualitative Study – Focus group meetings/interview Understanding patient’s perspectives on post-treatment physical needs (Exercise and Rehabilitation needs)

Patients are grouped by cancer type

Patients participate in an online exercise test and assessment of physiologic parameters The measurement of these parameters help to determine patients current exercise capacity and fitness

Patients participate in a 12-week personalised exercise programme via supervised exercise sessions Patients receive a personalised exercise programme based on their current capacity, fitness and symptoms Progression in made based on individual responses to exercise

Participants use a mobile application and web-portal to receive instructions and monitor progress The mobile application and website support the delivery of the exercise programme, exercise instructions, progress reports, nutritional advice and motivational webinars

60 | FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

The Can-React a ‘Personalised’ Exercise Programme significantly improves patient’s Cardiorespiratory fitness and Muscle Strength

 Reduces Pain and Fatigue  Improves Flexibility and Balance  Improves Muscle strength  Improves Cardio-Respiratory fitness (CRF)  Improves Health Related Quality of Life (HRQoL) Muscle strength

morbidity and mortality and must self-isolate. This further impairs participation in physical activity essential to maintain health-related-fitness (HRF) and to manage side-effects of chronic disease. There is a need to develop alternative strategies to provide patient care without increasing the health risk. Homebased exercise provides an alternative for cancer survivors, that can overcome various accessibility hurdles. Of late delivery of “at-home” exercise interventions have become feasible, utilizing virtual platforms to deliver supervised exercise sessions and consultations.

Recent investigations of “athome” interventions have shown evidence of both safety and efficacy. Particularly during the current COVID-19 pandemic, such an alternative model of remote access is crucial for long-term support of cancer survivors.

Based on the preliminary faceto-face pilot study, Dr Gupta’s team of researchers at NUI Galway developed the can-react programme into an “at-home” personalised exercise programme for improving physical function and HRQoL in cancer survivors (https://www.nuigalway.ie/canreact/). This program involves an online assessment of patients’ health-related fitness, based on which the patient receives a personalised exercise programme consisting of aerobic, resistance and flexibility exercises aiming to improve cardiorespiratory capacity, muscle strength and range of motion and reduce cancer fatigue. The exercise programme is delivered through supervised one-to-one weekly online sessions for 12 weeks.

The participants are assessed at regular intervals and the exercise

intensity, type and duration are adapted based on the progress made (Figure 1). The efficacy and feasibility of this programme was evaluated in a preliminary study which concluded in December 2021. There were two cohorts consisting of 56 cancer patients recovering from mainly breast, ovarian, blood and colon cancer who participated in this programme from May to December 2021. These patients were located across Ireland and were able to take part in the programme remotely from their home. Patients wishing to participate in on campus evaluation and exercise were facilitated to do so. Of the 56 patients who completed the initial programme many have enrolled in an advance exercise programme for further 12 weeks.

The programme showed significant improvements in patients cardiorespiratory fitness, muscle strength, flexibility and balance.

The regular exercise as a part of Can-React helped to reduce pain and fatigue. Patients reported “sleeping better and feeling better”.

Patients participating in the Can-React programme showed significant improvements in all aspects of their physical function evaluated (Figure2). The most significant improvement was seen in muscle strength and flexibility. Patients also reported reduced pain and fatigue. The quality of life was assessed using a standard questionnaire and showed a marked improvement in HRQoL. The feedback received from patients highlighted the importance of the exercise programme being personalised.

Each participant is different and responds differently to disease and treatment. Therefore a “personalised” programme

CRF

HRQoL

Flexibility Balance

that assessed the individual’s needs, current side-effects and is adapted to their functional capacity and level of fitness was most beneficial. Also the programme was flexible and patients could progress based on the improvements made. This made it possible for patients to start slow and low without the fear of injury and progress at a level and pace that best suited them. Despite being online the weekly supervised sessions were a great source of motivation. The video instructions, personalised exercise brochures and other tools provided online and via emails was a useful guidance for patients to be exercising on their own at-home. The exercise physiologist was always available to answer questions and provide personalised support to the participants. This was a crucial aspect of the personalised program, as it allowed participants who may previously have been inactive, or have reduced activity due to treatment and disease side effects to regain confidence and motivation from achieving their “individualised” exercise target.

Dr Gupta and team found that home-based exercise interventions can be “equally effective” when compared with face-to-face interventions, if delivery is supported by proper technology and communication.

“Tele-rehabilitation” is a remote access monitoring system which includes telephone calls, text messages, mobile-health or smartphone based applications, web-based platforms, and videoconferencing. Although these interventions are becoming more widely explored in health care, their quality and effectiveness in exercise oncology, in supporting a

Figure 2: The Promising Results, The diagram represents the relative improvements seen in physiologic parameters amongst participants taking part in the Can-react at-home exercise programme.

home-based exercise programme, is not known. Can-react programme also evaluated the effectiveness of using currently available technology to deliver the various components of the exercise programme and to monitor progress made by participants remotely. Based on the feedback received from patients the NUI Galway team is currently developing a web-based application which in addition to delivery of the exercise intervention will also provide patients with information and resources for the better management of long-term sideeffects of cancer treatment.

The number of patients 'living with and beyond' cancer have increased significantly. While earlier detection and availability of targeted therapy has improved survival and longevity, it has led to the emergence of long- term effects of the disease leading to poor HRQoL. The ongoing COVID-19 pandemic has affected the delivery of cancer support through traditional in person services. The Can-React programme has demonstrated that a home-based personalised program for patients with cancer while maintaining the benefits of targeted and high-fidelity exercise medicine is both effective and feasible in the given circumstances.

In the words of a patient advocate and participant: “The personalised approach of the Can-React programme provided me with the timely support and guidance needed to perform exercise safely.

I feel the benefits in my daily life, I feel I have more energy to do my day to day chores.”

HOSPITALPROFESSIONALNEWS.IE | HPN • FEBRUARY 2022 | 61

GYNAECOLOGICAL CANCER

An Overview of Gynaecological Cancers Figure 1. Website www.thisisGO.ie as part of the Women’s Health Initiative in an attempt to improve earlier diagnosis. (Figure 3).

Ovarian cancer comprises a wide variety of different histopathological subtypes, all of which behave different, have specific associated features and widely varied management algorithms. The most common Written by Dr Dearbhaile Collins, type is high grade serous Consultant Medical Oncologist, ovarian cancer (HGSOC), Cork University Hospital and Senior but endometrioid, clear cell, Lecturer in Cancer Research, mucinous, low grade serous University College Cork and carcinosarcoma can also occur. In addition, germ cell tumours and sex cord stromal tumours can also develop. Each of the pathological subtypes Gynaecological cancers comprise Figure website www.thisisGO.ie offers continue to call 1. Website www.thisisGO.ie as part of theNevertheless, Women’s Healthwe Initiative have been shown to have very a one-stop-shop for pertinent tubo-ovarian, endometrial, it ovarian cancer from habit and diverse molecular and mutational resources cervical, vulval and vaginal ease. It is a disease that generally Ovarian cancerand professional advice on cervical cancer of and includes cancers. This article sets out to in evidence few symptoms its early Traditionally considered purely ovarian origin,results but recent suggests aatfallopian tube profiles underlying the distinct behaviours and biologies of these overfor 130 and audio give an overview on the three most source often only causes signs thearticles, malignantvideos cells. Thus, this cancerstages is moreand appropriately termed tubo-ovarian content (Figure 1). The cervical common types of gynaecological cancer, and symptoms advanced and that cancer subtypes. For example, but we continue to call it ovarian cancer from habit and at ease.

It is a disease cancerresults programme was launched cancers (ovarian, endometrial, ultimately generally in few symptoms at its early stages and often incurable only causesstages. signs andThe symptoms high grade serous ovarian cancer on Worldand Gynaecological Oncology at advanced ultimately incurable stages. The National Cancer Registry IrelandIreland (NCRI) data usually results from loss of the cervical) and their common National Cancer Registry day)aton tumour suppressor TP53, whereas ovarian cancerDay and(GO its stage diagnosis is illustrated Figure treatment strategies in addition to on Awareness (NCRI)indata on2.ovarian cancer and Monday September 20th 2021, mucinous ovarian cancers, often recent research breakthroughs & its stage at diagnosis is illustrated with the ovarian cancer programme have KRAS and BRAF mutations practice-changing trials. below in Figure 2. planning for launch in February and indeed behave more akin A first-of-its-kind website for Despite much research 2022. Patients with gynaecological to colorectal cancers. Clear cell patients with gynaecological attempting to identify ovarian cancers can be directed to this cancers display PIK3CA mutations cancers has been developed cancer at an earlier stage, no website at all stages in their and ARID1A and PTEN loss. through an Irish Cancer Society effective screening tool(s) has cancer journey and the platform They are also strongly associated personalizes the resources grant, the Women’ Health been identified that impacts on with thromboembolic events. available to the patient themselves Initiative, in addition to further patient survival, including the Translational laboratory research in a safe and accurate way. funding from Pfizer. The project use of the serum cancer marker led by Dr Sharon O’Toole and led by Professor Donal Brennan, Ca125. There have been multiple Figure 2. National Cancer Registry Ireland (NCRI) data regarding incidence and diagnostic Ovarian cancer Mater Misericordiae University awareness programmes globally stage of ovarian cancer in Ireland, available at www.ncri.ie Hospital and Ms Yvonne O’Meara, to encourage women to recognise Traditionally considered of purely Figure 2. National Cancer Registry University College Dublin, is the most common symptoms ovarian origin, recent evidence Ireland (NCRI) data regarding developing a relevant, reliable of ovarian cancer including the suggests a fallopian tube source incidence and diagnostic stage of and evidence-based information BEAT symptoms of abdominal for the malignant cells. Thus, ovarian cancer in Ireland, available 2 platform for patients with swelling or bloating, pelvic pain, this cancer is more appropriately at www.ncri.ie gynaecological cancers. The loss of appetite or constipation termed tubo-ovarian cancer.

Figure 1. Website www.thisisGO.ie as part of the Women’s Health Initiative

Ovarian cancer

Traditionally considered of purely ovarian origin, but recent evidence suggests a fallopian tube source for the malignant cells. Thus, this cancer is more appropriately termed tubo-ovarian cancer, but we continue to call it ovarian cancer from habit and ease. It is a disease that generally results in few symptoms at its early stages and often only causes signs and symptoms at advanced and ultimately incurable stages. The National Cancer Registry Ireland (NCRI) data on ovarian cancer and its stage at diagnosis is illustrated in Figure 2.

Figure 2. National Cancer Registry Ireland (NCRI) data regarding incidence and diagnostic stage of ovarian in Ireland, available at www.ncri.ie 62 | FEBRUARY 2022 • HPN |cancer HOSPITALPROFESSIONALNEWS.IE

encourage women to recognise the most common symptoms of ovarian cancer including the BEAT symptoms of abdominal swelling or bloating, pelvic pain, loss of appetite or constipation (Figure 3).

Figure 3. The BEAT symptoms of ovarian cancer

Figure 3. The BEAT symptoms of ovarian cancer Dr Lucy Norris in St James’ Surgery remains the mainstay Hospital sets out to better identify

of treatment for most ovarian

female), ovarian cancer, prostate cancer, pancreatic cancer and melanoma among others. There are other, more rare inherited diseases that can increase ovarian cancer risk including Lynch syndrome and a myriad of others, so a significant family history should continue to be investigated by an oncogenetics specialist irrespective of BRCA status. A recent Irish-led Cancer Trials Ireland study, tBRCA, led

by Professor Bryan Hennessey, Beaumont Hospital, and Dr Roshni Kalachand, University Hospital Limerick, enrolled 200 Irish patients with a diagnosis of high grade serous or endometrioid cancer and performed BRCA analysis. We hope to see the results of this study this year.

This trial laid the framework for the National Cancer Control Programme (NCCP) reflex diagnostic testing of blood and tumour tissue for BRCA mutations in Ireland. Thus, all Irish patients with high grade serous or endometrioid ovarian cancer, irrespective of family history or age, treated in HSE hospitals are tested at diagnosis for these BRCA mutations.

ongoing controversy whether surgery should be performed first or after some chemotherapy, there is no definite evidence supporting either strategy at the present and a randomized clinical trial known as the TRUST trial will likely publish initial results in 2022 to answer this critical question once and for all. Further attempts at surgical resection upon cancer recurrence can be considered, in line with the results from some clinical trials including DESKTOP III. However, this may not be appropriate or suitable for all patients and should be decided with a multidisciplinary discussion.

The role of hyperthermic intraperitoneal chemotherapy (HIPEC) also remains controversial.

Professor Donal Brennan, Mater Misericordiae Hospital has recently opened the OVHIPEC-2 clinical trial in partnership with European gynaecological surgery colleagues to better understand what role HIPEC plays in this cancer type.

compounds, most commonly pegylated liposomal doxorubicin (Caelyx®) and gemcitabine.

Different subtypes of ovarian cancers having varying degrees of sensitivity to this platinum doublet regimen. High grade serous and endometrioid cancers exhibit the most sensitivity to chemotherapy, with clear cell, mucinous, low grade serous and carcinosarcoma having much lower response rates to chemotherapy. Ovarian cancers are common defined by their response to chemotherapy and the terms “platinum sensitive” and “platinum resistant” have been coined. These terms have direct therapeutic and prognostic implications. Platinum sensitive cancers have responded to the prior platinum-based chemotherapy regimen and have not relapsed before 6 months after cessation of chemotherapy.

Cancers that relapse or recur before this or during chemotherapy are considered to have lost sensitivity to the platinum agent and are thus termed “platinumresistant”. These cancers are more challenging to treat and often have less sensitivity to other chemotherapies and all other therapeutic attempts.

damage repair pathway and thus are effective in cancer cells with a pre-existing deficiency in these pathways, such as those with BRCA mutations in addition to a variety of other abnormalities.

There are now a number of PARP inhibitors available for use as maintenance treatment for ovarian cancer that has responded to chemotherapy strategies. While these oral agents are generally well tolerated, they do have a number of side effects that require regular monitoring and clinician awareness. They often cause fatigue and nausea, in addition to anaemia, lymphopaenia and thrombocytopenia. Rare toxicities, in the order of 1% incidence, include pneumonitis, an inflammation of the lungs, and myelodysplasia, a dysfunction of the bone marrow with consequent risk of the development of acute leukaemia.

Patients require monthly blood tests for the duration of their maintenance treatment to aid early identification of the development of myelodysplasia. Endocrine therapies also play a role in ovarian cancer, most commonly aromatase inhibitors and have been shown to delay time to disease progression in certain ovarian cancer sybtypes.

Low grade serous ovarian cancers are exquisitely sensitive to hormonal therapies. Indeed, the benefit of chemotherapy at all in this cohort of cancers is questionable. Dr Karen Cadoo, Consultant Medical Oncologist, St James’ Hospital will be the Irish and European lead on a global trial in low grade serous ovarian cancer to answer this question. This study will be delivered through Cancer Trials Ireland with the support of the Friends of Cancer Trials Ireland fundraising achievements.

with the overriding goal reasons for this increased risk of Ovarian comprises acancers wide variety of different histopathological subtypes, all of which being complete cytoreduction clotting andcancer ways in which we can or resection of all visible cancer. and widely varied management algorithms. improve patient care and reduce behave different, have specific associated features Patient survival and outcome thromboembolic risk in the future.

The most common type is high grade serous ovarian cancer (HGSOC), but endometrioid, clear has been directly linked to the High grade serous and amount of cancer remaining cell, mucinous, low grade serous carcinosarcoma can also occur. In addition, germ cell endometrioid ovarian cancers can at the end and of surgical removal. be associated with an inherited Thus the importance of surgeon tumours and sex cord stromal tumours can also develop.

Each of the pathological subtypes risk. Approximately 20% of these expertise and high throughput cancers are linked with BRCA1 or very have been shown to have diverse and mutational profiles underlying the distinct cancer centres molecular performing these 2 mutations. This is an autosomal operations is imperative to better behaviours andresulting biologies theseoutcome. cancer subtypes. For example, high grade serous ovarian dominant mutation in loss of patient’s In some of the BRCA tumour suppressor chemotherapy-sensitive subtypes cancer usually results from loss of the tumour suppressor TP53, whereas mucinous ovarian genes. Loss or dysfunction of of ovarian cancer, preoperative or cancers, KRAS neoadjuvant and BRAF mutations and indeed behave more akin to colorectal these genesoften leads tohave abnormal chemotherapy, usually functioning of our innate DNA platinum-based regimen, is given cancers.

Clear celland cancers display PIK3CA mutations and ARID1A and PTEN loss. They are damage repair pathways prior to surgery. The goal of this ultimately increased risk of pre-surgery chemotherapy strategy a general rule, thelaboratory earlier the also strongly associated with thromboembolic events. As Translational research led by cancer development. BRCAis to improve the gynaecological cancer is diagnosed and resected Dr Sharon O’Toole and Dr Lucy Norris in St James’ Hospital sets out to better identify reasons associated cancers can impact surgeon’s chances of resecting the greater the chance of a cancer all the cancer by reducing the women and men and are most cure.

As ovarian cancer often for this increased risk and ways in which we can improve patient care in the future. disease burden. While there is frequently breast cancer (male and presents at a more advanced stage, the disease is unlikely to

be cured at FIGO stage III and IV. High grade serous and endometrioid ovarian cancers can bebetter associated It is thus thought ofwith as a an inherited risk. relapsing remitting disease with Approximately 20% of these cancers are linked with BRCA1 or 2 mutations.

This is an widely variable remission periods, from shorttumour months tosuppressor long years, autosomal dominant mutation resulting in loss of the BRCA genes. Loss or and chemotherapy required during dysfunction of these genes leads to abnormal functioning of stages. our innate DNA damage repair the relapse pathways and ultimately increased risk of cancer development.

BRCA-associated cancers Maintenance therapies have There are othercan novel treatments become a popular addition to the in development in ovarian cancer. impact women and men and are most frequently breast cancer (male and female), ovarian management of ovarian cancer Notably Ireland has been involved for the purpose others. of prolonging the are in studies the SeaGen cancer, prostate cancer, pancreatic cancer and melanoma among There other,with more remission period, and delaying compound, tisotumab vedotin, rare inherited diseases that can increase ovarian cancer Lynch syndrome andanda ovarian the risk time toincluding cancer recurrence, in both cervical thus improving patientto survival. cancer. SGNTV-002 myriad of others, so a significant family history should continue be investigated by an was led by Dr The antiangiogenic agent, Dearbhaile Collins, Cork University oncogenetics specialist irrespective of BRCA status. A recent Irish-led Trials Ireland bevacizumab (Avastin®) is Cancer used, Hospital and recruited platinum most commonly, in patients with resistant ovarian cancer patients. study, tBRCA, led by Professor Bryan Hennessey,incompletely Beaumont Hospital, andAnother Dr agent, Roshni resected ovarian mirvetuximab cancer and/or those where sorvantansine is a folate receptor Kalachand, University Hospital Limerick, enrolled 200 Irish patients with a diagnosis of high recurrent ascites becomes a alpha (FRa) antagonist developed grade serous or endometrioid cancer and performed BRCA We hope to see the results clinical analysis. problem. Bevacizumab

by Immunogen.

Irish patients have

Chemotherapy for the majority of gynaecological cancers comprises a platinum, usually carboplatin and in the initial setting, a taxane, usually paclitaxel. Further regimens add carboplatin to a variety of

commonly causes fatigue, hypertension in 20% of recipients and proteinuria requiring regular urine testing. Rarely, it can lead to fistula formation or gastrointestinal perforation. It also increases the risk of bleeding and arteriovenous thromboembolic events. Most recently PARP inhibitors have entered the armamentarium in this cancer subtype. PARP inhibitors target another arm of the DNA

had the opportunity to access the FORWARD1 and most recently SORAYA clinical trials, both under the leadership of Dr Conleth Murphy, Bons Secours Hospital, Cork. Further clinical trials with this compound are in development and will be available in 2022. Clinical trials available in cancers in Ireland are available for review on the Cancer Trials Ireland website www.cancertrials.ie.

3

HOSPITALPROFESSIONALNEWS.IE | HPN • FEBRUARY 2022 | 63

Endometrial cancer, or cancer derived from the lining of the womb, is rapidly increasing in incidence and prevalence. This is primarily due to the association of endometrial cancer with obesity and increased body mass index. Approximately 40% of these cancers are directly associated with obesity. Irish incidence and stage of diagnosis are depicted in CANCER Figure 4.

GYNAECOLOGICAL

Figure 4. Cancer National Registry Irelandthe cancer (NCRI) incidence andthosediagnostic stage of than without abnormalities progression.

Hormone Endometrial cancer Figure 4. National Registry Cancer in this field. Current research agents, in particular aromatase Ireland (NCRI) incidence and endometrial cancer in Ireland, available Endometrial cancer, or cancerat www.nrci.ie and clinical trials are exploring diagnostic stage of endometrial inhibitors, can also be beneficial cancer in Ireland, available at www.ncri.ie

derived from the lining of the womb, is rapidly increasing in incidence and prevalence. This is primarily due to the association of endometrial cancer with obesity and increased body mass index.

Approximately 40% of these cancers are directly associated with obesity. Irish incidence and stage of diagnosis are depicted in Figure 4.

and efficacious with low toxicity profiles.

The adenocarcinoma subgroup is strongly driven by endometrial cancer Traditionally A lot of research internationally has explored the role of immunotherapy, in the form of immune checkpoint inhibitors, in ovarian cancer. The majority of ovarian cancer is not particularly responsive to these agents with tumour response rates in the order of 10%. However, there are specific subtypes of ovarian cancer that are more sensitive to these immunotherapeutic agents, in particular the clear cell cohort.

Current ongoing research has focused on the addition of immune checkpoint inhibitors to other agents such as the PARP inhibitors.

Cancer Trials Ireland was involved in the Athena clinical trial with principal investigator Dr Dearbhaile Collins, Cork University Hospital.

This study assessed different combinations of the immune checkpoint inhibitor, nivolumab, with the PARP inhibitor, rucaparib, following first chemotherapy treatment for newly diagnosed high grade ovarian cancer. Results are expected this year for this study regarding the benefit of combining immunotherapy with PARP inhibition.

was viewed as two distinct types – those that were low grade and hormonally driven (type 1) and those that were high grade and hormone independent (type 2).

Most recently endometrial cancer has been further broken down into newer molecular categories based on 2013 The Cancer Genome Atlas (TCGA) and illustrated in Figure 5. POLE ultramutated tumours contain a mutation resulting in the dysfunction of polymerase E, a key part of DNA transcription and DNA repair. These minority of cancers (~7%) do very well in the majority of cases, irrespective of treatment plan, but they respond remarkably well to immunotherapy agents such as immune checkpoint inhibitors.

Up to 30% of endometrial cancers express further abnormalities of DNA damage, specifically variants of the mismatch repair (MMR) proteins. Whilst a small proportion (3-5%) of these cancers that lose function of MMR proteins are associated with the inherited Lynch Syndrome, the vast majority are sporadic and tumourisolated abnormalities. These cancers are also more sensitive to immune checkpoint inhibitors

whether chemotherapy should no longer be the gold standard for these cancers with MMR loss and whether immunotherapy is the new standard-of-care. The two final subgroup; copy number low and copy number high, have the poorest overall prognosis (in particular the latter). They should be managed with chemotherapy, both in an adjuvant and palliative setting.

The majority of endometrial cancer is identified at an early stage due to its propensity to cause vaginal bleeding. Thus, is often amenable to radical resection in the form of hysterectomy or if inoperable, radiotherapy can be considered.

Chemotherapy less often features in the The majority of endometrial cancer is identified at an early stage due Recent research has set out management algorithmsto itsofpropensity endometrial cancers. When a higher risk of relapse is identified to cause vaginal to determine the appropriate bleeding. Thus, is often amenable treatment regimens for patients through multidisciplinary team discussion to radical resection in the form consideration can be given for what is known as the with and without mismatch of hysterectomy or if inoperable, repair (MMR) protein loss.

PORTEC 3 chemoradiation regimen.

This treatment comprises chemotherapy and radiotherapy can be considered.

KEYNOTE-016 & KEYNOTE-158 Chemotherapy less often features were basket studies examining chemotherapy with radiotherapy with the goal to reduce the risk of future relapse.

Endometria in the management algorithms the response of pembrolizumab of endometrial cancers. When a to any cancers with deficiencies cancer that has spread to distant organs or not amenable to surgery or radiation, is considered higher risk of relapse is identified in the MMR proteins. It became through multidisciplinary team part of a pooled dataset of five for chemotherapy. Again, thisconsideration regimen discussion can comprises a platinum chemotherapy in combination KEYNOTE studies analysing MMR be given for what is known as loss cancers that confirmed the with a taxane to control and slow the cancer progression.

Hormone agents, in particular the PORTEC 3 chemoradiation benefit of immune checkpoint regimen. This treatment comprises inhibitors in this group of patients, aromatase inhibitors, can also bewithbeneficial chemotherapy radiotherapy and efficacious. with the goal to reduce the risk of future relapse. Advanced, metastatic endometrial cancer that has spread to distant organs or not amenable to surgery or radiation, is considered for chemotherapy alone. As with ovarian cancer, this regimen comprises a platinum chemotherapy in combination with a taxane to control and slow

in particular endometrial cancer.

This dataset led to the first FDA approval of pembrolizumab in a tumour-agnostic or independent setting and purely based upon a biomarker result (in this case, MMR loss). A number of confirmatory studies of single agent immune checkpoint inhibitors in MMR deficient endometrial cancer followed including PHAEDRA (durvalumab) and GARNET (dostarlimab).

Once response in MMR deficient endometrial cancers was confirmed, trials set out to examine the rest of these tumours without

Traditionally endometrial cancer was viewed as two distinct types – those that were low grade and hormonally driven (type 1) and those that were high grade and hormone independent (type 2). Most recently endometrial cancer has been further broken down into newer molecular categories based on 2013 The Cancer Genome Atlas (TCGA) and illustrated in Figure 5. POLE ultramutated contain a mutation resulting in the dysfunction of polymerase E, a key part of DNA transcription and DNA repair. These minority of cancers (~7%) do very well in the majority of cases, irrespective of treatment plan, but they respond remarkably well to immunotherapy agents such as immune checkpoint inhibitors. Up to 30% of endometria cancers express further abnormalities of DNA damage, specificallyFigure variants of the mismatch 5. New molecular classification of endometrial cancer repair (MMR) proteins. Whilst a small proportion (3-5%) of these cancers that lose function of into (1) POLE ultramutated, (2) MSIthe hypermutated, copy MMR proteins are associated with the inherited Lynch Syndrome, vast (3)majority are number high (serous-like) and (4) copy number low (endometrioid) sporadic and tumour-isolated abnormalities. These cancers are also more sensitive to immune which has prognostic and therapeutic implications. checkpoint inhibitors than those without abnormalities in this field.

Current research and clinical trials are exploring whether chemotherapy should no longer be the gold standard of Figure 5. New molecular classification of endometrial cancer into (1) POLE ultramutated, (2) | HOSPITALPROFESSIONALNEWS.IE 64 | FEBRUARY 2022 • HPN care for these cancers with MMR loss. The and two(4)final copy number low and copy MSI hypermutated, (3) copy number high (serous-like) copy groups; number low

OYAVAS®: THE NEW BEVACIZUMAB BIOSIMILAR FROM CLONMEL HEALTHCARE1 SIMPLY CONVINCING – with similar efficacy, safety and quality to the reference product*2 SIMPLY RELIABLE – with European production supported by over 20 years of biosimilars experience† SIMPLY DEDICATED – with a continuously expanding oncology portfolio ABBREVIATED PRESCRIBING INFORMATION Oyavas 25 mg/ml concentrate for solution for infusion. Each ml contains 25 mg of bevacizumab. Each 4 ml vial contains 100 mg of bevacizumab.

Each 16 ml vial contains 400 mg of bevacizumab. Presentation: Glass vial. Indications: 1) Oyavas in combination with fluoropyrimidine based chemotherapy is indicated for treatment of adult patients with metastatic carcinoma of the colon or rectum. 2) Oyavas in combination with paclitaxel is indicated for first line treatment of adult patients with metastatic breast cancer. 3) Oyavas in combination with capecitabine is indicated for first line treatment of adult patients with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate. Patients who have received taxane and anthracycline containing regimens in the adjuvant setting within the last 12 months should be excluded from treatment with Oyavas in combination with capecitabine. 4) Oyavas in addition to platinum-based chemotherapy is indicated for first line treatment of adult patients with unresectable advanced, metastatic or recurrent non-small cell lung cancer other than predominantly squamous cell histology. 5) Oyavas in combination with erlotinib, is indicated for first line treatment of adult patients with unresectable advanced, metastatic or recurrent non squamous non-small cell lung cancer with Epidermal Growth Factor Receptor (EGFR) activating mutations. 6) Oyavas in combination with interferon alfa 2a is indicated for first line treatment of adult patients with advanced and/or metastatic renal cell cancer. 7) Oyavas in combination with carboplatin and paclitaxel is indicated for the front line treatment of adult patients with advanced (International Federation of Gynecology and Obstetrics (FIGO) stages III B, III C and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer. 8) Oyavas in combination with carboplatin and gemcitabine or in combination with carboplatin and paclitaxel is indicated for treatment of adult patients with first recurrence of platinum sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents. 9) Oyavas in combination with topotecan or pegylated liposomal doxorubicin is indicated for the treatment of adult patients with platinum resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than two prior chemotherapy regimens and who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents. 10) Oyavas in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot receive platinum therapy, is indicated for the treatment of adult patients with persistent, recurrent, or metastatic carcinoma of the cervix.

Dosage: Refer to Summary of Product Characteristics. Method of administration: Oyavas is for intravenous use. The initial dose should be delivered over 90 minutes as an intravenous infusion. If the first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60 minute infusion is well tolerated, all subsequent infusions may be administered over 30 minutes.

Contraindications: Hypersensitivity to the active substance or excipients, hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies, pregnancy. Warnings and precautions: GI perforations and fistulae, GI vaginal fistulae, non-GI fistulae, wound healing complications, hypertension, posterior reversible encephalopathy syndrome, proteinuria, arterial thromboembolism, venous thromboembolism, haemorrhage, pulmonary haemorrhage/haemoptysis, aneurysms and artery dissections, congestive heart failure, neutropenia and infections, hypersensitivity reactions/infusion reactions, osteonecrosis of the jaw. Oyavas is not formulated for intravitreal use. Eye disorders, systemic effects following intravitreal use, female fertility impairment. Interactions: Refer to Summary of Product Characteristics. Fertility, pregnancy and lactation: Women of childbearing potential have to use effective contraception during (and up to 6 months after) treatment. Oyavas is contraindicated in pregnancy. Women must discontinue breast-feeding during therapy and not breast-feed for at least six months following the last dose of bevacizumab.

Repeat dose toxicity studies in animals have shown that bevacizumab may have an adverse effect on female fertility. Long term effects of the treatment with bevacizumab on fertility are unknown. Driving and operation of machinery: Bevacizumab has no or negligible influence on the ability to drive and use machines. However, somnolence and syncope have been reported with bevacizumab use. If patients are experiencing symptoms that affect their vision or concentration, or their ability to react, they should be advised not to drive and use machines until symptoms abate. Undesirable effects: Very common: Febrile neutropenia, leukopenia, neutropenia, thrombocytopenia, anorexia, hypomagnesaemia, hyponatraemia, peripheral sensory neuropathy, dysarthria, headache, dysgeusia, eye disorder, lacrimation increased, hypertension, thromboembolism (venous), dyspnoea, rhinitis, epistaxis, cough, rectal haemorrhage, stomatitis, constipation, diarrhoea, nausea, vomiting, abdominal pain, wound healing complications, exfoliative dermatitis, dry skin, skin discolouration, arthralgia, myalgia, proteinuria, ovarian failure, asthenia, fatigue, pyrexia, pain, mucosal inflammation, weight decreased.

A copy of the SmPC is available upon request or go to www.clonmel-health.ie Pack size: 1 vial of 4 ml or 16 ml. Marketing authorisation holder: STADA Arzneimittel AG, Stadastrasse 2-18, 61118 Bad Vilbel, Germany. Marketing authorisation number: EU/1/20/1510/001-002. Medicinal product subject to medical prescription. Date last revised: May 2021. *Avastin® (bevacizumab) † STADA founded Bioceuticals Arzneimittel AG in 2000 1. Oyavas® SmPC (Apr. 2021). 2. Oyavas® EPAR Public Assessment Report. Available at: https://www.ema.europa.eu/en/documents/ assessment-report/oyavas-epar-public-assessment-report_en.pdf. Last accessed Apr. 2021. 2021/ADV/OYA/027H.

oyavas.ie

GYNAECOLOGICAL CANCER MMR protein loss, termed MMR proficient. Combination strategies were employed in particular with chemotherapy or antiangiogenic agents. Ireland enrolled patients to KEYNOTE-775 led by Professor Cathy Kelly, Mater Mieericordiae Hospital. This randomized clinical trial explored the advantage of the immune checkpoint inhibitor Pembrolizumab plus Lenvatinib (a multi-tyrosine kinase inhibitor) over chemotherapy in the second line setting. The results in all endometrial cancers, irrespective of the status of MMR, was an improved overall survival approximately 6 months. LEAP001 was also open in Ireland exploring the same drug combination (Pembrolizumab plus Lenvatinib) but in the initial first line setting and the preliminary results of this study are expected soon.

Future research focus is exploring other compounds in development such as inhibitors against estrogen receptor, androgen receptor, mTOR and many other variants. These agents are explored in parallel to our growing knowledge of the underlying molecular abnormalities in endometrial cancer. While further therapeutic options are important, the importance of reducing obesity cannot be understated. The reduction in the global obesity pandemic would have an immediate and lasting impact on endometrial cancer incidence. Epidemiological work and population health initiatives focusing on obesity prevention strategies are critical.

Cervical cancer

vaccination programmes will soon result in a marked reduction in cervical cancer diagnosis, however in many less developed countries, cervical cancer can and will continue to be a significant source of patient morbidity and mortality into the future.

Cervical cancer can be subclassified on the basis of its pathological appearance into squamous, adenocarcinoma, adenosquamous and the rarer, neuroendocrine and undifferentiated subtypes.

Squamous cell carcinoma is by far the more common comprising up to 80% of all cervical cancer cases. Over half of cervical cancers are diagnosed at a locally advanced stage, with only a minority metastatic or stage IV at diagnosis. Relapse following initial cancer treatment however is common, developing in 15% - 60% of women, usually within the first 2 years of completing treatment. Irish incidence and stage of diagnosis statistics are available on the NCRI website and can be seen in Figure 6.

for a year after completion of chemotherapy if tolerated and no evidence of disease spread.

Remission periods following treatment are varied.

Immunotherapy, in particular immune checkpoint inhibitors, are used in Ireland in the second line setting but variably elsewhere in Europe. Single agent immune checkpoint inhibitors have not received European Medicine’s Agency (EMA) approval, despite USA FDA approval, due to low tumour response rates and no significant beneficial impact in the majority of women. Nevertheless, there is a small proportion of cancer patients who do obtain a durable response to immunotherapy that translates into a survival benefit.

Clinical trials have focused on maximizing this benefit and most recently KEYNOTE-826 revealed a survival benefit of Pembrolizumab in addition to chemotherapy (platinum+paclitaxel) in the first line setting. This study extended median patient survival from 16.5 months to 24.4 months in all enrolled patients (irrespective of PD-L1 status). This will become the new standard-of-care over the coming years. Trial focus has moved the immune checkpoint inhibitors even earlier. The KEYNOTE-A18 clinical trial is ongoing in Ireland. This Cancer Trials Ireland study is open in Cork University Hospital and St James’ Hospital and the national principal investigator is Dr Dearbhaile Collins, CUH. This study is randomizing patients with locally advanced unresectable cervical cancer to standard of care, chemoradiotherapy, with or without the immune checkpoint inhibitor, Pembrolizumab. This study is open and currently accruing until mid 2022. A similar study known as CALLA is also open in Europe and will answer the same question with a different immunotherapy agent, durvalumab. It will not be long until immune checkpoint inhibitors will be utilized in even early stage cervical cancer.

monoclonal antibody, tisotumab vedotin (TV), developed by SeaGen. Ireland has had, and continues to have, a number of the TV studies available for patients. The ENGOTcx12 randomised phase III study of TV versus chemotherapy is imminently due to open in Ireland with PI, Dr Paula Calvert, University Hospital Waterford at the helm. There are other compounds also in the development pipeline including HPV-targeted vaccines, antiangiogenic combinations, other immune checkpoint inhibitor combinations and autologous genetically modified immune cell transplantation.

Conclusion Gynaecological cancers comprise a diverse group of cancers involving the ovaries, womb, cervix, vulva and vagina. They have predominantly been managed with surgical resection as the backbone and a need for chemotherapy (often platinum paclitaxel combination regimen) and/or radiotherapy. The Irish Cancer Society Women’s Health Initiative has developed a patient platform where safe and reliable cancer articles can be found, in addition to videos by specialists in this field, to inform and empower patients with a diagnosis of gynaecological cancers. Patients and/or family members can access www. thisisGO.ie for further information.

Ongoing research is expanding our understanding of the molecular abnormalities underlying these cancers that can potentially be targeted in the future. This has resulted in the further development of a variety of novel treatments.

Clinical trials with these agents are ongoing and Cancer Trials Ireland constantly strives to open these trials in Ireland so that Irish patients can avail of them. Ongoing open clinical trials can be viewed at www.cancertrials.ie.

Cervical cancer is directly associated with human papilloma virus (HPV) infection, in stage cervical cancer, in particular exposure to theEarly more carcinogenic HPV subtypes 16 and 18. While the majority of general, is managed with surgical HPV infections are cleared by with thecurative individual’s resection intent. More innate immune system, a small minority go on advanced disease that involves the to develop a chronic HPV anddistant ultimately can lead to the development of cervical walls infection of the pelvis and/or nodes relies more on a combination cancer. The ongoing global initiative in HPV vaccination programmes will soon result in a of radiation and chemotherapy to obtain a cure, althoughdiagnosis, the risk marked reduction in cervical cancer however in many less developed countries, of relapse in the future is a real concern.

Those cancers that have cervical cancer can andevidence will ofcontinue to be a significant source of patient morbidity and spread beyond what mortality into the future. can be treated with surgery or definitive radiotherapy, requires chemotherapy alone to control and slow the disease progression, but without the hope of a cure. Over the past thirty years, the median overall survival of patients with stage IVB or recurrent disease has not significantly improved with a 5 year survival for stage IV patients of only 15-20%. Chemotherapy, again, is the mainstay of treatment and employs a platinum compound with paclitaxel and sometimes in combination with Bevacizumab if felt to be safe to deliver. Bevacizumab is continued

Cervical cancer Cervical cancer can be subclassified on the basis of its pathological appearance into squamous, Cervical cancer is directly adenocarcinoma, adenosquamous and the rarer, neuroendocrine and undifferentiated subtypes. associated with human papilloma virus (HPV) infection, Squamous cellin particular carcinoma is by far the more common comprising up to 80% of all cervical exposure to the more carcinogenic HPV subtypes 16 andOver 18. While cancer cases. half of cervical cancers are diagnosed at a locally advanced stage, with only the majority of HPV infections are by the individual’s innate acleared minority metastatic or stage IV at diagnosis. Relapse following initial cancer treatment immune system, a small minority however is acommon, the6.first years of National2Cancer Registry go on to develop chronic HPV developing in 15% - 60% of women, usually withinFigure Ireland (NCRI) incidence and infection and ultimately can lead to There are other agents in completing of diagnosis statistics diagnostic are available on thein stage of cervical cancer the development oftreatment. cervical cancer. Irish incidence and stage development in cervical cancer Ireland, available at www.ncri.ie The ongoing global initiative in HPV including the tissue factor NCRI website and can be seen in Figure 6.

Figure 6. National Cancer Registry Ireland (NCRI) incidence and diagnostic stage of cervical 66 | FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE cancer in Ireland, available at www.nrci.ie

IMFINZI is now reimbursed for the treatment of locally advanced, unresectable non‑small cell lung cancer (NSCLC) in adults whose tumours express PD‑L1 on ≥1% of tumour cells and whose disease has not progressed following platinum‑based chemoradiation therapy.1

50 mg/mL concentrate for solution for infusion

In a post‑hoc subgroup analysis of the PACIFIC study, WITH IMFINZI, 54.7% OF PATIENTS WITH PD‑L1 ≥1% REMAINED ALIVE AFTER FOUR YEARS1‑3 (HR: 0.60; 95% CI, 0.43‑0.84)

Primary analysis in the ITT population Median OS*: Not reached vs 28.7 months with placebo (HR=0.68; 95% CI, 0.53‑0.87; P=0.0025) Median PFS†: 16.8 vs 5.6 months with placebo (HR=0.52; 95% CI, 0.42‑0.65; P<0.0001)1 The primary 2‑year OS analysis was conducted after 299 deaths for 42% maturity (61% of targeted events) with a median follow‑up of 25.2 months. Reduction in the risk of death vs placebo was 32% (95% CI, 0.53‑0.87). Median OS was NR with IMFINZI (95% CI, 34.7‑NR) vs 28.7 months with placebo (95% CI, 22.9‑NR). †Measured based on RECIST v1.1 criteria by BICR. The primary PFS analysis was conducted after 371 events (81% of targeted 458 events) with a median follow‑up of 14.5 months. Reduction in the risk of progression or death vs placebo was 48% (HR=0.52; 95% CI, 0.42‑0.65). Median PFS was 16.8 months with IMFINZI (95% CI, 13.0‑18.1) vs 5.6 months with placebo (95% CI, 4.6‑7.8).

*

SAFETY INFORMATION The most frequent any grade (>10%) adverse reactions were cough/productive cough (21.5%), diarrhoea (16.3%), rash (16.0%), pyrexia (13.8%), upper respiratory tract infections (13.5%), abdominal pain (12.7%), pruritus (10.8%), and hypothyroidism (10.1%) Patients should be monitored for immune‑mediated adverse events. Immune‑mediated adverse events were generally manageable with appropriate monitoring and intervention1 ABRIDGED PRESCRIBING INFORMATION IMFINZI® ▼(durvalumab) 50mg/ml Concentrate for Solution for Infusion Consult Summary of Product Characteristics (SmPC) before prescribing.

Indication: IMFINZI as monotherapy is indicated for the treatment of locally advanced, unresectable non‑small cell lung cancer (NSCLC) in adults whose tumours express PD‑L1 on ≥ 1% of tumour cells and whose disease has not progressed following platinum‑based chemoradiation therapy. IMFINZI in combination with etoposide and either carboplatin or cisplatin is indicated for the first‑line treatment of adults with extensive‑stage small cell lung cancer (ES‑SCLC).

Presentation: Each ml of concentrate for solution for infusion contains 50mg durvalumab. Dosage and administration: Treatment must be initiated and supervised by a physician experienced in the treatment of cancer. Patients with locally advanced NSCLC should be evaluated for treatment based on the tumour expression of PD‑L1 confirmed by a validated test. For locally advanced NSCLC, the recommended dose of IMFINZI is 10 mg/kg administered as an intravenous infusion over 1 hour every 2 weeks or 1500 mg every 4 weeks, until disease progression, unacceptable toxicity, or a maximum of 12 months. For ES‑SCLC, the recommended dose for IMFINZI in combination with chemotherapy (etoposide and either carboplatin or cisplatin) is 1500mg, administered as an intravenous infusion over 1 hour, every 3 weeks (21 days) for 4 cycles, followed by 1500mg every 4 weeks as monotherapy, until disease progression or unacceptable toxicity. Patients with a body weight of 30kg or less must receive weight‑based dosing, please consult Section 4.2 in the SmPC for more information. Dose escalation or reduction is not recommended. Dose withholding or discontinuation may be required based on individual safety and tolerability. Suspected immune‑mediated adverse reactions: Adequate evaluation should be performed to confirm aetiology or exclude alternate aetiologies. Guidelines for the management of immune mediated adverse reactions are described in Table 2, Section 4.2 in the SmPC. Consider increasing dose of corticosteroids and/or using additional systemic immunosuppressants if there is worsening or no improvement. Upon improvement to ≤ Grade 1, corticosteroid taper should be initiated and continued over at least 1 month. After withhold, IMFINZI can be resumed within 12 weeks if the adverse reactions improved to ≤ Grade 1 and the corticosteroid dose has been reduced to ≤ 10 mg prednisone or equivalent per day. IMFINZI should be permanently discontinued for recurrent Grade 3 or 4 (severe or life‑threatening) immune‑mediated adverse reactions. For myasthenia gravis, if there are signs of muscular weakness or respiratory insufficiency, IMFINZI should be permanently discontinued. Non‑immune‑mediated adverse reactions: Consider withholding IMFINZI for Grade 2 and 3 adverse reactions until ≤ Grade 1 or baseline. IMFINZI should be discontinued for Grade 4 adverse reactions. Special populations: Elderly: No dose adjustment is required for elderly patients (≥ 65 years of age). Renal impairment: No dose adjustment is recommended in patients with mild or moderate renal impairment. Data from patients with severe renal impairment are too limited to draw conclusions on this population.

Hepatic impairment: Data from patients with moderate and severe hepatic impairment are limited. Due to minor involvement of hepatic processes in the clearance of durvalumab no dose adjustment of IMFINZI is recommended for patients with hepatic impairment as no difference in exposure is expected. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Warnings and precautions: Traceability: In order to improve the traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded. Immune‑mediated pneumonitis: Monitor for signs and symptoms of pneumonitis or radiation pneumonitis.

Suspected pneumonitis should be confirmed with radiographic imaging and other infectious and disease‑related aetiologies excluded. Immune‑mediated hepatitis: Monitor for abnormal liver tests prior to and periodically during treatment with IMFINZI, and as indicated based on clinical evaluation. Immune‑mediated colitis: Monitor for signs and symptoms of colitis or diarrhoea. Immune‑mediated hypothyroidism, hyperthyroidism and thyroiditis: Monitor for abnormal thyroid function tests prior to and periodically during treatment and as indicated based on clinical evaluation.

Immune‑mediated adrenal insufficiency: Monitor for clinical signs and symptoms of adrenal insufficiency.

Immune‑mediated type 1 diabetes mellitus: Monitor for clinical signs and symptoms of type 1 diabetes mellitus.

Immune‑mediated hypophysitis/hypopituitarism: Monitor for clinical signs and symptoms of hypophysitis or hypopituitarism. Immune‑mediated nephritis: Monitor for abnormal renal function tests prior to and periodically during treatment with IMFINZI. Immune‑mediated rash: Events of Stevens‑Johnson Syndrome or toxic epidermal necrolysis have been reported in patients treated with PD‑1 inhibitors. Patients should be monitored for signs and symptoms of rash or dermatitis (including pemphigoid). Other immune‑mediated adverse reactions: Myasthenia gravis, myocarditis, myositis, polymyositis, meningitis, encephalitis Guillain‑Barre syndrome and immune thrombocytopenia have been

observed. Events of pancreatitis have been reported in patients in the clinical study programme. Monitor for signs and symptoms. Infusion related reactions: Monitor for signs and symptoms of infusion related reactions. All immune‑mediated adverse events should be managed as recommended in Table 2 Section 4.2 of the SmPC. Patients excluded from clinical trials: Patients with: a baseline ECOG performance score ≥ 2; active or prior documented autoimmune disease within 2 years of initiation of the study; a history of immunodeficiency; a history of severe immune‑mediated adverse reactions; medical conditions that required systemic immunosuppression, except physiological dose of systemic corticosteroids (≤ 10 mg/day prednisone or equivalent); uncontrolled intercurrent illnesses; active tuberculosis or hepatitis B or C or HIV infection or patients receiving live attenuated vaccine within 30 days before or after the start of IMFINZI. Durvalumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis. The safety of concurrent prophylactic cranial irradiation (PCI) with IMFINZI in patients with ES‑SCLC is unknown. Drug Interactions: The use of systemic corticosteroids or immunosuppressants before starting durvalumab, except physiological dose of systemic corticosteroids (≤ 10 mg/day prednisone or equivalent), is not recommended because of their potential interference with the pharmacodynamic activity and efficacy of durvalumab. However, systemic corticosteroids or other immunosuppressants can be used after starting durvalumab to treat immune‑related adverse reactions. PK drug‑drug interaction between durvalumab and chemotherapy was assessed and showed concomitant treatment did not impact the PK of any of the drugs involved. Additionally, based on population PK analysis, concomitant chemotherapy treatment did not meaningfully impact the PK of durvalumab. Pregnancy and Lactation: Durvalumab may cause foetal harm when administered to a pregnant woman and is not recommended during pregnancy and in women of childbearing potential not using effective contraception during treatment and for at least 3 months after the last dose. A decision must be made whether to discontinue breast feeding or to discontinue or abstain from durvalumab therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Undesirable events: Consult SmPC for full list of adverse events. IMFINZI Monotherapy: Very common (≥ 1/10; any grades): Upper respiratory tract infections, hypothyroidism, cough/productive cough, diarrhoea, abdominal pain, rash, pruritus, pyrexia. Common (≥ 1/100 to < 1/10; any grades ): Pneumonia, dental and oral soft tissue infections, oral candidiasis, influenza, hyperthyroidism, pneumonitis, dysphonia, aspartate aminotransferase increased or alanine aminotransferase increased, night sweats, myalgia, blood creatinine increased, dysuria, peripheral oedema, infusion related reaction. Uncommon (≥ 1/1,000 to < 1/100; any grades): Thyroiditis, adrenal insufficiency, interstitial lung disease, colitis, hepatitis, dermatitis, myositis, nephritis. Rare (≥ 1/10,000 to < 1/1000; any grades): Type 1 diabetes mellitius, hypophysitis/hypopituitarism, diabetes insipidus, myocarditis, polymyositis, myasthenia gravis, meningitis, pemphigoid, immune thrombocytopenia. Not known: Noninfective encephalitis, Guillain‑Barre syndrome. IMFINZI Combined with Chemotherapy: Very common (≥ 1/10; any grades): Neutropenia, anaemia, thrombocytopenia, leukopenia, decreased appetite, cough/productive cough, nausea, constipation, vomiting, alopecia, fatigue. Common (≥ 1/100 to < 1/10; any grades): Upper respiratory tract infections, pneumonia, dental and oral soft tissue infections, febrile neutropenia, pancytopenia, hypothyroidism, hyperthyroidism, thyroiditis, adrenal insufficiency, pneumonitis, diarrhoea, abdominal pain, stomatitis, aspartate aminotransferase increased or alanine aminotransferase increased, hepatitis, rash, pruritus, dermatitis, myalgia, blood creatinine increased, dysuria, pyrexia, peripheral oedema, infusion‑related reaction. Uncommon (≥ 1/1,000 to < 1/100; any grades): Oral candidiasis, influenza, Type 1 diabetes mellitus, dysphonia, interstitial lung disease, colitis, night sweats. Legal Category: Product subject to prescription which may not be renewed (A). Marketing Authorisation Number: EU/1/18/1322/001; EU/1/18/1322/002. Marketing Authorisation Holder: AstraZeneca AB, SE‑151 85, Södertälje, Sweden. Further information available on request from: AstraZeneca Pharmaceuticals (Ireland) DAC, Block B, Liffey Valley Office Campus, Dublin 22. Tel: +353 1 6097100. IMFINZI® is a registered trade mark of the AstraZeneca group of companies.

Date of API Preparation: 01/2021 Veeva ID: IE‑2347 This medicinal product is subject to additional monitoring. Adverse events should be reported directly to: HPRA Pharmacovigilance.Website: www.hpra.ie. Adverse events should also be reported to AstraZeneca Patient Safety on Freephone 1800 800 899

References: 1. IMFINZI ‑ Ireland Summary of Product Characteristics. Date: February 2021. 2. Faivre‑Finn C, Vicente D, Kurata T, et al. Brief report: four‑year survival with durvalumab after chemoradiotherapy in stage III NSCLC ‑ an update from the PACIFIC trial [e‑pub ahead of print]. J Thorac Oncol. 2021;16(5):860‑867. https://doi.org/10.1016/j.jtho.2020.12.015. Accessed May 2021. 3. de Wit, et al. Durvalumab nach Radiochemotherapie im Stadium III NSCLC: Update zum 4‑Jahres‑Überleben aus der PACIFIC‑Studie. Presented at 2020 DGHO; October 9‑11, 2020.

IMFINZI is a trademark of the AstraZeneca group of companies. ©2021 AstraZeneca. All rights reserved. Veeva ID: IE‑2643 | DOP: May 2021

PROSTATE CANCER

Prostate Cancer Active Surveillance Written by Niall J O’Sullivan, Rowan G Casey - Consultant Urologist, MD FRCS Urol MBA

Niall J O’Sullivan

Rowan G Casey

Prostate cancer (PCa) is the second most commonly diagnosed cancer in men, with a reported incidence of 1.1 million worldwide in 2012.1 Ireland was estimated to have had the highest incidence of prostate cancer in Europe in 2006 which is expected to increase by 275% by 2025 based on current trends and our ageing population.2 PCa screening remains a controversial topic in the urological literature.3 A Cochrane review published in 2013 revealed that while PCa screening was associated with an increased diagnosis of PCa with detection of more low grade localised disease, no PCa-specific or overall survival benefit was demonstrated.4 Issues have emerged in regards to the increasing incidence of insignificant cancers that are unlikely to influence lifetime prognosis. In order to combat the “overtreatment” of these cancers, Active Surveillance (AS) should be considered to reduce the morbidity inflicted by definitive therapies such

as prostatectomy or radiotherapy.5 While its use is most established in PCa, active surveillance is also considered in the treatment of low grade non-muscle invasive bladder cancers, uveal melanomas and certain pre-malignant conditions such as Barrett’s oesophagus and gastric lesions.6-8

Since it was first described in 2002, AS has become a standard of care for low-risk PCa, particularly in patients with a limited life expectancy (<10 years).9 AS involves the use of PSA testing, clinical examination, mpMRI imaging and prostate biopsies at regular intervals to closely monitor patients for disease progression, while simultaneously preserving quality of life and giving patients the assurance of definitive therapy if or when deemed necessary down the line.9 Curative treatment is prompted by pre-defined thresholds indicative of potentially life-threatening disease that is remains potentially curable.1 AS is generally reserved for patients with the lowest risk of PCa progression for whom radical treatment is suitable. The parameters for ‘very low risk’ and ‘low risk’ PCa outlined by the National Comprehensive Cancer Network

Figures 1 PCa mpMRI Case courtesy of Dr Joachim Feger, Radiopaedia.org, rID: 73014, 72546 Red arrows: Large circumscribed, homogenous moderate hypointense focus, markedly hyperintense in DWI and markedly hypointense in ADC with early enhancement on DCE located in the right apical/ midglandular posterolateral peripheral zone (PZpl) Green arrow: Low signal intensity with obscured marings, isointense on DWI and markedly hypointense on ADC located in the eft basal/ midglandular transition zone

Figures 1 PCa mpMRI 68 | FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE Case courtesy of Dr Joachim Feger, Radiopaedia.org, rID: 73014, 72546

(NCCN) are presented in Table 1.1,10,11 Triggers for conversion to active management vary between centres but generally include a PSA velocity > 1 ng/ ml/year, a Gleason score >7 and/ or more than 50% positive cores on a repeat biopsy.12 The impact of AS on PCa mortality has been studied with mixed findings. A very modest absolute difference was found in PCa mortality between patients undergoing active surveillance followed by radical prostatectomy versus those undergoing active management from diagnosis. A model proposed

by Xia et. al suggested that the average projected increase in life expectancy associated with immediate radical prostatectomy was 1.8 months compared to AS, however men on AS would remain free of treatment for an additional 6.4 years in comparison.13 The risk for tumour metastasis and death is

low during active surveillance, with a rate of 4% and 0.5% respectively after ten years of surveillance.14 The ‘National Clinical Guideline for the Diagnosis, Staging and Treatment of Prostate Cancer’ published by the NCCP in conjunction with the NCEC in 2015 offers clinicians a protocol for men who have opted for active surveillance in the management of their PCa.10 The first five years of this protocol are presented in Figure 3. Upon reaching five years of progression-free survival, the patient should continue with six-monthly clinic visits with biopsies suggested every three years until either radical treatment is initiated, the patient reaches 75 years of age, the patient switches to an alternative ‘watch and wait’ protocol or until death.1,10 These guidelines are often considered

to be outdated as they fail to incorporate PSA-density, which has been shown to have improved sensitivity when compared to standard PSA testing.15 New up-to-date guidelines are currently in development, placing more emphasis on the use of mpMRI, PSA-density and transperineal biopsy.

Prostate-specific antigen (PSA) is a serine esterase produced almost exclusively by the prostatic epithelium. While its use as a tumour marker has been established over the last thirty years, it is not specific for PCa and has a high false positive rate when used as a screening tool.2 Prostate-specific antigen density (PSAD) refers to the ratio of PSA

level (ng/mL) to the volume of the prostate (mL) and is more specific to PCa than standard PSA testing.16 As PSA alone can be raised in a variety of both benign and malignant conditions, PSAD is more commonly employed in everyday practice to both detect new and surveil known prostate cancers.17 Multiparametric MRI (mpMRI) of the prostate is a novel promising tool for the diagnosis of PCa which may aid the reduction of overdiagnosis and overtreatment of insignificant prostate cancers.18 The incorporation of mpMRI into the diagnostic pathway has helped to address the

inadequacies of trans-rectal ultrasound (TRUS) guided biopsies in detecting PCa.19 mpMRI uses four sequences; T1-weighted images, T2-weighted images, diffusion-weighted images (DWI) and dynamic contrast-enhanced imaging (DCEI). Interpretation and reporting of these images is carried out using standardised scoring systems including ‘Prostate Imaging Reporting and Data System (PI-RADS).18 Several studies have been conducted to determine whether mpMRI could correctly identify patients suitable for active surveillance. In 2013,

TABLE 1: NCCN PCA RISK STRATIFICATION11 PARAMETER

VALUE Very low risk (All of the following)

TNM STAGE

</= cT1c

DESCRIPTION Low risk (All of the following)

T1-2a

T1c: Clinically inapparent non-palpable tumour identified by needle biopsy T2a: Tumour contained to less than half of one lobe

PSA

<10 ng/mL

<10 ng/mL

Prostate specific antigen; raised in both benign and malignant conditions

BIOPSY GLEASON SCORE

</= 6

</= 6

Histological classification based on degree of glandular de-differentiation.

Scored from 2-10 based on two most common cellular morphologies

POSITIVE CORES

</= 3

-

</= 2 cancer-containing biopsies out of all biopsies taken (∼10-12)

CORE INVOLEMENT

<50% cancer per biopsy

-

Proportion of positive core containing tumour cells

PSA DENSITY

<0.15 ng/mL/g

-

Ratio of PSA level (ng/mL) to the volume of the prostate (mL)

HOSPITALPROFESSIONALNEWS.IE | HPN • FEBRUARY 2022 | 69

PROSTATE CANCER

Prior to enrolment in AS: mpMRI, confirmatory repeat biopsy within 6 months of diagnostic biopsy

Year 1: PSA 3 monthly DRE 6 monthly

Year 2 + 3: PSA 6 monthly DRE 6 monthly Biopsy at end of year 2

Year 4 + 5: Annual PSA Annual DRE Biopsy at end of year 5 efficacy compared to standard Turkbey et. al compared mpMRI and is employed almost exclusively to various other clinic-pathological in the United Kingdom.25 A of care imaging of biochemically trans-rectal US probe is used to criteria such as CAPRA, Einstein recurrent PCa. This modality has Figure 3: Active Surveillance Protocol (NCCP/NECPguide 2015) the needle into the prostate and D’amico to predict active shown to significantly aid the where twelve core biopsies are surveillance eligibility. Results detection of otherwise occult taken.24 Contemporary MRI-guided showed that mpMRI proved to nodal and bone metastases, which strategies have been used to be the most accurate in doing so, may have a substantial impact on allow more selective sampling of with an overall accuracy of 92%.20 subsequent treatment decisions Similarly, the ‘Active Surveillance lesions previously identified as and patient outcomes.22,23 magnetic resonance Imaging suspicious on mpMRI. mpMRI Prostate biopsy remains the STudy’ (ASIST) trial revealed 50% data is mapped to a T2-weighted gold standard technique for fewer active surveillance failures in scan obtained prior to the biopsy the detection of PCa, however patients who received a baseline and a biopsy needle is used mpMRI and PSA-density testing mpMRI prior to confirmatory to target these areas of high appear to be the optimal methods biopsy than patients who received suspicion. This approach has been of surveillance.24 Ultrasound biopsy alone.21 While mpMRI has shown to be effective in detecting (US)-guided biopsy is the current evidently improved the selection cancer in patients with a rising standard of care and is performed of patients for active surveillance, PSA but previous negative TRUSvia either a trans-rectal or transthere is a lack of evidence to guided biopsy.26 A confirmatory 1 perineal approach. While both transperineal biopsy may also suggest that it can safely replace the transperineal and transrectal be performed following the initial surveillance biopsies in this approach appear to have a diagnosis of low risk PCa on cohort.19 Recently, targeting the similar diagnostic accuracy, the prostate-specific membrane TRUS-guided biopsy, as evidence transperineal route has been antigen (PSMA) with 68Ga-labelled suggests that approximately oneassociated with a significantly and 18F-labelled PET-agents has third of low risk PCa diagnosed demonstrated superior detection on TRUS-guided biopsy actually lower risk of infection and bleeding

70 | FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Figure 3: Active Surveillance Protocol (NCCP/NECP 2015) have more significant cancer on a subsequent transperineal template biopsy.27,28 In our practice, a confirmative transperineal biopsy would be performed after one year of active surveillance in patients with low risk disease on TRUSguided biopsy with concordant MRI findings.

Prostate cancer is on the rise in Irish men.2 As PSA screening becomes more accessible, more early stage localised cancers are being diagnosed. It is essential to combat the unnecessary overtreatment of these cancers by implementing an active surveillance protocol in suitable patients in order to both maintain an adequate quality of life as well as reduce treatment-related morbidity and mortality.

References upon request

CALQUENCE CONFIDENCE A selective BTKi1

CALQUENCE Indications available in the high tech scheme:

• Calquence as monotherapy for the treatment of previously untreated Chronic Lymphocytic Leukaemia (CLL) in the presence of 17p deletion or TP53 mutation in adult patients unsuitable for chemoimmunotherapy.* • Calquence as monotherapy for the treatment of adult patients with CLL who have received at least one prior therapy. *Please see the below prescribing information or SmPC for full detail on licensed indications.

ABRIDGED PRESCRIBING INFORMATION CALQUENCE® 100mg HARD CAPSULES (acalabrutinib) Consult Summary of Product Characteristics (SmPC) before prescribing.

Indication: Calquence as monotherapy or in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL). Calquence as monotherapy is indicated for treatment of adult patients with CLL who have received at least one prior therapy.

Presentation: Each hard capsule contains 100mg of acalabrutinib.

Dosage and Administration: Treatment should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. The capsules should be swallowed whole with water at approximately the same time each day, with or without food and should not be chewed, dissolved or opened. Recommended dose is 100mg acalabrutinib twice daily.

Refer to obinutuzumab prescribing information for recommended obinutuzumab dosing information. The dose interval is 12 hours approximately and treatment should be continued until disease progression or unacceptable toxicity. Refer to SmPC for recommended dose modifications of Calquence for Grade ≥ 3 adverse reactions and interactions with CYP3A inhibitors or inducers and gastric acid reducing agents. Elderly: No dose adjustment required for patients (aged ≥ 65 years). Renal impairment: No dose adjustment needed in patients with mild to moderate renal impairment (greater than 30mL/min creatinine clearance).

Maintain hydration and monitor serum creatinine levels periodically. Only use in patients with severe renal impairment (<30mL/min creatinine clearance) if benefit outweighs risk. Monitor closely for signs of toxicity. Hepatic impairment: No dose adjustment recommended in patients with mild or moderate hepatic impairment (Child-Pugh A, Child-Pugh B, or total bilirubin between 1.5-3 times the upper limit of normal [ULN] and any AST). Patients with moderate hepatic impairment should be closely monitored for signs of toxicity. Calquence is not recommended in patients with severe hepatic impairment (Child-Pugh C or total bilirubin >3 times ULN and any AST). Severe cardiac disease: Patients with severe cardiovascular disease were excluded from studies. Paediatric population: The safety and efficacy of Calquence in children and adolescents aged 0 to 18 years have not been established.

Contraindications: Hypersensitivity to the active substance or to any of the excipients.

Warnings and Precautions: Haemorrhage: Major haemorrhagic events including central nervous system and gastrointestinal haemorrhage, some with fatal outcomes, have occurred in patients with haematological malignancies treated with Calquence monotherapy and in combination with obinutuzumab. Patients receiving antithrombotic agents may be at increased risk of haemorrhage. Exercise caution with antithrombotic agents and consider additional monitoring for signs of bleeding when concomitant use is medically necessary.

Warfarin or other vitamin K antagonists should not be administered concomitantly with Calquence. Consider benefit-risk of withholding Calquence for at least 3 days pre- and post-surgery. Infections: Serious infections (bacterial, viral or fungal) including fatal events have occurred in patients with haematological malignancies treated with Calquence monotherapy and in combination with obinutuzumab. These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia. Infections due to hepatitis B virus (HBV) and herpes zoster virus (HZV) reactivation, aspergillosis and progressive multifocal leukoencephalopathy (PML) have also occurred. Viral reactivation cases of hepatitis B have been reported and therefore HBV status should be established before initiating treatment with Calquence. A liver disease expert should be consulted before initiation of treatment if patients have a positive Hepatitis B serology and the patient should be monitored and managed to prevent hepatitis B reactivation. Progressive multifocal leukoencephalopathy (PML): Cases of PML including fatal ones have been reported following use of Calquence within the context of a prior or concomitant immunosuppressive therapy. Consider PML in differential diagnosis where there are new or worsening neurological, cognitive or behavioural signs or symptoms. If PML is suspected, appropriate diagnostic evaluations should be undertaken and treatment with Calquence should be stopped until PML is excluded.

Prophylaxis should be considered in patients who are at increased risk for opportunistic infections. Monitor for signs and symptoms of infection. Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias, including neutropenia, anaemia and thrombocytopenia, occurred in patients with haematological malignancies treated with Calquence monotherapy and in combination with obinutuzumab. Monitor complete blood counts as medically indicated (refer to section 4.8 of the SmPC). Second primary malignancies: Skin and non-skin cancers, occurred in patients with haematological malignancies treated with Calquence monotherapy and in combination with obinutuzumab. Monitor for appearance of skin cancers and advise protection from sun exposure. Atrial fibrillation/flutter: Atrial fibrillation/flutter occurred in patients with haematological malignancies treated with Calquence monotherapy and in combination with obinutuzumab. Monitor for symptoms (e.g. palpitations, dizziness, syncope, chest pain, dyspnoea) and obtain ECG as medically indicated (see section 4.5 and 4.2 of the SmPC). If atrial fibrillation is developed on therapy

with Calquence, a thorough assessment of risk for thromboembolic disease should be undertaken. Patients at high risk for thromboembolic disease, tightly controlled treatment with anticoagulants and alternative treatment options should be considered.

Drug Interactions: Concomitant use with strong CYP3A/P-gp inhibitors should be avoided.

If strong CYP3A/P-gp inhibitors (e.g. ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole, ritinovair, telaprevir, posaconazole, voriconazole) are used short-term, treatment with Calquence should be interrupted. No dose adjustment is required in combination with moderate CYP3A inhibitors. Monitor patients closely for adverse reactions (see Section 4.2 of the SmPC). CYP3A inducers may decrease acalabrutinib plasma concentrations.

Concomitant use of strong inducers (e.g. phenytoin, rifampicin, carbamazepine) should be avoided. Concomitant use of St. John’s wort should be avoided. If treatment with a gastric acid reducing agent is required, consider using an antacid (e.g. calcium carbonate) or H2-receptor antagonist (e.g. ranitidine or famotidine). Due to the long-lasting effect of proton pump inhibitors, separation of doses with proton pump inhibitors may not eliminate the interaction with Calquence and therefore concomitant use should be avoided. Exercise caution if co-administering acalabrutinib with CYP3A4 substrates with narrow therapeutic range administered orally (e.g. cyclosporine, ergotamine, pimozide). Co-administration with CYP1A2 substrates (e.g. theophylline, caffeine) may decrease their exposure. Acalabrutinib may increase exposure to co-administered BCRP substrates (e.g. methotrexate) by inhibition of intestinal BCRP. To minimise the potential of an interaction in the gastrointestinal tract, oral narrow therapeutic range BCRP substrates such as methotrexate should be taken at least 6 hours before or after acalabrutinib. ACP-5862 (active metabolite of acalabrutinib) may increase exposure to co-administered MATE1 substrates (e.g. metformin) by inhibition of MATE1. Patients should be monitored for signs of changed tolerability as a result of increased exposure of the concomitant medication whilst taking Calquence.

Pregnancy and Lactation: Women of childbearing potential should be advised to avoid becoming pregnant whilst receiving Calquence. Calquence should not be used during pregnancy unless the clinical condition of the woman requires treatment with acalabrutinib.

A risk to the breast-fed child cannot be excluded therefore breast-feeding mothers are advised not to breast-feed during treatment with Calquence and for 2 days after receiving the last dose.

Ability to Drive and Use Machines: Fatigue and dizziness have been reported and patients who experience these symptoms should be advised not to drive or use machines until symptoms abate.

Undesirable Events: Consult SmPC for full list of side effects. For monotherapy: Very common (≥ 1/10): Upper respiratory tract infection, sinusitis, second primary malignancy (SPM); neutropenia, anaemia, headache, dizziness, bruising, contusion, petechiae, haemorrhage/haematoma, diarrhoea, nausea, constipation, vomiting, abdominal pain, rash, musculoskeletal pain, arthralgia, fatigue, haemoglobin decreased, absolute neutrophil count decreased, platelets decreased. Common (> 1/100 to < 1/10): Pneumonia, urinary tract infection, nasopharyngitis, bronchitis, herpes viral infections, non-melanoma skin malignancy, SPM excluding non-melanoma skin, thrombocytopenia, atrial fibrillation/flutter, ecchymoses, gastrointestinal haemorrhage, intracranial haemorrhage, epistaxis, asthenia. Uncommon (≥ 1/1,000 to < 1/100): Aspergillus infections, hepatitis B reactivation, lymphocytosis, tumour lysis syndrome. For combination therapy: Very common (≥ 1/10): Upper respiratory tract infection, sinusitis, nasopharyngitis, urinary tract infection, pneumonia, SPM, neutropenia, thrombocytopenia, anaemia, headache, dizziness, bruising, contusion, petechiae, haemorrhage/ haematoma, diarrhoea, nausea, constipation, vomiting, abdominal pain, rash, musculoskeletal pain, arthralgia, fatigue, absolute neutrophil count decreased, platelets decreased, haemoglobin decreased. Common (> 1/100 to < 1/10): Bronchitis, herpes viral infections, non-melanoma skin malignancy, SPM excluding non-melanoma skin, atrial fibrillation/flutter, ecchymoses, gastrointestinal haemorrhage, epistaxis, asthenia. Uncommon (≥ 1/1,000 to < 1/100): Progressive multifocal leukoencephalopathy, hepatitis B reactivation, lymphocytosis, tumour lysis syndrome, intracranial haemorrhage.

Legal Category: Product subject to medical prescription which may not be renewed (A) Marketing Authorisation Number: EU/1/20/1479/001, EU/1/20/1479/002 Marketing Authorisation Holder: AstraZeneca AB, SE-151 85 Södertälje, Sweden.

Further product information available on request from: AstraZeneca Pharmaceuticals (Ireland) DAC, Block B, Liffey Valley Office Campus, Dublin 22. Tel: +353 1 609 7100.

CALQUENCE is a trade mark of the AstraZeneca group of companies.

Date of API Preparation: 10/2021 Veeva ID: IE-3208 This medicinal product is subject to additional monitoring.

Adverse events should be reported directly to: HPRA Pharmacovigilance, Website: www.hpra.ie Adverse events should also be reported to AstraZeneca Patient Safety on Freephone 1800 800 899

1. CALQUENCE 100mg Hard Capsules Summary of Product Characteristics. November 2021.

BTki = Bruton tyrosine kinase inhibitor

Veeva ID: IE-3418 | Date of Preparation: January 2022

PROSTATE CANCER Prostate Cancer: Early detection Strategies and Survivorship Written by Dr David Galvin (left) and Catherine McGarvey (below)

Introduction Prostate cancer now represents the second leading cause of male cancer death globally, and its incidence in Ireland is expected to double over the next 20 years. With no national policy in place, no strategy for early detection and no national data on treatment or outcomes, Ireland lacks much of the infrastructure to manage prostate cancer now, and is certainly ill-prepared for the expected surge in cases.

Early Detection Strategies Prostate cancer is unique, where a blood test (serum PSA), that is

Figure 1 EAU Algorithm

widely available, can not only help to detect early, curable cancer, but can also risk-stratify men as to their risk of developing advanced disease and dying from prostate cancer over the subsequent 20 years. In other words, PSA can detect a high-risk group of men, in whom close observation can be used to detect, and effectively treat prostate cancer.1

72 | FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

PSA is effective as a population based screening test.2 The Goteborg arm of the European Randomised trial of Screening in Prostate Cancer (ERSPC) demonstrated a 42% reduction in prostate cancer mortality and a 60% reduction of metastases in men tested using PSA every 3 years (and this study did not utilise risk stratification, modern imaging (MRI) or targeted biopsy techniques all of which reduce over diagnosis and over treatment).3 Despite this no national screening program exists for prostate cancer. The argument against widespread screening centres on the poor sensitivity of PSA and the potential over investigation, over diagnosis and over treatment. However, due to the lack of screening programs, men still present with de-novo metastatic disease. A balanced, evidenced based algorithm approach to investigation of prostate cancer based upon risk stratified PSA levels could negate these issues.

Due to the strength of evidence that now exists as to the reduction of prostate cancer morbidity and mortality, the European Urology Association (EAU) has now

recommended the establishment of national population level testing across Europe and a detailed algorithm (figure 1) is suggested.4 Current PSA testing in Ireland is chaotic and random (opportunistic model). Testing depends on a number of factors including the patients’s own values, educational level, socio-economic status and access to primary care.5 In addition the GPs (or practice nurses) values and personal preferences may also play a role. The current ICGP guidelines state PSA should not be a routine test [ https://www. hse.ie/eng/services/list/5/cancer/ profinfo/ resources/gpreferrals/ nccp-prostate-cancer-gp-referralguideline.pdf ]. Many patients do not engage with their doctors unless they develop symptoms and even then, can present late with advanced disease.

Any early detection strategy must address the following issues: 1. Reliance on Primary care to perform PSA testing 2. Marked Social inequity in access to PSA testing 3. Opportunistic (random chaos) model of testing

The opportunistic approach to early detection currently in Ireland has been demonstrated to perform poorly when compared to an organised co-ordinated national pan for PSA testing.3 In fact the opportunistic model impacts little if any on mortality and may in fact do more harm to a population than good.

Based on the overwhelming evidence of the ERSPC trial, together with a number of advances in prostate cancer diagnostics (multiparametric MRI imaging, Trans-perineal and targeted prostate biopsies, and PSMA PET CT scans) and prostate cancer treatment (widespread use of active surveillance, minimally invasive surgery, hypofractionated radiotherapy, and new systemic therapies) the EAU has recommended to the European Commission that the algorithm described in figure 1 be adopted in to European clinical practice.

In order to provide a national population based testing environment in Ireland, a phlebotomy service and database would need to be developed. The current breast check, fixed and mobile units, would provide an ideal platform for a national PSA blood test service, and this would minimise capital costs. A database would need to be established of all men (or persons with a prostate) over the age of 45 who would be called for baseline PSA testing.

Men would be classified as to being either high risk or low risk based on this PSA result, and this will influence the frequency of follow up PSA tests.4 Once a threshold value for their age is reached, men are referred to the Rapid access prostate service (as per NCCP guidelines) that is already established in 8 diagnostic centers across Ireland, where multi-parametric MRI imaging is performed to assess for potential clinically significant prostate cancer, and if necessary a histological diagnosis is made using prostate biopsy. The Irish Prostate Cancer calculator is a nomogram that be utilised to further reduce the number of men undergoing biopsy.6

A key component of the National Cancer Strategy 2017-2026 is ‘Living with and Beyond Cancer in Ireland’. [ https://www.hse.ie/ eng/services/list/5/cancer/profinfo/ survivorship-programme/living%20 with%20and%20beyond%20 cancer%20in%20ireland.pdf ] The number of cancer survivors is currently almost 4% of the Irish population and this number will continue to increase.

Many common cancers, when diagnosed promptly and treated successfully, result in people being declared cured of cancer. Due to the heterogeneity of cancers, patients’ experiences are very different. A 50 year old man on active surveillance for low risk prostate cancer has a very different journey to a 70 year old man with recurrent metastatic prostate cancer. A prostate cancer patients survivorship encompasses many aspects, e.g. the psychological fear of risk of recurrence, the functional aspects of urinary incontinence, the emotional aspects resulting from relationship issues due to erectile dysfunction, pain management associated with metastatic disease.

Survivorship supports and treats all aspects of their patient’s disease: oncological, functional, psychological and social. Many healthcare professionals in our services already provide this care and support but we can strengthen, standardise and ensure access for patients to high quality survivorship services and supports. A key aspect of survivorship is enabling care in the community and at home following discharge from the cancer centre. The key to survivorship is co-ordination of care between the hospital (where the patients main oncological surveillance will occur), primary care and community allied health services.

Models of survivorship care include: physician-led, nurse-led, shared care models, community care models and survivorship care programmes. The HSE’s proposed model of care for adult survivorship incorporates: assess, link in and link out and onward; inform; empower; delivery of timely access to support and services (ALLIES for cancer survivorship care in figure 2).

Patients are risk stratified based upon a holistic needs assessment which encompasses multiple factors: age, disease, stage, comorbidities, social status, employment status, support structures and baseline resilience scores. Based upon this risk stratification, patients can have an individualised survivorship program. In Ireland, there has been some developments in this regard with the development of clinical psychologist and advanced nurse practitioner posts in cancer survivorship and funding support for the delivery of the “Cancer Thriving and Surviving“ programme. This is adapted by Stanford University from their Chronic Disease Self-Management Programme (CDSMP) which is based on rehabilitation best practice model.7 Currently it is being delivered across multiple sites by community and hospital based organisations.

Many studies have highlighted the many unmet needs of prostate cancer patients, and survivorship is a response to address those unmet needs.8 All men experience a range of psychological effects following diagnosis and in response to their treatments and beyond. Up to 60% of men

report significant anxiety following diagnosis, and 10% have clinical depression, and an increased risk of suicide. Not only is this a challenge to their survival, but it is also a threat to their health, their social and family integrity as well as financial security.9 Following treatment men fear the possibility of disease recurrence, and have to deal with poor urinary, bowel and sexual function and the consequences that may have on a relationship. The risk factors for poorer psychological outcomes are lower socio-economic status, younger age at diagnosis and being single. In a study of men’s health-seeking behaviour within 12 months of treatment, 82% of men reported unmet supportive care needs relating to sexuality, psychological, and health system and information issues.10 Survivorship remains under developed, and must become an embedded part of the cancer care journey in Ireland.

The multidisciplinary team have a valuable role to play in the implementation of survivorship care. Survivorship transcends the patient journey through primary care, acute care and community.

Research is required to inform the development of survivorship care in relation to prostate cancer and buy in from all stakeholders.

Achieving the best outcomes from the patient’s perspective is now considered the primary aim of treatment.

References available on request

Figure 2

Prostate Cancer Survivorship The National Cancer Registry data has demonstrated that there are as many survivors of prostate cancer in Ireland today as all other cancers affecting men combined (NCRI.ie). Prostate cancer survivorship is defined as the optimisation of both physical and mental well-being, to maximise long-term health related quality of life. All of these men are living with the consequences of their diagnosis and treatment(s).

Improving the quality of life for this cohort of men and their family is the essence of survivorship efforts.

HOSPITALPROFESSIONALNEWS.IE | HPN • FEBRUARY 2022 | 73 Acute sector cancer survivorship services in the Irish context NCCP 2018

PAEDIATRIC AML Management of Paediatric Acute Myeloid Leukaemia(s) Written by Dr Neil Barrett, MRCPI, MRCPCH, FRCPath - Clinical Fellow in Paediatric Haematology - Children’s Health Ireland at Crumlin, Dublin and Professor Owen Patrick Smith, CBE, Hon FTCD - NCCP National Clinical Lead for Children, Adolescent and Young Adult Cancers - Consultant Paediatric Haematologist, Children’s Health at Crumlin, Dublin Professor of Paediatric and Adolescent Medicine, University College Dublin - Academic Lead, Children’s Health Ireland resulting in anaemia, neutropenia and thrombocytopaenia. Direct consequences of this clonal hyperproliferation include lifethreatening leucocytosis, bone pain and extramedullary manifestations such as hepatosplenomegaly, skin infiltration, gingival hyperplasia, or granulocytic sarcomas (solid tumours of myeloid cells).

Childhood AML most commonly presents with symptoms and signs related to the aforementioned direct and indirect processes including; abnormal bleeding, pallor, fatigue, bone pain, fever or infection not responding to standard management. AML is rarely diagnosed incidentally in children.

Dr Neil Barrett

Professor Owen Patrick Smith

Introduction

with excellent outcomes with overall survival rate greater than 90% in high-income countries.

Acute Myeloid Leukaemia (AML), the second commonest leukaemia seen in children affects 8-10 children each year in Ireland.

Despite continued improvements in overall survival in recent years (Figure 1), AML still accounts for a disproportionate number of paediatric leukaemia deaths relative to Acute Lymphoblastic Leukaemia (ALL). ALL is the most common cancer seen in children and adolescents and is associated

Like ALL, AML is a heterogenous group of disorders characterised by malignant transformation of bone marrow stem and/or progenitor cells via a combination of enhanced self-renewal and differentiation blockade with resultant hyperproliferation of abnormal myeloid cells. This hyperproliferation indirectly overwhelms normal haematopoiesis

Paediatric and Adult AML are Biologically Distinct AML is considered by many as a disease of aging. Over an individual’s lifetime, leukaemia promoting mutations are acquired and selected for and clonal diversity reduces. This reduced clonal diversity, termed agerelated clonal haematopoiesis (ARCH) may manifest clinically as myelodysplastic syndrome MDS or AML. Studies of the genomic landscape of AML have shown distinct differences between adults and children. Supporting the theory

that AML is a disease of aging, the mutation burden, as quantified by the number of mutations per megabase of DNA, correlates with the patient’s age at presentation while chromosomal translocations are more common in children (Figure 2) and less frequent in adults, 50% of whom can have a normal karyotype (NK). Therefore, AML may be conceptually thought of as being secondary to a few or a single big driver event in children versus multiple more subtle events with clonal selection overtime in older adult cohorts.

Specific differential mutations worth highlighting include the marked prevalence of KMT2A (formally known as MLL (mixed lineage leukaemia)) fusions in infant cohorts seen in 35-60% of cases (Figure 2). WT1 and RAS signalling pathway mutations are also more common in childhood AML. These mutations have been chosen for specific mention as the deranged signalling pathways involved represent potentially attractive options for novel targeted drug therapies which is the subject of ongoing research.

The relative lack of “second hit” mutations in childhood cases makes ‘targeting’ these driver mutations particularly attractive.

Novel drug therapies targeting IDH2, which is commonly mutated in adult AML along with DMT2A and IDH1, interestingly, are not as useful in children as these genes are not frequently implicated in paediatric AML further reinforcing these two entities are biologically distinct.

Treatment of Paediatric AML in Ireland While various classifications systems exist for AML including modern WHO criteria and the more historical French American British classification (FAB), in terms of clinical management, paediatric AML can be generally broken down into three distinct groups which are each approached differently.

Fig 1: from Burnett et al Br. J. Haematol 20201

74 | FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

Fig 1: from Burnett et al Br. J. Haematol 20201

All-Trans-Retinoic Acid (ATRA) binds the PML-RARA protein directly, resulting in multiple effects including the recruitment of transcriptional coactivators rather than repressors, and activation of proteasomes which degrade PML-RARA protein thereby lifting the block in differentiation. ATRA has been shown to lead to the rapid resolution of the oftenlife-threatening DIC and early initiation of ATRA whenever APML is suspected can be life saving markedly reducing early mortality Beyond resolution of DIC, numerous published studies over the past 3 decades have shown that ATRA alone can induce remission in up to 90% of APML cases – however, this effect can be short lived without the additional effects of other agents including more traditional chemotherapeutic agents such as an anthracycline or cytarabine. More interestingly another non-traditional agent targeting the PML-RARA fusion, Arsenic Trioxide (ATO) can act in a synergistic manner with ATRA to produce “chemo-free” durable remissions and cures.

3 This centralisation paediatric e 2: from Bolouri al Natet Med. 20182 & Conneely et alof allCurr.

Oncol. Rep 2021the Figure 2: frometBolouri al ATO binds PML moiety of the

Nat Med. 20182 & Conneely et al Curr. Oncol. Rep 20213

cancer services in 2002 has greatly facilitated enrolment in clinical trials and all children with AML in Ireland, if eligible, are enrolled in an ongoing clinical trial as the standard of care.

PML-RARA fusion protein inducing degradation of the protein complex inducing both partial differentiation and caspase dependent apoptosis in the leukaemia blasts. As single 1 Acute Promyelocytic ATO can induce remission in fferentialLeukaemia mutations(APML) worthalso highlighting include the marked prevalenceagent of KMT2A between 65-80% of APML patients Treatment of Acute known as AML-M3 which is with a 30% 10-year survival, Promyelocytic leukaemia translocations nown as characterised MLL (mixedbylineage leukaemia)) fusions in infant cohorts seen– in 35-60% however to due its distinct involving the retinoic acid mechanism of action in targeting APML is considered separately receptor alpha (RARA). of PML-RARA the potential for from other forms of AML not only igure 2).

WT1 and RAS signalling mutations are but alsoit’smore synergism common with in ATRA therapy 2 Myeloid leukaemia of Down pathway due to its unique biology was obvious. syndrome (ML-DS) which is unusual combination of a clinical uniquely seen in children presentation with particularly AML. These mutations have with been chosen for specific mention as the Thederanged combination of ATRA and trisomy 21 (T-21), presents emergent and life-threatening ATO has been shown to be safe almost invariably before the age clinical manifestations yet a and effective in children and 4 years and is usually potentially related pathwaysofinvolved represent attractive options for novel targeted drug prospect of excellent clinical adults with APML with shorter to the clinical entity, transient response to a targeted therapeutic times to remission induction and leukaemia of Down syndrome approach with high curative more durable remissions – with which is the subject of ongoing research.

The relative lack of “second hit” mutations (DS) that has a specific genomic efficacy, which may not always increased overall survival. Current mutation in GATA1 (see later) require what would be considered paediatric protocols now advocate and can be seen in newborn standard chemotherapy d cases makes these driver mutations particularlyagents. attractive. for Novel drug “chemo-free” a completely infants ‘targeting’ with trisomy 21 (T-21). treatment of APML entirely based Clinically these patients can on ATRA/ATO combination therapy 3 All other AMLs that do not fit present with severe disseminated argeting IDH2, which1 or is 2. commonly andrisk patients. in all but high into category This is the mutated in adult AML along with DMT2A intervascular coagulopathy most common type and for the (DIC) which may rapidly be High-risk patients, defined by the purposes of this article will be fatal within hours to days of white cell count at presentation referred to as ‘Standard AML’. presentation and constitutes a of >10 x 109 /L. have traditionally been treated with additional haematological emergency.

Paediatric AML in Ireland is chemotherapy agents in addition managed in the National Children’s The characteristic genetic to ATRA. Adult protocols deliver Cancer Service based in Children’s lesion of this subtype is a Idarubicin in combination with Health Ireland at Crumlin. This is balanced translocation between ATRA for remission induction the central hub of a national hub the RARA (a transcriptional whilst most current and active and spoke shared care model regulator essential in normal clinical trial protocols in children with sixteen shared care centres cell differentiation) and the PML employ, in of place anthracycline across the country. This model of gene forming PML-RARA (t15:17) chemotherapy, a further targeted care allows expert treatment of fusion which acts as dominant approach with Gentuzimab this rare condition to be delivered negative inhibitor of wild type Ozogamycin (GO) - a monoclonal by experienced clinicians while antibody drug conjugate – simultaneously enabling supportive RARA causing a differentiation block in haematopoiesis at the care close to children’s homes or Ozogamycin conjugated to antiindeed within their homes.

CD33 (CD33 being a cell surface promyelocyte stage.

marker strongly expressed on APML blasts). The aim in paediatric APML is to cure even high-risk children with an entirely molecularly targeted approach that is ‘Chemofree”. With expected cure rates around 90% or better overall.

The presence of the unique PMLRARA fusion gene not only opens up the possibility of targeted therapies as discussed but also affords a unique marker that can be followed to assess disease response in the form of molecular monitoring (minimal residual disease - MRD) via reverse transcription PCR (RT-PCR) for the RNA transcript produced by the pathogenic gene fusion – with positivity after consolidation being associated with increased likelihood of relapse, ongoing studies are examining the role of such monitoring including if blood rather than bone marrow can be used for such monitoring to further improve patient outcomes while reducing impact of monitoring on children’s lives.

A small number (<5%) of APML occur with an alternative translocation partner for RARA other than PML – some of these partners including NPM1 and NUMA retain their sensitivity to ATRA therapy; however, a few partners (PLZF and STAT5b the latter caused by an interstitial deletion rather than translocation) are insensitive to these novel agents and must be treated as per a “standard” AML. Treatment of Myeloid Leukaemia of Down syndrome Children born with DS are at risk of a unique form myeloid leukaemia characterised by truncating mutations in the transcription factor GATA1. This mutation exerts profound effects on transient myeloid progenitors in the foetal liver in the setting of T21 and possibly mediated by specific microRNAs, these progenitors can expand. This can manifest as the entity known as Transient Leukaemia of Down syndrome (TLDS) in which the infant may be found to have raised blasts percentage in the peripheral blood at birth with or without more severe clinical symptoms and signs of leukaemia.

The leukaemia however is supported by progenitors of foetal liver origin and possibly due loss of this supportive niche or exhaustion this progenitor pool, there is usually a spontaneous resolution of this leukaemia without the need for treatment.

However, approximately 15-20%

HOSPITALPROFESSIONALNEWS.IE | HPN • FEBRUARY 2022 | 75

PAEDIATRIC AML of these infants can have acute life-threatening complications such as hyperleukocytosis, hepatic failure, DIC with bleeding and commencement on low dose cytarabine can be life-saving in the more serere phenotypes.

While the majority of children with TL-DS see resolution of their blood condition, they remain at risk of going on to developing ML-DS for the first 5 years of their life – is important therefore they are followed up regularly by a paediatric haematologist.

While 20% of all infants with DS will have a clonal population blood cells at birth with truncating GATA1 mutations - only those with peripheral blast percentages of 194 10% or greater in blood sampled in the first 3 days of life are at substantial risk of developing 195 ML-DS and blood film examination is recommended for all infants with down syndrome in the first few196 days of life to identify those at risk. Children in which TL-DS is 197 not recognised having not presented clinically or have not had screening with such assessments are of course also at risk of such transformation.

Children with DS who develop ML-DS tend to respond extremely well to therapy. A protocol consisting of a 4-cycle course of reduced anthracycline AML therapy, developed by European investigators (including some from Ireland), results in excellent responses with an event free survival in excess of 90%.

GO was trialled as a drug in the South West Oncology Group S0106 but the trial was stopped early due to adverse safety profiles with increasing treatment related mortality. However, further studies with reduced and fractionated dosing showed an acceptable safety profile, demonstrated a marked improvement in event free survival in “favourable” genetic risk groups, a marginal effect in intermediate risk groups in adults and is now standard of care in adults. These findings were also observed in the COG AAML 0531 trial however further exploration of how best to use this drug, including dose and frequency remains an important goal in order to optimise overall benefit.

pattern to adult AML with the exception that “complex karyotypes” , defined as those with greater than three abnormalities do not carry the same adverse prognosis that they do in adults.

Overall, more children than adults would fall into favourable cytogenetic categories with 40% expected to be in a good risk group, 35% in the intermediate group and only 25% in the higher risk category.

Minimal Residual Disease (MRD)

While MRD is still predictive of prognosis in AML, its negative predictive value for relapse risk is far lower than in ALL, with almost 25% of patients achieving MRD negativity experiencing a relapse (Table 2). Therefore, at present, in AML, MRD is a means of early identification of patients requiring escalation of therapy but unlike in ALL MRD cannot be used to deescalate therapy in AML. MRD in AML is commonly measured by multi-coloured flow cytometric immunophenotyping in which cells are identified based on size, complexity and surface marker proteins. This technique requires expert analysis of the diagnostic specimen and profiling of a characteristic “leukaemia associated aberrant immunophenotype” or LAIP.

In childhood ALL, multiple prospective national and international consortia studies have shown that response to treatment as measured by the MRD at the end of induction PROGNOSTIC FACTORS chemotherapy is strongly cytogeneticTypically, Overall, more children than adults would fall into favourable categories with 40% sensitivities of 1 in 1000 predictive of outcomes. MRD Cytogenetics cells are achievable but this can be negative patients have such high operator The presence expected to be in a good risk group, probabilities 35% in the intermediate group and only 25%dependent. in the higher Results from multiple clinical of cure that deof a skilled laboratory scientists trials have uncovered many escalation of treatment intensity and an informative LAIP is crucial. prognostically can safely be allowed without a risk category.significant cytogenetic findings. Broadly, drop in event free survival. The Molecular MRD monitoring by cytogenetics in paediatric AML role of MRD in AML; however, is RQ-PCR is possible on the 60% of follows a similar prognostic less well established. patients that may have informative

Table 1.

Cytogenetic Feature

Good Risk

t (8;21) RUNX1-RUNX1T1 inv(16) CBFB-MYH11 Double mutation of CEBPA without FLT3-ITD Mutation of NPM1 without FLT3-ITD

Intermediate t(9;11) MLL-MLLT3 Risk

Almost all cases of ML-DS are diagnosed before the age of 5 years. Children with DS presenting the AML after this age and are treated are unlikely to have the unique pathobiology alluded to above are treated according to standard AML therapy protocols.

t(11;19) MLL-MLLT1

Other MLL (aka KMT2a) rearrangements not classified as poor risk

All other abnormalities which are neither good or poor risk Including normal karyotype without NPM1/FLT3 mut

Treatment of ‘Standard’ AML Children with the most common form of AML are currently treated as part of an International Randomised Phase III Clinical Trial studying the treatment of AML in Children , Myechild 01.

This clinical trial builds on prior trials of the Medical Research Council (UK) and the Children’s Oncology Group (USA) and seeks to further improve outcomes by defining the role of minimal residual disease monitoring combined with cytogenetics in risk adapted therapy, the role of adding GO to traditional anthracycline & cytarabine chemotherapy and myeloablative vs reduced intensity transplant for high-risk cases.

Poor Risk

inv(3)

abn(3q26)

t(6;9) DEK-NUP214

-5/del(5q) -7 or monosomy 7 t(9;22)(q34;q11)/BCR-ABL1

12p abnormalities t(6;11) MLL-MLLT4 t(4;11) MLL-AFF1 t(10;11)MLL-MLLT10 t(5;11) NUP98-NSD1 t(7;12) MNX1-ETV6 inv(16) CBFA2T3-GLIS2 FLT3-ITD without NPM1 or CBF

198

76 | FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE 199 Minimal Residual Disease (MRD)

207

experiencing a relapse (Table 2). Therefore, at present, in AML, MRD is a means of early

208

identification of patients requiring escalation of therapy but unlike in ALL MRD cannot be

209

used to de-escalate therapy in AML.

210

211

212

213

214

215

216

217

Table 2. Minimal Residual Disease and Event Free Survival in ALL and AML Paediatric ALL

EFS

Paediatric AML

EFS

MRD Negative

>95%

MRD Negative

75%

MRD Positive

85-90%

MRD Positive

25%

patients will achieve a second remission whilst 1 out of 3 will be alive 5 years after the event.

The Future

MRD, Minimal Residual Disease; Event Free Survival, EFS

transplantation (RIC), as opposed molecular markers. RQ-PCR will be considered for SCT if not to more intense traditional meeting these criteria at the end of achieves sensitivities down to course three. myeloablative conditioning (MAC), 1 cell in 10,000 to possibly as MRD in AML is commonly measured by multi-coloured flow cytometric immunophenotyping based on promising data from low as 10,000,000. The level Role of Allogenic Stem Cell adult cohorts and some paediatric at which MRD demarcates transplantation (allo SCT) studies ismarker also being explored.This In prognostic in AML is an in which groups cells are identified based on size, complexity and surface proteins. simple terms, RIC is thought to area of active research. The hope Allogenic Stem Cell transplantation reduce treatment related mortality is that, in the future, refinements of bone marrow or peripheral technique requires expert of the diagnostic specimen and profiling of a characteristic although potentially at the cost in prognostically significant cut analysis blood mobilised stem cells, of disease control. The trade-off off levels that may permit further allows delivery of high dose may be a net benefit in terms of optimisation of risk stratification chemotherapy and moreor LAIP. “leukaemia associated aberrant immunophenotype” overall survival. Future studies including identification of “good importantly allows for the are needed to discern if RIC players” suitable for de-escalation development of a graft versus versus MAC transplantation can with resulting decreased toxicity as leukaemia (GVL) effect which can becan incorporated into risk adapted has been seen in ALL. Typically, sensitivities of 1 in 1000 cells even are achievable be operator dependent. be curative in high risk or but this therapy i.e.: should higher risk relapsed disease.

Integrating Prognostic Factors patients receive MAC conditioning. for Adapted TheRisk presence ofTherapy a skilled laboratory scientists LAIP is crucial.

However, toxicityand froman alloinformative SCT Relapse / Refractory is high, with significant treatment Risk adapted therapy refers to Paediatric AML related mortality (TRM) from the incorporation of prognostic direct toxicity, infections, and A shown above, the 5 year factors such as cytogenetics and graft versus host disease. While overall survival for paediatric MRD into treatment algorithms. improvements in supportive care ‘standard’ AML has plateaued at For AML, risk adapted therapy and immunomodulatory options appromimately 75%. Mortality effectively means that children have reduced TRM and disparity is caused by early death due to with known high-risk cytogenetics between transplants from related leukaemia, refractory disease, are considered candidates for an and unrelated donors, the point treatment related complications, allogenic Stem Cell Transplant of equipoise for the role of allo and relapse. Despite attempts to (SCT) in clinical remission after SCT for patients in first clinical course one (CR1) even without a remission (CR1) between treatment intensify therapy, relapse remains the most important cause of matched familial donor. Whereas related toxicities and the native treatment failure and occurs in patients with intermediate risk relapse risk remains a subject approximately 30% of patients genetics are deemed SCT of debate. who achieve complete remission candidates if they fail to meet MRD following initial diagnosis. Of those Increasing interest in the goals by end of course two and application of reduced intensity patients who relapse, 2 out of 3 those with good risk cytogenetics

Incremental improvement of survival in childhood AML has been seen over the past number of years however in the setting of a comparatively rare condition such as childhood AML, this can only be accomplished through multicentre international randomised controlled trials.

As illustrated by the exemplars of ML-DS and APML specific knowledge of the underlying biology of certain subsets of AML has been of diagnostic and therapeutic benefit and within the entity of paediatric AML as a whole, advances in genomics and epigenetics promise to add further depth to our knowledge assisting prognostication, risk adaptation and highlighting potential therapeutic targets.

Figure references – further refferences on request 1. Burnett, A. K., Hills, R. K. & Russell, N. Twenty five years of UK trials in acute myeloid leukaemia: what have we learned? Br. J. Haematol. 188, 86–100 (2020).

2. Bolouri, H. et al. The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and agespecific mutational interactions.

Nat. Med. 24, 103–112 (2018).

3. Conneely, S. E. & Stevens, A. M. Acute Myeloid Leukemia in Children: Emerging Paradigms in Genetics and New Approaches to Therapy. Curr. Oncol. Rep. 23, 16 (2021).

Oncology News Transforming Cancer Care in Ireland It has been revealed that a Health Research Board (HRB) investment of ¤21 million in cancer clinical trials will transform cancer care in Ireland.

The funding will tackle childhood and adult cancers, making a real difference to the lives of cancer patients, allowing them more access to cancer trials by increasing the resources and expertise required to conduct them.

It will do so by providing essential support for six Cancer Clinical Trials Groups and an overarching National Cancer Clinical Trials Network. This increases our investment in cancer clinical trials infrastructure* each

year by more than half a million to ¤4.27 million, making the Health Research Board (HRB) the lead public funder of cancer clinical trials infrastructure in Ireland**.

Network*** award will be led by Professor Ray McDermott (Clinical Lead, Cancer Trials Ireland) and hosted by RCSI University of Medicine and Health Sciences.

This HRB investment will enhance the volume, quality and reach of cancer clinical trials in Ireland by strengthening partnerships between hospital sites, Clinical Research Facilities/Centres and academic partners.

In addition, six cancer trials groups**** were awarded as follows:

4. UCC Cancer Trials Group led

by Professor Roisin Connolly and hosted at University College Cork

1. Children’s Health Ireland Cancer Trials Group led by Professor Owen Smith and hosted at University College Dublin

5. Ireland East Hospital Cancer Trials Group led by Professor Catherine Kelly hosted at University College Dublin

Following an extensive and rigorous application and peer review process by an independent and international panel of experts, the National Cancer Clinical Trial

2. Beaumont Hospital – RCSI University of Medicine and Health Sciences Cancer Trials Group led

by Professor Patrick Morris and hosted at RCSI

6. Trinity Academic Cancer Trials Group led by Professor Maeve Lowery hosted at Trinity College Dublin

3. Irish Research Radiation Cancer Trials Group led by Dr Sinead Brennan and hosted at Trinity College Dublin

HOSPITALPROFESSIONALNEWS.IE | HPN • FEBRUARY 2022 | 77

LYMPHEDEMA

A Snapshot of Lymphedema in Ireland: Results from LIMPRINT Written by Mary-Paula Colgan, MD, RVT, RPVI, MBA, Norah Kyne, MISCP, MSc, Cert MLD/CDT, Bernadette Hannon, MA, BNS, RN, RM, Elaine Grehan, Cert MLD/CDT, Kay Morris, MISCP, MSc, Monica Conway, MSc, Nina Murray, BA, HDip, Olive Carney BSc, R.G.N, and Meadbh MacSweeney RGN MPH,on Behalf of National Lymoedema Framework Ireland

Introduction

validation of the core tools used in phase 2. Phase 2 involved the roll out of these tools to 9 countries and 40 sites. Ireland joined in the last few months of phase 2.

Lymphedema is a chronic swelling due to lymphatic system failure.

It can be primary, resulting from failure of lymphatic development or function, or secondary, after damage to the lymphatic system (e.g., cancer treatment, injury). It can affect any part of the body, but most commonly affects the limbs. Its prevalence is often reported as increasing due to improved cancer survivorship, but equally important is its improved recognition in other diseases, for example, venous disease, cardiac failure, obesity, and immobility.1–4 Chronic edema (CE) is defined as edema that has been present for greater than three months regardless of its etiology.

LIMPRINT (Lymphoedema IMpact and PRevalence—INTernational) was an international study aimed at capturing the size and impact of CE in different countries and health services across the world.5 The project was co-ordinated by the International Lymphoedema Framework (ILF) through its participating national frameworks.

LIMPRINT was a two-phased study. Phase 1 was conducted from June 2013 to 2014 with the

LIMPRINT's primary aim was to identify the number of people with CE within differing countries and to determine its impact on patients. It believed that these data would • establish the size of the problem of CE, • provide the basis for evidencebased practice, and • be used to facilitate improved reimbursement.

An international data set of >13,000 patients was collected.

The study was supported by an electronic data capture system and data collection tools that had been previously validated (Clindex). The National Lymphoedema Framework Ireland (NLFI) was set up in November 2015 and as one of the ILF frameworks requested to and was invited to join the study despite proximity to its completion. The recent HSE Model of Care for Lymphoedema/Lipoedema6 has highlighted the lack of Irish data, and NLFI joined the international

study to help gather relevant local data as part of the effort to inform and influence education, management, and resources allocation for those medical conditions that can give rise to CE. Materials and Methods Data were collected using clinical assessments tools previously validated by the ILF. These tools included the Core Tool, Quality of Life Tool, EQ-5D, upper limb and lower limb-specific Lymqol Quality of Life Tool, details of Swelling tool, Cancer Tool and Wound Tool. Three hospital settings were chosen, both an in-patient and out-patient oncology unit in Galway and a vascular out-patient unit in Dublin. Patients attending an oncology clinic or in an inpatient ward on a specified day were invited to participate, and all patients attending vascular out-patients for a 4-week period were included in the study.

Inclusion was not age limited as it was considered important to gather information if possible, on children. Parental consent was obtained in this instance.

All participating patients were assessed for the presence of CE by clinically eliciting a positive

pitting test or a positive Stemmer Sign. The duration of swelling was obtained from the patient.

Patients who were diagnosed as having CE (present for >3 months) were then asked to complete a series of validated questionnaires, already described, depending on the etiology of their edema and/or the presence or absence of wounds. The collection of data was anonymized and was inputted to a central database (Clindex). Country-specific data were generated and returned to each individual country. The Irish data were also validated locally.

Results A total of 152 patients were assessed, 76 from the oncology service and 76 from the vascular service. Eighty-seven (57%) patients were female and 65 (43%) patients were male. The mean age was 65 years with a range 15–93 years. Twenty-five patients (16%) had CE: eight (11%) in the oncology service and 17 (22%) in the vascular service.

Figure 1 shows the age range of both the overall population and the patients with edema.

FIG. 1. Age distribution

FIG. 2. Length of history 9

80

8

70

7

60

6

40

5

30

4

No.

No.

50

20

3

10

2 1

0 <20 years

20-40 years

41-60 years

61-80 years

>80 years

Non-lymphodema patients

0 <6 months

Age Lymphodema patients

78 | FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

1-2 years

2-5 years

5-10 years

Length of History (yrs)

7-10 years

40 35 30

FIG. 3. Etiology of chronic edema

%

25

CE reduces quality of life in the majority of patients.

20

Discussion

15

Lymphedema/CE is a chronic swelling that is often overlooked by clinicians. It can occur at any age, and if left untreated can have debilitating consequences.

10 5 0 Primary

Cancer

Venous

The highest incidence of CE was found in the age group 41–60 years where the incidence was 27%. There were a total of 30 patients in this age group: 21 oncology patients and 9 vascular patients. Three of the 21 oncology patients had CE, whereas 5 of the 9 vascular patients had CE. Also of interest is the high incidence (21%) in the older age group (>80 years); all of these patients were in the vascular cohort.

There was a wide variation in the length of history of the presence of CE, varying from <6 months to >10 years (Fig. 2). Seventy percent of the vascular patients had a history in excess of 5 years.

Figure 3 shows the etiology of the lymphedema. Twenty-eight percent (n = 7) had primary lymphedema. Thirty-six percent (n = 9) had edema secondary to cancer, whereas 20% had edema associated with underlying venous disease (n = 5). Two patients had lipedema and in the remaining two patients their CE was considered secondary to immobility and obesity, respectively.

Obesity

Lipodema

Immobility

The lower limbs alone were affected in all the vascular patients. In the oncology group, three patients had unilateral upper limb swelling, two had unilateral lower limb swelling, and three had bilateral lower extremity swelling with one patient also complaining of abdominal edema.

None of the oncology patients were overweight, whereas 10 (59%) of the vascular patients were obese. Unfortunately, this information on the remaining cohort of patients who did not have CE is not available. Figure 4 shows the percentage obesity by age in the CE group. This varies from 100% in the younger age group to 50% in the old age groups.

A history of cellulitis was elicited in a total of nine patients: two in the oncology group (25%) and seven in the vascular group (41%). It was >1 year since either of the oncology patients suffered an episode of cellulitis and neither had ever required hospitalization for cellulitis. Only one of the vascular patients had been hospitalized for cellulitis in the past year.

Nine patients (36%) reported wounds, two in the oncology group and seven in the vascular group. One of the oncology wounds was a surgical wound and the other after cancer management. Seven of the 17 vascular patients (41%) had wounds related to their leg swelling. All were treated with compression bandages.

In terms of management of their edema, again there was wide variation (Fig 5) among patients. Unfortunately, nearly one in three patients received no treatment. Forty percent received compression alone and only six patients (24%) received the full range of treatment: two vascular and four oncology. Some of the main categories of treatment reported as received included skin care advice, wound dressings, antibiotics, massage (including MLD), physiotherapy (not massage), compression garments, exercise advice, and cellulitis advice.

Participating patients were asked to rate their quality of life on a 10-point visual analogue scale with 0 being poor and 10 excellent. Figure 6 shows that

More attention has been given of late to the noncancer secondary edema as this population is often

FIG. 5 Received treatment

FIG. 4. Obesity and age distribution 12

120 100

10

80

8

60

No.

%

LIMPRINT's primary aim was to identify the number of people with CE within differing countries and to determine its impact on patients.5 Unfortunately, there is no Irish data on the prevalence of lymphedema and the recent HSE Model of Care looked to the United Kingdom to extrapolate the number of patients in Ireland with lymphedema/CE. One of the first reports was by Moffatt in 2003,1 wherein a prevalence of 1.33 per 1,000 population was reported that rose to 5.4/1,000 in the >65-year olds. In 2017, Moffatt et al.2 reported a prevalence of 3.99/1,000 population, whereas in Northern Ireland, a prevalence of 4.83/1,000 was also reported.

An excellent meta-analysis from Torgbenu et al.7 in 2020 suggested a 27% incidence of arm lymphedema postbreast cancer. There were insufficient data to make meaningful assessment of leg lymphedema.

Although our incidence of 11% in cancer patients is lower than reported studies,7–9 our population was small, included a mix of cancer diagnoses and patients were at varying stages of their cancer treatment.

40

6 4

20

2

0 <20 years

20-40 years

41-60 years Age

61-80 years

>80 years

0 None

Skin Care

Compression

Full Range

HOSPITALPROFESSIONALNEWS.IE | HPN • FEBRUARY 2022 | 79

LYMPHEDEMA overlooked. This cohort may have complex underlying medical conditions and may have the greatest impact on the health service in the future in terms of morbidity and cost.10,11 We report an incidence of 22% in this group. If one looks at the combined LIMPRINT data, an in-hospital incidence of 38% was reported,12 whereas in nursing communities a staggering 56% were found to have CE.13 These findings emphasize the underestimation of CE in the population which, in turn, raises issues for health funding.

The HSE Model of Care concluded that “service provision for lymphoedema/lipedema is inadequate in most parts of Ireland with significant gaps

across the country and inequity of access for nononcology related lymphoedema.”6 Our findings would confirm this conclusion.

We found that only a quarter of all patients were receiving a full range of treatment. To our surprise, 25% of cancer-related lymphedema patients were receiving no treatment and only half were receiving a full range of treatments. Less surprisingly, only two of the vascular patients (12%) were receiving a full range of treatment. Fifty percent of the vascular patients were in compression and would have hopefully progressed from compression bandages to compression garments. However, in the absence of ancillary lymphedema care, one would have to question how good longterm compliance would be.

9 8

The association of CE and wounds is well accepted, and our findings mirror those of the Canadian Limprint group who reported an incidence of 40%.14 This emphasizes the additional costs associated with this patient cohort. Wound care costs have been estimated at £7600.00 for treating a single venous leg ulcer.15 Wounds secondary to CE are often more difficult to heal, suggesting this cost will be greater. Leg ulcer services should be utilized to help identify patients with CE and ensure adequate long-term care.

Collective LIMPRINT data from specialist Lymphedema Services in four countries found a history of cellulitis was reported in 32% with primary lymphedema compared with 35% of those with secondary edema.16 These findings are very similar to ours. Two of our five patients (40%) with primary lymphedema reported a history of cellulitis. Of the remaining 20 patients with secondary

Although our study is limited by small number of patients, our findings mirror those of others throughout the world. It is clear that the prevalence of CE is underestimated. It is associated with a high incidence of cellulitis and obesity. Our findings confirm the conclusions of the HSE Model of Care in terms of access to treatment. The provision of accurate epidemiological data is essential to provide a basis for accurate service provision and funding. We hope this snapshot of CE in Ireland will encourage others to collect data on this often overlooked patient group and will be an integral part of the HSE Model of Care as it is rolled out.

Acknowledgments We thank the personnel who helped with data collection.

These included Catherine O'Sullivan, Fionnuala Ginty, Fiona Melia, and Miriam Flatley from the Physiotherapy Department in Galway University Hospital and nursing students from Trinity College Dublin and St. James's Hospital.

7 6 No.

lymphedema, 8 (40%) reported a history of cellulitis with 1 being hospitalized in the past year. In a very recent report by Burian et al.,17 they reported a significant reduction in the incidence of cellulitis in CE by the simple use of compression.

5 4 3 2 1 0 0-2

2-4

4-6

6-8

8-10

Visual Analogue Score Oncology

Vascular

FIG 6. Quality of Life

This article is open access.

Lymphatic Research and Biology.

Oct 2021.473-478.http://doi. org/10.1089/lrb.2021.0061

Oncology News Impact of Covid-19 on Cancer A new project funded by the Irish Cancer Society will help to shed light on the impact of the COVID-19 pandemic on cancer diagnosis, treatment and survival in Ireland.

Through the course of the two-year project, researchers Professor Kathleen Bennett and Dr Maeve Mullooly from the Epidemiology & Modelling Research Group at the RCSI University of Medicine and Health Sciences will explore the effect of pandemic-related disruptions to cancer services and patient outcomes.

The project will be carried out in collaboration with colleagues at the National Cancer Registry

in Ireland (NCRI) and supported by the National Cancer Control Programme and Faculty of Pathology, Royal College of Physicians of Ireland (RCPI) and others.

The much-needed new project comes against a backdrop of disruption to healthcare services over much of the past two years due to COVID-19, and will look to build on findings from recent reports from the NCRI and RCPI indicating that around 10-14% of cancer diagnoses expected in 2020 were not diagnosed.

Commenting on the project, Professor Kathleen Bennett, RCSI

80 | FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

said, “Many routine cancer-related services were reduced or paused during the pandemic including screening, surgery, radiology and pathology services, and the short to long-term impact of these reduced services across the cancer spectrum is not yet clear.

“Through our project, supported by the Irish Cancer Society and in collaboration with the NCRI and others, we will examine data on the number of cancers diagnosed, as well as clinical characteristics of cancers before and during the pandemic to discover how the pandemic has impacted on new cases of

cancer, clinical management of cancer, and projected longer term consequences.”

Dr Maeve Mullooly, RCSI added, “We also want to build a picture of the long-term impacts of the pandemic on cancer outcomes, including survival. Information on the short, medium and longterm impacts on cancer care will help identify requirements and resources needed for future unmet needs of cancer patients.

This information will also provide knowledge to help identify future services needed to mitigate the impact of the pandemic on cancer management.”

Neutro-Predict Team Develop New Device neutrophil nadir and prevention of systemic infection will improve the outcome of cancer treatment.

Neutropenia is a condition of having abnormally low level of neutrophils, a type of white blood cell, required to fight infections, particularly those caused by bacteria.1,5 Patients having <1,500 neutrophils per microliter of blood are considered to be Neutropenic.5 Chemotherapyinduced neutropenia (CIN) occurs in cancer patients as an adverse side effect of treatment.1-3 The immune system of these patients become greatly impaired making them susceptible to infections, a condition known as Febrile Neutropenia (FN) associated with high body temperature.

FN is considered an oncologic emergency,1-3 with 60,000 cancer patients in the US hospitalized each year and a mortality rate of 21%.

The current system of management of febrile neutropenia involves administration of prophylactic antimicrobials and hematopoietic growth factor supplements (granulocyte colony stimulating factor G-CSF).

However, neutropenia is detected in these patients only after the onset of infection limiting the efficacy of these therapeutic interventions. Timely detection of

The Neutro-Predict© team at NUI Galway led by Dr Ananya Gupta has developed a hand-held near patient device that can measure neutrophil counts accurately.

Patients can use this device from the comfort of their home to monitor their blood cell counts following receiving chemotherapy.

The Neutro-predict device can accurately quantify neutrophil populations in a small droplet of blood. Such a device will enable the patients to monitor their own blood counts and allow early detection of neutropenia.

Timely detection of neutrophil loss and appropriate intervention will enable rapid and timely management of CIN and FN. Thus, Neutro-Predict will enable rapid and timely management of CIN and FN. It provides peace of mind and assurance to patients whose neutrophil counts do not fall below a critical level during chemotherapy. Timely detection and delivery of appropriate intervention will lead to prevention of sepsis, prolonged hospital stays, dose reduction and delay in receiving chemotherapy. This will in-turn improve the treatment outcome. Neutro-Predict thus aims to improve patient safety and quality of life, allowing for optimum use of antibiotics and GMCSF thus improving cancer treatment outcome.

This at home monitoring system will empower patients with the

The Neutro-Predict Device brings the following benefits:

For Patients • • • • • •

Reduces risk of mortality Reduces hospitalisation Prevents dose reduction and delay in treatment Provides timely delivery of needed interventions Improves cancer treatment outcome Provides peace of mind

For Nurses • • •

Aid triaging decisions Reduce case-load in emergency rooms Reduce patient mortality

• • • •

For Oncologists

For Healthcare System

Monitor patient responses Identify patients at risk of infection Treat with antibiotics and GMCSF as needed Optimize chemotherapy dose and time

• • • •

Free-up emergency room and acute resources Reduce costs Improve patient outcomes Reduce antibiotic resistance

Dr Ananya Gupta, Director of Exercise Physiology, NUI Galway option to monitor their blood counts from the comfort of their home without having to take repeated trips to the GP or hospital. It also equips healthcare professionals with the insights to make more informed and personalised clinical decisions about their patients undergoing chemotherapy. This innovative device will also help to identify patients who are at a greater risk of developing neutropenic sepsis during their chemotherapy treatment.

The Neutro-predict prototype device has been successfully evaluated in the laboratory in 400 patient samples and has shown great potential as it can predict the neutrophil count with a sensitivity of 100% and a specificity of 98.6% as compared to the hospital gold standard blood cell counter. The prototype device will be ready for testing amongst patients in the new year at the University Hospital Galway in collaboration with the Advanced Therapies and Cancer clinical research group, HRB Clinical Research Facility, Galway.

Neutro-predict is a fast, reliable, easy-to-use and low-cost device to monitor patients’ blood counts at home following chemotherapy, thus improving patient safety and quality of life, optimising chemotherapy treatment and timely delivery of antibiotic and GMCSF to protect patients from infection, and empowering doctors to treat their patients more efficiently.

If you would like to learn more about Neutro-predict please visit: https://www.nuigalway.ie/Neutropredict/ References available on request

HOSPITALPROFESSIONALNEWS.IE | HPN • FEBRUARY 2022 | 81

82 Clinical R&D YOUNG SPORTS STARS VOICE THEIR SUPPORT FOR OPEN CONVERSATIONS ABOUT DEPRESSION IN IRELAND Former Waterford hurler Maurice Shanahan and Dublin Ladies Senior Footballer Nicole Owens are lending their support to Talking Depression, a new campaign to encourage open and honest conversations. Launched by Janssen Sciences Ireland UC, the campaign comes as new research reveals that almost half of Irish adults (47%) do not feel equipped to have a conversation with a family member or friend who they suspect may be experiencing a mental illness, despite almost two thirds (62%) having more empathy towards mental illnesses, such as depression, compared to before the COVID-19 pandemic.

By taking the time to understand more about depression and encouraging conversations about mental illness, more people can have a chance to find the right support for them.

To help take that first step, a new resource, The Little Book of Big Conversations has been created to support people living with all forms of depression, their family members and friends. It is full of practical advice to help make those big conversations about depression a little easier. The book is part of a larger Global campaign created by Janssen in partnership with people living with depression and their loved ones and with the support of GAMIAN-Europe (the Global Alliance of Mental Illness Advocacy Networks Europe) and EUFAMI (European Federation of Associations of Families of People with Mental Illness).

The public survey of 1,000 people in Ireland, conducted by Empathy Research on behalf of Janssen, found that 78% of adults would be likely to have a conversation with a family member or friend who they suspect may be experiencing mental illness. However, there was concern about upsetting the person they are speaking to (81%), saying the wrong thing (79%), or not understanding the other person’s experience (73%).

Ireland has one of the highest rates of mental illness in Europe and it is estimated that approximately 150,000 people per year are living with severe depression (also known as Major Depressive Disorder or MDD) in Ireland. Recent patient research commissioned by Janssen, captured the prevalence and unmet needs of people living with the most severe forms of depression and shows how important it is to reach out for help.

This research, involving over 200 adults living with severe depression

in Ireland, shows that over 3 in 4 adults reported the COVID-19 pandemic has had a negative impact on their depression with half having had their access to support, therapy and treatment restricted. 3 in 5 adults living with severe depression say it has a major impact on their quality life as they experience a multitude of challenging symptoms daily including fatigue or loss of energy (74%), poor sleep patterns (66%), low mood and poor concentration (56%) and feelings of worthlessness (52%).

Dr. Thekiso B. Thekiso, Senior Lecturer and Consultant Psychiatrist, Trinity College Dublin, Navan Mental Health Services said, “Depression, and in particular severe depression also known as Major Depressive Disorder (MDD), is more than just a bout of the blues. It is where you stop doing the things you normally enjoy doing and you can’t simply “snap out” of it. Unfortunately, depression often goes undiagnosed and untreated in adults, and they may feel reluctant to seek help. The COVID-19 pandemic has without doubt made things much more challenging for people living with serious mental illness and now more than ever people need support. It is really important to reach out to your family, friends and in particular your HCP to get the help that you need.”

The Little Book of Big Conversations can be accessed at janssenwithme.ie/en-ie/little-bookbig-conversations UNDERSTANDING MS@WORK 9 out of 10 people (90%) living with multiple sclerosis (MS) in Ireland say that the COVID-19 pandemic has helped, or could help, steer conversations with their employer about how working from home could benefit them in the long-term1. That’s according to new research which was carried out by MS Ireland among its members ahead of the launch of Understanding MS@Work, a dedicated online employment resource for those living with MS and their employers.

The research found that 80% of people with MS say the way they work has changed as a result of the pandemic, while almost twothirds (64%) of those surveyed say that working from home has benefitted them over the past 18 months. Although the majority of respondents (85%) say that their employer knows they are living with MS, more than one-fifth (21%) of respondents cited ‘lack of understanding / empathy’ as the issue that most impacts their working life.

FEBRUARY 2022 • HPN | HOSPITALPROFESSIONALNEWS.IE

MS is the most common disabling neurological disease of young adults in Ireland, and affects the motor, sensory and cognitive functioning of the body. Symptoms of MS include impaired mobility and vision, severe fatigue and cognitive difficulties which can have a huge impact on an individual’s work and family life.

Understanding MS@Work, which is supported by Roche Products (Ireland) Ltd., aims to encourage and enable people living with MS to have beneficial conversations with their employers about their working environment. Videos of people with MS talking about their careers and their conversations with employers have been created along with advice on working during the pandemic. Sections have also been developed for employers so that they can become more informed and aware of the potential challenges faced by people living with MS and emphasize the benefits of providing a flexible work environment for employees with MS and other chronic conditions.

Simone Feresin, Patient Journey Partner, Roche Products (Ireland) Ltd. said, “Working life can be stressful for everyone, particular since the COVID-19 pandemic challenged the way many of us work and led to new ways of working for so many.

Understanding MS@Work aims to provide information and real life examples of flexible working environments so that people with MS and their employees can feel empowered to have important conversations which will benefit everyone in the long term.”

CLONMEL HEALTHCARE OFFERS IRELAND’S PHARMACIES A BROADER PORTFOLIO Clonmel Healthcare is now offering pharmacists, and their customers, a broader range of consumer healthcare brands such

as Pharmaton vitality/immunity, Telfast, Nasacort, Opticrom, and the Dulcolax laxative range, as well as Buscopan for IBS, and Maalox antacids. These attractive brands are covered by an agreement whereby Clonmel’s parent group STADA, is distributing and marketing Sanofi’s local portfolio of well-established consumer healthcare products across 20 countries.

The addition of such well known and strong brands like Pharmaton will enhance Clonmel’s existing portfolio of winter products, including the companies recently launched Medithyme cough syrup and long established Paralief (Paracetamol) and Easofen (Ibuprofen) ranges. With Clonmel Healthcare as a trusted partner, Irish pharmacists can be sure they are offering their customers an appealing and comprehensive offering for a range of symptoms.

“The addition of Sanofi’s portfolio to Clonmel Healthcare’s current offering will alter the companies ranked position in the market to No. 2 by volume, and will firmly place the company in the top 5 OTC companies in Ireland” according to Jim Hanlon, General Manager at Clonmel Healthcare.

He further added “Adding major brands like Buscopan and Dioralyte for rehydration further strengthens the companies’ position. We look forward to supporting pharmacy purchases with targeted and effective promotional campaigns for these brands.

Other brands in Clonmel Healthcare’s new offering included Antihistan Cream (Mepyramine Maleate) and Selsun anti -dandruff shampoo, which join Clonmel’s other products in the anti-fungal head care treatments such as Nizoral Shampoo.

Jim Hanlon, General Manager at Clonmel Healthcare

83 ¤1.8M FUND TO DEVELOP NOVEL MEDICAL DEVICES The COVID-19 pandemic has shone a light on the importance of the medtech industry’s ability to develop new solutions quickly in response to an urgent need.

Researching and developing novel medical devices can take many years and for some companies, especially SMEs, as the associated costs, often in millions, are hugely prohibitive.

The launch of MedPhab, Europe’s first pilot line for photonic-based medical devices, will leverage the experience, knowledge and capabilities of its research and business partners to drive collaboration, reduce R&D costs and accelerate commercialisation.

Photonics is the science of light and is fast becoming a key enabler for the advancement of medical devices. From its use in noninvasively monitoring the lung function of babies to enabling tissue recognition to distinguish between a tumour and healthy brain tissue, light is being used to improve treatment and diagnosis for patients around world. your diet?

Do you want tothe improve IPIC, the SFI Research Centre At UCD we study a new strategyfrom to improve diet quality using personalised dietary advice. research and technology The MedPhab team at Tyndall will for Photonics, led by researchers at Tyndall National Institute,

organisations with medtech

Dr David McGovern, Senior Business Development Manager at the Irish Photonics Integrated Centre, based at Tyndall National Institute, is calling on companies in the medtech sector to join MedPhab, which supports companies around the world to make novel photonic-based medical devices quicker, cheaper and more efficiently

help companies develop medtech

A healthy dietais key to and the prevention and treatment of non-communicable diseases such as solutions through technology UCC, play both technical industry leaders including Stryker diabetes disease. development support as well as commercialand role cardiovascular in MedPhab.

European Operations Limited,

funding of up to ¤125k to turn their Funded by Horizon 2020, the Philips Engineering Solutions, photonic-based diagnostic and initiative launched to support We arewas looking for adults who are 18 years or older, have a poor-quality diet Radisens Diagnostics and overweight, treatment devices into companies around the world Antelope Dx to accelerateAND/OR the and have any of the following: high blood pressure high cholesterol, AND/OR industrially-relevant demonstrators to make novel photonic-based commercialisation of photoniccurrently smoke. medical devices quicker, cheaper and is available for both SMEs based diagnostic devices and and more efficiently. and MNCs. instruments.

Photonics has01 been If you need more information, please contacting us at 716 6806 or a game changer for the medtech Dr David McGovern, Senior “MedPhab supports the scale metabomarkers@ucd.ie industry, driving innovation and Business Development Manager, up of Antelope Dx’s silicon advancements for both clinicians IPIC, explains, “MedPhab brings photonics functionalisation and Thank you – Teresa Grohmann and Aoife Courtney together international expertise and patients.” manufacturing processes. Having

access to the knowledge at the various partners will definitively speed up the development process and translation into actual manufacturing processes,” says Jan-Willem Hoste, COO at Antelope Dx. Companies interested in participating can visit www.medphab.eu or email david.mcgovern@tyndall.ie

DO YOU WANT TO IMPROVE YOUR DIET? At UCD we study a new strategy to improve diet quality using personalised dietary advice.

A healthy diet is key to the prevention and treatment of non-communicable diseases such as diabetes and cardiovascular disease.

We are looking for adults who are 18 years or older, overweight, have a poor-quality diet and have any of the following: high blood pressure AND/OR high cholesterol, AND/OR currently smoke.

If you need more information, please contacting us at 01 716 6806 or metabomarkers@ucd.ie Thank you – Teresa Grohmann and Aoife Courtney

HOSPITALPROFESSIONALNEWS.IE | HPN • FEBRUARY 2022

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‖

ENCLYXTO® REGIMENS: DEEP RESPONSE** AND LONGER PFS WITH FIXED TREATMENT DURATION1,2 ‖ Remission as measured by CR/CRi: 1L: VEN+O FTD 1 year1: CR/CRi(at 15 months): 50% (VEN+O) vs 23% (O+Clb) (P<0.0001)1; 2L+: VEN+R FTD 2 years1: CR/CRi‡(at 9 months): 27% (VEN+R) vs 8% (BR)1; ** Deep response as measured by CR/CRi and MRD negativity (PB): 1L: VEN+O FTD 1 year1: MRD negativity (PB)(at 15 months) 76% (VEN+O) (95% CI: 69–81) vs 35% (O+Clb) (95% CI: 29–42) (P<0.0001)1; 2L+ VEN+R FTD 2 years1: MRD negativity (PB)‡(at 9 months): 62% (VEN+R) (95% CI: 55.2–69.2) vs 13% (BR) (95% CI: 8.9– 18.9)1. PFS 4-year estimates‡: 1L: VEN+O FTD 1 year1: 74% (VEN+O) vs 35% (O+Clb) (HR=0.33; 95% CI: 0.25–0.45)2; 2L+: VEN+R FTD 2 years1: 54 months median PFS‡ (95% CI: 48.4– 57.0) (VEN+R) vs 17 months mPFS (95% CI: 15.5–21.7) (BR)1. ‡ Results are descriptive. PFS=progression free survival; CR(i)=complete remission (incomplete marrow recovery); 1L=1st Line; 2L+=2nd Line+; VEN=VENCLYXTO; O=Obinutuzumab; Clb=Chlorambucil; B=Bendamustine; MRD= Minimal Residual Disease; R=Rituximab; PB=peripheral blood; CI=Confidence Interval. FTD=Fixed Treatment Duration. References: 1. VENCLYXTO® SmPC available at www.medicines.ie. 2. Al Sawaf et al, HemaSphere, 2021;5(S2):27

VENCLYXTO®▼ (venetoclax) 10 mg/50 mg/100 mg film-coated tablets. PRESCRIBING INFORMATION. PRESENTATION: Each film-coated tablet contains 10mg, 50mg or 100mg of venetoclax. Please refer to the Summary of Product Characteristics (SmPC) before prescribing. INDICATION: Venclyxto in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) (see section 5.1)†. Venclyxto in combination with rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy*. Venclyxto monotherapy is indicated for the treatment of CLL in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B cell receptor pathway inhibitor or in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B cell receptor pathway inhibitor*. Venclyxto in combination with a hypomethylating agent is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy.† DOSAGE AND ADMINISTRATION: Oral. Treatment to be initiated and monitored by a physician experienced in the use of anticancer medicinal products. Patients treated with venetoclax may develop tumour lysis syndrome (TLS).

Refer to SmPC for specific details on TLS management by disease indication. See SmPC for full posology.

Posology (CLL): Dose-titration schedule: the starting dose is 20 mg of venetoclax, once daily for 7 days. The dose must be gradually increased over a period of 5 weeks up to the daily dose of 400 mg. Post-titration dose for venetoclax in combination with rituximab: The recommended dose of venetoclax in combination with rituximab is 400 mg once daily. Administer Rituximab after the patient has completed the dose-titration schedule and has received the recommended daily dose of 400 mg venetoclax for 7 days. Venetoclax is taken for 24 months from Cycle 1 Day 1 of rituximab. Venetoclax in combination with obinutuzumab: Venetoclax is given for a total of 12 cycles, each cycle consisting of 28 days: 6 cycles in combination with obinutuzumab, followed by 6 cycles of venetoclax as a single agent. Administer obinutuzumab 100 mg on Cycle 1 Day 1, followed by 900 mg which may be administered on Day 1 or Day 2. Administer 1000 mg on Days 8 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle, for a total of 6 cycles. Start the 5-week venetoclax dose-titration schedule (see Table 1) on Cycle 1 Day 22 and continue through Cycle 2 Day 28. After completing the dose-titration schedule, the recommended dose of venetoclax is 400 mg once daily from Cycle 3 Day 1 of obinutuzumab to the last day of Cycle 12. Post-titration dose for venetoclax monotherapy: the recommended dose of venetoclax is 400 mg once daily. Treatment should be continued until disease progression or no longer tolerated by the patient. Posology (AML): Day 1: 100mg; Day 2: 200mg; Day 3 (and beyond): 400mg. Azacitidine should be administered at 75 mg/m2 either intravenously or subcutaneously on Days 1-7 of each 28-day cycle beginning on Cycle 1 Day 1. Decitabine should be administered at 20 mg/m2 intravenously on Days 1-5 of each 28-day cycle beginning on Cycle 1 Day 1. Venetoclax dosing may be interrupted as needed for management of hematologic toxicities and blood count recovery. Venetoclax, in combination with a hypomethylating agent, should be continued until disease progression or unacceptable toxicity is observed. Patients should swallow the tablets whole with water at approximately the same time each day. The tablets should be taken with a meal. Prevention of tumour lysis syndrome (TLS): Prior to initiating venetoclax, tumour burden assessment, including radiographic evaluation must be performed for all patients.

The following prophylaxis measures should be followed to minimise the risk of TLS and more intensive measures should be employed as overall risk increases; adequate hydration, administration of antihyperuricaemic agents if necessary, blood chemistry monitoring and correction of abnormalities. Monitoring should be increased for patients at high risk of TLS. All patient comorbidities should be considered for riskappropriate prophylaxis and monitoring, either outpatient or in hospital. Dosing interruption and/or dose reduction for toxicities may be required. Dose modifications for TLS or other toxicities may need to be considered during treatment. See SmPC for full details of prophylaxis measures. Special Populations: Elderly: No dose adjustment required. Renal impairment: No dose adjustment is needed for patients with mild, moderate or severe renal impairment (CrCl ≥15 ml/min and <90 ml/min). Venclyxto should be administered to patients with severe renal impairment (CrCl ≥15 ml/min and <30 ml/min) only if the benefit outweighs the risk and patients should be monitored closely for signs of toxicity due to increased risk of TLS. Patients with reduced renal function may require more intensive prophylaxis to reduce the risk of TLS and closer monitoring.

Safety in patients with severe renal impairment or on dialysis has not been established, and a recommended dose for these patients has not been determined. Hepatic impairment: No dose adjustment is recommended in patients with mild or moderate hepatic impairment. Patients with moderate hepatic impairment should be monitored more closely for signs of toxicity. A dose reduction of at least 50% throughout treatment is recommended for patients with severe hepatic impairment. These patients should be monitored more closely for signs of toxicity. Paediatric Population: The safety and efficacy of Venclyxto in children aged less than 18 years has not been established. CONTRAINDICATIONS: Hypersensitivity to any of the active substances or excipients. In patients with CLL, concomitant use of strong CYP3A inhibitors at initiation and during the dosetitration phase. In all patients, concomitant use of preparations containing St. John’s wort. SPECIAL WARNINGS AND PRECAUTIONS: Tumour lysis syndrome (TLS): The risk of TLS is a continuum based on multiple factors, including comorbidities (particularly reduced renal function), tumour burden and splenomegaly.

Reduced renal function (CrCL < 80mL/min) further increases the risk. Assess patient-specific factors for level of risk of TLS and provide prophylactic hydration and anti-hyperuricaemics to patients prior to first dose of venetoclax to reduce risk of TLS. . Blood chemistries should be monitored and abnormalities managed promptly. Dosing should be interrupted if needed; when restarting venetoclax, dose modification guidance should be followed. More intensive measures should be employed as overall risk increases. Neutropenia and

infections: In patients with CLL, grade 3 or 4 neutropenia has been reported. In patients with AML, grade 3 or 4 neutropenia are common before starting treatment. The neutrophil counts can worsen with venetoclax in combination with a hypomethylating agent. Neutropenia can recur with subsequent cycles of therapy.

Complete blood counts should be monitored throughout the treatment period. Dose interruptions or reductions are recommended for patients with severe neutropenia. Serious infections, including sepsis with fatal outcome, have been reported. Monitoring of any signs and symptoms of infection is required. Suspected infections are to receive prompt treatment, including antimicrobials and dose interruption or reduction as appropriate and the use of growth factors (e.g., G-CSF) as appropriate. Immunisation: Live vaccines should not be administered during treatment and thereafter until B-cell recovery as the safety and efficacy has not yet been established. CYP3A inducers: Co-administration of CYP3A4 inducers may lead to decreased Venclyxto exposure and consequently a risk for lack of efficacy. Concomitant use of Venclyxto with strong or moderate CYP3A4 inducers should be avoided. Women of childbearing potential: Women of childbearing potential must use a highly effective method of contraception while taking Venclyxto. INTERACTIONS: See SmPC for full details. Venetoclax is predominantly metabolised by CYP3A. CYP3A inhibitors: In patients with CLL, concomitant use of venetoclax with strong CYP3A inhibitors is contraindicated at initiation and during the dose-titration phasedue to increased risk for TLS. Alternative treatments should be considered. In all patients, if a CYP3A inhibitor must be used, follow the recommendations for managing drug-drug interactions. If a moderate CYP3A inhibitor must be used, the doses must be reduced and patients should be monitored more closely. Refer to SmPC for full details. Grapefruit, Seville oranges and starfruit should be avoided during treatment. P-gp and BCRP inhibitors: Concomitant use of Venclyxto with P-gp and BCRP inhibitors at initiation and during the dose titration phase should be avoided; if a P-gp and BCRP inhibitor must be used, patients should be monitored closely for signs of toxicities. CYP3A inducers: For patients requiring concomitant use of Venclyxto with strong or moderate CYP3A inducers should be avoided. Preparations containing St. John’s wort are contraindicated during treatment with venetoclax. Bile acid sequestrants: Co-administration of bile acid sequestrants with Venclyxto is not recommended as this may reduce the absorption of venetoclax. If a bile acid sequestrant is to be co-administered with Venclyxto, the SmPC for the bile acid sequestrant should be followed to reduce the risk for an interaction, and Venclyxto should be administered at least 4-6 hours after the sequestrant. Warfarin: It is recommended that the international normalised ratio be monitored closely in patients receiving warfarin. Substrates of P-gp, BCRP, and OATP1B1; Co-administration of narrow therapeutic index P-gp, or BCRP substrates with Venclyxto should be avoided. If a narrow therapeutic index P-gp or BCRP substrate must be used, it should be used with caution. For an orally administered P-gp or BCRP substrate sensitive to inhibition in the gastrointestinal tract its administration should be separated from Venclyxto administration as much as possible to minimise a potential interaction. If a statin is used concomitantly with Venclyxto, close monitoring of statin related toxicity is recommended. FERTILITY PREGNANCY AND LACTATION: Women of childbearing potential/Contraception in females: Women should avoid becoming pregnant while taking Venclyxto and for at least 30 days after ending treatment. Pregnancy: Venclyxto is not recommended during pregnancy and in women of childbearing potential not using highly effective contraception. Breast-feeding: Breast-feeding should be discontinued during treatment with Venclyxto.

Fertility: Before starting treatment, counselling on sperm storage may be considered in some male patients.

SIDE EFFECTS: See SmPC for full details on side effects. In patients with CLL: Very common side effects (≥1/10): Pneumonia, upper respiratory tract infection, neutropenia, anaemia, lymphopenia, hyperphosphataemia, hyperkalaemia, hypocalcaemia, diarrhoea, vomiting, nausea, constipation and fatigue.

Common side effects (≥1/100 to <1/10): Sepsis, urinary tract infection, febrile neutropenia, tumour lysis syndrome, hyperuricaemia, and blood creatinine increased. In patients with AML: Very common side effects (≥1/10): Pneumonia, sepsis, urinary tract infection, neutropenia, febrile neutropenia, anaemia, thrombocytopenia, hypokalaemia, decreased appetite, dizziness, headache, hypotension, haemorrhage, dyspnoea, nausea, diarrhoea, vomiting, stomatitis, abdominal pain, arthralgia, fatigue, asthenia, weight decreased and blood bilirubin increased. Common side effects (≥1/100 to <1/10): Tumour lysis syndrome and cholecystitis. Tumour lysis syndrome (TLS): TLS is an important identified risk when initiating Venclyxto. ▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance; Website: www.hpra.ie. Suspected adverse events should also be reported to AbbVie Limited on 01-4287900.

LEGAL CATEGORY: POM (S1A). MARKETING AUTHORISATION NUMBERS/PRESENTATIONS: 10mg filmcoated tablet, 14 tablets, EU/1/16/1138/002; 50mg film-coated tablet, 7 tablets, EU/1/16/1138/004; 100mg film-coated tablet, 7 tablets, EU/1/16/1138/005;100mg film-coated tablet, 14 tablets, EU/1/16/1138/006; 100mg film-coated tablet, 112 tablets, EU/1/16/1138/007. MARKETING AUTHORISATION HOLDER: AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany. Further information is available from AbbVie Limited, 14 Riverwalk, Citywest Business Campus, Dublin 24, Ireland. † Indications are not reimbursed * Indications are reimbursed DATE OF REVISION: June 2021 | PI/1138/009 IE-VNCCLL-210037 | DATE OF PREPARATION: October 2021