Update Oncology and Haematology

NOW YOU CAN

Give them more

TALZENNA is a proven alternative to chemotherapy* that provides patients with greater efficacy in a convenient, once-daily oral dose1

LONGER MEDIAN PROGRESSION-FREE SURVIVAL (PFS)

TALZENNA significantly prolonged median PFS vs chemotherapy: 8.6 months vs 5.6 months (HR=0.54 [95% CI: 0.41-0.71]; P<0.0001)1

DOUBLED OBJECTIVE RESPONSE RATE (ORR) ORR for TALZENNA was 62.6% (95% CI: 55.8-69.0) vs 27.2% (95% CI: 19.3-36.3) with chemotherapy

(OR=4.99 [95% CI: 2.93-8.83]; P<0.0001)1†‡

CONVENIENT DOSING

TALZENNA provides convenient, once-daily oral dosing, with or without food1

Indication: TALZENNA is indicated as monotherapy for the treatment of adult patients with germline BRCA1/2-mutations, who have HER2-negative locally advanced or metastatic breast cancer. Patients should have been previously treated with an anthracycline and/or taxane in the (neo)adjuvant, locally advanced or metastatic setting unless patients were not suitable for these treatments (see section 5.1 of full SmPC). Patients with hormone receptor (HR)positive breast cancer should have been treated with a prior endocrine-based therapy, or be considered unsuitable for endocrine-based therapy.

CI=confidence interval; gBRCA=germline breast cancer susceptibility gene; HER2-=human epidermal growth factor receptor 2 negative; HR=hazard ratio; HR+=hormone receptor-positive; OR=odds ratio; RECIST=Response Evaluation Criteria in Solid Tumors.

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.

Talzenna®▼ 0.25 mg and 1 mg hard capsules IE Prescribing Information: Before prescribing Talzenna (talazoparib) please refer to the full Summary of Product Characteristics (SmPC). Presentation: Each 0.25 mg hard capsule contains talazoparib tosylate equivalent to 0.25 mg talazoparib. Each 1 mg hard capsule contains talazoparib tosylate equivalent to 1 mg talazoparib. Indications: Talzenna is indicated as monotherapy for the treatment of adult patients with germline BRCA1/2 mutations, who have HER2-negative locally advanced or metastatic breast cancer. Patients should have been previously treated with an anthracycline and/or a taxane in the (neo)adjuvant, locally advanced or metastatic setting unless patients were not suitable for these treatments. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine-based therapy, or be considered unsuitable for endocrinebased therapy. Dosage and Administration: Treatment should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. Patients should be selected for the treatment of breast cancer with Talzenna based on the presence of deleterious or suspected deleterious germline BRCA mutations determined by an experienced laboratory using a validated test method. Genetic counselling for patients with BRCA mutations should be performed according to local regulations, as applicable. The recommended dose is 1 mg talazoparib once daily. Patients should be treated until disease progression or unacceptable toxicity occurs. Complete blood count should be obtained prior to starting Talzenna therapy and monitored monthly and as clinically indicated. To manage adverse drug reactions, interruption of treatment or dose reduction based on severity and clinical presentation should be considered (see SmPC section 4.2). Special populations: Hepatic impairment: See SmPC section 4.2. No dose adjustment is required for patients with mild, moderate or severe hepatic impairment. Renal impairment: See SmPC section 4.2. No dose adjustment is required for patients with mild renal impairment. For patients with moderate renal impairment, the recommended starting dose of Talzenna is 0.75 mg once daily. For patients with severe renal impairment, the recommended starting dose of Talzenna is 0.5 mg once daily. Talzenna has not been studied in patients with CrCL < 15 mL/min or patients requiring haemodialysis. Elderly: No dose adjustment is necessary in elderly (≥ 65 years of age) patients. Paediatric population: The safety and efficacy of Talzenna in children and adolescents < 18 years of age have not been established. Method of administration: Talzenna is for oral use. To avoid contact with the capsule content, the capsules should be swallowed whole, and must not be opened or dissolved. They can be taken with or without food (See SmPC section 5.2). Contraindications: Hypersensitivity to the active substance or to any of the excipients. Breast-feeding. Special Warnings and Precautions: Myelosuppression: Myelosuppression consisting of anaemia, leucopenia/ neutropenia, and/or thrombocytopenia, have been reported in patients treated with talazoparib (see section 4.8). Talazoparib should not be started until patients have recovered from haematological toxicity caused by previous therapy (≤ Grade 1). Precautions should be taken to routinely monitor haematology parameters and signs and symptoms associated with anaemia, leucopenia/neutropenia, and/or thrombocytopenia in patients receiving talazoparib. If such events occur, dose modifications (reduction or interruption) are recommended. Supportive care with or without blood and/or platelet transfusions and/or administration of colony stimulating factors may be used as appropriate. Myelodysplastic

* Capecitabine, eribulin, gemcitabine, or vinorelbine.

† Conducted in the intent-to-treat population with measurable disease at baseline. Per RECIST v1.1, confirmation of response was not required.1

‡ ORR is the proportion of patients who have a partial or complete response to treatment.

Reference: 1. TALZENNA Summary of Product Characteristics.

syndrome/Acute myeloid leukaemia: Myelodysplastic syndrome/Acute Myeloid Leukaemia (MDS/AML) have been reported in patients who received poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, including talazoparib. Overall, MDS/AML has been reported in < 1% of solid tumour patients treated with talazoparib in clinical studies. Potential contributing factors for the development of MDS/AML include previous platinum-containing chemotherapy, other DNA damaging agents or radiotherapy. Complete blood counts should be obtained at baseline and monitored monthly for signs of haematologic toxicity during treatment. If MDS/AML is confirmed, talazoparib should be discontinued. Contraception in women of childbearing potential: Talazoparib was clastogenic in an in vitro chromosomal aberration assay in human peripheral blood lymphocytes and in an in vivo bone marrow micronucleus assay in rats but not mutagenic in Ames assay (see section 5.3), and may cause foetal harm when administered to a pregnant woman. Pregnant women should be advised of the potential risk to the foetus (see section 4.6). Women of childbearing potential should not become pregnant while receiving Talzenna and should not be pregnant at the beginning of treatment. A pregnancy test should be performed on all women of childbearing potential prior to treatment. A highly effective method of contraception is required for female patients during treatment with Talzenna, and for at least 7 months after completing therapy. Since the use of hormonal contraception is not recommended in patients with breast cancer, two non-hormonal and complementary contraception methods should be used. Male patients with female partners of reproductive potential or pregnant partners should be advised to use effective contraception (even after vasectomy), during treatment with Talzenna and for at least 4 months after the final dose. Interactions: Talazoparib is a substrate for drug transporters P-gp and Breast Cancer Resistance Protein (BCRP) and it is mainly eliminated by renal clearance as unchanged compound. Concomitant treatment with inhibitors of P-glycoprotein (P gp): Strong inhibitors of P gp may lead to increased talazoparib exposure. Concomitant use of strong P gp inhibitors (including but not limited to amiodarone, carvedilol, clarithromycin, cobicistat, darunavir, dronedarone, erythromycin, indinavir, itraconazole, ketoconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir, telaprevir, tipranavir, and verapamil) during treatment with talazoparib should be avoided. Co-administration should only be considered after careful evaluation of the potential benefits and risks. If co-administration with a strong P gp inhibitor is unavoidable, the Talzenna dose should be reduced to 0.75 mg once daily. When the strong P-gp inhibitor is discontinued, the Talzenna dose should be increased (after 3 5 half lives of the P-gp inhibitor) to the dose used prior to the initiation of the strong P gp inhibitor. No talazoparib dose adjustments are required when co administered with rifampin. However, the effect of other P-gp inducers on talazoparib exposure has not been studied. Other P-gp inducers (including but not limited to carbamazepine, phenytoin, and St. John’s wort) may decrease talazoparib exposure. BCRP inhibitors: The effect of BCRP inhibitors on PK of talazoparib has not been studied in vivo. Co-administration of talazoparib with BCRP inhibitors may increase talazoparib exposure. Concomitant use of strong BCRP inhibitors (including but not limited to curcumin and cyclosporine) should be avoided. If co administration of strong BCRP inhibitors cannot be avoided, patient should be monitored for potential increased adverse reactions. Effect of acid-reducing agents: Population PK analysis indicates that co-administration of acid-reducing agents including proton pump inhibitors and histamine receptor 2 antagonists (H2RA), or other acid reducing agents had no significant impact on the absorption of talazoparib. Systemic hormonal contraception Drug-drug interaction studies between talazoparib and oral contraceptives have not been conducted. Fertility, pregnancy and lactation: Fertility : There is no information on fertility in patients. Based

on non-clinical findings in testes (partially reversible) and ovary (reversible), Talzenna may impair fertility in males of reproductive potential. Women of childbearing potential should not become pregnant while receiving Talzenna and should not be pregnant at the beginning of treatment. A pregnancy test should be performed on all women of childbearing potential prior to treatment. Women of childbearing potential must use highly effective forms of contraception prior to starting treatment with talazoparib, during treatment, and for 7 months after stopping treatment with talazoparib. Since the use of hormonal contraception is not recommended in patients with breast cancer, two non-hormonal and complementary contraception methods should be used. Male patients with female partners of reproductive potential or pregnant partners should be advised to use effective contraception (even after vasectomy) during treatment with Talzenna, and for at least 4 months after the final. Pregnancy: There are no data from the use of Talzenna in pregnant women. Studies in animals have shown embryo foetal toxicity. Talzenna may cause foetal harm when administered to a pregnant woman. Talzenna is not recommended during pregnancy or for women of childbearing potential not using contraception. Breast-feeding: It is unknown whether talazoparib is excreted in human breast milk. A risk to breast-fed children cannot be excluded and therefore breast-feeding is not recommended during treatment with Talzenna and for at least 1 month after the final dose. Undesirable Effects: The overall safety profile of Talzenna is based on pooled data from 494 patients who received talazoparib at 1 mg daily in clinical studies for solid tumours, including 286 patients from a randomised Phase 3 study with germline BRCA-mutated (gBRCAm), HER2-negative locally advanced or metastatic breast cancer and 83 patients from a non-randomised Phase 2 study in patients with germline BRCA-mutated locally advanced or metastatic breast cancer. The most common (≥ 25%) adverse reactions in patients receiving talazoparib in these clinical studies were fatigue (57.1%), anaemia (49.6%), nausea (44.3%), neutropenia (30.2%), thrombocytopenia (29.6%), and headache (26.5%). The most common (≥ 10%) Grade ≥ 3 adverse reactions of talazoparib were anaemia (35.2%), neutropenia (17.4%), and thrombocytopenia (16.8%). Dose modifications (dose reductions or dose interruptions) due to any adverse reaction occurred in 62.3% of patients receiving Talzenna. The most common adverse reactions leading to dose modifications were anaemia (33.0%), neutropenia (15.8%), and thrombocytopenia (13.4%). Permanent discontinuation due to an adverse reaction occurred in 3.6% of patients receiving Talzenna. The median duration of exposure was 5.4 months (range 0.03-61.1). Very common adverse reactions (>1/10) are Thrombocytopenia, Anaemia, Neutropenia, Leucopenia, Decreased appetite, Dizziness, Headache, Vomiting, Diarrhoea, Nausea, Abdominal pain, Alopecia and Fatigue. Commonly reported adverse reactions (>1/100 to <1/10), are Lymphopenia, Dysgeusia, Stomatitis and Dyspepsia. Refer to SmPC section 4.8 for further information on side effects. Legal Category: Product subject to prescription which may not be renewed (A): S1A. Marketing Authorisation Number: Talzenna 0.25 mg hard capsules –EU/1/19/1377/001-004; Talzenna 1 mg hard capsules – EU/1/19/1377/005006. 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, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 + 353 1 4676500.

Date of Preparation: 11/2021.

Ref: TE 3_0.

When treating adult patients with gBRCA-mutated HR+/HER2or triple-negative locally advanced or metastatic breast cancer1

▼This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get to HPRA Pharmcoviglance, Earlsfort Terrace, Dublin 2, IRL. Tel: +353 1 676 4971, Fax: +353 1 676 2517, Website: www.hpra.ie, E-mail: medsafety@hpra.ie

Moving focus back to the real big C

A message from Priscilla Lynch, Editor

As we get more of a grip on living with Covid, the focus is now returning to the other ‘big C’ – cancer.

Cancer remains the single biggest cause of premature mortality in this country, accounting for almost one-in-three deaths, and we know pandemic-related restrictions and service pressures have led to poorer timely detection of cancer cases and limited in-person support services for patients, despite the best efforts of healthcare workers.

According to the World Health Organisation (WHO), 30-to-50 per cent of all cancers are preventable through changes to lifestyle and environmental factors. For World Cancer Day 2022, the Irish Cancer Prevention Network (ICPN) – comprised of the HSE National Cancer Control Programme (NCCP), Marie Keating Foundation, Irish Cancer Society, Breakthrough Cancer Research, National Screening Service, and the Irish Skin Foundation – announced plans to increase public awareness about modifiable cancer risk behaviours, empowering people to take action. These include smoking cessation, healthy eating and exercise, sun avoidance, etc, and every healthcare worker can make an impact in educating and supporting patients in how to address modifiable cancer risk factors, as outlined in an article from the NCCP in this issue.

As well as focusing on prevention, early detection is also key. A recent survey of 1,000 people carried out by Core Research for the Irish Cancer Society found that half of those who put off seeking medical advice are still experiencing symptoms and have yet to make an appointment to see their GP.

January marked the Society’s Lung Cancer

Awareness Month, a disease where late detection is a particular problem, with sixin-10 lung cancers being diagnosed at stage III or IV, according to the latest available data from the National Cancer Registry Ireland. Lung cancer claims nearly 2,000 lives in Ireland each year – more than any other form of cancer.

Lung screening should be added to Ireland’s list of cancer screening programmes to improve early detection and therefore achieve better outcomes for these patients, the Irish Cancer Society has urged.

In its submission to the National Screening Advisory Committee for the new programme, the Society has proposed that targeted lung cancer screening, involving a CT scan, be rolled out to current or former smokers aged 50-to-74, given this group is most at risk from the disease.

Dr Jarushka Naidoo, Thoracic Oncologist, Beaumont Hospital, Dublin, said: “We know that lung cancer screening programmes save lives. Several high-impact clinical trials have shown this and led to implementation of lung cancer screening in the US and other countries.”

She added that people who develop symptoms of lung cancer tend to be reluctant to come forward, due to concerns about poor outcome if a lung cancer is found. “However, more than 20 new treatments have been developed for lung cancer in the last five-to-10 years, these treatments have resulted in major improvements for our patients.”

So, there is growing momentum to see targeted lung cancer screening rolled out in Ireland, with the hope it could be as successful as BreastCheck, BowelScreen, and CervicalCheck in reducing late diagnoses and more serious outcomes.

Back to this issue of Update, in the area

of haematology, we feature an overview of the latest clinical UK guidelines for diagnosing and managing Waldenström macroglobulinaemia, as well as a CPD module on iron deficiency anaemia, one of the leading causes of years lived with disability burden, particularly in women, and an in-depth look at amyloidosis.

In relation to oncology, there is exclusive coverage of the latest annual Gathering Around Cancer meeting, an update on Cancer Trials Ireland’s radiotherapy clinical trials, details of the Irish Society of Medical Oncology’s (ISMO’s) Advanced Medical Oncology Fellowship at the Royal Marsden Hospital’s early phase trial and drug development unit for Irish medical oncology trainees, and an overview article from the Health Research Board (HRB) on its Cancer trials in Ireland funding model to support an overarching National Cancer Clinical Trials Network and six Cancer Clinical Trials Groups, with the goal of doubling the numbers of patients taking part in cancer clinical trials in Ireland, in line with the National Cancer Strategy (2017-2026).

There are also expert clinical articles on ovarian cancer, the benefits of partial breast irradiation, recent treatment advances in renal cell carcinoma, a case study on the role of exercise in prostate cancer care, as well as a CPD module on the latest approaches to metastatic colorectal cancer.

All-in-all, a packed edition that should hopefully prove interesting and informative to all our readers.

Thank you to our expert contributors for taking the time to share their knowledge and advice for the betterment of patient care.

We always welcome new contributors and ideas and suggestions for future content, as well as any feedback on our content to date. Please contact me at priscilla@mindo.ie if you wish to comment or contribute an article. ■

Editor Priscilla Lynch priscilla@mindo.ie

Sub-editor Emer Keogh emer@greenx.ie

Creative Director Laura Kenny laura@greenx.ie

Advertisements Graham Cooke graham@greenx.ie

Administration Daiva Maciunaite daiva@greenx.ie

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Abbreviated Prescribing Information - Xtandi (enzalutamide) 40 mg film-coated tablets. Please refer to the Summary of Product Characteristics (SmPC), available on www. medicines.ie, before prescribing. Presentation: Xtandi 40 mg film-coated tablets each containing 40 mg of enzalutamide. Indications: The treatment of adult men with metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy. The treatment of adult men with high-risk non-metastatic castration resistant prostate cancer (CRPC). The treatment of adult men with metastatic CRPC who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. The treatment of adult men with metastatic CRPC whose disease has progressed on or after docetaxel therapy. Posology and administration: Treatment with enzalutamide should be initiated and supervised by specialist physicians experienced in the medical treatment of prostate cancer. The recommended dose is 160 mg enzalutamide (four 40 mg film-coated tablets) as a single oral daily dose. The tablets should be swallowed whole with water, and can be taken with or without food. Medical castration with a luteinising hormone-releasing hormone (LHRH) analogue should be continued during treatment of patients not surgically castrated. If a patient experiences a ≥ Grade 3 toxicity or an intolerable adverse reaction, dosing should be withheld for one week or until symptoms improve to ≤ Grade 2, then resumed at the same or a reduced dose (120 mg or 80 mg) if warranted. For further details, please refer to the SmPC. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Women who are or may become pregnant. Special warnings and precautions for use: Risk of seizure: Use of enzalutamide has been associated with seizure. The decision to continue treatment in patients who develop seizures should be taken case by case.

Posterior reversible encephalopathy syndrome: There have been rare reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving Xtandi. PRES is a rare, reversible, neurological disorder which can present with rapidly evolving symptoms including seizure, headache, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinuation of Xtandi in patients who develop PRES is recommended. Second Primary Malignancies: Cases of second primary malignancies have been reported in patients treated with enzalutamide in clinical studies. In phase 3 clinical studies, the most frequently reported events in enzalutamide treated patients, and greater than placebo, were bladder cancer (0.3%), adenocarcinoma of the colon (0.2%), transitional cell carcinoma (0.2%) and bladder transitional cell carcinoma (0.1%). Patients should be advised to promptly seek the attention of their physician if they notice signs of gastrointestinal bleeding, macroscopic haematuria, or other symptoms such as dysuria or urinary urgency develop during treatment with enzalutamide. Concomitant use with other medicinal products: Enzalutamide is a potent enzyme inducer and may lead to loss of efficacy of many commonly used medicinal products. A review of concomitant medicinal products should therefore be conducted when initiating enzalutamide treatment. Concomitant use of enzalutamide with medicinal products that are sensitive substrates of many metabolising enzymes or transporters should generally be avoided if their therapeutic effect is of large importance to the patient, and if dose adjustments cannot easily be performed based on monitoring of efficacy or plasma concentrations. Co-administration with warfarin and coumarin-like anticoagulants should be avoided. If Xtandi is co-administered with an anticoagulant metabolised by CYP2C9 (such as warfarin or acenocoumarol), additional International Normalised Ratio (INR) monitoring should be conducted. Renal impairment: Caution is required in patients with severe renal impairment as enzalutamide has not been studied in this patient population. Severe hepatic impairment: An increased half-life of enzalutamide has been observed in patients with severe hepatic impairment, possibly related to increased tissue distribution. The clinical relevance of this observation remains unknown. A prolonged time to reach steady state concentrations is however anticipated, and the time to maximum pharmacological effect as well as time for onset and decline of enzyme induction may be increased. Recent cardiovascular disease: The phase 3 studies excluded patients with recent myocardial infarction (in the past 6 months) or unstable angina (in the past 3 months), New York Heart Association Class (NYHA) III or IV heart failure except if Left Ventricular Ejection Fraction (LVEF) ≥ 45%, bradycardia or uncontrolled hypertension. This should be taken into account if Xtandi is prescribed in these patients. Androgen deprivation therapy may prolong the QT interval: In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating Xtandi. Use with chemotherapy: The safety and efficacy of concomitant use of Xtandi with cytotoxic chemotherapy has not been established. Co-administration of enzalutamide has no clinically relevant effect on the

XTANDI™ is indicated for the treatment of adult men with metastatic castrationresistant prostate cancer who are asymptomatic or mildly symptomatic after failure of androgendeprivation therapy, in whom chemotherapy is not yet clinically indicated.1

XTANDI is also indicated for the treatment of adult men with metastatic castration – resistant prostate cancer whose disease has progressed on or after Docetaxel.1

pharmacokinetics of intravenous docetaxel; however, an increase in the occurrence of docetaxel-induced neutropenia cannot be excluded. Hypersensitivity reactions: Hypersensitivity reactions manifested by symptoms including, but not limited to, rash, or face, tongue, lip, or pharyngeal oedema have been observed with enzalutamide. Severe cutaneous adverse reactions (SCARs) have been reported with enzalutamide. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. Interactions: Potential for other medicinal products to affect enzalutamide exposures: CYP2C8 plays an important role in the elimination of enzalutamide and in the formation of its active metabolite. Strong inhibitors (e.g. gemfibrozil) of CYP2C8 are to be avoided or used with caution during enzalutamide treatment. If patients must be co-administered a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced to 80 mg once daily. No dose adjustment is necessary when Xtandi is co-administered with inducers of CYP2C8. CYP3A4 plays a minor role in the metabolism of enzalutamide. No dose adjustment is necessary when Xtandi is co-administered with inhibitors or inducers of CYP3A4. Potential for enzalutamide to affect exposures to other medicinal products: Enzalutamide is a potent enzyme inducer and increases the synthesis of many enzymes and transporters; therefore, interaction with many common medicinal products that are substrates of enzymes or transporters is expected. Enzymes that may be induced include CYP3A in the liver and gut, CYP2B6, CYP2C9, CYP2C19, and uridine 5’-diphosphoglucuronosyltransferase (UGTs - glucuronide conjugating enzymes). The transport protein P-gp may also be induced, and probably other transporters as well, e.g. multidrug resistance-associated protein 2 (MRP2), breast cancer resistance protein (BCRP) and the organic anion transporting polypeptide 1B1 (OATP1B1). In vivo studies have shown that enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. The full induction potential of enzalutamide may not occur until approximately 1 month after the start of treatment, when steady-state plasma concentrations of enzalutamide are reached, although some induction effects may be apparent earlier. Patients taking medicinal products that are substrates of CYP2B6, CYP3A4, CYP2C9, CYP2C19 or UGT1A1 should be evaluated for possible loss of pharmacological effects (or increase in effects in cases where active metabolites are formed) during the first month of enzalutamide treatment, and dose adjustment should be considered as appropriate. In consideration of the long half-life of enzalutamide (5.8 days), effects on enzymes may persist for one month or longer after stopping enzalutamide. A gradual dose reduction of the concomitant medicinal product may be necessary when stopping enzalutamide treatment. In vitro data indicate that enzalutamide may be an inhibitor of the efflux transporter P-gp. The effect of enzalutamide on P-gp substrates has not been evaluated in vivo; however, under conditions of clinical use, enzalutamide may be an inducer of P-gp via activation of the nuclear pregnane receptor (PXR). Medicinal products with a narrow therapeutic range that are substrates for P-gp (e.g. colchicine, dabigatran etexilate, digoxin) should be used with caution when administered concomitantly with Xtandi and may require dose adjustment to maintain optimal plasma concentrations. Based on in vitro data, inhibition of BCRP and MRP2 (in the intestine), as well as organic anion transporter 3 (OAT3) and organic cation transporter 1 (OCT1) (systemically) cannot be excluded. Theoretically, induction of these transporters is also possible, and the net effect is presently unknown. Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Xtandi with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes should be carefully evaluated. Fertility, pregnancy and lactation: There are no human data on the use of Xtandi in pregnancy and this medicinal product is not for use in women of childbearing potential. This medicine may cause harm to the unborn child or potential loss of pregnancy if taken by women who are pregnant. It is not known whether enzalutamide or its metabolites are present in semen. A condom is required during and for 3 months after treatment with enzalutamide if the patient is engaged in sexual activity with a pregnant woman. If the patient engages in sexual intercourse with a woman of childbearing potential a condom and another form of birth control must be used during and for 3 months after treatment. Enzalutamide is not for use in women. Enzalutamide is contraindicated in women who are, or who may become, pregnant. It is not known if enzalutamide is present in human milk. Enzalutamide and/or its metabolites are secreted in rat milk. Animal studies showed that enzalutamide affected the reproductive system in male rats and dogs. Driving and use of machines: Xtandi may have a moderate influence on the ability to drive and use machines as psychiatric and neurologic events including seizure have been reported. Patients should be advised of the potential risk of experiencing a psychiatric or neurological event while driving or operating machines. Undesirable effects: Summary of the safety profile: The most common adverse reactions are asthenia/fatigue, hot flush, hypertension, fractures, and fall. Other important adverse reactions include cognitive disorder and neutropenia. Seizure occurred in 0.5% of

enzalutamide-treated patients, 0.1% of placebo-treated patients, and 0.3% in bicalutamidetreated patients. Rare cases of posterior reversible encephalopathy syndrome have been reported in enzalutamide-treated patients. List of adverse reactions: Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (≥ 1/10); 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Adverse reactions identified in controlled clinical trials and post-marketing (Listed by MedDRA System organ class frequency and adverse reaction): Blood and lymphatic system disorders Uncommon: leucopenia, neutropenia; Not known*: thrombocytopenia Immune system disorders Not known*: face oedema, tongue oedema, lip oedema, pharyngeal oedema Psychiatric disorders Common anxiety; Uncommon: visual hallucination Nervous system disorders

Common: headache, memory impairment, amnesia, disturbance in attention, dysgeusia, restless legs syndrome; Uncommon: cognitive disorder, seizureҰ; Not known*: posterior reversible encephalopathy syndrome Cardiac disorders Common: ischemic heart diseaseǂ; Not known* QT-prolongation Vascular disorders Very common: hot flush, hypertension Gastrointestinal disorders Not known*: nausea, vomiting, diarrhoea Skin and subcutaneous tissue disorders Common: dry skin, pruritus; Not known*: rash

Musculoskeletal and connective tissue disorders Very common: fractures**; Not known*: myalgia, muscle spasms, muscular weakness, back pain Reproductive system and breast disorder Common: gynaecomastia General disorders and administration site conditions Very common: asthenia, fatigue Injury, poisoning and procedural complications Very common: fall. *Spontaneous reports from post-marketing experience. ҰAs evaluated by narrow SMQs of ‘Convulsions’ including convulsion, grand mal convulsion, complex partial seizures, partial seizures and status epilepticus. This includes rare cases of seizure with complications leading to death. ǂAs evaluated by narrow SMQs of ‘Myocardial Infarction’ and ‘Other Ischemic Heart Disease’ including the following preferred terms observed in at least two patients in randomized placebo-controlled phase 3 studies: angina pectoris, coronary artery disease, myocardial infarctions, acute myocardial infarction, acute coronary syndrome, angina unstable, myocardial ischaemia and arteriosclerosis coronary artery. **Includes all preferred terms with the word ‘fracture’ in bones. Description of selected adverse reactions: Seizure In controlled clinical studies, 22 patients (0.5%) experienced a seizure out of 4168 patients treated with a daily dose of 160 mg enzalutamide, whereas three patients (0.1%) receiving placebo and one patient (0.3%) receiving bicalutamide experienced a seizure. Dose appears to be an important predictor of the risk of seizure, as reflected by preclinical data, and data from a dose-escalation study. In the controlled clinical studies, patients with prior seizure or risk factors for seizure were excluded. In the 9785 CL 0403 (UPWARD) single-arm trial to assess incidence of seizure in patients with predisposing factors for seizure (whereof 1.6% had a history of seizures), 8 of 366 (2.2%) patients treated with enzalutamide experienced a seizure. The median duration of treatment was 9.3 months. The mechanism by which enzalutamide may lower the seizure threshold is not known but could be related to data from in vitro studies showing that enzalutamide and its active metabolite bind to and can inhibit the activity of the GABA gated chloride channel.

Ischemic Heart Disease

In randomized placebo-controlled clinical studies, ischemic heart disease occurred in 3.7% of patients treated with enzalutamide plus ADT compared to 1.5% patients treated with placebo plus ADT. Fifteen (0.4%) patients treated with enzalutamide and 2 (0.1%) patients treated with placebo had an ischemic heart disease event that led to death. Legal category: POM/S1A. Marketing Authorisation number: Xtandi 40 mg filmcoated tablets: EU/1/13/846/002 Marketing Authorisation Holder: Astellas Pharma Europe B.V., Sylviusweg 62, 2333 BE Leiden, The Netherlands. Further information is available from: Astellas Pharma Co. Ltd., 5 Waterside, Citywest Business Campus, Dublin 24. Tel.: +353 1 467 1555. SmPC with full prescribing information available upon request. Job number: XTD_2021_0085_IE Date of preparation of API: May 2021

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the bene t/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

HPRA Pharmacovigilance

Website: www.hpra.ie Astellas Pharma Co. Ltd. Tel: + 353 1 467 1555

E- mail: irishdrugsafety@astellas.com

Gathering Around Cancer 2021, virtual, 4-5 November

ALL REPORTS BY PAT KELLY

Getting it right with Her2+ breast cancer

The Gathering Around Cancer 2021 conference showcased a wide range of national and international speakers who addressed a variety of topics, from cancer treatment, to oncology services, to palliative care, among others. The event was chaired by Prof John McCaffrey, Consultant Medical Oncologist, Mater Misericordiae University Hospital (MMUH), Dublin; and Prof David Gallagher, Consultant Medical Oncologist and Consultant Medical Geneticist, St James’s Hospital, Dublin, and featured more than 30 expert speakers who presented on a virtual platform. The conference also featured interactive Q&A sessions following each presentation, in which delegates could put their comments to the speakers and chairs.

The event also hosted a moderated panel and audience discussion on the theme, ‘Dying with Dignity Private Member’s Bill,’ which debated the medical and ethical aspects of the Bill and featured Mr Gino Kenny TD of the People Before Profit – Solidarity party; Dr Anne Doherty, Psychiatry PsychoOncology Service, MMUH; and Dr Regina McQuillan of St Francis Hospice and Beaumont Hospital, Dublin.

The conference also heard from Prof John Crown, Consultant Medical Oncologist, St Vincent’s University Hospital, who provided an update on ‘Her2+ breast cancer’. Prof Crown explained that Her2+ breast cancer has been a particular interest of his for more than 25 years and he spoke about early-stage and metastatic disease, as well as the area of new therapies for the disease.

Prof Crown provided an overview of data from translational studies conducted in his own laboratory and he also spoke about how therapies for early-stage disease “have had a quite extraordinary effect on the nature of metastatic breast cancer”.

Prof Crown told the attendees: “In any attempt to look at adjuvant treatment for early-stage breast cancer, we have to remember there has been a major move towards neoadjuvant treatment instead,” said Prof Crown. “We do not have any clean, head-to-head, random assignment comparisons of the same therapy given adjuvantly versus neoadjuvantly. We do, however, have some indirect evidence,” he said. “There is a move towards neoadjuvant therapy based on the high rate of pathological complete response that has been reported, but in addition to that, data from our own group in St Vincent’s suggests that there may be a benefit associated with the use of the same drugs given in the neoadjuvant rather than the adjuvant setting.”

Prof Crown provided an overview of trials and briefly discussed the need to minimise toxicity associated with treatment in the context of the duration of both drug therapy and chemotherapy. “In early-stage Her2+ breast cancer, in my approach, trastuzumab remains the standard for adjuvant therapy, although there are data to support the use of neratinib and pertuzumab,” he said. “Neoadjuvant therapy in general, I believe, is preferable to adjuvant therapy, although it may result in the over-treatment of some patients.

T-DM1 is superior to trastuzumab for residual disease in the post-adjuvant setting and de-escalating therapy can be justified, especially in patients who are more frail or at lower risk, and an abbreviated schedule of trastuzumab is likely to be very acceptable for the great majority of patients.”

Prof Crown also discussed trial data on metastatic disease and told the attendees: “Metastatic Her2+ breast cancer is now a different disease to the disease that we have seen heretofore,” he told the conference. “De novo metastatic Her2+ disease is now a much higher percentage of the global burden of Her2+ disease than was previously the case… the typical demographic of a patient with Her2+ breast cancer in the early years of this century was that they had relapsed from prior adjuvant therapy – that is a much lower burden now, and far more patients are presenting now with de novo metastatic disease.

“The reason for this is obvious – anti-Her2+ adjuvant therapy has been so successful that it has in fact reduced the number of patients with relapsed disease,” Prof Crown continued. “More tellingly, the outcomes for patients who are treated for de novo metastatic disease in our dataset is strikingly superior to those who are treated following a relapse from prior adjuvant therapy. So, not only has antiHer2+ adjuvant therapy given patients with early-stage disease a better outlook, but it appears to have also given a better outlook for patients with Her2+ metastatic disease.”

Advances in kidney cancer treatment

The Gathering Around Cancer 2021 conference also heard from Prof Ray McDermott, Consultant Medical Oncologist, St Vincent’s University Hospital, who presented a ‘Renal cancer update’ and provided an overview in the evolution of kidney cancer treatment over the years in Ireland and beyond.

“The biggest issue today is choosing which doublet to use in treatment,” said Prof McDermott, “and in the future, it may be about choosing which triplet to use. The biggest question people ask at the moment is, ‘should I be using an immunotherapy (IO) doublet, or a TKI [tyrosine kinase inhibitor]/IO doublet?’”

Prof McDermott provided the attendees with an overview of data from a range of trials and outlined the efficacy of a variety of different combinations, depending on the patient’s disease status and typical response rates. “The nice thing about an IO doublet – and we also know this from other diseases – is that if you get a complete response, that response may translate into a cure,” said Prof McDermott. “The thing to remember about this combination is that the toxicity is mainly based

around the first few months,” he added. “If you can get through the first three months of the doublet, basically the toxicity is from the singleagent IO, which is very manageable.”

He described the various drug combination options that were studied in clinical trials, as well as the durability of their response rates and benefits, including in patients who had undergone a nephrectomy. “For the first time ever, we are seeing a benefit for adjuvant therapy in renal cancer, so much so that we are hoping to open a study with MSD on pembrolizumab and an alpha inhibitor versus pembrolizumab alone for patients following resection of high-risk disease,” said Prof McDermott. “This is not yet licensed in Europe or the US, but as it has been granted priority review in the US, I would anticipate it will be licensed early next year.”

Summarising the data, he told the conference: “Adjuvant pembrolizumab post-nephrectomy demonstrated a statistically-significant and clinically meaningful improvement in DFS [death-free survival] versus placebo, although additional follow-up is planned for the key

secondary end-point of overall survival.

“The benefit was consistent across subgroups, including the M1 NED [no evidence of disease] population, potentially extending the use of pembrolizumab to these patients. Although the number of participants who had partial nephrectomy was small, DFS benefit was consistent in this population, the safety results were in line with expectations, and no new safety signals were observed. Pembrolizumab is a potential new standard of care for patients with RCC [renal cell carcinoma] in the adjuvant setting.”

Prof McDermott also stressed that the combination given to each patient as first-line therapy should be based on individual patient characteristics, including the distribution of disease and what the next step in the treatment plan is. “Most patients are not going to be cured by whatever treatment we give them, but if you have a relatively low burden of disease and they don’t need an immediate response, I think the immunotherapy doublet up-front is a nice option. That potentially gives them the option of getting off treatment with a good quality-of-life.”

Forward momentum in melanoma

The Gathering Around Cancer 2021 conference heard from Dr Derek Power, Consultant Medical Oncologist, Cork University Hospital (CUH), who provided an ‘Update on systemic therapy in melanoma’. Dr Power described how this treatment has “changed dramatically over the past decade… now we have so many drugs, when for many years there was nothing that was definitively proven to confer a survival advantage. Now, we have many drugs in a variety of different settings that have been shown to confer a major benefit. The algorithm, which was distinctly bland 15 or 20 years ago, is now very busy, analogous to other solid tumour cancers.”

Melanoma tumours have been sequenced and the BRAF gene identified, among others,

which has led in large part to these dramatic changes, said Dr Power. BRAF mutation has led to discovery of drugs that target this pathway, with “remarkably consistent results across trials”, Dr Power added.

He provided an overview of trial data on targeted therapies, as well as other BRAF and MEK inhibitor drugs and told the attendees: “As we know, cancers are chaos and there is significant mutational burden, and this appears to correlate with efficacy for checkpoint inhibitors – it’s no surprise that melanoma is top of the list due to its aetiology of damage to DNA from skin.”

He also delivered a brief overview of drug development in melanoma and said there is now increased interest in the combination

of immune checkpoint inhibition and targeted therapies.

He also discussed adjuvant therapies and told the conference: “Really, we have gone from nothing with interferon, to ipilimumab in 2016, and since 2017, with anti-PD1 immunotherapy such as nivolumab and pembrolizumab, and targeted therapies such as vemurafenib and dabrafenib + trametinib, with promising survival rates with selected combinations.

“We have come a long way in melanoma and in my opinion, a really interesting area is the neoadjuvant setting,” said Dr Power. “This is interesting in melanoma because significant amounts of patients in the adjuvant studies, particularly those with macro-metastases, progressed before being enrolled in the adjuvant studies, so this is a real area of interest.”

He continued: “The evidence for this is accumulating. Survival is poor with adjuvant therapy, surgery can be morbid when resecting stage 3 disease, there are no curative biomarkers to guide prognosis, and we need to better understand why patients develop resistance,” he said. “There is a precedence for this strategy in other solid tumour cancers. The neoadjuvant landscape is becoming very busy and there are many trials that have been published, albeit with small populations,

but with very provocative pathological complete response rates from giving run-ins of dabrafenib + trametinib, run-ins of nivolumab + ipilimumab, and we really need combination immunotherapy run-ins in the neoadjuvant trials to get significant results.”

Whilst this does not represent level 1 evidence and is hypothesis-generating, the trials show very early promise, he added. During an interactive Q&A session, Dr Power commented

on the need for patient education in terms of treatment strategies. “That’s absolutely critical,” he told the conference. “Education of patients before any treatment is given, including the targeted therapies, is totally crucial and really underlines the importance of patients reading the literature we give them, clinical nurse specialists in the clinic educating patients – that’s all so important because some of these side-effects are permanent, such as the endocrine side-effects, for example.”

Thrombosis: The hidden cancer comorbidity

Attendees at the Gathering Around Cancer

2021 conference heard from Dr Barry Kevane, Consultant Haematologist, MMUH, who delivered a talk titled ‘Cancer-associated thrombosis’. Dr Kevane outlined how venous thromboembolism (VTE) is a major global health burden and a leading cause of cardiovascular mortality each year, with acute VTE frequently being rapidly fatal. “Mortality data on VTE in Ireland is somewhat patchy, but we do know that thousands of Irish patients experience thrombosis each year and unfortunately, many of them do not survive,” he said.

The burden of VTE in cancer patients has historically been underestimated, but “we now know that the risk of thrombosis among patients with cancer is at least five-to-seven times higher than seen in the general population,” he told the conference. “Interestingly, even in our thrombosis clinics, we would expect that about 20 per cent of patients we see are presenting with thrombosis related to active cancer,” he said. “It has also been estimated that between 10 and 20 per cent of patients with cancer will experience a thrombotic complication of some kind at some point in their disease course.”

He outlined the complex mechanisms and aetiology underlying thrombotic risk in patients with cancer and how this likely relates to an interaction between various risk factors, including those related to the individuals; requirements for cancer therapy, including major surgery and prothrombotic chemotherapy; and factors relating to the tumours themselves, including site, stage, and grade. The vast majority of cancer-associated

thrombotic events appear to occur in the first six-to-12 months following diagnosis of cancer, he added, and there is also an increased risk during periods of relapse or the end-of-life phase, where tumour activity is increased.

He provided a synopsis of the mechanisms by which tumours can induce a pro-thrombotic state via the direct activity of tumour cells in activating intervascular coagulation. Whilst the exact mechanism of this is unknown, “circulating tumour cells have the ability to express various substances, such as tissue factor and cysteine proteases on the cell surface, which can directly activate circulating clotting factors. Tumour cells can also release a variety of prothrombotic microparticles, and through the release of certain inflammatory mediators, can induce direct platelet activation and epithelial dysfunction, which can all combine to [influence] in situ thrombosis,” said Dr Kevane.

“It’s also important to remember that the interaction between coagulation and cancer activity is not a one-way process,” he continued. “We know that products or coagulation activation can themselves support tumour growth and dissemination through various mechanisms. For example, we know that thrombin, which is a coagulation protease, via signalling on protease-activated receptors on the surface of tumour cells can promote tumour growth and dissemination, and indeed support neo-angiogenesis at the site of metastatic deposits.”

In the interaction between coagulation and

cancer, it is vital to consider the impact that a thrombotic diagnosis can have on cancer patients, Dr Kevane stressed – there is a fivefold increased risk of VTE in these patients compared to patients in the non-cancer population. In the cancer patient population, there is also evidence that survival is shorter in cancer patients with VTE compared to those without thrombosis, he added.

“We often hear it reported that thrombosis is potentially the second-leading cause of death among patients with cancer, second to cancer progression, so clearly, the optimisation of strategies directed at treating and preventing thrombosis among patients with cancer needs to be prioritised,” he told the attendees.

He also briefly addressed the complex question of the role of prophylaxis for the prevention of cancer-associated thrombosis.

“We know that the risk of thrombosis is very high among newly-diagnosed cancer patients who are commencing chemotherapy, so the question is, which ones should receive preventative anticoagulant therapy with low-dose treatment?” said Dr Kevane. “It is recommended that when cancer patients are admitted to hospital, provided there are no specific contraindications, that they should receive low molecular-weight heparin thromboprophylaxis, and this can be extended in certain scenarios, such as when patients are being discharged following major abdominal surgery.”

In myeloma, which is a very pro-thrombotic haematological malignancy, patients

Use

Con dence, Convenience,

ABBREVIATED PRESCRIBING INFORMATION

Please refer to the Summary of Product Characteristics (SmPC) before prescribing Pelgraz▼(peg lgrastim) 6 mg solution for injection in pre- lled syringe or prelled injector. Presentation: Each pre- lled syringe or pre- lled injector contains 6 mg of peg lgrastim* in 0.6 mL solution for injection. The concentration is 10 mg/mL based on protein only**. *Produced in Escherichia coli cells by recombinant DNA technology followed by conjugation with polyethylene glycol (PEG). ** The concentration is 20 mg/mL if the PEG moiety is included. Indications: Reduction in the duration of neutropenia and the incidence of febrile neutropenia in adult patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes). Dosage and Administration: Pelgraz therapy should be initiated and supervised by physicians experienced in oncology and/or haematology. Posology: One 6 mg dose (a single pre- lled syringe or pre- lled injector) of Pelgraz is recommended for each chemotherapy cycle, given at least 24 hours after cytotoxic chemotherapy. Safety and e cacy of Pelgraz in children and adolescents has not yet been established and no recommendation on a posology can be made. No dose change is recommended in patients with renal impairment, including those with end-stage renal disease. Method of administration: Pelgraz is for subcutaneous use. The injections should be given subcutaneously into the thigh, abdomen or upper arm. See SmPC for instructions on handling of the medicinal product before administration. Contraindications: Hypersensitivity to peg lgrastim or any of the excipients in Pelgraz. Warnings and precautions: To improve the traceability of biological medicinal products, the trade name of the administered product should be clearly recorded. The long-term e ects of peg lgrastim have not been established in acute myeloid leukaemia (AML); therefore, it should be used with caution in this patient population. Granulocytecolony stimulating factor (G-CSF) can promote growth of myeloid cells in vitro and similar e ects may be seen on some non-myeloid cells in vitro. The safety and e cacy of peg lgrastim have not been investigated in patients with myelodysplastic syndrome, chronic myelogenous leukaemia, and in patients with secondary AML; therefore, it should not be used in such patients. Particular care should be taken to distinguish the diagnosis of blast transformation of chronic myeloid leukaemia from AML. The safety and e cacy of peg lgrastim administration in de novo AML patients aged < 55 years with cytogenetics t(15;17) have not been established. The safety and e cacy of peg lgrastim have not been investigated in patients receiving high dose chemotherapy. This medicinal product should not be used to increase the dose of cytotoxic chemotherapy beyond established dose regimens. Pulmonary adverse reactions, in particular interstitial pneumonia, have been reported after G-CSF administration. Patients with a recent history of pulmonary in ltrates or pneumonia may be at higher risk. The onset of pulmonary signs such as cough, fever, and dyspnoea in association with radiological signs of pulmonary in ltrates, and deterioration in pulmonary function along with increased neutrophil count may be preliminary signs of adult respiratory distress syndrome (ARDS). In such circumstances peg lgrastim should be discontinued at the discretion of the physician and the appropriate treatment given. Glomerulonephritis has been reported in patients receiving lgrastim and peg lgrastim. Generally, glomerulonephritis resolved after dose reduction or withdrawal

of lgrastim and peg lgrastim. Urinalysis monitoring is recommended. Capillary leak syndrome has been reported after G-CSF administration and is characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. Generally asymptomatic cases of splenomegaly and cases of splenic rupture, including some fatal cases, have been reported following administration of peg lgrastim. Spleen size should be carefully monitored (e.g. clinical examination, ultrasound). A diagnosis of splenic rupture should be considered in patients reporting left upper abdominal pain or shoulder tip pain. Treatment with peg lgrastim alone does not preclude thrombocytopenia and anaemia because full dose myelosuppressive chemotherapy is maintained on the prescribed schedule. Regular monitoring of platelet count and haematocrit is recommended. Special care should be taken when administering single or combination chemotherapeutic medicinal products which are known to cause severe thrombocytopenia. Peg lgrastim in conjunction with chemotherapy and/or radiotherapy has been associated with development of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) in breast and lung cancer patients. Patients treated in these settings should be monitored for signs and symptoms of MDS/AML. Sickle cell crises have been associated with the use of peg lgrastim in patients with sickle cell trait or sickle cell disease. Therefore, use caution when prescribing peg lgrastim in patients with sickle cell trait or sickle cell disease, monitor appropriate clinical parameters and laboratory status and be attentive to the possible association of this medicinal product with splenic enlargement and vasoocclusive crisis. White blood cell (WBC) counts of 100 × 109/L or greater have been observed in less than 1% of patients receiving peg lgrastim. No adverse reactions directly attributable to this degree of leukocytosis have been reported. Such elevation in WBCs is transient, typically seen 24 to 48 hours after administration and is consistent with the pharmacodynamic e ects of this medicinal product. Consistent with the clinical e ects and the potential for leukocytosis, a WBC count should be performed at regular intervals during therapy. If leukocyte counts exceed 50 × 109/L after the expected nadir, this medicinal product should be discontinued immediately. Hypersensitivity, including anaphylactic reactions, have been reported with peg lgrastim. Permanently discontinue peg lgrastim in patients with clinically signi cant hypersensitivity. Do not administer peg lgrastim to patients with a history of hypersensitivity to peg lgrastim or lgrastim. If a serious allergic reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days. Stevens-Johnson syndrome (SJS), which can be life-threatening or fatal, has been reported rarely in association with peg lgrastim treatment. If the patient has developed SJS with the use of peg lgrastim, treatment must not be restarted at any time. As with all therapeutic proteins, there is a potential for immunogenicity. Rates of generation of antibodies against peg lgrastim is generally low. Binding antibodies do occur as expected with all biologics; however, they have not been associated with neutralising activity at present. Aortitis has been reported after lgrastim or peg lgrastim administration in healthy subjects and in cancer patients. The symptoms experienced included fever, abdominal pain, malaise, back pain and increased in ammatory markers (e.g. C-reactive protein and WBC count). In most cases aortitis was

diagnosed by CT scan and generally resolved after withdrawal of lgrastim or peg lgrastim. The safety and e cacy of Pelgraz for the mobilisation of blood progenitor cells in patients or healthy donors has not been adequately evaluated. Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging ndings. This should be considered when interpreting bone-imaging results. The additive e ect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account. Pelgraz contains less than 1 mmol sodium (23 mg) per 6 mg dose, that is to say essentially ‘sodium-free’. The needle cover contains dry natural rubber (a derivative of latex), which may cause allergic reactions. Pregnancy and Lactation: Peg lgrastim is not recommended during pregnancy and in women of childbearing potential not using contraception. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from peg lgrastim therapy taking into account the bene t of breastfeeding for the child and the bene t of therapy for the woman. Adverse Events include: Adverse events which could be considered serious include: Common: Thrombocytopenia. Uncommon: Myelodysplastic syndrome, acute myeloid leukaemia, sickle cell anaemia with crisis, capillary leak syndrome, glomerulonephritis, hypersensitivity reactions (including angioedema, dyspnoea, anaphylaxis), splenic rupture (including some fatal cases), Sweet’s syndrome (acute febrile neutrophilic dermatosis), pulmonary adverse reactions including interstitial pneumonia, pulmonary oedema and pulmonary brosis have been reported. Uncommonly cases have resulted in respiratory failure or ARDS which may be fatal. Rare: Aortitis, pulmonary haemorrhage, Stevens-Johnson syndrome. Other Very Common adverse events: Headache, nausea, bone pain. Other Common adverse events: Leukocytosis, musculoskeletal pain (myalgia, arthralgia, pain in extremity, back pain, musculoskeletal pain, neck pain), injection site pain, non-cardiac chest pain. See SmPC for details of other adverse events. Shelf Life: 3 years. Store in a refrigerator (2∞C – 8∞C). Pelgraz may be exposed to room temperature (not above 25°C ± 2°C) for a maximum single period of up to 72 hours. Pelgraz left at room temperature for more than 72 hours should be discarded. Do not freeze. Accidental exposure to freezing temperatures for a single period of less than 24 hours does not adversely a ect the stability of Pelgraz. Keep the container in the outer carton in order to protect from light. Pack Size: One pre lled syringe or pre lled syringe injector with one alcohol swab, in a blistered packaging. Marketing Authorisation Numbers: Pre- lled syringe: EU/1/18/1313/001, Prelled injector: EU/1/18/1313/002. Marketing Authorisation Holder (MAH): Accord Healthcare S.L.U, World Trade Center, Moll de Barcelona, s/n, Edi ci Est, 6a planta, Barcelona, 08039 Spain. Legal Category: POM. Full prescribing information including the SmPC is available on request from Accord Healthcare Ireland Ltd, Euro House, Little Island, Co. Cork, Tel: 021-4619040 or www.accord-healthcare.ie/products Adverse reactions can be reported to Medical Information at Accord Healthcare Ltd. via E-mail: medinfo@accord-healthcare.com or Tel: +44(0)1271385257.

Date of Generation of API: May 2021. IE-01426

Adverse events should be reported. Reporting forms and information can be found on the HPRA website (www.hpra.ie), or by e-mailing medsafety@hpra.ie. Adverse events should also be reported to Medical Information via email; medinfo@accord-healthcare.com or tel:0044 (0) 1271 385257

who are receiving treatment with IMiDs (immunomodulatory drugs) should also receive pharmacological thrombo-prophylaxis, even as an outpatient, he added.

Dr Kevane presented data to illustrate the huge risk of VTE in cancer patients, with one trial showing that only 4.5 per cent of patients with asymptomatic occult DVT were picked up in the study. “I think this speaks very clearly to the huge burden and the huge risk of VTE within the cancer population,” said Dr Kevane. “I think a certain proportion of these patients would

have no doubt progressed to a symptomatic VTE event, and potentially pulmonary embolism.”

Dr Kevane summarised by telling the conference: “It’s clear that thrombosis represents a major cause of morbidity and mortality in the cancer population and despite advances in all our therapeutics, particularly in regards to the role of DOACs, we continue to see high rates of thrombotic recurrence and major bleeding,” said Dr Kevane. “Novel targets, such as the contact pathway of coagulation activation, is something that may come down the line, and we eagerly

await that data. The role of low-dose DOACs from the point of view of primary thromboprophylaxis is something that is increasingly being considered as an important component of cancer care, but I think we are not quite ready in most centres to implement that widely.”

He concluded: “One of the most important things I would say is, increasing our own awareness of thrombotic risk and educating patients in the same way that we educate patients with regards to risk of infection is a key target for the future.”

The Gathering Around Cancer 2021 conference hosted a presentation titled ‘Lung cancer update’, which was delivered by Dr Sinead Noonan, Consultant Medical Oncologist, CUH and University Hospital Kerry. Dr Noonan spoke about adjuvant and neoadjuvant therapy in non-small cell lung cancer (NSCLC) and provided updates on immunotherapy trials in first-line stage IV NSCLC. She also discussed targeted therapies and previously undruggable targets that are now becoming druggable, as well as managing resistance to targeted therapies and the impact of Covid-19 on NSCLC treatment.

She presented National Cancer Registry Ireland data showing that even with curative intent, 60 per cent of NSCLC patients who are treated will relapse and in stage 1 disease, at five years, over 40 per cent of these patients were still alive. She provided a brief synopsis of some trial data and told the conference: “Looking at surgical outcomes for these patients, the big concern with neoadjuvant treatment would be, do patients get to surgery, which is ultimately the curative treatment?” She presented research to show that numerically, according to some of the data, more patients received surgery in an experimental arm compared to a chemotherapy arm, regardless of the baseline stage of the disease.

“Really, it’s about watching the space, as there is a huge amount of activity here, with multiple studies looking at adjuvant immunotherapy

plus chemotherapy, and also in the neoadjuvant setting,” said Dr Noonan, who also provided a brief overview of trial data on stage IV NSCLC.

Regarding Covid-19 and cancer care, Dr Noonan said: “Unsurprisingly, the pandemic has caused significant decreases in lung cancer screening, diagnosis rates and patient encounters in multiple health systems,” she commented. “[US] Data show that there was a 20-to-60 per cent decrease in lung cancer biopsies compared to 2019, there was a 50 per cent decrease in screening rates, and there was a 59 per cent decrease in the diagnosis of new lung cancer patients. Certainly in Ireland, we have found that we are seeing patients at a much later stage and the pandemic has impacted on the lung cancer community, resulting in fewer diagnoses, less-frequent access to care, and less support due to patients’ fear of engaging with the healthcare landscape.”

Dr Noonan summarised: “There is no doubt that immunotherapy is moving into the neoadjuvant or adjuvant space and it will likely be combined with chemotherapy – we are eagerly awaiting the survival data in this space,” she said.

“We already know that there is a significant overall survival benefit in the metastatic setting with IO and IO/chemotherapy combinations, and it remains to be seen how this will be impacted by the changes in the treatment of early-stage disease.

“There is a lot of research, and we have promising new therapies for, new targets, and also in the setting of overcoming resistance,” she continued. “This will have implications for our practise, particularly for molecular testing, and probably [increases] the need for repeat biopsies in these patients. Also, the impact of Covid-19 will be felt for years to come in terms of the management of our NSCLC patients.”

During an interactive Q&A session, Dr Noonan postulated that immunotherapy offers the chance of cure based on its mechanism of action in terms of cell-to-cell destruction.

“There is still a question as to whether adjuvant TKIs are just delaying a progression… when you look at pathological complete response rates with combined immunotherapy and chemotherapy, it’s hard to see that we will eliminate chemotherapy altogether, but perhaps we might [in future] be able to use less chemotherapy. The advantage of using neoadjuvant treatment in lung cancers is that in patients who don’t have complete pathological responses, maybe they are the ones who need more intensive treatment with perhaps the combination of chemotherapy plus immunotherapy, whereas if they have a complete pathological response, perhaps they may just need maintenance immunotherapy, so I think we can tailor the treatment that way,” she said. “I think that’s the big advantage of the neoadjuvant setting – I think it gives us a lot of prognostic data and allows us to escalate or de-escalate treatment as appropriate.”

‘Watching this space’ in non-small cell lung cancer

Cancer Trials Ireland –radiotherapy study updates

Recently closed/pending closure

NRG GU005 (CTRIAL-IE 18-02) is an international cooperative group study which examines how well stereotactic ablative radiotherapy (SABR) works compared to intensity-modulated radiation therapy (IMRT) in treating patients with localised intermediate risk prostate cancer. The study has been open in the Beacon Hospital since 2019 under the Irish National Lead Investigator Dr Alina Mihai, and is due to close shortly. Beacon is currently the third highest recruiting centre of 125 international sites. NRG Oncology is the international sponsor.

PORTEC-4a (CTRIAL-IE 18-

27) ‘Randomised phase 3 trial of molecular profile-based versus standard recommendations for adjuvant radiotherapy for women with early-stage endometrial cancer’. The primary objective of this international cooperative group study is to establish and compare the rates of vaginal relapse in patients with high-intermediate risk endometrial carcinoma treated after surgery with molecular risk profile-based recommendations (experimental arm) for no additional treatment (observation), vaginal brachytherapy or external beam radiotherapy, or with vaginal brachytherapy (standard arm). The study closed to accrual on 24-Dec-2021. It had been open at St Luke’s Radiation Oncology Network (SLRON), Dublin, under the Irish National Leaf Investigator Dr Charles Gillham. Pathology and molecular profiling were carried out by the Pathology Lab at St James’s Hospital (SJH) (Prof Stephen Finn and Dr Ciarán Ó Riain). Twelve patients were enrolled to the study at SLRON. Leiden University Medical Centre is the international sponsor.

ROAM (CTRIAL-IE 15-41) ‘Radiation versus observation following surgical resection of atypical meningioma: A randomised controlled trial (The ROAM trial)’ is a UK cooperative group study in follow up at SLRON Beaumont. Patients enrolled on the study were randomised to radiotherapy or active monitoring to determine whether early adjuvant fractionated radiotherapy reduces the risk of tumour recurrence or death due to any cause compared to active monitoring in newly diagnosed atypical meningioma. The study closed to accrual early in May; 157 patients were enrolled globally on the study, with three Irish patients being enrolled at SLRON Beaumont. Dr David Fitzpatrick (SLRON) is the Irish National Lead Investigator, and the Walton Centre NHS Foundation Trust is the international sponsor.

Open

PACE C (CTRIAL-IE 15-46) is a cohort of the PACE trial comparing conventional radiotherapy (RT) vs stereotactic body radiotherapy (SBRT) for intermediate/ high-risk prostate cancer patients who are non-surgical candidates or who decline surgery. PACE is a phase 3 randomised controlled study comprising three parallel randomisations (PACE-A, PACE-B, and PACE-C) with a common experimental arm (SBRT). The study is open at three sites in Ireland; Beacon Hospital, Bons Secours Radiotherapy Cork in Partnership with UPMC Hillman Cancer Centre, and SLRON at Beaumont Hospital. The target global accrual is 1,182 patients and the study is due to close to recruitment in mid-2022. PACE is a collaborative group study sponsored (globally) by the Royal Marsden NHS Foundation Trust and coordinated by the Cancer Research

UK-funded Clinical Trials and Statistics Unit at the Institute of Cancer Research, London. Prof John Armstrong is the Irish National Lead Investigator.

SABR COMET-3 (CTRIAL-IE 19-21)

‘Phase 3 randomised controlled trial and economic evaluation of stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic (1-3 metastases) cancer’. This international cooperative group study assesses the impact of SABR plus standard of care treatment, compared to standard of care treatment only, on overall survival, oncologic outcomes, and qualityof-life in patients with one controlled primary tumour and one-to-three metastatic lesions. The study is coordinated internationally by BC Cancer, Canada. The overall international accrual target is 297 patients. In Ireland the study is currently open at SLRON (National Lead Investigator for Cancer Trials Ireland sites: Prof John Armstrong), Bon Secours Radiotherapy Cork in Partnership with UPMC Hillman Cancer Centre and Beacon Hospital.

SOURCE Lung – ‘Stereotactic ablative radiation therapy Of UltRaCEntral LUNG tumours’ (CTRIAL-IE 18-33) is an Irish investigator-led trial which is open at SLRON and Beacon Hospital. This study aims to assess the safety/ impact on side-effects of delivering the same overall dose of radiotherapy, in fewer fractions, to lung tumours, through SABR. Prof Armstrong (SLRON) is the study Chief Investigator (CI). Two translational sub-studies are associated with this research study, and they involve Raman spectroscopic analysis (Focas Research Institute, TU Dublin) and proteomic analysis (Conway Institute, UCD).

Pending

PRESERVE (CTRIAL-IE 20-04) ‘Preservation of swallowing in resected oral cavity squamous cell carcinoma: Examining radiation volume effects (PRESERVE): A randomised trial’ is a Canadian cooperative group study. The purpose of this study is to compare the usual treatment area of radiation to a reduced treatment area to see if radiation to a smaller area on the neck is associated with acceptable rates of regional recurrence and will improve quality-of-life. The study has ethics approval to open at SLRON and CUH. Dr Sinéad Brennan (SLRON) is the Irish National Lead Investigator, and Lawson Health Research Institute is the global sponsor.

CompARE (CTRIAL-IE 17-14) ‘Phase 3 randomised controlled trial comparing alternative regimens for escalating treatment of intermediate and high-risk oropharyngeal cancer’ is a study sponsored by the University of Birmingham, UK. The main objectives of this study are to examine the outcomes of alternative treatments aiming to improve overall survival time in intermediate and high-risk oropharyngeal cancer and to compare quality-of-life, toxicity outcomes and swallowing function of these alternative treatments. The study is planned to open at SLRON and SJH shortly, and at CUH and UHG thereafter.

The target overall accrual is 695 patients. Dr Sinéad Brennan (SLRON) is the Irish National Lead Investigator.

Two new Irish Investigator-led trials are currently in development and will open later in 2022: DP-IMRT Pancreas (CTRIAL-IE 17-12) ‘A non-randomised phase 1/2 study of dose-escalated hypofractionated dose-painted intensity modulated radiotherapy (DP-IMRT) in resectable/borderline resectable pancreatic adenocarcinoma’ (CI: Dr Gerard McVey), and Spine SABR (CTRIAL-IE 20-03) ‘Dose-escalated SABR for solid tumour spine metastases’ (CI: Prof Clare Faul).

Advanced Medical Oncology Fellowship at the Royal Marsden

The Irish Society of Medical Oncology (ISMO) has recently developed a new Advanced Medical Oncology Fellowship at the Royal Marsden Hospital early phase trial and drug development unit for Irish medical oncology trainees. This Fellowship has been developed by Dr Dearbhaile Collins, Consultant Medical Oncologist, Cork University Hospital, who wished to forge a training link with Royal Marsden Hospital following her own oncology Fellowship there. The Fellowship has been generously supported by Janssen, Pfizer, MSD and AstraZeneca.

ISMO is delighted to announce that the 2022 Award has been awarded to Dr Lynda Corrigan, who is starting her Fellowship in the Royal Marsden Hospital this month. Prof Michaela Higgins, lead of ISMO and Consultant

Medical Oncologist, St Vincent’s University Hospital, stated: “This is a life-changing opportunity for Dr Corrigan and she is a well deserving recipient of this ISMO Fellowship award.”

Dr Collins commented: “I am thrilled to be able to offer this Fellowship to Dr Corrigan, who is an exceptional medical oncology trainee. After my

own unforgettable experience at the Royal Marsden, I wanted to support other Irish doctors to do the same. With the help of educational grants from pharmaceutical companies, initially Janssen and then further funding from Pfizer, MSD, and AstraZeneca, I was able to create this fellowship through ISMO. I am so happy for Dr Corrigan and her achievement in obtaining this award. I wish her the very best as she starts in London.”

Dr Corrigan is a graduate of University College Dublin and has recently completed Higher Specialist Training in Medical Oncology with the Royal College of Physicians in Ireland. She is currently pursuing an MD degree in Trinity College Dublin in the field of oncogenomics, under the auspices of Prof Maeve Lowery. She is also a member of Precision

Oncology Ireland, a collaborative academic, charity and industry consortium that is working to advance the diagnostic and therapeutic management of cancer, with a focus on a personalised medicine approach. Throughout her training, Dr Corrigan has been enthusiastically involved in clinical research, through participation in larger clinical trials and institutional research projects. Dr Corrigan’s interest in clinical research and oncogenomics places her well to take up a position in the Drug Development Unit in the Royal Marsden Hospital. She is looking forward to an immersive experience in early phase clinical trial research in a worldrenowned unit, and is eager to develop new expertise which she hopes to bring back to Ireland.

Dr Lynda Corrigan

MYLOTARGTM is indicated for combination therapy with daunorubicin (DNR) and cytarabine (AraC) for the treatment of patients age 15 years and above with previously untreated, de novo CD33‑positive acute myeloid leukaemia (AML), except acute promyelocytic leukaemia (APL)1,2

REINFORCE YOUR AML TREATMENT

FOR LONGER REMISSION COMPARED WITH STANDARD OF CARE CHEMOTHERAPY1,2

MYLOTARG™ significantly extends EFS and RFS* for patients with previously untreated de novo AML compared with the standard of care, chemotherapy with DNR and AraC1,2

▼ MYLOTARG® (gemtuzumab ozogamicin)

PRESCRIBING INFORMATION

Please refer to the Summary of Product Characteristics (SmPC) before prescribing MYLOTARG 5 mg powder for concentrate for solution for infusion.

Presentation: Each vial contains 5 mg gemtuzumab ozogamicin. After reconstitution the concentrated solution contains 1 mg/mL gemtuzumab ozogamicin. Gemtuzumab ozogamicin is an antibody-drug conjugate composed of the CD33-directed recombinant monoclonal antibody humanized hP67.6; recombinant humanised immunoglobulin [Ig] G4, kappa antibody covalently linked to the cytotoxic agent N-acetyl gamma calicheamicin.

Indications: MYLOTARG is indicated for combination therapy with daunorubicin (DNR) and cytarabine (AraC) for the treatment of patients aged 15 years and above with previously untreated, de novo CD33positive acute myeloid leukaemia (AML), except acute promyelocytic leukaemia (APL). Dosage: Administer under the supervision of a physician experienced in the use of cancer therapy and in an environment where full resuscitation facilities are immediately available. MYLOTARG should be used only in patients eligible to receive intensive induction chemotherapy. The recommended induction dose of MYLOTARG is 3 mg/m 2/dose (up to a maximum of one 5 mg vial) infused over a 2 hour period on Days 1, 4, and 7 in combination with DNR 60 mg/m2/day infused over 30 minutes on Day 1 to Day 3, and AraC 200 mg/m2/day by continuous infusion on Day 1 to Day 7. If a second induction is required, DNR should be infused at a dose of 35 mg/m2/day on Day 1 to Day 2 and AraC at a dose of 1 g/m2/every 12 hours on Day 1 to Day 3. MYLOTARG should not be administered during a second induction. For patients experiencing a complete remission (CR) following induction, defined as fewer than 5% blasts in a normocellular marrow and an absolute neutrophil count (ANC) of more than 1.0 × 109 cells/L with a platelet count of 100 × 109/L or more in the peripheral blood in the absence of transfusion, up to 2 consolidation courses of intravenous DNR (60 mg/m2 for 1 day [first course] or 2 days [second course]) in combination with intravenous AraC (1 g/m2 every 12 hours, infused over 2 hours on Day 1 to Day 4) with intravenous MYLOTARG (3 mg/m2/dose infused over 2 hours up to a maximum dose of one 5 mg vial on Day 1) are recommended. Dose modification of MYLOTARG may be required based on individual safety and tolerability.

References

Management of some adverse drug reactions may require dosing interruptions and/or dose reductions, or permanent discontinuation of MYLOTARG. See SmPC for dose modification guidelines for haematological and non haematological toxicities.

Special populations: Hepatic impairment: No adjustment of the starting dose is required in patients with hepatic impairment defined by total bilirubin ≤ 2 × upper limit of normal (ULN) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 × ULN. Postpone MYLOTARG until recovery of total bilirubin to ≤ 2 × ULN and AST and ALT to ≤ 2.5 × ULN prior to each dose. Renal impairment MYLOTARG has not been studied in patients with severe renal impairment. Paediatric population: The safety and efficacy of MYLOTARG in patients less than 15 years has not been established. Contra-indications : Hypersensitivity to the active substance or to any of the excipients. Special warnings and precautions for use: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Premedication with a corticosteroid, antihistamine and acetaminophen (or paracetamol) is recommended 1 hour prior to MYLOTARG dosing due to the potential for infusion related reactions. In patients with hyperleukocytic AML, leukoreduction should be considered with hydroxyurea or leukapheresis to reduce the peripheral WBC count to below 30,000/mm3 prior to administration of MYLOTARG to reduce the risk of inducing tumour lysis syndrome.

Appropriate measures to help prevent the development of tumour lysis-related hyperuricaemia, such as hydration, administration of antihyperuricemics (e.g., allopurinol) or other agents for treatment of hyperuricaemia (e.g., rasburicase) must be taken.

Hepatotoxicity: Hepatotoxicity, including severe, life-threatening, and sometimes fatal hepatic failure and VOD/SOS have been reported in patients treated with MYLOTARG.

Adult patients who received MYLOTARG as monotherapy, either before or after a haematopoietic stem cell transplant (HSCT), and patients with moderate or severe hepatic impairment are at increased risk for developing VOD. Signs and symptoms of VOD/SOS should be monitored closely in all patients. For patients who develop abnormal liver tests, more frequent monitoring of liver tests and clinical signs and symptoms of hepatotoxicity is recommended. For patients who

1. Pfizer MYLOTARG™ (gemtuzumab ozogamicin) Summary of Product Characteristics.

2. Pfizer Cytarabine Summary of Product Characteristics.

PP-MYL-IRL-0094

Date of preparation February 2022

proceed to HSCT, close monitoring of liver tests is recommended during the post-HSCT period, as appropriate. Management of signs or symptoms of hepatic toxicity may require a dose interruption, or discontinuation of MYLOTARG (see section 4.2).

In patients who experience VOD/SOS, MYLOTARG should be discontinued and patients treated according to standard medical practice.

Myelosuppression/cytopenias : Neutropenia, thrombocytopenia, anaemia, leukopenia, febrile neutropenia, lymphopenia, and pancytopenia, some life-threatening and some with complications, were reported. Blood counts should be monitored prior to dosing and signs of myelosuppression should be monitored during treatment. Infusion related reactions: Infusion should be interrupted immediately for patients who develop evidence of severe reactions, especially dyspnoea, bronchospasm, or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinuation of treatment should be strongly considered for patients who develop signs or symptoms of anaphylaxis, including severe respiratory symptoms or clinically significant hypotension. The efficacy of MYLOTARG has been shown in AML patients with favourable- and intermediate-risk cytogenetics, with uncertainty regarding the size of the effect in patients with adverse cytogenetics (see smPC section 5.1). For patients being treated with MYLOTARG in combination with daunorubicin and cytarabine for newly diagnosed de novo AML, when cytogenetics testing results become available it should be considered whether the potential benefit of continuing treatment with MYLOTARG outweighs the risks for the individual patient (see smPC section 5.1) Fertility, pregnancy and lactation: Women of childbearing potential receiving this medicinal product, or treated male partners should use effective contraception during therapy and for at least 7 months or 4 months after completing therapy for females and males, respectively. There are no or limited amount of data from the use of MYLOTARG in pregnant women. Non-clinical studies have shown reproductive toxicity.

MYLOTARG must not be used during pregnancy unless the potential benefit to the mother outweighs the potential risks. The potential hazard to the foetus of MYLOTARG treatment must be explained to pregnant women, patients becoming pregnant while receiving treatment, or treated male partners of pregnant women. Because of the potential for adverse reactions in breast-fed children, women must not breast-feed during treatment

with MYLOTARG and for at least 1 month after the final dose. Based on non-clinical findings, male and female fertility may be compromised by treatment with MYLOTARG. Driving and operating machinery: MYLOTARG may cause fatigue and patients should exercise caution when driving or using machines. Undesirable effects: The overall safety profile of MYLOTARG is based on data from patients with acute myeloid leukaemia from the combination therapy study ALFA-0701, monotherapy studies, and from post-marketing experience. In the combination therapy study, safety data consisting of selected treatment emergent adverse events (TEAEs) considered most important for understanding the safety profile of MYLOTARG consisted of all grades haemorrhages, all grades VOD, and severe infections. The most common adverse reactions (> 30%) in the combination therapy study were haemorrhage and infection. In patients who received MYLOTARG in the combination therapy study ALFA-0701, clinically relevant serious adverse reactions were hepatoxicity including VOD/ SOS (3.8%), haemorrhage (9.9%), severe infection (41.2%), and tumour lysis syndrome (1.5%). See relevant SmPC (Table 5) for full details on specific comprehensive list of AEs for combination therapy. Instructions for reconstitution and dilution: Use appropriate aseptic technique for the reconstitution and dilution procedures. Following reconstitution and dilution, the solution should be protected from light and should be used immediately. If the product cannot be used immediately, the diluted solution may be stored up to 18 hours in a refrigerator (2°C–8°C) from the time of initial vial puncture with not more than 6 hours at room temperature (below 25°C). Legal Category: S1A. Marketing

Authorisation Number: EU/1/18/1277/001 – 5mg 1 vial. The 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.

▼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: 11/2020

Ref: ML 4_0

*RFS is a secondary endpoint. Only EFS and RFS achieved significance in the ALFA-0701 study.1 AML, acute myeloid leukaemia; APL, acute promyelocytic leukaemia; AraC, Cytarabine; DNR, Daunorubicin; EFS, event-free survival; RFS, relapse-free survival.

HRB investment in Irish cancer clinical trials

AUTHOR: Dr Claire O’Connell

Clinical trials make the world of difference for cancer patients, but how can we build our capacity to run them in Ireland? By investing in the people and expertise needed, according to the Health Research Board (HRB), which has gone back to the drawing board to align cancer trials funding with strategic priorities and expertise.

The result is Cancer trials in Ireland, a new HRB funding model to support an overarching National Cancer Clinical Trials Network and six Cancer Clinical Trials Groups, with the goal of doubling the numbers of patients taking part in cancer clinical trials in Ireland, in line with the National Cancer Strategy (2017-2026).

“In Ireland, one in every two people is likely to develop cancer in their lifetime, and clinical trials are essential to improve how we screen, prevent, diagnose, and treat cancer,” says Oonagh Ward, Head of Research and Innovation Infrastructures with the HRB.

“High-quality clinical trials not only offer hope and survival to the lives of cancer patients, but we also know that running clinical trials strengthens health services, and there are benefits to the economy through increased engagement with industry. This new funding programme from the HRB is all about supporting high quality cancer clinical trials in Ireland.”

The aim is to resource clinical infrastructure, or put more plainly, people, notes Ward. “You need a broad spectrum of people to run high-quality clinical trials, including data managers, statisticians, regulatory and methodology experts, nurses, and clinicians,” she explains. “So,

when we talk about supporting clinical trials infrastructure, you might think of buildings and equipment, and those are needed, but these HRB awards are to ensure that we have the expertise and skills to co-ordinate and run more cancer clinical trials in Ireland.”

The Cancer trials in Ireland call, which went out in August 2020, was informed by a HRB review. “We engaged an international panel to look at the barriers and challenges for cancer clinical trials in Ireland,” she says. “It was particularly concerning that Ireland was not on the trajectory to meet the National Cancer Strategy target of doubling participation from 3-to-6 per cent. The HRB report concluded that the funding model needed to be changed.”

Based on the findings of the review, the HRB designed the new, open and competitive funding call and applications were put to international review. The result is that the HRB is now funding an overarching National Cancer Clinical Trial Network (led by Prof Ray McDermott, Clinical Lead of Cancer Trials Ireland, and hosted by the RCSI) that will ensure the trials most relevant to patients in Ireland are prioritised and supported, and six separate cancer clinical trials groups aligned to existing infrastructure in clinical research facilities and centres, hospital groups and academic institutions.

The HRB investment of just over €21 million for cancer trials infrastructure during the five-year period from 2022 represents a step up from the previous five years, notes Ward.

“The resulting model has increased HRB investment into cancer clinical trials by

more than half a million euro each year to €4.2 million,” says Ward. “And the funds are disbursed strategically, to ensure that you have people with the right expertise and patient engagement for designing, developing and running trials that meet all regulatory and transparency requirements. This opens up the opportunity for more trials happening in Ireland.”

The funding scheme is also providing awards to enable other groups to build their cancer trials capacity, she adds. “This HRB funding round is a first step, we have a vision to continue to build across the system to increase the quality and volume of cancer trials that are available to patients. And to ensure excellence, the HRB has adopted a new metrics framework to enable us to monitor and appraise performance of the groups and the Network and to adapt accordingly.”

HRB supports new radiation oncology group

The new HRB funding model is supporting the establishment of a new Irish Research Radiation Oncology Group (IRROG), which joins together radiotherapy centres in Dublin, Cork, and Galway and links with the Wellcome HRB Clinical Research Facility at St James’s Hospital, Dublin, and Trinity College Dublin.

The field of radiation oncology is constantly evolving, says IRROG leader Dr Sinead Brennan, Director of Research at St Luke’s Radiation Oncology Network and Consultant Radiation Oncologist at St James’s Hospital, and improvements in technology and how radiotherapy is designed and delivered can make real impacts on patients’ chances of cure and also reduce side-effects.

Such changes need to be evaluated through randomised clinical trials, and the HRB grant funding will support skilled staff, such as radiation therapy and oncology nurse trial coordinators, data managers and physicists, as well as an IRROG project manager to coordinate the project and link the sites.

“IRROG will signpost Ireland as a site to international research groups and will be a point of contact for national and international collaboration with our stakeholders and partners,” says Dr Brennan. “This will facilitate greater access to international academic trials involving radiotherapy, including trials involving combinations of chemotherapy and immunotherapy with radiotherapy. By working together efficiently as a national group with an enhanced international profile, IRROG can deliver more trials to more patients, but also the right trial to the right patient in the right place.”

Patients will be an integral part of the organisation, including the governance board, she adds, and will be involved in the design and selection of clinical trials. “There is a significant survival benefit

NEW HRB FUNDING FOR NATIONAL CANCER CLINICAL TRIALS NETWORK AND GROUPS

The HRB Cancer Trials in Ireland awards started in January 2022 for:

 The National Cancer Clinical Trial Network led by Prof Ray McDermott (Clinical Lead, Cancer Trials Ireland) and hosted by RCSI University of Medicine and Health Sciences.

 Children’s Health Ireland Cancer Trials Group led by Prof Owen Smith and hosted at University College Dublin.

 Beaumont Hospital – RCSI University of Medicine and Health Sciences Cancer Trials Group led by Prof Patrick Morris and hosted at RCSI.

 Irish Research Radiation Cancer Trials

for cancer patients who participate in clinical trials, and this is especially true in radiotherapy trials. Cancer centres that participate in clinical trials have superior outcomes for all their patients. The National Cancer Strategy has stated that every patient has the right to access a clinical trial. A dedicated radiotherapy trials group, with patients at the heart of our organisation, will allow us to select the most important and impactful trials for patients. Our vision is to improve cancer outcomes through equal access to high-quality clinical trials for all patients wherever they live in Ireland.”

HRB funding to expand paediatric, adolescent and young adulthood cancer trials

“Well-resourced clinical trials increase the curve upwards for outcome, it never goes back,” says Prof Owen Smith, Consultant Paediatric Haematologist at Children’s Health Ireland (CHI) Crumlin, who has been running paediatric cancer trials in Ireland for almost three decades. “But running a clinical trial is not easy. You are under a microscope of regulators, as you should be, and it takes a lot of time and effort and people.”

Group led by Dr Sinead Brennan and hosted at Trinity College Dublin.

 UCC Cancer Trials Group led by Prof Roisin Connolly and hosted at University College Cork.

 Ireland East Hospital Cancer Trials Group led by Prof Catherine Kelly and hosted at University College Dublin.

 Trinity Academic Cancer Trials Group led by Prof Maeve Lowery and hosted at Trinity College Dublin.

HRB grants were also awarded to the SAOLTA University Healthcare Group and to University Hospital Limerick to enable and enhance their cancer clinical trials capacity and capability over the next 15 months.

For more information visit www.hrb.ie.

That’s why Prof Smith, who leads the CHI Cancer Trials Group now funded by the HRB, welcomes the agency’s focus on building up the people and expertise needed to design, co-ordinate and run cancer clinical trials in Ireland.

“The HRB award is a great new development that will allow us to streamline patients for cancer clinical trials on the island of Ireland, to run more investigator-led phase 1 and 2 trials for children with cancer, to develop better ways of reducing the chronic toxicity of childhood cancer treatments and to include more adolescents and young adults in cancer clinical trials,” he says.

He describes adolescents and young adults aged 16-24 years with cancer as the forgotten tribe. “Cancer kills more individuals in this age group than any other disease and the incidence is rising, and they have unique needs around survivorship and preserving fertility,” he says. “The HRB award will provide the resources to ensure that more adolescents and young adults take part in relevant cancer trials, whether they are in adult or paediatric settings.”

Prof Smith is also excited about the new opportunities to better understand the cell and molecular biology of both cancer and host, working with Systems Biology Ireland and Precision Oncology Ireland at University College Dublin, where he is Professor of Paediatric and Adolescent Medicine.

“Clinical trials often involve collecting large amounts of blood and bone marrow from patients, and analysing these samples is opening a brand new vista,” he says. “With this genomic approach we can learn from clinical trials and redefine what we call cure – being without your cancer five years after you develop it, without chronic toxicities, your fertility is preserved, you don’t have bone disease and you are not worried about your heart or brain. This is our goal and the HRB will help us to get there.” 

In HR+/HER2– aBC KISQALI

–RECOGNISED GLOBALLY FOR STATISTICALLY SIGNIFICANT OVERALL SURVIVAL RESULTS

ONLY CDK4/6i cited by all these 3 expert panels1-3:

ESO-ESMO Advanced Breast Cancer Fifth International Consensus Conference (ABC5)1

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)2

KISQALI received high scores from ESO-ESMO ABC51,4

1,2,3

Clinical Cancer Advances 2020: Annual Report on Progress Against Cancer from ASCO3

KISQALI

Only KISQALI + ET received an ESMO-MCBS clinical benefit score of 5 — for the first-line treatment of premenopausal women

Only KISQALI + fulvestrant received an ESMO-MCBS clinical benefit score of 4 — for the first-line treatment of postmenopausal women

Only KISQALI Only KISQALI

ABC5 2019 was the ESO-ESMO Advanced Breast Cancer Fifth International Consensus Conference.

ABC5 2019 was

The ESMO-MCBS is a standardized tool that quantifies the likely magnitude of clinical benefit. Grades for efficacy, QoL, and overall benefit in the non-curative setting range from 1-5, with 4 and 5 denoting substantial benefit.4

NCCN GUIDELINES®: 3 Category 1 preferred recommendations for KISQALI2

The ESMO-MCBS range from 1-5, NCCN GUIDELINES

First line: AI + Kisqali ^ (category 1)

First line: AI

First line: Fulvestrant + Kisqali (category 1)

Second Line: Fulvestrant + Kisqali (category 1)

First line: Fulvestrant

The National Comprehensive Cancer Network ® (NCCN ®) confers a Category 1 designation if, based on high-level evidence, there is uniform NCCN consensus that the intervention is appropriate. NCCN makes no warranties of any kind whatsoever regarding their content, use or application, and disclaims any responsibility for their application or use in any way.

^In premenopausal women Kisqali + AI used in combination with LHRH agonist

The National Comprehensive the intervention application or use ^In premenopausal

The

only CDK4/6 inhibitor regimen recognised by ASCO’s Clinical Cancer Advances 20203

Ribociclib + ET was recognised among “the most important clinical research advances of the past year” based on a “clear overall survival benefit” demonstrated in pre and peri menopausal women.

Clinical Cancer Advances 2020: Annual Report on Progress Against Cancer highlights the most important clinical research advances of the past year, including the Advance of the Year, and identifies priority areas where ASCO believes research efforts should be focused moving forward.

The only CDK4/6 Ribociclib + ET demonstrated Clinical Cancer the Advance of

References:

References: 1. Cardoso F. Highlights from ABC5. Presented at: European School of Oncology e-Learning Session 511; January 23, 2020. 2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.5.2020. ©National Comprehensive Cancer Network, Inc. 2020. All right reserved. Published July 15, 2020. Accessed August 21, 2020. To view the most recent and complete version of the guideline, go online to NCCN.org. 3. Markham MJ, Wachter K, Agarwal N, et al. Clinical cancer advances 2020: annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol. 2020;38(10):1081-1101

4. ESMO-Magnitude of clinical benefit scale scorecards. ESMO.org. Accessed August 25, 2020. https:// www.esmo.org/guidelines/esmo-mcbs/esmo-magnitude-of-clinicalbenefit-scale/scorecard-[6-1, 7-1, 8-1, 9-1, 158-1, 159-1, 160-1, 161-1]. aBC, advanced breast cancer; ASCO, American Society of Clinical Oncologists; ESMO, European Society for Medical Oncology; ESO, European Society of Oncology NCCN, National Comprehensive Cancer Network

1. Cardoso Oncology (NCCN Guidelines®) complete version of Oncology. J Clin Oncol. benefit-scale/scorecard-[6-1, aBC, advanced breast

ABBREVIATED PRESCRIBING INFORMATION

Please refer to Summary of Product Characteristics (SmPC) before prescribing.

Kisqali ▼ (ribociclib) 200 mg film-coated tablets

Dose adjustment is required, and the starting dose of 400 mg once daily is recommended. ♦Elderly (>65 years): No dose adjustment is required. ♦Pediatrics(<18 years): Safety and efficacy have not been established.

pneumonitis has been reported with CDK4/6 inhibitors including Kisqali. Based on the severity of the ILD/ pneumonitis, which may be fatal, Kisqali may require dose interruption, reduction or discontinuation as described in

ABBREVIATED PRESCRIBING Please refer to Summary (SmPC) before prescribing.

Kisqali ▼ (ribociclib)

SmPC

CYP3A4 should be considered. ♦Caution is recommended when Kisqali is administered with sensitive CYP3A4 substrates with narrow therapeutic index (including, but not limited to, alfentanil, ciclosporin, everolimus, fentanyl, sirolimus, and tacrolimus), and their dose may need to be reduced.

Presentation: Film‑coated tablets (FCT) containing 200 mg of ribociclib and 0.344 mg soya lecithin.

Indications: Kisqali is indicated for the treatment of women with 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 fulvestrant as initial endocrine based therapy, or in women who have received prior endocrine therapy

In pre‑ or perimenopausal women, the endocrine therapy should be combined with a luteinising hormone‑releasing hormone (LHRH) agonist.

Dosage and administration:

Contraindications: Hypersensitivity to the active substance or to peanut, soya or any of the excipients.

Warnings/Precautions: ♦Neutropenia was most frequently reported ADR A complete blood count (CBC) should be performed before initiating treatment. CBC should be monitored every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, then as clinically indicated. Febrile neutropenia was reported in 1.4% of patients exposed to Kisqali in the phase III clinical studies. Patients should be instructed to report any fever promptly.Based on the severity of the neutropenia, Kisqali may require dose interruption, reduction, or discontinuation.

Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis which may include hypoxia, cough and dyspnoea and dose modifications should be managed in accordance with Table 5 (see section 4.2)

♦Concomitant administration of Kisqali at the 600 mg dose with the following CYP3A4 substrates should be avoided: alfuzosin, amiodarone, cisapride, pimozide, quinidine, ergotamine, dihydroergotamine, quetiapine, lovastatin, simvastatin, sildenafil, midazolam, triazolam.

Presentation: Film‑coated of ribociclib and 0.344

♦Blood creatinine increase ribociclib may cause blood creatinine increase – if this occurs it is recommended that further assessment of the renal function be performed to exclude renal impairment.

Indications: Kisqali women with hormone epidermal growth factor advanced or metastatic an aromatase inhibitor based therapy, or in endocrine therapy In pre‑ or perimenopausal should be combined hormone (LHRH) agonist.

Adults: The recommended dose is 600 mg (3 x 200 mg FCT) taken orally, once daily for 21 consecutive days followed by 7 days off treatment, resulting in a complete cycle of 28 days.

Kisqali should be used together with 2.5 mg letrozole or another aromatase inhibitor or with 500 mg fulvestrant.

When Kisqali is used in combination with an aromatase inhibitor, the aromatase inhibitor should be taken orally once daily continuously throughout the 28‑day cycle. Please refer to the Summary of Product Characteristics (SmPC) of the aromatase inhibitor for additional details.

When Kisqali is used in combination with fulvestrant, fulvestrant is administered intramuscularly on days 1, 15 and 29, and once monthly thereafter. Please refer to the SmPC of fulvestrant for additional details.

♦Hepatobiliary toxicity increases in transaminases have been reported. Liver function tests (LFTs) should be performed before initiating treatment. LFTs should be monitored every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, then as clinically indicated. If grade 2 abnormalities are noted, more frequent monitoring is recommended.

♦CYP3A4 substrates.ribociclib may interact with medicinal products which are metabolised via CYP3A4, which may lead to increased serum concentrations of CYP3A4 substrates (see section 4.5). Caution is recommended in case of concomitant use with sensitive CYP3A4 substrates with a narrow therapeutic index and the SmPC of the other product should be consulted for the recommendations regarding co‑administration with CYP3A4 inhibitors Pregnancy, Fertility and Lacation

Dosage and administration:

Adults: The recommended FCT) taken orally, once followed by 7 days off cycle of 28 days.

Recommendations for patients who have elevated AST/ ALT grade 3 at baseline have not been established. Based on the severity of transaminase elevations, Kisqali may require dose interruption, reduction, or discontinuation.

♦Pregnancy: Pregnancy status should be verified prior to starting treatment as Kisqali can cause foetal harm when administered to a pregnant woman.

♦Caution and monitoring for toxicity are advised during concomitant treatment with sensitive substrates of drug transporters P gp, BCRP, OATP1B1/1B3, OCT1, OCT2, MATE1 and BSEP which exhibit a narrow therapeutic index, including but not limited to digoxin, pitavastatin, pravastatin, rosuvastatin and metformin. ♦Co administration of Kisqali with medicinal products with known potential to prolong the QT interval should be avoided such as anti arrhythmic medicinal products (including, but not limited to, amiodarone, disopyramide, procainamide, quinidine and sotalol) and other medicinal products known to prolong the QT interval including, but not limited to, chloroquine, halofantrine, clarithromycin, ciprofloxacin, levofloxacin, azithromycin, haloperidol, methadone, moxifloxacin, bepridil, pimozide and intravenous ondansetron. Kisqali is not recommended for use in combination with tamoxifen.

Kisqali should be used another aromatase inhibitor When Kisqali is used inhibitor, the aromatase daily continuously throughout to the Summary of Product aromatase inhibitor for When Kisqali is used fulvestrant is administered 15 and 29, and once the SmPC of fulvestrant

Treatment of pre‑ and perimenopausal women with the approved Kisqali combinations should also include an LHRH agonist in accordance with local clinical practice

Management of severe or intolerable adverse drug reactions (ADRs) may require temporary dose interruption, reduction or discontinuation of Kisqali. Please see section 4.2 of SmPC for recommended dose modification guidelines. Kisqali can be taken with or without food (see section 4.5). The tablets should be swallowed whole and should not be chewed, crushed or split prior to swallowing.

Special populations: ♦Renal impairment: Mild or moderate:

No dose adjustment is necessary. Severe: A starting dose of 200 mg is recommended in patients with severe renal impairment. Kisqali has not been studied in breast cancer patients with severe renal impairment. Caution should be used in patients with severe renal impairment with close monitoring for signs of toxicity. ♦Hepatic impairment: Mild: No dose adjustment is necessary. Moderate or severe:

♦QT interval prolongation has been reported with Kisqali. The use of Kisqali should be avoided in patients who have already or who are at significant risk of developing QTc prolongation. The ECG should be assessed prior to initiation of treatment. Treatment with Kisqali should be initiated only in patients with QTcF values <450 msec. The ECG should be repeated at approximately Day 14 of the first cycle and at the beginning of the second cycle, then as clinically indicated. In case of QTcF prolongation during treatment, more frequent ECG monitoring is recommended Appropriate monitoring of serum electrolytes (including potassium, calcium, phosphorous, and magnesium) should be performed prior to initiation of treatment, at the beginning of the first 6 cycles, and then as clinically indicated. Any abnormality should be corrected before the start of Kisqali treatment. Based on the observed QT prolongation during treatment, Kisqali may require dose interruption, reduction, or discontinuation. Based on the E2301 study QTcF interval data, Kisqali is not recommended for use in combination with tamoxifen ♦Critical visceral disease. The efficacy and safety of ribociclib have not been studied in patients with critical visceral disease.

♦Women of childbearing potential who are receiving Kisqali should use effective contraception (e.g. double barrier contraception) during therapy and for at least 21 days after stopping treatment with Kisqali. ♦Breast‑feeding: Patients receiving Kisqali should not breast‑feed for at least 21 days after the last dose. ♦Fertility: There are no clinical data available regarding effects of ribociclib on fertility. Based on animal studies, ribociclib may impair fertility in males of reproductive potential.

Adverse reactions: ♦Very common: Infections, neutropenia, leukopenia, anaemia lymphopenia, decreased appetite, headache, dizziness, dyspnoea, cough, nausea, diarrhoea, vomiting, constipation, stomatitis, abdominal pain, dyspepsia alopecia, rash, pruritus, back pain, fatigue, peripheral oedema, asthenia, pyrexia, abnormal liver function tests.

♦ Common:, thrombocytopenia, febrile neutropenia, hypocalcaemia, hypokalaemia, hypophosphataemia, vertigo, lacrimation increased, dry eye, syncope, dysgeusia, , hepatotoxicity, erythema, dry skin, vitiligo, dry mouth, oropharyngeal pain, blood creatinine increased, electrocardiogram QT prolonged. ♦Please refer to SmPC for a full list of adverse events.

♦Severe cutaneous reactions Toxic epidermal necrolysis

♦Effects on ability to drive and use machines Patients should be advised to be cautious when driving or using machines in case they experience fatigue, dizziness or vertigo during treatment with Kisqali.

Legal Category: POM

Pack sizes: Unit packs containing 21, 42 or 63 FCTs. Not all pack sizes may be marketed.

Marketing Authorisation Holder Novartis Europharm Limited Vista Building, Elm Park, Merrion Road, Dublin 4 Ireland

Treatment of pre‑ and approved Kisqali combinations LHRH agonist in accordance Management of severe (ADRs) may require temporary or discontinuation of SmPC for recommended Kisqali can be taken with The tablets should be chewed, crushed or Special populations: ♦ No dose adjustment of 200 mg is recommended impairment. Kisqali has patients with severe used in patients with monitoring for signs

(TEN) has been reported with Kisqali treatment. If signs and symptoms suggestive of severe cutaneous reactions (e.g. progressive widespread skin rash often with blisters or mucosal lesions) appear, Kisqali should be discontinued immediately. ♦Interstitial lung disease/pneumonitis ILD/

Interactions: ♦Concomitant use of strong CYP3A4 inhibitors should be avoided, including, but not limited to, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir, ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, verapamil, and voriconazole. Alternative concomitant medicinal products with less potential to inhibit CYP3A4 should be considered. Patients should be monitored for ADRs. If concomitant use of a strong CYP3A4 inhibitor cannot be avoided, the dose of Kisqali should be reduced (see section 4.2 of SmPC). ♦Grapefruit or grapefruit juice should be avoided. ♦Concomitant use of strong CYP3A4 inducers should be avoided, including, but not limited to, phenytoin, rifampicin, carbamazepine and St John’s Wort (Hypericum perforatum). An alternative medicinal product with no or minimal potential to induce

Marketing Authorisation Numbers : EU/1/17/1221/003 & 005.

Full prescribing information is available on request from Novartis Ireland Ltd, Vista Building, Elm Park Business Park, Dublin 4. Tel: 01 2601255 or at www.medicines.ie

Mild: No dose adjustment

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.

Prescribing information last revised : October 2020

ESO-ESMO International

Partial breast irradiation: Is it a new standard?

AUTHOR: Dr Esam Abdelaal, Consultant Radiation Oncologist, UPMC, Whitfield Clinic, Waterford

Breast cancer is a worldwide problem, accounting for 10.4 per cent of all cancer incidence among women, making it the second most common type of non-skin cancer (after lung cancer) and the fifth most common cause of cancer death. Breast cancer is the most common malignant tumour diagnosed in Irish women, with 3,700 new cases of breast cancer diagnosed each year during 2016-2018, and one-in-nine women will develop breast cancer in the course of their lifetime.

A historical review for the role of radiotherapy in breast cancer management

Radiotherapy has come to be an important resource in the treatment of breast cancer. After the discovery of X-rays in 1895, postoperative irradiation has been important in selected patients who have undergone mastectomy and locoregional irradiation and has proved to be beneficial.

In the UK, Robert McWhirter of Edinburgh was the foremost proponent of radiotherapy in the mid-20th century and he reported the results of simple mastectomy followed by radiotherapy to the supraclavicular, internal mammary, and axillary lymph nodes in 759 patients (McWhirter, 1948).

Post-mastectomy radiotherapy in high-risk breast cancer has demonstrated not only a reduction in locoregional recurrences, but also prolonged overall survival.

The era of screening and breast conservative surgery

In Ireland, there has been a consistent increase in the proportion of women diagnosed at stage 1 of breast cancer, up from 20 per cent in 1994 to 33 per cent in 2012, and about 26 per cent of all invasive

breast cancers in Ireland were diagnosed through screening during 2015.

With the increasing use of breast cancer screening by mammography, more and more patients will have their breast cancer diagnosed at an early stage.

The emerging role for conservative breast surgery

The management of localised breast cancer has changed dramatically over the past three to four decades. Breast-conserving therapy (BCT), which involves lumpectomy followed by adjuvant irradiation, is now widely considered the standard of care

BCT has been shown to have equivalent rates of local control and overall survival (OS) compared with mastectomy, with improvements in patient quality-of-life.

Why do we give radiotherapy after BCS?

The rationale for this approach is based upon two principles. First, higher doses of radiotherapy are given to the ‘tumour bed’ in an attempt to control small foci of cancer which may be left behind after excision alone. Second, WBI is used to eliminate possible areas of occult multicentric in situ or infiltrating cancer in remote areas of the breast.

in women with early-stage breast cancer. Landmark trials such as the National Surgical Adjuvant Breast and Bowel Project’s (NSABP’s) B-06 trial and the European Organisation for Research and Treatment of Cancer (EORTC) 10801 trial showed that mastectomy was equivalent to breast-conserving surgery (BCS) followed by postoperative irradiation.

In these trials, the addition of whole breast irradiation (WBI) after BCS decreased the chance of ipsilateral breast tumour recurrence by 50 per cent or more, indicating the need for radiotherapy to address any residual microscopic disease.

With more than 20 years of follow-up,

The question that arises therefore is, ‘can similar rates of local control be achieved with radiation therapy delivered only to the area at highest risk for recurrence?’. If so, radiation could be delivered in a significantly shortened period? This is the concept of accelerated partial breast irradiation (APBI).

An additional theoretical advantage of APBI is a decreased dose to normal tissue. With a smaller target volume, it may be expected that adjacent organs such as the heart and lungs will receive less radiation.

Evidence from trials

There are now at least five prospective randomised trials that have been conducted comparing the outcome of patients treated

Post-mastectomy radiotherapy in high-risk breast cancer has demonstrated not only a reduction in locoregional recurrences, but also prolonged overall survival

with excisional biopsy alone or followed by WBI. In all of these trials, the majority of recurrences in the breasts of patients who did not receive radiotherapy occurred at or in the area of the tumour bed.

In addition, the rate of development of new cancers in remote areas of the breast (unrelated to the index lesion) was similar whether or not WBI was administered. Thus, it would appear that radiotherapy after tumour excision exerts its maximal effect upon reducing breast cancer recurrence at or near the tumour site.

In a similar pattern to invasive breast cancer, in non-invasive breast cancer (ductal

FIGURE 1: Breast cancer staging

FIGURE 2: MammoSite Balloon for PBI

carcinoma in situ, DCIS), 75 per cent of recurrences developed in or adjacent to the original tumour site following breast conservation surgery with or without the use of radiation.

Alternative approach

APBI, which involves focal irradiation of the lumpectomy cavity over a short period of time, has developed over the past two decades as an alternative to WBI.

APBI is an approach that treats only the lumpectomy bed plus a 1-2cm margin, rather than the whole breast in a shorter duration.

Methods of delivery of APBI

A number of methods of APBI exist, using photons, electrons, or brachytherapy.

Brachytherapy can be delivered using lowdose rate (LDR), pulsed-dose rate (PDR), and high-dose rate (HDR) isotopes delivered by way of a single catheter or multiple catheter implants or using a special balloon called MammoSite (Figure 2).

External beam radiotherapy can be used to deliver a partial breast treatment with electrons, conventional beam approaches, or intensity-modulated radiotherapy (IMRT) techniques (Figure 3).

Efficacy of APBI

Long-term outcomes with APBI encompass data from randomised trials, prospective data, and single-institution series, which have highlighted the efficacy as well as comparable recurrence risks compared with WBI. Prospective randomised comparisons of APBI with WBI have demonstrated similar rates of tumour control.

EBRT has many potential advantages, over the other techniques

1) The technique is non-invasive and no need for anaesthesia, thereby reducing the potential risk of complications.

2) The treatment can wait until the completion of pathological analysis about the original tumour and the status of the resection margins are available.

3) The technique has potential for widespread availability since most radiation therapy centres already perform 3D-CRT or IMRT for other cancers.

A famous trial called the Florence trial has randomised 520 patients, more than 90 per cent of whom had characteristics associated with low recurrence (WBI, n=260; APBI, n=260), between 2005 and 2013. The 10year cumulative ipsilateral breast tumour recurrence incidence in early breast cancer treated with external APBI using IMRT technique in five once-daily fractions is low and not different from that after WBI. Acute and late treatment-related toxicity and cosmesis outcomes were significantly in favour of APBI.

4) It is likely that an external beam approach will be easier for radiation oncologists to adopt than brachytherapy techniques because the technical demands and quality assurance issues are much simpler.

5) Treatment results with external beam may be more uniform between radiation oncologists because the outcome depends less on the experience and operative skills of the person performing the procedure than for brachytherapy (especially using interstitial implantation).

APBI patient selection

Patient selection is critical to the successful application of APBI. In a recent review, Polgar

FIGURE 3: Partial breast irradiation using IMRT

Patient selection is critical to the successful application of APBI

et al argued that the relatively poorer results of early APBI studies, with high local recurrence rates, could be attributed to inadequate patient selection criteria and/or suboptimal treatment technique and lack of appropriate QA procedures.

Multiple society-sponsored consensus guidelines for appropriate patient selection are available and are generally reflective of the eligibility criteria from the large prospectively randomised trials.

American Brachytherapy Society guidelines

The most recent set of guidelines published by the American Brachytherapy Society (ABS) support APBI for patients aged 50 or older, with tumours 3cm or less, all invasive cancers and DCIS histologies, negative margins, no lymphovascular space invasion (LVSI), and negative lymph nodes.

European Society of Therapeutic Radiology and Oncology guidelines

According to the latest European Society

of Therapeutic Radiology and Oncology (ESTRO) guidelines, APBI might be considered an acceptable treatment option in patients at least 50 years old with unicentric, unifocal, node-negative, non-lobular breast cancer up to 3cm in size without the presence of an extensive intraductal component or lymphovascular invasion and with negative margins of at least 2mm. Patients with microscopic multifocality are eligible as long as the total pathologic tumour size is 3cm or less.

Drawing on evidence published in the last eight years, the guideline suggests that more breast cancer patients can benefit from APBI, including younger patients and those with DCIS.

Technical feasibility for APBI

Proper patients selection is the cornerstone for APBI, however, its feasibility will be determined by the size, shape, and location of the lumpectomy cavity and the lumpectomy cavity/whole breast volume ratio which is required to be ≤30 per cent.

Radiotherapy dosed for APBI

Different doses and fractionation schemes have been reported in the literature, however, 30 grays (Gy) in five fractions is a very reasonable regimen.

Cost-effectiveness

In the age of rapidly increasing healthcare costs, evaluation of techniques has to include costeffectiveness. APBI approaches, in general, were favoured over whole-breast techniques when considering costs.

Quality-of-life

Some investigators performed a prospective quality-of-life study of patient-reported outcomes related to cosmesis, function, pain, fatigue, treatment-related symptoms, and convenience. In general, quality-of-life outcomes were similar in both whole breast and APBI, although favouring APBI for some measures in patients who did not receive chemotherapy.

UPMC experience

We have introduced this technique recently in UPMC and have treated a handful of patients. Although it is very early to draw any conclusion, it is very clear that patient perception is very high and the majority were delighted.

Conclusion

At this time, APBI represents an appropriate treatment option for appropriately selected women with early-stage breast cancer. Mature results from randomised trials and prospective series have consistently demonstrated comparable clinical and survival outcomes with low rates of toxicity when compared to whole breast radiotherapy. On the basis of level-1 evidence, postoperative APBI should supersede whole breast radiotherapy as the preferred option in a significant proportion of patients with early-stage breast cancer. 

References on request

TABLE 1: Summary of APBI consensus statement from the American Society for Therapeutic Radiology and Oncology (ASTRO)

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 daily 1

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

information visit www.pfizerpro.ie/product/ibrance

For more information visit www.pfizerpro.ie/product/ibrance

IBRANCE® (PALBOCICLIB) PRESCRIBING INFORMATION:

Warnings and Precautions: Ovarian ablation LHRH agonist is mandatory when pre/ administered IBRANCE in combination inhibitor, due to the mechanism of action of Palbociclib in combination with fulvestrant in women has only been studied in combination interruption, dose reduction, or delay in recommended for patients who develop Appropriate monitoring should be performed 4.8). Severe, life-threatening, or fatal ILD in patients treated with cyclin dependent inhibitors, including IBRANCE when taken in therapy. Across clinical studies (PALOMA-1, 1.4% of IBRANCE-treated patients had ILD/ 0.1% had Grade 3, and no Grade 4 or fatal

Additional cases of ILD/pneumonitis have been post-marketing setting, with fatalities reported. monitored for pulmonary symptoms and IBRANCE immediately interrupted in patients suspected ILD/pneumonitis, see SmPC section 4.2, 4.4 and myelosuppressive properties, it may predispose Infections have been reported at a higher rate IBRANCE in randomised clinical studies in the respective comparator arm. Grade occurred respectively in 5.6% and 0.9% of IBRANCE in any combination (see SmPC section monitored for signs and symptoms of infection appropriate (see SmPC section 4.2). Physicians promptly report any episodes of fever. may lead to increased toxicity (see SmPC concomitant use of strong CYP3A inhibitors during Coadministration should only be considered of the potential benefits and risks. If strong CYP3A inhibitor is unavoidable, reduce once daily. When the strong inhibitor is IBRANCE should be increased (after 3–5 halfdose used prior to the initiation of the SmPC section 4.5). Coadministration of to decreased palbociclib exposure and of efficacy. Therefore, concomitant use of CYP3A4 inducers should be avoided. No dose for coadministration of palbociclib with SmPC section 4.5). Women of childbearing partners must use a highly effective method

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

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

(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

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

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.

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:

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) 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

Last revised: 07/2021

Ref: IB 9_0

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.

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.

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.

HR+/HER2- locally advanced or mBC:

who have received prior ET should be combined with an LHRH agonist

Facing Ireland’s cancer challenge

AUTHORS: Dr Una Kennedy, GP Advisor to the National Cancer Control Programme (NCCP); Dr Heather Burns, Public Health Specialist, NCCP; and Ms Aine Lyng, Cancer Prevention  Officer, NCCP

One-in-two people in Ireland will be diagnosed with cancer at some point in their lifetime.1 It is the single biggest cause of death in this country, accounting for almost one-in-three deaths (31 per cent) in 2019.1

The five most commonly diagnosed invasive cancers in Ireland (excluding nonmelanoma skin cancer) combined account for approximately six-out-of-every-10 (58 per cent) newly-diagnosed cancer cases.2 These five cancers and the percentage of cancer cases they account for are:2

 Prostate cancer – 16 per cent

 Female breast cancer – 15 per cent

 Colorectal cancer – 11 per cent

 Lung cancer – 11 per cent

 Melanoma skin cancer – 5 per cent

The number of cancer cases diagnosed annually in Ireland is projected to rise, potentially doubling between 2015 and 2045.3 This is largely due to demographic factors, such as our growing and ageing population,1 but is also influenced by the prevalence of modifiable risk factors, including smoking, alcohol consumption, overweight and obesity, and physical inactivity.4

How do healthcare workers face the challenge presented by the projected increase in cancer incidence and what steps can we take to protect our patients?

STEPS TO REDUCE YOUR CANCER RISK

Prevention

Prevention offers the most effective longterm strategy to control cancer. According to the World Health Organisation (WHO), 30-to-50 per cent of all cancers are preventable through changes to lifestyle and environmental factors.5 The National Cancer Registry Ireland (NCRI) estimates that almost one-in-three (29 per cent) cancers in this country are attributable to modifiable risk factors, including those listed below.4

 Smoking

 Overweight and obesity

 Sun and ultraviolet (UV) light exposure

 Alcohol consumption

 Ionising radiation (including radon)

 Processed meat consumption

 Air pollution – fine particulate matter

 Lack of physical activity

Practical steps

What practical steps can healthcare professionals take to help reduce their patients’ cancer risk?

 Encourage healthy lifestyles, inform your patients, and refer them to appropriate supports Brief interventions and motivational interviewing techniques can be effective in inducing lifestyle change. The National Cancer Control Programme (NCCP) has developed a suite of evidence-based resources to promote cancer awareness and prevention, such as the ‘Steps to Reduce Your Cancer Risk’ poster (Figure 1) available at www.hse.ie/eng/ services/list/5/cancer/prevention/. Healthcare workers can access resources on the HSE Health and Wellbeing website: www.hse.ie/ healthandwellbeing/, and can direct their patients to appropriate supports such as smoking cessation support www.hse.ie/quit-smoking/ and healthy eating guidelines www.hse.ie/eng/about/ who/healthwellbeing/our-priority-programmes/heal/ healthy-eating-guidelines/.

Tobacco smoking remains the single biggest contributor to preventable disease and death in Ireland. Tobacco smoking increases the risk of 15 different types of cancer.4 Smoking cessation is the single most important measure that smokers can take to improve their health.

FIGURE 1: Steps to reduce your cancer risk

While 18 per cent of the Irish population currently smoke, almost one-in-three (29 per cent) are either trying to quit or actively planning to do so.6 Healthcare professionals have an important role in supporting and encouraging smoking cessation. Nicotine replacement therapy is available to medical cardholders on the General Medical Scheme (GMS) and the HSE offers a range of support services to help people who smoke to quit at www.quit.ie. Ireland’s first National Stop Smoking Clinical Guidelines were recently launched, containing clear guidelines for healthcare professionals to support people who smoke to quit smoking. These can be accessed here: www.hse.ie/eng/about/who/tobaccocontrol/ national-clinical-guidelines/.

 Promote vaccination

Human papillomavirus (HPV) causes up to 90 per cent of all cervical cancers4 and also causes cancer of the anus, vagina, vulva, penis, oral cavity, and oropharynx. Currently, all children aged 12-to-13 years in Ireland are offered the HPV vaccine free of charge.7

Hepatitis B is associated with an increased risk of developing hepatocellular carcinoma.8 Hepatitis B vaccination is freely available to all infants in Ireland as part of the National Childhood Immunisation Schedule. Further information on vaccines can be found at www.immunisation.ie.

Early detection of cancer

Age-standardised five-year net survival for all cancers in Ireland combined (ex-NMSC) has increased from just 42 per cent in 1989-1993 to 65 per cent in 2014-2018.2 This is partly due to improved treatments, but is also influenced by improvements in the early detection of cancer. Where cancer cannot be prevented, early detection is crucial to achieving higher survival rates, reducing treatment severity and improving quality-of-life for patients. For many cancers, stage at diagnosis is the most important predictor of survival. The difference in survival, by stage at diagnosis, for Ireland’s commonest cancers is illustrated in Figure 2 9

Achieving early detection of cancer

is complex. Population-based cancer screening programmes, such as BreastCheck, CervicalCheck, and BowelScreen, aim to detect cancer, or precancerous lesions, at an early stage, before they have caused any symptoms.

Early detection of symptomatic cancer requires a different approach, and is influenced by factors including patient awareness and willingness to act on signs and symptoms of cancer, healthcare worker index of suspicion, and systems factors including access to diagnostics and referral pathways to secondary care.

Practical steps

What practical steps can healthcare professionals take to improve the early detection of cancer for their patients?

Early detection of cancer in symptomatic patients

 Know the signs and symptoms

To improve the early detection of cancer in symptomatic patients, healthcare workers need to know the signs and symptoms of cancer and how to guide patients to the next step on their journey to a possible cancer diagnosis. Most patients with cancer present to their GP in the first instance and GPs are responsible for referring patients with suspected cancer for diagnostic investigations or specialist review. However, other primary care professionals, such as community pharmacists, public health nurses, and general practice nurses, also have a role in recognising the signs and symptoms of cancer and encouraging patients to make an appointment with their GP if they have signs or symptoms that may be cancer. Information and resources on the early detection of cancer, including posters, leaflets, and factsheets, are available on the NCCP website: www.hse.ie/eng/services/ list/5/cancer/prevention/early-detection-of-cancerhow-to-spot-cancer-early.html.

 Know the referral pathways and guidelines

Ireland has national rapid access clinics that offer a diagnostic pathway for patients with suspected breast, lung, and prostate cancer. Pigmented lesion clinics are available for patients with suspected melanoma skin cancer. The NCCP GP guidelines and referral forms, are available on the NCCP website www.hse. ie/eng/services/list/5/cancer/profinfo/resources/ gpreferrals/gp-guidelines-and-referral-forms. html. Eligible patients should be referred electronically wherever possible. GPs can access electronic referral forms via their ICGPaccredited software (Socrates, Helix Practice Manager, Health One, and Complete GP) or by logging in to Healthlink (www.healthlink.ie).

 Trust your instincts

For most patients subsequently diagnosed with cancer (72 per cent), their initial contact with the healthcare services is with their GP.10 However, up to half of symptomatic patients

FIGURE 2: Five-year survival 2010-14 for common cancer types by stage (NCRI)9

Remarkable PFS benefit >79% RRR* in disease progression or death vs Vd of patients with 1PL of therapy2

Meaningful response

3x DVd complete response (CR) or better vs Vd2

Unlocking hope

≥5x increase in rate of MRD negativity2

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.

Date

with cancer do not present with classical signs and symptoms, such as a prolonged cough or haemoptysis, that would prompt referral to a dedicated rapid access clinic. Instead, a significant proportion of patients present with vague, non-specific ‘low-risk, but not no-risk’ signs and symptoms (eg, fatigue, unexplained weight loss, anaemia).10 Cancer diagnosis may be delayed in these patients. The UK and Denmark have introduced referral pathways for patients with non-specific, but concerning signs and symptoms possibly indicative of cancer. These pathways demonstrate significant cancer detection rates of up to 11 per cent,12 a finding that may be useful in the Irish context. A UK study of multidisciplinary diagnostic clinics for patients with suspected cancer found that while patient age was the most significant predictor of cancer (p<0.001),11 there was also a significant association between GP ‘clinical suspicion’ or ‘gut instinct’ (described as ‘an uneasy feeling, typically triggered by a rapid summing up of multiple verbal and non-verbal cues’13) and subsequent cancer diagnosis in patients referred to this service.

Early detection of cancer in asymptomatic patients

 Discuss cancer screening with eligible patients. Ireland has three national cancer screening programmes:

1. Breast cancer screening (BreastCheck) is available to all women aged 50-69 years in Ireland. Almost one-third of newly diagnosed breast cancers in Ireland are detected through BreastCheck.14 While overall uptake of BreastCheck is relatively high (70 per cent), there are some pockets of low uptake, particularly in inner city areas of large urban centres.13

2. Cervical cancer screening (CervicalCheck) is available to all women aged 25-65 years in Ireland. CervicalCheck is working with other stakeholders, including the National Immunisation Office (NIO) and National Cancer Control Programme (NCCP), to progress plans to eliminate cervical cancer in Ireland.15

3. Bowel cancer screening (BowelScreen) is available to all men and women aged 60-69 years in Ireland. Uptake of BowelScreen is

low at just 25 per cent and 31 per cent for men and women, respectively.16 Increasing uptake of BowelScreen has the potential to markedly improved bowel cancer outcomes in Ireland. For more information visit www.screeningservice.ie/.

Conclusion

Despite the anticipated increase in cancer cases over the coming decades, there is much that healthcare workers can do to help protect the health of their patients. A

References

1. Central Statistics Office (2019). Vital Statistics Summary. www.cso.ie/ en/releasesandpublications/ep/p-vsys/ vitalstatisticsyearlysummary2019/

2. National Cancer Registry Ireland (2021). Cancer in Ireland 1994-2019: Annual Report of the National Cancer Registry. NCRI, Cork, Ireland. www.ncri.ie

3. National Cancer Registry Ireland (2019). Cancer incidence projections for Ireland 2020-2045. www.ncri.ie

4. Modifiable risk factors and cancer in Ireland. National Cancer Registry Ireland, 2020. www.ncrie.ie

5. World Health Organisation (WHO). Preventing cancer. www.who.int/activities/ preventing-cancer

6. Healthy Ireland, Department of Health (2021). Healthy Ireland Survey 2021. www.gov. ie/en/publication/9ef45-the-healthy-irelandsurvey-2021/

7. HSE (2020). Immunisation Schedule (Primary Childhood Programme). www.hse.ie/ eng/health/immunisation/pubinfo/pcischedule/ immschedule/

8. WHO. IARC Monographs on the evaluation of carcinogen risks to humans. Vol 59. Hepatitis viruses. 1994. https://publications.iarc.fr/ Book-And-Report-Series/Iarc-Monographs-OnThe-Identification-Of-Carcinogenic-Hazards-ToHumans/Hepatitis-Viruses-1994

9. National Cancer Registry Ireland. Survival statistics. www.ncri.ie/data/ survival-statistics

10. Swann R, et al. Diagnosing cancer in primary care: Results from the National Cancer Diagnosis Audit. Br J Gen

substantial proportion of cancers (30-to-50 per cent) can be prevented through changes to modifiable lifestyle and environmental factors. All healthcare workers can support their patients in making healthier lifestyle choices. Community healthcare professionals play a key role in the early detection of cancer. Healthcare professionals (pharmacists, nurses and doctors) are Ireland’s most trusted professionals and our advice can contribute to positive lifestyle changes and better outcomes for our patients.17 

Pract (2018); 68 (666): e63e72. doi: 10.3399/ bjgp17X694169

11. Chapman D, et al. First results from fi ve multidisciplinary diagnostic centre (MDC) projects for non-speci fi c, but concerning symptoms, possibly indicative of cancer. Br J Cancer (2020). doi: org/ 10.1038/s41416-020-0947-y

12. Forster AS, Renzi C, Lyratzopoulos G. Diagnosing cancer in patients with ‘non-alarm’ symptoms: Learning from diagnostic care innovations in Denmark. Cancer epidemiology. 2018 Jun;54:101-103. doi: 10.1016/j. canep.2018.03.011

13. Smith CF, Drew S, Ziebland S, Nicholson BD. Understanding the role of GPs’ gut feelings in diagnosing cancer in primary care: A systematic review and meta-analysis of existing evidence. Br J Gen Pract. 2020 Aug 27;70(698):e612-e621. doi: 10.3399/bjgp20X712301.

14. BreastCheck and National Screening Service. Programme report 2018 and 2019. www.breastcheck.ie/sites/default/files/bcheck/ documents/BC-PR-PM-12-Rev0-BreastCheckProgramme-Report_2018_and_2019.pdf

15. HSE and National Screening Service. National Screening Service joint project brings Ireland closer to realising target of cervical cancer. 2021 Nov 17. www. cervicalcheck.ie/_fileupload/news/Cervical%20 Cancer%20Elimination%20Day%2017_11_21.pdf

16. HSE. BowelScreen. www.Bowelscreen.ie

17. IPSOS. Doctors become the world’s most trusted profession. 2021. www.ipsos.com/en/ global-trustworthiness-index-2021

KEYTRUDA (Pembrolizumab) is Now Publicly Available* as Monotherapy or in Combination with platinum and 5-fluorouracil (5-F U) chemotherapy for the first-line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma in adults whose tumours express PD-L1 with a CPS ≥ 1.

The ESMO Clinical Practice Guidelines recommends Keytruda Monotherapy or in Combination with Platinum/5-FU for Metastatic or recurrent/persistent disease not amenable to curative RT or surgery in the ‘No platinum-based ChT during the last 6 months and PD-L1-positive tumour’ subset of recommendations.2

KEYTRUDA® (pembrolizumab) ABRIDGED PRODUCT INFORMATION

Refer to Summary of Product Characteristics before prescribing. PRESENTATION KEYTRUDA 25 mg/mL: One vial of 4 mL of concentrate contains 100 mg of pembrolizumab. INDICATIONS KEYTRUDA as monotherapy is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults. KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with Stage III melanoma and lymph node involvement who have undergone complete resection. KEYTRUDA as monotherapy is indicated for the first-line treatment of metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a ≥50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations. KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of metastatic non-squamous NSCLC in adults whose tumours have no EGFR or ALK positive mutations. KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of metastatic squamous NSCLC in adults. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic NSCLC in adults whose tumours express PD-L1 with a ≥1% TPS and who have received at least one prior chemotherapy regimen. Patients with EGFR or ALK positive tumour mutations should also have received targeted therapy before receiving KEYTRUDA. KEYTRUDA as monotherapy is indicated for the treatment of adult and paediatric patients aged 3 years and older with relapsed or refractory classical Hodgkin lymphoma (cHL) who have failed autologous stem cell transplant (ASCT) or following at least two prior therapies when ASCT is not a treatment option. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy and whose tumours express PD L1 with a combined positive score (CPS) ≥ 10. KEYTRUDA as monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy, is indicated for the firstline treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) in adults whose tumours express PD-L1 with a CPS ≥ 1. KEYTRUDA as monotherapy is indicated for the treatment of recurrent or metastatic HNSCC in adults whose tumours express PD-L1 with a ≥ 50% TPS and progressing on or after platinum-containing chemotherapy. KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of advanced renal cell carcinoma (RCC) in adults. KEYTRUDA, in combination with lenvatinib, is indicated for the first line treatment of advanced renal cell carcinoma in adults. KEYTRUDA as monotherapy is indicated for the first line treatment of metastatic microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer in adults. KEYTRUDA, in combination with platinum and fluoropyrimidine based chemotherapy, is indicated for the first-line treatment of locally advanced unresectable or metastatic carcinoma of the oesophagus or HER-2 negative gastroesophageal junction adenocarcinoma in adults whose tumours express PD-L1 with a CPS ≥ 10. KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of locally recurrent unresectable or metastatic triple negative breast cancer in adults whose tumours express PD L1 with a CPS ≥ 10 and who have not received prior chemotherapy for metastatic disease. KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of advanced or recurrent endometrial carcinoma in adults who have disease progression on or following prior treatment with a platinum containing therapy in any setting and who are not candidates for curative surgery or radiation.

DOSAGE AND ADMINISTRATION See SmPC for full details. Therapy must be initiated and supervised by specialist physicians experienced in the treatment of cancer. The recommended dose of KEYTRUDA in adults is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. The recommended dose of KEYTRUDA as monotherapy in paediatric patients aged 3 years and older with cHL is 2 mg/kg bodyweight (up to a maximum of 200 mg), every 3 weeks administered as an intravenous infusion over 30 minutes. For use in combination, see the Summary of Product Characteristics (SmPC) for the concomitant therapies. KEYTRUDA must not be administered as an intravenous push or bolus injection. When administering KEYTRUDA as part of a combination with intravenous chemotherapy, KEYTRUDA should be administered first. Treat patients until disease progression or unacceptable toxicity (and up to maximum duration of therapy if specified for an indication). For the adjuvant treatment of melanoma, KEYTRUDA should be administered until disease recurrence, unacceptable toxicity, or for a duration of up to one year. KEYTRUDA, as monotherapy or as combination therapy, should be permanently discontinued (a) For Grade 4 toxicity except for: endocrinopathies that are controlled with replacement hormones; or haematological toxicity, only in patients with cHL in which KEYTRUDA should be withheld until adverse reactions recover to Grade 0-1; (b) If corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks; (c) If a treatment-related toxicity does not resolve to Grade 0 1 within 12 weeks after last dose of KEYTRUDA; (d) If any event occurs a second time at Grade ≥ 3 severity. Patients must be given the Patient Alert Card and be informed about the risks of KEYTRUDA. Special populations Elderly: No dose adjustment necessary. Renal impairment: No dose adjustment needed for mild or moderate renal impairment. No studies in severe renal impairment. Hepatic impairment: No dose adjustment needed for mild hepatic impairment. No studies in moderate or severe hepatic impairment. Paediatric population: Safety and efficacy in children below 18 years of age not established except in paediatric patients with cHL. CONTRAINDICATIONS Hypersensitivity to the active substance or to any excipients. PRECAUTIONS AND WARNINGS Assessment of PD-L1 status When assessing the PD-L1 status of the tumour, it is important that a well-validated and robust methodology is chosen to minimise false negative or false positive determinations. Immune-related adverse reactions Immune-related adverse reactions, including severe and fatal cases, have occurred in patients receiving pembrolizumab. Most immune related adverse reactions occurring during treatment with pembrolizumab were reversible and managed with interruptions of pembrolizumab, administration of corticosteroids and/or supportive care. Immune related adverse reactions have also occurred after the last dose of pembrolizumab. Immune-related adverse reactions affecting more than one body system can occur simultaneously. Immune-related adverse reactions are immune-related pneumonitis, immune-related colitis, immune-related hepatitis, immune-related nephritis, immune-related endocrinopathies (including adrenal insufficiency, hypophysitis, type 1 diabetes mellitus, diabetic ketoacidosis, hypothyroidism, and hyperthyroidism), Immune-related skin adverse reactions (also including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)), Refer to SmPC for more information and management of immune-related adverse reactions. Complications of allogeneic Haematopoietic Stem Cell Transplant

For more information on Keytruda in HNSCC visit MSDConnect.ie or scan the QR code below with your phone

(HSCT): Cases of graft-versus-host-disease (GVHD) and hepatic veno-occlusive disease (VOD) have been observed in patients with classical Hodgkin lymphoma undergoing allogeneic HSCT after previous exposure to pembrolizumab. Infusion-related reactions: Grades 1, 2, 3 or 4 infusion reactions including hypersensitivity and anaphylaxis, could be seen with pembrolizumab treatment. Refer to SmPC for more information and management of infusion-related reactions. Overdose: There is no information on overdose with pembrolizumab. In case of overdose, monitor closely for signs or symptoms of adverse reactions and treat appropriately. INTERACTIONS No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab. No metabolic drug drug interactions are expected. The use of systemic corticosteroids or immunosuppressants before starting pembrolizumab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of pembrolizumab. Corticosteroids can be used as premedication, when pembrolizumab is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions. FERTILITY, PREGNANCY AND LACTATION Women of childbearing potential Women of childbearing potential should use effective contraception during treatment with pembrolizumab and for at least 4 months after the last dose of pembrolizumab. Pregnancy No data on use in pregnant women. Do not use during pregnancy unless the clinical condition of the woman requires treatment with pembrolizumab. Breast-feeding It is unknown whether pembrolizumab is secreted in human milk. A risk to newborns/ infants cannot be excluded. Fertility No clinical data available. SIDE EFFECTS Refer to SmPC for complete information on side effects. Pembrolizumab is most commonly associated with immune-related adverse reactions. Most of these reactions resolved with appropriate medical treatment or withdrawal of pembrolizumab. The most serious adverse reactions were immune-and infusion-related adverse reactions. When pembrolizumab is administered in combination with axitinib or lenvatinib, refer to the SmPC for axitinib or lenvatinib prior to initiation of treatment. For additional lenvatinib safety information related to advanced RCC see the SmPC for Kisplyx and for advanced EC see the SmPC for Lenvima. Monotherapy: Very Common: anaemia, hypothyroidism, decreased appetite, headache, dyspnea, cough, abdominal pain, nausea, vomiting, constipation, musculoskeletal pain, arthralgia, asthenia, oedema, pyrexia, diarrhoea, rash, pruritus, fatigue. Common: pneumonia, thrombocytopenia, neutropenia, lymphopenia, hyponatraemia, hypokalaemia, hypocalcaemia, insomnia, neuropathy peripheral, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), hypertension, hyperthyroidism, thyroiditis, insomnia, dizziness, dysgeusia, pneumonitis, colitis, dry mouth, severe skin reactions, vitiligo, dry skin, alopecia, eczema, dermatitis acneiform, erythema, dermatitis, myositis, pain in extremity, arthritis, influenza like illness, chills, AST and ALT increases, hypercalcaemia, increase in blood alkaline phosphatase, blood bilirubin increased, blood creatinine increased, infusion related reaction. In combination with chemotherapy: Very Common: pneumonia, neutropenia, anaemia, thrombocytopenia, leukopenia, hypothyroidism, hypokalaemia, decreased appetite, insomnia, neuropathy peripheral, headache, dizziness, dyspnoea, cough, nausea, vomiting, diarrhoea, abdominal pain, constipation, alopecia, rash, pruritus, musculoskeletal pain, arthralgia, pyrexia, fatigue, asthenia, oedema, ALT increase, AST increased, blood creatinine increased. Common: febrile neutropenia, lymphopenia, infusion related reaction, hyperthyroidism, hyponatraemia, hypocalcaemia, lethargy, dysgeusia, dry eye, cardiac arrhythmia (including atrial fibrillation), hypertension, pneumonitis, colitis, dry mouth, gastritis, hepatitis, severe skin reactions, erythema, dermatitis, dry skin, myositis, pain in extremity, arthritis, acute kidney injury, influenza-like illness, chills, hypercalcaemia, blood alkaline phosphatase increased, blood bilirubin increased. In combination with axitinib or lenvatinib: Very Common: urinary tract infection, anaemia, hypothyroidism, decreased appetite, headache, dysgeusia, hypertension, dyspnoea, cough, diarrhoea, abdominal pain, nausea, vomiting, constipation, rash, pruritus, arthralgia, musculoskeletal pain, myositis, pain in extremity, fatigue, asthenia, oedema, pyrexia, lipase increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased. Common: pneumonia, neutropenia, thrombocytopenia, lymphopenia, leukopenia, infusion-related reaction, adrenal insufficiency, hyperthyroidism, thyroiditis, hyponatraemia, hypokalaemia, hypocalcaemia, insomnia, dizziness, neuropathy peripheral, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), pneumonitis, colitis, pancreatitis, gastritis, dry mouth, hepatitis, severe skin reactions, dermatitis, dry skin, erythema, dermatitis acneiform, alopecia, arthritis, nephritis, influenza like illness, chills, amylase increased, blood bilirubin increased, blood alkaline phosphatase increased, hypercalcaemia. PACKAGE QUANTITIES KEYTRUDA 25 mg/mL: 4 mL of concentrate in a 10 mL Type I clear glass vial. Legal Category: POM. Marketing Authorisation numbers EU/1/15/1024/002 Marketing Authorisation holder Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands. Date of revision: November 2021. © Merck Sharp & Dohme B.V. 2021. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin D18 X5K7 or from www. medicines.ie. II0104_105

Adverse

Keytruda is the first and only immunotherapy approved in the first-line treatment of M/uR HNSCC in Ireland1

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®: THE NEW BEVACIZUMAB BIOSIMILAR FROM CLONMEL HEALTHCARE1

Metastatic colorectal cancer

AUTHORS: Dr Patrick Owens, FRCSI (Gen), Specialist Registrar in General and Colorectal Surgery, Beaumont RCSI Cancer Centre, Beaumont Hospital, Dublin; and Prof Deborah McNamara, FRCSI (Gen), Consultant General and Colorectal Surgeon, Beaumont RCSI Cancer Centre, Beaumont Hospital, Dublin; Clinical Professor in Surgery RCSI University of Medicine and Health Sciences; Co-Lead, National Clinical Programme for Surgery; and Chair, Rectal Cancer Lead Clinician Group, National Cancer Control Programme

doctorCPD.ie

To complete this module and earn free CPD points, go to www.doctorCPD.ie and answer the 10 true or false questions and complete the five MCQs based on this case study.

Colorectal cancer (CRC) is the second most common cause of cancer-related death in Ireland with 1,000 deaths occurring per year. Rates of overall survival at five years have improved from 49.9 per cent in the 1990s to 62.6 per cent over the past decade. Unfortunately, a fifth of patients still present with metastatic CRC (mCRC), reducing five year survival rates to 10.3 per cent.1 mCRC may arise as distant recurrence of disease in patients following prior treatment for nonmetastatic CRC, or occur in those presenting with de novo stage IV disease.

The most common site for mCRC is the liver (70 per cent in colon cancer/70 per cent in rectal cancer), followed by the thorax (32 per cent/47 per cent) with the third most common site being the peritoneum (21 per cent) for colon cancer and bone (12 per cent) for rectal cancer. Nervous system metastases occur in 5 per cent of patients with colon cancer, and in 8 per cent of those with rectal cancer. 2 Although widespread metastatic disease at one or more sites may preclude treatment with curative intent, a potentially curative approach is possible in patients with oligometastatic disease (OMD). OMD is generally characterised by

disease in up to three sites, with less than five total lesions. For patients with this disease pattern; long-term survival can be achieved for 20-to-50 per cent of patients who undergo complete resection (R0) of their primary and metastatic disease, particularly where the metastases involve liver and lung.3

The finding of metastatic colorectal cancer is particularly difficult for patients. Clinical decision-making is complex and requires input from all members of the multidisciplinary team to achieve the best outcomes. When curative treatment is not possible, avoiding treatments that

and proximal two-thirds of the transverse colon, all embryologically derived from the midgut. Due to the more occult nature of these tumours, patients typically present at a more advanced stage with symptoms of anaemia, fatigue, weight loss and sometimes diarrhoea. Left-sided hindgut tumours affect the distal third of the transverse colon, descending colon, sigmoid colon and rectum. Tumours at these sites more commonly cause constipation, narrow stool calibre, and bleeding. Rectal tumours may cause tenesmus.4 National Cancer Registry Ireland report that 44 per cent of patients present with node negative, non-metastatic disease (stages I-II), 32 per

do not enhance quality or duration of life is important. There is a central role for clinical nurse specialists in supporting patients and their families through their cancer journey. At all stages in care, twoway communication with families, GPs and community services is essential.

Clinical presentation

The clinical presentation of CRC varies depending on the affected site. Approximately 40 per cent of colorectal cancers occur in ‘right’ colon, which includes the caecum, ascending colon

cent with stage III disease, and 24 per cent with metastatic stage IV disease.1 More than a fifth of patients are diagnosed with colorectal cancer following an emergency presentation, most commonly with bleeding or abdominal pain, and are more likely to have poorer clinical and patient-reported outcomes. 5 Symptoms from metastatic lesions are less common but may include jaundice in liver disease, bloating from ascites in liver or peritoneal disease, pain with bony metastases, and confusion, seizures or focal neurology with brain metastases.

Following initial history and examination, colonoscopy is the investigation of choice to assess for CRC since it facilitates pathological confirmation of CRC, which is necessary prior to any invasive therapies, including chemotherapy or surgery

Diagnosis and staging

Following initial history and examination, colonoscopy is the investigation of choice to assess for CRC since it facilitates pathological confirmation of CRC, which is necessary prior to any invasive therapies, including chemotherapy or surgery.

In cases of obstructing lesions, where complete assessment of the colon proximal to the lesion is not possible, CT colonography may be considered to assess for more proximal synchronous lesions; completion colonoscopy following treatment is required.6

Contrast enhanced CT of the thorax, abdomen and pelvis is the primary staging modality for all patients with CRC and should be undertaken prior to surgery if possible.

Pelvic MRI should be undertaken for patients with rectal tumours, primarily due to its superiority in assessing T-stage and involvement of the mesorectal fascia or sphincter complex, which may alter management.

Hepatocytespecific contrast enhanced MRI of the liver is superior to CT for evaluation of CRC liver metastases and should be undertaken in patients being considered for surgical resection.

The Irish National Cancer Control Programme (NCCP) recommend that PET-CT not be considered first-line in CRC staging, but may be used as a problemsolving tool in patients with equivocal imaging findings following discussion at a multidisciplinary team meeting. A PETCT scan at baseline may also be useful in patients being considered for surgically curable metastatic disease in order to evaluate for other unrecognised metastatic disease that may preclude surgery.6,7 Biopsy of metastatic lesions is not always required where there is a characteristic appearance on cross-sectional imaging modalities in a patient with known diagnosis of CRC and elevated carcinoembryonic antigen (CEA).

Surgery

Advances in surgical techniques and systemic therapies have significantly improved outcomes following surgery for metastatic disease in recent decades. The finding of metastatic disease requires careful evaluation of the suitability of proceeding with resection of the primary tumour and if so, the timing of that intervention. For metastases of CRC, surgery is most commonly performed for liver and lung lesions.

Approaches for more extensive bilobar disease include may include staged strategies, such as initial resection, induction chemotherapy, liver remnant hypertrophy with portal vein embolisation followed by another interval hepatic metastasectomy. Management strategies are further complicated where mCRC occurs synchronously with the primary colorectal tumour, whereby consideration must be given to the timing and sequence of surgical therapies and must be individualised to each patient depending on symptom severity, disease burden and patient preference.

Regional therapies available for the management of liver metastases include surgical resection, thermal ablation, intra-arterial chemotherapy, transarterial chemoembolisation (TACE), radioembolisation, and radiotherapy, however, surgery with an R0 resection remains the gold standard and confers the best chance for cure in OMD.

Traditionally, hepatic metastectomy was reserved for patients with up to three lesions in the same lobe and without portal nodal disease, however, in the modern era, the paradigm has shifted such that any patient with liver metastases may be considered for resection if complete (R0) resection is possible while leaving an adequate functional liver remnant (FLR). Up to 20 per cent of patients with liver metastases initially deemed unresectable, may convert to resectable following induction chemotherapy, although care must be taken given the increased risk of chemotherapy-induced liver failure affecting the FLR. 8

Liver resection has traditionally been undertaken at an interval surgery after resection of the primary tumour, following adjuvant chemotherapy, however, synchronous resection and a reverse (liverfirst) approach are also possible. The greater use of laparoscopic and robotic platforms for primary and metastatic resections is likely to enhance care and facilitate staged approaches in particular. Timing of neoadjuvant therapies for the primary lesion must also be considered, in particular for locally advanced rectal cancer (LARC) where chemoradiotherapy (CRT) is often required. In this setting, a reverse (liverfirst) approach after total neoadjuvant therapy (TNT) may be preferable.9,10

Patients with lung metastases of colorectal origin represent one of the most favourable subgroups of those with pulmonary metastatic disease. Overall survival rates of 68 per cent at five years have been reported in patients with pulmonary metastases from CRC undergoing metastectomy with complete R0 resection.11 Furthermore, repeat resections for patients with recurrent, isolated pulmonary metastases may also be appropriate, as data show that long-term overall survival can be achieved.12 Procedures may include wedge resection, segmentectomy, lobectomy or pneumonectomy. Open thoracotomy may be required, particularly for central lesions, however, wedge resection or lobectomy by

Peritoneal carcinomatosis is a poor prognostic indicator, and its management in the absence of other distant disease is controversial

video-assisted thoracoscopic surgery (VATS) is generally preferred where possible. Similar to patients with liver metastases, ablative techniques, such as stereotactic radiation therapy or radiofrequency ablation, are also options in disease not suitable for surgery.

Peritoneal carcinomatosis is a poor prognostic indicator, and its management in the absence of other distant disease is controversial. Longterm disease control may be facilitated by aggressive cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC), although recurrence rates are high.13 The National Comprehensive Cancer Network (NCCN) recommends that this approach should only be undertaken in centres with appropriate expertise, and in the context of a clinical trial. 8

Molecular profiling

Patients with mCRC should undergo molecular tumour profiling to identify patients with disease amenable to novel targeted therapies and to identify molecular subtypes which may confer prognostic value.14 This assessment may be undertaken using tissue biopsies obtained during initial investigations or using tissue from a primary CRC even if it was resected many years ago. Commonly, this includes immunohistochemical assessment for mismatch repair deficiency (MMRD) or PCR assessment for high microsatellite instability (MSI-H). MMRD occurs as a germline mutation in patients with Lynch syndrome, however, it also occurs as a somatic mutation and is observed in up to 15 per cent of sporadic CRC cases and 5 per cent of mCRC cases.15 Patients with MSI-H/MMR-D tumours, may be treated with immune checkpoint inhibitors (eg, pembrolizumab, nivolumab or ipilimumab), which significantly extend survival compared to traditional cytotoxic chemotherapy alone.

Patients without KRAS or NRAS gene mutations respond to treatment with

monoclonal antibodies that inhibit the epithelial growth factor receptor (EGFR) (eg, cetuximab or panitumumab) and have a prolonged overall survival compared to treatment with traditional chemotherapy alone. Similarly, up to 10 per cent of tumours exhibit BRAF 600E sequence variations, which confer a poor prognosis and these patients also exhibit higher rates of microsatellite instability.

delayed wound healing and increased risk rates of bowel perforation.

Following first-line systemic therapy for three-to-six months, many patients will respond to therapy and then have stable disease. Ongoing therapy with first-line regimes is typically limited due to side effects, such as peripheral neuropathy with FOLFOX or fatigue and diarrhoea with FOLFIRI. At this stage patients may choose to discontinue therapy until disease progression is evident on cross sectional imaging or begin maintenance treatment with a more tolerable regime, such as fluorouracil plus leucovorin, with or without biologic agents. Targeted biological therapies are typically included as second-line options depending on the molecular profile of the tumour.4

This cohort of patients have improved overall survival when treated with BRAF and EGFR inhibitors compared to those treated with standard chemotherapy alone. Half of all patients affected by metastatic CRC have KRAS/NRAS/BRAF wild-type tumours. 4

Systemic therapies

While a small cohort of patients with mCRC may be amenable to complete surgical resection of metastases with curative intent, mCRC is not curable for the majority of patients and the median survival duration with treatment is 30 months.4

The mainstay of treatment for all patients with mCRC is systemic chemotherapy. The most commonly used combination treatment regimens for patients with colorectal cancer who have good performance status and organ function include fluorouracil/leucovorin/oxaliplatin (FOLFOX), capecitabine/oxaliplatin (XELOX or CAPOX) and fluorouracil/ leucovorin/irinotecan (FOLFIRI). The anti-vascular endothelial growth factor (VEGF) antibody bevacizumab may also be used as first-line therapy for mCRC, although it may not be used immediately following surgery due to its antiangiogenic properties and resulting increased risk of

Patients with mCRC who have disease progression despite FOLFOX, FOLFIRI or XELOX in combination with appropriate targeted therapies, are deemed to have refractory disease. Unfortunately, there are currently no approved therapies for use in Ireland that further prolong survival greater than three months in this cohort. Certain histological subtypes, like mucinous tumours, are often resistant to existing therapies and are a key research interest of our group at the Beaumont RCSI Cancer Centre.16

Increasing access to cancer trials for patients with mCRC is a priority if better outcomes are to be achieved.

Conclusion

mCRC has a generally poor prognosis, however, significant improvements in surgical technique and systemic therapies have been made in recent years giving rise to improving rates of overall and diseasefree survival. A priority for ongoing research is to address resistance to current immunotherapies and in particular develop immune checkpoint inhibitors for patients with KRAS/ NRAS variant tumours. 

The mainstay of treatment for all patients with mCRC is systemic chemotherapy

References

1. National Cancer Registry Ireland. Cancer Factsheet Colorectal. Central Statistics Office: NCRI; 2018

2. Riihimäki M, Hemminki A, Sundquist J, Hemminki K. Patterns of metastasis in colon and rectal cancer. Scientific Reports. 2016;6(1):29765

3. Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016;27(8):1386-422

4. Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: A review. JAMA 2021;325(7):669-85

5. Renzi C, Lyratzopoulos G, Card T, Chu TPC, Macleod U, Rachet B. Do colorectal cancer patients diagnosed as an emergency differ from nonemergency patients in their consultation patterns and symptoms? A longitudinal data-linkage study in England. B J Cancer. 2016;115(7):866-75

6. National Cancer Control Programme (NCCP). Diagnosis, staging and treatment of patients with

TRUE/FALSE QUESTIONS

Q1 Colorectal metastases most commonly occur in the lung.

True or false?

Q2 Metastatic disease is considered ‘oligometastatic’ only when confined to a single organ.

True or false?

Q3 Right-sided colon cancers usually present with rectal bleeding.

True or false?

Q4 Tumours of the midtransverse colon arise from the

colon cancer2020. Available from: www.hse.ie/eng/ services/list/5/cancer/consultations/nccp-rectalcancer-guideline.pdf

7. National Cancer Control Programme (NCCP). Diagnosis, staging and treatment of patients with rectal cancer2020. Available from: www.hse.ie/eng/ services/list/5/cancer/consultations/nccp-rectalcancer-guideline.pdf

8. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology 2021 [16 Jan 2022]. Available from: www.nccn.org/professionals/physician_gls

9. Shah AS, Patel SH. Hepatic resection for colorectal cancer liver metastasis 2021. Available from: www.uptodate.com/contents/hepatic-resectionfor-colorectal-cancer-liver-metastasis/

10. Nierop PMH, Verseveld M, Galjart B, Rothbarth J, Nuyttens JJME, van Meerten E, et al. The liver-first approach for locally advanced rectal cancer and synchronous liver metastases. Eur J Surg Oncol 2019;45(4):591-6

11. Okumura T, Boku N, Hishida T, Ohde Y, Sakao Y, Yoshiya K, et al. Surgical outcome and prognostic stratification for pulmonary

metastasis from colorectal cancer. Ann Thorac Surg. 2017;104(3):979-87

12. Menna C, Berardi G, Tierno SM, Andreetti C, Maurizi G, Ciccone AM, et al. Do repeated operations for recurrent colorectal lung metastases result in improved survival? Ann Thorac Surg. 2018;106(2):421-7

13. Breuer E, Hebeisen M. Site of recurrence and survival after surgery for colorectal peritoneal metastasis. J Natl Cancer Inst. 2021;113(8):1027-35

14. National Institute for Health and Care Excellence. Colorectal cancer: Diagnosis and management. Clinical Guideline 151. London: NICE; 2020

15. Shaikh T, Handorf EA, Meyer JE, Hall MJ, Esnaola NF. Mismatch repair deficiency testing in patients with colorectal cancer and nonadherence to testing guidelines in young adults. JAMA Oncol 2018;4(2):e173580-e

16. Reynolds IS, O’Connell E, Fichtner M, McNamara DA, Kay EW, Prehn JHM, et al. Mucinous adenocarcinoma is a pharmacogenomically distinct subtype of colorectal cancer. Pharmacogenomics J 2020;20(3):524-32

embryological midgut.

True or false?

Q5 Metastatic deposits from colorectal tumours are usually asymptomatic.

True or false?

Q6 Contrast enhanced CT of the thorax, abdomen, and pelvis is the primary staging modality of choice for patients with newly diagnosed colorectal cancer.

True or false?

Q7 PET-CT is routinely used for staging of colorectal cancer.

True or false?

Q8 Only patients with Lynch syndrome exhibit mismatch repair deficiency or high microsatellite instability.

True or false?

Q9 Patients with KRAS variant metastatic colorectal cancer may be considered for treatment with immune checkpoint inhibitors.

True or false?

Q10 Fluorouracil is a commonly used chemotherapeutic agent for patients with metastatic colorectal cancer.

True or false?

Answer these questions and complete the module by answering five MCQs to earn free CPD points at www.doctorcpd.ie

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overall survival for patients in 3rd line mCRC1

Extend

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

Ovarian cancer: A silent killer

AUTHOR: Theresa Lowry-Lehnen, RGN, GPN, RNP, PhD, CNS and Associate Lecturer, Institute of Technology Carlow

Ovarian cancer is one of the most common cancers in women and more than 400 women in Ireland are diagnosed with the disease annually.1,6 Four-out-of-five cases are diagnosed in women over the age of 50 years.6 The lifetime risk of developing ovarian cancer is 1.4 per cent in a woman with ovaries.8 Ovarian cancer is the fifth most frequent cause of death in women globally, and the leading cause of death in women diagnosed with gynaecological cancers. The World Ovarian Cancer Coalition 2018 stated that “in 2012 there were 239, 000 cases, and 152,000 deaths worldwide from ovarian cancer, with some 600,000 women living within five years of a diagnosis. It is estimated that by 2035, incidence will increase to 371,000 a year (55 per cent) and deaths will increase by 67 per cent to 254,000.”3 Early

continue to apply (‘demographic’ projection), annual numbers of cases of ovarian cancer are projected to increase from 407 in 2015 to 731 in 2045 (+80 per cent).9,10,11,12

In Ireland the majority of ovarian cancer cases are diagnosed as stage III-IV.9 Ovarian cancer was ranked the fourth most common cause of cancer deaths among women in Ireland 2013-2015, with an average of 269 deaths annually.

Ovarian cancer is also one of the costliest cancers for household production losses per death. A productivity loss analysis carried out in an Irish context (Pearce et al, 2016) projected that by 2030, premature death will cost a value of €367,284 household production losses per ovarian cancer death.9

does not conceive.6,8 Several studies have shown an increased risk caused by smoking, especially the risk of mucinous epithelial tumours.4,5 Protective factors include previous pregnancies, breastfeeding, oral contraceptive use, IUD insertion, and tubal ligation.8

Histopathology

Ovarian neoplasms are a heterogeneous group of tumours classified according to morphological and clinical features. The main subgroups are epithelial tumours, sex cord-stromal tumours, germ cell tumours, miscellaneous, and metastatic tumours. Approximately 60 per cent of all ovarian tumours and up to 90 per cent of all primary ovarian malignancies are epithelial. Epithelial tumours can be further classified as serous, mucinous, endometrioid, carcinosarcoma, clear cell, transitional cell, mixed epithelial, and undifferentiated carcinomas. The four most common histological types of epithelial ovarian cancer are serous, endometrioid, clear cell, and mucinous tumour.2

detection offers the best chance of survival; however, most cases of ovarian cancer are diagnosed at an advanced stage, leading to poorer outcomes.2 Approximately 75 per cent of cases are diagnosed at an advanced stage due to non-specific symptoms.8

Ireland has one of the highest rates of ovarian cancer in Europe. Figures from the European Cancer Information System for 2018 estimated that in Ireland the incidence rate of ovarian cancer is 16.1 per 100,000, compared with an average of 11.8 across the EU.9,13 The incidence of ovarian cancer in Ireland is projected to rise – by 2045 cases of ovarian cancer are projected to increase by between 67-to-80 per cent with proportionate increases in treatment rates. Assuming that the average age-standardised rates during 2011-2015

Risk factors

Ovarian cancer mostly affects post-menopausal women, where increasing age is associated with an increased incidence, advanced stage of the disease, and lower reported survival rates. The strongest risk factor for ovarian cancer is a positive family history of breast or ovarian cancer, where a personal history of breast cancer augments the risk.2

Other risk factors include a personal/family history of endometrial, prostate or colon cancer; faulty inherited genes including BRCA1 and BRCA2; increasing age – over half of all ovarian cancers occur in women over the age of 65; unexplained infertility, nulliparity, early menarche, late menopause, no history of oral contraceptive pill usage, and prolonged use of fertility drugs, especially if a woman

Ovarian cancer can be classified into two subtypes, type I or type II tumours, with the latter being a more fatal variant, thought to be caused by continuous ovarian cycles leading to inflammation and endometriosis.

Type I tumours includes low-grade serous, endometrioid, clear-cell, and mucinous carcinomas, with the rare subtypes being seromucinous and Brenner tumours.

Type I tumours mostly arise from atypical proliferative tumours, and usually present at an early stage and are low-grade except for clear cell which is considered high grade. Their proliferative activity is usually low. They are diagnosed early and carry a good prognosis.

Type II tumours include high-grade serous carcinoma, carcinosarcoma, and undifferentiated carcinoma, which mainly originate from serous tubal intraepithelial carcinoma. Type II tumours, in comparison,

Ovarian cancer is the fifth most frequent cause of death in women globally, and the leading cause of death in women diagnosed with gynaecological cancers

are high-grade and almost always of advanced stage. They have high proliferative activity with rapid and aggressive progression and a high degree of chromosomal instability compared to type I, with the presence of p53 mutations in most cases.2

Symptoms

Currently, there is no screening programme for ovarian cancer because there is no screening test that is accurate and reliable enough to detect ovarian cancer in the general population.6 Initial symptoms of ovarian cancer can be vague and non-specific and easily missed in the early stages. Symptoms often become apparent in the later stages –stage III or stage IV. Presenting symptoms can include a combination of abdominal fullness, bloating, nausea, abdominal distention, early satiety, fatigue, changes in bowel movements, urinary symptoms, back pain, dyspareunia, and weight loss.2

Diagnosis

Investigation is guided by a complete history of the presenting symptoms, a thorough physical examination and assessment for risk factors.

Physical examination includes rectovaginal examination on an empty bladder to look for pelvic and abdominal masses in clinical cases of high suspicion. In advanced cases, a palpable pelvic mass or ascites or diminished breath sounds due to the presence of pleural effusions can also be found.2

In patients with a high degree of clinical suspicion, radiological imaging including transvaginal ultrasonography (TVUS) and/ or abdominal and pelvic ultrasonography is carried out. This provides information on the size, location, and complexity of the ovarian mass. Further imaging with chest and abdomen pelvis CT scan, pelvic MRI, and/or PET scan can be required.2

CA-125 levels are checked in adjunction with the imaging. CA-125 is elevated in most epithelial ovarian cancers overall, but only half of early-stage epithelial ovarian cancers. The specificity and positive predictive value is found to be higher in postmenopausal women than in premenopausal women. CA-125 levels can

also be used to calculate the risk of malignancy index (RMI).2 Increased CA-125 levels are also observed in other physiological or benign pathological conditions, such as endometriosis, pregnancy, ovarian cysts, inflammatory peritoneal diseases, therefore other biomarkers are currently being studied to improve specificity for ovarian cancer biomarkers.

Human epididymis protein 4 (HE4) is a new biomarker that is currently being evaluated. It is more sensitive for ovarian cancer and found in approximately 100 per cent of serous and endometrioid subtypes.2

Differential diagnoses for ovarian cancer can include colon cancer; embryologic remnants; gastric adenocarcinoma; metastatic gastrointestinal carcinoma; ovarian torsion; peritoneal cyst; retroperitoneal mass; uterine fibroids; endometriosis; papillary adenocarcinoma; serous adenocarcinomas; undifferentiated adenocarcinomas; small-cell adenocarcinomas; and Brenner tumours.2

Genetic testing

It is recommended that all patients with tubo-ovarian carcinoma be offered germline mutation testing appropriate to sub-type. Specifically, testing of all high-grade nonmucinous carcinoma for BRCA gene mutations is recommended.9 All tubo-ovarian carcinoma patients with a genetic test which shows either a pathogenic variant or a variant of uncertain significance should be offered post-test counselling. If the patient has a significant cancer family history, even if BRCA1/2 testing is normal, a referral to genetic services is advised.9

Ovarian cancer staging and grading7

The stage of a cancer determines its size and whether it has spread. The grade refers to how abnormal the cells look under a microscope, and how quickly the cancer is likely to grow and spread. The four main stages of ovarian cancer are stage 1, 2, 3, and 4 using the International Federation of Gynaecology and Obstetrics (FIGO) staging system.7 The FIGO staging system is a surgical staging system which does not incorporate the grade of the tumour.

 Stage 1: The cancer is only found in the ovaries. It is divided into three groups:

Stage 1A – the cancer is completely inside one ovary.

Stage 1B – the cancer is completely inside both ovaries.

Stage 1C is divided in to three groups:

● Stage 1C1 – the cancer is in one or both ovaries and the ovary ruptures during surgery.

● Stage 1C2 – the cancer is in one or both ovaries and the ovary ruptures before surgery or there is some cancer on the surface of an ovary.

● Stage 1C3 – the cancer is in one or both ovaries and there are cancer cells in fluid taken from inside the abdomen during surgery.

 Stage 2: This means the cancer has grown outside the ovary or ovaries, and is growing within the pelvis. There may also be cancer cells in the abdomen. It is divided into two groups:

● Stage 2A – the cancer has grown into the fallopian tubes or the womb.

● Stage 2B – the cancer has grown into other tissues in the pelvis, for example, the bladder or rectum.

 Stage 3: The cancer has spread outside the pelvis into the abdominal cavity or to lymph nodes. It is divided into three groups – 3A, 3B and 3C.

Stage 3A is divided into two groups:

● Stage 3A1 – cancer has spread to the lymph nodes in the back of the abdomen.

● Stage 3A2 – cancer cells are found in tissue samples taken from peritoneum, and it might also be in the lymph nodes.

● Stage 3B – means there are cancer growths 2cm or smaller in size in the peritoneum and there might also be cancer in the lymph nodes.

● Stage 3C – means there are cancer growths larger than 2cm in size in the peritoneum and there might also be cancer in the lymph nodes.

 Stage 4: The cancer has spread to other body organs such as the liver or lungs.

● Stage 4a – means the cancer has caused a pleural effusion with positive cytology.

● Stage 4b – means the cancer has spread to the inside of the liver or spleen; lymph

nodes outside the abdomen; other organs such as the lungs.

There is no single universally accepted system for grading ovarian cancers. Many studies have used different systems proposed either by the FIGO, the World Health Organisation (WHO), or the American Gynecologic Oncology Group (GOG).9 Grading refers to the cancer cells size and appearance under the microscope and how much they are like or unlike normal cells. They are graded 1 to 3.

Grade 1 or low grade (well differentiated): The cancer cells are very like normal cells in the ovary. They usually grow slowly and are less likely to spread.

Grade 2 or moderate grade (poorly differentiated): These cancer cells look less like normal ovarian cells.

Grade 3 or high grade: These cancer cells are very unlike normal ovarian cells. They usually grow quicker and are more likely to spread.14 Current recommendations are that serous carcinomas are graded as low and high grade; endometrioid and mucinous tumours are graded using the FIGO system for endometrioid carcinomas of the endometrium, and clear cell carcinomas, carcinosarcomas and undifferentiated carcinomas are considered by definition grade.3,9

Treatment and management

Treatment of ovarian cancer conventionally includes a combination of chemotherapy and surgery. The type of surgery depends on the stage of the cancer, and the FIGO staging system for ovarian cancer is applied to determine patient management and prognosis. The patient should be counselled about all the treatment options available along with prognosis at the time of diagnosis, depending on the stage of presentation.2 A holistic and empathetic approach for communications is required regarding disease prognosis and disease-related treatment choices, in addition to management of symptoms and psychosocial issues. All patients with ovarian cancer should have access to a gynaecology nurse specialist.9

In the early stage of invasive epithelial ovarian carcinoma and if the cancer is

only in one ovary, unilateral salpingooophorectomy while preserving the uterus and contralateral ovary may be carried out, with comprehensive surgical staging where lesions show a low likelihood of progressing to malignancy.

However, for advanced-stage ovarian cancer, a debulking surgery is carried out, comprising peritoneal washing, total hysterectomy and bilateral salpingooophorectomy (BSO), inspection of all abdominal organs and peritoneal surfaces, sampling suspicious areas for biopsy, total omentectomy and para-aortic lymphadenectomy.1,2,8 Primary debulking surgery consists of complete macroscopic tumour removal which could involve splenectomy, diaphragmatic resection, liver, intestinal or any other abdominal resection required to achieve complete cytoreduction.8

First-line chemotherapy involves intravenous platinum/taxane regimes, carried out every three weeks for six cycles. For patients with FIGO stage 1A/1B and grade 1 and 2 tumours no further treatment is usually required.

Outcome is assessed by imaging results, usually CT scan, after completion of first-line chemotherapy.8 For women with residual disease of <1cm the risk of recurrence is estimated at 60-70 per cent, while for women with large volume residual disease, the risk is estimated at 80-85 per cent.8 Patients with complete response are followed up for at least five years. Increasing CA-125 levels can be a symptom of recurrence, however, if not accompanied by clinical symptoms second-line treatment is not recommended.8

Debate continues whether neoadjuvant chemotherapy, which involves giving three cycles of chemotherapy prior to surgery and interval debulking surgery, may be superior to massive primary debulking surgery in advanced ovarian cancer.8

Intraperitoneal chemotherapy (where cisplatin and paclitaxel are injected into the abdominal cavity through a catheter) may be an option in select patients, but controversy remains about its usage and benefit.16

Although there is a high response rate to initial treatment, the majority of patients will develop recurrence.8 About 80 per cent of women with advanced-stage ovarian cancer more commonly have tumour progression or recurrence. Platinum free interval (PFI) is one of the most reliable predictors indicating the response of recurrent ovarian cancer to subsequent chemotherapy. PFI refers to the interval between the completion of the last platinum-based chemotherapy and the occurrence of relapse. However, platinum sensitivity is generally used to refer to an interval of greater than six months between the last platinum-based chemotherapy (PBC) cycle and commencement of subsequent PBC.2

Radiotherapy is not a common treatment for ovarian cancer, although it may be used with chemotherapy and surgery to treat cancer. It can also be used to help relieve symptoms in patients with more advanced disease. The treatment may be as short as one session or continue for several weeks, depending on the stage of ovarian cancer.1,2

Targeted therapies, eg, bevacizumab, a monoclonal antibody directed at vascular endothelial growth factor (VEGF), may be given along with chemotherapy, and it has been proven to be useful as maintenance therapy.1,14

PARP inhibitors are used to treat some women with advanced ovarian cancer that has returned after earlier treatment; eg, olaparib, niraparib and rucaparib in platinum-sensitive recurrent ovarian cancer.16 Results from clinical trials show that these drugs might also benefit women who are newly diagnosed with advanced ovarian cancer.15 Side-effects can be an issue in PARP inhibitors and must be carefully monitored for and assessed against quality-of-life. Nausea, vomiting, fatigue, anaemia, diarrhoea and arthralgia, and neutropaenia can all be observed across the PARP inhibitors, and niraparib also has thrombocytopaenia as a potential side-effect.16

Immunotherapy, also called checkpoint inhibitor immunotherapy, in ovarian cancer is being studied in advanced disease with varied results. However, there have been no practice-changing trials so far.16

FOR ALL THAT MATTERS

Prognosis

The prognosis of ovarian cancer is directly dependent on the disease stage at the time of diagnosis. It is also associated with baseline performance status, FIGO stage, and volume of residual disease post-primary cytoreductive surgery. The median survival of ovarian cancer patients is approximately 40-to-50 per cent at 10 years, with stage-related survival for stage I between 70-to-92 per cent compared to stage IV being less than 6 per cent.2 In women with cancer that has spread to adjacent tissues, five-year survival rates drop to 80 per cent, and 25 per cent for those with metastatic disease. Patients with recurrent disease can be treated, however, they are usually incurable. Recurrent platinum-sensitive ovarian cancer median survival is approximately three years; however, survival is approximately one year for platinum-resistant patients.2

Outlook

Ovarian cancer remains one of the most lethal malignancies in women despite ongoing clinical trials and the introduction of new treatments in the past few decades. The poor

References

1. Irish Cancer Society (2021). Ovarian Cancer. Available at: www.cancer.ie/cancerinformation-and-support/cancer-types/ ovarian-cancer

2. Arora T, Mullangi S (2021). Ovarian Cancer. StatPearls. Available at: www.statpearls.com/ ArticleLibrary/viewarticle/95586

3. The World Ovarian Cancer Coalition (2018). The Every Woman Study. The world ovarian cancer coalition atlas: Global trends in incidence, mortality, and survival. Available at: https:// worldovariancancercoalition.org/wp-content/ uploads/2018/10/THE-WORLD-OVARIANCANCER-COALITION-ATLAS-2018.pdf

4. Torre L, Trabert B, DeSantis C, Miller K, Samimi G, Runowicz C, et al (2018). Ovarian cancer statistics, 2018. CA: Cancer J Clin. 2018 Jul;68(4):284-296. doi: 10.3322/caac.21456

5. Momenimovahed Z, Tiznobaik A, Taheri S, Salehiniya H. Ovarian cancer in the world: Epidemiology and risk factors. Int J Women’s Health. 2019 Apr 30;11:287-299. doi: 10.2147/

clinical outcomes to date are mainly due to the failure of effective strategies for the early detection of ovarian cancer, chemotherapy resistance, and increased heterogeneity of the disease. With the goal for ovarian cancer to be diagnosed at an earlier and more curable stage, we are still in need of the development of effective strategies.2

New agents are mainly directed against molecular target cancer cells proliferation pathways, tumour growth and escape from immune surveillance and death signals. These agents include anti-angiogenic factors, inhibitors of growth factor signalling, PARP inhibitors or folate receptor inhibitors. While not shown to be curative, these new agents are a step forward and may lead to the delay of recurrence or stabilisation of the illness.8 Targeted therapy is one of the fastest growing modalities for cancer treatment. The use of targeted therapies have extended progressionfree survival, but there is more work to be done and research and clinical trials are ongoing.

Vaccines are currently being studied for

ovarian cancer, where the basis lies in activating the immune cells to destroy the cancer cells. The potential tumourassociated antigen molecules targeted in ovarian cancer in ongoing ovarian cancer vaccine research are CA-125, p53 protein, and HER-2, among others. There are ongoing pilot and phase 1 or 2 trials for the use of therapeutic vaccines in ovarian cancer patients employing novel techniques. Other emerging therapies being studied in clinical trials are using adoptive T-cell transfer and chimeric antigen receptor therapy (CAR-T) as a part of future strategies to ensure reduced cancer burden and improve life expectancy in this patient population. 2

Immune and cellular therapies coupled with genetic testing and precision assays (biomarkers) are promising strategies for better clinical outcomes. Novel strategies and research in this field will lead to better approaches to minimise ill health and improve life expectancy for patients with ovarian cancer. 

IJWH.S197604

6. Marie Keating Foundation (2021). Ovarian cancer. Available at: www.mariekeating.ie/ cancer-information/ovarian-cancer/

7. Cancer Research UK (2021). Ovarian cancer: Stages and grading. Available at: www. cancerresearchuk.org/about-cancer/ovariancancer/stages-grades

8. Javaid A, Kamran W. (2021). Ovarian Cancer a silent killer. Hospital Professional News. Issue 89; pp 57-57; October 2021

9. Department of Health (2019). Diagnosis and staging of patients with ovarian cancer: National Clinical Guideline No 20. Available at: www.hse.ie/eng/services/list/5/cancer/profinfo/ guidelines/diagnosis-and-staging-of-patientswith-ovarian-cancer.pdf

10. National Cancer Registry Ireland (NCRI) (2018a). Cancer factsheet: Ovary. NCR, Cork, Ireland. Available at: www.ncri.ie

11. National Cancer Registry Ireland (NCRI) (2018b). Cancer in Ireland 1994-2016 with estimates for 2016-2018: Annual Report of the

National Cancer Registry. NCR, Cork, Ireland. Available at: www.ncri.ie

12. National Cancer Registry Ireland (NCRI) (2019). Cancer incidence projections for Ireland 2020-2045. National Cancer Registry, Cork, Ireland. Available at: www.ncri.ie

13. European Cancer Information System (2018). Available at: https://ecis.jrc.ec.europa.eu

14. Irish Cancer Society (nd). Cancer of the ovary: Caring for people with cancer. Available at: www.cancer.ie/sites/default/files/2019-10/ ovary_2015_web.pdf

15. NIH National Cancer Institute (2019). PARP inhibitors show promise as initial treatment for ovarian cancer. Available at: www.cancer.gov/news-events/cancercurrents-blog/2019/parp-inhibitors-ovariancancer-initial-treatment

16. Chauhan P, and Westrup J. Updates in the management of ovarian cancer. Medical Independent. 2022 January 10. Available at: www. medicalindependent.ie/updates-in-themanagement-of-ovarian-cancer/

Genomics sequencing and testing are transforming the future of cancer care

AUTHOR: Prof Stephen Finn, Associate Professor, Consultant Pathologist and Principal Investigator at Trinity College Dublin and St James’s Hospital, Dublin. Prof Finn is also a member of the Irish expert panel for the FutureProofing Personalised Health Index, which is supported by Roche

We learned a long time ago that there will be no singular ‘cure’ for cancer, no one silver bullet that will stop this deadly disease. Yet cancer treatment has improved dramatically in recent years.

One of the many new approaches yielding impressive results is tumour-agnostic therapy, where a treatment targets a specific genetic mutation in the DNA of a cancer, rather than simply a specific tumour type or stage of cancer. By using sophisticated genomic testing to help identify or sequence the DNA alterations that may be driving the growth of a specific tumour, we can learn the tumour’s unique ‘genetic fingerprint’ and then target it specifically. Furthermore, by sequencing the patient’s germline DNA in parallel we can optimise and clarify tumour genomics.

Genomics can help us treat everyone with cancer in a personalised way. Yet Ireland has been slow to embrace the potential of genomics. In contrast, other countries, cognisant of the role it will play in our future healthcare, have poured funding into this area. The discrepancies across countries were highlighted by the FutureProofing Healthcare Personalised Health Index recently, which analysed the health systems of 34 international countries to evaluate how healthcare is progressing towards a more personalised, digital, and data-driven standard. Ireland was ranked 19th overall.

One example of prioritising funding in genomics is the 100,000 Genomes Project in the UK, which is focused on rare diseases, some common types of cancer, and infectious diseases. In the US, many hospitals are now sequencing each patient’s tumour and in some institutions the patient’s germline DNA in parallel as a fundamental step in their diagnosis and treatment.

While the standard of care tumour genomic sequencing is available to Irish patients, there is an urgent need for more comprehensive diagnostic assessment to allow patients access to the newest and most promising therapies earlier, including those available through clinical trials. In many cases, a drug may be available, but oncologists do not know if a patient will be suitable for it because they do not have access to the necessary molecular information about the patient’s cancer. As this field grows, we will see more and more patients lose out on ground-breaking treatments that could extend or even save their lives.

The National Cancer Control Programme has been pivotal in reacting to patients’ needs and securing sanction for innovative treatments as quickly as possible. But what we are missing is a national, cohesive strategy in cancer genetics and genomics. What has been developed has been in response to the broader national need, seeking to meet the requirements of the service in real time. And what it lacks is the bigger picture outlook, looking to the longer-term so that we futureproof cancer care for generations to come.

Ireland must be proactive and not reactive when it comes to genomic testing, because it is about to completely transform cancer care. By giving patients more opportunities for genetic sequencing and testing, they will be able to participate in clinical trials for cutting edge therapies. But this will require State funding and the HSE and research groups need to collaborate closely on this. We need to integrate research and funding into service delivery so that when we extract genomes used for testing, everything draws together cohesively. The National Cancer

Registry Ireland has done phenomenal work in helping us build a picture of what cancer incidence in Ireland looks like, but by linking registry data and genomic data, we can ultimately take better care of people with cancer. A good example of a great initiative and superb effort for the future of genomics in Ireland is the SFI Centre for Research Training in Genomics Data Science in Galway. In collaboration with six universities across Ireland, it aims to train a new generation of highly skilled genomics data scientists.

This shows the importance of why Ireland must focus on building genetic and genomic capabilities among our own workforce, infrastructure, and services. Currently, we are forced in many cases to outsource testing to foreign jurisdictions, which is detrimental to the long-term development of Irish expertise in this crucial field.

Integral to all of this will be a national reporting system for these test results. Adequate data storage facilities and enhanced IT infrastructure will be required in order for this to work properly and for it to be secure to protect patient confidentiality appropriately.

The Covid-19 pandemic has shown philosophically that we as a country can deal with a problem rapidly, where there’s a will and the necessary investment. The potential for individualised treatment that a genomics approach offers is enormous. However, it will require significant investment, not just in terms of resources, both human and infrastructural, but also from a system-wide IT perspective. This ship is moving forward, with or without us. Ireland needs to be on board. 

Advances in first-line management of renal-cell cancer

AUTHORS: Dr Maeve Hennessy, 1 Medical Oncology Specialist Registrar; and Dr Emmet Jordan, 1 Consultant Medical Oncologist. 1Department of Medical Oncology, University Hospital Waterford

Renal-cell carcinoma (RCC) represents 2-to-3 per cent of all cancers and most commonly occurs between the sixth and seventh decades of life.1

Approximately 15 per cent of patients with RCC present with locally advanced or metastatic disease and the prognosis for long-term disease-free survival in this patient cohort is generally poor. RCC is comprised of several histological subtypes, with clear-cell carcinoma being the most frequent, representing 75-to-80 per cent cases of RCC. 2

The optimal management approach to metastatic RCC has evolved over the last two decades – therapies from high-dose bolus treatment with interleukin-2 to the use of interferon alpha, to molecularly targeted agents targeting vascular endothelial growth factor (VEGF) receptor and mammalian target of rapamycin (mTOR). 3 The recognition of the VEGF pathway as an important therapeutic target led to the development of the anti-VEGF tyrosine kinase inhibitors (TKIs), such as sunitinib, pazopanib and sorafenib.4 These agents were the first new therapies approved for advanced RCC and have been available in the European Union since 2006. Targeted therapy with VEGF-TKIs in the first-line treatment of metastatic RCC has been the standard of care over the last 10 years, with newer agents, such as cabozantinib and lenvatinib also emerging. 5,6

In the last three years, there has been a rapid shift in the treatment landscape for newly diagnosed metastatic RCC,

with combination immune checkpoint inhibitor therapy demonstrating improved efficacy over single agent TKI in several phase 3 clinical trials. In addition, the combination of a checkpoint inhibitor with a VEGF inhibitor has been evaluated. These combination regimens typically include treatment with a programmed death protein 1 (PD-1) inhibitor combined with either a VEGF-TKI or an anti-cytotoxic T lymphocyte-associated (CTLA-4) agent and have shown improved clinical outcomes as compared with sunitinib, thus establishing a new standard of care for first-line treatment of patients with metastatic RCC.7-10

2. Time from diagnosis to treatment <one year.

3. Haemoglobin concentration less than the lower limit of normal.

4. Serum calcium greater than the upper limit of normal.

5. Neutrophil count greater than the upper limit of normal.

6. Platelet count greater than the upper limit of normal.

Favourable risk patients have none of these risk factors, intermediate risk have one or two factors, and those with three or more factors are classified as poor risk.11

In general, systemic treatment with targeted therapy and/or immunotherapy is initiated at diagnosis and the recent evidence supporting frontline combination therapy is discussed below. It is important to note that active surveillance can be considered in selected individuals who have low-volume indolent disease, and there is also a role for cytoreductive surgery, including nephrectomy and metastasectomy in certain scenarios.12

The choice of therapy for a patient with advanced RCC is informed by assessment of risk factors. The International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) prognostic model classifies patients into favourable, intermediate, and poor-risk categories, using the following six parameters:11

1. Karnofsky Performance Status Scale (KPS) <80 per cent.

Frontline systemic therapy –immunotherapy-based combination therapy Dual immunotherapy approach CheckMate 214

The CheckMate 214 trial examined the combination of nivolumab (anti-PD-1 antibody) and ipilimumab (anti-CTLA-4 antibody) versus sunitinib in patients with untreated advanced clear-cell RCC. Initial results were published in the New England Journal of Medicine (NEJM)

The recognition of the VEGF pathway as an important therapeutic target led to the development of the anti-VEGF tyrosine kinase inhibitors (TKIs)

in 2018. A total 1,096 patients were randomised 1:1 to receive nivolumab at 3mg/kg with ipilimumab at 1mg/kg every three weeks for four cycles, followed by nivolumab monotherapy 3mg/kg every two weeks, or standard dosing of sunitinib (50mg orally daily for four weeks of a six-week cycle).7

Updates from the trial with five years minimum follow-up duration continued to show improved outcomes for intermediate and poor risk patients treated with dual immunotherapy as compared to sunitinib. Progression free survival (PFS) with ipilimumab/ nivolumab as compared to sunitinib was 12.3 months versus 12.3 months, (HR 0.86; 95% CI 0.73-1.01, P=0.06). Median overall survival (OS) was improved in the combination immunotherapy arm; 55.7 months versus 38.4 months, (HR 0.72; 95% CI 0.62-0.85, P<0.0001). The overall response rate was 39 per cent. Higher rates of grade III/ IV adverse events were observed in the ipilimumab/nivolumab arm, however, this most frequently occurred in the first six months of therapy.13

An exploratory analysis of patterns of progression in CheckMate 214 was presented at the American Society for Clinical Oncology Genitourinary meeting (ASCO GU) in February 2021. Findings identified that ‘new lesion only’ progression was more commonly observed in patients who received combination therapy with ipilimumab/nivolumab as compared with sunitinib, and in particular in those patients who progressed postresponse to treatment. This may have important therapeutic implications going forward, for example, in the selection of patients who may benefit from focal metastasis-directed therapy.14

Immunotherapy plus targeted therapy approach

KEYNOTE-426

The KEYNOTE-426 trial examined the combination of pembrolizumab plus

axitinib (VEGF-TKI) versus sunitinib in previously untreated metastatic clear-cell RCC. In total, 861 patients were stratified according to IMDC risk and were randomised in a 1:1 ratio to pembrolizumab 200mg every three weekly for up to 35 cycles plus axitinib 5mg orally twice daily or sunitinib on standard dosing schedule.

The results of extended follow-up were recently published in The Lancet The pembrolizumab plus axitinib arm continued to show an improved objective response rate (60.4% vs 39.9%; P<0.0001), PFS 15.7 months versus 11.1 months (HR 0.68; 95% CI 0.6–0.84; P<0 .0001), and OS 45.7 months versus 40.1 months (HR 0.73; 95% CI 0.6–0.85; P<0.0001) compared with sunitinib.15

A total 37.6 per cent of the patients who received axitinib/pembrolizumab remained progression free at two years, and longer-term follow-up will reveal whether these results will be durable. A subgroup analysis of those with favourable-risk disease did not yet demonstrate differences in OS (HR 1.06; 95% CI 0.60–1.86, P=0.58) or PFS (HR 0.79; 95% CI 0.57–1.09; P= 0.078).15

CheckMate 9ER

Another checkpoint inhibitor plus antiVEGF was evaluated in CheckMate 9ER and results published in the NEJM in March 2021. This multinational phase 3 trial randomised 651 patients with untreated advanced clear cell RCC 1:1 to nivolumab at 240mg every two weeks plus oral cabozantinib at 40mg daily versus sunitinib at standard dosing. The lower dose of cabozantinib was chosen on the basis of a phase 1 dose-finding study of nivolumab plus cabozantinib in patients with advanced genitourinary cancers, where the 40mg dose demonstrated similar efficacy but less toxicity compared to the standard 60mg daily dose. 8

Improvements in PFS were seen for the nivolumab/cabozantinib arm, 17 versus

8.3 months, (HR 0.52; 95% CI 0.43-0.64; P<0.0001). OS results appeared to favour the combination arm, however, longer term follow-up is needed. In terms of response rate, ORR was 54.8 per cent for nivolumab/cabozantinib versus 28.4 per cent for sunitinib (P<0 .0001), and complete response rates were doubled at 8 per cent versus 4.6 per cent in favour of the combination. Although the overall rate of serious adverse events was similar between the two arms, liver toxicity was more common with nivolumab and cabozantinib. Elevation in liver enzymes was noted in 25 per cent versus 6 per cent with sunitinib. 8

JAVELIN Renal 101

The JAVELIN Renal 101 study adds further evidence that combination treatment and targeting multiple pathways is an effective strategy for treatment of advanced RCC. In this phase 3 trial by Motzer et al, 886 patients with metastatic RCC were randomised 1:1 to receive first-line systemic therapy with avelumab (anti-PD-L1) at 10mg/kg intravenously every two weeks plus axitinib 5mg orally twice daily or sunitinib. At the second interim analysis, the avelumab/axitinib group had a significantly improved PFS at a median follow-up of 13 months, 13.3 versus eight months (HR 0.69; 95% CI 0.57–0.83; P<0.0001), and the benefit was demonstrated across all subgroups including all IMDC risk groups. The lack of an OS benefit demonstrated to-date perhaps makes this combination less appealing.10

CLEAR

The phase 3 CLEAR trial was published in the NEJM in February 2021 and explored further combination approaches for advanced RCC. This was a three-arm study, which randomly assigned treatment-naïve patients to lenvatinib 20mg orally once daily plus pembrolizumab 200mg intravenously once every three weeks, lenvatinib 18mg orally once daily plus everolimus 5mg orally once daily, or standard dose of sunitinib.9 A significant OS benefit was noted for the lenvatinib/pembrolizumab

arm as compared with sunitinib alone (HR 0.66, 95% CI 0.49-0.88, P=0.005) [median OS not reached (NR)]. PFS and ORR was also improved for the lenvatinib/pembrolizumab arm [RR 71% versus 36%; PFS HR 0.39 (95% CI 0.320.49; P<0.001)], median PFS 23.9 months versus 9.2 months. The combination of lenvatinib/everolimus did result in improved PFS compared with sunitinib [HR 0.65, 95% CI 0.53-0.80, P<0.001, median PFS 14.7 months (95% CI 11.116.7) versus 9.2 months (95% CI 6.0-11.0)], however, there was no improvement

in OS (HR 1.15, 95% CI 0.88-1.50).9 Although cross-trial comparisons must be interpreted cautiously, the 23.9 month PFS, ORR of 71 per cent and complete response of 16.1 per cent noted in the lenvatinib/pembrolizumab arm are impressive when compared to other recent trials in this field. The lenvatinib/pembrolizumab combination received US FDA approval for the first-line treatment of advanced RCC in 2021 on the basis of the CLEAR trial. Lenvatinib/everolimus should not be considered as a standard treatment

for metastatic RCC in the first-line, however, it may have a role in later lines of therapy.12

Choice of therapy

The aforementioned studies provide evidence for the introduction of an array of new combination therapies in the frontline treatment of advanced RCC. However, none of these approaches have been directly compared with each other in prospective clinical trials, thus the optimal first-line therapy remains undetermined as of yet.

JAVELIN Renal 101 N=886

13

Avelumab/axitinib vs sunitinib

P<0.0001)

13.3 vs 8 (HR 0.69; 95% CI 0.57-0.83; P<0.0001)

NR vs 29.5 (HR 0.66; 95% CI 0.50-0.87; P=0.003)

54.8 per cent vs 28.4 per cent

CLEAR N=1069

26.6 Lenvatinib/ pembrolizumab vs sunitinib

Lenvatinib/everolimus vs sunitinib

23.9 vs 9.2 (HR 0.39; 95% CI 0.32-0.49; P<0.001)

14.7 vs 9.2 (HR 0.65; 95% CI 0.53-0.83; P<001)

(HR 0.66, 95% CI 0.490.88, P=0.005)

(HR 1.15, 95% CI 0.88-1.5, P=0.3)

71 per cent vs 36.1 per cent

53.5 per cent vs 36.1 per cent

TABLE 1: Summary of first-line immunotherapy combination therapies for metastatic clear-cell RCC

Latest module

Metastatic colorectal cancer

A comprehensive overview of the latest treatment strategies for metastatic colorectal cancer

Authors: Dr Patrick Owens, SpR in General and Colorectal Surgery, Beaumont Hospital, Dublin; and Prof Deborah McNamara, Consultant General and Colorectal Surgeon, Beaumont Hospital; Clinical Professor in Surgery, RCSI University of Medicine and Health Sciences Co-Lead, National Clinical Programme for Surgery; and Chair, Rectal Cancer Lead Clinician Group, National Cancer Control Programme

On the basis of the published data, for the 20-to-25 per cent of patients falling into the favourable risk category, treatment with either pembrolizumab/axitinib or single agent sunitinib are reasonable options. For those with intermediate or poor risk disease, options include nivolumab plus ipilimumab, pembrolizumab plus axitinib or nivolumab plus cabozantinib. All of these combinations have demonstrated improved OS and good tolerability (as compared with sunitinib) in randomised phase 3 trials.13,8,15 Of note, the combination of avelumab plus axitinib has not yet demonstrated an OS benefit.10 For patients who are not suitable for immunotherapy, single agent antiangiogenic treatment with a VEGF inhibitor is an option.

The potential benefits of a dual immunotherapy approach with nivolumab plus ipilimumab include the ability to achieve durable responses, an ability to avoid chronic toxicities associated with TKI therapy, and the availability of mature follow-up data demonstrating an OS benefit. However, this is countered by higher rates of immune-related adverse events (irAEs), particularly in the first six months of treatment.16 In addition, PFS and response rates are lower as compared to IO/VEGF combination therapies. In Ireland, nivolumab in combination with ipilimumab was approved and reimbursed for the first-line treatment of adult patients with intermediate/poor-risk advanced RCC in February 2021. Pembrolizumab in combination with axitinib for the firstline treatment of advanced RCC in adults is not yet reimbursed.

The immunotherapy/TKI combinations have also shown improved PFS, OS, and ORR and are associated with a lower rate of irAEs. When adverse events do occur, it can be difficult to ascertain whether they are related to the targeted therapy or the immunotherapy and this can pose management challenges.

Longer follow-up data is needed to determine durable response to treatment. Other questions relate to the optimal sequence of therapy and whether or not a similar survival benefit could be achieved by giving immunotherapy and targeted therapy sequentially as opposed to concurrently.16

At the ASCO GU Symposium 2021, the results of outcomes of first-line combination therapy in advanced RCC from the IMDC database were presented. Patients treated with immunotherapy/ VEGF inhibitors were compared with those treated with dual immunotherapy

with untreated advanced RCC will be randomised to either the experimental arm of cabozantinib, nivolumab, and ipilimumab followed by cabozantinib and nivolumab or the control arm of nivolumab plus ipilimumab followed by nivolumab monotherapy.18

The currently recruiting PDIGREE trial aims to address the question of how to sequence therapies and is examining a ‘response adapted approach’. Patients will receive combination ipilimumab/nivolumab initially and then based on response, cabozantinib will be added. Patients with progressive disease on ipilimumab/ nivolumab will commence cabozantinib, patients with a complete response will stop treatment for a certain period of time, while patients with stable disease or a partial response will be randomised to maintenance treatment with either nivolumab or cabozantinib.19

and a subgroup analysis of those with intermediate/poor risk disease was performed. The conclusion was that no significant OS difference was detected between groups, serious irAEs were associated with improved OS, and that dual immunotherapy or immunotherapy/targeted therapy were both appropriate options in this setting.17

Future directions for advanced RCC

Based on the above results, future clinical trials will likely move away from the use of sunitinib as a suitable control arm. The phase 3 COSMIC 313 study is attempting to shed further light on the optimal regimen by evaluating a TKI plus immunotherapy combination versus an immunotherapy control arm. Patients

In terms of novel therapies, an oral small molecule inhibitor of hypoxia inducible factor (HIF)-2alpha has shown efficacy in patients with von HippelLindau (VHL)-associated RCC, with a manageable toxicity profile. Currently, a phase 3 trial is ongoing looking at the HIF 2 alpha inhibitor belzutifan versus everolimus in patients with advanced RCC that has progressed following treatment with immunotherapy and VEGF-targeted therapies. 20

In summary, we have seen rapid advances in the management of RCC over the last few years, with combination therapy emerging as the new standard of care. Ongoing studies are needed to further inform treatment selection and determine the optimal combination approach for patients with advanced RCC. Additionally, while much progress has been made in frontline therapy, questions remain regarding how to sequence therapy and the approach to treatment upon progression of disease. 

In summary, we have seen rapid advances in the management of RCC over the last few years, with combination therapy emerging as the new standard of care

References

1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al (2015). Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136 (5):E359-E386. doi:10.1002/ijc.29210

2. Bedke J, Gauler T, Grünwald V, Hegele A, Herrmann E, Hinz S, et al (2017). Systemic therapy in metastatic renal-cell carcinoma. World J Urol 35 (2):179-188. doi:10.1007/s00345-016-1868-5

3. Klapper JA, Downey SG, Smith FO, Yang JC, Hughes MS, Kammula US, et al (2008). High-dose interleukin-2 for the treatment of metastatic renal-cell carcinoma: A retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer 113 (2):293-301. doi:10.1002/cncr.23552

4. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al (2007). Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. NEJM 356 (2):115-124. doi:10.1056/NEJMoa065044

5. Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, et al (2016). Cabozantinib versus everolimus in advanced renal-cell carcinoma (METEOR): Final results from a randomised, openlabel, phase 3 trial. Lancet Oncol 17 (7):917927. doi:10.1016/S1470-2045(16)30107-3

6. Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, et al (2015). Lenvatinib, everolimus, and the combination in patients with metastatic renal-cell carcinoma: A randomised, phase 2, open-label, multicentre trial. Lancet Oncol 16 (15):1473-1482. doi:10.1016/S14702045(15)00290-9

7. Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al (2018). Nivolumab plus Ipilimumab versus sunitinib in advanced renal-cell carcinoma. NEJM 378 (14):1277-1290. doi:10.1056/NEJMoa1712126

8. Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, et al (2021). Nivolumab plus cabozantinib

versus sunitinib for advanced renalcell carcinoma. NEJM 384 (9):829-841. doi:10.1056/NEJMoa2026982

9. Motzer R, Alekseev B, Rha S-Y, Porta C, Eto M, Powles T, et al (2021). Lenvatinib plus pembrolizumab or everolimus for advanced renal-cell carcinoma. NEJM 384 (14):1289-1300. doi:10.1056/ NEJMoa2035716

10. Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et al (2019). Avelumab plus axitinib versus sunitinib for Advanced renal-cell carcinoma. NEJM 380 (12):1103-1115. doi:10.1056/NEJMoa1816047

11. Heng DYC, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, et al (2013). External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: A population-based study. Lancet Oncol 14 (2):141-148. doi:10.1016/S14702045(12)70559-4

12. Powles T, Albiges L, Bex A, Grünwald V, Porta C, Procopio G, et al (2021). ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal-cell carcinoma. Ann Oncol 32 (12):1511-1519. doi:10.1016/j. annonc.2021.09.014

13. Albiges L, Tannir NM, Burotto M, McDermott D, Plimack ER, Barthélémy P, et al (2020). Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal-cell carcinoma: extended four-year follow-up of the phase III CheckMate 214 trial. ESMO Open 5 (6):e001079-e001079. doi:10.1136/ esmoopen-2020-001079

14. Tannir NM, Motzer RJ, Albiges L, Plimack ER, George S, Powles T, et al (2021). Patterns of progression in patients treated with nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) for first-line treatment of advanced renal-cell carcinoma (aRCC) in CheckMate 214. J Clin Oncol 39 (6_suppl):313-313. doi:10.1200/ JCO.2021.39.6_suppl.313

15. Powles T, Plimack ER, Soulières D, Waddell T, Stus V, Gafanov R, et al

(2020). Pembrolizumab plus axitinib versus sunitinib monotherapy as firstline treatment of advanced renal-cell carcinoma (KEYNOTE-426): Extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol 21 (12):15631573. doi:10.1016/S1470-2045(20)30436-8

16. Navani V, Heng DYC (2021). Treatment selection in dirst-line metastatic renal-cell carcinoma – The contemporary treatment paradigm in the age of combination therapy: A review. JAMA Oncol doi:10.1001/jamaoncol.2021.4337

17. Gan CL, Dudani S, Wells JC, Schmidt AL, Bakouny Z, Szabados B, et al (2021). Outcomes of first-line (1L) immunooncology (IO) combination therapies in metastatic renal-cell carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC). J Clinical Oncol 39 (6_suppl):276-276. doi:10.1200/ JCO.2021.39.6_suppl.276

18. Choueiri TK, Albiges L, Powles T, Scheffold C, Wang F, Motzer RJ (2020). A phase III study (COSMIC-313) of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in patients (pts) with previously untreated advanced renal-cell carcinoma (aRCC) of intermediate or poor risk. J Clin Oncol 38 (6_suppl):TPS767-TPS767. doi:10.1200/ JCO.2020.38.6_suppl.TPS767

19. Zhang T, Ballman KV, Choudhury AD, Chen RC, Watt C, Wen Y, et al (2020).

PDIGREE: An adaptive phase III trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal-cell cancer (Alliance A031704). J Clin Oncol 38 (6_suppl):TPS760-TPS760. doi:10.1200/ JCO.2020.38.6_suppl.TPS760

20. Choueiri TK, Albiges L, Fan L, Perini RF, Zojwalla NJ, Powles T, Rini BI (2020). Phase III study of the hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 versus everolimus in previously treated patients with advanced clear-cell renalcell carcinoma (ccRCC). J Clinical Oncol 38 (15_suppl):TPS5094-TPS5094. doi:10.1200/ JCO.2020.38.15_suppl.TPS5094

A care report on the role of exercise in cancer management

CASE REPORT

A 66-year-old male presented for a clinical exercise prescription (July 2021) while undergoing radiation therapy for prostate cancer. The man was reporting significantly increased symptoms of fatigue after two weeks of radiation therapy. He had also become concerned with breathlessness based on only mild exertion (such as walking up the stairs). He was advised by a nurse specialist on the radiation oncology team that a supervised exercise programme could be beneficial in improving symptoms associated with cancer treatment.

Background and diagnosis

Prior to radiation therapy the patient had some insight to the likelihood of a prostate cancer diagnosis having been briefed initially by his GP. Together they had been monitoring his prostate specific antigen (PSA) levels in recent years. While he was aware that small amounts of PSA in the blood were normal, a significantly increased reading in May 2021 was flagged. His GP initially explained that multiple reasons could explain this finding and not all automatically suggested cancer. However, the GP had been performing an annual digital rectal exam (DRE) and had now also detected a change in prostate shape and size based on previous examinations. These two issues prompted a referral for a transperineal biopsy under general anaesthetic, which unfortunately confirmed the presence of prostate cancer. There was a combined Gleason score of 7 (4+3 = Grade 3), suggesting the cancer was likely to grow at a moderate rate.

Psychosocial impact

While the news still came as a shock,

the patient did feel somewhat prepared having received excellent guidance from his GP and consultant urologist throughout the diagnostic process. However, despite feeling initially braced for a diagnosis, some underlying ‘nagging’ concerns began to materialise. He had become fearful around the likelihood of the cancer spreading. He had also not shared these concerns with anybody, including his wife. He had become quite anxious as a result. He had further concerns around his future sexual function and a noticeable change in urination frequency was causing sleep disruption, tiredness, and irritability. He had noticed a loss of appetite in recent weeks. Finally, the patient is a farmer and while he had recently employed a farm manager to assist in the daily workload, he was now quite concerned around his ability to make a meaningful contribution to farm life going forward.

Ongoing medical management

Upon presentation for an exercise assessment the patient was completing week two of a six-week radiation therapy programme alongside hormone therapy. The type of radiation administered was external beam radiation (EBRT). The type of hormone therapy being administered was androgen deprivation therapy (ADT) using luteinising hormone-releasing hormone (LHRH) agonists to lower the amount of testosterone made by the testicles. While the radiation therapy was planned to conclude after week six, the hormone therapy was prescribed to continue for two months post the cessation of radiation therapy.

Cancer is a cellular disorder and although there are several hundred different types of cancer, generally they share similar characteristics. Cancer cells experience uncontrolled and disorganised growth. Healthy tissue cells typically divide up to 50 times before they die. However, cancer cells continue to divide and tend to reproduce over and over again. In vivo, a cancer cell will continue to divide until forming a growth, or tumour, that invades and destroys neighbouring healthy tissue. This new growth is termed ‘neoplasia’ and is composed of cells that are disorganisedotherwise known as ‘anaplasia’. To support their growth, cancer cells release a growth factor that causes vascularisation of neighbouring blood vessels to branch into the cancer tissue. Furthermore, cancer cells may detach from the primary tumour and spread around the body. After travelling through the blood and/or lymphatic system, cancer cells may start a new tumour elsewhere in the body, through the process known as metastasis. Benign tumours remain in one place while malignant tumours metastasise. If the original tumour is detected before metastasis has occurred the chances of survival after medical treatment are greatly increased.

Research in physical activity, exercise and cancer – a brief history

Over the past three decades exercise oncology has rapidly developed. From 1985-2005 only 26 studies had been published globally, on the efficacy (or otherwise) of guided exercise programmes in cancer cohorts. In the last decade there has been a rapid ascendancy in research with strong evidence to support:

 Reduced treatment related side-effects;

 Improved physical outcomes;

 Improved psychological outcomes;

 Potential survival benefits.

AUTHORS: Andrew Dunne, Chartered Physiotherapy and Clinical Exercise Specialist, Personal Health Medical Exercise Clinic, Rathmines, Dublin; and Dr Fergal MacNamara, GP with experience in surgical and radiation oncology

An exponential rise in epidemiological studies have shown strong evidence to support survival benefits linked to increased physical activity. Furthermore, preclinical studies have shown positive changes in tumour biology that can be directly linked to exercise medicine.

Exercise prescription needs to be an integral part of the medical oncology treatment plan

While the list of cancer treatment sideeffects is not exhaustive, typically the most common presentations include fatigue, body composition changes, pain, peripheral neuropathy, cognitive disturbance (‘brain fog’), lymphoedema, pulmonary toxicity, cardiac toxicity, anxiety, depression, incontinence, sexual dysfunction, and (non biological) psychosocial factors, such as financial distress or relationship problems.

A structured and supervised exercise programme is proven to reduce treatment related side-effects from within the biological and psychosocial spheres. An increase of one metabolic equivalent (MET) in the cardiorespiratory fitness (CRF) of a cancer survivor has been shown to be associated with a 12 per cent reduction in mortality in men, 17 per cent in women. Indeed, good CRF is highly inversely associated with death from cancer. Regardless of these facts, the current figures suggest that the CRF of cancer survivors is estimated ~30 per cent below that of agematched sedentary individuals without a cancer history. Resistance training can increase lean muscle mass, has resultant reductions in fatigue, and associated improvements in physical function and quality-of-life (QoL). In 2019, the American College of Sports Medicine (ACSM) International Multidisciplinary Roundtable on Physical Activity and Cancer Prevention and Control presented high-quality evidence that ‘aerobic plus resistance’ training reduces anxiety, depressive symptoms and fatigue, while maintaining or improving lean muscle mass and bone density.

How we designed a personalised exercise prescription for this prostate cancer patient

ACSM ‘FITT’ recommendations for cancer survivors advise that the exercise prescription

has four key component parts: Aerobic, strength training, flexibility, and neuromotor.

Aerobic – Three-to-five days per week at an intensity of 40-to-60 per cent of VO2Max for not lower than 30 minute bouts. The patient had no cardiology history prior to treatment, however, on initial exercise testing he scored a VO2Max of 23ml/kg/min, which is classified as ‘poor’ when compared to age-related normative data. On recent imaging there was no evidence of cardiac toxicity (such as left ventricular atrophy) and as such a target heart rate (HR) zone of 92-123 was advised. The patient was encouraged to do outdoor activities that complemented his desire to make a meaningful contribution to farming work. A Polar H10 heart strap and monitoring app was used to assist in distance monitoring of this target. By week six the patient was achieving an average of 130 minutes per week in the target HR zone from a mix of dedicated hill walking (with his wife) and general physical activity levels on the farm. Strength training – A minimum of two sessions per week with 48 hours rest between sessions; 60-to-80 per cent of calculated one rep max (1RM), using eight major muscle groups. The patient did these sessions supervised by a chartered physiotherapist via Zoom (to reduce barriers such as time constraints related to travel) or in the clinical setting. During the Zoom sessions the patient used a set of adjustable dumbbells that he purchased and the Polar H10 heart strap provided reassurance around appropriate exertion levels. The patient reported significant improvements in mood after eight weeks of gradually progressive strength training. This helped to combat the ADT, which was having a negative impact on maintenance of lean muscle mass.

Flexibility – Static stretches for all major muscle/tendon groups. These were performed actively and occasionally by the patient with low levels of compliance, citing lack of enjoyment and work-related ‘stiffness’ over years of farming as a barrier.

Neuromotor – Given the age profile and gradual decline in strength and conditioning,

the neuromotor component in this case included balance, agility and co-ordination drills. The patient learned these drills while supervised in a clinical setting. He showed genuine enthusiasm towards this aspect of the programme, as it was fun and interactive while simultaneously challenging. The programme took on personalised aspects by incorporating the patient’s love of hurling by using a sliotar, a hurl and various ladder drills for improved footwork. These ladder drills had a dual impact by facilitating optimal loading of cortical bone for bone density preservation, again a valid consideration during ongoing ADT.

Patient update and summary of improving fitness markers

By November 2021 the patient had completed his radiation and ADT oncology treatment plan. At this juncture the patient was consistently maintaining his baseline requirements for weekly exercise as outlined previously. A number of key metrics were obtained 12 weeks post commencement of radiation therapy. The most noteworthy objective improvement showed a Vo2Max score of 31.4ml/kg/min on re-testing which now classified his CRF as ‘above average’.

Summary

 Improved CRF with a statistically significant shift in fitness classification from ‘poor’ to ‘above average’ as per sub maximal Vo2Max testing.

 100 per cent adherence to personalised strength training programme of two sessions per week at three months post initial intervention.

 Improved hand-held dynamometry measure as an indicator of improved strength/vitality.

 Improved functional and balance scores as per TUG, Mini-Best.

 The patient reported significant improvement in QoL.

Regardless of clinical rigour and collaboration, the most rewarding aspect of the exercise programme was when the patient declared himself ‘ available for selection’ in the 2022 All Ireland Hurling Championship! 

References on request

New BSH guidelines on Waldenström macroglobulinaemia

Waldenström macroglobulinaemia (WM) is a distinct B-cell lymphoproliferative disorder characterised by an immunoglobulin IgM monoclonal gammopathy and bone marrow infiltration by lymphoplasmacytic lymphoma (LPL).

WM is more common in the elderly and Caucasians and has a male predominance. There is an increased risk of WM when there is a personal or family history of a wide range of autoimmune (Sjögren syndrome, autoimmune haemolytic anaemia), inflammatory and infective disorders or other B-cell disorders amongst relatives of patients with WM, but screening of family members is not recommended due to low absolute risk.

A significant proportion of WM patients are asymptomatic at presentation and can be safely observed

at three-to-six-monthly intervals. The risk of progression to symptomatic disease is 59 per cent at five years.

The indications for the introduction of treatment include constitutional symptoms, symptomatic or bulky lymphadenopathy or splenomegaly, cytopenias secondary to marrow infiltration, paraprotein-related indications including hyperviscosity, and IgM-related syndromes, such as cryoglobulinaemia, amyloidosis, peripheral neuropathy, and cold agglutinin disease (CAD).

Developing evidence-based treatment algorithms in WM is hindered by a lack of robust data, according to the British Society for Haematology. Optimal choice and sequence of therapies is therefore unknown. Patients should be considered for clinical trials where possible.

 Assessment of CXCR4 and TP53 should be considered and should be performed prospectively in all clinical trials (Grade A1).

Imaging

 CT scan (neck, chest, abdomen, pelvis) is recommended in all patients prior to the commencement of each line of therapy (Grade B1).

 The value of FDG-PET remains to be determined and is not recommended outside of a clinical trial. It may have a role in detection of high-grade transformation (Grade C2).

Prognostic assessment

The British Society for Haematology has just published new guidelines on the diagnosis and management of Waldenström macroglobulinaemia (WM).

The Grading of Recommendations

Assessment, Development, and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations.

A summary of the guidelines’ key recommendations are as follows:

Diagnosis

 Sequential monitoring of IgM/ monoclonal protein should be performed in a single laboratory using a single methodology (Grade A1).

 There is no evidence currently to support the use of SFLC assessment for routine monitoring outside clinical trials (Grade C2).

 Tests for neuropathy, cryoglobulinaemia, amyloidosis, cold agglutinins, bleeding

diathesis and CNS disease should be tailored to the clinical scenario (Grade A1).

 Alternative causes apart from WM should also be considered for symptoms and should be investigated where appropriate (Grade A1).

 Screening for hepatitis B and C and HIV is required prior to the introduction of treatment (Grade A1).

Pathological diagnosis and genomic assessment

 Bone marrow aspirate and trephine biopsy is needed to make a definitive diagnosis of WM and is recommended in all patients with suspected symptomatic WM or other IgM-disorder (Grade A1).

 Flow cytometry is preferred method for establishing B-cell immunophenotype (Grade A1).

 In all patients undergoing bone marrow assessment, MYD88 L265P should be assessed using an assay of established sensitivity (Grade A1).

 Whilst potentially useful to guide discussions with patients, there is no evidence to support the use of the International Prognostic Scoring System for WM (ISSWM) or other prognostic scoring systems in determining treatment approaches for individual patients and they need further validation in the era of newer agents (Grade B1).

Treatment

Frontline treatment

 Dexamethasone, rituximab and cyclophosphamide (DRC), bendamustine and rituximab (BR), bortezomib regimens (bortezomib, cyclophosphamide and rituximab [BCR] and bortezomib, dexamethasone and rituximab [BDR]) and BTKi are all acceptable frontline treatments (Grade B1).

 Chlorambucil or rituximab monotherapy remain suitable therapy in some elderly frail patients (Grade B1).

 Given the risk of IgM flare, careful monitoring of all patients receiving rituximab is required with monitoring of sequential IgM levels, clinical assessment for hyperviscosity syndrome (HVS) and monitoring of plasma viscosity if available (Grade A1). The introduction of rituximab should be deferred (or

prophylactic plasmapheresis performed) in patients considered at a higher risk of hyperviscosity, this being defined by an IgM/ M-protein >40g/L (Grade C1).

 There is a lack of evidence to support the use of maintenance rituximab at present (Grade B1).

Treatment of relapsed disease

 Treatment with a BTKi, rituximabcontaining regimens and bortezomibcontaining regimens are options for patients at relapse. Clinical phenotype of the patient is critical in deciding treatment choice (Grade B1).

 Autologous SCT (ASCT) can be considered as a second or later line of therapy in selected chemotherapy-responsive patients, but remains contentious in the novel drug era (Grade C2).

 Autologous SCT (ASCT) should not be offered to patients with less than a partial response (PR) (Grade C1).

 Allogeneic SCT should be considered only for highly selected patients who have progressed after immunochemotherapy and BTK inhibitor therapy (Grade C2).

Response assessment

 Treatment response should be evaluated using uniform response criteria (Grade A1).

 Repeat BM assessment is recommended in patients with suboptimal response, especially to rituximab-based therapies. Evaluation should be at maximal response, which can be delayed many months (Grade A1).

 Detailed and systematic evaluation of BM and extramedullary disease should be evaluated in clinical trials (Grade A1).

Investigation and treatment of histological transformation

 Tissue biopsy is required in all patients with suspected histological transformation (Grade A1).

 Tissue biopsy may be directed by PET-CT scanning (Grade A1).

 Treatment of high-grade transformation to DLBCL is with similar regimens used to treat de novo DLBCL, but prognosis is less favourable (Grade B1).

 Autologous SCT should be considered as consolidation for high-grade transformation

for suitable patients responding to induction chemotherapy (Grade C2).

Complications of WM

 Hyperviscosity is a haematological emergency and is an indication for therapeutic plasma exchange. This is also an indication for definitive treatment (Grade A1).

 Cold agglutinin disease should be managed with conservative measures and if definitive treatment is required, consider single-agent rituximab or rituximab-bendamustine as first-line treatment (Grade B2).

 Organ involvement by AL (IgM-related) amyloid is an indication for definitive treatment, with the aim being to reduce the light chains as quickly and as deeply as possible to minimise end-organ damage. Consider rituximab–bendamustine as firstline treatment in patients considered fit for this regimen (Grade A1).

 Symptomatic cryoglobulinaemia is an indication for definitive treatment. Treatment choice should be guided by severity of symptoms (Grade B1).

 Investigation and management of IgM-related neuropathy should follow International Workshop on Waldenstrom’s Macroglobulinaemia (IWWM)-8 consensus guidelines (D’Sa et al, 2017).

 Investigation and management for Bing–Neel syndrome should follow the guideline by Minnema et al.

 Collaborative working with other specialists is advised where appropriate, for example, amyloidosis unit, haematologists with an expertise in coagulation, neurologists, nephrologists (Grade A1).

 Clinicians should have a low threshold for investigating symptoms that could represent complications of WM, as some can occur regardless of the level of the paraprotein and may be an indication for definitive treatment (Grade A1).

Supportive care

 Selected patients with anaemia, low disease burden, and low transferrin saturation (ie, <10-to-12 per cent) unrelated to gastrointestinal bleeding can respond to parenteral iron (Grade B2).

 Anti-Pneumocystis jirovecii prophylaxis is recommended in patients requiring

intensive and/or immunosuppressive treatment including BTKi (Grade B1).

 Anti-herpes simplex virus (HSV) and herpes zoster (HZV) prophylaxis is recommended in patients requiring intensive, immunosuppressive or bortezomib-based therapy (Grade B1).

 All patients with WM should be offered seasonal influenza and SARS-CoV-2 vaccinations (Grade A1).

 All patients with WM should be offered pneumococcal vaccination in the form of pneumococcal conjugate vaccine (PCV13 or Prevenar 13®) followed by pneumococcal polysaccharide vaccine (PPV23 or Pneumovax®), at least two months later (UK Department of Health Guidance) (Grade B1).

 Live vaccines, such as polio, HZV, and yellow fever, are not recommended. Those patients who are eligible for the shingles vaccine are now able to receive the non-live vaccine, Shingrix® (Grade B1).

 Antimicrobial prophylaxis should be considered for patients with hypogammaglobulinaemia who develop recurrent bacterial infections, according to local antimicrobial protocols. Patients with secondary hypogammaglobulinaemia and recurrent infection despite antimicrobial prophylaxis should be considered for immunoglobulin replacement in accordance with the current UK Department of Health clinical guidelines (Grade B1).

 Patients should be tested for previous viral hepatitis infection prior to each line of therapy, due to the risk of viral reactivation. Prior to commencing treatment, consider discussion with a hepatologist for advice on monitoring and the use of antiviral therapies in those with evidence of current or past infection (Grade B1).

 Patients receiving purine analogues and bendamustine should receive irradiated blood products lifelong (Grade B1). 

Reference Pratt G, et al. Guidelines on the diagnosis and management of Waldenström macroglobulinaemia – A British Society for Haematology guideline. Br J Haematol. 2022 Jan 12. doi: 10.1111/bjh.18036

Amyloidosis in focus

AUTHOR: Dr Moustafa Abdou, Consultant Haematologist, Lister Hospital, UK, and https://askhematologist.com

CASE REPORT

A 68-year-old Caucasian man was admitted to the internal medicine department of the hospital with a condition of generalised oedema and nephrotic syndrome. After performing a renal biopsy that tested positive using Congo red and immunohistochemistry, lambda light chain amyloidosis was diagnosed.

Amyloidosis is the name for a group of rare, serious conditions caused by a build-up of amyloid in organs and tissues throughout the body. Amyloid is an abnormal insoluble protein that is produced in the bone marrow and can be deposited in any tissue or organ. The build-up of the amyloid proteins (deposits) can make it difficult for the organs and tissues to work properly.

The word ‘amylon’ was first used in 1834 by the German botanist Matthias Schleiden to describe the waxy starch in plants. Rudolph Virchow then coined the word ‘amyloid’ in 1854 to describe tissue deposits that stained like cellulose when exposed to iodine. Pathologists now know that amyloid, using the Congo red stain introduced in the 1920s, looks pink with normal lighting ( Figure 1) and demonstrates applegreen birefringence under polarised light ( Figure 2). The various types of amyloid are indistinguishable using light microscopy. It is therefore essential for the pathologist to perform additional studies to definitively identify the type of protein involved since the prognosis and treatment of amyloidosis can vary widely depending on the protein responsible.

Amyloidosis can affect different organs in different people, and there are different types of amyloid. Amyloidosis frequently affects the heart, kidneys, liver, spleen, nervous system, and digestive tract. Without treatment, severe amyloidosis can lead to life-threatening organ

failure. There is no cure for amyloidosis, but treatment can help to manage the symptoms and limit the production of amyloid protein.

Types of amyloidosis

AL amyloidosis (immunoglobulin light chain amyloidosis)

The most common type of amyloidosis, which used to be called primary amyloidosis, results when light chains are produced in excess by clonal or frankly malignant plasma cells. It occurs in 10to-15 per cent of patients with full-blown multiple myeloma, but can also be seen when the affected patient has less than 10 per cent bone marrow plasma cells; the quantity typically required to make a diagnosis of myeloma.

Light-chain amyloidosis may also arise in association with non-Hodgkin’s lymphoma and Waldenström macroglobulinaemia. It is a relatively rare disease with an incidence of 5.1–12.8 per

FIGURE 1: Amyloidosis node Congo red

FIGURE 2: Apple-green birefringence under polarised light. Positive lambda light chain stain in a glomerulus

million person-years and 1,275–3,200 new cases being diagnosed in the US annually. The male-to-female ratio is 3:2. Although healthy individuals have a preponderance of kappa free light chains (K/λ) =2:1), the reverse is true in most patients with primary amyloidosis, as excess lambda light chains have a greater propensity to be amyloidogenic.

AA amyloidosis

Previously known as secondary amyloidosis, this condition is the result of another chronic infectious or inflammatory diseases such as rheumatoid arthritis, Crohn’s disease, or ulcerative colitis. It mostly affects the kidneys, but it can also involve the digestive tract, liver, and heart. AA means the amyloid type A protein causes this type.

Dialysis-related amyloidosis (DRA)

This is more common in older adults and people who have been on dialysis for more

than five years. This form of amyloidosis is caused by deposits of beta-2 microglobulin that build up in the blood. Deposits can build up in many different tissues, but it most commonly affects bones, joints, and tendons.

Other types include familial, or hereditary amyloidosis, age-related (senile) systemic amyloidosis, and organ-specific amyloidosis.

Familial, or hereditary, amyloidosis

This is a rare form passed down through families. It often affects the liver, nerves, heart, and kidneys. Many genetic defects are linked to a higher chance of amyloid disease. For example, an abnormal protein like transthyretin (TTR) can be the cause.

Age-related (senile) systemic amyloidosis

This is caused by deposits of normal TTR in the heart and other tissues. It happens most commonly in older men.

Organ-specific amyloidosis

This causes deposits of amyloid protein in single organs, including the skin (cutaneous amyloidosis). Though some types of amyloid deposits have been linked to Alzheimer’s disease, the brain is rarely affected by amyloidosis that happens throughout the body.

Symptoms and signs of amyloidosis

Amyloidosis presents in a variety of ways and can make diagnosis difficult. It is helpful to separate the presentation into two patterns: Localised and systemic.

Localised amyloidosis is confined to one site and is generally non-lethal. Skin is a common site of deposition and can manifest as asymptomatic plaques, fissures or nodules ( Figure 3).

Systemic amyloidosis implies the involvement of visceral organ(s) or multiple tissues. Patients may present with symptoms limited to one organ or with multiorgan failure.

The kidney is the most common organ involved. Proteinuria is present in 73 per cent of the AL amyloidosis patients with 30 per cent exhibiting nephrotic syndrome. Renal insufficiency is noted in nearly half of the patients, which is usually associated with proteinuria. Renal involvement is nearly universal (97 per cent) in AA amyloidosis.

The heart is the next most common organ involved in AL amyloidosis with abnormal echocardiographic findings noted in 65

There is no cure for amyloidosis, but treatment can help to manage the symptoms and limit the production of amyloid protein

FIGURES 4A and 4B: Cardiac amyloidosis. Amyloid fibrils make the heart’s walls appear thicker when they accumulate in the heart. Notice how much thicker the wall is in the patient with amyloidosis (4B )

FIGURE 3: Cutaneous amyloidosis

per cent of patients. Presentation varies from asymptomatic to a subtle decreased in exercise capacity to fatigue, dyspnoea, and lower extremity oedema to angina, syncope, ascites, and anasarca, which are associated with more advanced disease.

Overt heart failure can be seen in 24 per cent of these patients. Low voltage on electrocardiogram (ECG) and concentric thickened ventricles on echocardiogram are classic signs of cardiac involvement by amyloidosis (Figures 4A and 4B). Cardiac involvement, on the other hand, is rare in AA amyloidosis occurring in only 1 per cent of patients.

The nervous system is a prominent feature in some forms of amyloidosis and can involve the central, peripheral nerves or both. Peripheral nerve involvement can present with bilateral distal progressive paraesthesia or carpal tunnel syndrome. Autonomic nervous system involvement is characterised by syncope, erectile dysfunction, gastroparesis, and diarrhoea.

Gastrointestinal presentation is not common and usually presents with macroglossia (Figure 5), nausea, vomiting, and pseudo obstruction which accounts for <10 per cent of AL amyloidosis cases. Hepatomegaly is present in 24 per cent of AL amyloidosis patients, but only 9 per cent of AA amyloidosis.

Bruising is common and often occurs after minor trauma or procedure especially around the eyes.

Symptoms common to most types of amyloidosis include fatigue and weight loss, which are reported by over half of the patients. Weight loss, however, is unreliable in patients with nephrotic syndrome since many will gain weight as their oedema worsens.

Diagnosis

The diagnosis of amyloidosis is often delayed because the symptoms are so varied. Patients often get treated for heart or kidney failure for months before the underlying root of the problem is identified, typically by a biopsy.

Blood and urine tests may reveal an abnormal immunoglobulin protein in the body in those patients with AL amyloidosis, but the only way to diagnose amyloidosis for certain is to take a sample of tissue for analysis under a microscope. The tissue is often taken from the fat around the abdomen, which can be done on an outpatient basis in patients suspected as having the condition. This fat aspiration test will show a confirmatory positive result in 80 per cent of patients with amyloidosis. Alternatively, a biopsy of the organ that is not functioning properly, such as the heart, kidney or nerve, can more reliably identify the condition but can be more cumbersome to obtain. This method of identification is becoming more common in our experience

and often leads to the diagnosis in patients not suspected of the condition beforehand. A biopsy of the bone marrow is another useful method of detection and is critical to perform in patients suspected as having AL amyloidosis since it can identify and quantify the bone marrow lymphocytes or plasma cells, which typically live there and are causing the problem. All of the above samples are stained with a dye called Congo red that reacts with amyloid, which can then be identified under a microscope.

It is critical to characterise the nature of the amyloid protein that is present since each of the various types of amyloidosis (such as AL, ATTR, or AA) is treated quite differently. Mass spectroscopy is a special technique that can be used on tissue samples to reliably determine the type of protein present. Blood samples can be used to sequence the various genes, such as transthyretin or fibrinogen, to determine if a predisposing gene variant exists. For patients with AL amyloidosis, the free light chain assay is extremely useful to monitor the response to treatment. Patients suspected of heart involvement can get a cardiac MRI, which can typically demonstrate findings suggestive of amyloidosis in those patients afflicted.

Treatment

Treatment of amyloidosis is given to improve symptoms and extend life.

FIGURE 5: Amyloid deposits in the lip and tongue

FIGURE 6: Late gadolinium enhancement (LGE) images typically show circumferential subendocardial contrast enhancementor bilateral septal subendocardial LGE with dark mid-wall (zebra pattern)

Treatment can limit further production of amyloid proteins and, in some instances, promote the breakdown of amyloidosis proteins in affected organs. The type of treatment required varies depending on the type of amyloidosis and the patient’s symptoms.

With secondary amyloidosis, the main goal of therapy is to treat the underlying condition – for example, taking an antiinflammatory medication for rheumatoid arthritis or antibiotics for an infection.

In hereditary amyloidosis, liver transplantation has been the most effective therapy. The new liver does not produce the abnormal amyloid proteins and consequently, the disease improves. Investigational drugs are also being evaluated to try and prevent this type of amyloid protein from depositing in organs.

For primary amyloid, treatments include the same agents used to treat multiple myeloma, such as chemotherapy, corticosteroids, immunomodulatory drugs (lenalidomide or thalidomide), and/or bortezomib. These treatments slow organ deterioration and some have been shown to prolong life, but none provide a cure.

Because primary amyloidosis is such a difficult disease to treat and survival is limited, researchers have begun to investigate the use of high-dose chemotherapy with autologous stem cell transplantation as a means of prolonging survival. The initial results with autologous stem cell transplantation are encouraging.

Autologous stem cell transplantation

Patients with primary amyloid undergo an extensive workup to evaluate organ function and the effects that amyloidosis has had on the body. Those with adequate heart, liver, and lung function are encouraged to proceed to autologous stem cell transplantation. High-dose melphalan chemotherapy is administered over one day. Then the patient’s own stem cells are re-

administered two-to-three days later. An additional three-to-four weeks are spent in the hospital awaiting recovery and growth of the bone marrow. The hope is that this therapy will delay the progression of the disease, and in some cases, improve symptoms through the removal of the abnormal proteins from the organs. However, this therapy is not a cure, and amyloidosis will return in every patient.

That said, we have had patients who have been successfully treated with stem cell

References

1. de Mello RA, Marques Santos DS, Freitas-Silva MP, Andrade JA. Renal failure due to primary amyloidosis: A case report and literature review. Sao Paulo Med J. 2011 May;129(3):176-80. doi: 10.1590/s151631802011000300009

2. Baker KR, Rice L. The amyloidoses: Clinical features, diagnosis, and treatment. Methodist Debakey Cardiovasc J. 2012 JulSep;8(3):3-7. doi: 10.14797/mdcj-8-3-3

3. Leung N, Nasr SH, Sethi S. How I diagnose amyloidosis: The importance of accurate diagnosis and amyloid typing. Blood. 2012 Oct 18;120(16):3206-13. doi:10.1182/blood-2012-03-413682

4. Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. N Engl J Med 2003 Aug 7;349(6):583-96. doi: 10.1056/ NEJMra023144

5. Amyloidosis – Stanford Health Care. Available at: https://stanfordhealthcare.org/ medical-conditions/blood-heart-circulation/ amyloidosis.html

6. Gillmore JD, Wechalekar A, Bird J, Cavenagh J, Hawkins S, Kazmi M, Lachmann HJ, Hawkins PN, Pratt G; BCSH Committee. Guidelines on the diagnosis and investigation of AL amyloidosis. Br J Haematol. 2015 Jan;168(2):207-18. doi: 10.1111/bjh.13156

7. Mayo Clinic. Amyloidosis – symptoms and causes. Available at: www.mayoclinic. org/diseases-conditions/amyloidosis/ symptoms-causes/syc-20353178

8. Kyle RA. Amyloidosis: a convoluted

transplantation and when their disease progressed, have been able to receive another stem cell transplant.

Several new investigational agents are being evaluated in the treatment of multiple myeloma, another plasma cell disorder. The hope is that some of these agents also may be effective in treating amyloidosis. For patients who are not candidates for stem cell transplantation, these agents may prove to be the best available treatment. 

story. Br J Haematol. 2001 Sep;114(3):52938. doi: 10.1046/j.1365-2141.2001.02999.x

9. Lachmann HJ, Booth DR, Booth SE, Bybee A, Gilbertson JA, Gillmore JD, et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med 2002 Jun 6;346(23):1786-91. doi: 10.1056/ NEJMoa013354

10. Comenzo RL. How I treat amyloidosis. Blood. 2009 Oct 8;114(15):3147-57. doi: 10.1182/blood-2009-04-202879

11. Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med. 1997 Sep 25;337(13):898-909. doi: 10.1056/ NEJM199709253371306

12. Dubrey SW, Cha K, Anderson J, Chamarthi B, Reisinger J, Skinner M, Falk RH. The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement. QJM. 1998 Feb;91(2):141-57. doi: 10.1093/ qjmed/91.2.141

13. William C Shiel Jr. Amyloidosis. MedicineNet. Available at: www. medicinenet.com/amyloidosis/article.htm

14. Miller K. Amyloidosis. WebMD. Available at: https://wb.md/2ziYn7i

15. Cedars Sinai. Multiple myeloma and amyloidosis conditions, diagnostics, and treatments. Available at: www.cedars-sinai. org/programs/cancer/we-treat/multiplemyeloma-and-amyloidosis/conditions/ diagnosis.html

16. University of California San Francisco. Amyloidosis. Available at: www.ucsfhealth. org/conditions/amyloidosis/

Iron deficiency anaemia

AUTHOR: Theresa Lowry-Lehnen, RGN, GPN, RNP, PhD, Clinical Nurse Specialist, and Associate Lecturer, Institute of Technology Carlow

doctorCPD.ie

To complete this module and earn free CPD points, go to www.doctorCPD.ie and answer the 10 true or false questions and complete the five MCQs based on this article.

Iron deficiency anaemia (IDA) is a major cause of morbidity and burden of disease. It affects approximately two billion people worldwide, is a global health concern and a common comorbidity in multiple medical conditions. 3,9 Iron deficiency in the absence of anaemia occurs more frequently. Particularly affecting growing children, pre-menopausal and pregnant women, IDA is increasingly a clinical condition that can also affect older people and those with chronic conditions.1,2 Several chronic diseases are frequently associated with IDA, notably chronic kidney disease, chronic heart failure, cancer, and inflammatory bowel disease. 3

Anaemia can be defined as a haemoglobin (Hb) concentration below the lower limit of normal for the relevant population and laboratory performing the test.6 The World Health Organisation (WHO) defines anaemia as a haemoglobin concentration below 130g/L in men over 15 years of age, below 120g/L in non-pregnant women over 15 years of age, and below 110g/L in pregnant women in the second and third trimester.6 IDA, according to the Global Burden of Disease Study 2016, is one of the five leading causes of years lived with disability burden and is the first cause in women. 2,7 Globally, IDA has medical and social impacts, accounting for impairment

of cognitive performance in young children, adverse outcomes of pregnancy for both mothers and new-borns, decreased physical and working capacities in adults, and cognitive decline in older people. 2

The aetiology of IDA is variable and attributed to several risk factors; decreasing iron intake and absorption or increasing demand and loss, with multiple aetiologies often coexisting in an individual patient.1 There are multiple physiological, environmental, pathologic and genetic causes of iron deficiency that lead to IDA. The many causes of iron deficiency include poor dietary intake and malabsorption of dietary iron, as well as a number of significant gastrointestinal pathologies.6 The multiple aetiologies and nonspecificity of symptoms can challenge the diagnosis, and the availability of different formulations of iron supplementation can complicate treatment decisions.1

Iron homeostasis involves a number of important processes, including the regulation of intestinal iron absorption, the transport of iron to the cells, the storage of iron, the incorporation of iron into proteins, and the recycling of iron after red blood cell degradation. As there is no active iron excretion mechanism, under normal physiological conditions iron homeostasis is strictly controlled at the level of intestinal absorption.9

Iron deficiency occurs in two main forms: absolute or functional. Absolute iron deficiency arises when total body iron stores are low or exhausted. Absolute iron deficiency may occur in instances of increased demand, decreased intake, decreased or malabsorption, or chronic blood loss.1 Functional iron deficiency is a disorder in which total body iron stores are

normal or increased, but the iron supply to the bone marrow is inadequate. Absolute and functional deficiencies can coexist. 3

Pathophysiology

Iron, a micronutrient, is essential for life. It is an essential component of haemoglobin in red blood cells and of myoglobin in muscles, which contain around 60 per cent of total body iron. Iron is also necessary for the functioning of various cellular mechanisms, including respiration, enzymatic processes, DNA synthesis, and mitochondrial energy generation. In adults, the body contains 3-to-5g of iron and 20-to-25mg is needed daily for production of red blood cells and cellular metabolism. Because dietary intake is limited (1-to-2mg per day), other sources are needed for iron homoeostasis including recycling of ageing erythrocytes in macrophages, exchange of iron in iron-containing enzymes, and iron stores. About 1-to-2mg of iron is lost daily as a result of menstrual bleeding, sweating, skin desquamation, and urinary excretion. 3 Iron does not have an excretion regulation pathway, and dietary intake, intestinal absorption, and iron recycling have to be finely regulated. 3

Dietary iron is available in two forms; haem and non-haem iron. Haem iron is estimated to contribute 10-to-15 per cent of total iron intake in meat-eating populations, but because it is generally better absorbed than non-haem iron, it can account for more than 40 per cent of total absorbed iron. Foods which include haem iron are liver, beef, lamb, pork, chicken, and oily fish, such as salmon and sardines. Some components of diet directly affect iron bioavailability. Non-haem iron is found mainly in non-meat foods, such as fortified breakfast cereals, bread, broccoli,

cabbage, peas, beans, lentils, eggs, and nuts. Eating foods which contain vitamin C at the same time as eating non-haem iron helps with its absorption. Vitamin C can be found in berries, fruit juices, vegetables, and salads. Phytates, found in cereals and vegetables, polyphenols found in vegetables, fruits, some cereals and legumes, tea, coffee, wine, calcium, and proteins inhibit iron absorption. By contrast, ascorbic acid and muscle tissue enhance iron absorption. 3

Hepcidin plays a crucial role in the control of iron availability to tissues. High expression of hepcidin decreases plasma iron concentrations and low expression increases concentrations.3 Hepcidin is a naturally occurring protein, secreted by the liver. It acts as a regulatory hormone controlling the amount of iron in the body. In inflammation, hepcidin levels rise causing iron to be trapped within macrophages and liver cells, therefore, serum iron levels fall. This typically leads to anaemia due to an inadequate amount of serum iron being available for developing red cells. This leads to functional iron deficiency, which develops under conditions where the demand exceeds iron availability.9

Risk factors

The maximum absorption of iron from the diet is less than the body’s requirements for iron, resulting in a risk of iron deficiency. In infants and young children aged 0-to-15 years, rapid growth consumes the iron stores that accumulated during gestation, which can lead to an absolute deficiency. Adolescent girls and women of childbearing age are particularly at risk of IDA, because of menstrual iron losses. During pregnancy, iron needs are tripled because of expansion of maternal red cell mass and growth of the foetus and placenta. Anaemia is the most common medical disorder in pregnancy. Pregnancy causes a two- to three-fold increase in the requirement of iron, and a 10- to 20-fold increase in folate requirement. Daily iron supplementation is significantly associated with reduced risk of anaemia at term.9

Both pregnancy and lactation place heavier demands on the body for the use of iron and iron stores, particularly as the baby develops and when the body responds to the demands to nurture the baby during feeding. In addition, there are greater physical demands on the body when caring for a newborn, with the change in sleep and dietary patterns of the mother. 8

There are, however, many other recognised causes of IDA including blood loss, malabsorption, poor dietary intake, chronic disease, genetic alterations, and the use of non-steroidal anti-inflammatory drugs (NSAIDs).6 Regular blood donors are also at increased risk of iron deficiency.3 Blood

a complete history of the presenting symptoms, physical examination and assessment for risk factors. IDA is diagnosed by blood tests that include a full blood count (FBC), and additional tests may be ordered to evaluate the levels of serum ferritin (SF), iron, total iron-binding capacity, and/or transferrin.8 Haemoglobin normal range values for males is 13.8-17.2g/ dL and for females is 12.1-15.1g/dL. If the FBC result shows a low haemoglobin and mean cell volume (MCV – normal range 80-100fL), ferritin levels should be checked. Ferritin levels may be less reliable in pregnancy. 8 SF level is considered to be a reliable indicator of iron deficiency in the first trimester of pregnancy in the absence of infection or inflammation, however, in the second and third trimesters it is of limited use, as SF levels fall independently of iron stores. 8

loss is the most common cause, especially from the digestive tract. The most common causes of iron malabsorption are coeliac disease, gastrectomy, bypass gastric surgery and Helicobacter pylori colonisation.1 Anaemias caused by genetic defects are a large group of rare, heterogeneous disorders including haemolytic anaemias, and anaemias arising from mutations in genes that control duodenal iron absorption.3 A ferritin deficiency can deplete iron stores quickly and lead to IDA. 5

Symptoms

Symptoms of IDA include lethargy, fatigue, dizziness, shortness of breath, palpitations, and pale skin. Less common symptoms include headache, tinnitus, pruritus, sore tongue, hair loss, pica, dysphagia, angular stomatitis, spoon shaped nails, and restless leg syndrome.4

Investigations and diagnosis

Investigations for IDA are guided by

Serum markers of iron deficiency include low ferritin, low transferrin saturation, low iron, raised total iron-binding capacity, raised red cell zinc protoporphyrin, increased serum transferrin receptor (sTfR), low reticulocyte Hb (Retic-Hb), and raised percentage hypochromic red cells. SF is the most specific test and useful marker of IDA, but other blood tests, such as transferrin saturation, can be helpful if a false-normal ferritin is suspected.6

An SF less than 15µg/L is highly specific for iron deficiency (specificity 0.99). A cut-off of 45µg/L provides a respectable specificity of 0.92, and figures below this may warrant consideration of GI investigation, especially in the context of a chronic inflammatory process with anaemia.6

Vitamin B12 and folate levels should be considered if the person is anaemic and the anaemia is normocytic with a low or normal ferritin level; vitamin B12 or folate deficiency is suspected; if there is inadequate response to iron supplements in proven IDA; and in elderly patients. 8

Initial investigation of confirmed IDA should include urinalysis or urine

Symptoms of IDA include lethargy, fatigue, dizziness, shortness of breath, palpitations, and pale skin

microscopy, screening for coeliac disease and in appropriate cases, endoscopic examination of the GI tract.6

Once a diagnosis of IDA has been established, every effort must be made to determine the pathogenesis of the disease. Coeliac disease should be considered in all patients, particularly those with a history of IDA refractory to oral iron.11

Treatment and management

The treatment of IDA aims to restore normal circulating Hb levels, replenish body iron stores, and improve quality-oflife and physiological function.6

Oral iron supplements

Oral iron supplements should be considered for all people diagnosed with iron deficiency to help correct anaemia and replenish iron stores. However, there are some instances when it is inappropriate to take oral iron, particularly if the person has inflammatory bowel disease that is active, has an oral iron intolerance, or is taking erythropoiesis-stimulating agents. There are several iron compounds available as tablets including ferrous sulphate, ferrous fumarate, and ferrous gluconate. Oral iron preparations contain varying amounts of ferrous iron and the frequency of gastrointestinal side-effects related to each different preparation tends to be directly related to the content of ferrous iron. When people are able to take and tolerate iron supplements effectively, haemoglobin should rise by 2g/l every three weeks.9 British Society of Gastroenterology 2021 guidelines for the management of IDA in adults suggest that a good response to iron therapy (Hb rise ≥10g/L within a two-week timeframe) in anaemic patients is highly suggestive of absolute iron deficiency, even if the results of iron studies are equivocal.6

There are several limitations to taking iron supplements. Only a small amount is actually absorbed, particularly if there is inflammation. Between 10-to-40 per cent of people taking oral iron supplements experience gastrointestinal side-effects,

including diarrhoea or constipation and do not fully adhere to the prescribed course.9

Regular Hb monitoring is recommended to ensure a satisfactory response and FBC and iron levels should be checked monthly until the Hb is in the normal range. Once Hb is normal, oral iron is continued for three months, but may need to be continued for longer. The patient should be advised of potential GI side-effects including constipation and dark stools and that taking ascorbic acid (vitamin C) can help with iron absorption.9 After the restoration of Hb and iron stores with iron replacement therapy (IRT) the blood count should be monitored periodically, every six months initially to detect recurrent IDA.6

Traditional oral iron salts, ferrous sulfate, ferrous gluconate and ferrous fumarate are inexpensive, effective, safe, and readily available, and remain the standard therapies for IDA.6 Iron supplements should be taken either two hours before or four hours after administration of antacids. Iron as a ferrous salt is more easily absorbed. Iron salts should not be taken with food, because the phosphates, phytates, and tanates in food bind to the iron and affect absorption. Other factors that can affect absorption of iron salts include antacids, H2 receptor antagonists, proton pump inhibitors, antibiotics; for example, quinolones and tetracyclines, and food and drinks containing calcium.11 The most economic iron preparation is ferrous sulphate. Each tablet contains 325mg of iron salts, of which 65mg is elemental iron. Adverse effects occur in the digestive tract, and include abdominal discomfort, nausea/ vomiting, diarrhoea and/or constipation and are directly related to the amount of elemental iron ingested.11

Intravenous iron

Intravenous iron is given when there is an oral iron intolerance/poor adherence, or if there is a poor response to oral iron. It needs to be given in a specialist environment. The intravenous route for iron replacement therapy (IRT) may

be preferable from the outset in those with ongoing significant bleeding, malabsorption due to GI disease, the combination of iron deficiency and anaemia of inflammation, or issues with administration, such as severe dysphagia or compliance.6 However, there are a number of contraindications including known hypersensitivity to intravenous iron, anaemias not caused by iron deficiency, iron overload, and first trimester of pregnancy. Precautions to take into account include asthma, eczema or other atopic allergy, liver dysfunction, acute or chronic infection, and hypotension.9

Parenteral IRT preparations are more expensive than traditional oral iron preparations, and there are additional associated costs relating to the facilities, staffing, and equipment required for administering infusions.6 All IV iron preparations should be administered in a setting where resuscitation facilities are available and appropriately trained staff are present. The patient should be observed for adverse effects for at least 30 minutes following each administration.9

Although intravenous iron is more reliably and quickly distributed to the reticuloendothelial system than oral iron, it does not provide for a more rapid increase in haemoglobin levels. The most common adverse effect of intravenous iron is nausea. While rare, anaphylaxis may occur with intravenous iron infusions.12 Infusion-related reactions are uncommon with modern intravenous iron preparations, but hypersensitivity-type and infusion reactions (approximate incidence – 0.5 per cent) are more common than with oral iron. Serious adverse reaction rates are low, however, and similar for oral and parenteral iron preparations.6 Hypophosphataemia has been reported with all parenteral iron preparations. This relates to the molecules complexed to the iron, rather than the iron itself.6

While most oral iron supplements are cheap, they are not always well-tolerated, often due to GI side-effects. Intravenous

IRT is often necessary for patients with comorbidities, which impair iron absorption. While there are several studies reporting the cost-effectiveness of intravenous iron preparations in comparison to oral IRT for specific conditions, such as chronic kidney disease, chronic heart failure, and inflamatory bowel disease, it is the associated comorbidity which accounts for the improved cost-effectiveness of intravenous iron in these circumstances.6

Blood transfusion

Red blood cell transfusions may be given to patients with severe iron-deficiency anaemia who are actively bleeding or who have significant symptoms, such as chest pain, shortness of breath, or weakness. Transfusions are given to replace deficient red blood cells and will not completely correct the iron deficiency. Red blood cell transfusions will only provide temporary improvement. It is important to find and treat the cause as well as the symptoms.10

Dietary recommendations

In general, a broad range of foods should be incorporated in the diet to prevent iron deficiency. A normal balanced diet contains a total of 12-to-18mg of iron per day. However, only a small amount of iron ingested is absorbed (3-to-5mg per day).9 Iron in the diet comes in two forms: Haem iron and non-haem iron. Haem iron is found in animal derived foods and nonhaem iron in plant derived foods. Nonhaem iron is less easily absorbed therefore a balanced diet with iron enhancers is recommended. Foods that enhance iron intake include lean red meat, oily fish, vitamin c in fresh fruit and juices, and fermented products, such as soy sauce and bread. Foods that inhibit iron absorption include calcium, particularly from milk and dairy products, phytates present in cereal brans, grains, nuts and seeds, and polyphenols and tannin in tea and coffee.9

Iron deficiency anaemia in the elderly

Anaemia is common in older people, affecting more than 20 per cent over the

age of 85 years, and more than 50 per cent of residential/nursing home residents. Aetiologies responsible for anaemia in this age group are complex and often multiple. Iron deficiency is a contributory factor in about half of cases, sometimes associated with deficiencies of vitamin B12 and/ or folate. Anaemia in older patients has been shown to contribute to worsening of physical performance, cognitive function and frailty.6 Iron deficiency in the elderly has many potential contributory causes including poor diet, reduced iron absorption, occult blood loss, medication, and chronic disease. Blood loss from mucosal lesions may be compounded by concurrent antiplatelet/anticoagulant therapy. Older patients are more likely than younger people to have more than one contributing cause. The diagnosis can be confirmed by measurement of ferritin and transferrin saturation, although the former may be difficult to interpret in the presence of coexisting inflammatory conditions.6 The potential risks and benefits of invasive investigation should be carefully weighed up in older adults, particularly those who are frail, have significant comorbidities or reduced life expectancy.

Outlook

Although iron deficiency is one of the oldest and most common medical disorders, the condition has still not received adequate clinical attention and evaluation. IDA presents in primary care and across a range of specialties in secondary care, and because of the insidious nature of the condition it has not always been optimally managed despite the considerable burden of disease, with investigation sometimes being inappropriate, incorrectly timed or incomplete. Many children, elderly patients, and pregnant women continue to have undiagnosed IDA or remain under-treated. IDA is a significant global public health concern that can cause debilitating clinical consequences across age groups, genders, geographies and clinical conditions. Early diagnosis and effective management is required to avoid associated sequelae. Although

effective means for iron supplementation exist, making the right and timely choice of treatment is essential to avoid unnecessary delays in iron repletion and correction of anaemia. This can be achieved with increased awareness of the prevalence and causes of IDA, as well as the benefits of treatment, amongst all healthcare professionals in secondary and primary care settings. Primary care healthcare providers especially GPs and general practice nurses (GPNs) play a pivitol role and are often the first to investigate and treat the presence of IDA in patients. Other practitioners involved in IDA include laboratory technologists, haematologists and pharmacists.

Patient education, improving health literacy and health awareness is an important intervention in the prevention and treatment of IDA. The role of the clinician is to provide ongoing assessment, management, support and education. Key roles are to establish a therapeutic relationship with the patient, assess their understanding of the condition, establish goals and expectations for successful management of the condition and evaluate the patient’s physical, emotional, and psychological wellbeing. By implementing person-centred care, monitoring and evaluating symptoms, outcomes, and responses to therapy, clinicians play a pivotal role in managing IDA and improving the patient’s quality-of-life.

The design and implementation of preventative and therapeutic interventions to combat disorders of iron metabolism, most commonly IDA, are greatly aided by a clearer understanding of the precise mechanisms regulating iron metabolism. Pharmaceutical companies are actively developing hepcidin agonists and antagonists to combat iron overload and anaemia. Ongoing research in science and medicine to better understand iron metabolism and the role of hepcidin as a diagnostic tool and treatment target could bring advances and more novel diagnostic and therapeutic interventions for IDA in the future. 

References

1. Cappellin M, Mussalam K, Taher A. (2020). Iron deficiency anaemia revisited. Journal of Internal Medicine. doi: 10.1111/joim.13004

2. Camachella C. (2019). Iron deficiency: Iron metabolism and its disorders. Blood. doi: 10.1182/blood-2018-05-815944

3. Lopez A, Cacoub P, MacDougall I, PeyrinBiroulet L. (2015). Iron deficiency anaemia. Lancet. doi: 10.1016/SO140-6736(15)60865-0

4. HSE (2021). Iron deficiency anaemia. Health Service Executive, Ireland. Available at: www.hse. ie/conditions/iron-deficiency-anaemia/

5. Gastrolife (2020). Ferritin and iron. Available at:

TRUE/FALSE QUESTIONS

Q1 Iron homeostasis involves a number of important processes, including the regulation of intestinal iron absorption, the transport of iron to the cells, the storage of iron, the incorporation of iron into proteins, and the recycling of iron after red blood cell degradation.

True or false?

Q2 Iron deficiency occurs in two main forms: Functional and non-functional.

True or false?

Q3 Absolute iron deficiency (ID) is a disorder in which total body iron stores are normal or increased, but the iron supply to the bone marrow is inadequate. Functional ID arises when total body iron stores are low or exhausted. Functional ID may occur in instances of increased demand, decreased intake, decreased or malabsorption, or chronic blood loss. Absolute and functional deficiencies cannot coexist.

True or false?

https://gastrolife.ie/ferritin-and-iron/

6. BSG (2021). British Society of Gastroenterology guidelines for the management of iron deficiency anaemia in adults. www.bsg.org.uk/wp-content/ uploads/2011/05/Iron-Deficiency-Aneamia-inAdults-gutjnl-2021-325210.pdf

7. GHDx (2016). Global burden of disease study 2016 (GBD 2016) data resources. Available at: http://ghdx.healthdata.org/gbd-2016

8. NICE (2021). Anaemia-iron deficiency: What investigations should I arrange to confirm iron deficiency anaemia? National Institute of Clinical Excellence. UK. Available at: https://cks.nice.org.uk/topics/ anaemia-iron-deficiency/diagnosis/investigations/

9. Royal College of Nursing. UK. (2019). Iron deficiency and anaemia in adults. Available at: www.rcn.org.uk/professional-development/ publications/pub-007460

10. American Society of Haematology (2021). Iron-deficiency anaemia. Available at: www. hematology.org/education/patients/anemia/ iron-deficiency

11. Science Direct (2015). Iron deficiency anaemia. Available at: www.sciencedirect.com/science/ article/pii/S0185106315000918#bib0335

12. Warner M, Kamran M. (2021). Iron deficiency anaemia. StatPearls Publishing; 2021. Available at: www.ncbi.nlm.nih.gov/books/NBK448065/

Q4 Iron is an essential component of haemoglobin in red blood cells and of myoglobin in muscles, which contain around 60 per cent of total body iron. Iron is also necessary for the functioning of various cellular mechanisms, including respiration, enzymatic processes, DNA synthesis, and mitochondrial energy generation.

True or false?

Q5 In adults, the body contains 13-15g of iron and 25-30mg is needed daily for production of red blood cells and cellular metabolism.

True or false?

Q6 Hepcidin, plays a crucial role in the control of iron availability to tissues. High expression of hepcidin increases plasma iron concentrations and low expression decreases concentrations.

True or false?

Q7 Ferritin is a protein in cells that contains iron and reflects the level of stored iron in the body. A ferritin deficiency can deplete iron stores quickly and lead to iron deficiency anaemia.

True or false?

Q8 Serum markers of iron deficiency include low ferritin, high transferrin saturation, low iron, low total iron-binding capacity, low red cell zinc protoporphyrin, low serum transferrin receptor (sTfR), raised reticulocyte Hb (Retic-Hb) and low percentage hypochromic red cells.

True or false?

Q9 The treatment of iron deficiency anaemia aims to restore normal circulating Hb levels, replenish body iron stores, and improve quality-of-life and physiological function.

True or false?

Q10 A broad range of foods should be incorporated in the diet to prevent iron deficiency. A normal balanced diet contains a total of 12-to-18mg of iron per day.

True or false?

Answer these questions and five MCQs at www.doctorCPD.ie to earn free CPD points.

Author: Theresa Lowry-Lehnen, RGN, GPN, RNP, PhD, Clinical Nurse Specialist, and Associate Lecturer, Institute of Technology Carlow

ENCLYXTO® REGIMENS: DEEP RESPONSE** AND

PFS WITH FIXED TREATMENT DURATION1,2

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 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 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: 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 1L=1st Line; 2L+=2nd Line+; VEN=VENCLYXTO; O=Obinutuzumab; Clb=Chlorambucil; B=Bendamustine; MRD= Minimal Residual Disease; R=Rituximab; PB=peripheral

Treatment Duration. References:

1. VENCLYXTO® SmPC available at www.medicines.ie.

mg/100 mg film-coated tablets. PRESCRIBING INFORMATION. contains 10mg, 50mg or 100mg of venetoclax. Please refer to the before prescribing. INDICATION: Venclyxto in combination with adult patients with previously untreated chronic lymphocytic combination with rituximab is indicated for the treatment of least one prior therapy*. Venclyxto monotherapy is indicated for deletion or TP53 mutation in adult patients who are unsuitable for or in the absence of 17p deletion or TP53 mutation in adult chemoimmunotherapy and a B cell receptor pathway inhibitor*. Venclyxto in indicated for the treatment of adult patients with newly are ineligible for intensive chemotherapy.† DOSAGE AND initiated and monitored by a physician experienced in the use of with venetoclax may develop tumour lysis syndrome (TLS). management by disease indication. See SmPC for full posology. starting dose is 20 mg of venetoclax, once daily for 7 days. The of 5 weeks up to the daily dose of 400 mg. Post-titration dose

The recommended dose of venetoclax in combination with Rituximab after the patient has completed the dose-titration daily dose of 400 mg venetoclax for 7 days. Venetoclax is taken Venetoclax in combination with obinutuzumab: Venetoclax consisting of 28 days: 6 cycles in combination with obinutuzumab, agent. Administer obinutuzumab 100 mg on Cycle 1 Day 1, on Day 1 or Day 2. Administer 1000 mg on Days 8 and 15 of 28-day cycle, for a total of 6 cycles. Start the 5-week venetoclax Day 22 and continue through Cycle 2 Day 28. After completing dose of venetoclax is 400 mg once daily from Cycle 3 Day 1 of Post-titration dose for venetoclax monotherapy: the once daily. Treatment should be continued until disease patient. Posology (AML): Day 1: 100mg; Day 2: 200mg; Day 3 (and administered at 75 mg/m2 either intravenously or subcutaneously on Cycle 1 Day 1. Decitabine should be administered at 20 mg/m2 cycle beginning on Cycle 1 Day 1. Venetoclax dosing may be hematologic toxicities and blood count recovery. Venetoclax, in should be continued until disease progression or unacceptable tablets whole with water at approximately the same time each Prevention of tumour lysis syndrome (TLS): Prior to initiating including radiographic evaluation must be performed for all patients. followed to minimise the risk of TLS and more intensive risk increases; adequate hydration, administration of antichemistry monitoring and correction of abnormalities. Monitoring TLS. All patient comorbidities should be considered for riskoutpatient or in hospital. Dosing interruption and/or dose modifications for TLS or other toxicities may need to be details of prophylaxis measures. Special Populations: Elderly: impairment: No dose adjustment is needed for patients with mild, ml/min and <90 ml/min). Venclyxto should be administered to ml/min and <30 ml/min) only if the benefit outweighs the risk signs of toxicity due to increased risk of TLS. Patients with intensive prophylaxis to reduce the risk of TLS and closer monitoring. or on dialysis has not been established, and a recommended determined. Hepatic impairment: No dose adjustment is recommended impairment. Patients with moderate hepatic impairment should be A dose reduction of at least 50% throughout treatment is impairment. These patients should be monitored more closely safety and efficacy of Venclyxto in children aged less than 18 CONTRAINDICATIONS: Hypersensitivity to any of the active substances or of strong CYP3A inhibitors at initiation and during the doseuse of preparations containing St. John’s wort. SPECIAL lysis syndrome (TLS): The risk of TLS is a continuum based on (particularly reduced renal function), tumour burden and splenomegaly. further increases the risk. Assess patient-specific factors for level of and anti-hyperuricaemics to patients prior to first dose of chemistries should be monitored and abnormalities managed needed; when restarting venetoclax, dose modification guidance should be employed as overall risk increases. Neutropenia and

2. Al Sawaf et al, HemaSphere, 2021;5(S2):27

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