Eliminating the Burden of Cervical Cancer

Written by Dr Robert O’Connor, Director of Research & Yvonne O’Meara, Psychotherapist, Irish Cancer Society

Each year over three hundred women are diagnosed with cervical cancer, and those living with and beyond extend into their thousands.

Globally and nationally, attention about this malignancy has increased in recent years. Buoyed by the recognition that the advent of vaccination and HPV testing means that cervical cancer is increasingly preventable, ambitious targets have been set by international health and policy organisations such as the EU parliament and WHO. However, truly eliminating the burden of cervical cancer will require a broader range of action by us all over multiple decades. In line with the agreed pillars of this strategy, we can group the needs and opportunities for a comprehensive burden elimination strategy into the three areas: vaccination, screening, and treatment and care.

Vaccination

Almost all squamous cell cervical cancers are directly caused by one of approximately a dozen HPV virus strains, HPV-16 being particularly carcinogenic and accounting for 50% of that burden alone, with other factors such as smoking amplifying that risk. Safe and effective vaccines have been widely available now for more than a decade and are already causing a precipitous fall in pre-cancer and early cancer rates among high uptake populations. Asymptomatic HPV infections are common when young people first become sexually active, and the vaccine works when immunity is established prior to such exposure, hence the vital importance of a national programme for vaccination of young people which establishes that protection. We are fortunate in Ireland that the HPV vaccine is delivered for free through the national schools vaccination programme, and all teenagers in first year are eligible. With compulsory involvement among schools, a school-based programme boosts equity of access. Males too get HPV-caused cancers and can transmit to their partners, so our gender-neutral scheme is also a major aid to reducing community levels of HPV, thereby preventing six types of cancer including cervical. Valiant efforts by parents, schools and the National Immunisation Office have kept HPV vaccination levels high, but there is no question that COVID has impacted uptake rates in several ways. At a cost of approximately ¤800, missing the free programme likely puts later access out of the reach of many young people. Hence, a national catch up is strongly indicated now. Vaccine hesitancy is not going away, and maintaining high uptake will require an ongoing multiannual effort to educate parents as their children come to the relevant age and ‘immunise’ them with facts against emotive and highly targeted misinformation and disinformation.

In the fantastically multicultural community of modern Ireland, these efforts will also need to be communicated through means more suitable to the information sources commonly used by discreet communities, bearing in mind that some in society have significant reason to question state authorities based on historical and legacy challenges from their country of origin. There are also emerging indications that vaccination of older women, especially those immediately being treated for HPV-caused cervical cell abnormalities, may greatly reduce the chances of recurrence and later cancer risk.

Screening

Screening has been hugely successful at bringing down the levels of cervical cancer in this country, with rates more than half those seen prior to the introduction of a national testing programme. However, cervical pre-cancer and cancer remains all too common.

With over 7,000 women needing intervention to prevent the emergence of cervical cancer annually, this translates to an approximate 1 in 10 lifetime risk of cervical pre-cancer treatment which has a health burden in its own right, with just less than a 1 in 100 lifetime risk of a cancer diagnosis, and a 3 in 1000 risk of cervical cancer death.

The successful transition of that programme to HPV-based testing will more sensitively and accurately identify those in need of intervention before cancer emerges, however there will still

“Screening has been hugely successful at bringing down the levels of cervical cancer in this country, with rates more than half those seen prior to the introduction of a national testing programme. However, cervical pre-cancer and cancer remains all too common”

be challenges to reap the full benefits of such testing. While effective for many, the current administration of an uncomfortable test by a third party can be a significant hurdle for some people with a cervix, or the many in our community who have sadly been exposed to sexual trauma. Screening rates can also be lower in underprivileged communities facing challenges with healthcare access.

A vastly disproportionate burden of cervical cancer is found among those who cannot make use of the screening currently available. There are now strong indications that the use of an adjunct of HPV-based self-sampling may open up even wider access to prevention and early detection by such individuals. The effectiveness of screening will continue to rely heavily on maintaining high colposcopy standards, and this will be challenged initially by increased demand driven by HPV positivity, and then declining demand as the impact of vaccination and HPV detection reduces positivity rates. Despite all that we know about the symptoms of cervical cancer, it is clear that educational, communication and access hurdles remain, and continued progress will require ongoing education of the public and professionals as to warning signs and ready and rapid access for women to compassionate symptom assessment.

Treatment and care

The need for improvements in treatment and care often gets least attention in the conversation around cervical cancer.

Management of this cancer may be through surgery, radiotherapy, or chemotherapy or a combination of these. Short and long-term side effects are an inevitable component in each patient’s care pathway. New treatments and combinations of treatment are gradually pushing up survival and giving hope to those impacted, but these often come at a devastating cost. Patients can be left with a variety of life-changing side effects including chronic sexual dysfunction, lymphoedema, infertility, treatment-induced menopause, and gastrointestinal and urinary toxicity from radiotherapy, among others. Cervical cancer patients have been found to have worse quality of life scores when compared to the general population and other gynaecological cancer survivors. Many patients receive multiple treatment modalities, each with its own long-term effects. Given the high five-year survival for cervical cancer, evaluation, and improvement of long-term quality of life are essential.

Due to the physical location of cervical cancer, it can be embarrassing and more challenging for women to talk about these side effect to their treating teams. Often, these women suffer in silence, unsure how to manage these side effects. Some of these can be easily addressed if they are spoken about and normalised during a patient consultation. The most obvious of these is vaginal dryness. Ignorance of the personal and relationship burdens of cervical cancer treatment has left many suffering devastating consequences, often in lonely isolation. This was one of the drivers behind the Irish Cancer Society establishing its Women’s Health Initiative, a programme established in Cork and Dublin and now extending to Galway researching the best way to provide state-of-the-art customised interventions to assist women to manage and overcome the impacts of cancer treatment, especially in cervical cancer. The Irish Cancer Society’s Women’s Health Initiative research programme has taken great strides in addressing the needs of such women.

ThisisGO.ie

Donal Brennan, Professor of Gynaecological Oncology in UCD who leads the Dublin arm of the programme, has along with his team designed, populated, and launched an online resource addressing the needs of these women, their partners and health care professionals supporting them. This web-based virtual platform is called www.thisisGO.ie. The idea is quite simple. Users create a personalised profile and get information tailored to their situation, with information provided on their disease site, stage and treatment modalities received.

Phase one of www.thisisGO. ie focused on cervical cancer and has received universal praise from patients and health care professionals. It has been designed as a safe online space where women and their families can access accurate, reliable, evidence-based information about their cancer, treatment options, long and short-term complications, psychological and social issues.

The importance of Patient and Public Involvement, or PPI, is fundamental to improving quality of life for these women. www.thisisGO.ie has been developed as an institutionally neutral platform with extensive voluntary input from PPI and health care professionals throughout Ireland. The scope of the information available is vast. There is a very useful symptom tracker for patients as well as a detailed service directory which allows women access local supports in all areas of the country. It also contains practical articles on topics such as ‘How to talk to children about cancer’, death and dying, vulvovaginal health, diet and exercise, lymphoedema management, decoding the science, and menopause, to mention some of the most commonly searched topics. People using the platform will find it useful right across the disease trajectory from diagnosis to treatment, through to living well with and beyond cancer. Equally, the platform is designed to be of use to professionals working in the field, with relevant information shared through a hybrid approach of papers, videos and podcasts. Articles on subjects including breaking bad news and how to take a psychosexual history are particularly relevant to professionals working directly in oncology, but also to those who may not be. A phase two of the platform focusing on the ovarian cancer was also recently launched to coincide with World Cancer Day in February, with further content set to be added on other gynaecological conditions throughout the course of 2022.

Advanced NSCLC

Written by Dr Ahmed Al Badi and Dr Brian Healey Bird

Dr Ahmed Al Badi

Introduction

Lung cancer is the commonest cancer diagnosis in both sexes. Half of these diagnoses are locally advanced or associated with distant metastasis.(2) Immunotherapy is now the first line treatment of choice for stage IV Non-Small Cell Lung Cancer (NSCLC) without driver mutations.(3) This article will review these agents combined with chemotherapy or as single agents, and the associated immune related autoimmune side effects (irAE) We will also explore treatment options following immunotherapy, including novel agents targeting KRAS G12C mutations. 2 cases will be used to illustrate these learning points.

Immunotherapy

Immunotherapy capitalises on the body’s ability to recognize self and non self and destroy non self. Tumour cells escape immune surveillance by upregulation of

Dr Brian Healey Bird, Senior Lecturer in Clinical Education University College Cork programmed cell death ligand 1(PD-L1) expression which causes exhaustion of effector T cells when they attempt to attack the cancer cell.(4) Testing for PD-L1 tumour proportion score (TPS Tumour cells positive for PD-L1/ viable tumour cells*100%) is now one of the pillars of the initial treatment of NSCLC. Immune checkpoint inhibitors (ICI) such as Pembrolizumab disrupt PDL1 signalling and activate the immune system to attack the cancer in a substantial minority of patients. The KEYNOTE-024 trial compared the use of first line pembrolizumab to platinum based chemotherapy in advanced NSCLC with PD-L1 >50% and no driver mutations; the group that received pembrolizumab showed a significant overall survival (OS) and longer progression free survival (PFS).(5) In Ireland first line monotherapy with ICI is limited to frail patients who would not tolerate chemotherapy and who have a TPS score >50%. In the USA based on KEYNOTE-042 lung cancer with any PD-L1 score can receive single agent immunotherapy as they accept inferior response rates and financial toxicity more readily. TPS is an imperfect biomarker. The KEYNOTE-189 trial randomized a patient population of non-squamous NSCLC to either a chemoimmunotherapy group (cisplatin or carboplatin plus pemetrexed combined with pembrolizumab) compared to a placebo. This was followed by pembrolizumab maintenance therapy or placebo. The chemoimmunotherapy arms had increased OS with all subgroups of TPS as demonstrated below. Similar results were demonstrated in the KENOTE-407 trials with squamous cell carcinoma NSCLC (Carboplatin and Paclitaxel ± pembrolizumab or placebo). In Ireland Pembrolizumab, Nivolumab and Atezolizumab are all funded for second line treatment of NSCLC post chemotherapy alone.

Immune Related Autoimmune Side Effects

CTLA-4 is an immune checkpoint found in naïve T cells being exposed to antigen by antigen presenting cells early in T cell maturation. Their use leads to rapid expansion of T cell clones some of which may recognize self-antigen causing autoimmune disease. PD-L1 inhibitors tend to have a lower risk of irAE thanCTLA-4 inhibitors as the T cells have already been through selection in the lymph node and are quiescent but unleashed to attack the cancer cells. In moderate to severe cases treatment cessation and steroids yield good responses. Differential diagnoses

Table 1. Summary of Selected trials of Pembrolizumab in NSCLC

TRIAL ARM PD-L1 TPS IHC Score using Dako 22C3

Single Agent Pembrolizumab (Adeno and Squam) KEYNOTE 024(5, 7-9) (Number of patients receiving Pembrolizumab)

≥ 50%

(154) 44.8 10.3 0.5 (0.370.68, < 0.001) 26.3 (95% CI 18.3 –40.4) 0.62 (0.480.81, 0.002) Ireland, EMA, FDA

Overall Response Rate (95% CI) (%) Median PFS in months (05% CI) PFS HR compared to chemo alone (95% CI, p-value) Median OS in months (95% CI) OS HR compared to chemo alone (95% CI, p-value)

KEYNOTE 042(10)

All patients

(636) ≥50%

(298) ≥ 20%

(412) ≥ 1%

(636) 1-49%

Pembro and Chemo (AdenoCA) KEYNOTE 189 (11, 12)

Pembrolizumab and Chemotherapy (First Line SCC) KEYNOTE-407

(338) All patients receiving Pembrolizumab (410) 48 (43.1 53) 9 (8.1 –9.9) 0.48 (0.4 –0.58) 22 (19.5 – 25.2) 0.56 (0.45 -0.70) Ireland, EMA, FDA

≥ 50% (132)

1-49% (128)

< 1% (127)

All Patients (278)

≥50% (73) 39 (34-45) 7.1 (5.9 – 9)

33 (29 –38)

27 (24 31) 6.2 (5.17.8) 5.4 (4.3 – 6.2) 0.81 (0.67 -0.99, 0.017) 0.94 (0.81.11,)

1.07 (0.941.21) 16.7 0.81 (0.71 -0.93, 0.0036)

20 (15 –24.9)

17.7 (15.3 –22.1) 16.7 (13.9 19.7) 13.4 (10.718.2) 0.69 (0.560.85, 0.003) 0.77 (0.640.92, 0.002) 0.81 (0.710.93, 0.0018) 0.92 (0.771.11,)

62.1 (53.3 -70.4)

49.2 (40.3 -58.2)

32.3 (24.3 -41.2)

57.9% (51.9–63.8)

60.3 (48.1–71.5) 11.1 (9.1 14.4) 9.2 (7.8 -13.1)

6.2 (4.9 -8.1)

6.4 (6.2–8.3)

8.0 (6.1–10.3) 0.36 (0.26 -0.51)

0.51 (0.36 – 0.73)

0.64 (0.47 -0.89)

0.56 (0.45–0.70; <0.001) 0.37 (0.24–0.58) NR (20.4 – NR)

21.8 (17.7 25.9) 17.2 (13.8 22.8) 15.9 (13.2–NE)

NR (11.3–NE) 0.59 (0.39 -0.86)

0.62 (0.42 -0.92)

0.52 (0.36 -0.74)

0.64; (0.49–0.85; <0.001) 0.64 (0.37–1.10)

Approval

FDA

Ireland, EMA, FDA FDA

FDA

FDA

Ireland, EMA, FDA uncertain a colonoscopy may be useful. In unresponsive cases a switch to infliximab within 72 hours may be considered.(14) Hepatitis occurs in about 10% of patients, usually after 8-12 weeks from initiation. This is usually a rise in liver function tests (LFTs) but can manifest as a fever. Consider alternative diagnoses such as thromboembolic events, alcoholic or viral hepatitis and metastatic disease as causes for liver function derangement. A CT scan and hepatitis panel can aid this differential. Normalisation of LFTs can be aided with 0.5mg-1mg of Prednisolone as a 3-week taper. Treatment can be recommenced for mild to moderate hepatitis secondary to immunotherapy after recovery of liver function tests (which may take up to 8 weeks) but should be discontinued in severe hepatitis.(14) Thyroid dysfunction can happen quite early at 42 days in 6.6% of patients. Usually, presentation is mild symptoms of hypothyroidism but can initially be preceded by hyperthyroid symptoms. This is because it is commonly associated with thyroid autoantibodies and progresses like a thyroiditis. Symptomatic therapy with Levothyroxine for hypothyroidism or non-selective beta blockers for the temporary hyperthyroidism may be beneficial. These patients may recover with time. Other endocrine dysfunction is extremely rare but one emergency to look out for would be adrenal insufficiency in 0.7% of patients who may present with non-specific symptoms or in an adrenal crisis. The latter need hospitalization, aggressive fluid resuscitation and stress dose steroids.(14) Patients whose immune system attacks pancreatic islet cells may present with Diabetic Keto Acidosis.

Pneumonitis can occur in 5% of patients. Patients can present with shortness of breath, coughing, or reduced exercise tolerance. It is a potentially fatal complication. CT is imaging of choice and can show bilateral ground glass opacities. Prednisolone at 1-2mg/kg with a long taper over 4-6 weeks to avoid relapse can help reduce inflammation. Consider infectious causes and a bronchoscopy to out rule these especially in moderate to severe disease or in poor response.(14) Other irAEs to look out for include inflammatory arthritis, cytopenia and ocular manifestations . Consider discussion with the respective specialties to consider other differentials but if related to immunotherapy treatment discontinuation (temporarily or permanently) and steroids can help treat these side effects.(14)

1–49% (103)

≥1% (183) 49.5 (39.5–59.5) 7.2 (6.0–11.4) 0.56 (0.39–0.8) 14.0 (12.8–NE) 0.57 (0.36–0.90)

0.49 (0.38–0.65)

<1% (95) Adapted from Healey Bird B, Nally K, Ronan K, Clarke G, Amu S, Almeida AS, et al. Cancer Immunotherapy with Immune Checkpoint Inhibitors-Biomarkers of Response and Toxicity; Current Limitations and Future Promise. Diagnostics. 2022;12(1):124.(13)

63.2 (52.6–72.8) 6.3 (6.1–6.5) 0.68 (0.47–0.98) 15.9 (13.1–NE)

0.61 (0.38–0.98) Adapted from Healey Bird B, Nally K, Ronan K, Clarke G, Amu S, Almeida AS, et al. Cancer Immunotherapy with Immune Checkpoint Inhibitors-Biomarkers of Response and Toxicity; Current Limitations and Future Promise. Diagnostics. 2022;12(1):124.(13)

including sepsis, thrombosis and chemotherapy side effects need to be considered especially in patient with other comorbidities and polypharmacy.(14) Rashes and pruritis are common and tend to effect about 40% of patients. These occur early in treatment at the 2–3-week HOSPITALPROFESSIONALNEWS.IE | HPN • MAY 2022

mark and in most cases can be observed and symptomatically managed. Interestingly Vitiligo rashes are usually associated with a good response to immunotherapy. Blistering rashes need a broader differential and other causes investigated.(14) Diarrhoea and colitis can happen

in 1.8% of patients at around 6-7 Immune Related Autoimmune Side Effects weeks. Bowel rest and hydration can be sufficient but in moderate CTLA-4 is an immune checkpoint to severe disease steroids and found in naïve T cells being exposed to antigen by antigen presenting cells early in T cell maturation. Their hospitalization is warranted. use leads to rapid expansion of T cell clones some of which may recognize self-antigen causing 0.5-1mg/kg of prednisolone with a 4–6-week taper to avoid early autoimmune disease.. PD-L1 inhibitors tend to have a lower risk of irAE thanCTLA-4 inhibitors relapse is recommended. Consider as the T cells have already been through selection in the lymph node and are quiescent infectious pathogens and a CT but unleashed to attack the cancer cells. In scan early. If the diagnosis is moderate to severe cases treatment cessation and steroids yield good responses. Differential diagnoses including sepsis, thrombosis and chemotherapy side effects need to be considered especially in patient with other comorbidities and polypharmacy. (14) Rashes and pruritis are common and tend to effect about 40% of patients. These occur early in

Immunotherapy combined with chemotherapy

After recognizing the therapeutic benefits of immunotherapy it may be helpful to review the current strategy to treat stage IV lung cancer. Targeted therapies for druggable mutations must be screened for early on.(15) However, if there are no targetable mutations then immunotherapy (ideally combined with cytotoxic chemotherapy) is the best option. The options are pembrolizumab alone or pembrolizumab combined with chemotherapy doublet of choice (cisplatin or carboplatin with pemetrexed for Adenocarcinoma).

Case 1. Combination Chemotherapy and Immunotherapy and beyond.

A 60-year-old female ex-smoker with a 15-pack year (PY) smoking history presented in July of 2021 with haemoptysis and shortness of breath on exertion. CT thorax abdomen and pelvis (CT TAP) showed a malignant mass in left hilum with central mediastinal invasion, invasion into left atrium, left pulmonary vein and left upper lobe collapse. There was a small ipsilateral effusion which contained malignant cells. A bronchoscopy was performed, and tissue was sent for an Next Generation Sequencing panel and PD-L1 TPS. There were no actionable mutations and PD-L1 TPS was over 90%. She received carboplatin/pemetrexed and pembrolizumab. After 2 cycles of chemotherapy, she was admitted with febrile neutropenia and pancytopenia. This was attributed to her cytotoxic chemotherapy, and she had a dose reduction and continued full dose pembrolizumab. She had a restaging CT TAP which showed some decrease in tumour bulk in November of 2021. After 3 further months of maintenance pembrolizumab a staging CT was performed, and the disease had progressed in the aforementioned regions. She was switched to Docetaxel and Nintedanib. This decision was based on a retrospective, real world analysis of Docetaxel plus Nintedanib after treatment failure (chemotherapy followed by ICI or combined chemotherapy/ICI) from seven German centres. The study concluded that of 93 patients enrolled overall response rate (ORR) was 41.4% with disease control rate (DCR) of 75.9%.(16)

Beyond First- and Second-Line Treatment

A 60-year-old female former smoker presented initially in August 2018 with back pain. She had imaging which revealed a small lung primary with a metastatic T8 pathological fracture. Tissue samples revealed lung adenocarcinoma. Next Generation Sequencing showed a KRAS G12C mutation and immunohistochemistry a PD-L1 TPS of 1-49% She underwent vertebrectomy and spinal reconstruction followed by Stereotactic Body Radiotherapy (SBRT) to the small lung primary. She was then referred to medical oncology. At that time Ireland did not have immunotherapy available in first line lung cancer. She was given 4 cycles of Carboplatin and Pemetrexed and remained free of progression for 15 months, On progression she received pembrolizumab as monotherapy. Her immunotherapy was halted due to grade 3 colitis managed with inpatient IV hydrocortisone and discharged with a 3-week oral taper of prednisolone. This was unsuccessful and the patient was readmitted due to refractory colitis and required an infliximab infusion. After recovery from the complication a staging scan was performed in early 2021 to discuss treatment options. This unfortunately showed disease progression. Following review of the literature on sotorasib and discussion with the patient she was commenced on sotorasib 960mg once a day. She has tolerated it very well for almost one year now and her scan at 6 weeks showed an interval reduction in tumour burden. Sotorasib targets the KRAS G12C mutation. KRAS a guanosine triphosphatase that acts as a

Baseline Baseline 3 Months of chemo/Pembro3 Months of chemo/Pembro Disease progression after 3

months of Pembro

switch for guanosine triphosphate maintenance Beyond First- and Second (GTP) the active form and guanosine diphosphate (GDP) the -Line Treatment inactive form. The G12C mutation selects the active form GTP which promotes downstream oncogenic A 60-year-old female former smoker presented initially in August 2018 and uninhibited cell growth. Through irreversible binding and with back pain. She had imaging which revealed a small lung primary with a metastatic inhibition of KRAS this mutation is T8 pathological fracture. Tissue suppressed. Some studies report samples revealed lung adenocarcinoma. Next Generation Sequencing that as many as 13% of lung showed a KRAS G12C mutation and immunohistochemistry a PD-L1 TPS of 1-49% adenocarcinoma tumours harbour this mutation(17)She underwent vertebrectomy and spinal reconstruction The use of Sotorasib was explored followed by Stereotactic Body Radiotherapy (SBRT) to the small lung primary. She was then referred to medical oncology. in the CodeBreaK100 trial currently in phase 1/2. They have recruited At that time Ireland did not have immunotherapy available in first line lung cancer. patients with an ECOG 0-1, having advanced or metastatic NSCLC, She was given 4 cycles of Carboplatin and Pemetrexed and remained free of progression for disease progression after first line treatment which is either platinum-15 months, On progression she received pembrolizumab as monotherapy. Her immunotherapy was halted due to based chemotherapy or receipt grade 3 colitis managed with inpatient IV hydrocortisone and discharged with a 3-week of PD-1/PD-L1 monotherapy or a combination treatment. They oral taper of prednisolone. This was unsuccessful and the patient was readmitted measured the primary endpoints of objective response either complete due to refractory colitis and required an infliximab infusion. or partial. Responsiveness was reported as per the RESIST standards (see below). In 126 patients, 124 were selected. There After recovery from the complication a staging scan was performed in was an objective response in 37.1% (95% confidence interval early 2021 to discuss treatment options. This unfortunately showed disease progression. [CI], 28.6-46.2), 3.2% had a complete response the remaining had a partial response. Disease control defined as a minimum Following review of the literature on sotorasib 5-week period with stable disease and discussion with the patient she was commenced on occurred in 80.6% of patients (95% CI, 72.6 to 87.2). Most patients sotorasib 960mg once a day. She has tolerated it very well for almost one year now and her scan at 6 weeks showed an interval reduction in tumour tolerated sotorasib well and there were no major safety concerns. (7)burden.

References available on request

Sotorasib targets the KRAS G12C mutation. KRAS a guanosine triphosphatase that acts as a switch for guanosine triphosphate (GTP) the active form and guanosine diphosphate (GDP) the inactive form. The G12C mutation selects the active form GTP which promotes downstream oncogenic and uninhibited cell growth. Through irreversible binding and inhibition of KRAS this mutation is suppressed. Some studies report that as many as 13% of lung adenocarcinoma tumours harbour this mutation(17)

Disease progression after 3 months of Pembro maintenance The use of Sotorasib was explored in the CodeBreaK100 trial currently in phase 1/2. They have recruited patients with an ECOG 0-1, having advanced or metastatic NSCLC, disease progression after first line treatment which is either platinum-based chemotherapy or receipt of PD-1/PD-L1 monotherapy or a combination treatment. They measured the primary endpoints of objective response either complete or partial. Responsiveness was reported as per the RESIST standards (see below). In 126 patients, 124 were selected. There was an objective response in 37.1% (95% confidence interval [CI], 28.6-46.2), 3.2% had a complete response the remaining had a partial response. Disease control defined as a minimum 5-week period with stable disease occurred in 80.6% of patients (95% CI, 72.6 to 87.2). Most patients tolerated sotorasib well and there were no major safety concerns. (7)

RECIST 1.1

Complete response Disappearance of lesions and pathological lymph nodes Partial response More than 30% decrease in sum of longest diameters (SLD) No new lesions or progression of non-target lesions.

Stable disease

Disease progression

No response as above criteria but no disease progression. More than 20% increase in SLD, progression of non-target lesions or new lesions.

Taking Control of Blood Pressure Taking Control of Blood Pressure

World Hypertension day is celebrated annually on the 17th May. The main aim of the day is to educate the public and increase awareness of hypertension, which is also commonly known as high blood pressure. Hypertension is a major cause of a range of health problems such as strokes, heart attacks and kidney disease, and can also contribute to dementia. Many people who suffer from hypertension are not aware that they have it as there can be no symptoms, often people only find out after suffering a heart attack or stroke. The day is organised by the World Hypertension League (WHL) which is an umbrella organisation composed of 85 hypertension societies and leagues from all over the world. The theme for this year is Know Your Numbers, and the WHL would like to encourage as many people as possible to get involved in May Measurement Month. In this initiative which started in 2017, volunteer manned screening sites will be setting up in a range of venues around the world to check the blood pressure of as many people as possible. Startlingly, it is estimated that over half of all adults in Ireland over the age of 45 are living with high blood pressure. High blood pressure is a sign that the heart and blood vessels are being overworked which in turn increases the risk of having a heart attack or a stroke. It can also lead to other conditions such as aneurysm, heart failure, problems with your vision and kidney failure. The number of adults aged 30-79 years with hypertension or high blood pressure has increased from 650 million to 1.28 billion in the last thirty years, according to the first comprehensive global analysis of trends in hypertension prevalence, detection, treatment

World Hypertension day is and control, led by Imperial College London and the World celebrated annually on the 17th Health Organization (WHO), and May. The main aim of the day is to published in The Lancet. Nearly educate the public and increase half these people did not know awareness of hypertension, which they had high blood pressure.is also commonly known as high blood pressure. The UK was one of the top ten countries with the lowest Hypertension is a major cause of a range of health problems prevalence of high blood pressure such as strokes, heart attacks among women in 2019 at 23 per and kidney disease, and can cent while in Ireland this figure also contribute to dementia. was 26.6 per cent. The study Many people who suffer from found that the country with the highest prevalence of high blood hypertension are not aware that pressure in men was Paraguay they have it as there can be no at 62 per cent compared to 22 symptoms, often people only find per cent in Eritrea which had the out after suffering a heart attack or stroke. lowest prevalence among men. A team of consultants in Galway, The day is organised by the World Hypertension League (WHL) including Professor Faisal Sharif, Consultant Cardiologist, are which is an umbrella organisation composed of 85 hypertension now leading the way in treating societies and leagues from all this problem at the Difficult over the world. to Treat Hypertension Clinic, based in Merlin Park Hospital, which assesses patients and investigates the reason for poor blood pressure control. Despite lifestyle changes and medication changes, if the blood pressure remains elevated patients can be referred for medical device based treatment for high blood pressure. One such treatment is known as Renal Denervation (RDN). RDN is a minimally invasive procedure The theme for this year is Know Your Numbers, and the WHL would like to encourage as many people as possible to get involved in May Measurement Month. In this initiative which started in 2017, volunteer manned screening sites will be setting up in a range of venues around the world to check the blood pressure of as many people as possible. Startlingly, it is estimated that specifically used to treat resistant hypertension. This procedure over half of all adults in Ireland over the age of 45 are living can be performed with multiple emerging technologies, including with high blood pressure. High blood pressure is a sign that radio-frequency, ultrasound, and chemical ablation methods to the heart and blood vessels are modify sympathetic nerves in the being overworked which in turn increases the risk of having a renal arteries, which decreases heart attack or a stroke. It can blood pressure. “Uncontrolled high blood pressure is a leading cause of heart attacks and stroke. Because there are no obvious symptoms, very often also lead to other conditions such as aneurysm, heart failure, problems with your vision and kidney failure. people assume it’s nothing to The number of adults aged 30-79 worry about. However, high blood years with hypertension or high blood pressure has increased pressure needs to be treated and managed so as to avoid a serious from 650 million to 1.28 billion in the last thirty years, according heart event or a catastrophic stroke,” says Professor Sharif.to the first comprehensive global analysis of trends in hypertension prevalence, detection, treatment and control, led by Imperial College London and the World Health Organization (WHO), and published in The Lancet. Nearly half these people did not know they had high blood pressure. The UK was one of the top ten countries with the lowest prevalence of high blood pressure among women in 2019 at 23 per cent while in Ireland this figure was 26.6 per cent. The study found that the country with the highest prevalence of high blood pressure in men was Paraguay at 62 per cent compared to 22 per cent in Eritrea which had the lowest prevalence among men. A team of consultants in Galway, including Professor Faisal Sharif, Consultant Cardiologist, are now leading the way in treating this problem at the Difficult to Treat Hypertension Clinic, based in Merlin Park Hospital, which assesses patients and investigates the reason for poor blood pressure control. Despite lifestyle changes and medication changes, if the blood pressure remains elevated patients can be referred for medical device based treatment for high blood pressure. One such treatment is known as Renal Denervation (RDN). RDN is a minimally invasive procedure specifically used to treat resistant hypertension. This procedure can be performed with multiple emerging technologies, including radio-frequency, ultrasound, and chemical ablation methods to modify sympathetic nerves in the renal arteries, which decreases blood pressure. “Uncontrolled high blood pressure is a leading cause of heart attacks and stroke. Because there are no obvious symptoms, very often people assume it’s nothing to worry about. However, high blood pressure needs to be treated and managed so as to avoid a serious heart event or a catastrophic stroke,” says Professor Sharif.

Radiotherapeutic Management of Breast Cancer Brain Metastases

Brain metastases have a significant impact on quality of life and clinical outcomes of patients with cancer. Although the incidence of brain metastases in patients with breast cancer is low, brain metastases are relatively common in patients with metastatic breast cancer, particularly in patients with human epidermal growth factor receptor 2 (HER2)-positive or triple-negative breast cancer (TNBC) subtype. Despite the extracranial efficacy of many systemic therapies for patients with breast cancer, the bloodbrain barrier limits penetration of many systemic agents into the brain, and patients often experience intracranial progression. Therefore, radiation, in the form of whole brain radiotherapy (WBRT) or now more commonly stereotactic radiation, is the mainstay of the therapy for many patients with breast cancer and brain metastases. The management choice in patients with newly diagnosed brain metastases depends on number of brain metastasis, histological subtype, performance status, estimated prognosis, and extent of extracranial disease.

Thankfully brain radiation treatment has evolved over the past decade to lead to better outcomes for patients from a cancer perspective but also side effects and toxicities have been reduced. This article highlights two such developments.

Hippocampal avoidance Whole brain radiotherapy (HA-WBRT)

Whole-brain radiotherapy (WBRT) remains an important treatment modality in many patients with brain metastases because it reduces symptoms, improves intracranial control, and diminishes the chance of death. However, numerous patients experience cognitive deterioration after WBRT, which highlights concerns about the toxicity of WBRT. Preclinical and clinical studies have suggested that relatively low doses of radiation to neural stem cells within the subgranular zone of the hippocampus may contribute to radiotherapy (RT)–induced cognitive toxicity. A recent prospective multi-institutional randomized phase III trial investigated the role of WBRT with or without HA in patients with brain metastases. The use of HA during WBRT (Figure 1) was shown to effectively spare the neurocognitive damage from radiation to better preserve cognitive function and patientreported symptoms. This is fantastic news for patients with breast cancer and brain metastases. However even with the use of HA-WBRT, patients can still experience side effects. Thus, in patients with limited number of brain metastases stereotactic radiation is the preferred treatment course.

Stereotactic Radiation (SRS)

SRS is a novel radiation technique developed by a Swedish neurosurgeon, Lars Leksell, for lesions not amenable to surgical resection. SRS is a distinct discipline that utilises x-rays to inactivate defined target(s) in the head and spine without the need to make an incision. The target is identified by high-resolution imaging. SRS is mainly performed in a single session, using a mask and a stereotactic image guidance system, but can be conducted up to a maximum of five days. Brain metastases tend to be spherical with sharp demarcation from brain tissue. They are thus ideal for SRS because precision targeting can be easily generated using radiosurgical systems. Compared with resection, SRS is advantageous as it can treat surgically inaccessible lesions and multiple lesions. In general, asymptomatic patients with up to four lesions smaller than 4 cm are regarded as suitable for SRS. Local tumour control rates with SRS are consistently greater than 80%. Patients with newly diagnosed brain metastases may be treated with wholebrain radiotherapy alone versus whole-brain radiotherapy and SRS boost. In practice we tend to omit whole brain radiotherapy from this treatment paradigm due to enhanced toxicity, impact on quality of life and no improvement in overall survival. Whole brain radiotherapy is then reserved for future salvage use if required. SRS, unlike whole brain radiotherapy, has the additional advantage of being able to integrate with systemic treatment. Patients with brain metastasis treated with SRS can be treated without chemotherapy treatment breaks thus optimizing extracranial disease control in addition to their intracranial disease.

Despite the efficacy and improvements radiation delivery, many patients ultimately progress intracranially, both locally and in distant or uninvolved regions of the brain. The challenge and unanswered question for doctors and patients is how to sequence all the treatments, both local and systemic, to optimize the patient's quality of life and survival. This is an area of intense clinical research. The treatment of patients with breast cancer brain metastases should be discussed by a multidisciplinary team of breast cancer experts including a neurosurgeon, medical oncologist, and radiation oncologist. Important clinical features that help determine appropriate first line therapy include number of brain metastasis, resectability, breast cancer subtype, performance status, and the presence of extracranial disease.

Written by Dr Daniel Cagney, Clinical Director, Radiation Oncology, Mater Private Hospital Dublin

Hippocampal avoidance Whole Brain Radiation (HA-WBRT)

LATEST HEALTH TECHNOLOGIES SHOWCASED

The Irish Digital Health Leadership Strategy Group (IDHLSG) together with the HSE Digital Transformation team, recently hosted a national conference in Tullamore bringing together key interested parties to discuss current initiatives and opportunities in relation to digital innovation. The conference, supported by key industry, academic and clinical leaders, exhibited a range of examples of digital health solutions, some of which are already demonstrating multiple benefits through their pilot initiatives around the country. Professor Martin Curley, Director, Digital Transformation and Open Innovation, HSE explains, “We are building on an ecosystem of over 50 Digital Living Labs located across hospital and community health services. Digital Health Living Labs provide test beds for new digital technologies through high impact projects. In collaboration with our partners, these innovative projects focus on enhanced benefits and services for patients in hospitals and local communities as well as delivering value for money and providing real world evidence of the value of innovation and technology. “A key aim of the technologies is to keep people safe and well in their homes for as long as possible, and in parallel use digital technologies to improve patient flow from hospital to a community setting and their home.” A number of examples from the Digital Living Labs will be demonstrated at the conference, these include:

• A Remote Heart Failure

Monitoring Solution in conjunction with Centric

Healthcare and Roche, which could reduce hospitalisation rates and improve clinical review rates.

• A unique integrated rapid screen,

Personal Electronic Health

Record and wellness device and app, which proactively identifies risk and provides tools to help people manage their wellness and health. Early detection of disease and early intervention can dramatically improve patient quality of life and longevity.

Partners in this living lab include

Careplus Pharmacies, Google,

Fitbit, Full Health M. • A Remote Respiratory

Monitoring Solution which allow patients to remain in their homes instead of hospitalisation, deployed in Cork University

Hospital, Beaumont Hospital, and the Mater Hospital. • A mobile X-Ray solution (Mobile

Medical Devices) which brings the X-Ray machine to a nursing home or an elderly patient’s home after a fall. Transfers to hospital reduced by 88%, improving quality of life and reducing costs. • An automated respiratory monitoring solution has been deployed to 23 hospitals across the country providing >10 hours’ notice of a patient desaturation.

The same solution is now being tested with COPD patients in the community in Donegal. • A falls detection systems allows a fall of an elderly person to be detected in real time and a conversation to be initiated with the person within 5 seconds through a smart watch and their GPS coordinates to be dispatched in real-time if necessary for emergency services – deployed in Wexford in association with Wexford

County Council, HSE and

Tunstall. Proactive Monitoring of a patients’ vital signs allows early intervention for chronic disease exacerbations.

LATE-BREAKING PHASE 3 DATA ON DUPIXENT® (DUPILUMAB)

Detailed positive results from the Phase 3 PRIME2 trial evaluating the safety and efficacy of Dupixent® (dupilumab) was presented in a late-breaking session at the American Academy of Dermatology (AAD) 2022 Annual Meeting. The companies previously announced topline results from PRIME2 and a second trial called PRIME investigating the use of Dupixent in adults with uncontrolled prurigo nodularis. In both trials, Dupixent significantly reduced itch and skin lesions compared to placebo. In total, 21 scientific abstracts evaluating the safety and efficacy of Dupixent in patients with atopic dermatitis in different age groups, as well as investigational indications – prurigo nodularis and chronic spontaneous urticaria – will be presented at the congress. The randomized, placebocontrolled PRIME2 trial met primary and all key secondary endpoints with data presented at AAD 2022 showing: • 37% of Dupixent patients experienced a clinically meaningful reduction in itch from baseline compared to 22% of placebo patients (p=0.0216) at week 12, the primary endpoint. • Nearly three times as many

Dupixent patients experienced a clinically meaningful reduction in itch from baseline at week 24: 58% of Dupixent patients compared to 20% of placebo patients (p<0.0001). • Nearly three times as many

Dupixent patients achieved clear or almost clear skin at week 24: 45% of Dupixent patients compared to 16% of placebo patients (p<0.0001). The safety results of the trial were generally consistent with the known safety profile of Dupixent in its approved dermatology indications. For the 24-week treatment period, overall rates of adverse events were generally similar between Dupixent and placebo groups (57% Dupixent, 51% placebo). Adverse events that were more commonly (>5%) observed with Dupixent were herpes viral infections (7% Dupixent, 0% placebo). A lower rate of skin infections were observed with Dupixent (5% Dupixent, 9% placebo). Additionally, 3% of Dupixent patients and 30% of placebo patients discontinued prior to week 24.

Results from the confirmatory PRIME trial will be presented at an upcoming medical congress. Data from both trials will form the basis of regulatory submissions around the world for Dupixent in prurigo nodularis, which are planned to begin in the first half of 2022. The potential use of Dupixent in prurigo nodularis is currently under clinical development, and the safety and efficacy have not been fully evaluated by any regulatory authority.

NEW DIAGNOSTIC IMAGING SUITE

laya healthcare has announced the opening of a brand-new, fully functioning Diagnostic Imaging Suite, which will provide MRI, X-ray and Dexa scanning services at its Health and Wellbeing Clinic in Galway. Available to both laya healthcare members and non-members the new diagnostic imaging services are helping to meet the increasing demand for healthcare services and provide access within a community-based setting. The additional services announcement also ties in with Laya Health and Wellbeing Clinic in Galway marking its second anniversary, which has seen over 8,000 people use the Clinic’s services since opening (1,000 of which were non-members), with footfall increasing by 58% year-on-year. With an easy referral pathway, the new addition to the diagnostic imaging services adds to the Health and Wellbeing Clinic’s existing portfolio of advanced services, which includes urgent care with treatment typically within one hour as well as Heartbeat cardiac screenings for members over the age of 12. It also makes access to healthcare experts for laya members and the general public, much easier and quicker. There are currently three Laya Health and Wellbeing Clinics open across Ireland – Cherrywood, Dublin; Limerick; and Galway. By 2023, laya healthcare plans to have a network of five Clinics offering urgent care, wellbeing, and advanced healthcare services to patients nationwide. Since the first Clinic opened, over 52,000 people – of whom 15% were non laya healthcare members – have been seen across the network of three Clinics.

The Laya Health and Wellbeing Clinics are open 365 days a year from 10am to 10pm providing urgent care services within one hour for adults and children as young as 12 months. Video consultations for minor illnesses are also available.

Dr Jose Miguel Flores, radiographer Virdea Santos, Alliance Medical regional manager David Dooley, staff nurse Paul Grealish, and Site Manager Leanne O’Shea at the launch