Peritoneal malignancy is diagnosed in approximately 500 patients annually in Ireland. The incidence is increasing, having approximately doubled in the last decade. The vast majority of cases arise as a result of metastatic spread from intra-abdominal primary cancer (colorectal, appendiceal, ovarian, gastric, pancreatic).
Approximately 10 per cent of cases are the result of metastatic spread from extra-abdominal cancer, in particular breast cancer, lung cancer and malignant melanoma. Primary peritoneal malignancy (eg, peritoneal mesothelioma and primary peritoneal cancer) is extremely rare, affecting only a hand-ful of patients annually. Symptoms are difficult to manage and typically include: Abdominal distension, anorexia, vomiting and abdominal pain due to the progressive intra-abdominal tumour burden and secondary ascites. Once established, peritoneal malignancy is invariably a fatal diagnosis, with median survival in Ireland of six months (source National Cancer Registry Ireland (NCRI), 2012). Patients with metastatic spread to the peritoneum have worse outcomes than their counterparts with stage IV disease not involving the peritoneum.
Palliative chemotherapy has traditionally been the mainstay of treatment. Supporting data in this setting is however limited, as few studies have been specifically performed in patients with stage IV disease involving the peritoneum. Surgery, termed cytoreduction, may be considered in highly-selected patients with resectable disease. Cytoreductive surgery (CRS) may require all or a combination of total abdomino-pelvic peritonectomy, greater and lesser omentectomy, colectomy, rectal resection, small bowel resection, hysterectomy with bilateral salpingo-oophorectomy, cholecystectomy, splenectomy, liver capsulectomy and occasionally gastrectomy.
This surgery is performed with the intention of removing all macroscopic tumour and the surgical cytoreduction may be augmented by the delivery of intra-peritoneal chemotherapy (typically mitomycin C or oxaliplatin as a single dose for 60-to-90 minutes) at the end of the procedure, with the aim of eradicating any residual microscopic tumour. The chemotherapy is typically heated to 41-to-43°C in order to improve cytotoxicity and increase chemopenetration, hence the term ‘HIPEC’ (heated intra-peritoneal chemotherapy). The entire procedure can take up to 10 hours and is typically followed by a two-week inpatient stay. Multidisciplinary input is required, including a team of surgeons from different disciplines, critical care, radiology, and the allied disciplines including nursing, dietetics and physiotherapy. With evolving international experience, the risk of major morbidity after CRS HIPEC has reduced significantly to approximately 4-to-8 per cent, with a postoperative mortality rate of less than 1 per cent. After surgery, patients typically require three months or more to make a complete recovery. Approximately 50 patients in Ireland are suitable for and undergo CRS combined with HIPEC annually at the Mater University Hospital, Dublin. The vast majority of these patients have either colorectal cancer peritoneal metastases or a condition known as pseudomyxoma peritonei (PMP). Peritoneal mesothelioma is a very rare indication for CRS HIPEC, while the approach is not as yet established in patients with peritoneal spread from upper gastrointestinal or extra-abdominal cancer.
Colorectal cancer peritoneal metastases (CRC PM)
Peritoneal metastases are seen in approximately 5 per cent of patients with colorectal cancer at initial diagnosis (synchronous disease), while a further 10 per cent subsequently develop metachronous peritoneal spread. Surgery may be considered in medically-fit patients with fully-resectable disease of low-to-moderate volume, as determined by a scoring system known as the peritoneal carcinomatosis index (PCI).
This system divides the abdomen into 13 regions and allocates a score of 0-3 to each region proportionate to its disease volume. The PCI may be estimated using a combination of imaging (contrast-enhanced CT and in selected cases, diffusion-weighted MRI) and staging laparoscopy but ultimately, can only be reliably determined at exploratory laparotomy.
Disease progression during systemic therapy, the presence of non-peritoneal distant metastases, multi-focal small bowel involvement, biliary and/or ureteric obstruction, signet ring features and PCI greater than 20 are considered relative contraindications to surgery. Patients are selected following multidisciplinary discussion with input from surgeons, oncologists, radiologists and pathologists. Based on current criteria, approximately 40 per cent of patients referred to a peritoneal malignancy centre with CRC PM will be candidates for CRS. The evidence supporting this multimodal approach first came from a randomised, controlled trial performed by Verwaal in the Netherlands and published in 2003. Patients in the treatment arm underwent CRS with HIPEC, followed by systemic chemotherapy, while those in the control arm received systemic chemotherapy, with or without palliative surgery. In the CRS HIPEC group, median survival was 22 months, compared to 13 months in patients randomised to systemic chemotherapy only.
In the same study, median survival in the subgroup of patients who had a complete cytoreduction (all tumour removed) was 48 months (45 per cent five-year survival), emphasising the importance of selecting those patients with fully-resectable disease. Multiple observational studies have since been performed, including large national cohorts, and have reported median survival following CRS HIPEC in selected patients of up 47 months. The best available data suggest a cure rate (disease-free at five years) of approximately 15 per cent. The majority of patients will, however, relapse and of those who do, one-third will recur in the peritoneum, one-third in non-peritoneal distant organs, and one-third at both sites. Reported survival in patients treated with modern systemic chemotherapy only is in the order of 24 months, however the lack of recent controlled studies should be emphasised.
The long-awaited PRODIGE 7 study was reported at ASCO in June of this year. This multi-centre, randomised, controlled trial compared CRS alone to CRS with HIPEC (oxaliplatin-based) in patients with resectable colorectal peritoneal metastases. Nearly all patients also received systemic chemotherapy.
Median overall survival in both arms was excellent (approximately 42 months), however, there was no additional survival benefit with the addition of HIPEC to cytoreductive surgery. The subgroup analysis suggested a potential gain from HIPEC in those patients with intermediate volume disease, as scored by the PCI system. Overall, the findings support a multimodal approach of systemic chemotherapy and CRS, combined with a more selected and tailored use of HIPEC in patients with CRC PM.
Pseudomyxoma peritonei (PMP), commonly referred to as ‘jelly-belly’, is a rare condition characterised by the formation of mucinous tumour plaques throughout the abdominal cavity, which produce large volumes of gelatinous ascites. The primary source is most commonly a mucinous tumour of the appendix, from which cells were shed during asymptomatic perforation. Over time, these cells, transported by normal physiological movement of peritoneal fluid, deposit and replicate at predictable sites, including the sub-diaphragmatic spaces, the omentum, the pelvic cul-de-sac, and the ovaries in females. While invasive features are unusual, a spectrum of low-to-high cytological grade is seen. Elevation in tumour markers (CEA, Ca 19-9, Ca125) is a predicator of a more aggressive phenotype and worse prognosis. Traditionally, the incidence of PMP was thought to be approximately one/million/year, however the Mater experience would suggest that the true rate is at least four times higher.
A low-grade mucinous tumour of the appendix is a relatively common incidental finding following appendicectomy performed for acute appendicitis. A subset of these patients are at future risk of developing PMP and as a precaution, should be kept under surveillance with regular clinical assessment and imaging.
Once established, PMP is invariably a progressive and fatal condition which responds poorly to systemic therapy. It was for this reason that Sugarbaker pioneered surgical approaches to PMP, and the concept of CRS HIPEC was born. The largest single-centre experience stems from Basingstoke, UK, where more than 1,000 patients with PMP have undergone CRS HIPEC. Their results show that after complete cytoreduction (all tumour resected), approximately 80 per cent of patients will be alive and disease-free at 10 years. Patients with unresectable disease may also benefit from surgery in the form of maximal tumour debulking, combined with HIPEC.
Future directions in peritoneal malignancy
In recent years, there has been a significant increase internationally in the number of centres offering CRS HIPEC, with a corresponding increase in the number of patients undergoing surgical treatment for peritoneal malignancy. This development is to be welcomed and should act as an impetus for increased focus on improving outcomes in patients with peritoneal cancer. There is, however, also an onus on the peritoneal malignancy community to standardise approaches and generate robust data to support patient selection for surgery and document outcomes.
Patient selection for CRS HIPEC remains a crucial and challenging area. For certain conditions, such as PMP, the decision to proceed to surgery is often reasonably straightforward. For patients with CRC PM, on the other hand, the decision is often difficult. Current criteria are a useful means of identifying those patients who might benefit from surgery, however our knowledge of disease behaviour in this heterogenous group is still in its infancy. Improved understanding of the histopathological and molecular subtypes of both colorectal cancer and the corresponding peritoneal disease should in time allow us to better tailor treatment for patients with CRC PM and select those who are most likely to benefit from CRS, with or without HIPEC. It would also now seem timely to re-examine the relative merits of systemic chemotherapy and surgery (with or without HIPEC) in the management of CRC PM by repeating the original Dutch study using modern agents and current selection criteria.
The results of a number of randomised, controlled trials are eagerly awaited and have the potential to significantly influence practice, particularly for CRC PM. The full report from PRODIGE 7 is awaited and will likely lead to a more selected use of HIPEC in patients undergoing CRS for colorectal peritoneal metastases. Other randomised trials have examined the application of CRS HIPEC as a prophylactic intervention in patients at high risk of developing peritoneal metastases (eg, T4 right colon cancer). These studies have finished recruiting and results are awaited. The role of intensive systemic treatment aimed at down-staging patients with a large tumour burden with a view to making them candidates for surgery has also been examined and again, results are awaited.
The future may bring an expansion beyond the current established indications for CRS HIPEC. For example, recently-published randomised data has shown a survival benefit to CRS HIPEC for patients with stage III epithelial ovarian cancer. In this study, and unlike PRODIGE 7, the addition of (cisplatin-based) HIPEC to CRS was found to significantly improve survival when compared to CRS alone (median overall survival, 45.7 vs 33.9 months). Many of these and other issues will be debated at the 11th International Workshop on Peritoneal Surface Malignancy to be held in Paris later this year.
The Hepatitis C Conference 2018, which was supported by Gilead, was held under the theme ‘Hidden Disease: The Future of Hepatitis C Treatment in Community and Primary Care’. The Irish College of General Practitioners (ICGP) convened a distinguished panel of national and international speakers to share their expertise and discuss treatment advances with a packed auditorium.
The meeting was attended by Minister of State with Responsibility for Health Promotion and the National Drugs Strategy, Ms Catherine Byrne. She told the attendees that Ireland is seeing “the tip of the iceberg” in terms of treating “hidden diseases”. Ms Byrne also stressed the importance of treating hepatitis C in the community, based on the fact that “70 per cent of hep C sufferers acquire the virus by injecting drugs and often, these people do not engage with hospital services”.
The keynote address was delivered by Prof John Dillon, who spoke on the theme of ‘Models of HCV Screening and Treatment: An Evidence-Based International Perspective’.
Prof Dillon, who is Professor of Hepatology and Gastroenterology at Dundee University, UK, provided an outline of the screening model in Dundee, which involves a flexible and creative approach. “There is no ‘one-size-fits-all’ approach to this; you have to choose the screening model that’s right for your area,” he told the Conference.
“At every step in a care pathway, you lose people [from treatment],” he explained, “so the less steps there are, the less people you lose.” He provided an overview of the WHO target to make hepatitis C a disease of the past by the year 2030 and explained that there are currently only eight nations “who are even close to being on track for that, and the UK and Ireland are not among those nations”.
He also showed figures from his area in Tayside that emphasised the need for early treatment to reduce a wide range of mortalities that result from hepatitis C.
Prof Dillon gave an overview of statistics to show dramatic improvements in screening efficiency and treatment outcomes: “If we can do it in our area, with our geography and resources, anyone can do it,” he said. “It’s about detailing your plans and then addressing how you actually implement them,” he concluded.
The next section of the conference was dedicated to the theme of ‘Epidemiology, Screening and Treatment — The Irish Context’ and heard from Ms Michele Tait, Manager of the National Hepatitis C Treatment Programme. Ms Tait delivered a presentation on ‘Update on Plans for HCV Treatment in Ireland for 2018’, and explained that there has been difficulty in obtaining hard, accurate data on the prevalence of the condition.
Ms Tait outlined the National Hepatitis C Strategy, which was published in 2012, noting that the treatments available now were not available at that time. Ms Tait added that a set of clinical treatment guidelines have been produced and the hope is to integrate treatment in other facilities outside the hospital setting.
She also pointed out that data protection legislation presents difficulties in terms of collating data but efforts are ongoing to build a full, national disease registry. More than 2,000 people have been successfully treated since 2015, she added.
Pilot programmes are in operation and meetings are being held with prison services representatives to expand care in that setting, said Ms Tait.
Point of care
The meeting also heard from Dr Margaret Bourke, GP Co-Ordinator in Addiction, CHO7, who addressed the meeting on the subject of the ‘HCV Community Treatment Pilot’ and described her “new vision for HCV treatment, which would involve “community-based general practice, central service and prisons, all linking to provide HCV treatment at the point of care”.
Speaking about stigma, Dr Bourke explained that in her practice, the term ‘liver nurse’ is used, rather than the title ‘hepatitis nurse’, as this carries less stigma from the patients’ point of view.
She told the Conference: “The WHO recommends reducing the pool of infection by treating localised areas to contain infection. With this in mind, we are now investigating the level of PCR-positive patients in three Dublin 8 clinics with a view to treating them at the Castle Street pilot site, possibly in a joint venture with their addiction treatment clinic.”
The conference then heard from Prof Walter Cullen, Professor of Urban General Practice in University College Dublin, on the topic of ‘HCV Disease in Irish General Practice’. Prof Cullen noted that when GPs receive resources and support, there is a more than 2.5-fold increase in screening rates for HCV, as well as a significant increase in the numbers of patients referred to hospital for treatment. He also cited the current improved access to direct-acting antivirals and their advantages over older treatment regimens — but reiterated that stigma still exists around hepatitis C, which deters many patients from seeking treatment.
Dr Cullen also presented research to illustrate how a strong relationship between a patient and their healthcare provider improves treatment compliance and emphasised the importance of shared-care models in screening, prevention and treatment.
He explained that his team in UCD has been working with several hospitals in the Mater Hospital, Dublin, catchment area and a follow-up evaluation of 35 patients referred to hospital services is planned for spring 2018. “What we do know is that general practice has a major role to play in addressing hepatitis C,” said Prof Cullen, who also noted that nurse support is vital in ensuring that patients attend their appointments and comply with treatments.
“We need to resource primary care,” he said. “In the new GP contract, we need to include substance misuse in general as well as mental health and we need to find ways to support and incentivise GPs to systematically and routinely address these issues. These have been a ‘Cinderella aspect’ of general practice in the past.
“But we also need to resource secondary care and make sure that acute hospitals have more doctors, more nurses, more machines, more pharmacists and peer-support workers, all to support the patients who need assessments in those units.”
The meeting also heard from Dr Magdalena Harris, Associate Professor in the Sociology of Health at the London School of Hygiene and Tropical Medicine, UK, on the topic of ‘Peer Involvement in HCV Management: An International Perspective’. She stated: “As we have heard today, direct-acting antivirals can transform hepatitis C treatment access, primarily for the most marginalised groups, and there is an important role for primary care in that regard.”
She gave an overview of peer intervention programmes put in place in three drug treatment centres in the UK and also referred to the Australian model of care for those with HCV, whereby direct-acting antiviral therapy is fully reimbursable and there are no restrictions in terms of liver disease staging or substance misuse. This has resulted in the removal of many barriers to treatment for these marginalised groups in the community, she said.
The need for trust is heightened among very vulnerable patients, which is compounded by a “power imbalance” that occurs between the patient and doctor in a clinical setting. This is where peers can be instrumental, Dr Harris added.
She outlined a study comparing two models of peer involvement — a community-controlled model, and a service-generated model.
A broad conclusion was made that larger numbers of patients could be engaged by the service-generated model, but the community-based model was shown to create strong levels of trust between the peer and the patient.
Date of preparation: May 2018
Repeat electroencephalography (EEGs) are overused and uncommonly result in a change in electroclinical diagnosis, the Irish Neurological Association annual meeting heard. Speaking on behalf of members of the Department of Clinical Neurophysiology and Neurology at Our Lady’s Children’s Hospital, Crumlin, Ms Aisling McCarthy presented a study titled ‘Understanding the Value of Repeat EEG Testing in Children’.
Ms McCarthy, who was soon to graduate from her medical undergraduate course, explained that the research was a prospective, five-year outpatient study running from 2012 to 2017. The study analysed 4,162 consecutive outpatient EEGs and found that sleep was achieved in more than 93 per cent of cases and repeat tests were identified.
Ms Aisling McCarthy
“The results of this study can be considered based on departmental activity and patient experience,” she told members of the audience.
Ms McCarthy added that one-in-four EEG studies carried out was a duplicate study and one-in-six patients attending for an EEG will have multiple EEG studies.
The primary role of EEG in children is the investigation of seizures, where it can assist in both the diagnosis and classification of different epileptic syndromes.
While EEG is useful in assessing childhood seizures, Ms McCarthy told the meeting that the team identified a number of key observations during their research. There is a high volume of requests for repeat EEGs, but most do not result in material diagnostic change or treatment modification. Furthermore, most of these repeat tests are requested without specifying any particular question. Indications for repeating routine EEGs in children are also not clearly defined in international guidelines.
“This can lead to overuse of the resource, wasted time for the patient and parent and health professionals involved. And most importantly, delayed access to EEG for those who need it more urgently,” she said.
While NICE guidelines recommend that early EEG be performed within six weeks of referral, the majority of centres in Ireland struggle to meet this recommendation.
“Seeing that there is rarely a diagnostic change on a repeat EEG, it is important to question the utility of repeat investigation, she added.
Citing Camfield et al’s 2000 study ‘How Often Does Routine Paediatric EEG Have an Important Unexpected Result?’, she said that if a test’s result is predictable, then the test may be unnecessary. She also highlighted an example of a repeat request where the EEG was asked to provide information that belongs in the collateral history.
But she stressed it is important to acknowledge that repeating an EEG is justifiable in certain cases where a change in the underlying diagnosis is not expected.
The aim of the study was to quantify the practice and pattern of repeat EEG requests and to analyse the outcomes of follow-up EEGs in relation to prior EEG study. The primary outcome measure was to identify how often a significant outcome change takes place.
“This was defined as a shift from an abnormal code or diagnosis to normal and vice-versa. We tried to identify factors that might predict when repeat EEG is most likely to produce change and thus would be of most clinical value,” she said. The team also tried to identify factors that might predict when repeat EEG is more likely to produce change.
Repeated studies were identified and these EEGs were outcome-coded by a single consultant reporter in a nine-point scheme that identified normal studies, non-epileptiform and epileptiform abnormal studies, and EEGs of uncertain clinical significance.
“A further subdivision of this scale identified detailed electro-clinical correlations, including infantile spasm,” she said. “If you are working in the neurophysiology lab, one-in-four of the EEGs you perform are duplicates. If you are a patient in the waiting room, you have a one-in-six chance of returning for a repeat exam.
“If you do return for a further study, 85 per cent of you will have one repeat study, or two in total.”
The most frequent interval for the repeated EEG is within the first six months of the previous one. The median interval is 12 months and the mean is 15 months.
In the majority of cases, the outcomes do not change with both focal and generalised epilepsy. She also highlighted the low rate of normalisation for juvenile myoclonic epilepsy (JME).
“There is an important clinical point here. Transient EEG normalisation can occur in JME; however, JME is regarded as a life-long or enduring seizure liability. So EEG normalisation is materially irrelevant, because it does not and should not alter the way epilepsy is managed in childhood.”
In terms of the normal studies (‘normal with certainty’, the other being ‘normal in all probability’), the key finding was that “definitely normal EEGs are highly likely to stay the same in repeat testing, whereas EEGs which showed a minor change but were otherwise within normal limits are more likely to become abnormal,” Ms McCarthy said. “If an EEG that is within normal limits becomes abnormal, it is most likely to show an epileptiform abnormality.”
In terms of the overall value of repeating an outpatient EEG, the study looked at 555 duplicated EEGs. Only 15 per cent resulted in a consecutive change from normal to abnormal code, or vice-versa. There was an 11 per cent change from normal to abnormal and a 16 per cent change from abnormal to normal
“Based on this information, is it more helpful to repeat an EEG if the initial EEG is normal or abnormal?” she asked the audience. “It is more helpful to repeat a normal EEG, as chi square analysis shows that a higher proportion of normal EEGs become abnormal. In fact, a normal EEG is twice as likely to change to abnormal than vice-versa.”
Of the normal EEGs that become abnormal, the most common change is to an epileptiform abnormality.
“This provides justification for repeating EEG when suspicion of epilepsy is high, but the first EEG is normal.”
The overall rate of normalisation of repeat EEG in the time frame of this study is modest, at 24 per cent; broadly similar rates of normalisation are seen across the epilepsy groups, although the rates of normalisation are higher for focal rather than generalised epilepsy, as expected.
“We were surprised by the relatively high rates of normalisation of generalised infantile epilepsy, at 13 per cent. In general, these children have severe brain injuries and severe epilepsy, which persists into later childhood.”
Only one-in-five patients with a defined epilepsy syndrome normalised, whereas two-in-five with non-epileptiform or unclassifiable epileptiform abnormalities showed normalisation on EEG, the study found.
“This is significant as it calls into question the utility of the repeat EEGs in many of these defined epilepsy syndromes. If an EEG is unlikely to change, then it is unlikely to guide management or provide new information. Again, if the test is predictable, then the test may be unnecessary.”
The study also found that 38 per cent of non-epileptiform or unclassifiable epileptic abnormalities normalise, whereas only 20 per cent of specified epileptic abnormalities normalise.
The study concluded that EEG is a valuable resource in the investigation of childhood epilepsy but guidelines on indications for repeat EEG are lacking, which is contributing to EEG overuse.
It is more useful to repeat a normal EEG than an abnormal EEG, especially when the suspicion is high. Abnormal EEGs normalise less frequently than normal EEGs, with the lowest rates of normalisation seen in infantile spasm and JME.
“Based on this study, we found more utility in repeating a normal EEG when the suspicion of epilepsy is high, compared to an abnormal EEG, as a normal EEG is twice as likely to change to abnormal than vice-versa,” Ms McCarthy said.
“The take-home message of this study is, when requesting EEG, recognise that the rates of significant change are low and that you should have a clear clinical question to be answered.”
She hoped that the study would lead to more research on the indications for repeat EEGs on children and contribute to the development of guidelines on appropriate EEG referral.
During the questions and answers section, it was asked why repeat tests for abnormal results were being ordered.
“A lot of the time, people are referring in to show that the EEG is normal if the patient is seizure-free for two years and off medication, and that shouldn’t happen. And that’s why we think there needs to be guidelines on this to stop that kind of inappropriate referral burdening the service.”
It was also mentioned during the Q&A that patients with IGE [idiopathic generalised epilepsy] and whose symptoms may be subtle could be a reason to repeat an EEG in someone where the diagnosis is established.
Biologics an exciting new option in uveitis
Rheumatology and ophthalmology should improve their interdisciplinary working relationships to improve patient outcomes for those with crossover conditions, the Irish College of Ophthalmologists (ICO) 2018 Annual Conference heard.
Speaking during the dedicated uveitis symposium was Dr Millicent Stone, a Consultant Rheumatologist in the Department of Ophthalmology, Guys and St Thomas Hospital, UK, who was recruited in 2014 to create a programme to support patients with inflammatory eye diseases who require immunosuppressant drugs, the first of its kind in the UK.
Not only may uveitis lead to loss of sight, it may be associated with loss of life because of underlying life-threatening systemic diseases that drive the inflammation in the eye, Dr Stone explained.
She noted that biologic agents have revolutionised the care of rheumatoloid conditions such as rheumatoid arthritis, ankylosing spondylitis and Behcet’s disease since their introduction to clinical care over two decades ago.
The treatment paradigm and approach to management of inflammatory eye diseases is now undergoing “a revolutionary change” because of the recent approval of adalimumab, an anti-TNF for use in adult- and childhood-onset uveitis, Dr Stone said.
She outlined a number of case examples where systemic disease was an important driver behind sight-threatening inflammatory eye disease and how biologic agents may help dramatically.
“Gone are the days, for instance, when our rheumatoid patients end up with a life in a wheelchair. They can live full, normal, healthy, productive lives when these drugs are used in the right context. The biologic drugs achieve this for our patients by reducing disease activity, preventing damage and improving quality of life, and now perhaps gone will be the days when people lose their sight from uveitis.”
She also discussed the benefits and learning points for ophthalmologists when setting-up their own biologic services, particularly rapid access to services like rheumatology, who are familiar with dealing with complex cases and potentially toxic drugs.
“Together with new drugs, novel technologies and a more effective multidisciplinary way of working, we can all greatly enhance how we manage our uveitis patients with systemic disease and improve their outcomes,” she said.
Speaking to the Medical Independent (MI), Dr Stone said: “As a rheumatologist, make sure you ask the patient if they have any visual problem or any blurred vision, or does the light affect their eyes. As an ophthalmologist, it is always worthwhile asking them about back pain.”
Dr Stone carried out a survey a number of years ago on 300-plus ophthalmology patients to figure out if they had inflammatory back pain, with a useful questionnaire that could help trigger earlier referral.
“So awareness is the key component here and thinking about associated diagnosis and being willing to refer onwards and develop good working relationships with each other, ” she told MI.
Uveitis third-leading cause of blindness in the modern world
Uveitis is the third-leading cause of blindness in the modern world, with a disproportionate socioeconomic impact, as it primarily affects the working age population, the 2018 ICO Annual Conference heard.
Dr Dara Kilmartin, Consultant Ophthalmologist, Royal Victoria Eye and Ear Hospital, and immediate past Honorary Secretary of the International Uveitis Study Group, the oldest international society of uveitis specialists, chaired a dedicated session on uveitis and gave a comprehensive talk on the latest management approaches to the disease.
Once diagnosed (after answering the infectious versus not infectious or masquerade questions), uveitis treatment usually involves some form of local or systemic therapy, he said.
“We’ve been using oral steroids now for over 60 years and they are the main way of controlling sight-threatening anterior uveitis. For about 30 years, we’ve been using systemic immunosuppressive therapy (IST) of all classes,” Dr Kilmartin stated. He noted that there has been a move from using cyclosporine to tacrolimus, while intravitreal IST like methotrexate or sirolimus are promising, but there is a fear of alkylating agents due to their DNA-altering effects, and they are used in a stepladder approach to minimise the side-effects.
As IST can have significant toxic side-effects, it is hoped that the advent of biologic therapies and more targeted treatment will mean less risk for patients, though real-world efficacy and cost are current issues.
Local intravitreal therapy has many advantages, including rapid and targeted delivery and avoidance of systemic side-effects, but is restricted to uniocular disease or marked asymmetry, which is uncommon, he noted, while intraocular implants do not have superior visual outcomes versus systemic treatment and have more adverse side-effects, according to the latest studies.
Dr Kilmartin also highlighted the value of therapeutic vitrectomy, particular in paediatric patients, for suitable uveitis cases.
The uveitis session also heard how a highly malignant but rare form of lymphoma can be mistakenly diagnosed as uveitis, representing a major diagnostic and therapeutic challenge.
Prof Conor Murphy, Professor of Ophthalmology, RCSI, spoke about primary intraocular lymphoma, a very rare intraocular malignancy that masquerades as autoimmune uveitis, and he outlined a detailed case study, which highlighted the difficulty of diagnosing and treating this disease.
This form of lymphoma represents a significant diagnostic challenge for the ophthalmologist and pathologist, as it requires cytological analysis of ocular fluid samples of limited size and cellularity, he explained. A lack of prospective studies to identify optimum therapy adds further complexity to this disease, which frequently spreads to the central nervous system (CNS), giving it a poor long-term prognosis, which is not helped by delays in diagnosis, Prof Murphy added.
Notable symptoms to watch out for include behavioural and cognitive changes and a contrast MRI should be carried out, he said. Once diagnosed, a key management goal is eradication of the reservoir of malignant cells in the eye that can lead to fatal CNS dissemination and to preserve vision.
Treatment options include orbital and ocular radiotherapy, intravitreal methotrexate or rituximab, and high-dose chemotherapy with autologous stem cell Tx, but efficacy versus toxicity must be carefully considered and multidisciplinary team management is vital, “although contrasting views exist, even among experts,” Prof Murphy noted.
Cataract surgery best value for quality-of-life
Cataract surgery is the best surgical value for improving quality-of-life for patients, but this so-called ‘simple operation’ is down to extensive training, experience and teamwork, according to the immediate past-President of the American Academy of Ophthalmology.
Dr Cynthia Bradford, Professor of Ophthalmology at the Dean A McGee Eye Institute/Department of Ophthalmology at the University of Oklahoma Health Sciences Centre gave the annual Mooney Lecture at this year’s 2018 ICO Annual Conference, on the challenges of cataract surgery.
“There have been remarkable advances in cataract surgery and the public perception is often that the procedure itself is ‘nothing’. Do we as surgeons trivialise the procedure or are ophthalmologists victims of their own success?” Dr Bradford asked.
Dr Cynthia Bradford
She noted that making cataract surgery so successful requires years of training, likening the process to athletic training.
In contrast to professional athletes, however, every surgery is expected to be a ‘win’. In order to have a win, the surgeon must understand the patient’s needs, what is possible to achieve and offer the spectrum of options available to achieve their goals, Dr Bradford outlined.
There are a multitude of possible complicating factors, with some patients having several complex problems. It takes teamwork with operating staff and anaesthesia to give every patient a win, she commented, showing the audience video clips of what surgical complications can occur.
Dr Bradford also stressed the importance of listening to the patient and finding out what they want the outcome of their eye surgery to be.
“It is important to know all about the patient. We have to know what really bothers the patient about their vision. In other words, if they have surgery, what do they want improved?”
Cataracts were a hot topic at the conference, following the revelation that the average wait for public cataract surgery across the country is now 28 months — and up to five years in some parts of the country — according to a survey carried out by the Association of Optometrists (AOI) and released on the opening day of the ICO conference.
The ICO told the Medical Independent (MI) that it has been working and collaborating with the HSE to “provide our medical expertise and proposed solutions required to tackle the cataract waiting times for patients. There needs to be an investment in ophthalmology services and an increase in theatre capacity to facilitate the patient numbers and demands for this procedure.”
Currently, approximately 12,000 cataract operations are carried out by the HSE annually; nowhere near enough to meet increasing demand.
Speaking to MI, HSE Clinical Lead for Ophthalmology Prof William Power said that dedicated cataract theatres are key to helping reduce cataract waiting lists.
He confirmed that a new dedicated cataract theatre is due to open in Nenagh during the summer, where ophthalmic surgeons from Limerick will rotate on a daily basis, with a new modular, dedicated cataract theatre also planned for Waterford.
These dedicated theatres should reduce cataract operation waiting times in the mid west and south east, which have particularly long waiting lists, he said.
Prof Power, an ophthalmic surgeon in the Royal Victoria Eye and Ear Hospital (RVEEH), Dublin, and former President of the ICO, said surgeons can usually perform about one cataract procedure every 30 minutes in a dedicated theatre. The RVEEH opened one such theatre last year, which it had to fund itself, and now also treats public cataract patients waiting very long times through NTPF funding.
According to the latest NTPF public hospital waiting list figures, there were 11,070 people waiting for an ophthalmology inpatient procedure, while the outpatient waiting list was 40,928 at the end of April.
This does not capture the community waiting lists, where there are nearly another 30,000 wait listed, the ICO noted.
ICO frustrated at lack of roll-out of Primary Care Eye Services Review plan
The ICO has called on the HSE and Department of Health to expedite the roll-out of the Primary Care Eye Services Review Group Report.
Under the review, published last June after a number of delays, each HSE Community Health Organisation (CHO) will have a community ophthalmic physician-led primary care eye team, with dedicated premises and equipment, and staffed with optometrists, orthoptists, nurses and ophthalmic technicians.
New revenue funding of approximately €23 million is required to implement the recommendations of the report, which would see approximately 60 per cent of the current adult and paediatric outpatient ophthalmology work transition to the community. However, despite positive praise for the review by Minister for Health Simon Harris, only €1 million in extra funding was allocated to the roll-out of the report last year, with no extra funding given this year.
“It is of huge frustration to the College that despite the public approval by the Minister for Health last year to the implementation of the recommendations contained in the Primary Care Eye Services Review Group Report, the funding required has not been forthcoming,” said the ICO.
The College called on the HSE and the Minister “to ensure implementation of this approved care pathway by all stakeholders gets underway without further delay in the interest of patient care and ensuring patients are not losing vision unnecessarily. The ICO has made the proposed solutions… ”
In terms of investment, primary care centres are in situ around the country and require just the primary care eye teams to be put in place, the College pointed out.
HSE Clinical Lead for Ophthalmology Prof William Power also expressed disappointment that the plan did not receive any extra funding for 2018, after only receiving €1 million in 2017. He called on the HSE to prioritise rolling-out the plan, adding that dedicated cataract theatres are also key to reducing waiting lists.
“Ophthalmology is a small specialty but we have a huge number of patients. After death, patients fear blindness most,” ICO President Dr Alison Blake told MI at the ICO 2018 Annual Conference in Kilkenny, calling for the HSE to prioritise eye care and fund the roll-out of the plan.
Responding to questions from MI about the issue, HSE National Director of Quality Improvement Dr Philip Crowley said he hoped the plan would be implemented, and there had been some progress but “I will be asking why it is stalling”.
Burnout and uncertainty on workforce plans an issue for ophthalmologists
Risk of burnout, uncertainty about what the future holds, and the need for more investment in ophthalmology were the focus of a very lively session on the future of the specialty at this year’s ICO Annual Conference in Kilkenny.
Dr Cynthia Bradford, Professor of Ophthalmology, Dean McGee Eye Institute, Department of Ophthalmology, University of Oklahoma Health Sciences Centre, US, gave a sobering presentation on the impact and reasons for doctor burnout. Burnout can lead to depression and worse; around 400 doctors a year die by suicide in the US, she said.
Factors leading to medical burnout include lack of control over working conditions and decision-making, excessive workload pressures, chaotic and inefficient work environments, and onerous administration tasks, Dr Bradford outlined. The most susceptible doctors are dedicated, conscientious, responsible, motivated and often idealistic with perfectionist qualities, she said.
Burnout not only impacts doctors, it also impacts patients negatively in relation to the quality of care they receive, and leads to higher healthcare costs. Primary care doctors are worst affected by burnout in the US, Dr Bradford reported.
Concluding, she said a major culture change is needed to help better support doctors, which would include returning trust to doctors, with less-onerous regulation and administrative processes, and “letting them concentrate on the work only they can do”.
Some of Dr Bradford’s points were echoed by ICO Dean of Education and Ophthalmic Surgeon Miss Yvonne Delaney during her presentation on educating the doctors of tomorrow and building resilience.
“People love their job — they just want to be able to do it,” Miss Delaney told delegates. She discussed how training and performance assessments are being improved to be less about box-ticking, and made more reflective and thorough in relation to competence assessment.
Simulation is going to be an increasing feature of medical and surgical training in the future, including ophthalmology, but it has to be carefully developed and its value reviewed and assessed, as people can react very differently in real-life situations, she noted.
Miss Delaney also highlighted the importance of communication in medicine. Around 50-to-65 per cent of complaints against doctors are related to communication errors, and 10 per cent of health budgets are spent on error/negligence.
During his presentation in this session, HSE National Director of Quality Improvement Dr Philip Crowley noted that Ireland has one of the lowest numbers of ophthalmologists per head of population compared to other Western countries.
He acknowledged that ophthalmology waiting lists are high and more staff are needed but added that health funding is finite, so we must try and learn from those with less resources about how they maximise services and outcomes.
Dr Philip Crowley, HSE
Dr Crowley stressed it is vital that healthcare staff are involved in health service decision-making and that roles for clinical leaders are developed and supported. “While it is important to learn from our mistakes, we must also learn from excellence,” he commented.
UK Royal College of Ophthalmologists (RCO) President Mr Michael Burdon also spoke during this session and called for increased collaboration between the two countries, saying that the UK currently has similar issues regarding ophthalmology waiting lists, staff shortages and a lack of political interest in eye care.
The final speaker in this session was Dr Michael O’Rourke, SpR in Ophthalmology at the Royal Victoria Eye and Ear Hospital, Dublin.
He noted that while it is a very exciting time for ophthalmology in terms of ongoing treatment and diagnostic advances, being able to meet increasing patient expectations and needs is a challenge. Excessive HSE ophthalmology waiting lists, inadequate staffing and uncertainty over contracts, career pathways and the implementation of the Primary Care Eye Services Review Report must be addressed, he said, adding that the specialty must advocate for its patients, and the HSE must realise it is not all about money, but also about different ways of doing things.
Chairing the session, ICO President Dr Alison Blake said the speakers gave much food for thought and while there are many challenges, the future of ophthalmology is bright.
“I think, as Philip [Crowley] said, and as I commented, there will never be enough ‘health euro’. We have to find a way to make the most of what we have, to do the best for the most people. That is not easy,” she told the Medical Independent (MI).
100 year anniversary celebrated by ICO
The three-day ICO Annual Conference took place in Kilkenny from 16-18 May. Over 200 ophthalmologists from across the country gathered for the three-day meeting to hear the latest clinical and scientific updates and developments in the specialty from national and international eye experts.
2018 marks the 100th anniversary of the founding of the Irish Ophthalmological Society, the forerunner of the ICO, and the centenary and what the next 100 years will bring was a key theme of this year’s Annual Conference.
The College said the “centenary provided an opportune time for the College to reflect on how practice and training, both within the specialty and in the wider context of healthcare delivery, has evolved to where we are now and most importantly, to consider what the direction of travel will be over the coming years”.
“During the past 100 years, there have been many changes in ophthalmology, in Ireland and in Irish ophthalmology. This does not stop now; one of the qualities we have as doctors is how we adapt to change and incorporate it in our practice and care of patients, not impulsively, but with evidence and experience,” ICO President Dr Alison Blake said during her opening address to the conference.
Speaking to the Medical Independent (MI) about the challenges facing the specialty, including frustration at the stalled roll-out of the Primary Care Eye Services Review Report, Dr Blake also raised concern about treatment waiting times for aged-related macular degeneration (AMD) patients, who have to be injected with anti-VEGF agents promptly and at regular intervals to maximise vision outcomes.
Acknowledging the costs of anti-VEGF agents, which are in increasing demand, Dr Blake said how Ireland pays for expensive medicines has to be examined, and suggested negotiating European-wide deals could be a potential option to reduce costs.
The impact of Brexit on healthcare is also an issue that is being considered by the ICO. The UK RCO has reached out to the ICO to talk about working more closely together, and ensure future joint recognition of exams and training with that process now ongoing, Dr Blake said, as well as ensuring that the UK remains an option for employment for Irish doctors.
The research winners were as follows:
Sir William Wilde Medal —Best Poster 2018
‘Lamina Cribrosa Cell Bioenergetics in Glaucoma: Role of Glycolysis and Glutaminolysis.’
Dr Diamaid Hickey
Barbara Know Medal — Best Paper 2018
‘Predisposing Risk factors, Clinical and Microbiological Characteristics of Moraxella Keratitis.’
Dr Terence MacSwiney
When to believe what you’re seeing — unusual visual symptoms
Unexplained, unusual and unexpected visual symptoms were the focus of a fascinating session dedicated to neuro-ophthalmology, chaired by Miss Patricia Logan, Consultant Ophthalmic Surgeon specialising in Neuro-ophthalmology at Beaumont Hospital, Dublin, at this year’s ICO Annual Conference.
Eminent Irish-born US speaker Prof Patrick Lavin, Professor of Neurology and Neurosciences and Vanderbilt Headache Tennessee, US, gave three presentations at the conference.
After delivering an interactive neuro-ophthalmology workshop with a number of useful video case studies, Prof Lavin’s next talk focused on patients who appear to be faking their disease but have real problems that may be overlooked because of the rarity or subtlety of the disorders, complicated by behavioural characteristics that might be misinterpreted as simulating real disease or exaggeration of minor problems for pecuniary gain.
His final talk focused on unusual visual symptoms that can be normal but occasionally herald serious disease. These included entopic phenomenon such as benign floaters, more serious floaters, and migraine aura, which can be present in 25 per cent of migraines and is not harmful.
Prof Lavin discussed visual conditions like palinopsia, the persistent recurrence of a visual image after the stimulus has been removed which can be brought on by certain medications, and synaesthesia, a perceptual phenomenon in which stimulation of one sensory or cognitive pathway leads to automatic, involuntary experiences in a second sensory or cognitive pathway, eg, words and numbers can have certain colours for those with the condition.
While visual hallucinations can be caused by drug and alcohol abuse, some visual symptoms may be the manifestation of various serious health issues like stroke, brain tumours or seizures (epilepsy) or certain psychiatric disorders, he explained.
Speaking to the Medical Independent (MI), Prof Lavin said the key to trying to determine the cause of any unusual visual symptoms is taking a thorough patient history and symptom review.
“Listen to your patient. They are trying to tell you what’s wrong and it up to you to interpret the clues. Examine the patient based on their complaint, and, generally speaking, don’t get side-tracked by other issues, unless they’re relevant. If you don’t know what is wrong, don’t be afraid to ask for help.”
Also speaking during this session was Mr Michael Burdon, Consultant Ophthalmologist, Queen Elizabeth Hospital, Birmingham, who discussed how a few of his cases with unusual visual symptoms turned out to be Creutzfeldt-Jacob Disease (CJD).
Cortical blindness, dysmetria and hallucinations are among the visual issues that can signal a potential diagnosis of this very rare but devastating disease.
“I also noticed very distinct anxiety in these cases. Patients experiencing visual loss are anxious, or depressed or worried, but this acute anxiety of ‘I can’t see, I can’t see’; that repetitive concern on their vision I’ve never seen in any other neurological disease,” Mr Burdon told MI.
Another unusual visual issue he discussed was night-vision blindness caused by vitamin A deficiency, which can often occur in patients who have had bariatric surgery.
Also during the neuro-ophthalmology symposium there was an interesting paper study presented on ‘visual snow’, which was carried out by Dr Emer Doolin under Miss Logan’s supervision at Beaumont Hospital.
Although seldom recorded in the medical literature, visual snow can be distressing for patients and often lead to multiple unnecessary investigations and inappropriate treatments. Visual snow is syndromically consistent from one case to the next and this phenomenon is reported by young and healthy individuals, with neither ophthalmic nor neurological disease, said Dr Doolin.
Her study of eight patients confirmed that all had normal ocular examinations, normal neuroimaging, and normal electrophysiological studies.
The study concluded that patients could be reassured that the condition, although sometimes disabling, is benign, in the sense that it does not lead to visual loss. Special investigations may still be required for patient reassurance, but in this group of patients did not assist in the diagnosis, which must be made on a clinical basis, the study found.
Now in its fourth year, the John Fitzpatrick Irish Genitourinary Cancer Conference continues to attract an international faculty of leading multidisciplinary specialists across a range of specialties, from urology, medical and radiation oncology, to pathology, scientific and allied health professionals, all of whom are committed to delivering state-of-the-art care for the urological cancer patient.
The meeting is dedicated to Prof John M Fitzpatrick (1948-2014), Professor Emeritus of Surgery, University College Dublin, Consultant Urologist and Chair of the Department of Surgery at the Mater Misericordiae University Hospital, Dublin. He was an Irishman with a truly global reputation in urology and fondly remembered by his colleagues, at home and abroad, many of whom were delegates at the two-day meeting in the Aviva Stadium.
Initially a prostate cancer meeting, the scope was broadened last year to include all urological cancers and this format was continued once again, with faculty from Ireland, the UK, France, Spain, the US and Australia participating in the meeting.
Following a welcome address by Dr Jerome Coffey, Director of the National Cancer Control Programme, the first session on prostate cancer was opened by Prof David Gallagher, St James’s Hospital, Dublin, who provided an overview of the current state of genetic testing in genitourinary cancers in Ireland. While this area has witnessed considerable evolution, the challenge of direct consumer genetic testing poses potential problems in the future and there is clearly a need for regulation.
Dr Niall Corcoran, Royal Melbourne Hospital, Australia, both a urologist and research scientist, provided some emerging evidence from translational studies on the persistence of castration disease in high-risk prostate cancer.
Mr Rick Popert, Guy’s Hospital, London, challenged the 40-year-old dogma of obtaining prostate biopsies using the transrectal route and discussed the implementation of ambulatory day case transperineal prostate biopsy performed under local anaesthetic in Guy’s Hospital. This is an exciting advance in prostate cancer diagnostics and Mr Popert provided a very compelling argument that transperineal prostate biopsies improve detection of clinically-significant prostate cancer and a general anaesthetic is no longer a barrier to performing these biopsies.
Dr Thomas Keane, Medical University of South Carolina, Charleston, US, closed the session with a very engaging review of the current controversies in androgen-deprivation therapy, advocating that androgen deprivation in prostate cancer should be carefully tailored to a man’s cardiovascular risk. The risk of a cardiovascular event is highest in the first six months after commencing androgen deprivation and the use of luteinising hormone-releasing hormone (LHRH) antagonists have a better cardiovascular risk profile compared to LHRH agonists.
The second session focused on bladder cancer and was opened by Dr Nuria Malats, Spanish National Cancer Research Centre, Madrid, Spain, who provided some emerging data from the Spanish Bladder Cancer/EPICURO Study, of which she is a co-Principal Investigator. This is a hospital-based case-control study being conducted in 17 Spanish hospitals to evaluate clinical, environmental, molecular and genetic factors associated with bladder cancer. Data from this study suggests that asthma is associated with a decreased risk of bladder cancer, whereas low levels of vitamin D may be associated with an increased risk of bladder cancer.
Prof Shamim Khan discussed the development of the innovative robot-assisted radical cystectomy programme in Guy’s and St Thomas’s Hospital, London, advocating that this will become the standard of care in the future, whereas open radical cystectomy will be reserved for highly-selected patients unsuitable for robotic surgery. He argued that the robot is just another surgical tool and the surgeon is still the most important factor in these challenging and difficult surgeries.
Dr Andrea Apolo from the National Cancer Institute, Bethesda, US, provided an overview of some of the novel drugs for the treatment of locally-advanced and metastatic bladder cancer, which target PD-1/PD-L1 pathway, including atezolizumab, nivolumab, durvalumab and pembrolizumab. These novel ‘checkpoint’ inhibitors are an exciting development in the treatment of bladder cancer, an area that has seen relatively little novel drug development until recently.
The session closed with a summary from Prof Ray McDermott, St Vincent’s Hospital, Dublin, on the valuable contribution that Clinical Trials Ireland (CTI) has made in recruiting Irish patients with genitourinary cancers to a number of important landmark international clinical trials.
The second day of the conference opened with a further session on prostate cancer, with another outstanding talk from Dr Niall Corcoran, Royal Melbourne Hospital, Australia, on the genomic drivers of prostate cancer metastasis.
Ms Netty Kinsella, a uro-oncology nurse consultant from the Royal Marsden Hospital, London, discussed the development of a ‘pre-habilitation’ programme for men prior to radical prostatectomy. This novel programme uses patient-reported outcome measures pre- and post-operatively, blending patient seminars, telephone contact and multi-professional survivorship clinics at regular intervals to enable men to be transferred back to their GPs earlier following their surgery for prostate cancer.
Mr Jim Adshead, the Lister Hospital, Stevenage, Hertfordshire, UK, reviewed his experience and validation of the NeuroSAFE method of nerve-sparing during radical prostatectomy. This innovative method, developed at the Martini-Klinik in Hamburg, Germany, uses intra-operatively frozen section analysis of the prostate specimen to ensure negative surgical margins, while allowing the urologist to preserve the neurovascular bundle critical for post-operative erectile function without compromising the oncological outcome. Using this method, Mr Adshead has been able to achieve almost 80 per cent potency rates if bilateral nerve-sparing is performed. The session was closed with a very succinct and clear description of the more unusual subtypes of prostate cancer by a recognised leader in the field of urological pathology, Prof Jonathan Epstein, Johns Hopkins Hospital, Baltimore, US.
The plenary session of the meeting opened with Dr Darren Feldman, Memorial Sloan Kettering Cancer Centre, New York, US, outlining some of the many contemporary challenges in the management of testicular germ cell tumours, particularly relating to the salvage treatment of relapsed metastatic germ cell tumours.
Dr Bernard Escudier, Institut Gustave Roussy, Paris, France, gave an in-depth insight into the current and rapidly-evolving landscape of treatments for metastatic kidney cancer and in particular, discussed the emergence of the novel agents nivolumab and cabozantinib as second-line treatment.
Dr William Dahut, National Cancer Institute, Bethesda, US, outlined the contemporary role for immunotherapy in prostate cancer, proposing that chemotherapy and radiotherapy can synergise with immunotherapy in prostate cancer.
The keynote address of the plenary session was delivered by Prof Anthony Costello, Royal Melbourne Hospital, Australia, who vividly reviewed the surgical advances in performing radical prostatectomy over a 40-year period from the late 1970s, when men spent three weeks in hospital post-operatively having sustained a major blood loss with very poor functional outcomes, to the advent of contemporary robot-assisted surgery, with a 24-hour stay in surgery, minimal blood loss and excellent functional outcomes. Prof Costello eloquently debunked several prostatectomy surgical ‘gimmicks’ and techniques which have gained popularity without any solid evidence of benefit, including that performing pelvic node dissection in high-risk disease has no oncological benefit; nerve-sparing is not related to continence outcomes; posterior bladder-neck repair does not improve continence outcomes; and seminal vesicle tip-sparing does not affect functional outcomes. The advent of modern imaging techniques in prostate cancer, such as multi-parametric MRI and PSMA-PET, remain a challenge for the clinician to determine their role in current practice. Prof Costello challenged the premise that men with a ‘negative’ multi-parametric MRI prostate can safely avoid a prostate biopsy. He also proffered that PSMA-PET is a useful adjunct in both the pre-surgical setting and following biochemical recurrence prior to considering salvage radiotherapy or metastasis-directed therapy. He cautioned that metastasis-directed therapy should be performed in the context of a clinical trial and a multidisciplinary setting. Finally, Prof Costello advocated that the future of robotic surgery is dependent on urology residency programmes embracing the technology by harnessing simulation, virtual reality and emerging, cheaper robotic platforms.
The final session was opened by Dr Paul Kelly, Cork University Hospital, who recounted the varied, and at times very colourful, history of the isotope radium-223. Traditionally, the indications of radium-223 have centred on treating castration-resistant metastatic bone disease, however, there are now ongoing trials in Ireland using radium-223 in combination with enzalutamide.
Dr Chris Sweeney, Dana-Farber Cancer Institute, Boston, US, summarised the data from the many trials using androgen deprivation in combination with docetaxel or abiraterone in the setting of metastatic castration-sensitive prostate cancer. He concluded by providing rational advice on the many complex treatment choices now available for men with hormone-sensitive metastatic prostate cancer and which men may benefit most from chemotherapy.
Prof Epstein summarised the deficiencies with the current Gleason grading system for prostate cancer needle biopsies, which dates from the 1960s. He discussed the new, simplified system of five grades adopted by the World Health Organisation (WHO) in 2016, which he was instrumental in developing. This was developed based on a study of over 20,000 prostate cancer cases treated with radical prostatectomy and over 5,000 cases treated by radiotherapy. The new system distils the grades of prostate cancer down to five grades, each with a unique prognosis.
The final speaker of the session, Dr Alberto Bossi, Institut Gustave Roussy, Paris, outlined the current evidence for utilising radiotherapy in advanced prostate cancer.
The meeting concluded with a lively panel discussion of some challenging genitourinary cancer cases provided by Mr Kilian Walsh, University Hospital Galway.
Once again, the meeting combined some impressive scientific and clinical insights on the latest advances in genitourinary cancer from an outstanding international faculty and is a wonderful, enduring tribute to the memory of Prof John Fitzpatrick.
Nearly 30 years after the hepatitis C virus (HCV) was first discovered by scientists, we now have a cure — in fact, we have a few. Dubbed the ‘silent killer’ — it does not have any noticeable symptoms until the liver has been significantly damaged — many people do not even know they are infected. The next challenge for the National Hepatitis C Treatment Programme (NHCTP) is to find these infected people and offer them the cure and wipe out this deadly virus.
HCV is a major cause of liver disease worldwide, with an estimated 80 million people chronically infected. Tackling this issue, the World Health Assembly adopted the first Global Health Sector Strategy on Viral Hepatitis, 2016-2021 in 2016. This strategy highlights the critical role of universal health coverage and the targets of the strategy are aligned with those of the Sustainable Development Goals. The Strategy’s vision is eliminating viral hepatitis as a public health problem. This is encapsulated in the global targets of reducing new viral hepatitis infections by 90 per cent and reducing deaths due to viral hepatitis by 65 per cent by 2030. The World Health Organisation (WHO) European region adopted the first ever Action Plan for Viral Hepatitis in September 2016. The Action Plan follows the 2016 WHO Global Health Sector Strategy on Viral Hepatitis. It addresses viral hepatitis as a public health threat and paves the way towards its elimination from the European region by 2030.
The current estimate of HCV prevalence in Ireland is somewhere in the region of 20,000-30,000 persons. At the end of 2017, a total of 14,704 cases of HCV were notified to the Health Protection Surveillance Centre (HPSC) since it became a notifiable disease in 2004.
The HSE’s NHCTP was established in 2015, following a key recommendation from the 2014 Department of Health (DoH) report, A Public Health Plan for the Pharmaceutical Treatment of Hepatitis C. The Programme is a multi-annual public health plan, which aims to provide treatment across a range of healthcare settings to all persons living with HCV in Ireland. The programme’s ultimate goal is to make HCV a rare disease in Ireland by 2026.
This goal is now within grasp, as transformative therapeutic drug regimens become available for HCV. Advancements in therapeutic treatments for HCV have allowed patients to be successfully treated and fully cured from the blood-borne virus using a range of direct-acting antiviral medicines (DAAs) and therefore, making it a rare disease in Ireland is a reality.
There are numerous challenges facing the Programme that persist, despite the introduction of all-oral therapies. People at risk of contracting HCV are often the most vulnerable and hard to reach in society. High-risk groups can cover populations from a wide range of backgrounds. The Programme is currently rolling out a new model to integrate screening and treatment in the community setting, to specifically target populations that have a high risk of infection, in a number of pilot sites based within the HSE addiction services. The Programme also aims to treat significantly more patients during 2018 in the acute hospital setting.
Prof Aiden McCormick, Clinical Lead for the NHCTP, reports that in the two years since the formal establishment of the National Programme, a lot of progress has been made.
Plans for 2018 include the further development of community-based HCV treatment programmes and extending treatment to greater numbers of patients generally.
Over 2,500 patients have been commenced on treatment since 2015 using DAAs, beginning with those most in critical need. All patients with haemophilia who were infected with HCV through contaminated blood products have been offered treatment and since the end of 2016, HCV has been eradicated in this community. All patients infected with HCV through contaminated blood transfusions and other blood products such as anti-D immunoglobulin have been offered treatment since the end of 2017, with over 95 per cent rates of cure within this population.
Treatment for HCV using DAA medicines has been extended to paediatric patients through the Rainbow Clinic in Our Lady’s Children’s Hospital, Crumlin, and the Children’s University Hospital in Temple Street, Dublin.
Criteria for access to treatment have been expanded so that clinicians can prioritise patients for treatment based on a number of factors and not solely on disease severity. A treatment as prevention (TasP) approach has been endorsed by the NHCTP Advisory Group (PAG), which allows clinicians to treat infection and reduce the risk of onward transmission, in addition to treating disease.
The PAG is the Programme’s oversight group, whose role is to advise strategically in relation to the implementation of the multi-annual treatment plan and has representation across a number of specialist areas, including public health, patient advocacy, research, clinicians and service planners.
The NHCTP CAG, which is chaired by Prof McCormick and includes representation from all treatment sites across a number of disciplines, meets monthly and actively advises the Programme on issues such as clinical treatment guidelines, prioritisation criteria, appropriate drug regimens, and models of care in the context of international best practice. Treatment sites are all working to a national set of treatment guidelines, which support equity of access for patients, regardless of where the treatment is provided.
The Programme has worked extensively to achieve improved commercial terms in the costs of the DAAs and is in the final stages of agreeing commercial terms with suppliers for 2018, following a public procurement exercise. This process, along with other drug procurement processes in 2016 and 2017, has allowed expanded access to treatment for greater numbers of patients and the Programme hopes that the numbers of patients accessing treatment can continue to rise in the coming years.
Further treatment access
In order to continue growing access to treatment for patients and work towards eliminating HCV in Ireland, the Programme has undertaken to concentrate on two particular areas in 2018.
Firstly, the Programme intends developing the extension of HCV treatment away from the traditional hospital-based model (where appropriate) and integrating it into community-based healthcare.
Given that a significant proportion of those infected with HCV acquired their infection through current or former injecting drug use, the Programme has been working initially with opiate substitution therapy (OST) clinics within the HSE addiction services to identify patients who could be provided with their treatment for HCV in the same place as their OST clinic.
A model for HCV treatment in the community setting has been developed by a steering group, reporting to the PAG, and two pilot treatment sites commenced in Q2 and Q3 2017 where patients infected with HCV and who are engaged in OST programmes have been commenced on treatment. The sites are based in the National Drug Treatment Centre in Trinity Court and Castle Street Clinic in Dublin 8. Over 40 patients have been commenced on treatment across the two sites, with further patients being commenced each week.
While a full evaluation of the feasibility, acceptability and sustainability of these pilot programmes has yet to be carried out, initial outcomes from these programmes are extremely positive, with each patient engaging fully with their treatment and for those who have completed their treatment, they have each received a sustained virological response (SVR).
A third community treatment site is due to commence during May 2018 in Patrick Street Clinic in Dun Laoghaire and plans for further similar treatment sites within the community setting are being considered by the Programme. Additionally, the Programme is hoping to begin looking at GP prescribing within the community setting outside of OST clinics and how it might work with community pharmacies, similar to work already underway in other countries, such as Scotland and Australia.
Secondly, the Programme is looking at ways in which patients can be identified for treatment. It is estimated that at least 50-to-60 per cent of the potential number of people in Ireland with HCV are not aware of their diagnosis and so therefore, in order for the Programme to achieve its aim of making HCV a rare disease by 2026, focus needs to turn to identifying the population and case-finding.
Globally, the availability of DAAs has shifted the focus towards elimination of HCV. The WHO has stated that national testing policies, in addition to increased screening, are essential so that the goal of elimination can be reached.
A set of National Screening Guidelines for Hepatitis C were developed by the HPSC and the National Centre for Clinical Effectiveness of the Department of Health and published in 2017, and their implementation will be critical to the successful implementation of the National Programme.
So where are we with the roll-out of the NHCTP?
When the NHCTP was established in 2016, one of the first tasks was to outline a plan for rolling-out the programme over the coming years, with the ultimate objective of making HCV a rare disease in Ireland by 2026. The Programme has achieved many of its objectives planned for 2016-2017 and has commenced the second major phase of the Programme, which will see an extension of treatment availability within the community setting through a number of pilot sites based within the HSE addiction services. The NHCTP also aims to treat significantly more patients during 2018 in the acute hospital setting.
Making HCV a rare disease in Ireland by 2026 — are we on track?
The Centre for Disease Analysis (CDA) is an international public health body with expertise in epidemiology and disease modelling. The CDA has conducted research internationally in relation to HCV elimination strategies and has provided data/evidence-based models to the EU as part of its support of the WHO Global Hepatitis Strategy. Data from Ireland relating to HCV prevalence, rates of treatment, screening, etc, have been incorporated into the CDA studies, which have allowed an assessment of the potential impact of an interventional strategy for HCV treatment in Ireland to be developed. The methodology used was a combination of analysis of published data, experts’ input, review of unpublished data, and modelling. The CDA recommended a treatment interventional strategy for Ireland (and internationally) that supports the implementation of the Department of Health model, including:
Continued treatment using DAAs that have a significantly higher rate of patients achieving SVR or cure.
Increase in numbers of patients being treated to achieve >60 per cent reduction in liver-related deaths and 90 per cent reductions in total and new infections.
Expansion of screening programmes to identify all infected patients.
Expansion of treatment criteria to treat all infected patients, ie, treatment as prevention and treatment to elimination.
CDA data (for Ireland) indicates that Ireland is on the road to achieving elimination of hepatitis C by 2026. This is an extremely positive development (http://cdafound.org/polaris/).
More information on the NHCTP can be found at www.hse.ie/hepc or by contacting NHCTP Manager Ms Michele Tait at email@example.com.
As a psychiatrist, when I am invited to lecture non-psychiatric medical colleagues, the topic that I get asked about more than others is that of personality disorders. These conditions, which are not rare (4-to-15 per cent of the general population and 25 per cent of those attending general practice), cause so much distress and are also associated with a reduced life expectancy of up to 19 years.
Yet despite the common prevalence (much higher than diabetes, for example), doctors can have difficulties in conceptualising where the disorder sits within the medical framework. In my opinion, the main reason for this is that the basic background on personality theory is almost completely ignored in most undergraduate medical programmes. In the following article, I hope to provide some context to the theory of what ‘personality’ is and show that it is an important factor in general health, as well as in mental health.
This will be a whistle-stop tour rather than a comprehensive review and, at times, I have taken a few liberties for the sake of clarity. However, I do hope that after reading this, one will have a better understanding of the basics of what is probably the single-most fascinating aspect of human biology, that is, what makes us all so different.
What is a ‘personality’?
‘Personality’ is a word and concept that we all use in conversation every day. We all have a sense of what it means, but when put on the spot to define it and identify what the core elements are, it can become a little difficult. The concept that different people have an individual way of reacting to events has been well understood since ancient times. The father of medicine himself, Hippocrates, wrote about four fundamental temperaments (sanguine; choleric; melancholic; and phlegmatic) and also associated each one with particular illnesses, as well as physical characteristics.
Despite the awareness of personality as a concept for such a long time, it has been difficult for experts and researchers to arrive at a common definition. There have been over 50 different definitions proposed in the academic literature. The definition below is one that is clear and sufficiently precise to act as a base in this discussion.
Personality is “a person’s characteristic pattern of behaviours in the broad sense (including thoughts, feelings and motivation)”, which is “relatively stable across time and can be used to differentiate this individual from others” (Bauert et al, (2017)).
There have been many different theories of personality proposed, such as ‘type theories’, which would define each person’s personality as having to sit in one or other of a small number of distinct categories (ie, you were either sanguine or phlegmatic); there are theories rooted in psychoanalysis and other schools of psychology. Multiple theories throughout history trying to link personality to body shape have also come and gone (such as ectomorphs); however, these were not supported by systematic research.
Over time, the ‘trait model’ has come to be the most accepted model within the literature and the one that is used in most research. This theory first proposes that human personality can be broken down into a number of distinct ‘traits’ or ‘characteristics’. This model underwent a number of evolutions throughout the 20th Century, until the work of Costa and McCrea produced the ‘five-factor model’ (FFM), which has achieved predominance as the most accepted theory (see Figure 1). In essence, the model proposes that the human personality can be divided into five higher-order factors (or domains).
Of note, each factor is named after one end of the spectrum that it describes. So, for example, extraversion could just as easily be called ‘introversion or agreeableness antagonism’. The five factors can be further divided into lower order factors as well.
Based on this model, each person’s personality is thus a blend of different positions on a number of different spectra, with different traits interacting in ways specific to each individual. For example, if we encountered someone with a high level of extraversion but a higher level of neuroticism, their natural anxiety could seriously temper their desire to socialise and in certain environments, they may appear quite introverted or ‘shy’. However, in environments where their neuroticism is calmed, they may be able to display their extraversion more.
The above description is a very crude and simple explanation to show that while people have certain personality traits, how these are manifested is significantly affected by their environment; learned patterns of behaviour and other factors that may be meaningful to them but not to others.
How and where do we develop our personalities?
The question: ‘Are we born with a predetermined personality or are we shaped by our experiences into the people we become?’ is one that has burned for centuries and remains contentious. The short answer is, there are definite genetic influences over the personality traits that we have; however, how these are shaped and manifested over time depends on the experiences that we encounter (with childhood experiences probably being more important than those in our adult life).
Interaction of personality and medicine
One of the reasons I feel it is important that doctors have a basic understanding of personality theory is that evidence shows that even outside the realm of personality disorder, personality can have a significant bearing on our health.
One of the best-studied areas where personality and health interact is in cardiovascular disease. Multiple studies have shown relationship features, such as neuroticism and extraversion, with a higher risk of stroke and coronary artery disease. As expected, high levels of conscientiousness are associated with a lower risk.
Often, this difference in risk has been explained through different personalities being more or less likely to result in different lifestyle choices (eg, a very extraverted person living in Western Europe is more likely to drink and smoke, as they are more likely to socialise). However, in a study published by Jokela et al in 2014, it was reported that the associations between personality and vascular disease (the study looked at both stroke and coronary artery disease) were only partially explained by the major cardiovascular risk factors. Other possible mechanisms proposed were via physiological pathways, such as dysregulation of the autonomic nervous system and abnormalities of the hypothalamic-pituitary-adrenocortical axis. It was also proposed that there might be some common developmental factors between personalities and cardiovascular health.
The importance of these studies is that they show identifying people who have certain personality traits, and encouraging them to engage in exercises or practices to modify how the traits are manifested (ie, mindfulness, relaxation, etc) may have longer-term benefits in physical as well as mental health.
The other area of medicine where personality factors are of interest has been in the areas of somatisation (or medically-unexplained symptoms) and disorders where pain plays a central role, such as fibromyalgia and irritable bowel syndrome. Given that neuroticism is linked with our ability to feel negative emotions, it is not surprising that patients who present with these problems tend to score higher than control groups.
Personality affects our perception, not just of the outside world, but also of our internal environment. Those with higher levels of neuroticism are more likely to catastrophise when experiencing discomfort, which can lead to seeking out medical assistance more than others. Also, they are more sensitive to comments about them and are more likely to remember negative statements.
How these patients are communicated to and interacted with can be very important in their journey through the health service. An understanding of personality theory allows doctors to realise that when interacting with patients, not only does the content of the consultation need to be planned, but also the style and manner in which it is delivered. Personality theory teaches us that people are different and while there are definite wrong ways to communicate with patients, there are often many different correct ways and choosing which one to use, at which time, is important.
I have often thought that one of the key skills we learn as doctors is the ability to break down and describe what everybody can spot is obviously wrong. For example, which patient will come into the clinic with a rash and know it is abnormal, but the doctor’s job is to be able to describe it as macular or papular, etc, and then, from those descriptions, work out a diagnosis and eventually a treatment.
The fact that people are different is also obvious to every person once they have gone past the age of about five years. We quickly work out that one aunt is jolly and will always listen to a joke, while another aunt is more serious and will ask us about our homework. As clinicians, we work out that one patient is a short consultation and ‘just wants the facts’, while another patient takes longer and needs more reassurance. A better understanding of personality theory, I feel, arms a doctor with the ability to break down and analyse why those patients are different and how we can better help them.
In December 2016, a report was published by the National Cancer Registry Ireland (NCRI) showing that the number of patients with ‘primary liver cancer’ had increased by over 300 per cent in the 21-year period from 1994 to 2014. This is perhaps unsurprising, given that hepatocellular carcinoma (HCC) arises almost entirely in patients with liver cirrhosis and Ireland is currently facing a growing epidemic of deaths related to advanced liver disease. The publication of this report just before Christmas was particularly apt, given that the sharp rise in liver cirrhosis is attributable to obesity and excess alcohol consumption in this country. This review looks critically at the current state of liver disease in Ireland and the climbing incidence of HCC, drawing on relevant comparisons to the UK. We discuss the management structures and pathways established to triage and manage patients with a new diagnosis of HCC. Finally, we examine the Irish healthcare infrastructure, which is struggling to deal with an epidemic of liver disease.
Background and epidemiology
The incidence of HCC is rising globally. This is perhaps unsurprising, given deaths from liver cirrhosis have increased steadily over the past 30 years, exceeding one million worldwide in 2010. Deaths from liver cirrhosis are slowly declining in Western Europe, with the exception of the UK, Ireland and Finland, where cirrhosis mortality rates have continued to increase since the late 1980s. Liver disease is now one of the five ‘big killers’ in England and Wales, alongside heart disease, cancer, strokes and respiratory disease. Additionally, the Office of National Statistics in the UK has described liver disease as the third-biggest cause of premature mortality, as many patients die from liver disease during working age (18-to-65 years). In contrast to the other ‘big killers’, however, deaths from liver disease in the UK are rising sharply (Figure 1). Patients with established cirrhosis have a 1-to-5 per cent cumulative annual risk of developing HCC. Surveillance strategies, including a targeted liver ultrasound (US) and alpha feto-protein (AFP) measurement every six months, are recommended by European and American guidelines for these patients.
Sadly, the situation in Ireland mirrors that of the UK. A recent analysis of data from Ireland’s Hospital in-Patient Enquiry (HiPE) scheme has revealed that the rate of hospital admissions for alcoholic liver disease increased by 247 per cent between 1995 and 2007 in Ireland. Similarly, deaths from alcohol-related liver disease have almost doubled over the same time period. Concurrently, Ireland is facing an epidemic of obesity. It has been predicted that we will be the most obese nation in Europe by 2030. The majority of the obese population will have non-alcoholic fatty liver disease (NAFLD) and many (up to one-in-20 of the Irish citizens) will have ongoing inflammation and scarring, which ultimately leads to cirrhosis. Of those patients with cirrhosis, 5-to-10 per cent will get liver cancer during their lifetime. It is not surprising, therefore, that the number of HCC diagnoses are rising in parallel with the increase in liver cirrhosis over the past decade.
Diagnosis and management of HCC in Ireland
HCC is a vascular tumour and as such, demonstrates typical characteristics on contrast-enhanced imaging, ie, CT or MRI. A nodule in a cirrhotic liver, which hyper-enhances during the arterial phase and demonstrates washout on the portal venous and delayed phases, meets non-invasive criteria for the diagnosis of HCC. Such lesions do not require biopsy to establish a definite diagnosis of HCC. Notably, the NCRI database is comprised primarily of biopsy-proven tumours, suggesting that the real incidence of HCC in Ireland is significantly underestimated.
There is currently no mention or plan for HCC in the recently-published National Cancer Strategy 2017-2026.
In 2014, a dedicated HCC clinic was established in St Vincent’s University Hospital (SVUH), Dublin, to deal with the growing number of HCC referrals to our centre. Between January 2014 and December 2016, there were 278 patients newly diagnosed with HCC at SVUH alone. Predictably, over 90 per cent of the patients referred had established cirrhosis most frequently caused by viral hepatitis, alcohol, NAFLD, and autoimmune liver disease. All cases referred to our unit are discussed at the weekly radiology multidisciplinary meeting, where a firm diagnosis of HCC is established and different treatments are discussed. The treatment for this cancer is guided by the Barcelona Clinic Liver Cancer (BCLC) staging system (Figure 2). This staging system considers both tumour burden and the stage of the underlying liver disease, ie, the level of liver function and patient performance status. Treatment options range from curative to palliative and supportive therapies. Curative options include liver transplantation, liver resection and thermal ablation (radiofrequency ablation (RFA) and microwave ablation (MWA)). Non-curative options include transarterial chemoembolisation (TACE), selective internal radiation therapy (SIRT) and sorafenib, an oral chemotherapeutic agent. Each of these therapies has proven survival benefit. Some patients may be eligible for a combination of these treatments, depending on their tumour burden and performance status.
Treatments for HCC offered in SVUH
The number and volume of different treatments administered to patients with HCC in SVUH are captured in Table 1. Treatment for HCC can be broken down into four categories: Surgical therapy; loco-regional therapy; chemotherapy; and supportive and palliative treatments. These will be briefly reviewed here.
When considering the best treatment for patients with HCC, the presence of liver cirrhosis, with or without liver decompensation, must be considered. Resection is usually reserved for solitary tumours located in a favourable position. The presence of portal hypertension or poor synthetic function increases the risk for liver failure following surgery. Following successful surgery, there is a risk of developing de novo tumours in the background cirrhotic liver and ongoing surveillance is therefore required. Liver transplantation (LT) offers a predicted five- and 10-year survival of 80 per cent and 70 per cent, respectively. Patients must fulfil strict criteria (a single HCC ≤5cm, or no more than three HCCs each ≤3cm, and a serum AFP level <1,000kU/l) to be considered eligible for LT.
Those patients who are deemed appropriate candidates for LT go through a series of testing to assess their mental and physical ability to withstand the operation and transplantation process.
Locoregional therapy for HCC can be delivered in a number of ways, including thermal ablation, TACE and SIRT. These techniques are available and carried out weekly in the Interventional Radiology (IR) Department in SVUH, under the care of a consultant interventional radiologist and their team. Thermal ablation refers to the use of heat energy to burn and kill the cancer cells. This can be done in the form of RFA and MWA, performed under general anaesthesia. The treatment is suitable for small solitary tumours only. TACE is used to deliver drug-eluting beads impregnated with chemotherapy into the arterial blood supply feeding the tumour, as well as blocking-off this blood supply. It is performed under conscious sedation. The aim is that the tumour becomes necrotic and dies. TACE is primarily used for patients with HCC who are BCLC stage B, but can also be used as a bridging therapy for those patients with earlier-stage disease awaiting LT. SIRT is a similar technique to TACE but delivers microscopic radioactive beads into the arterial blood supply feeding the tumour. The beads become permanently lodged in the small blood vessels of the tumour and emit radiation for several weeks or months after the treatment. The radiation destroys the tumour cells from within, with minimal impact to the surrounding healthy liver tissue.
Systemic chemotherapy and palliation
Sorafenib is the only systemic chemotherapeutic agent shown to have any impact on overall survival. Patients with HCC BCLC stage C, with compensated liver cirrhosis are offered this form of therapy. These patients are reviewed monthly in the dedicated HCC clinic and assessed for side-effects. Their management requires a good working relationship with their local GP and community-based nursing teams. If a patient is deemed to be BCLC stage D, ie, poor performance status with advanced liver disease, they are cared for in conjunction with palliative services. Supportive therapy includes symptom management for pain, nausea and encephalopathy, as well as endoscopy for variceal surveillance and escalation of diuretic dose and/or large-volume paracentesis for the management of ascites.
Prognosis of patients with HCC
The NCRI report evaluates patient survival over a 20-year period and concludes that survival from liver cancer is poor. The latest estimate of five-year net survival in Ireland was just 17 per cent. These data contrast sharply with our experience in SVUH, where survival depends upon stage at presentation. In January 2014, a prospective database of all new referrals to the HCC clinic at SVUH was established. We analysed the survival probability, depending upon BCLC stage at the time of referral. In total, we had a complete dataset on 274 patients (BCLC stage 0 (n=18), A (n=112), B (n=68), C (n=40) and D (n=36)). A survival curve was generated to estimate the actuarial survival probability of each patient type over the study period. At the end of follow-up, the proportion of patients alive in each of the groups were as follows: BCLC stage 0 — 94.4 per cent; A — 77.7 per cent; B — 58.8 per cent; C — 45 per cent; and D — 25 per cent. The predicted median survival time for BCLC stage A, B, C and D patients was 66, 26, seven and one month, respectively. This data highlights the importance of appropriate screening strategies (US liver and AFP level every six months) for all patients with liver cirrhosis, and early detection of cancers. In our experience, the minority of patients with HCC (<40 per cent) were referred from outside the Dublin area and sadly, only 19 per cent of these cases were at a stage to be offered curative therapy. These cases were generally referred at an advanced stage of disease. In contrast, over 60 per cent of the referrals from within the Dublin area were at an early stage (>50 per cent) and suitable for curative therapy.
Tackling liver disease and HCC in Ireland
The epidemic of liver disease and rising incidence of HCC needs to be tackled in a number of ways. Firstly, as described previously, liver cirrhosis is a silent condition and often progresses until patients develop signs or symptoms of liver failure. Frequently, at this stage it is difficult to reverse the liver disease and/or treat the HCC, which is all too often at an advanced stage. GPs are perfectly positioned to identify patients with emerging cirrhosis. Screening and early identification of these patients is undoubtedly cost-effective and will save lives. To this end, there are a variety of non-invasive scoring systems that can be used to identify patients with fibrosis and cirrhosis in the community. For example, Fibrosis 4 (Fib4), aspartate aminotransferase-to-platelet ratio index (APRI), and the NAFLD fibrosis scores use the basic blood tests, including AST and ALT values, INR and platelet count, and give a reasonable indication as to the presence of fibrosis or cirrhosis. Where there is a concern, patients should be referred to the local hepatology service for a FibroScan (US-based technology) that can reliably measure liver stiffness and thereby exclude or confirm the presence of advanced fibrosis and cirrhosis.
Secondly, there is a significant lack of trained hepatologists and specialist-trained liver nurses in the vast majority of Irish hospitals. There is an urgent need to create a number of dedicated hepatology centres in selected hospitals around the country. Each centre would be staffed with a dedicated hepatologist, radiologist and clinical nurse specialists. The hepatology unit would act as a referral centre for inpatient transfers (decompensated cirrhotic, variceal haemorrhage, acute severe hepatitis) and outpatient referrals (patients with progressive fibrosis and cirrhosis) from primary care and local hospitals. These centres would have the appropriate skill set to deal with liver emergencies, including bleeding oesophageal and gastric varices and reliably diagnose and deliver selected therapies to patients with HCC. These designated hepatology centres would feed data directly into a national cirrhosis registry, ensuring appropriate HCC screening is carried out, allowing early detection of HCC and thereby improving overall patient survival. The cost of implementing such a strategy would be significantly offset by preventing progression of liver disease and development of HCC, leading to a lesser requirement for LT and various other treatment modalities.
Thirdly, dramatic public health interventions are required to curb the rise in liver disease. A Public Health (Alcohol) Bill was introduced by the then Minister for Health Leo Varadkar in 2015 and passed all stages of the Seanad at the end of last year. The Bill proposed a suite of initiatives aimed at reducing harmful drinking in Ireland. The Bill includes five main provisions: 1) Minimum unit pricing; 2) health labelling of alcohol products; 3) regulation of advertising and sponsorship of alcohol; 4) structural separation of alcohol products in mixed trading outlets; and 5) regulation of the sale and supply of alcohol in certain circumstances. It is imperative that each part of this Bill is implemented in the short term. There is also a requirement to formally tackle the growing epidemic of obesity in Ireland. Promotion of healthy lifestyles to reduce obesity in the country and its results on health; Governmental regulations to reduce sugar content in food and drink; and use of new diagnostic pathways to identify people with NAFLD are critical elements of such a strategy.
Significant progress has been made in the treatment of the hepatitis C virus (HCV) over the past three years in Ireland. This followed the arrival of new, curative, direct-acting antiviral (DAA) medications and the establishment of an effective treatment infrastructure, funded by the Department of Health and HSE, in late 2014. To date, over 2,000 patients have been treated in Ireland. Total eradication of infections from chronic HCV in Ireland by 2025 will pose additional challenges, including identification and treatment of silent infection and ‘difficult-to-treat’ groups. Finally, there is an urgent need for increased awareness of liver disease in the general population with a national campaign led by the HSE, supported by the regional specialist hepatology centres.
Deaths from liver disease and HCC are increasing at an alarming rate in Ireland. The current healthcare infrastructure is ill-prepared to deal with this epidemic. There is an urgent need to develop a national strategic plan to tackle this. We would strongly support the development of dedicated regional hepatology centres. These centres would not only deal with the acute complications of liver failure, but also establish registries for patients with a diagnosis of cirrhosis. Appropriate surveillance of these patients will translate into earlier detection of HCC and improved patient survival.
References on request
The latest figures from the National Cancer Registry Ireland (NCRI) show that over 1,000 cases of melanoma are now diagnosed in Ireland annually and comprise 9 per cent of all skin cancers and 3 per cent of all invasive cancers.
The incidence rate of melanoma has almost trebled in the last 20 years. This rise has affected men more than women, with incidence rates in men rising 125 per cent in the past 20 years, compared to a 54 per cent increase in women over the same period.
Survival rates have also improved and approximately 89 per cent of patients survive for at least five years after their diagnosis. However, Ireland still has the highest mortality rate in Europe for melanoma, with 159 people dying from this disease on average annually.
In an effort to address this, the Irish Cancer Society’s annual SunSmart campaign collaborated with the Irish Farmers’ Association and the Construction Industry Federation last year to highlight the fact that almost 23 per cent of skin cancer deaths in Ireland are in the largely male-focused construction, outdoor and farming industries.
According to UK research, working in the sun could lead to one death and around five melanoma cases a week. The report in the British Journal of Cancer stated that construction workers diagnosed with melanoma skin cancer had the highest number of deaths (four-in-10), followed by agriculture workers (over two-in-10).
Dr Derek Power, Consultant Oncologist, Cork University Hospital, supported the Society’s campaign.
Dr Power is a Fellow of the Memorial Sloan Kettering Cancer Centre, New York. He returned to Cork to take up his consultant position in 2010 and was jointly appointed as an honorary Clinical Lecturer in University College Cork.
Dr Power spoke to the Medical Independent (MI) about the latest positive advances in melanoma treatments, noting that research into the disease has led the way in the development of successful immunotherapies.
“Melanoma cases are rising, but thanks to research advances, there are more ways to treat this form of cancer than ever.
“Before 2010, the treatment available for advanced melanoma was ineffective. Chemotherapy did not work and the older immunotherapy drugs such as interferon and interleukin were very toxic and overall results were poor in advanced disease.
“The last decade, however, has seen major improvements in the drug treatment of advanced and localised melanoma, to such an extent that this disease is now seen as the ‘poster-child’ for modern targeted therapy and immunotherapy. We now have many treatments in both tablet and injection forms that can prolong life and have tolerable side-effects.
“There are now several treatment options for melanoma patients, including [for] metastatic disease, which can very realistically offer long-term survival. Many of the new drugs are now showing activity in localised melanoma, which is at high risk of returning after surgery,” he noted.
“It is a very exciting time for a doctor like me, who sees many patients with melanoma. It is wonderful to see patients benefitting from modern therapies and living a good-quality life. It is a privilege to be involved in the treatment of melanoma and to have seen the progress that has been made over the last 15 years.”
However, Dr Power also stressed that the “best treatment” for melanoma is prevention. “There are about 1,200 cases of melanoma now a year and an awful lot of them could be prevented by taking proper advice from dermatologists regarding sun protection. Our Celtic skin burns more easily than Latin skin, for example… ”
There are about 100-to-150 cases of metastatic melanoma a year, estimated Dr Power.
“Up until seven years ago, this was largely incurable, with the median survival being 10-to-12 months, so now fast-forward seven years, with the advent of the immunotherapies like ipilimumab and nivolumab and pembrolizumab, the three licensed ones, and the BRAF and MEK targeted therapies, of which there are four licensed at the moment (dabrafenib, trametinib, vemurafenib, and cobimetinib).
“So with the advent of those four in addition to the immunotherapies, the median survival has now increased dramatically and would be closer to 18-to-24 months, and even together with the more modern immunotherapy drugs like ipilimumab and nivolumab combined, the three-year survival is around 60 per cent… with the targeted therapies, of which about 30-to-35 per cent are suitable with the BRAF and MEK tablets, in and around 40 per cent of people would be alive and doing well at three years with the combination of those targeted therapies. So it is great to have all these different treatment options open to us now and give these, relatively speaking, amazing figures. Not everybody can be expected to do equally well and therein lies the challenge; with the immunotherapies, you don’t know who is going to respond and who isn’t, as there is no validated biomarker.”
In addition, toxicity is a significant issue with the newer therapies, “especially with the combination immunotherapies. Ipilimumab and nivolumab together have toxicity three-fold higher, significant toxicity; I’m taking about grade three, four — that is a big challenge.
“Also, the sequencing of the drugs [is a challenge]. Around 30-to-35 per cent of patients will be technically suitable for all the drugs and of course, that leads to the question of which ones do you give first? Do you give the BRAF and MEK tablets together first, followed by the immunotherapies when disease ultimately progresses, or do you do it the other way round — do you give the immunotherapies first and the targeted therapies second? So this is the subject of at least two international clinical trials that are looking at this sequencing… there are even studies looking at combining those modalities altogether.”
Dr Power also acknowledged that such medical progress in melanoma treatment has come at a high economic cost.
“Immunotherapy drugs are very expensive. With around 120 cases of metastatic disease a year, you could say in and around 80 per cent of those cases would be suitable for combination immunotherapy and that is very expensive for the State, which has approved these drugs, but it really becomes expensive when we don’t know the exact duration that they should be given.
“Now people are saying that two years of treatment of immunotherapy is enough, but that is investigational. The bottom line is, the treatment is open-ended and it [metastatic melanoma] becomes almost like a chronic disease, so how much is enough? We don’t know that either, so that’s another problem with advanced disease, but obviously the huge progress outweighs the problems.
“There’s been massive progress, nothing short of a quantum leap compared to what it was 10 years ago and there is still the possibility — I’m always hesitant to say this, but it’s true and it is no consolation to those it doesn’t happen to — that advanced melanoma can be cured with immunotherapy drugs. That is a possibility for a distinct percentage of patients. We don’t have enough survival yet with nivolumab or pembrolizumab on their own or ipi and nivo in combination, any long-term survival, but we do have long-term survival with ipi on its own, and it is about 18 per cent of patients are alive at 10 years after receiving ipi.
“In randomised studies, nivolumab is at least twice as good as ipi, as is pembrolizumab, so it is very realistic to expect that 18 per cent figure to go up to 35 or 36 per cent and then with the immunotherapy combination, we have 60 per cent alive at three years, so it is distinctly possible that that could be 40-to-50 per cent at least at 10 years. We don’t have that long-term data yet as the drugs aren’t around that long, but that is quite amazing compared to 10 years ago.”
The other significant developments in melanoma have been in adjuvant stage 3 disease treatment, Dr Power noted. “The standard of care heretofore for stage 3 disease has been surgery and then observation; scans, and how frequent they should be, is very controversial, dermatology follow-up and so on… Since late last year, we have two separate new strategies for stage 3 disease after surgery [node-positive disease] approved in the US; nivolumab, which was licensed by the US FDA last December for one year of treatment, one injection every two weeks for a year, and it has been shown to have a huge survival advantage versus observation, which is the standard treatment. Ipi had been approved in the adjuvant setting as well but the toxicity was a problem… and the other big development was giving dabrafenib and trametinib, the BRAF and MEK inhibitor, for a year in stage 3 disease. That has been proven as well to have a survival advantage over observation, so that has been fast-tracked for approval by the FDA.”
While these treatments have not been approved yet in Europe, where observation remains the standard of treatment for stage 3 disease, Dr Power believes they will be approved within a year. “We will follow the Americans; we always do. There are huge international clinical trials that have been published in the New England Journal of Medicine on these [two new strategies in the] adjuvant setting for stage 3 disease.
“So that is a huge development in the adjuvant setting because melanoma has lagged very far behind other diseases like breast, bowel and ovarian cancer, where there are very standard adjuvant treatment options that have a survival benefit, while melanoma had nothing for years and years. It was really an awful disease… but this is a very significant development.”
The next step will be identifying biomarkers to predict treatment response in melanoma, as that is “a major problem with immunotherapy”, Dr Power acknowledged, explaining that PD1 expression and epigenetic signatures in tumours are being examined.
Concluding, he reiterated that melanoma treatment has seen a seismic leap forward in the last decade, with great treatment options now available for even advanced disease and further hope for long-term survival and cure.
“Melanoma has really led the way in the immunotherapies and the targeted therapies. It is amazing, as when I first qualified as a consultant about eight years ago, we were still giving chemotherapy and interferon, whereas now it is quite amazing — in less than a decade, the differences are phenomenal.”
According to the National Cancer Registry Ireland (NCRI), the estimated annual incidence of breast cancer in Ireland is 2,919 cases per year, with approximately 694 deaths caused by breast cancer each year. For women in Ireland, the lifetime risk of developing breast cancer is one-in-11.
Breast cancer mortality is decreasing. The latest report from the NCRI shows that the five-year net survival rate for female breast cancer in Ireland is just over 83 per cent, an increase from 71 per cent in the 1990s. This is likely related to the discontinuation of hormone replacement therapy (HRT) use, as well as the contribution of national screening programmes and increased awareness.
Some 77 per cent of female breast cancers are diagnosed over the age of 50 years. The median age of diagnosis of breast cancer is 62.
BreastCheck is the national breast cancer screening programme in Ireland. It currently offers mammograms for women aged 50-to-64 years old. This age group is being extended so that all women currently being screened will be offered screening until age 69 years. Overall, approximately one-third of female breast cancers are detected by screening.
Since the initial implementation of BreastCheck in 2000, the proportion of cases of breast cancer presenting through screening has increased, rising from 7 per cent in 2000, to 28 per cent in 2010 for invasive cases and from 32 per cent to 54 per cent for the same years, respectively, for in situ carcinoma.
Approximately one-third of breast cancers are detected by abnormal mammography at screening. Outside of screening, the most common presentation of breast cancer is a breast mass. It is possible for a breast mass to be clinically palpable and mammographically occult; therefore, triple assessment breast clinics are an important referral point.
Characteristics of a malignant mass include hardness, immobility and border irregularity.
Signs of locally-advanced disease include axillary lymphadenopathy and skin findings such as erythema, skin thickening and skin dimpling.
Signs of metastatic disease may also be apparent at initial presentation and are dependent on the organ involved, most commonly bone, liver, lung and brain.
Family history is strongly associated with an increased risk for developing breast cancer. If a woman has a first-degree relative with a history of breast cancer, then her risk is increased two-fold compared with the general population. If a woman has two affected first-degree relatives, then her risk is increased three-fold.
The age of the affected relative at diagnosis is also important, with risk increasing with relatives diagnosed in their 30s.
Between five-to-10 per cent of breast cancers are believed to be hereditary. Approximately 20 per cent of women with a family history of breast cancer have a mutation in the breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2), inferring an increased lifetime risk of breast cancer, as well as ovarian cancer.
A woman’s reproductive history is also important when considering her risk of developing breast cancer. Factors including nulliparity/low parity, late age at first pregnancy, late natural menopause, early menarche, oral contraceptive use and HRT use are associated with an increased risk.
Other factors that increase a woman’s risk of developing breast cancer include high body mass index (BMI), alcohol intake, ionising radiation exposure, benign breast disease and high socioeconomic status.
The treatment of breast cancer is generally dependent on multiple factors, including type of breast cancer, stage of the disease, sensitivity to hormones, HER2 status and patient’s overall health, performance status and preference. A complete review of all treatment options is beyond the scope of this article; however, a brief overview of the modalities of treatment include:
In patients with stage I-III breast cancer, surgery is the most important modality of curative treatment. Surgery may involve breast-conserving surgery or may require mastectomy, depending on the size and location of the tumour and whether there is coexisting in situ disease or multifocal disease.
The status of the axillary lymph nodes is important for staging, management and prognosis. An axillary lymph node dissection is considered if the sentinel node biopsy is positive for malignancy, or if there are multiple positive nodes in the clinical context.
The discussion of surgical options, management of the axillae, immediate or delayed reconstruction and the potential for breast radiation are important considerations for the patient and for the multidisciplinary group and are generally well planned prior to definitive surgery.
Radiotherapy is widely used in breast cancer, particularly in the setting of stage I-III disease with curative intent and also in stage IV disease with palliative intent. In general, most patients with breast-conserving surgery are considered for radiotherapy. This adjuvant treatment is given five days a week for three-to-six weeks’ duration. Palliative radiotherapy is frequently used in advanced breast cancer patients. It is utilised to reduce pain or decrease tumour mass effect on adjacent structures for symptomatic control.
Systemic chemotherapy does not provide a benefit in every breast cancer diagnosis. Oncologists have become more refined in the approach to systemic treatment and utilise tools such as the pathology and biomarkers, age and performance status, mathematical decision models, and genomic tumour profiling to decide on chemotherapy benefit. The most recent advancement in lymph node-negative, HER2-negative breast cancer is to offer oncotype testing. This is a tumour profiling test to determine the benefit of chemotherapy. In women with low- or intermediate-risk oncotype scores, chemotherapy is less likely to provide benefit and influences the treatment decision.
Standard adjuvant chemotherapy regimens combine a taxane, cyclophosphamide with or without an anthracycline, depending on the clinical and genomic risk features. Neoadjuvant chemotherapy (NAC) refers to chemotherapy delivered before surgery and is considered for patients with locally-advanced or inflammatory breast cancer (IBC). NAC, compared to adjuvant chemotherapy, is associated with higher rates of breast conservation, with equivalent rates of overall survival and locoregional recurrence, provided that surgery is part of the received treatment.
In metastatic breast cancer, European Society for Medical Oncology (ESMO) guidelines recommend sequential monotherapy as a preferred choice, starting with endocrine therapy if at all possible. Combination chemotherapy should be reserved for patients with rapid clinical progression, life-threatening visceral metastasis or need for rapid symptom/disease control.
Endocrine therapy should be offered to patients with hormone receptor-positive breast cancer in the adjuvant setting and continued for at least five years. In metastatic breast cancer, it is continued until there is evidence of progressive disease.
In premenopausal women, tamoxifen remains the standard of care. If it is not tolerated, one option is to suppress ovarian function chemically or surgically and introduce an aromatase inhibitor. For postmenopausal women, multiple endocrine therapy options exist, including aromatase inhibitors, oestrogen receptor antagonists, and irreversible steroidal inhibitors.
Resistance to endocrine therapy can develop in any stage of breast cancer, and in this setting there are new options to extend a patient’s time on oral endocrine therapy, including the addition of everolimus to endocrine therapy, or the addition of a CDK4/6 inhibitor, such as palbociclib or ribociclib.
These are new, oral targeted therapies that are well tolerated in metastatic breast cancer patients. There is no significant alopecia, there is a lower risk of infection, and patients do not require infusions, thus adding to their quality-of-life.
The HER2 protein is an overexpressed receptor signature in breast cancer and is considered a relevant biomarker for treatment. Trastuzumab is a monoclonal antibody that targets HER2 and is the first targeted HER2 drug that was approved by the US FDA in 1998. Other drugs in clinical use that target HER2 include pertuzumab (intravenous), lapatinib (an oral inhibitor), and TDM-1 (an antibody-drug conjugate).
Triple-negative breast cancers (TNBC) lack oestrogen, progesterone and HER2 receptors. TNBC tend to be a subtype of aggressive breast cancers with no targetable mutations. In recent months, PARP-inhibitors have been approved for use in America for patients with BRCA-mutated breast cancers, many of which are triple-negative subtype.
Breast cancer updates from recent conferences
Numerous studies have associated high BMI with increased breast cancer risk. According to data presented by Chlebowski et al at the 2017 San Antonio Breast Cancer Symposium (SABCS), postmenopausal women who lose weight may have a significantly reduced chance of developing breast cancer. Of the 61,335 patients enrolled in the study, 3,061 developed invasive breast cancer during an average of 11.4 years of follow-up. Compared to women with stable weight, those who lost weight (≥5 per cent weight change) were 12 per cent less likely to develop breast cancer. Weight loss of ≥15 per cent was associated with a 37 per cent reduction in breast cancer risk. Although weight gain (≥5 per cent weight change) was not associated with an increased overall breast cancer risk, it was associated with more than a 50 per cent increased risk of triple-negative breast cancer.
Many women diagnosed with breast cancer, especially younger women, are concerned about the ability to have children after cancer treatment. Some breast cancer treatments can cause temporary infertility or make it harder to get pregnant after treatment ends. Other treatments, especially certain chemotherapy regimens, can cause early menopause and infertility. A meta-analysis of individual patient data from five randomised clinical trials provided a high level of evidence that treatment with gonadotropin-releasing hormone analogue (GnRHa) during chemotherapy could safely and effectively protect ovarian function and potentially preserve fertility in premenopausal women receiving chemotherapy for early-stage breast cancer, according to a study presented by Lambertini et al at 2017 SABCS. The study found that the premature ovarian insufficiency rate in the GnRHa group was 14.1 per cent vs 30.9 per cent in the control group; patients in the GnRHa group had a 62 per cent less risk of developing premature ovarian insufficiency as compared to those treated with chemotherapy alone. Some 37 patients in the GnRHa group had at least one post-treatment pregnancy during the follow-up period vs 20 patients in the control group.
After surgery, women diagnosed with hormone-receptor positive breast cancer usually take adjuvant hormonal therapy to reduce the risk of recurrence. There are several types of hormonal therapy. Tamoxifen is one of the most well-known. The aromatase inhibitors have been shown to be more effective at reducing recurrence risk in postmenopausal women and are used more often than tamoxifen to treat women who have gone through menopause.
In recent years, published data reports that extending the adjuvant endocrine setting from five to 10 years provides additional benefit in terms of reducing the risk of breast cancer recurrence. Presentations at the 2017 SABCS showed an additional two years of an aromatase inhibitor is sufficient, while an additional five years in the extended adjuvant setting led to more clinical fractures.
An early study presented at 2017 SABCS hints that pembrolizumab, an immune checkpoint inhibitor, may offer benefits for certain metastatic HER2-positive breast cancers.
HER2-positive breast cancer is trastuzumab resistant because most patients with HER2-positive breast cancer receive trastuzumab in the adjuvant or neoadjuvant setting. In the PANACEA study, investigators examined if immunotherapy can work in patients with advanced HER2-positive breast cancer that is resistant to trastuzumab. The combination of pembrolizumab and trastuzumab may offer benefits to people diagnosed with metastatic HER2-positive breast cancer with high levels of tumour-infiltrating lymphocytes (TILs) that has stopped responding to trastuzumab.
Three cyclin-dependent kinase (CDK) 4/6 inhibitors have been approved by the FDA for treatment of ER-positive, HER2-negative metastatic breast cancer in combination with an endocrine therapy. It has been shown that the estimated progression-free survival (PFS) was improved to 23.5 months, compared to 13.5 months for those treated with the combination CDK4/6 inhibitor and endocrine therapy.
For women with BRCA1 or 2 mutations diagnosed with breast cancer, the EMBRACA trial utilising talazoparib was presented at 2017 SABCS. This trial reported that treatment with a PARP inhibitor, which blocks one of the enzymes that assists DNA repair, resulted in longer PFS than chemotherapy.
Myeloma is one of the great success stories of modern haemato-oncology. The survival of patients has greatly improved over the last 20 years, firstly following the introduction of autologous stem cell transplantation (ASCT), and thereafter following the development of two new drug classes, proteasome inhibitors (bortezomib, carfilzomib, ixazomib) and immunomodulatory drugs (thalidomide, lenalidomide and pomalidomide).
For younger transplant-eligible patients, the median survival is currently approximately eight years. In parallel, refinements in diagnostic criteria and prognostic markers have facilitated the application of more risk-stratified approaches. For many patients, myeloma is therefore a chronic disease, albeit a malignancy, and the model of patient care is increasingly one of chronic disease management.
Despite these advances, myeloma remains an incurable malignancy of plasma cells, which accounts for approximately 10 per cent of all haematological malignancies in international registries.
According to the Multiple Myeloma Cancer Factsheet of the National Cancer Registry Ireland (NCRI) (May 2017), the annual incidence of myeloma in Ireland is 7.1 per 100,000 in men and 4.1 per 100,000 in women and a total of 271 new cases are diagnosed here every year. In general, the median age at diagnosis is around 70 years and, in a large Mayo Clinic series, 15 per cent of patients were below the age of 50 years. The NCRI found that the survival rate at five years had improved from 27.5 per cent (1994-1998) to 49.6 per cent (2009-2013) and that the estimated 10-year survival is 30.2 per cent.
A 57-year-old schoolteacher had increasing mid-back discomfort over three months. One weekend, she developed a fever and a cough productive of green sputum, and her partner found her to be confused. She was brought to the GP, who referred her to the local emergency department. On presentation, she was disoriented, febrile to 38.5 degrees and had bilateral crepitations on auscultation. A chest x-ray revealed pneumonia. She was anaemic (Hb 10g/dl), had an elevated creatinine (140umol/l) and was hypercalcaemic (3.1mmol/l). Her total protein was 99g/L (66-87) and albumin 32g/l (35-to-50). She was rehydrated, commenced on intravenous antibiotics and treated for hypercalcaemia.
Serum protein electrophoresis (SPEP) detected an IgG kappa paraprotein of 45g/L and kappa light chains were present in her urine. She was referred to the haematology service with probable myeloma. There was an infiltrate of plasma cells on her bone marrow aspirate and an urgent CT scan of her spine revealed multiple thoracic vertebral compression fractures. Fluorescent in situ hybridisation (FISH) cytogenetic analysis detected the translocation, t(4;14).
She was started on treatment with the combination of oral cyclophosphamide, subcutaneous bortezomib and oral dexamethasone. Following discharge six days later, she went on to attend the day ward on a weekly basis over the next four months. Her paraprotein was 9g/L following completion of this induction therapy. As she had no significant medical history, she had been referred for stem cell collection. These were harvested by leukapheresis and she proceeded to an autologous stem cell transplant. The transplant admission lasted three weeks and was complicated by infection, mucositis and hair loss. At her assessment three months’ post-transplant, the paraprotein has fallen further to 2g/L, consistent with a further deepening of her remission. She was then commenced on maintenance treatment with oral lenalidomide and further follow-up consisted of once-monthly visits for clinical review, laboratory tests, her high-tech prescription for lenalidomide and an intravenous bisphosphonate for bone protection.
Symptomatic myeloma requiring treatment evolves from the pre-malignant condition, monoclonal gammopathy of undetermined significance (MGUS), although this asymptomatic precursor state has often gone undetected prior to the diagnosis of myeloma. MGUS is present in 3 per cent of the population over the age of 50 years and is increasingly common with age. The risk of progression to myeloma has been reported to be approximately 1 per cent per year over the following 25 years.
Although often an incidental finding on screening, the detection of a serum paraprotein understandably leads to concern. It is important to be aware that the risk of progression to myeloma varies widely and can be assessed based on the isotype (IgG, IgA, etc) of the paraprotein, its size and whether the serum-free light chain ratio is normal or not.
If SPEP detects an IgG paraprotein of less than 15g/L and if the serum free light chain kappa:lambda ratio is normal, these criteria identify a group of patients with low-risk disease, constituting almost 40 per cent of all MGUS patients, who only have a 5 per cent risk of progression to myeloma at 20 years. As a result, the MGUS guidelines of the British Committee for Standards in Haematology recommend that such patients be discharged from haematology clinics back to GPs for routine monitoring (https://www.b-s-h.org.uk/guidelines/).
Smouldering multiple myeloma (SMM) is an intermediate state between MGUS and myeloma. It is diagnosed when the plasma cells infiltrate within the bone marrow increases to greater than 10 per cent and/or the paraprotein increases to more than 30g/L in the continuing absence, however, of end-organ damage. The risk of progression to symptomatic myeloma is 10 per cent per year.
Diagnosis of myeloma
The diagnosis of symptomatic myeloma requires the presence of an infiltrate of malignant plasma cells (>10 per cent) in the bone marrow (see Figure 1), a monoclonal paraprotein in the serum and/or urine, and either the presence of end-organ damage as evidenced by the so-called CRAB criteria of hypercalcaemia (C), renal insufficiency (R), anaemia (A), and bone (B) lesions, or the presence of one of three biomarkers highly predictive of early progression to such end-organ damage: (1) greater than 60 per cent plasma cells within the bone marrow; (2) a highly skewed ratio of the involved to the uninvolved serum free light chain (>100:1), and; (3) more than one focal lesion greater than 5mm in diameter on MRI.
The commonest symptoms at presentation are fatigue and bone pain. Mid-to-low back pain has often been present for several months before cross-sectional imaging reveals damage, commonly vertebral fractures and co-existing asymptomatic lytic lesions. Occasionally, patients present with pathological fractures (Figure 2).
Be alert to an unexplained gap between the total protein (60-to-80g/L) and the serum albumin (35-to-50g/L) on the ‘liver profile’, as this may indicate the presence of a paraprotein and should prompt consideration of a request for a SPEP.
The following laboratory investigations should be performed in a patient suspected of having myeloma: FBC; renal profile; calcium level; and serum and urine protein electrophoresis. The serum free light chain assay is an expensive confirmatory assay and is usually ordered in the haematology clinic.
Except in rare cases of non-secretory MM, the identification and quantification of a monoclonal protein (M-protein) in the serum or urine is essential to the diagnosis and monitoring of myeloma. SPEP provides a measurement of the three principal immunoglobulins, IgG, IgA and IgM. If a monoclonal band or paraprotein is detected on the gel, immunofixation with antibodies to heavy chains (G, A, M) and light chains (kappa, lambda) is automatically performed to identify the paraprotein, eg, IgG kappa or IgA lambda.
The serum free light chain assay is a test using an antibody specific for free circulating immunoglobulin light chains. This test is reported as the ratio of kappa to lambda light chains. This test has improved our ability to diagnose and monitor light chain myeloma and has removed the need for sequential 24-hour assessments of urinary light chain excretion, a difficult test to perform in an older, frailer population and one that is often incomplete.
A urine collection should still be performed at diagnosis to assess for nephrotic syndrome. The spot protein to creatinine ratio (PCR) may be used as a surrogate for a 24-hour urinary protein in patients with newly-diagnosed myeloma. It is important to be aware that the standard urinalysis reagent strips do not detect light chains. If there is a discrepancy between such a urine dipstick test for protein and a separate test for urinary protein excretion, this raises the possibility of light chain proteinuria.
Until recently, a skeletal survey comprised of plain x-rays of the skull, trunk and limbs was the principal imaging modality used to assess for myeloma-related bone disease. However, this is a relatively insensitive technique and guidelines from the International Myeloma Working Group (IMWG) in 2017 recommended either whole-body, low-dose CT, whole-body MRI or, occasionally, PET/CT as the imaging techniques of choice.
The encouraging improvements in survival rates mask the fact that myeloma, though always a clonal malignancy of plasma cells, is a disease characterised by marked clinical and biological variability. Host factors such as age or frailty, the disease burden and tumour biology all combine to determine overall survival in any given patient. The Revised International Staging System (R-ISS) incorporates serum albumin, beta-2 microglobulin, LDH and FISH cytogenetic results as markers in a robust prognostic tool for newly-diagnosed patients.
FISH is a genetic test consisting of the use of labelled probes on plasma cells from a bone marrow aspirate to assess for the presence of specific known chromosomal abnormalities, principally hyperdiploidy, a good prognostic marker, and translocations involving the immunoglobulin-heavy chain enhancer at 14q, generally conferring a worse prognosis, eg, t(4;14), t(14;16) or t(14;20). FISH results are used to stratify patients in clinical trials and can also usefully inform treatment decisions in routine clinical practice.
There are several phases to treatment: Induction chemotherapy following diagnosis; ASCT for younger, fitter ‘transplant-eligible’ patients; maintenance treatment until disease progression; and treatment at relapse.
Bortezomib is a first-in-class proteasome inhibitor, which has been available for use in Ireland since 2004. The main complications are transient gastrointestinal upset and peripheral neuropathy. This latter complication has been found to be less common when it is administered subcutaneously rather than intravenously and on a once-weekly rather than a twice-weekly schedule.
Immunomodulatory drugs are derived from the parent compound, thalidomide, which tragically led to an epidemic of foreshortened limbs (phocomelia) when it was used as treatment for ‘morning sickness’ in the first trimester of pregnancy in the 1950s in Europe. In 1999, thalidomide was found to be effective in the treatment of relapsed myeloma and prompted the development of the more potent, less-toxic compounds, lenalidomide and pomalidomide. As they are teratogenic, strict prescribing guidelines are in place to avoid inadvertent foetal exposure.
Modern induction chemotherapy usually consists of a ‘triplet regimen’ incorporating a proteasome inhibitor, usually bortezomib, or an immunomodulatory drug, usually thalidomide or lenalidomide, in combination with corticosteroids and cyclophosphamide. The woman in the case report described in this article received cyclophosphamide, bortezomib and dexamethasone (CyBorD). Alternatives would include lenalidomide, bortezomib and dexamethasone (RVD) or bortezomib, thalidomide and dexamethasone (VTD). Most patients will respond to any of these regimens. A notable change over the last decade has been the use of lower doses of dexamethasone, usually now given in weekly pulses rather than in longer four-day blocks.
As the median age at diagnosis of myeloma is around 70 years, many newly-diagnosed patients are frail and have multiple coexisting illnesses. Dose-reduced triplet regimens or orally-administered doublets, such as lenalidomide and dexamethasone, are likely to be better tolerated in this population. In the absence of transplantation, longer courses of less intensive treatment are often an effective, less toxic approach.
ASCT remains the standard-of-care for the treatment of younger, fitter patients. In a large MRC UK randomised controlled trial, those in the transplant arm survived, on average, one year longer. The upper age limit is based upon biological rather than chronological age although, for practical purposes, it is approximately 70 years. The transplant admission lasts for three weeks and the main complications are myelosuppression and mucositis.
At St James’s Hospital, Dublin, 557 patients underwent ASCT for myeloma between 1999 and 2016, 503 ‘up-front’ shortly after diagnosis and 54 as a second transplant, usually several years later (see Figure 3). The population consisted of 306 (60.8 per cent) men and 197 (39.2 per cent) women. The median ages at transplant were: 53 (35-to-67) years (I), 57 (31-to-69) years (II) and 59 (29-to-70) years (III), respectively.
During this period, novel drug classes have included proteasome inhibitors (bortezomib, carfilzomib (Named Patient Programme (NPP)) (2016-2017)), immunomodulatory drugs (thalidomide, lenalidomide and pomalidomide) and, more recently, monoclonal antibodies (daratumumab (NPP) (2016-2017)). These developments have led to consistently improving five-year overall survival rates in younger transplant-eligible patients in these three consecutive six-year cohorts, as follows: 62 per cent (I), 67 per cent (II) and 80 per cent (III), respectively (see Figure 4).
Maintenance treatment consists of the continued use of a therapy until disease progression. Two large, randomised, controlled trials evaluated the efficacy of maintenance low-dose lenalidomide in the post-transplant setting. A recent meta-analysis reported improved overall survival at seven years of follow-up in those patients who received maintenance.
There have been two main advances in the treatment of myeloma in the last three years. The first has been the development of several antibodies targeting proteins on the plasma cell surface. Daratumumab is a humanised IgG1κ monoclonal antibody against CD38, which has shown promising single-agent activity in relapsed and refractory myeloma. It is available for use in Ireland from April 2018. Other novel antibodies include isatuximab, also targeting CD38, and elotuzumab, targeting the protein SLAMF7.
Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary new approach to the treatment of haematological malignancies, including myeloma.
This technique involves the collection of peripheral blood lymphocytes from patients by apheresis. These are then genetically engineered in vitro to target cell surface proteins expressed by a given cancer cell and re-infused back into the patient following immunosuppressive treatment.
The most promising results so far in myeloma have been based on CAR-T cells targeting the B-cell maturation antigen (BCMA), a protein whose expression is largely restricted to plasma cells. High response rates have been reported in heavily pre-treated patients who had become refractory to all other treatment options. These are, however, early days and although highly promising, challenges include toxicity, cost and patient selection. Clinicians are working with the pharmaceutical industry to bring CAR-T cell clinical trials to Ireland over the coming year.
In summary, the last 20 years have seen a complete transformation of the field of myeloma therapies, which has resulted in deeper remissions and greatly improved survival rates (see Figure 5). Although currently incurable, the range of available therapies and the prospect of CAR-T cell approaches raise the possibility that we may achieve cures in some patients in the coming years.
Sickle cell disease (SCD) is an autosomal recessive haemoglobinopathy that we now encounter with increasing frequency in clinical practice in Ireland. The clinical hallmark is a triad of painful vaso-occlusion, micro-infarct end organ damage and a haemolytic anaemia. The disease is characterised by a point mutation in the beta globin gene leading to the substitution of valine for glutamic acid in the beta haemoglobin chain. This seemingly simple amino acid substitution causes a life-threatening and complex multi-organ disease with multiple pathophysiological pathways. Mortality has been high in SCD especially in the early childhood years.
Modern treatment approaches including new-born screening, pneumococcal prophylaxis, transcranial Doppler ultrasound and the introduction of early disease-modifying treatment has seen mortality decrease, the mean age at death increase, and fewer children dying from infection. Aggressive management strategies in childhood yield a sickle-related survival rate of 94 per cent at 18 years and 99 per cent at 16 years. This improvement in childhood mortality has not yet been seen in the adult population who have a median life expectancy in the US of 42 years for males and 48 years for females.
Most patients with SCD will experience vaso-occlusive events at some point in their life and these episodes account for over 90 per cent of all emergency hospital admissions. They can lead to acute organ failure or chronic organ damage affecting all systems. Diagnosis is now typically achieved in the neonatal period due to the introduction of a screening process where haemoglobin electrophoresis is performed on cord blood at delivery. This allows for the early detection of the condition, initiation of parental education and commencement of supportive therapy including antibiotic prophylaxis, pneumococcal vaccination and folic acid supplementation. The morbidity of SCD is highly variable, but can be devastating. Early introduction of disease-modifying treatment is essential to prevent or ameliorate the consequences of this disease.
Pain is a commonly seen presentation in children with SCD. The first episode of pain typically affects the small bones of the hands and is referred to as dactylitis. This affects approximately 50 per cent of children with SCD by two years of age. As these children get older the long bones become affected and by adolescence pain is typically associated with the ribs and vertebrae. This pain can be severe and debilitating.
Many other acute complications of SCD have life-threatening consequences. Acute chest syndrome is the most common cause of hospitalisation for patients with SCD, with a peak incidence in early childhood, and is responsible for approximately 25 per cent of sickle-related deaths. The neurological system can also be affected with the occurrence of stroke. Prior to the findings of the STOP study, 10 per cent of children with SCD had a stroke before the end of the second decade of life. Now children are screened with transcranial Doppler ultrasound, which has reduced the stroke risk rate to approximately 1 per cent. Acute splenic sequestration is a life-threatening complication that occurs in up to 30 per cent of patients with SCD up to six years of age. It is characterised by rapid enlarging of the spleen followed by circulatory collapse. All organs of the body are at risk of severely debilitating and life-threatening chronic complications. Some of the more commonly encountered complications include avascular necrosis (AVN), pulmonary hypertension and retinopathy. Avascular necrosis occurs with an incidence of 2.5 per 100 patient years and has even been described in children as young as five years old. It often requires treatment with joint replacement.
The primary defect in the pathogenesis of SCD is that the resulting haemoglobin is less soluble when exposed to deoxygenated conditions and forms polymers within the red blood cell (RBC). These polymers aggregate causing the RBC to enlarge and deform. This provides it with the characteristic sickle shape. Upon re-oxygenation the RBC cell typically resumes its normal biconcave form, however after numerous episodes of sickling, the cells become irreversibly sickled. These sickle shape cells also are more easily dehydrated when deoxygenated and as a result acquire abnormal intracellular signalling pathways, which activate RBC adhesion molecules on the RBC membrane. These adhesion molecules are involved in the adhesion of RBCs, endothelial cells, neutrophils, monocytes and platelets, inducing the activation of multiple pro-inflammatory pathways. The resulting abnormal RBC has a shorter life span and has increased adhesive interactions. The clinical implication is that the RBC haemolyses and there is a slowing of blood flow in the microcirculation leading to painful vaso-occlusion and micro infarct end organ damage.
The management of SCD is multidisciplinary and is comprised of strategies to treat acute sickle cell crisis and long-term disease modifying approaches to prevent complications. This long-term approach is divided into supportive measures, disease modifying treatment and curative options.
Hydroxyurea was approved by the US Food and Drug Administration (FDA) in 1998 and the European Medicines Agency in 2007 for the management of patients with SCD although its use in children is still considered to be off-label by the FDA. It has proven successful in the prevention of complications in SCD and reduces mortality. In spite of our two decades of experience of hydroxyurea we still do not have a full understanding of its mechanism of action. Primarily it affects cell division by inhibiting the enzyme ribonucleotide reductase and thus depletes the cell of deoxyribonucleotide triphosphates (dNTPs). This leads to arrest of cell division or cell death.
Hydroxyurea also works by increasing foetal haemoglobin (HbF) production at the expense of normal adult haemoglobin (HbA). It does this by interfering with beta globin gene expression at the beta globin locus. HbF is the predominant haemoglobin in foetal life and early infancy and binds to oxygen with higher affinity than normal adult haemoglobin. This allows adequate oxygen transfer to the foetus during gas exchange in the intervillous space between mother and baby where there is mixing of both oxygenated and deoxygenated maternal blood. By six months of age it becomes almost entirely replaced by adult haemoglobin. Hydroxyurea reverses this natural post-natal switch from HbF to HbA and this results in reduced polymerisation, sickling, adhesion and haemolysis. The microcirculation blood flow improves and vaso-occlusive events are reduced. Hydroxyurea’s ability to increase nitric oxide further improves blood flow in the microcirculation. Nitric oxide is a potent vasodilator that becomes depleted in haemolysis. Free haemoglobin released by haemolysed RBCs scavenges nitric oxide and depletes it. By reducing haemolysis and inhibiting the scavenging effect of free haemoglobin, the vasodilatory effect of nitric oxide is preserved.
Hydroxyurea is not helpful in the acute management of a crisis as it takes weeks to months to become effective. There is no specific marker in clinical use to determine if the treatment will be of any benefit to the patient and in clinical practice it is offered to any patient who may achieve benefit. Many reproducible studies demonstrate that hydroxyurea reduces mortality with long-term use and reduces long-term complications in both adults and children. The 2011 Baby HUG trial showed that infants treated with hydroxyurea had improved splenic function, reduced pain episodes, reduced chest syndromes, reduced dactylitis and reduced need for transfusion. The treatment is largely very well tolerated and the predominant side effect is cytopaenias. As a result, these patients require regular full blood counts.
Blood transfusion therapy in SCD is of benefit in both the acute management of vaso-occlusive events and in the chronic management to prevent micro-infarct end organ damage. Most patients with SCD will undergo numerous transfusions in their lifetime putting them at risk for transfusion-associated complications. A simple top-up red RBC transfusion dilutes the volume of sickle cells containing haemoglobin S and replaces them with normal RBCs containing haemoglobin A. The resulting normal RBCs have a longer lifespan than their sickled counterparts. There is feedback to the kidneys to reduce erythropoietin production and the production of new sickle cells is slowed. The transfused blood increases the oxygen saturation of the circulation, increasing oxygen delivery to the tissues. This principle of increasing oxygenation is used in the pre-operative setting where a top-up RBC transfusion to a haemoglobin value of 10g/dL is associated with a reduced incidence of post-operative vaso-occlusive events.
In the long-term management of SCD, reducing the haemoglobin S percentage to below 30 per cent leads to a reduction in vaso-occlusive pain and acute chest syndromes. Many patients with SCD are commenced on chronic transfusion programmes scheduled at patient specific intervals guided by the patient’s clinical findings, haemoglobin level and haemoglobin S percentage. Regular transfusions are required for secondary prevention of stroke, acute chest syndrome, painful events and priapism. The SIT trial randomly assigned children with SCD and silent cerebral infarcts to monthly transfusions versus observation for three years and found that there were significant improvements in the quality-of-life of patients receiving regular transfusions. There were also reduced rates of pain, acute chest syndrome and symptomatic avascular necrosis.
In July 2017 the US FDA-approved L-glutamine oral powder for patients five years and older to reduce the complications of SCD. This was the first drug licensed for the management of SCD since hydroxyurea in 1998. Many studies have demonstrated that RBCs that are sickled have increased susceptibility to oxidative stress. Oxidative stress is measured by changes in nicotinamide adenine dinucleotide (NAD) homeostasis and is defined as the NAD redox potential. NAD redox potential is 20-30 per cent lower in sickle RBCs, but NAD is found in higher levels in sickle cells than in controls. This suggests that in the event of oxidative stress there is increased uptake of NAD by the sickle RBC. Sickle RBCs absorb glutamine, a precursor of NAD at increased rates compared to non-sickle cells. A hypothesis was formed that with increased glutamine supplementation, increased transport and utilisation of glutamine in sickled RBCs will lead to increased NAD and NADH levels thus providing increased defence against oxidative stress. The benefits of administering both L-glutamine and hydroxyurea together appear to be greater than either agent alone.
It is known that activation of the inflammatory system plays an important role in the pathogenesis of SCD. Cytokines are released and they quickly activate white blood cells. These activated white and red blood cells then bind to the endothelial cells via several selectins and integrins expressed by endothelial cells. Adhesion of inflammatory and red blood cells to the endothelium is primarily initiated by P selectin. Both animal and human studies have identified that deficiency of P selectin in those with SCD leads to defective adhesion of white blood cells to endothelial walls. This ultimately protects from vaso-occlusion. There are numerous potential treatments targeting P selectin in various stages of investigation.
One of promise is crizanlizumab. It is a humanised monoclonal antibody that binds selectively to P selectin. A phase 2 multicentre randomised controlled trial known as SUSTAIN was reported in the New England Journal of Medicine (NEJM) in 2016. In this trial high-dose treatment was associated with reduced frequency of sickle cell pain events compared to placebo. The annual sickle cell-related pain event rate was reduced by 32.1 per cent in patients already treated with hydroxyurea and by 50 per cent in those who were not already receiving hydroxyurea. The treatment was well-tolerated and there is much promise for this therapy as it undergoes further investigation
Haematopoietic stem cell transplant
Haematopoietic stem cell transplant (HSCT) is recognised as a potentially curative treatment for SCD. The current gold standard is myeloablative HLA matched sibling donors due to the reduced risk of both graft versus host disease and graft rejection. There have also been approaches using less myeloablative conditioning regimens. There are trials ongoing exploring the use of unrelated donors and despite the successes of this technique in the treatment of malignant blood disorders, results in SCD patients have largely had unsatisfactory results. The major difficulty in employing HSCT as a curative treatment for patients with SCD remains patient selection. This is attributed to disease heterogeneity, challenges in identifying patients at high risk of developing advanced disease, patient eligibility due to advanced multi-organ disease and concerns relating to transplant-related mortality. In clinical practice the experience of HSCT and SCD has yielded a five-year survival rate of 90-97 per cent, a transplant-related mortality rate of 7-10 per cent and an SCD-free survival rate of 80-90 per cent. The role of early transplantation in children to reduce SCD mortality has not been fully explored, but remains an area of ongoing investigation. HLA-haploidentical transplant is an appealing treatment due to the expansion of the donor. A ‘half matched’ related donor, usually the mother or father is used. An optimal conditioning regimen has not yet been identified, but it remains an area of advancing research.
Less than 18 per cent of eligible patients have a HLA-matched sibling donor for transplant. As a result, gene therapy is an increasingly exciting area of research in SCD and it may provide a long-term, potentially curative, treatment. Successful, sustained gene therapy has been reported previously in mouse models by lentiviral transfer of an anti-sickling beta-globin variant. In 2017 the NEJM published the outcome of a 13-year-old boy who was enrolled in a clinical trial to receive gene therapy using a LentiGlobin BB305 vector. This lentiviral vector is currently being used in seven patients with SCD and 22 patients with beta thalassaemia. It has a stable safety profile and has no evidence of insertional oncogenesis at 30 months. In this boy the transduced cells engrafted and normal cell counts followed across all lineages by day 88 post-transplant. The investigators did not report any vector-related side effects and the child remains well.
The complications of SCD are devastating to patients and until now progress has been slow in the achievement of cure. Thankfully, due to the recent advances in our knowledge of SCD pathogenesis we have, however, reached an exciting time. We have more potential treatment targets than ever and it is likely that considering the numerous pathological mechanisms involved, optimal therapy will require a multi-targeted treatment approach. Dynamic international collaboration and availability of funding is essential to support the ongoing research required to treat this highly complex disease.
References on request