From the outset, doctors are taught when hearing hoof beats, to think of horses, not zebras; focus on the most likely possibilities when making a diagnosis, not the unusual ones. But a new group of multidisciplinary specialists in Ireland are advising colleagues that sometimes they must look for a zebra. 

Neuroendocrine tumours

The Irish Neuroendocrine Tumour Group (I-NET) is the first of its kind in Ireland, bringing together a diverse range of physicians and surgeons with an interest in this rare malignant disease. Neuroendocrine tumours (NETs) are an uncommon group of cancers, often small and slow growing, which develop from cells in the diffuse endocrine system. As a result, NETs can form in multiple locations throughout the body, including the lungs, pancreas, and difficult-to-pinpoint areas within the midgut. 

Notoriously difficult to identify, even after the onset of symptoms, which are often non-specific and vague, a NET diagnosis can take an average of five to seven years,¹ by which time the cancer is usually at an advanced stage. 

For these reasons, the I-NET is urging doctors to adopt a high index of suspicion, particularly in patients with a long history of vague abdominal symptoms. Their message is simple: If you don’t suspect it, you can’t detect it.

Leading Irish expert, Professor Dermot O’Toole says there are between 2,500 and 3,000 people in Ireland with NETs, a figure probably underestimated due to a lack of knowledge and awareness regarding NETs, both within the medical profession and the wider public. 

“There are in excess of 200 new NET cancer patients diagnosed every year in Ireland, but the prevalence is far higher because a significant number of patients with slow growing tumours live for quite a long period of time. This contrasts starkly with pancreatic cancer, for example, for which the incidence rate and the death rate would be similar as the median survival is only about six months, even with therapy. 

“With neuroendocrine tumours, the incidence rate is much lower than the prevalence and this is quite characteristic of these NET tumours,” explains Prof O’Toole, a consultant gastroenterologist/pancreatologist and associate professor at St James’s Hospital and Trinity College Dublin.

Years to diagnosis

Due to the indolent nature of most of these tumours, over 50% of patients with NETs are incorrectly diagnosed and initially treated for the wrong disease. It is not unusual for patients to make many visits to the doctor over several years before an actual diagnosis is made, as symptoms are often very ambiguous, can be intermittent, and are similar to more common health problems.

Prof O’Toole adds: “For example, neuroendocrine tumours of the small bowl have symptoms that mirror irritable bowel syndrome, so the patient may only get a little abdominal pain and some diarrhoea and/or facial flushing. I’ve seen numerous cases that are misdiagnosed or diagnosed late; sometimes it’s genuine ignorance, sometimes it’s poor exploration, but certainly heightened awareness will probably improve diagnostic potential.”

International awareness of NET cancers among decision makers, health professionals and the general public has increased in recent years, spurred primarily by co-operative groups, such as the European Neuroendocrine Tumour Society (ENETS) – a society of almost 1,000 medical professionals in oncology, pathology, radiology, nuclear medicine, endocrinology, surgery and gastroenterology – as well as the hugely successful worldwide NET Cancer Awareness Day, which commenced in 2010.

Public awareness

However, it was the death of Steve Jobs, the iconic co-founder of Apple that catapulted this once obscure cancer into the international spotlight. The 56-year-old lost his lengthy battle with an islet cell pancreatic NET on October 5, 2011, stimulating a maelstrom of media coverage, albeit inaccurately reported at first as ‘pancreatic cancer’. 

Last year, on the first anniversary of Steve’s death, an iCancer campaign was launched to raise £2 million for research into an oncolytic virus that may help treat neuroendocrine cancer. This promising work is being carried out by a Swedish research team, led by Prof Magnus Essand, professor at the Department of Immunology, Genetics and Pathology, at Uppsala University.²

This growing awareness of such a rare cancer was also evident in Ireland where RTE journalist Tommie Gorman, who has been living with a NET for almost 20 years, spoke out about his cancer, chronicling his battle with this rare illness and his treatment in Uppsala, Sweden – a recognised international centre of excellence for the treatment of NETs – in the TV documentary ‘Europe, Cancer and Me’. 

The veteran broadcaster has also been involved in organising World Neuroendocrine Cancer Day events in Ireland, including the first Neuroendocrine Tumour Patient day, which was held in Trinity College Dublin in November 2012, during which hundreds of cancer patients had the opportunity to hear from leading Irish and international NET experts. 

I-NET

Coinciding with this event, two new groups were formally launched: A NET patient support group ‘NET Patient Network’, and the Irish Neuroendocrine Tumour Group. Commenting on the I-NET inaugural meeting, organiser Prof O’Toole said the educational day served as the first step towards developing a recognised Irish network of multidisciplinary experts with interest in this field to provide care for NETs patients. The I-NET group will now work towards concentrating efforts and resources in this regard, aligning practices according to recognised international standards. 

“There has been a lot of progress in Ireland; we have considerable interest in NETs from a diverse group of experts in different fields of medicine, pathology, radiology and surgery, which is very positive as if there’s one group of tumours that typifies the requirement of what we call a multidisciplinary team, it’s this group of tumours,” says Prof O’Toole, who is currently serving on the executive committee of the European Neuroendocrine Tumour Society (ENETS) and is chairman of the ENETS Centre of Excellence programme. 

The I-NET group is progressing a new model of care for the Irish health service for people with NETs, which is supported by the National Cancer Control Programme and based on guidelines set out by the ENETS in terms of diagnostic, management and future therapeutic strategies, as well as scientific endeavour and training. 

In addition, gaining recognition as a European centre is an achievable goal, according to Prof O’Toole. “There are currently 19 centres throughout Europe that are all working exactly on the same model and have undergone a rigorous external audit and received standards certification by an independent group. This network of centres allows NET patients to access specialists who can best treat them, and also unifies the care and research being conducted in the NET field across Europe. It’s our ambition to set up a similar model in Ireland,” Prof O’Toole confirms.

“This proposed model is to have a multidisciplinary care pattern provided by a parent NET group that includes a range of experts in the field, and we have these experts here in Ireland now. We will establish a hub and probably two satellite groups that would feed into the main centre. At this stage, it’s reasonable to say that a kernel centre of excellence in Dublin with satellite centres in Cork and Galway would be largely adequate to deal with the patient population in an Irish context.

“Ultimately, this would mean that where some patients may previously have had to travel to European centres, such as Uppsala, for treatment, we are increasingly able to offer these treatments and the expertise here in Ireland. 

“There are a few therapies that are not available to us, for example, we don’t have a centre for Peptide Receptor Radionuclide Therapy (PRRT) and, for the moment, it’s almost certainly cost effective to send patients who need this therapy abroad. However, only about 15% of patients with NETs at an advanced stage may require this type of therapy. Most patients are treated with surgical or endoscopic resection, chemotherapy, or just hormonal therapies, such as somatostatin analogues, which are frequently used.”

Pictured at the inaugural meeting of the Irish Neuroendocrine Neoplasm Group in the Long Room Hub, Trinity College Dublin were (l-r): Dr Dermot O’Toole, consultant gastroenterologist/pancreatologist and senior lecturer, St James’s Hospital and Trinity College Dublin; Dr Derek Power, consultant medical oncologist, Mercy University Hospital, Cork; Barbro Eriksson, University Hospital, Uppsala, Sweden; Dr Susan O’Reilly, head of National Cancer Control Programme; Dan Granberg, University Hospital, Uppsala, Sweden; Marcia Bell, Galway University Hospital; and Justin Groghegan, consultant surgeon, St Vincent’s University Hospital(click to enlarge)

Meeting the challenge

The management of patients with NETs represents a considerable challenge, due to their relatively infrequent and diverse presentations and the variable clinical course and response to treatment, underscoring the vital importance of collaboration between disciplines, such as endocrinologists, gastroenterologists, oncologists, surgeons, radiologists, nuclear medicine physicians and pathologists.

Recently, the European Neuroendocrine Tumour Society published the 2012 ENETS Consensus Guidelines for the Diagnosis and Treatment of Neuroendocrine Tumors,³ taking cognisance of novel diagnostic tools and therapies that have emerged in the last five years, as a substantial result of the continuous effort in the field.

The number of NET cases has increased worldwide in recent years to 40-50 cases per million, but in addition to a real change in the incidence of the disease, better diagnosis methods in imaging has certainly contributed to this. Regardless, further diagnostic efforts have to be made. 

“What we need and don’t have at present is a simple diagnostic test to help latch on to this disease at an early period. The biomarkers that we currently use have only about 70% sensitivity so they’re not perfect. Also, using simple biological or urinary markers is not adequate, especially in the early stage of the disease because many of these tumours have to achieve a critical mass or volume before they’ll secrete a detectable amount of the marker in the blood or urine. 

“Imaging, such as CT and MRI, and endoscopic techniques are also useful for localising primary tumours and their metastases, and new imaging and biochemical testing continue to be developed by researchers. But we should never underestimate the importance of clinical awareness because that’s from where all investigations stem,” Prof O’Toole stresses. 

“Our patients are extremely enthusiastic about the developing model of care in Ireland, which is wonderful because patient advocacy is very important in any disease and I’m really thrilled that they’re involved and so pro-active,” he adds.

NET registry planned

Plans are also at an advanced stage for the first Ireland NET Registry to gain new insights into this elusive cancer in Ireland. It is expected to commence collecting data on patients later this year. The registry will not only gather raw patient data but will also capture important demographic information, all of which can feed into service development and clinical research. 

Prof O’Toole remarks that progress in the diagnosis and management of patients with neuroendocrine tumours is unlikely to occur without the development of centres of excellence, such as the I-NET group is planning to establish in Ireland. 

“We need multidisciplinary expertise working together in clinical teams to co-ordinate multicentre studies, maintain clinical databases, and optimise the care of patients,” he continues. 

“We need to bridge the knowledge gap for this challenging disease, whether it’s facilitating a timely diagnosis or the best treatment strategy or new therapeutic innovations, it all translates into patient benefit.”

References

1. Modlin IM, Oberg K, Chung DC, et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncology 2008; 9(1): 161-172
2. Leja J, Yu D, Nilsson B, et al. Oncolytic adenovirus modified with somatostatin motifs for selective infection of neuroendocrine tumor cells. Gene Ther 2011; 18(11): 1052-1062 
3. The 2012 ENETS Consensus Guidelines for the Diagnosis and Treatment of Neuroendocrine Tumors. Available online: www.enets.org/guidelines_tnm_classifications.html&OPEN=menu,14