Neuroendocrine Cancer: Fibrosis – an unsolved mystery?

Background

It has long been observed that certain Neuroendocrine Tumours (NETs) are often associated with their ability to secrete hormones and these substances are thought to be responsible for the collection of symptoms which include (but not limited to) diarrhea, flushing and wheezing. One of the lesser known aspects of this disease is the development of fibrosis, both local and distant. These fibrotic complications may lead to considerable morbidity. They can also result in incidental diagnoses of NETs after causing abdominal obstructions.

The most well known form of fibrosis is ‘Hedinger Syndrome’ (so-called Carcinoid Heart Disease) tightly associated with midgut NETs and will not be covered further. However, mesenteric fibrosis is actually more common and also associated with midgut NETs. There are other less common locations involved including retroperitoneal fibrosis, pleural and pulmonary fibrosis and skin fibrosis.

According to a paper (abstract linked below) by Professor Martyn Caplin (et al) regarding mesenteric fibrosis, “it often has a characteristic appearance of a mesenteric mass with linear soft tissue opacities radiating outward in a “wheel spoke” pattern associated with distortion of the surrounding tissues” (see graphic below).

The mesentery and retroperitoneum areas

The mesentery and retroperitoneum are complex to describe but think of the mesentery as something holding the small intestine together with all its folds and the retroperitoneum describes the part of the abdomen that is generally closer to your backbone than to your belly button, i.e. behind the intestines.

Often labelled ‘Desmoplasia’, it is easily spotted on CT and MRI scans and is one of the unusual features of NETs vs other types of cancer. Some examples are below:

Desmoplastic-reaction-The-characteristic-desmoplastic-reaction-comprises-a-mesenteric — Desmoplastic reaction. The characteristic desmoplastic reaction comprises a mesenteric mass (black asterisks) with linear soft tissue opacities radiating outwards in a ‘spoke-wheel’ or stellate pattern (black arrows) and associated indrawing of the surrounding tissues . Distortion and retraction of the adjacent soft tissues results in kinking of the small bowel and can cause partial or complete bowel obstruction. The mesenteric mass is often associated with coarse calcification (black arrowhead).

Metastatic-carcinoid-tumor-to-the-root-of-the-mesentery-arrow-causing-typical — Metastatic Neuroendocrine Tumor to the root of the mesentery (arrow) causing typical circumferential desmoplastic

Axial CT image of a patient with a metastatic neuroendocrine tumor that demonstrates retroperitoneal thickening and fibrosis (arrow).

Small intestinal neuroendocrine tumor with characteristic serosal fibrosis causing kinking of the bowel wall (hematoxylin-eosin, original magnification 3 1; scanned slide) Grin, Andrea & Streutker, Cathy. (2015). Neuroendocrine Tumors of the Luminal Gastrointestinal Tract. Archives of pathology & laboratory medicine. 139. 750-756. 10.5858/arpa.2014-0130-RA.

What causes it, what problems does it cause and how can it be treated?

As with Hedinger Syndrome, which mostly causes right-sided fibrosis in the heart, mesenteric and retroperitoneal fibrosis (and others) is thought to be caused by the excess secretion of serotonin (5-HT) from NETs. I say ‘thought’ but no-one really knows for sure. There’s a few quite recent studies on the subject which I’ll provide abstracts here.

Uppsala Hospital Sweden. In one study entitled “Clinical signs of fibrosis in small intestinal neuroendocrine tumours” first published in November 2016 by Uppsala Hospital Sweden, it said that it was caused by serotonin and other cytokines released from tumour cells and which may induce fibrosis, leading to carcinoid heart disease and abdominal fibrotic reactions. A cohort study of patients with SI NETs diagnosed between 1985 and 2015 was carried out – a total of 824 patients. Clinically significant abdominal signs and symptoms of fibrosis occurred in 36 patients. Of these, 20 had critically symptomatic central mesenteric fibrosis causing obstruction of mesenteric vessels, and 16 had retroperitoneal fibrosis causing obstructive uropathy with hydronephrosis (the swelling of a kidney due to a build-up of urine). Extensive fibrosis causing mesenteric vessel obstruction and/or obstructive uropathy was more often associated with symptomatic and advanced disease encompassing lymph node metastases in the mesenteric root, para‐aortic lymph node metastases, as well as liver metastases and peritoneal carcinomatosis. Palliative intervention in terms of superior mesenteric vein stenting or resection of central mesenteric metastases and/or percutaneous nephrostomy and J stent treatment was beneficial in the majority of the patients. They concluded by saying that extensive abdominal fibrosis associated with clinically significant symptoms of intestinal ischaemia and/or obstructive uropathy was linked to advanced disease in patients with SI NETs. Prompt recognition and minimally invasive intervention was effective in disease palliation.

Royal Free Hospital. In another fairly recent paper entitled “Neuroendocrine tumors and fibrosis: An unsolved mystery?”, published by Professor Martyn Caplin of the Royal Free (and others), where this issue is discussed alongside the role of serotonin, growth factors, and other peptides in the development of NET related fibrotic reactions. They also suggested serotonin as the main culprit in both CHD fibrosis and in mesenteric/retroperitoneum and expressed many of the factors above. This study suggested that up to 50% of SI NET patients may be involved but looking at both reports together indicates that the first study above only isolated clinically significant cases whereas Royal Free looked for signs in all cases.

Another recent paper (also a paid subscription) from Royal Free (Caplin et al) indicated that the severity of mesenteric desmoplasia did not seem to demonstrate a statistically significant effect on overall survival or long-term outcome (taken from a study of 147 patients at Royal Free London). Sounds like good news but there are clearly consequences that could arise from the issue.

I do not have access to all the texts above, only the abstracts which I’ve linked above (all only available from paid subscriptions).

One older publication authored by known UK NET expert endocrinologist, covered some of the above issues but added that fibrosis in the pleural/pulmonary areas and the skin could also be associated. For ease of reference, the following extracts are cited to Fibrosis and carcinoid syndrome: from causation to future therapy Maralyn Druce, Andrea Rockall and Ashley B. Grossman Druce M. et al. Nat. Rev. Endocrinol. 5, 276–283 (2009); doi:10.1038/nrendo.2009.51

“Mesenteric fibrosis and carcinoid syndrome. Intestinal fibrosis in a series of 37 patients with jejunoileal carcinoid tumors, 8 of 12 patients with bowel obstructions had evidence of fibrosis or kinking of the bowel.6 among 36 patients with carcinoid syndrome who were seen at Yale university, 15 either had fibrosis at the time of surgery, or developed it subsequently. In a surgical series of 121 patients with midgut carcinoid tumors, 75 required laparotomy, due to abdominal pain; of these patients, 59 were noted to have marked mesenteric fibrosis at the time of surgery. Spread of the primary tumor into the mesentery and peritoneum can result in a marked fibrotic reaction. This fibrosis can mat together multiple loops of bowel and result in kinking, ischemia, volvulus and obstruction.

Retroperitoneal fibrosis. True retroperitoneal fibrosis is a rare clinical entity, in which inflammation results in fibrosis throughout the retroperitoneum. In two-thirds of patients this condition is idiopathic. The majority of cases that are not idiopathic are associated with drugs, such as antihypertensive agents and methysergide. Although retroperitoneal fibrosis is not commonly seen in the context of carcinoid syndrome and has not been reported in any recent, major review, several cases have been reported in literature.

Pleural and Pulmonary Fibrosis. In a review of 50 patients with carcinoid tumors who presented to a single unit over 9 years and were examined using CT, 14 patients had pleural thickening, and in 9 of these cases no other attributable cause was established. All 14 patients had developed this pleural thickening within 2 years of being diagnosed as having carcinoid syndrome, and 7 of the 9 patients also had fibrosis elsewhere, for example, in the heart valves, skin or mesentery. Carcinoid syndrome has rarely been described as a cause of alveolar fibrosis, but fibrosis elsewhere in the lung occurs more frequently. in a series of 25 patients known to have peripheral carcinoid tumors of the lung, 19 displayed hyperplasia of neuroendocrine cells elsewhere in the lung, and 8 patients (25%) had lesions of obliterative bronchiolitis, including 2 with asymptomatic obstruction of airflow. These data suggest that bronchiolar fibrosis is not uncommon, although it is usually subclinical.

Skin fibrosis. Dermal fibrosis may be primary or secondary to peripheral vasospasm, which occurs in response to vasoconstrictor substances that are secreted by the tumor. Carcinoid syndrome associated with scleroderma has been reported: in one series, its prevalence was 2 cases in 25 individuals. This complication of carcinoid syndrome is usually a late feature and may be attenuated by the use of cyproheptadine hydrochloride, parachlor phenylalanine and prednisolone, which suggests a causative role for tryptophan metabolism and 5-HT”

What happened to me?

Since I was diagnosed in 2010, I’ve always known I’ve had a fibrosis issue in the retroperitoneal area, as it was actually identified on my very first CT Scan, which triggered my diagnosis. Here’s how the radiologist described it – “There is a rind of abnormal tissue surrounding the aorta extending distally from below the renal vessels. This measures up to 15mm in thickness”. He went on to describe that “almost certainly malignant”. The second and third scans would go on to describe as “retroperitoneal fibrosis” and “a plaque like substance”. Interestingly the fibrosis itself does not appear to ‘light up’ on nuclear scans indicating it was not cancerous (see below).

I really didn’t know what to make of this issue at diagnosis, although I did know the aorta was pretty important! Fortunately I had a surgeon who had operated on many NET patients and has seen this issue before. After my first surgery, he described it as a “dense fibrotic retroperitoneal reaction encircling his aorta and cava (inferior vena cava (IVC))”. My surgeon was known for difficult and extreme surgery, so as part of the removal of my primary, he also spent 3 hours dissecting out the retroperitoneal fibrosis surrounding these important blood vessels and managed 270 degree clearance. The remnant still shows on CT scans. Some of the removed tissue was tested and found to be benign, showing only florid inflammation and fibrosis (thankfully). That said, the abstract papers above has led me to believe that my retroperitoneal fibrosis is clinically significant.

Routine surveillance in 2018 has picked up that retroperitoneal fibrosis is potentially impinging on important vessels in this area, particularly the left ureter but including some blood vessels. A follow up Ga68 PET confirms active lymph nodes in the retroperitoneal area that might be contributing to continued or new fibrosis growth.

In order to further assess risk to my kidneys, I had a different nuclear can known as a Renal MAG3. This scan looks at the blood supply, function and flow of urine from the kidneys. The output will inform my MDT and surgical team looking at treatment options to counter the risk of damage and the timing of potential surgery to correct the issue. I’m happy to report that the MAG3 scan confirmed there are no blockages to my kidneys or bladder. It did confirm my right kidney is doing 60% of the work, the suspected left one is covering the remaining 40% effort. Apparently it’s pretty normal that it isn’t exactly 50/50. Surgery is now on the back burner (phew!). The kidney function will be monitored closely going forward.

Summary

These issues need to be identified early on in diagnostics, preventative treatment considered and then monitored going forward. Potential complications may include (but not be limited to) bowel and blood vessel obstructions. Retroperitoneal fibrosis also needs to be monitored as potential complications may include (but not be limited to) obstructive uropathy.

For those worried about this issue, please note that when you look at the statistics from Uppsala, only 4.5% of cases are classed as clinically significant and with the retroperitoneal area, the figure reduces to 2%.

Neuroendocrine Cancer is normally slow growing BUT …..

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ASCO 2017 – Let’s talk about NETs #ASCO17

ASCO (American Society of Clinical Oncology) is one of the biggest cancer conferences in the world normally bringing together more than 30,000 oncology professionals from around the world to discuss state-of-the-art treatment modalities, new therapies, and ongoing controversies in the field. As Neuroendorine Tumors is on a roll in terms of new treatments and continued research, we appear to be well represented with over 20 ‘extracts’ submitted for review and display. This is fairly complex stuff but much of it will be familiar to many. I’ve filtered and extracted all the Neuroendocrine stuff into one list providing you with an easy to peruse table of contents, complete with relevant linkages if you need to read more. For many the extract title and conclusion will be sufficiently educational or at least prompt you to click the link to investigate further. Remember, these are extracts so do not contain all the details of the research or study. However, some are linked to bigger trials and linkages are shown where relevant. I’ve also linked to some of my blog posts to add context and detail.

I’m hoping to capture any presentations or other output from the meeting which appears to be relevant and this will follow after the meeting. I will also be actively tweeting any output from the live event (for many cancers, not just NETs).

There’s something for everyone here – I hope it’s useful.

68Ga-DOTATATE PET/CT to predict response to peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumours (NETs). Conclusions: Objective response to PRRT defines a subset of patients with markedly improved PFS. SUVave 21.6 defines a threshold below which patients have a poor response to PRRT. This threshold should be taken forward into prospective study. Check out my recent blog discussing ‘Theranostic pairing” – click here	Rohini Sharma	4093
A multicohort phase II study of durvalumab plus tremelimumab for the treatment of patients (PTS) with advanced neuroendocrine neoplasms (NENs) of gastroenteropancreatic (GEP) or lung origin (the DUNE trial-GETNE1601-). News of a trial – no conclusion included. However, see trial data NCT03095274	Ignacio Matos Garcia	TPS4146
Association between duration of somatostatin analogs (SSAs) use and quality of life in patients with carcinoid syndrome in the United States based on the FACT-G instrument. Conclusions: The duration of SSA use was positively associated with QoL benefit among CS patients. This may be explained by long-term effectiveness of SSAs or selection bias favoring patients with more indolent disease. Future studies will be needed to distinguish between these possibilities.	Daniel M. Halperin	e15693
Association of weight change with telotristat ethyl in the treatment of carcinoid syndrome. Conclusions: The incidence of weight gain was dose-related on TE and was greater than that on pbo. It was possibly related to a reduction in diarrhea severity, and it may be a relevant aspect of TE efficacy among patients with functioning metastatic NETs. Clinical trial information: NCT01677910 See my blog post Telotristat Ethyl	Martin O Weickert	e15692
Blood measurements of neuroendocrine tumor (NET) transcripts and gene cluster analysis to predict efficacy of peptide radioreceptor therapy. Conclusions: A pre-PRRT analysis of circulating NET genes, the predictive quotient index comprising “omic” analysis and grading, is validated to predict the efficacy of PRRT therapy in GEP and lung NETs.	Lisa Bodei	4091
Capecitabine and temozolomide (CAPTEM) in neuroendocrine tumor of unknown primary. Conclusions: CAPTEM shows activity in neuroendocrine tumor of unknown primary. Currently FDA approved treatment options for grade I and grade II GI NETs includes somatostatin analogs and everolimus. Both of which are cytostatic and of limited use in case of visceral crisis or bulky disease where disease shrinkage is required. CAPTEM should be considered for grade II NETS of unknown primary.	Aman Chauhan	e15691
Clinical and epidemiological features in 495 gastroenteropancreatic neuroendocrine patients in Mexico. Conclusions: This is the first multi-center study in Mexico. Which reflects the clinical characteristics of the NET_GET. The results differ in their epidemiology from that reported in other countries. However, the clinical and therapeutic results are very similar.	Rafael Medrano Guzman	e15687
Effect of lanreotide depot (LAN) on 5-hydroxyindoleacetic acid (5HIAA) and chromogranin A (CgA) in gastroenteropancreatic neuroendocrine (GEP NET) tumors: Correlation with tumor response and progression-free survival (PFS) from the phase III CLARINET study. Conclusions: These data suggest that serotonin is secreted by nonfunctioning tumors, but does not reach the threshold required for clinical carcinoid symptoms. Monitoring 5HIAA and CgA may be useful during LAN treatment of nonfunctional GEP NETs. Clinical trial information: NCT00353496	Alexandria T. Phan	4095
Final progression-free survival (PFS) analyses for lanreotide autogel/depot 120 mg in metastatic enteropancreatic neuroendocrine tumors (NETs): The CLARINET extension study. Conclusions: CLARINET OLE suggests sustained antitumor effects with LAN 120 mg in enteropancreatic NETs irrespective of tumor origin, and suggests benefits with LAN as early treatment. Clinical trial information: NCT00842348	Edward M. Wolin	4089
Lanreotide depot (LAN) for symptomatic control of carcinoid syndrome (CS) in neuroendocrine tumor (NET) patients previously responsive to octreotide (OCT): Subanalysis of patient-reported symptoms from the phase III elect study. Conclusions: Pts showed improvement in CS symptoms of flushing and diarrhea and reduction in 5HIAA levels with LAN treatment, indicating efficacy of LAN regardless of prior OCT use. Transition from OCT to LAN was well tolerated among prior OCT pts in ELECT. Clinical trial information: NCT00774930 Check out my blog post about Lanreotide and Lanreotide vs Octreotide	George A. Fisher	4088
Molecular classification of neuroendocrine tumors: Clinical experience with the 92-gene assay in >24,000 cases. Conclusions: These findings highlight the utility of molecular classification to identify distinct NET tumor types/subtypes to improve diagnostic precision and treatment decision-making. In addition, significant differences in the distribution of molecular diagnoses of NET subtype by age and gender were identified.	Andrew Eugene Hendifar	e15700
Multi-omic molecular profiling of pancreatic neuroendocrine tumors. Conclusions: In PNETS, multi-omic profiling through the KYT program identified targetable alterations in several key pathways. Outcome data will be explored.	Rishi Patel	e15685
Outcomes of peptide receptor radionuclide therapy (PRRT) in metastatic grade 3 neuroendocrine tumors (NETs). Conclusions: In this poor prognosis G3 NET cohort of whom 77% had received prior chemotherapy, a median OS of 18 months from start of PRRT is encouraging and warrants further study. PRRT is a promising treatment option for patients with G3 NET with high somatostatin-receptor expression selected by SSRI.	Mei Sim Lung	e15694
Periprocedural management of patients undergoing liver resection or liver-directed therapy for neuroendocrine tumor metastases. Conclusions: Occurrence of documented carcinoid crisis was low in this high-risk population. However, a significant proportion of patients developed hemodynamic instability, suggesting that carcinoid crisis is a spectrum diagnosis and may be clinically under-recognized. Use of octreotide was not associated with risk of carcinoid crisis or hemodynamic instability; however, this analysis was limited by our modest sample size at a single institution. There remains a need to establish an objective definition of carcinoid crisis and to inform standardization of periprocedural use of octreotide for at-risk patients. See my blog on “Carcinoid Crisis”	Daniel Kwon	e15689
Predictive factors of carcinoid syndrome among patients with gastrointestinal neuroendocrine tumors (GI NETs). Conclusions: By assessing patients with GI NET from two independent US claim databases, this study suggested that patients diagnosed with CS were 2-3 times more likely to be diagnosed with liver disorder, enlargement of lymph nodes, or abdominal mass, than those without CS during the one year prior to CS diagnosis. Future studies using patient medical charts are warranted to validate and interpret the findings. These findings, when validated, may aid physicians to diagnose CS patients earlier.	Beilei Cai	e15690
Predictors of outcome in patients treated with peptide radio-labelled receptor target therapy (PRRT). Conclusions: Radiological progression within 12 months of completion of PRRT is associated with a worse outcome in terms of OS. Patients with greater liver involvement and highest CgA levels are more likely to progress within 12 months of treatment completion. Earlier treatment with PRRT in patients with radiological progression not meeting RECIST criteria may need to be considered. There may be a greater survival benefit if PRRT is given prior to the development of large volume disease.	Dalvinder Mandair	4090
Pre-existing symptoms, resource utilization, and healthcare costs prior to diagnosis of neuroendocrine tumors: A SEER-Medicare database study. Conclusions: To the best of our knowledge, this is the first population-based study to examine potentially relevant pre-existing symptoms, resource utilization and healthcare costs before NET diagnosis. NET patients were more likely to have certain conditions and incurred higher resource utilizations and costs in the year preceding diagnosis of NET.	Chan Shen	4092
Prevalence of co-morbidities in elderly patients with distant stage neuroendocrine tumors. Conclusions: This population-based study showed that elderly NET pts have significantly different prevalence of co-morbidities compared to non-cancer controls. The impact of these conditions on survival and therapeutic decisions is being evaluated.	A. Dasari	e15699
Prognostic factors influencing survival in small bowel neuroendocrine tumors with liver metastasis. Conclusions: In patients with SBNET with liver metastasis, higher tumor grade and post-operative chemotherapy increased risk of death. However, resection of the primary tumor along with liver metastasis improves the 5-year OS with complete cytoreduction providing the most benefit.	Nicholas Manguso	e15688
Role of 92 gene cancer classifier assay in neuroendocrine tumor of unknown primary. Role of 92 gene cancer classifier assay in neuroendocrine tumor of unknown primary. \| 2017 ASCO Annual Meeting Abstracts Conclusions: Tissue type ID was able to identify a primary site in NETs of unknown primary in majority (94.7%) of cases. The result had direct implication in management of patients with regards to FDA approved treatment options in 13/38 patients (pNETs, merkel cell and pheochromocytoma).	Aman Chauhan	e15696
Surgery in combination with peptide receptor radionuclide therapy is effective in metastatic neuroendocrine tumors and is definable by blood gene transcript analysis. Conclusions: Radical loco-regional surgery for primary tumours combined with PRRT provides a novel, highly efficacious approach in metastasised NET. The NETest accurately measures the effectiveness of treatment.	Andreja Frilling	e15697
The impact of pathologic differentiation (well/ poorly) and the degree of Ki-67 index in patients with metastatic WHO grade 3 GEP-NECs. Conclusions: Grade 3 GEP-NECs could be morphologically classified into well and poorly differentiated NETs. Additionally, among grade 3 GEP-NECs, there was a significant difference in ranges of Ki67 index between well and poorly differentiated NECs. Higher levels ( > 60%) of Ki67 index might be a predictive marker for efficacy of EP as a standard regimen in grade 3 GEP-NECs. Check out my blog post on Grading which has incorporated latest thinking in revised grade 3 classification	Seung Tae Kim	e15686
Theranostic trial of well differentiated neuroendocrine tumors (NETs) with somatostatin antagonists ⁶⁸Ga-OPS202 and ¹⁷⁷Lu-OPS201. Conclusions: In this trial of heavily treated NETs, preliminary data are promising for the use of ⁶⁸Ga-OPS202/¹⁷⁷Lu-OPS201 as a theranostic combination for imaging and therapy. Additional studies are planned to determine an optimal therapeutic dose and schedule. Clinical trial information: NCT02609737	Diane Lauren Reidy	4094
Use of antiresorptive therapy (ART) and skeletal-related events (SREs) in patients with bone metastases of neuroendocrine neoplasms (NEN). Conclusions: SREs in NEN patients with BM were not uncommon, especially in patients with grade 3 NEN and osteolytic metastases. Application of ART did not significantly alter median OS or TTSRE, no subgroup with a benefit of ART could be identified. The use of ART in NEN should be questioned and evaluated prospectively.	Leonidas Apostolidis	4096
Targeted radiopeptide therapy Re188-P2045 to treat neuroendocrine lung cancer Conclusions: Rhenium Re 188 P2045, a radiolabeled somatostatin analog, may be used to both identify and treat lung cancer tumors. The ability to image and dose patients with the same targeted molecule enables a personalized medicine approach and this highly targeted patient therapy may significantly improve treatment of tumors that over express somatostatin receptor.	Christopher Peter Adams, Wasif M. Saif	e20016

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Don’t believe the hype – Neuroendocrine Cancer Myths debunked

OPINION.

There’s a lot of inaccurate and out of date information out there. Some is just a lack of understanding, often with a combination of patient forum myth spreading. Some can only be described as propaganda.

Myth 1: All Neuroendocrine Tumours are benign

Not true. By any scientific definition, the word ‘tumour’ means ‘an abnormal mass of tissue that results when cells divide more than they should or do not die when they should. Tumours may be benign (not cancerous), or malignant (cancerous)’. Sure, some NETs will be benign. However, The World Health Organisation (WHO) 2010 classification for digestive system is based on the concept that all NETs have malignant potential, and has therefore abandoned the division into benign and malignant NETs and tumours of uncertain malignant potential. This has been reinforced in the 2017 update to include clarification for other endocrine organ types of NET including Pheochromocytoma. Read more here. The word ‘Carcinoid’ is inextricably linked with this issue – read here why we need to stop using the term to help fight the benign myth.

Myth 2: Neuroendocrine Tumours is a terminal condition

Not true. By any definition of the word terminal in a medical diagnostic context, most NET patients have a good prognostic outlook, even those with metastatic and incurable variants of the disease. Read more here.

being_there_front — Graphic courtesy of Ellie McDowell

Myth 3: Carcinoid is another word for Neuroendocrine Tumours

Not true. Carcinoid is a very old term and was phased out years ago. Carcinoid is not mentioned in the latest WHO Classification schemes for Neuroendocrine Neoplasms (a term covering Neuroendocrine Tumours and Neuroendocrine Carcinoma). Unfortunately, the problem is exacerbated by organisations and individuals who still use the word. Also, those who use the following terms:

“Carcinoid Neuroendocrine”,
“Neuroendocrine Carcinoid”,
“Carcinoid and Neuroendocrine”,
“Neuroendocrine and Carcinoid”,
“Carcinoid NETs” or “CNET”

These are all contextually incorrect and misleading terms (not to mention the bad grammar). ENETS, NANETS and NCCN publications are gradually phasing the word out except in relation to Carcinoid Syndrome (and even then there could be easy solutions for this). Read more here and here.

Myth 4: All NET patients get ‘carcinoid syndrome’

Not true. Firstly, many NET cancers are non-functional; and secondly, carcinoid syndrome is only one of a number of “NET Syndromes” associated with the various types of NET. However, the issue is further confused by those who use the word ‘Carcinoid‘ to incorrectly refer to all NETs and use Carcinoid Syndrome to refer to all NET Syndromes. Read more here.

Myth 5: Neuroendocrine Neolasms are rare

Not true. As a collective grouping of cancers, this is no longer accurate. Read more here. Also check out my post about the “Invisible NET Patient Population“.

Myth 6: Steve Jobs had Pancreatic Cancer

Not true. Steve Jobs had a Neuroendocrine Tumour of the Pancreas. Ditto for a few other famous names. Read more here.

steve jobs 2010 — The last few years have reminded me that life is fragile

Myth 7: I’m not getting chemotherapy, I must be doing OK?

Not true. For some cancers or some sub-types of cancers, although it remains an option, chemotherapy is not particularly effective, e.g. some types of Neuroendocrine Cancer (NETs). In general, well differentiated NETs do not normally show a high degree of sensitivity to chemotherapy, although some primary locations fare better than others. However, many of the treatments for NET Cancer are somewhat harsh, have long-term consequences, and have no visible effects. NET patients are often said to “look well” but that doesn’t mean they are not struggling behind the scenes or under the surface. Read more here. P.S. Afinitor (Everolimus), Sutent (Sunitinib) are not chemo – Read more here.

Myth 8: All diarrhea is caused by carcinoid syndrome

Not true. It could be one of the other syndromes or tumor types or a side effect of your treatment. Check out this post.

Myth 9: Neuroendocrine Tumours is a ‘good cancer’

Not true. Simply, no cancer is good. Some are statistically worse than others in prognostic terms, that’s true…… but living with NETs is very often not a walk in the park. However, no one cancer is better to get than any other – they’re all bad. Read more here.

Myth 10: Every NET Patient was misdiagnosed for years

Not true. Many NET Patients are correctly diagnosed early on in their investigation and in a reasonable time. This myth is perpetuated because of two things: firstly, on forums, the ratio of long-term misdiagnosis is high creating a false perception; and secondly, the method of capturing patient surveys is not extensive enough – again creating a false perception. In fact, the latest and largest database analysis from US indicates earlier diagnosis is improving, with more and more NETs being picked up at an early stage. Read more here.

Myth 11: Somatostatin Analogues are a type of Chemotherapy

Not true. Somatostatin Analogues (e.g. Octreotide and Lanreotide) are not chemotherapy, they are hormone inhibiting drugs. They are more biotherapy. As the drugs latch onto somatostatin receptors, they are more targeted than systemic. For the record, Everolimus (Afinitor) and Sunitinib (Sutent) are not chemotherapy either. Read more here.

Myth 12: Stuart Scott (ESPN) and Audrey Hepburn had Neuroendocrine Cancer.

Not true. This is a common misunderstanding within the community. They both had Pseudomyxoma Peritonei (PMP). Read more about PMP here.

Myth 13: I’ve been diagnosed with Neuroendocrine Tumours – my life is over

Not true. Many patients live a very long time and lead fairly normal lives with the right treatment and support. It’s difficult but I try not to use ‘I can’t’ too much. Read more here.

Myth 14: There are only a handful of Neuroendocrine specialists in the world

Not true. There are many specialists in many countries. Get links to specialists by clicking here

Myth 15: The Ga68 PET scan is replacing the CT and MRI scan in routine surveillance for all NET Patients

Not true. It is actually replacing the Octreotide Scan for particular purposes, or will eventually. Read more by clicking here.

Myth 16: All NET Patients are Zebras

Not true. They are in fact human beings and we should treat them as such. Please don’t call me a zebra, I and many others don’t appreciate it. Please don’t use the term on my social media sites, the comment or post will be removed. Sorry but I refuse to perpetuate this outdated dogma. Read why here:

Myth 17: Multiple Endocrine Neoplasia (MEN) is a type of Neuroendocrine Tumour

Not true. Multiple Endocrine Neoplasia are syndromes and inherited disorders not tumours. You can actually have MEN and not have any tumours. However, these disorders can put people at more risk of developing Neuroendocrine or Endocrine Tumours. Read more here

Myth 18: Palliative Care means end of life or hospice care

Not true. Palliative care is specialized medical care that focuses on providing patients relief from pain and other symptoms of a serious illness. A multidisciplinary care team aims to improve quality of life for people who have serious or life-threatening illnesses, no matter the diagnosis or stage of disease. Read more here

Myth 19: Serotonin is found in foods

Not true. Serotonin is manufactured in the body. Read more here

Myth 20: NETs cannot be cured

Not true. If caught early enough, some NETs can be treated with curative intent (totally resected with margins) with little or no further follow up. It says this in ENETS and NANETS publications which are authored by our top specialists. If we can’t believe them, who can we believe? Read more here.

Myth 21: Pancreatic Enzyme Replacement Therapy (Creon etc) is only for pancreatic patients

Not true. It’s for any patient who is exhibiting exocrine pancreatic insufficiency. Read more here.

Myth 22: High Grade NETs are Carcinomas

Not entirely true. Grade 3 (high grade) comprises well differentiated tumours and poorly differentiated tumours. Only poorly differentiated tumour are carcinomas. Read more here.

More to follow no doubt

For general cancer myths and the dangers of fake health news, please see my ARTICLE HERE

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Ronny

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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

Does your body now have an extra organ? The MESENTERY

One of the very first words I heard at diagnosis was the word “Mesentery“. In the news today is the announcement that is now might just be a new organ following accepted findings from research conducted in the University of Limerick Ireland. I always knew it was something which held the small and large intestines in place within the abdomen so like many others, I just thought it was some kind of membrane type structure and I also knew there was some kind of interaction with the peritoneum, another word which I was to become familiar with.

This is an important area for NET patients as many will have mesenteric involvement in their disease. I’ve read reports of a primary mesenteric tumour although it’s mainly a site for secondary disease (metastasis). It’s no surprise when you consider the geography – the small and large intestines are inextricably linked to this new organ. There is pancreatic involvement too. The mesentery contains many lymph nodes (the main place for metastasis for small intestinal NETs and other types) and has important blood vessels adding complexity to surgery. It’s also a place where there’s likely to be fibrotic reactions (desmoplasia) from the excess release of serotonin which can also complicate surgery.

When I check my own records, I can see statements such as “mesenteric disease”, “bulky mesenteric nodes”, “further nodal disease situated on the superior mesenteric artery and vein” and “dense retroperitoneal reaction encircling his aorta and cava from just below the level of the superior mesenteric artery”. When I also look at the post surgical reports, I can see that I had something called a “mesenteric root dissection” which needed a “superior mesenteric vein reconstruction”.

So there you have it, the anatomic description that had been laid down over 100 years of anatomy was incorrect. This organ is far from fragmented and complex. It is simply one continuous structure. According to the article I read, medical students started being taught that the mesentery is a distinct organ and the world’s best-known series of medical textbooks, Gray’s Anatomy, has even been updated to include the new definition. Finally, so what you might be thinking? Here’s a quote from the person who led the work:

“The next step is the function,” Coffey explained. “If you understand the function you can identify abnormal function, and then you have disease. Put them all together and you have the field of mesenteric science … the basis for a whole new area of science.”

Reference material:

http://www.sciencealert.com/it-s-official-a-brand-new-human-organ-has-been-classified

http://www.chicagotribune.com/lifestyles/health/ct-mesentery-new-human-organ-20170104-story.html

https://www.ul.ie/research/blog/irish-surgeon-identifies-emerging-area-medical-science

Thanks for listening

Ronny

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Neuroendocrine Cancer: Hurry up and wait

When I was diagnosed with metastatic Neuroendocrine Cancer on 26 July 2010, I just wanted them to hurry up and fix my body so I could get back to normal. My expectations of speed turned out to be wildly inaccurate and in hindsight, I was also wildly naive. You see, with Neuroendocrine Cancer, particularly well-differentiated, low or medium grade tumours, it sometimes doesn’t work as fast as you would think and there are good reasons for that.

The complexity of the condition needs some consideration as the physicians work up a treatment plan. I’m quite happy and content they took their time, rather than rush into the wrong decisions. If you think about it, this is an advantage with low and medium grade NETs……you normally have some time to get the ducks in a line (and there are some pretty important ducks in that line).

Here’s a very short video discussing this during a patient video shoot: Click here.

I had a confirmed biopsy result following some incidental CT scans and other tests. However, they now needed further checks and marker tests to work out the extent of the disease. So the timeline leading up to major surgery ended up like this:

Diagnosis: 26 July 2010. Met with Oncologist. Grade 2 Small Intestine NET with distant metastasis (Stage 4)

Chromogranin A and 5HIAA: submitted 28 July. Results received 13 August – both elevated, indicating and confirming tumour bulk and function status respectively

Octreotide Scan: 17-19 August. Report issued 24 August – confirmed CT plus additional distant hotshots. Also confirmed my tumour receptors were avid to somatostatin analogues.

Daily Octreotide Injections: Started 9 September to control syndrome (derisk surgery)

Referred to NET Multi-Disciplinary Team (MDT): 15 September – they now had sufficient data to form a treatment plan.

Holiday: Late September (it was booked and I felt OK, why not!)

Further MDT assessment and consultations: 1- 7 October

Bland Liver Embolisation: 19 October

First Surgery: 9 November – to remove primary and debulk local and regional spread.

You can read the rest of my treatment background here.

So it took 75 days from diagnosis to opening me up to remove the first batch of tumours. With reasonably slow-growing tumours, that isn’t really a long time when you consider they had probably been growing inside me for several years. I’m sure others waited even longer.

Sometimes rushing straight into the operating theatre isn’t really the best option. I’m still here!

Keep calm and hurry up and wait!

Thanks for reading

Ronny

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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

Ronny Allan is an award winning patient leader and advocate for Neuroendocrine Cancer.

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Neuroendocrine Cancer Nutrition Series Part 4 – Food for Thought?

Nutrition is an important subject for many cancers but it is particularly important for Neuroendocrine Cancer. In the previous parts of this series I focussed on the following:

Article 1 – Vitamin and Mineral Challenges. This was co-authored by Tara Whyand, UK’s most experienced NET Specialist Dietician. This blog provides a list of vitamins and minerals which NET Cancer patients are at risk for deficiencies, together with some of the symptoms which might be displayed in a deficiency scenario.

Article 2 – Malabsorption. Overlapping slightly into Part 1, this covers the main side effects of certain NET surgical procedures and other mainstream treatments. Input from Tara Whyand.

Article 3 – ‘Gut Health’. This followed on from the first two blogs looking specifically at the issues caused by small intestine bacterial overgrowth (SIBO) as a consequence of cancer treatment. Also discusses probiotics. Input from Tara Whyand.

Article 5 – ‘Pancreatic Enzyme Replacement Therapy’. The role of PERT (Creon etc) in helping NET Patients. Input from Tara Whyand.

I said in Article 1 that my intention is not to tell you what to eat, even though that might be a challenge for many and this theme continues. The issue with Nutrition and Diet in general, is that it’s very individual and what works for one may not work for another. Rather I’d like to focus in on why such things might have an effect – patients can then experiment and see what works for them. NET patients may have multiple problems and issues (including the effects of eating) which people may be relating to their cancer or the effects of a particular syndrome or treatment (working that out can be difficult!). Even if I link you to an authoritative site, it will most likely only show GENERAL GUIDELINES, since patients with NET Cancer should really be assessed on a case-by-case basis. However, I can say that from personal experience, these guidelines are a good base to start in understanding the issue. You should always seek professional advice from a reliable ‘NETs aware’ nutritionist that can help you determine what your nutritional needs are and also can guide you in the right direction regarding food and supplement intakes. Be wary of the internet on diet and nutrition, there is much ‘quackery’ out there and normally they want to sell something regardless of whether it’s good for you or not. Fake healthcare news is big business unfortunately. You may also enjoy article 2 and article 3 of this series in internet dangers.

In this article, I want to cover the ‘knotty’ problem of what is in food that might be provoking a reaction and why. The other thing I would emphasise is that the cause of ‘provocation’ might not just be from what you have eaten, but how much. Moreover, whether the cause is syndromic, due to treatment; or from a comorbidity. For example, if you’ve had classic small intestinal NET surgery, you’re likely to be missing a few feet of small intestine and at least your ascending colon and all that goes with that (i.e. you’ve had a right hemicolectomy). It follows that your food might transit quicker than normal on its journey from mouth to toilet. There are no doubt other issues which might cause you to ‘move quickly’ and most of these issues will have been covered in Series Articles 1, 2 and 3. For those with Carcinoid Syndrome, you may also find my blog on the 5 E’s useful.

A high level of serotonin is something people might be looking to avoid due to its relationship with midgut NETs and in particular those with Carcinoid Syndrome. One thing I noticed is that experienced dietitians are not saying you must totally avoid foods associated with serotonin. I say “associated” because serotonin is not found in foods (another NET myth), it is manufactured from the amines in food. The only time dieticians would recommend staying totally away from these foods is before and during a 5HIAA urine test (5HIAA is a by-product of serotonin) as this could skew the results. Experienced NET dieticians will also tell you that amines in foods containing the precursor to Serotonin will not affect tumour growth.

It’s not just a serotonin problem – it is actually a much wider issue with something ‘vasoactive amines’ (or pressor amines). They are precursors for catecholamines such as adrenaline, which trigger some NETs to secrete vasoactive substances, which cause symptoms or in extreme cases, carcinoid crisis. Tyramine is the most active of these amines. Other strongly active vasoactive amines found in food include histamine that can cause strong dilation of capillaries, and also cause hypertensive crisis. Reported reactions from these vasoactive amines are acute hypertension, headache, palpitations, tachycardia, flushing and unconsciousness. As a general rule, Tyramine and other pressor amines are usually only present in aged, fermented, spoiled protein products, but quite often, it’s food containing a precursor amine that is what you are looking for (for example Tryptophan is a precursor to Serotonin).

Personally I cannot think of a single food which causes me to have a ‘reaction’ other than if I eat too much or eat something with a high fat content. Basically for someone who has had abdominal surgery, the system cannot cope for one reason or more – see Series Article 2. It’s important to distinguish this type of reaction which is actually something caused by the consequences of cancer treatment rather than one of the ‘syndrome’ effects. The answer might simply be to reduce or adjust food intake rather than cut foods out, particularly foods that you may need for nutrition and energy. And of course, foods you enjoy which don’t cause issues, are related to quality of life.

What I do know from masses of experimentation and running a diary, is that large meals can give me issues. However, as hinted above, I put that down to surgery – NOT syndrome. I also reduced consumption of fatty foods but that was mainly to combat malabsorption caused by my surgery and exacerbated by Somatostatin Analogues. Again NOT syndrome. I reduced alcohol but mainly because I was concerned about my compromised liver after surgery.

So what are the most provocative foods? This diagram here is extremely handy BUT I must emphasise that the cause of the provocation may not have been caused by the food itself, just what people think and reported (clearly scientific intervention might prove it was caused by something else). Everyone is different, so some people might not have any reaction to these foods. As you can see, a large meal is top and I can almost guarantee much of this was caused by people having a shorter bowel due to surgery.

foods provoking — Graphic courtesy of The Carcinoid Cancer Foundation (CCF)

What are the foods containing high levels of these vasoactive amines? It is here that I refer you to a site which was one of the very first things I read after my diagnosis, and I re-read it after my initial treatment when I discovered that my debulking and cytoreductive surgery came with some consequences. This is an amazing piece of research put together by the late Monica Warner (wife of Dr Richard Warner) who herself said “It has not been an easy task to put these guidelines together“. I don’t believe there is another source of such detailed research and guidelines on the Nutritional Concerns for the NET Patient (note the term Carcinoid is used throughout, therefore it tends to be focused on carcinoid syndrome. Many other NET Syndromes have associated diet and nutrition constraints and problems too.

This is not an exact science and as the author said “I must emphasize at this point that these are only GENERAL GUIDELINES since patients with carcinoid (sic) may have multiple problems and must be assessed on a case-by-case basis.”. So for example eating a big meal comes out top of the survey and does not necessarily mean that is caused by carcinoid syndrome – as I said above, it’s very frequently caused by having a shorter gut, or no gallbladder, and other issues. You can eat a large meal containing very low levels of the offending amines and still run to the bathroom because your waste disposal system can’t cope with the amount – that is not a syndrome problem. One person’s perceived ‘syndrome’ problem is another person’s cancer treatment ‘side effect’. Working out which one is not easy but it’s worth the effort to try to understand which one might be causing the problem.

I hope you found my ‘food for thought’ tasty 🙂

Other useful links which have an association to this blog:

{a} Read a Gut Surgery Diet Booklet authored by Tara – CLICK HERE

{b} Follow Tara on Twitter – CLICK HERE

{c} Watch a video of Tara presenting to a group of NET Patients – CLICK HERE

{d} Now Watch Tara answering the Q&A from patients – I enjoyed this – NET patients are very inquisitive! CLICK HERE

[e] There is an excellent video from the NET Research Foundation (what to eat and why) – CLICK HERE

You can hear me talk about my diagnosis by clicking here

Thanks for reading

Ronny

I’m also active on Facebook. Like my page for even more news. I’m also building up this site here: Ronny Allan

Disclaimer

My Diagnosis and Treatment History

Most Popular Posts

Sign up for my twitter newsletter

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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

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Neuroendocrine Cancer Surgery – a patient experience (part 1)

Chris and I with our friend and hero Mr Neil Pearce – my surgeon.

First Surgery – 8th – 26th November 2010

Memories of my 18 day stay in hospital from 8 – 26 Nov 2010, are not only reminding me of how important that particular treatment was to be, but also how surreal it felt at the time. Some of it is still a blur, particularly the early days where the morphine was in control. For many NET patients, surgery can be a mainstay treatment, even for those with metastatic disease. In fact, I now know from my own research that NET Cancer is one of a small number of cancers for which surgical debulking can in many cases confer some survival advantage in a metastatic scenario. However, the nature of Neuroendocrine Cancer means that treatment and surveillance will need to continue for many patients.

Prior to being diagnosed with Cancer, my experience with hospitals was very limited and I had always been a tad squeamish when it came to routine injections. So having major surgery with a projected 10-14 day stay in hospital was a massive challenge. However, I remember being fairly relaxed leading up to this event. I suspect I had accepted my situation; and that a combination of pragmatism and trust in my surgical team had conquered any fear.

The surgery, which lasted 9 hours, was really in two parts, firstly to get rid of my primary in the small intestine plus any accessible locoregional stuff. Basically the surgeon removed 3 feet of my small intestine, carried out a right hemicolectomy, and also removed ‘oodles’ of lymph nodes in the mesenteric region, with careful blood vessel reconstruction required. The second part comprised a careful removal of retroperitoneal fibrosis which was threatening major vessels. This is an issue which has returned in 2018 and you can find an update by clicking here.

Spookily, I woke up from the anaesthesia just after midnight on 10th November, I woke up on NET Cancer Day.

I’ve not spoken too much about the first week in the hospital after surgery – mainly because some of the details remain scant. However, there are four stories I remember in some detail and they even make me smile, although I wasn’t laughing at the time!

Physio (a synonym for pain!)

One of the key things I remember was the extraordinary amount of tubes and other things connected to my body. Had I drawn a picture, it would have looked like the map of the London Underground. Some of them were taking things out of my body (temporary ‘toilet’, wound drains, etc) and others were for putting things in (drugs, pain killers, nutrition, etc). My legs had ‘circulating leg wraps’ to prevent the formation of blood clots. They were very uncomfortable and sweaty but important. I appeared to be pinned very tightly to the hospital bed – any thoughts of escape were quickly subdued by the sheer weight of equipment. It was, therefore, a total surprise to me how soon the Physiotherapists arrived to administer torture 🙂 The difficulty of arranging all the tubes in order that I could just even sit up led me to believe it would not be possible. However, they persevered and I had of course forgotten, this is what they do for a living! Putting the tube issue to one side, the very act of sitting up and putting your feet on the floor with a 12″ north to south abdominal wound still repairing is one of the most difficult and painful things I’ve ever done (even after activating my Pain Controlled Analgesia (PCA) – more drugs!). However, and I say this in hindsight, this is a very important part of the healing process and patients need to be compliant! I eventually got used to it and starting off with a walk around my bed, a walk to the nurse desk, a walk up and down the ward….. this eventually led to a walk around the hospital once some of the tubes were removed. However, I was feeling so bad one day, I refused physio which resulted in a lecture from my surgeon (see photo above) later that night – the discussion ended with the words “You are a winner”. It helped as I sprinted up and down the ward corridor next day! Isn’t it amazing how a kick in the ‘ass’ can also function as medicine?

Pain Control

The Pain Controlled Analgesia (PCA) button was never far from my hand. After surgery, it isn’t completely painless, but the PCA does help. It normally contains morphine which helps kill the pain but comes with other side effects including sleepiness (handy), foggy brain, inability to focus, strange dreams and on occasion mild hallucinations (I swear the people on the wall picture opposite my bed were moving!). After a few days, this was replaced by drip fed paracetamol (I think).

Re-establishing the food trail

I hadn’t given this too much thought prior to the surgery but when they remove sections of your intestines (in my case the terminal ileum and the ascending colon), there has to be a new join (anastomosis) and this needs time to heal. This means a gradual and gentle return to normal eating. One of the most annoying tubes was the nasogastric tube (NG tube). I woke up with this tube already inserted but around day 3 it was removed whilst I was awake (a little bit scary). However, I was sick a few times (quite scary), so it was re-inserted (a little more scarier than removal). However, once it came out for the second time (still a little bit scary), they gave me a rather tasteless drink called ‘Fortisip’ which apparently had the proteins and nutrients I needed whilst I waited to move onto normal food. My first proper food after a few days was ‘heaven’ – chicken soup followed by ice cream and jelly (for North Americans, please note jelly is not jam!)

Re-establishing the ‘poop’ trail

Technically, this is just an extension of the ‘food trail’ info above. However, a story that I have hardly ever recounted follows. I think this was around day 15/16 Nov or thereabouts. My surgeon kept quizzing me on ‘gut feelings’ i.e. burping, hiccups, wind etc. I hadn’t realised he was working out when to offer some help re-establishing this element of my recovery. I think I was late so some milk of magnesia was given one morning. That evening, nothing happened and so the night shift nurses were primed to offer me a ‘special’ suppository which I was assured would be a great help in moving things in the right direction. I declined their very kind offer to carry out the ‘insertion’ instead opting for some dignity retention – there wasn’t much left at this point but I was determined to hang onto it! As I was laying there, I quickly scanned the remaining tubes (by this stage, I was down to 5 or 6), I reached round and it very quickly dawned on me that this was ‘mission impossible’. I rang the bell as a signal that sometimes practicality overrules dignity. Like the physio thing above, I had forgotten that Nurses do this all the time. Ten minutes later, the bell again summoned the nurses who helped me and my tubes to the toilet. The toilet/bathroom was to become a familiar place over the coming weeks.

Following the surgery and when I was mobile, I weighed myself and found had lost a complete stone (14 lbs). Weight loss led up to my diagnosis and continues to be an issue today – read more here.

Part two covers the second period of my 18 day stay and can be read by CLICKING HERE

Almost 8 years later, please check out my new challenge – click here.

Neuroendocrine Cancer Nutrition Series Article 3 – Gut Health

OPINION. Nutritional issues are one of the biggest challenges affecting most Neuroendocrine Cancer patients. It is also a key factor in maintaining a decent quality of life and for most countries without adequate NET Specialist Dietitian support, it remains an unmet need. In this article, I’m discussing the use of probiotics to combat the potential issue of small intestine bacterial overgrowth (SIBO) in Neuroendocrine Tumours.

When I first indicated this nutrition series was under construction, a few people got quite excited anticipating me to produce advice on what to eat. However, that was never my intention. What people should or should not eat is such a varied problem (or solution?) that anything I said would only really be of help to those for whom it worked – this area is not an exact science. I’ve seen several ‘what to or not to eat’ publications/articles out there aimed at NET patients; some more up to date than others – all I would say is to interpret them carefully.

What my nutrition series actually covers is what causes the nutritional related issues and to a certain extent, try to work out how to tell if these issues are caused by either treatment or an associated syndrome, leaving fellow patients to make up their own minds about what to eat; or arm themselves with the necessary knowledge whether this applies to them or not.

The first two articles in the series were Article 1 – Vitamin and Mineral Challenges and Article 2 – Malabsorption. These remain popular and have a constants stream of views – no surprises as these are well known side effects of many types of NETs…… or at least they should be well known.

This particular article “Gut Health” is not as ‘clear cut’ or simple as the first two and I suggest you read Articles 1 and 2 first if you are not familiar with the issues. Again I’m grateful to Tara Whyand (NET Specialist Dietician and researcher from Royal Free London) for some of the input below. Although I marked this with ‘Opinion’, some of it has references but I still decided to use ‘Opinion’ as the science is not yet 100%.

What is the “Gut” ?

When I first met my surgeon, I found one of his favourite words was ‘Gut‘. Like me before diagnosis, many of you will have heard or used the word but in an intentionally non-medical context, e.g. guts (bravery), ‘gut feeling’ or ‘gut instinct’ (intuition). I’ll return to that theme later but when you look at these contextual uses of the word, it’s no surprise why some scientists refer to our gut as a ‘second brain’.

I always thought the gut referred to just the ‘belly’ area but in medical parlance, the gut has a much bigger geography. It is sometimes used interchangeably with the term Gastrointestinal (GI) Tract and stretches from the throat to the anus and is responsible (in the most general terms) for food intake, digestion/absorption, waste processing and finally waste ejection. NET patients should be familiar with the terms ‘foregut’, ‘midgut’ and ‘hindgut’ which are sometimes used to define the embryological origin and grouping of Neuroendocrine primary tumours, although the boundaries and constituent parts can vary from site to site. The inclusion of certain anatomical locations as a sub-section of the gut is clearly for convenience rather than anatomical accuracy (e.g. Lung).

This is a massive subject but I wanted to ‘cut to the chase’ in this article and focus on the use of probiotics to combat the potential issue of small intestine bacterial overgrowth (SIBO) in Neuroendocrine Tumours. The symptoms and signs of SIBO can be similar to they symptoms and side effects of treatment that many patients report anecdotally on patient forums. I also found the science is complex and not really 100% tied down.

Probiotics

One of the first pieces of advice I was given after my initial surgery was to take probiotics – to keep up my stocks of ‘good’ bacteria. I didn’t really understand why, I just complied. I started with the liquid drinks you can buy in most supermarkets and supplemented this by eating bioactive yoghurt. I didn’t really notice any difference from either but the yoghurt was nice to eat!

Tara Whyand then confirmed this advice when I first met her in 2012 at a NET Patient conference. In 2013 when I started looking for a new normal, I realised that the supermarket drinks and yoghurts were simply not enough good bacteria for my ‘new plumbing’, and decided to take a high-grade daily capsule containing 5 billion friendly bacteria multiple strains (Tara does recommend at least 2 billion and multiple strain). Within weeks I was noticing a difference in bowel motility although I confess to changing other elements of my lifestyle at the same time given that I was embarking on finding my new normal. Nonetheless, I sense probiotics are helping and I won’t be reducing or stopping them any time soon. If you look at several NET specific dietician/nutrition presentations, most appear to promote the use of probiotics for NET patients.

Bacteria

One of the terms you find in this complex area is the ‘human gut microbiota‘, sometimes known as ‘gut flora‘. Our ‘gut’ harbours a complex community of over 100 trillion microbial cells, approx 3% of our body mass! The human gut microbiota is known to have an influence on every part of our body (including the brain…..) and disruption of this ‘community’ has been linked with several gastrointestinal conditions such as Inflammatory Bowel Disease (IBD) and obesity.

Probiotics are said to help keep the balance and mix of bacteria stable within the gut which can be affected by many different factors, including the use of antibiotics, aging, illnesses (such as IBD), following infective gastroenteritis and (of interest to NET patients) after cancer treatment or gastrointestinal surgery. {1} Incidentally, the reference here is authored by Tara Whyand and Professor Martyn Caplin (a Neuroendocrine Tumour expert who also happens to be a Gastroenterologist). Useful reading if you have any of the conditions in the report or have had gut surgery (or like me you are a total geek!). They are also frequently used in Irritable Bowel Syndrome (IBS).

Small Intestine Bacterial Overgrowth (SIBO)

Another interesting area of research into something called Small Intestinal Bacterial Overgrowth (SIBO), a condition where the small intestine is populated by an abnormal amount and/or types of bad bacteria. It follows that probiotics (good bacteria) may be useful in combatting this by helping to maintain balance.

So how does SIBO potentially and specifically affect NET patients?

It can be caused or exacerbated by abdominal surgery to stomach, duodenum, pancreas or via whipples, small & large intestine,
poorly controlled diabetes,
the long-term use of Proton Pump Inhibitors (PPI) (e.g. omeprazole and lansoprazole, etc). Several studies link to these drugs including this one,
possibly long term use of antibiotics which can kill good bacteria.Some evidence of surgical involvement can be found here – this link – particularly the bit about the prevalence of patients who have had an “abdominal surgery” or an “Ileocaecal valve resection”. I guess that would include many NET patients? (this is a big article so just focus on table 1 near the beginning).

Symptoms vary for everyone from watery diarrhoea suddenly starting 20 times a day to just bloating and wind in both directions, to nothing at all. These symptoms are regularly reported by patients so working out the root cause might need some professional help.

Is there any testing for SIBO?

There is a test to check for SIBO is called the Hydrogen breath test. This test uses lactulose ingestion to measure the hydrogen in the breath. If SIBO is diagnosed, treatment is normally via antibiotics. However, advice is to leave a 2 hour gap between taking probiotics and antibiotics and a high dose multi-strain probiotic should be applied. Our friend Tara has done some work on this alongside Professor Martyn Caplin which was featured at ENETS 2017.

ENETS Research – Assessment of Small Intestinal Bacterial Overgrowth (SIBO) in NET Patients Abstract #1698

Introduction: SIBO is not uncommon in NETs. Hydrogen Breath testing (HBT) using glucose may be more sensitive to proximal SIBO as glucose rarely reaches the colon. Many NET patients are likely to have distal SIBO however, as factors such as ileocecal valve removal apparently increase distal SIBO risk. Thus glucose BT alone may limit sensitivity for detecting SIBO in some NET diagnoses.

Aim(s): Assess likely risk factors for SIBO. Assess sensitivity of additional lactulose HBT and CH4 BT.

Materials and methods: Retrospective data (n=55) of NET patients undergoing HBT was examined. Twelve patients (12/55) who tested negative for glucose HBT but continued to have diarrhoea +/- wind had repeat BT using lactulose. These patients had both H2 & CH4 BT.

Results: Midgut NET diagnoses were most frequently referred for BT (n=43, 78%). Twenty four (24/55, 44 %) had prior right hemicolectomy. Ten (10/24 ,42%) of those were SIBO positive. Ten patients were positive for HBT prior to being given the glucose substrate, they all had abdominal surgery in the past. Twelve patients who tested negative for glucose HBT had repeat testing using lactulose and measured both H2 and CH4 production. This led to an additional 3 (25%) positive results.

Conclusion: Abdominal surgery, especially right hemicolectomy increases the likelihood of a positive glucose HBT. Glucose may still be sensitive in those with risk factors for distal SIBO. Additional lactulose use with H2 and CH4 measurement increases the sensitivity in diagnosing SIBO.

Conference: 14th Annual ENETS conference (2017)

Presenting Author: Tara Whyand

Authors: Whyand T, Koffas A, Toumpanakis C, Mandair D, Caplin M

Keywords: nets, sibo, dysbiosis

My own Experience

I personally take a 5 billion dosage and am happy to recommend the source offline. However, in addition to obtaining from a reputable provider (i.e. in UK, MHRA approved supplier), there is evidence to suggest as long as it has some or all of the following strains that are widely available, they should provide benefit: Lactobaccilus plantarum, Lactobaccilus acidophilus, Lactobaccilus brevis, Bifidobacterium lactis and Bifidobacterium longum.

This article could have been 10 x longer! I didn’t even get to the bit about the relationship between the gut and the brain – perhaps another day?

None of this should be considered medical advice.

Article 2 – Malabsorption. Overlapping slightly into Part 1, this covers the main side effects of certain NET surgical procedures and other mainstream treatments. Input from Tara Whyand.

Article 4 – Food for Thought. This is a blog about why certain types of foods or particular foodstuffs can cause issues.

Article 5 – ‘Pancreatic Enzyme Replacement Therapy’. The role of PERT (Creon etc) in helping NET Patients. Input from Tara Whyand.

Read a Gut Surgery Diet Booklet authored by Tara – CLICK HERE

You may also appreciate these articles where there is overlap:

The Diarrhea Jigsaw – different things can cause diarrhea, it’s not all about syndromes.

The Constipated NET Patient – yes they exist!

Very grateful to Tara for the input.

Other useful links which have an association to this blog:

{a} Read a Gut Surgery Diet Booklet authored by Tara – CLICK HERE

{b} Follow Tara on Twitter – CLICK HERE

{c} Watch a video of Tara presenting to a group of NET Patients – CLICK HERE

{d} Now Watch Tara answering the Q&A from patients – I enjoyed this – NET patients are very inquisitive! CLICK HERE

Thanks for listening

Neuroendocrine Cancer Nutrition Series Article 2 – Gastrointestinal Malabsorption

This is the second article in the Neuroendocrine Cancer Nutrition series. In the first article, I focused on Vitamin and Mineral deficiency risks for patients and there is a big overlap with the subject of Gastrointestinal Malabsorption. Those who remember the content will have spotted the risks pertaining to the inability to absorb particular vitamins and minerals. This comes under the general heading of Malabsorption and in Neuroendocrine Cancer patients, this can be caused or exacerbated by one or more of a number of factors relating to their condition. It’s also worth pointing out that malabsorption issues can be caused by other reasons unrelated to NETs. Additionally, malabsorption and nutrient deficiency issues can form part of the presenting symptoms which eventually lead to a diagnosis of Neuroendocrine Cancer; e.g. in my own case, I was initially diagnosed with Iron Deficiency Anemia in association with some weight loss. Even after diagnosis, these issues still need to be carefully monitored as they can manifest as part of the consequences of having cancer and cancer treatment.

Malabsorption will present via several symptoms which may be similar to other issues (i.e. they could masquerade as, or appear to worsen the effect of a NET Syndrome). These symptoms may include (but are not limited to) tiredness/fatigue/lethargy, stomach cramps, diarrhea, steatorrhea (see below), weight loss. Some of these symptoms could be a direct result of nutrient deficiencies caused by the malabsorption. Some patients (and perhaps physicians?) could mistake these for symptoms of Neuroendocrine disease including certain syndromes, perhaps leading to prescribing expensive and unnecessary drugs when a different (and cheaper) strategy might be better.

Crash Course……. We eat food, but our digestive system doesn’t absorb food, it absorbs nutrients. Food has to be broken down from things like steak and broccoli into its nutrient pieces: amino acids (from proteins), fatty acids and cholesterol (from fats), and simple sugars (from carbohydrates), as well as vitamins, minerals, and a variety of other plant and animal compounds. Digestive enzymes, primarily produced in the pancreas and small intestine (they’re also made in saliva glands and the stomach), break down our food into nutrients so that our bodies can absorb them. If we don’t have enough digestive enzymes, we can’t break down our food—which means even though we’re eating well, we aren’t absorbing all that good nutrition.

What is malabsorption?

The malabsorption associated with Neuroendocrine Cancer is most prevalent with the inability to digest fat properly which can lead to steatorrhea. Patients will recognise this in their stools. They may be floating, foul-smelling and greasy (oily) and frothy looking. Many patients confuse steatorrhea with diarrhea but technically it’s a different issue although both issues may present concurrently. Whilst we all need some fat in our diets (e.g. for energy), if a patient is not absorbing fat, it ends up being wasted in their stools and in addition to the steatorrhea, it can also potentially lead to (unwanted) weight loss and micronutrient deficiencies of the fat-soluble vitamins A, D, E and K. Certain water-soluble vitamins, particularly B3 and B12, are also at risk. Many NET Patients are prescribed a supplement of pancreatic enzymes to combat these issues – see Article 5 in this series – Pancreatic Enzyme Replacement Therapy (PERT).

What causes it with NET Patients?

Structural Changes (i.e. Surgery)

This can play a very big part in malabsorption issues. For example, if a patient has undergone Pancreatic surgery, this will most likely effect the availability of pancreatic (digestive) enzymes needed to break down food. Many Small Intestine NET (SI NET) patients will suffer due to the removal of sections of their ileum, an area where absorption of water-soluble vitamins and other nutrients take place. In fact, the terminal ileum is really the only place where B12 is efficiently absorbed. Low B12 is known to cause fatigue. Some patients with Gastric tumours succumb to pernicious anemia with the most common cause being the loss of stomach cells that make intrinsic factor. Intrinsic factor helps the body absorb vitamin B12 in the intestine. Although a less common tumour location, jejunum surgery could result in loss of nutrients as this section of the small intestine is active in digestive processes. Malabsorption issues for SI NETs are an added complication to the issues caused by a shorter bowel (e.g. faster transit time), something which is regularly assumed to be the effects of one of the NET Syndromes (particularly diarrhea and fatigue), when in actual fact, it’s a simple consequence of cancer treatment and may need a different treatment regime.

Evidence of the problems being caused by the effects of small intestinal surgery can be found in a recently published Swedish study which you can read here: Click here. This particular study recommends supplementation of B12 and D3 for those affected. If you’re having trouble getting your physician to monitor your vitamin levels, show them these studies. I get these vitamins checked annually.

The Gallbladder and Liver

The Gallbladder plays an important part in the digestive system – particularly in fat breakdown. The liver continually manufactures bile, which travels to the gallbladder where it is stored and concentrated. Bile helps to digest fat and the gallbladder automatically secretes a lot of bile into the small intestine after a fatty meal. However, when the gallbladder is removed, the storage of bile is no longer possible and to a certain extent, neither is the ‘on demand automation’. This results in the bile being constantly delivered/trickled into the small intestine making the digestion of fat less efficient. One of the key side effects of Somatostatin Analogues (Octreotide and Lanreotide) is the formation of gall stones and many Neuroendocrine Cancer patients have their gallbladder removed to offset the risk of succumbing to these issues downstream. However, the removal of the gallbladder increases the risk of Bile Acid Malabsorption (BAM) as described below. Any issues with Bile Ducts can also have a similar effect.

The Liver has multiple functions including the production of bile as stated above. However, one of its key functions within the digestive system is to process the nutrients absorbed from the small intestine. If this process is affected by disease, it can potentially worsen the issues outlined above.

Bile Acids Malabsorption

Another risk created by the lack of terminal ileum is Bile Acids Malabsorption (BAM) (sometimes known as Bile Salts Malabsorption and some texts described the resultant diarrhea as ‘Bile Acid Diarrhea”). Bile Acids are produced in the liver and have major roles in the absorption of lipids in the small intestine. Following a terminal ileum resection which includes a right hemicolectomy, there is a risk that excess Bile Acids will leak into the large intestine (colon) via the anastomosis (the new joint between small and large intestines). This leakage can lead to increased motility, shortening the colonic transit time, and so producing watery diarrhea (or exacerbating an existing condition).

Somatostatin Analogues

Somatostatin Analogues can also impact (or worsen) the ability to digest fat as they inhibit the production of pancreatic digestive enzymes (amongst other things). This is a well-known side effect of both Octreotide and Lanreotide. The levels of the fat-soluble vitamins (ADEK) and B vitamins such as B12, need to be monitored through testing and/or in reaction to symptoms of malabsorption. If necessary these issues need to be offset with the use of supplements as directed by your dietician or doctor. Supplements are less affected by malabsorption of nutrients but their efficiency can be impacted by fast gut transit times (thus why testing is important). The evidence and recommendations for malabsorption caused by somatostatin analogues is here: Click Here.

Overlapping Areas

Deficiencies of these vitamins and certain minerals can lead to other conditions/comorbidities, some more serious than others. For a list of the vitamins and minerals most at risk for Neuroendocrine Cancer patients, have a read of my article which was co-authored by Tara Whyand – Vitamin and Mineral deficiency risks.

There is a third article in this series discussing a related issue with Neuroendocrine Cancer, particularly where gut surgery has been performed. You can link directly to this article here – “Gut Health” – (Gut Health, Probiotics and Small Intestinal Bacterial Overgrowth (SIBO)).

The fourth article looks at Amines and why they can cause food reactions or exacerbate syndromes.

Many people also confuse steatorrhea with diarrhea (although these issues can appear simultaneously), again leading to wrong conclusions about the causes and effects, and worryingly, the treatment required. Check out my diarrhea article – click here.

Article 5 in this series looks at how to combat malabsorption caused by pancreatic insufficiency – Pancreatic Enzyme Replacement Therapy (PERT)

My article ‘The Diarrhea Jigsaw’ is complementary to this nutrition series.

Read a Gut Surgery Diet Booklet authored by Tara – CLICK HERE

Summary

A common problem in patients and from what I see, many just assume this is part of their various syndromes leading to the wrong therapy or no therapy as it’s simply ignored. Again, I remain very grateful to Tara Whyand for some assistance.

This is a big and complex subject and I only intended to cover the basics. Everyone is different and nothing in here should be accepted as medical advice for you or anyone you know. If you need professional advice, you should speak to your doctor or registered dietitian.

Thanks for reading

Ronny

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Neuroendocrine Cancer – not as rare as you think

Background

Although initially considered rare tumours up until 10 years ago, the most recent data indicates the incidence of NETs has increased exponentially over the last 4 decades and they are as common as Myeloma, Testicular Cancer, and Hodgkin’s Lymphoma. In terms of prevalence, NETs represent the second most common gastrointestinal malignancy after colorectal cancer. Consequently, many experts are now claiming NETs are not rare (see below). A recent study published on 5 Dec 2018 reports that even if you isolate Small Intestine NETs in the USA population, the incident rate is 9/100,000. Contrast this against the US incident rate as at 2012 of 7/100,000 for all NETs. The rare threshold in Europe is 5/100,000 and below.

And on 7th January 2019, an internationally known NET Specialist described NETs as very common.

In fact, the graph of the SEER database figures for NETs in both 2004 and 2012 indicates the rate of incidence increase is faster than any other cancer on the planet, particularly attributed to lung, small intestine, and rectal NETs. The World Health Organisation’s revised classification of Neuroendocrine Neoplasms in 2010, abandoned the division between benign and malignant NET as all NETs have malignant potential and should be graded accordingly. The 2004 SEER data compiled did not take into account what might have been considered to be benign NETs.

However, the most recent USA study up to 2012 has confirmed the incidence beyond 2004 has continued to rise (and rise, and rise, and rise) and this is covered below in the section entitled “Meanwhile in USA”. One of the principal authors of both database studies has now gone public and said NETs are no longer rare.

Incidence and Prevalence

Before I continue, it’s important to understand the difference between incidence and prevalence. In the crudest of terms, incidence is the number of new cases of a disease being diagnosed (normally aligned to a specific quota of the population per year, generally 100,000). Prevalence normally indicates an amount of people living at any one time with a disease. It’s also important to note that different nations or groups of nations classify ‘rare’ in different ways – not really helpful when looking at worldwide statistics.

So why the increase? I suspect the reasons include (but are not limited to), more awareness (population and medical staff), better detection techniques and probably more accurate reporting systems, at least in USA, Norway, Canada and now in the UK i.e. a mixture of underdiagnoses and misreporting. The Canadian study is important as it also noted the proportion of metastases at presentation decreased from 29% to 13%. This is the first study that suggests an increased incidence of NETs may be due to an increased (and earlier?) detection. This has the knock on effect of increasing prevalence as most NET Cancer patients will normally live for longer periods. Add to this the plethora of better treatments available today, you have a highly prevalent cancer. Most of that is good news.

However, their true incidence may be higher owing to the lack of diagnosis until after death. For example, in USA, a respected NET specialist stated that the autopsy find for (excuse the outdated terminology) ‘carcinoid‘ is 4 times the recorded diagnosis rate. In Australia, one study claimed that 0.05% of all autopsies found a Pheochromocytoma or Paraganglioma. A very interesting slideshow from a well respected NET expert claimed there are 200,000 undiagnosed NET patients in USA. Slide below: You may also wish to check out my article “The Invisible NET Patient Population” where this is explored further.

US SEER 2004 – The Trigger and Turning Point

In the largest study of its kind up to that point, well-known Neuroendocrine Cancer expert James C. Yao researched the Surveillance, Epidemiology and End Results (SEER) database. His team studied 35,825 cases of Neuroendocrine Cancers in the United States covering data between 1973 and 2004. The report concluded that in 2004 there were 5.25 new cases of NETs per 100,000 people, compared with 1.09 per 100,000 in 1973 [1]. This is in contrast to the overall incidence of malignancies, which has remained relatively constant since 1992 (see the yellow line on the graph). The study also pointed out that due to increased survival durations over time, NETs are more prevalent than previously reported. If you analyse the NET data for 1994 (10 years before the end of the study period), you will see an incidence rate of approx 3.25/100,000. In 2004, the incidence rate had risen to 5.25/100,000. Although not an exact science, it does suggest the potential incidence rate at 2014 (10 years after the study period) might possibly have climbed well beyond 6/100,000 and even further if the same rate of increase displayed by the study had continued (spoiler alert – it actually came out as 7/100,000 see below under ‘Meanwhile in USA’). This study also confirmed a prevalence of 103,000 NET patients as at 2004. As this is regarded as the most accurate NET statistic ever produced, it is interesting to note that was at a time when the prognostics for NET were not as good as they are today indicating there must be a very significant increase if extrapolated to the current time. Moreover, this was prior to the WHO 2010 reclassification of NETs so more diagnoses will be counted today that were not counted in 2004. See below to see the significance of this figure (see section ‘Do the math’).

The 2004 data was an astonishing set of statistics – particularly as they were based on 12 year old data. However, there is now new data up to 2012 that overtakes the above-mentioned groundbreaking study and confirmed the incidence is now even higher. See section entitled “Meanwhile in USA …….”

Meanwhile in Norway ……

Data from the Norwegian Registry of Cancer showed a similar incidence of Neuroendocrine Cancers with a 72% increase between 2000 and 2004 compared with 1993–1997 [2]. Also in Norway, an article published in 2015 entitled “Epidemiology and classification of gastroenteropancreatic neuroendocrine neoplasms using current coding criteria” indicated a high crude incidence of GEP-NEN, at 5·83 per 100 000 inhabitants over the period 2003-2013 (adjusting to 7.64 for Europe in 2013 – see diagram below extracted from cited article 2a). It was also noted together with the statement “….a significant increasing trend over time”. [2a] Citation [2b]

Meanwhile in Canada …….

CNETs have highlighted an article published in the magazine ‘Cancer’, February 15, 2015, showing that the incidence of Neuroendocrine Tumours has markedly increased in Canada over the course of 15 years (1994-2009). The results showed that the incidence of Neuroendocrine Tumours has increased from 2.48 to 5.86 per 100,000 per year. [3] [4]

Meanwhile in UK …….

The latest figures from Public Health England (PHE) indicate the incidence of NETs has risen to almost 9/100,000 (i.e. not rare) using the latest International Classification of Diseases for Oncology (ICD-O) methodology version 3 – ICD-O-3. Even that figure is understated because it does not include Lung Neuroendocrine Carcinomas (i.e. SCLC and LCNEC). As at 31 Mar 2016, the age-standardised incidence rate for NETs in England (excluding small and large cell neuroendocrine carcinomas, SCLC and LCNEC respectively) was 8.84, 8.37 in males and 9.30 in females – rising from 3.9 in 2001. These figures are from the NET Patient Foundation and were issued as a result of a NPF and PHE (NCRAS) partnership project which has been compiling statistics on the incidence, prevalence and survival of NET Patients in England using English cancer registry data. They also have an aim to also access the rest of UK cancer registry data to get UK wide figures.

That means a new NET diagnosis every 2 hours. You can see a summary of the report NEW: Public Health England release new incidence data for Neuroendocrine Cancer

A slide from the recent UKINETS 2017 conference indicating an agreement from UK and Ireland NET Specialists.

IMG_20171204_214918 — as presented at UKINETS 2017

Meanwhile in New Zealand …….

as presented by Unicorn Foundation NZ on 11 Mar 2017

Meanwhile in USA …….

The latest evidence of its rise is contained in the largest ever study ever conducted. It is based on data up to 2012 so it’s worth noting that this data is now 5 years old (3 years for the project prevalence figure), so even these figures may still be conservative. The document, which was published in 2017 can be found here: Click here. A short summary follows:

In this population-based study that included 64 971 patients with neuroendocrine tumors, age-adjusted incidence rates increased 6.4-fold between 1973 and 2012, mostly for early stage tumors. Survival for all neuroendocrine tumors has improved, especially for distant stage gastrointestinal and pancreatic neuroendocrine tumors.

Of the 64 971 cases of NETs, 34 233 (52.7%) were women. The age-adjusted incidence rate increased 6.4-fold from 1973 (1.09 per 100 000) to 2012 (6.98 per 100 000). This increase occurred across all sites, stages, and grades. In the SEER 18 registry grouping (2000-2012), the highest incidence rates were 1.49 per 100 000 in the lung, 3.56 per 100 000 in gastroenteropancreatic sites, and 0.84 per 100 000 in NETs with an unknown primary site. The estimated 20-year limited-duration prevalence of NETs in the United States on January 1, 2014, was 171 321

Conclusion: The incidence and prevalence of NETs have continued to rise in the United States, owing to the increased diagnosis of early-stage disease and possibly stage migration. The survival of patients with NETs has improved, and this improvement has been greater for those with distant gastrointestinal NETs and, in particular, distant pancreatic NETs.

Combine that with a revised annual incidence rate of 23,000 and the very well known fact that NETs is a highly prevalent disease, it must be mathematically impossible for the figure not to be above the USA rare threshold of 200,000 in 2017. As you can see from the graph below, the incidence rate for NETs continues to outstrip the incidence rate for all malignant neoplasms (another word for tumour). Amazingly, the report authors even state “…….. it is likely that we have underestimated their true incidence and prevalence”.

incidence 2012 jama — NET Cancer diagnoses continues to outstrip all other cancer diagnoses

The NET Research Foundation published an amazing infographic which summarises the output of the SEER 2012 study (although it does omit the prevalence figure ‘as at’ date). See it below and you can read the accompanying text here.

dasari-infographic-2 — Graphic from the NET Research Foundation – https://netrf.org/study-shows-rising-rates-of-net-incidence-prevalence-and-survival/

Let’s do the Math

Neuroendocrine Cancer is not only the fastest growing cancer in incidence terms but as a group of cancers, given the mounting epidemiological evidence, it can no longer be rare as a grouping of cancers. Neuroendocrine disease IS NOT RARE.

For example, if you roughly extrapolate the US SEER data graph above to 2017 and recalculate the prevalence rate based on 23 000 per year from the 2014 figure of 171 321. Unfortunately, some people will have passed, but it’s well documented as a highly prevalent cancer and therefore more people live. The prevalence of neuroendocrine tumors in USA was higher than the combined estimated prevalence of esophageal cancer (n = 36,857), gastric adenocarcinoma (n = 79,843) and pancreatic adenocarcinoma (n = 49,620) in 2013. In fact, one of the conclusions of the 2012 SEER report is that we are living longer with NETs. This is in line with many other cancers due to improved diagnostic and treatment regimes. Cleary more work still needs doing.

hendifar not rare — Dr Hendifar has done the math

not rare yao netrf — Dr Yao has done the math

simron singh nets not rare — Dr Singh has done the math

strosberg not rare — Dr Strosberg has done the math

The Invisible NET Patient Population

The heading of this section is my name for those who have not yet been diagnosed with NETs but are walking around having been either misdiagnosed, diagnosed with another cancer in the same part of the anatomy, living and putting up with the symptoms whilst the tumours grow. To add to this part of the underdiagnoses of NETs is this most amazing piece of research published in 2018 – Pan-cancer molecular classes transcending tumor lineage across 32 cancer types, multiple data platforms, and over 10,000 cases. It was published in the American Association of Cancer Research (AACR) journal ‘Clinical Cancer Research and authored by Chad Creighton et al. DOI: 10.1158/1078-0432.CCR-17-3378. This was a pan cancer piece of research which indicated that Neuroendocrine disease may be more prevalent than anyone had ever thought. There’s a summary article here which I suggest you read fully. The rather explosive extract is as follows:

Go figure

Whilst reporting has been improved, it is most likely still not 100% accurate. Therefore, even the figures above may be understated due to an incorrect cause of death reporting and incorrect diagnosis/recording of the wrong cancers (e.g. pNETs recorded as Pancreatic Cancer, Lung NETs recorded as Lung Cancer, etc). This is certainly still happening in UK and I suspect in most other countries. Add to that the regular reports of Neuroendocrine Tumours being found during autopsies and you have the potential for an even further unrecorded increase had these been found prior to death. In fact, according to SEER 2012, the true incidence and prevalence is most likely underestimated. In fact here is a statement straight from the horse’s mouth:

The issue is also complicated by the method used in USA for naming a disease ‘rare’. Rather than use incidence rates, the USA uses the number of people living with the disease at any one time (i.e. essentially the prevalence). This is currently 200,000 as a threshold – anything below that is considered rare. It seems mathematically impossible for NETs to be less than 200,000 given the data provided above.

When I first started researching NETs back in 2010, the US figure (which varies from source to source) was around 125-150,000. Why are people quoting figures less than this in 2017 when the 2014 figure has now been confirmed above? There also seems to be a selective omission of the new US incidence rate of 7/100,000.

You will also see that Dana Farber is estimating more than 200,000 people are as yet undiagnosed. Even if that were 50% accurate, it would put the current prevalence figure in US over 300,000.

Let’s cut to the chase – NETs are not rare, they are just less common

Are we shouting loud enough about this? I don’t think so. ‘Rare’ is very frequently used within the NET community almost to the point of being a status symbol. Based on these figures, this looks like an outdated approach along with its associated icons. The evidence above is so compelling that saying the group of cancers officially called Neuroendocrine Neoplasms is rare is starting to sound like fake news.

“A neoplasm on the rise. More prevalent than you may think. Incidence increased dramatically during past 3 decades” (Novartis)

“it’s less rare than we used to think. It’s more malignant than we previously thought” (Dr Richard Warner)

“…..it is one of the most rapidly increasing cancers in the U.S. There has been a 500-percent increase in the last 30 years” (Dr Edward Wolin)

“Estimated more than 200,000 undiagnosed cases in the US” (Dana Farber)

“I actually think NETs are not a rare cancer” (Dr James Yao)

“NETS will no longer be rare” (UKINETS 2017 one of the opening slides)

“NETs are no longer rare” (Dr Andrew Hendifar)

“…..when you think of prevalence, NETs are actually quite common” (Dr Jonathan Strosberg)

“One study showed that the number of people diagnosed has risen 50% over the last decade and unfortunately, I worry that is an underestimate” (Dr Eric Liu)

“Neuroendocrine Cancer – NETs are not rare, just less common. We need a new paradigm” (Ronny Allan since 2015)

You may also wish to check out my article “The Invisible NET Patient Population” where this is explored further.

Carcinoid vs Neuroendocrine

OPINION

There’s a constant debate regarding the validity of the term ‘Carcinoid‘. I’ve posted about this a few times and as far as I know, the debate has been raging for some years.

You may have noticed that ‘Carcinoid’ is often used as a standalone word and tends not to be suffixed with the word ‘Cancer’ or ‘Tumour’ – unlike Bowel Cancer, Breast Cancer, Prostrate Cancer, Lung Cancer, Brain Tumour, etc. Nobody goes around saying “Breast” or “Bowel” do they? But they happily say “Carcinoid”. Unfortunately, the term ‘Carcinoid’ has become entrenched in both pathology and clinical literature over the past 100 years. The main problem with the word Carcinoid is that it means different things to different people. Some use the term almost exclusively to designate serotonin-producing tumours that arise from the enterochromaffin cells that can result in carcinoid syndrome i.e. most commonly in the appendix, small intestine, stomach, lung, rectum and uncommonly in other places. Some use it to (incorrectly) refer to all Neuroendocrine Tumours. The most worrying connotation of the use of the word ‘Carcinoid’ is the belief that they all have benign clinical and biological behaviour. That is dangerous thinking and has the potential to kill people. Fortunately, NET specialists are starting to move away from using the word – check out the quote below:

The Origins

The following history of ‘Carcinoid’ is well documented: Siegfried Oberndorfer (1876-1944) became the first to adequately characterise the nature of Carcinoid tumours and refer to them as “benign carcinomas.” During his tenure at the Pathological Institute of the University of Munich, Oberndorfer noted in 1907 that the lesions were distinct clinical entities and named them “karzinoide” (“carcinoma-like“), emphasizing in particular their benign features. However, In 1929 he amended his classification to include the possibility that these small tumours could be malignant and also metastasise. (Author’s note – a name change would have been handy at this point).

100 years later

NANETS, UKINETS and ENETS seem to defer to the WHO classification nomenclature and it is here another term is introduced – Neuroendocrine Neoplasms (NENs). NANETs state that “all of the entities under discussion are neoplastic, and neoplasm is therefore a more accurate term than tumor, which means only a mass“. These organisations tend to use the term Neoplasm as a catch-all for all Neuroendocrine disease and then the term ‘tumor’ and ‘carcinoma’ applies to well and poorly differentiated respectively. It’s worth noting that since 2010, the WHO classification is based on the concept that all NETs have malignant potential, and has therefore abandoned the division into benign and malignant NETs and tumours of uncertain malignant potential. Neuroendocrine Carcinoma is malignant by defintion. All of this has been reinforced in the 2017 publication. The term ‘Carcinoid’ is conspicuously missing from these texts.

To put it simply – the term ‘carcinoid’ is no longer credible

Due to its historical meaning, Carcinoid does not adequately convey the potential for malignant behaviour that accompanies many of these neoplasms as described above. The term Carcinoid decodes to ‘Carcinoma like’. Contextually “Carcinoid Cancer” decodes to “carcinoma like cancer” which is, of course, totally misleading and its use simply perpetuates the claim by some that it is ‘not a proper cancer’. If we only needed one reason to ditch the word ‘Carcinoid’, this would be it.

I mentioned confusion above and this has led to a hybrid effect of naming the condition. For example, there is a tendency by some (including medical establishments and patient organisations) to use the term ‘Carcinoid’ and ‘Neuroendocrine Tumors’ interchangeably which is patently incorrect. Neither is it helpful that many patients and organisations continue to refer to this disease as “Carcinoid Neuroendocrine Tumor”, “Neuroendocrine Carcinoid Tumor”, “Neuroendocrine Carcinoid Cancer”, “Carcinoid/Neuroendocrine”, “CNET”; and many other variations along these lines. Many seemingly credible organisations will say “Carcinoid and Neuroendocrine Tumors” not realising it’s a contradiction in terms. Continued use of the term in any phrase or standalone context is not doing our case for recognition any good – it’s bad enough that some seem to cling to outdated and invalid diagnostic clichés and icons from the 1980s. All of it needs to go.

I know I’m not alone in this thinking given the decrease of its use in the NET world, including NET Specialists (see lead graphic) and NET Specialist organisations (some have changed their names). There’s an interesting article written by a NET specialist where the term ‘carcinoid’ is described as “unfortunate”, “misleading”, “outmoded”, “archaic”, “confusing” and “misnomer”. Exactly! In the recent SEER NET study, a NET specialist reaffirmed this thinking by stating that “the belief these tumors did not metastasize, did not reach any great size, and appeared harmless, has since been proven false”. Continued use of the term ‘Carcinoid’ has the potential to regress this thinking. We must not let this happen.

So what terms should we be using?

People and organisations will be out of date with modern Neuroendocrine Neoplasms nomenclature and some will still want to continue with their own nomenclature (….. and because of the confusion, some will fall into both categories not realising they’re out of date). Here’s a classic example of the problem we face – the American Cancer Society(ACS) does not even list Neuroendocrine Tumor as a cancer type. Instead you can find “Gastrointestinal Carcinoid Tumors” and “Lung Carcinoid Tumor”. You’ll find Pancreatic NETs inside Pancreatic Cancer. Americans should harangue the ACS to get this right. I could go on with many similar observations on seemingly respectable sites. I intentionally used a US example as this country appears to be way behind in the changes to NET nomenclature, pretty surprising as they tend to be at the forefront of many other aspects in the world of NETs.

Personally, I think the acceptance of a common worldwide nomenclature should come from the World Health Organisation (WHO) classification for Neuroendocrine Neoplasms. They are divided into a number of chapters including ‘Endocrine Organs’, Digestive System, Lung Tumours….. and no doubt some others. Frustrating, but medical people tend to look at things in anatomical terms. Nonetheless, the agreed classification nomenclature for the whole group of Neuroendocrine Neoplasms can be found with some research and access to clinical publications. The correct nomenclature should then be flowed down in regional groupings, e.g. ENETS representing Europe, NANETS representing North America, etc. As I understand it, ENETS and UKINETS are already essentially aligned with WHO and NANETS appears to be. From these organisations, the use of the correct terminology should then rub off on patients, patient advocate organisations and general cancer sites. However, the biggest challenge will be with hospitals/medical centres, cancer registries and insurance companies whose medical record processing is run using reference data (think drop down selections and database structures). Easier said than done but ‘change’ always has to start somewhere. Technically it has started (albeit late) as the big NET medical organisations are already starting to reduce the use of outmoded words such as ‘carcinoid’.

I once argued that the term ‘carcinoid’ needed to be retained as it represented a histopathological grouping of a particular type of NET comprising mostly appendiceal, stomach (gastric), rectal, small intestine and lung NETs. However, reading through the ENETS 2016 guidance in conjunction with the most up to date WHO classification publications, I’ve changed my mind after noticing they no longer use the word ‘Carcinoid’ in relation to a tumor type. Rather, they use the latest WHO terms above and then use the anatomy to distinguish the different types of NET (like we already do for Pancreatic NET or pNET).

Perhaps patients can lead the way here ………

Rather than say:

‘Carcinoid’ or ‘Carcinoid Tumor’….. why not say Neuroendocrine Tumor or NET (adding your primary location if required – see below);

‘Carcinoid Cancer; ….. why not say Neuroendocrine Cancer;

‘Lung Carcinoid’ ….. why not say Lung NET (adding typical or atypical if required);

‘Small intestine Carcinoid’, why not say Small Intestine NET (or ‘SiNET which is becoming popular); p.s. I’m not a fan of ‘small bowel’ due to the potential for confusion with the widely used term ‘bowel cancer’);

‘Gastric Carcinoid’, why not say Gastric NET (adding your type if required);

‘Rectal Carcinoid’, why not say Rectal NET;

‘Appendiceal Carcinoid’, why not say Appendiceal NET;

…. and so on. And you can add your stage and grade/differentiation for a richer picture.

You can listen to a very well known NET Specialist say something similar in this video here.

Worth noting that even ENETS and NANETS cannot agree on tumor type terminology – the latter uses Small Bowel NETs (SBNETs) whereas ENETS uses Small Intestine NENs (SiNENs). I did say it’s easier said than done.

As I said above, the term ‘Carcinoid’ has become entrenched in both pathology and clinical literature over the past 100 years so it will still appear in many texts and need to be searchable online to support medical and advocacy business. However, these are technical issues and I don’t therefore believe people need to use the terms to make them searchable online. I tag all my posts with ‘Carcinoid’ even if I don’t mention the word in my text. I have started only using the term for context when it is required and am currently reviewing all of my posts to ensure that is still the case.

Hang on…what about Carcinoid Syndrome

When someone wants to know which syndrome you have, you can’t just state (say) “small intestine syndrome” or “midgut syndrome”. ‘NET Syndrome’ doesn’t work either as there are several NET syndromes. This has led to the situation where people try to drop the word ‘carcinoid’ and just say “the syndrome” which is even more confusing! I accept this one is a difficult challenge but I don’t believe it’s insurmountable, just needs some willpower and agreement. I could come up with other terms in about 5 minutes.

What about Carcinoid Heart Disease

Personally I don’t see why this cannot be renamed to ‘Neuroendocrine Heart Disease’ or its technical name – ‘Hedinger syndrome’.

What about Carcinoid Crisis

World renowned NET specialists already make statements that these issues can apply to all types of NET; and it’s well-known that a similar crisis situation already applies to other types e.g. Pheochromocytomas. I cannot see why something along the lines of ‘Neuroendocrine Crisis’ or ‘NET Crisis’ would not be acceptable.

Summary

We as patients are unlikely to be able to force changes on the medical and insurance communities but we can be a ‘force for change’ by setting the example of using a correct and more apt terminology to describe our disease.

Thanks for listening

Ronny

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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

Background

The mesentery and retroperitoneum areas

What causes it, what problems does it cause and how can it be treated?

What happened to me?

Summary