PDR001 (anti-PD-1) is an investigational immunotherapy being developed by Novartis to treat both solid tumors and lymphomas (cancers of the blood). It is currently being trialled on many cancers including Neuroendocrine. It’s brand name is SPARTLIZUMAB.
How PDR001 works
PDR001 is a type of immunotherapy, meaning that it acts by activating the body’s own immune system to recognize and fight cancer cells. Normally, an immune system cell called T-cells recognizes and kills infected or abnormal cells, including those that are cancerous. To prevent T-cells from accidentally damaging healthy and essential tissues, however several immune system checkpoints exist to inhibit, or block, them from going about this work. One example is the programmed cell death 1 (PD-1) pathway. Healthy cells produce and display a protein called programmed cell death ligand-1 or ligand-2 (PD-L1 or PD-L2) on their surface. These proteins bind to and activate a receptor called PD-1 that is produced by T-cells. When activated, PD-1 sends a message to the T-cells that prevents them from attacking that particular cell. Cancer cells can hijack this system by producing PD-L1 or PD-L2, effectively hiding from T-cells and evade destruction.
PDR001 is an antibody, a protein designed to interact with and block a specific target. It acts by binding to PD-1, blocking it from interacting with both PD-L1 and PD-L2. This binding blocks the PD-1-mediated inactivation of the T-cells, so that they are able to recognize and target cancer cells. This should result in a reduction in tumor growth and size.
Novartis presented results from an ongoing first-in-human Phase 1/2 clinical trial (NCT02404441) of PDR001 at the American Society of Clinical Oncology (ASCO) meeting in 2016. Preliminary trial results suggested that the drug is well-tolerated and safe, with a similar profile to other anti-PD-1 drugs currently being developed. The trial is still recruiting patients with various types of advanced cancer at 43 sites across North America, Europe, and Asia; more information is available by clicking on its identification number.
Novartis then initiated several dozen other Phase 1, 2 and 3 trials, all registered on clinicaltrials.gov, to continue investigating the safety and anti-tumor activity of PDR001 in a wide range of cancer types, and in combination with other investigational and approved therapies. For example, a Phase 3 trial (NCT02967692) is comparing the safety and efficacy of PDR001 to a placebo, in combination with Tafinlar (dabrafenib) and Mekinist (trametinib), as a treatment for advanced melanoma.
What about Neuroendocrine?
A phase 2, multi-center study assessed the efficacy and safety of PDR001 in patients with non-functional well and poorly-differentiated Neuroendocrine Neoplasms. According to the clinical trial document, the types of NENs covered are:
Well-differentiated Non-functional NET of Thoracic Origin
Well-differentiated Non-functional NET of Gastrointestinal Origin
Well-differentiated Non-functional NET of Pancreatic Origin
The clinical trial indicates the trial is active but not recruiting but it would look like they have all the patients needed and are currently analysing the trial data so far awaiting the next phase perhaps. In fact I have discovered two pieces of evidence from the trial sponsors:
In another analysis of the results: “Patients with well-differentiated advanced NETs were eligible if they had progressed on prior therapy, including everolimus, while the GEP-NEC patients were eligible if they had progressed on one line of chemotherapy. All patients in the trial received spartalizumab via a 30-minute infusion once every 4 weeks until disease progression or unacceptable toxicity.
In the full well-differentiated cohort, there were 7 partial responses (7%), and 55% had stable disease, while 31% had progressive disease. The confirmed objective response rate was 7%, and the disease control rate was 63%. In the GEP-NEC cohort, the objective response rate was 5%, and the disease control rate was 19%.
The thoracic NETs patients fared best with spartalizumab, with limited responses seen in the pancreatic and GI NETs groups; responses seemed to be associated with PD-L1 expression. In the thoracic NETs cohort, two of five PD-L1–positive patients had a partial response. PD-L1 positivity was more common in the GEP-NEC cohort; among 14 PD-L1–positive patients in that group, the partial response rate was 43%.
The most common adverse events regardless of cause included abdominal and back pain, anemia, dyspnea, and hypertension.
Kjell Öberg, MD, PhD, of Uppsala University in Sweden, discussed the study for ESMO. “We have hope,” he said. “We see that maybe there are some tumor types that might respond to immunotherapy.” In general, NETs are considered an “immunological desert.” There is usually very low infiltration of immune cells in these tumors, and there are a low number of genetic mutation events.”
You can also listen to two very well known NET experts (Simron Singh and Jonathan Strosberg) talk about this trial and the drug ……. “the highest response rate was seen in atypical lung neuroendocrine tumors. It was approximately 20%, but in most cases was not durable”. See the remainder of the discussion by clicking here.
On the heels of the approval of PRRT in USA and whilst we all wait on positive national announcements of PRRTapproval in UK and elsewhere, here’s news of a new PRRT compound undergoing a phase 3 clinical trial. Isotopen Technologien München AG (ITM), a specialized radiopharmaceutical company, today announced the enrolment of the first patient recruited in Europe for the COMPETE phase III clinical trial at theUniversity Hospital Marburg, Germany. The CEO of ITM said “This marks the starting point of COMPETE in Europe, whereby we expect a rapid increase in the number of recruits.” I actually met these guys at ENETS 2018 – sounds great.
What is the COMPETE trial?
COMPETE is led as an international pivotal multi-center phase III clinical trial evaluating the efficacy and safety of (no-carrier-added) n.c.a.177Lu-Edotreotide (Solucin®) and the trial is comparing it to Everolimus (Afinitor). The trial runs until Dec 2020. The enrolment requires patients with inoperable, progressive, somatostatin-receptor positive neuroendocrine tumors of gastroenteric or pancreatic origin (GEP-NET). The primary endpoint is progression-free survival (PFS). The study will be conducted predominantly in Europe, North America, South Africa and Australia (ITM is waiting on FDA clearance to include North American locations in the trial). The first patient to be enrolled and treated was in Australia. The clinical trial document (see references below) indicates its for non-functional GI tumours but for non-functional and functional pNETs. The list of locations can also be found in the clinical trial document. The usual inclusion/exclusion rules apply but the most notable would appear to be an exclusion for those with prior exposure to any PRRT or mTor inhibitor such as Everolimus (Afinitor).
What is 177Lu-Edotreotide (Solucin®) ?
The compound under investigation, Solucin®, is known as a Targeted Radionuclide Therapy (TRT) agent, which consists of the targeting molecule Edotreotide, an octreotide-derived somatostatin analogue and ITM´s EndolucinBeta® (no-carrier-added Lutetium-177). EndolucinBeta® is a synthetic, low-energy beta-emitting isotope of Lutetium, a recently EMA approved pharmaceutical precursor. The radiopharmaceutical Solucin® is administered as an intravenous infusion, specifically targeting and destroying the tumor cells with ionizing radiation. Solucin® received an Orphan Designation (EMA/OD/196/13) for the treatment of GEP-NET, based on early clinical experience, which has demonstrated a substantial clinical benefit with increased PFS and quality of life.
From ITM’s website … “Edotreotide contains DOTA which functions as a chelator for radioisotopes and TOC, a synthetic Somatostatin receptor ligand” (chelator and ligand are just fancy names for ‘bonding’ or ‘binding’). “The compound Edotreotide binds with high affinity Somatostatin receptors and retains both its receptor binding properties and its physiological function when labeled with 177Lu. Somatostatin receptors are predominantly overexpressed by neuroendocrine tumors. 177Lu-Edotreotide, upon binding to Somastotatin receptors in vivo is internalized and retained by tumor cells.”
“Compared to 90Y-Edotreotide, 177Lu-Edotreotide Targeted Radionuclide Therapy in NET was found to be less haematotoxic and associated with a longer median overall survival. That was highly significant for patients with low tumor uptake as well as for patients with extra hepatic and solitary metastases. In a retrospective Phase II trial 177Lu-Edotreotide showed a low uptake/dose delivered to normal organs and very high tumor-to-kidney ratio.”
Other Spin offs from ITM
Interestingly the company is also working on a ‘theranostic pair’ for imaging and treating bone metastases – see graphic below. It does not say whether this includes NET bone metastases but I don’t see why not given the connection with Solucin. However, please note this is some years away from fruition.
In my article ‘Ever wonder what caused your NET’, I concluded that currently, the only known scientifically explained causes for NETs were hereditary/genetic in nature. This is mostly associated with those who have MEN syndromes (yes, they are a syndrome not a type of tumour) and a few other less common types of NET including Pheochomocytoma/Paraganglioma (Pheo/Para) and Medullary Thyroid Carcinoma (MTC) (the familial version of MTC is often referred to as FMTC). However, please note this does not mean that all those diagnosed with pancreatic, parathyroid, pituarity, Pheo/Para and MTC tumours, will have any hereditary or genetic conditions, many will simply be sporadic tumors.
In recent years, it has become increasingly apparent that a number of Neuroendocrine tumours arise as a result of germline genetic mutations and are inherited in an autosomal dominant pattern. The number of genes implicated is increasing.
Apparently, 5-10% of Gastroenteropancreatic NETs (GEP NETs) are estimated to have a hereditary background. Hereditary syndromes associated with these include Multiple Endocrine Neoplasia (MEN), Von Hippel Lindau (VHL), Neurofibromatosis Type 1 (NF1), Tuberous Sclerosis (TS) and others. People who have a genetic condition may present with the tumors (perhaps along with an associated functional hormone syndrome) and so the genetic condition if there is one, may not be known at this point.
How will I know if I am affected?
Some people do worry about this, often because of what they find on the internet including inside patient forums. I suspect some people already know via family connections and as an example (there are many), I guess if you have 2 tumors found in (say) parathyroid and pancreas, it should at least raise a suspicion for MEN1 and be investigated.
Many people say how do I know, how do I check and this is obviously a delicate subject. Of course, your first port of call should be your NET specialist if you suspect or know of any connection.
Thus why I was interested in a paper published in Springer Link – titled “When should genetic testing be performed in patients with neuroendocrine tumours.” When reading, you’ll find it’s actually much more than that! Check it out here:
When should genetic testing be performed in patients with neuroendocrine tumours?
In this review, the authors examined the features which may lead a clinician to suspect that a patient may have an inherited cause of a NET and they outlined which underlying conditions should be suspected. They also discussed what type of screening may be appropriate in a variety of situations. If there is a way to identify which patients are likely to have a germline mutation, this would enable clinicians to counsel patients adequately about their future disease risk, and allows for earlier detection of at-risk patients through family screening. There’s a couple of minor errors in the text but I’ve contacted the authors who also agreed they should have included the pituitary.
The authors focused on presentations of NETs of the gastrointestinal system, chromaffin cell tumours (Pheochromocytoma and Paraganglioma) and Medullary Thyroid Carcinoma. Pituitary tumors (normally associated with MEN1), were not considered in scope for the review. Interesting thought, the review includes news of a move by endocrinologists to reclassify ‘Pituitary Adenomas’ as Pituitary NETs (PitNETs). Read the abstract here. This would appear to be in line with a gradual shift from the benign nomenclature associated with certain NETs to the ‘malignant’ potential of these type of tumors. The abbreviation is also in line with others, e.g. pNET, SiNET, etc. A useful reminder that we must stop using the term ‘Carcinoid‘ as this is regressing this extremely useful initiative to highlight the malignant potential of all NETs.
There also appears to be some linkage to the study looking at the possibility of familial Small Intestine NETs (SiNETs). You can read more about a US registered trial here (with apologies for use of the now defunct term ‘Carcinoid‘).
This is a complex subject and the text above is very basic. If you wish to dig further, the quoted reference is a good read. Just to emphasise, it’s aim is to provide advice about when to recommend genetic testing for NETs, and in doing so provides some useful reference information. Please also note they are finding new genetic links all the time so there could be some omissions of recently discovered genes but the article remains good enough as a primer on the subject. It’s broken down into 4 distinct tumor groupings:
There’s been a lot of action in the area of what is termed Gastro-Entero-Pancreatic Neuroendocrine Tumors (GEP-NETs). It can therefore sometimes appear that Lung NETs are the poor relation. There are certainly some unmet needs in this area of the anatomy including a lack of research. Thus far, no prospective trials specifically for patients with lung NETs appear to have been reported.
However, there has been some recent movement. Last year, the use of Afinitor (Everolimus) was approved for progressive, non-functional NET of GI or Lung origin.
SPINET Trial for Lung NETs
In late 2016, I tipped you off about an Ipsen sponsored trial for Lung NETs involving Lanreotide (Somatuline). SPINET is a Phase 3, prospective, multi-center, randomized, double-blind, study evaluating the efficacy and safety of Lanreotide plus “Best Supportive Care” (BSC) versus placebo plus BSC for the treatment of well-differentiated, metastatic and/or unresectable, typical or atypical lung NETs. The aim of the SPINET study is to evaluate the safety and antitumor efficacy of Lanreotide 120 mg in patients with advanced lung NETs. I suspect that many Lung NET patients are already receiving somatostatin analogues (Octreotide/Lanreotide) but prescribed only for syndrome/symptom control.
SPINET is now recruiting in many locations (see below).
The countries involved in the SPINET trial are as follows (in case my post goes out of date – see the latest update to the trials document here). Please also check the inclusion and exclusion criteria.
USA, Austria, Canada, Denmark, France, Germany, Italy, Netherlands, Poland, Spain, UK.
In addition to the trial document linked above, you can read more about the SPINET trial here with commentary from a well-known NET Specialist – Dr Diane Reidy-Lagunes, who is the principal investigator for the trial.
How do I get on the trial?
You may be interested in this organisation – Trialbee. They are a company helping Ipsen to raise awareness of the SPINET trial using a cloud based platform to connect patients, investigators and sponsors (I’ve authenticated their participation with Ipsen). There is no fee for using their services. There’s a useful questionnaire which can help you decide if this trial is for you – here.
Please note, if you are concerned about participating in clinical trials, you should always consult your specialist for advice.
If you are a patient advocate or an advocate organisation, please share with your communities in order that Lung NET patients are at least made aware of the trial.
Diarrhea can be a symptom of many conditions but it is particularly key in Neuroendocrine Tumour (NET) Syndromesand types, in particular, Carcinoid Syndrome but also in those associated with various other NET types such as VIPoma, PPoma, Gastrinoma, Somatostatinoma, Medullary Thyroid Carcinoma.
Secondly, it can be a key consequence (side effect) of the treatment for Neuroendocrine Tumours and Carcinomas, in particular following surgery where various bits of the gastrointestinal tract are excised to remove and/or debulk tumour load.
There are other reasons that might be causing or contributing, including (but not limited to) endocrine problems such as hyperthryoidism, mastocytosis or Addison’s disease (which may be secondary illnesses in those with NETs). It’s also possible that ‘non-sydromic’ issues such as stress and diet are contributing. It could be caused by other things such as Irritable Bowel Syndrome (IBS). Yes, believe it or not, NET Patients can get normal diarrhea causing diseases too!
I want to give a general definition of diarrhea as there are many variants out there. In general, they all tend to agree that diarrhea is having more frequent, loose and watery stools. Three or more stools per day seems to be the generally accepted threshold, although some sites don’t put a figure on it. It’s not pleasant and just about everyone on the planet will suffer it at some point in their life, perhaps with repeated episodes. Normally it’s related to some kind of bug, or something you’ve eaten and will only last a few days before it settles (acute diarrhea). Diarrhea lasting more than a couple of weeks is considered chronic and some people will require medical care to treat it. It can also be caused by anxiety, a food allergy/intolerance or as a side effect of medicine. Pharmacists and GPs will be seeing many patients with this common ailment every single day of business.
Diarrhea induced by a Syndrome
When you consider the explanation above, it’s not really surprising that diarrhea related symptoms can delay a diagnosis of Neuroendocrine Cancer (and most likely other cancers too, e.g. pancreatic cancer, bowel cancer). For example, diarrhea is the second most common symptom of Carcinoid Syndrome (Flushing is actually the most common) and is caused mainly by the oversecretion of the hormone Serotonin from the tumours. Please note diarrhea in other types of syndromes or NETs may be caused by other hormones, for example it may also be caused by excess calcitonin in the case of Medullary Thyroid Carcinoma or VIP in the case of a functional pNET known as VIPoma. I’ve heard stories of people being told they have IBS or something similar for years before they received what is now a late diagnosis and at an advanced cancer stage. This is only one of the reasons why NETs is not an easy condition to diagnose, although it is possible that some people actually had IBS and it was masking the NET. Even after treatment to remove or reduce tumours, many people will remain syndromic and need assistance and treatment to combat diarrhea induced by a NET syndrome (see below).
Diarrhea as a Consequence (Side effect) of Treatment for Neuroendocrine Cancer and Other Conditions
All cancer treatments can have consequences and Neuroendocrine Cancer is definitely no exception here. For example, if they chop out several feet of small intestine, a chunk of your large intestine, chunks (or all) of your stomach or your pancreas, your gallbladder and bits of your liver, this is going to have an effect on the efficiency of your ‘waste disposal system’. One effect is that it will now work faster! Another is that the less effective ‘plumbing’ may not be as efficient as it was before. There are also knock-on effects which may create additional issues with the digestive system including but not limited to; Malabsorption and SIBO. I recommend you read my posts on Malabsorption and SIBO.
Surgery can often be the root cause of diarrhea. A shorter gut for example, means shorter transit times presenting as increased frequency of bowel movements. Another example is the lack of terminal ileum can induce Bile Acids Malabsorption (BAM) (sometimes known as Bile Salts Malabsorption) in degrees of severity based on size of resection. Lack of a gallbladder (common with NETs) can also complicate. 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). Although this condition can be treated using bile acid sequestrants (i.e. Questran), it can be difficult to pinpoint it as the cause.
Surgery of the pancreas can also produce effects such as exocrine pancreatic insufficiency which can lead to a malabsorption condition known as steatorrhea which may be confused with diarrhea (although some texts call it a type of diarrhea). It isn’t really diarrhea but it may look like it given the presentation of the faeces and patients may suffer both diarrhea and steatorrhea concurrently. Patients will recognise it in their stools which may be floating, foul-smelling, greasy (oily) and frothy looking. Treatment options will mainly include the use of Pancreatic Enzyme Replacement Therapy or PERT for short (Creon etc).
Many non-surgical treatments can also cause diarrhea, including but not limited to; somatostatin analogues (see below), chemotherapy, biological targeted therapy (e.g. Everolimus, Sunitinib), radiotherapy.
Somatostatin analogues are an interesting one as they are designed to inhibit secretion of particular hormones and peptides by binding to the receptors found on Neuroendocrine tumour cells. This has the knock-on effect of inhibiting digestive/pancreatic enzymes which are necessary to break down the fat in our foods leading to Malabsorption of important nutrients. This may worsen the steatorrhea in pancreatic NET patients but also lead to steatorrhea in others with non-pancreatic locations who have been prescribed these drugs.
Other conditions may actually be the cause of the diarrhea or the treatment for those conditions. For example, it is possible that people actually do have Irritable Bowel Syndrome (IBS). Treatment therapy for common conditions may also be contributing, for example the use of Proton Pump Inhibitors for acid reflux.
Treatment for Syndrome Induced Diarrhea
Like many other NET patients, I’m on a 28 day injection of somatostatin analogues (in my case Lanreotide). Both Octreotide and Lanreotide are designed to reduce the effects of NET syndromes and therefore can often make a difference to syndrome induced diarrhea. These drugs also have anti-tumour effect and so even if you are not syndromic or they do not halt or adequately control syndrome induced diarrhea, they are still a valuable contribution to NET treatment.
Some syndromic patients find they still have diarrhea despite somatostatin analogues and they end up having ‘rescue shots’ or pumps for relief (both of these methods tend to be Octreotide based). (Hopefully they are not getting confused between diarrhea caused by the non-syndrome effects – see above). Some have more frequent injections of the long acting versions of somatostatin analogues which has the effect of increasing the dosage. There’s a new drug available for those whose carcinoid syndrome induced diarrhea is not adequately controlled or perhaps they are unable to have somatostatin analogues as a treatment. Telotristat Ethylworks by inhibiting tryptophan hydroxylase (TPH), a chemical reactor involved in the manufacture of serotonin, which is the main cause of syndrome induced diarrhea. It was approved by the US FDA in February 2017, EU areas in September 2017, and is on the way to being approved elsewhere. Read about this drug here.
Sorting out the symptoms – post diagnosis
I like to describe this as the Neuroendocrine Cancer jigsaw. It’s a really difficult one and sometimes you cannot find a piece, or the pieces won’t fit. However, metaphorically speaking, the missing piece might be a NET specialist presentation, a comment, statement or view from another patient, a link to an article from a reputable source, or even something you do to improve your lot – there might even be trial and error involved. It might even be this blog post!
How do you work out whether diarrhea is caused by a hormone producing tumour or by the side effects of treatments? There’s no easy answer to this as both might be contributing. One crude but logical way is to just accept that if you have normal hormonemarkers, for example 5HIAA (there could be more for other tumour/syndrome types), and you’re not really experiencing any of the other classic symptoms, then your syndrome might be under control due to your treatment (e.g. debulking surgery and/or somatostatin analogues, or another drug). My Oncologist labels me as ‘non-syndromic’ – something which I agree with. I’m 99.999999% sure my issues are as a result of the treatment I’ve had and am receiving.
This disease is so individual and there are many factors involved including the type of syndrome/NET, patient comorbidities and secondary illnesses, consequences of the surgery or treatments performed, side effects of drugs – all of which is intermingled with suspicion and coincidence – it’s that jigsaw again! I always like to look in more detail to understand why certain things might be better than others, I always challenge the ‘status quo’ looking to find a better ‘normal’. I really do think there are different strategies for syndrome induced diarrhea and that which is a result of treatment or a side effect of treatment. There’s also different prices, with inhibitors costing thousands, whilst classic anti-diarrhea treatments are just a few pennies. Adjustments to diets are free!
When I was discharged from hospital after the removal of my small intestinal primary, I was in the toilet A LOT (I was actually in the toilet a lot before I was discharged – check out my primary surgery blogs here) . My surgeon did say it would take months to get back to ‘normal’ – he was right and it did eventually settle – although my new ‘toilet normal’ was soft and loose and several times daily. My previously elevated CgA and 5HIAA were eventually back to normal and my flushing had disappeared. I didn’t have too many issues with diarrhea before diagnosis. Deduction: my issues are most likely not syndrome induced.
I read that many people find basic ‘Loperamide’ (Imodium) helps and I tend to agree with that if you are non syndromic and just need that little bit of help. I decided long time ago I would not become ‘hooked’ and only really take it for two purposes: 1) if I have a bad patch and 2) if I’m going on a long journey (i.e. on a plane perhaps). I estimate I’ve used 4 packets in as many years. Loperamide decreases the activity which causes intestinal motility (peristalsis). This has the effect of increasing the time material stays in the intestine therefore allowing more water to be absorbed from the fecal matter. Ideal for those with a shorter bowel due to surgery and advice from a medical professional is always advisable. To reduce the risk of malabsorption induced diarrhea and steatorrhoea, both of which can lead to loss of valuable nutrients, the use of Pancreatic Enzyme Replacement Therapy (PERT) might need to be introduced as required by your NET specialist.
Have a look at Enterade – the results from trials look good.
Clearly, I cannot offer any professional medical advice on coping with diarrhea, I can only discuss my own situation and what I found worked for me. Don’t forget, like many diseases, what works for one, might not work for another. However, I did tackle my problems following the advice of an experienced dietitian who specialises in NET Cancer. That said, I was ‘sleep walking’ for over 2 years thinking my issues were just part of the way things were after my treatment. I was wrong about that!
As for my own strategy, here’s things that helped me:
made some changes to diet(they were not huge changes),
maintained a diary to help with monitoring progress or setbacks,
hydration is also important (….still working on that one).
started taking PERT (Creon) on 23 Dec 2017 (changed to Nutrizym Feb 2019) but looks reasonably positive so far.
With no fancy and expensive drugs, I’ve gone from 6-8 visits to 1-2 visits (as a daily average, it’s actually 1.5). This didn’t happen overnight though, it took a lot of time and patience. All of this doesn’t mean to say I don’t have issues from time to time …… because I do!
In summary, I think it’s important that people be sure what is actually causing their diarrhea after diagnosis so that the right advice and the optimum treatment can be given.
Listen to Dr Wolin talking about this particular jigsaw puzzle – click here
Also see a nice article that come out of NANETS 2017 – click here
Of course, some people sometimes have the opposite effect but that’s in another blog here – Constipation
EIGHT years ago. I was diagnosed with metastatic Neuroendocrine Cancer – 26th July 2010. Until I arrived at my 5th anniversary, I hadn’t thought much about how (or if) I should mark these occasions. I never thought I would dwell on such things as ‘Cancerversaries‘ but I now totally get why many patients and survivors do.
There are various types of ‘Cancerversary‘ that for some, could trigger a mix or range of emotions including gratitude, relief and fear of cancer recurrence or growth. These milestones could be the date of a cancer diagnosis, the end of a particular type of treatment (anniversary of surgery etc) or a period since no signs or symptoms of cancer were reported. Everybody will most likely handle it their own way – and that’s perfectly understandable.
The 5 year milestone was significant, mainly I suspect, because it’s a time period very frequently used in prognostic outcome statistics. When I was researching after my diagnosis, the 5 year figure for metastatic Neuroendocrine Cancer wasn’t that great, in fact it looked less favourable than more aggressive cancers. Then I gradually worked out that the prognostic figures for Neuroendocrine Cancer were very dated (like many other things) and did not take into account improved diagnostic techniques and the introduction of a plethora of new treatments, in particular somatostatin analogues. Consequently, I no longer pay any attention to prognostic statistics – I’m actually more influenced by the large number of long-term survivors I see out there.
Check out the fantastic response to my 7th year cancerversary post. Click here to be inspired.
My cancer is treatable but not curable but I will never call it terminal. Despite some issues this year so far, I’m still here and I intend to be here next year, and for many more years after that!
I once met some fellow cancer advocates and the conversation turned to what inspired us to ‘do what we do’. When it came to my turn as the only Neuroendocrine Cancer patient, I was already prepared to regurgitate my usual ‘spiel’. As sometimes happens, a listener queried me with the words “Neuroendocrine – what’s that?“. Another focused on ‘Neuro‘ enquiring whether my nervous system or my brain had somehow become cancerous. Deja vu – here we go again!
Two days later, I was speaking to one of my online friends who was having similar problems explaining this cancer to family and friends. Again ‘Neuro‘ was proving difficult with the assumption that it’s somehow related to the brain. Technically not far from the truth but context is really important given that most people look at cancer in anatomical terms. As we know this can often lead to incorrect headlines for famous cancer patients.
I’ve struggled since 2010 to explain this disease in layperson terms. It’s actually one of the reasons for my ‘study’ and my blog. It’s getting easier, particularly when answering questions. However, if Neuroendocrine Cancer knowledge was an iceberg, I’d still be at the tip! I did write a post entitled Horrible Hormones which supports an explanation. You might like to read it– perhaps helpful to aid your overall understanding of this post.
The other difficult aspect of explaining Neuroendocrine Cancer is the extent of the Anatomy and Physiology of the Neuroendocrine system which appears in numerous parts of the body. I’ve written about this before at a time when I was fed up with newspaper reports and on-line articles implying that Neuroendocrine Cancer didn’t exist – e.g. by frequently describing Neuroendocrine Tumours of the Pancreas as Pancreatic Cancer and Neuroendocrine Tumours of the Lung as Lung Cancer. During some of my own verbal discussions, mention of the small intestine was frequently met with “so you have Bowel Cancer“. NO I DON’T! Good time to refresh yourself with my article The Human Anatomy of NET Cancer. This thinking needs to be challenged at every opportunity including while explaining to family and friends.
I’ve therefore decided to attempt a short, generic but still sufficiently detailed explanation of the word ‘Neuroendocrine‘ in relation to my Cancer. I suspect by the end of this article, it will not be as short as I had wished. I do like a challenge 🙂 Here goes:
The neuroendocrine system is made up of a network of cells that are distributed throughout the body. The word neuroendocrine refers to 2 qualities of these cells: they have a similar structure to nerve cells (neurons) and produce hormones like endocrine cells. Neuroendocrine cells release hormones into the bloodstream in response to chemical signals from other cells or messages from the nervous system. Basically hormones travel in the bloodstream and makes things happen in another part of the body.
These neuroendocrine cells are scattered throughout the body performing different roles based on location, e.g. Neuroendocrine cells in the digestive system regulate intestinal movements and the release of digestive enzymes
When Neuroendocrine tumours develop in these cells, they can not only then spread to other locations but they can also secrete excess amounts of hormones and substances which can cause an adverse effect on the body’s natural rhythm. A collection of these symptoms is known as a syndrome. There are several different syndromes depending on the location and type of Neuroendocrine Tumour.
The presence of the syndrome nearly always indicates the tumours are functional. Sometimes tumours are non-functional (i.e. they do not overly secrete excess hormones or cause symptoms), these non-functional types can be even more difficult to diagnose.
Most Neuroendocrine Tumours are slow-growing and therefore offer good outlook if identified as early as possible and treated. Even for metastatic patients, the outlook is relatively good with the right treatment and surveillance. Some are more aggressive behaving like adenocarcinomas and need a different approach to treatment.
I found it very difficult to write a short and generic explanation of the word ‘Neuroendocrine‘ in relation to cancer – no wonder I seem to spend 10 minutes verbally explaining to people and…… no wonder they sometimes look at me with glazed eyes 🙂 However, this is my offer. This is as brief as I can make it to provide understanding. I’ve cut out more than I’ve left behind and feel like I’m short-changing you! However, it needs to be basic and it needs to be short.
Explanations which comprise lists of complex and unpronounceable words each with their own constraints and variable meanings leads to chaos and people switching off. I could have just referred to one of the excellent publications on the web but this isn’t really practical when in an impromptu conversation with wide-eyed listeners. That said, I believe the combination of this post and (if you see light-bulbs) the other 2 linked posts within, is a good way to answer the question if someone is willing to listen (and read a short reference). You may therefore need to follow-up the ‘verbal’ with the ‘written’.
To summarise, I intentionally made this explanation as generic as possible. Trying to explain every single type of Neuroendocrine Cancer will confuse and tire the best listener. If I was using this today, I would add my own additional comment about where my tumours were found and what treatment I’ve had – this I can do without a script! However, if you think this explanation is of use when verbally explaining Neuroendocrine in relation to your cancer, please feel free to share my blog post to aid understanding.
Neuroendocrine – what’s that? I didn’t have a clue …… until I was diagnosed with it!
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 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 videohere.
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.
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
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