Diarrhea is a huge subject for NET patients, whether it’s caused by the tumor itself (i.e. a syndrome), due to treatment, knock on effects of treatment, or some other reason, it can dramatically limit qualify of life. Working out the root cause can be problematic even for medical teams. I wrote about these issues before in my article Neuroendocrine Cancer – the diarrhea jigsaw. So when I saw the data from a trial of something called enterade®, I was immediately drawn to investigate. I don’t normally write articles on over the counter commercial products but this one is an exception given that it has been classed as a medical food since 2012 and is also used to rehydrate patients undergoing radiotherapy and chemotherapy for cancer (so not just for NETs).
What is enterade® ?
It’s a drink currently produced in 8oz bottles. It’s a first-in-class, glucose-free medical food i.e. it is intended to be used under the supervision of a healthcare provider. The solution comprises five critical amino acids – Valine, Aspartic Acid, Serine, Threonine, Tyrosine and electrolytes – potassium and sodium.
What does it do?
It’s designed to help manage debilitating gastrointestinal (GI) side effects. With no sugar to exacerbate the GI tract, enterade® supports the small bowel’s ability to absorb fluids, nutrients, and electrolytes and leads to improved digestive function. By helping to restore normal GI function, enterade® reduces diarrhea and dehydration, leading to a significant improvement in the patient’s overall quality of life and a healthier GI tract.
Is there evidence that it works?
Since May 2017, it’s been trialled by University of Kentucky Markey Cancer Center (MCC) for potential use by NET patients – trial coordinators include the well-known NET specialist Dr Lowell Anthony. The results so far are very interesting. The recent conference reported revised data as follows:
33 of 41 patients (80%) reported subjective improvement in diarrheal symptoms.
51% (21/41) reported more than 50% reduction in diarrhea frequency.
click here or on the poster below to see the trial poster data output.
As you will see from the poster, there were a wide range of patient types including (but not limited to) small intestinal NETs, bronchial NETs, NETs of unknown primary, gastric NETS, pancreatic NETs and one high grade neuroendocrine carcinoma of the prostate.
A follow on Phase 2 trial is now recruiting with the following detail available:
1. Up to 30 patients will be recruited.
2. The trial is coordinated by Markey Cancer Centre, Kentucky.
3. There will be two cohorts, those with carcinoid syndrome and those without.
4. The trial will run from December 2018 to August 2020.
Click here to see the trial information – important to note the inclusion and exclusion criteria.
Please also note there’s a plan for a follow on trial covering more locations. I will update further when known.
Can I buy Enterade now?
The product is available in North America on Amazon.com, www.enterade.com and 1-855-enterade. However, the parent company (Entrinsic Health) recently announced a partnership with global company Nestlé Health Science to provides worldwide commercial license and supply agreement for enterade®. The announcement is linked here:
NORWOOD, Mass., November 15, 2018 – Entrinsic Health Solutions (EHS), an innovative health sciences company, today announced that they have entered into a partnership with Nestlé Health Science (NHSc), a global innovative leader pioneering premium-quality, science-based nutritional health solutions. The partnership gives NHSc the exclusive rights to market EHS’s enterade® product.
Please note this is not a recommendation to go out and buy the product. It is actually described as a ‘medical food’ and is formulated to be consumed or administered under the supervision of a physician.
3. Recent output from ASCO 2018 – click here. (contact data update for 2018)
4. If you are interested in more information about how enterade® works, check out this short video
Please note this is not a recommendation to go out and buy the product. It is actually described as a ‘medical food’ and is formulated to be consumed or administered under the supervision of a physician.
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
Most people have perceptions of cancer in their heads, fairly fixed perceptions too. They think about all the stuff they see daily on TV, in the main press, and people they know. The big cancers set the scene.
Most doctors know about the big cancers. They also know how to treat them, many of them have a fairly fixed regime of surgery/chemotherapy/radiotherapy. Many survivors will have side effects of their treatments, e.g.perhaps temporarily losing their hair. More people are now surviving these cancers and many will be declared disease-free or placed into some sort of remission status (no evidence of disease is a common term I see).
Most NETs are not like that! Whilst it has a reputation for being a generally slow-growing type of tumour at the lower grades (but very sneaky though!), offers a good outlook/prognosis for many, has many different types of treatment modalities, it can frequently present at an advanced stage and become incurable; and/or offer some quality of life challenges. For example:
Not many doctors know a lot about it.
Many patients will have gone through extended diagnostic periods, perhaps months, years in extreme cases. In many cases it can be ‘silent‘.
Only doctors who know a lot about it, really know how to quickly diagnose it. Only they know how to properly treat it. It’s a very individual disease, there are many factors involved.
Another key difference with NET Cancer is that many people will have an associated ‘syndrome‘ and this might have been with them for some time before diagnosis. The symptoms of these syndromes can sometimes be rather debilitating, even after treatment.
Many people will never be disease free nor will be they given a status of full remission. Their surveillance (scans etc) could continue indefinitely.
Many people will live with the consequences of this cancer for a long time and this plays on their mind as well as the effect on their body.
There’s a lot of talk about something called ‘unmet needs’ and quite right too. However, there’s not appear to be enough action to deliver those unmet needs in our community. This is a highly prevalent cancer and many people live a long time with the consequences of the cancer.
Before you receive treatment, always ask what the side effects might be, how long they might last and what support you will get to treat or lessen them. Don’t be afraid to ask, you deserve to be told.
I personally don’t see myself as ‘disabled’ but I do have an invisible illness. I’m fit, can walk for miles, I even look quite healthy. However, I live with the consequences of Neuroendocrine Cancer. These consequences differ from person to person but I know that some people with this disease have even met the criteria to be officially classed as ‘disabled’ through government schemes. Judging by what I read, I have less debilitating issues than others, so I feel quite fortunate. That’s not to say I don’t have any issues at all – because I do!
I was therefore delighted to see news of an initiative supporting invisible illnesses by Asda (for those outside UK, Asda is a major UK wide supermarket chain). Asda have now recognised that many conditions can be classed as ‘invisible disabilities’ and this need is now recognised in the availability of toilet facilities (see picture below). This is particularly relevant to my own disease, all types of Inflammatory Bowel Disease (Crohn’s, Ulcerative Colitis) or anyone who has issues due to the consequences of their cancer or treatment (e.g. GI surgery, Chemo, Radiotherapy).
I wrote an earlier blog on this subject called “Things are not always how they seem“. This was a great ‘invisible illness’ awareness message in the form of a reference to a newspaper article about a lady who had Inflammatory Bowel Disease (IBD) and was ridiculed by someone who saw her use a disabled toilet clearly unaware of her invisible illness. This is definitely worth a read!
I also wrote a blog about my own concerns focussing in on the issue of ‘Stomach Cramps’. This is something that causes me issues from time to time and I dread a painful occurrence if I’m ‘out and about’. I generally don’t let Cancer stop me doing stuff. Consequently, I will still visit remote places as I have done so for the last few years and have intentions of continuing to do so in the future. Fortunately I have been lucky with my experiences to date. If I’m out and about including on holiday, I have no reservations about waltzing into hotels or restaurants where I know there will be toilet facilities. I’ll also use a disabled toilet if others are not vacant. My worst and most painful experience was in 2014 whilst I was walking along Hadrian’s Wall in remote Northern England – this is covered in my blog “My stomach sometimes cramps my style“.
I have not yet been challenged in my use of toilet facilities (without being a customer) but I always carry some ‘Get me out of jail’cards just in case. I have two, one from NET Patient Foundationand one from Macmillan Cancer Support. You can order these online (links given) and I’m sure other national advocate organisations do similar things.
I applaud Asda for their initiative. Lets hope it catches on anytime soon!
Sorry to have been quiet for a while but I’ve been so busy with house, family and cancer campaigning activities. Additionally, I’ve been continuing my research into Neuroendocrine Cancer. Why do I do this? Whilst I have a great medical team, I’d also like to be my own advocate and this means understanding what medical people tell me! Moreover, I don’t want to be a passive patient, I want to be an active advocate for my own health. I found this infographic on the internet which sums up my own views nicely (special thanks to Know your Own Health Ltd).
I actually enjoy researching neuroendocrine disease and I’d like to think it was all in one book somewhere – this simply isn’t the case! From what I’ve read in the past 4 years, I suspect the ‘all encompassing’ book would need to be about 10 feet thick. I also suspect I’m still at the tip of the iceberg! I don’t have room in my house for a 10 feet thick book, so I have to rely on ‘Professor Google’ a lot. I learnt early on to be careful not to believe everything I find on the internet (…..including on patient forums).
Once you have been researching NETs for some years you learn which are the best sites and what is the sort of thing to ignore. This wisdom came in handy recently when I was studying neuroendocrine tumours of the thyroid – apparently rarer than hen’s teeth. To understand the subject, I also researched the Thyroid (in the anatomical sense) and then all types of Thyroid Cancer. It didn’t take long before my head was hurting but it will be the subject of a future blog post.
One of the issues with Neuroendocrine Cancer is the diversity of locations and symptoms in terms of the anatomy and presentational difficulties. Neuroendocrine tumours (NETs) are rare and they present complex challenges to diagnosis and treatment. Even in the case of metastatic spread to the liver and beyond, there are some important differences in the nature of these tumours compared to gastrointestinal and pancreatic cancers. Many patients are first thought to be suffering from other ailments before finally being diagnosed with Neuroendocrine Cancer, thus delaying their treatment. It’s not just confusion over vague symptoms leading to misdiagnosis of common ailments, I even found a story of someone who had been misdiagnosed with Pancreatic Cancer and been given 12 months to live. One year later, the person asked a doctor friend why he was still alive and feeling OK which led to further checks and the discovery that this person actually had a Neuroendocrine Tumour of the Pancreas – a less aggressive form of cancer (normally) which was treatable and offered a better prognosis. Amazing story but this person’s treatment was delayed by 12 months. NET cancer in any part of the body is best left to (or overseen by) Neuroendocrine specialists (in my opinion). However, had this guy done his own homework, he might have asked some key questions making his doctors at least think of some alternative scenarios. Food for thought?
Thanks for reading
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