Neuroendocrine Cancer is one of a number of “difficult to diagnose” conditions. Many types of Neuroendocrine Cancer come with an associated syndrome and these syndromes can mimic everyday illnesses. In some cases, many people don’t feel ill while the tumours grow. Most types of this cancer are slow-growing but there are also aggressive versions. Although things appear to be improving in diagnostic terms, it can sometimes take years for someone to be finally diagnosed correctly and get treatment, albeit in some cases, too late for any hope of a curative scenario. It’s a very sneaky type of cancer and if left too long it can be life threatening – CLICK HERE to find out why.
The road to a diagnosis of Neuroendocrine Cancer is often not straight or easy to navigate. It’s not only a sneaky type of cancer but it’s also very complex. It’s a heterogeneous group of malignancies with a varied and confusing histology and nomenclature to match. As I said above, many people are asymptomatic for years whilst the tumor grows and some might say that it’s somewhat ‘lucky’ to have symptoms to help aid a diagnosis. Many find that a lack of knowledge of Neuroendocrine Cancer in primary care, doesn’t always produce results. Common misdiagnoses include (but not limited to), Irritable Bowel Syndrome (IBS) and other common digestive diseases, menopause, appendicitis, hypertension, gastritis, asthma. Neuroendocrine Cancer is much more likely to be diagnosed at secondary care if a referral for ‘something’ can be achieved.
……..cue internet searches (Dr Google)
I think the rise and the power of the internet and rise of social media applications is very much helping generate awareness and knowledge of Neuroendocrine Cancer and those looking for a diagnosis may find help in this way. I suspect this instant access to information has played its part in the diagnostic improvements I mentioned above. Take my own efforts for example, I’m a wee Scottish guy with a computer and I’m already accelerating towards a million blog views – there’s clearly a market for what I produce. In terms of those looking for a diagnosis, if only one gets an earlier diagnosis due to my site, I’ll be happy.
Unfortunately, the internet can often be a minefield and in many cases, can lead to quite unnecessary worry for those looking for a solution.
Incoming Questions
I’m contacted almost daily by the ‘undiagnosed’ who suspect they have Neuroendocrine Cancer, often because they appear to be displaying the symptoms of one of the associated syndromes. These are some of my most difficult questions. I’m always very wary of initially agreeing with their assumptions and logic, instead opting for straightforward detective work based on my knowledge of the different types of Neuroendocrine Cancer, knowledge of the best scans, tumour markers, hormone markers. And I always warn them that statistically, they are more likely to have a common condition than the less common Neuroendocrine Cancer.
Many have already had multiple doctor’s appointments and tests. If they have not yet had a scan, I encourage them to try to get one ‘by hook or by crook’. Despite what you read on patient forums and surveys, the vast majority of Neuroendocrine diagnoses will be triggered by a conventional imaging such as CT and/or MRI. If you can see it, you can detect it.
When I first chat with the ‘undiagnosed’, I find many of them are fairly knowledgeable about Neuroendocrine Cancer and other health conditions, again confirming the power of the internet and the savvy ‘internet patient’. This is fine if you look in the right places of course – for certain things there are more wrong places on the internet than right ones.
If I have time, I’m happy to chat with these people, some are very frustrated – in fact some are so frustrated that they just want a diagnosis of something even if that something is really bad. Some are not showing anything on any scan but in certain cases, it can be likened to finding a needle in a haystack.
What do you say to someone who is utterly convinced they have Neuroendocrine Cancer but CT/MRI/Octreoscan/Ga68 PET are all clear, Chromogranin A and 5HIAA are in range but they still say they have (say) diarrhea with its potential for literally thousands of differential diagnoses. It’s a tough gig.
Example:
My scan came back normal. That should be good news. But, if there is no tumor, how can I be suffering from all the symptoms of carcinoid syndrome? Is that diagnosis wrong? Are the urine and blood test results wrong? I’m awaiting a MRI scan to take another look to see if the doctor can find anything. I don’t know what they’ll find. I don’t want them to find anything. But I’m afraid of what will happen if they don’t.
Anon
Patient Forums
I always let the undiagnosed know that Neuroendocrine Cancer patients are some of the most friendliest and helpful people you can meet, they will treat you as one of their own. There will be a number of diagnosed people online who have gone through what the undiagnosed are going through, so they will both sympathise and emphasise. But … this can often have the adverse effect of pushing them into believing they must have Neuroendocrine Cancer. This makes for interesting discussions given the number of people who automatically assume that ‘flushing’ or ‘diarrhea’ (as described by the undiagnosed) must be Neuroendocrine Cancer without any reference to the many differential diagnoses and the context of what that actually means in Neuroendocrine Cancer terms.
10 Questions to ask your doctor/specialist for those Diagnosed with Neuroendocrine Cancer (and where to find a specialist)
I once wrote an article for DIAGNOSED NET Patients suggesting 10 Questions to ask their doctor. So I wanted to take a step back in context, using the knowledge I now have, and put myself in the shoes of someone who thinks they may have Neuroendocrine Cancer but is not yet diagnosed.
Key questions to ask your doctor/specialist for those trying to confirm or discount Neuroendocrine Cancer
Dear undiagnosed people. I totally understand your fear. There’s nothing worse than being ill and not knowing what illness you have. I’ve therefore compiled a list of 3 key questions for you to ask – think of it as a tick list of things to ask your doctor to do or check . I have linked several background articles for you to prepare your case. However, I cannot promise your doctor will agree or take any action, in fact some might be annoyed about the lack of trust. However, doing your homework really helps, including diaries and other evidence.
I also wouldn’t say that a negative to all the questions will mean you definitely do not have Neuroendocrine Cancer but at least these questions might provide your doctor and yourself with some food for thought, perhaps leading to the diagnosis of ‘something’. The questions below assume that routine blood tests have been done, including Full Blood Count, Liver, Renal, Bone, Glucose.
Questions for the UNDIAGNOSED to ask their treating physician
“I think I might have a type of cancer known as Neuroendocrine Cancer or Neuroendocrine Tumours (NET) because <<< insert your own story>>>. Would you please consider the following tests and checks:”
1. Chromogranin A (CgA) is a marker which is quite sensitive for Neuroendocrine Tumours, essentially measuring tumour bulk potentially indicating the presence of Neuroendocrine Tumours. There can be other reasons for an elevated CgA figure, including the patient’s use of proton pump inhibitors (PPI) (see the article for an alterative test where this is the case). Read more here – Neuroendocrine Cancer – Tumour and Hormone Marker tests.
2. 5HIAA is a hormone marker for the most common type of NET, particularly if the patient is presenting with flushing and diarrhea. Many NETs have associated syndromes and hormone markers can be a guide to help with diagnostics. Read more about 5HIAA and other hormone markers for different types of NET and different syndromes here Neuroendocrine Cancer – Tumour and Hormone Marker tests.
3. Scans. Most NETs can be seen on a CT scan although liver metastasis can often show more clearly on an MRI. There are also nuclear scan options to confirm conventional imaging findings. Some NETs may be accessible via endoscopy and ultrasounds can also give hints for further investigation. In some cases, nuclear scans will find things that conventional imaging cannot because radionuclides can normally pick up oversecreting tumours. Read more in my article “If you can see it, you can detect it”.
You can hear two NET specialists talking about the issues surrounding the diagnostics here.
Eight years ago today, I was sat in front of a secondary care consultant, his speciality was colorectal. I asked specifically for this consultant for two reasons, firstly, he carried out a colonoscopy some 20 months previously which turned out to be negative. Secondly, my GP had referred me to the iron deficiency anaemia clinic, and they wanted to do ….. a colonoscopy. I changed that plan because this “non-issue” was dragging on; quite frankly I wanted it to be resolved quickly, and I wanted it to be resolved in my favour – after all, I wasn’t actually ill!
Rewind two months, I had an incidental set of blood tests ordered by a nurse following a routine visit to my local medical centre (……. “I think I’ve lost a bit of weight”). My haemoglobin was low (even lower on repeat testing). The GP compared my results to someone in their eighties with malnutrition. In hindsight, I should have been alarmed by that statement but instead I went on holiday to Barbados. Apparently low haemoglobin is a sign of iron deficiency anaemia. I suspected it would pass, either my blood results would revert to normal naturally, or they would after a prescription for some pills. That’s what normally happens, isn’t it? I was so indifferent to the issue, I even delayed the blood tests by three weeks.
Back to 8th July 2010 ….I hadn’t really given him many clues but within minutes of chatting with the secondary care consultant (who was armed with the results of the negative colonoscopy test), he said “what are you doing this afternoon“. I had no hesitation in saying “whatever you want me to do“. I’m still not getting it as I saw this as a chance to get an all clear, get some pills, get back to normal. To cut a long story short, the results confirmed I had a metastatic cancer. If you can see it, you can detect it.
Following the scan results, I had a dozen other tests to narrow it down to Neuroendocrine Cancer (eventually confirmed by biopsy). During these 2 weeks of tests, I finally confessed for the first time that I had been experiencing facial flushing and intermittent diarrhea. In those days, I wasn’t really in tune with my body.
I had been sitting on a beach in Barbados sipping piña coladas with my wife and neither of us had any inkling that I had a serious life threatening illness and that it had been growing inside of me for some years. Slow but sneaky? You betcha. They did some damage too – check out my treatment summary here.
I remain thankful to all those involved in the triggering of my ‘incidental’ diagnosis. The Nurse who ordered the ‘just to be sure’ blood tests, the GP who immediately referred me to secondary care (increased my chances of being diagnosed with cancer), the secondary care specialist who was instrumental in getting to the bottom of the problem in double-quick time.
My intransigence, denial and withholding vital symptoms from the doctors didn’t really help – there’s a lesson for all there.
You can hear me talk about my diagnosis by clicking here
This is an excellent and positive video based overview of where we are with the Management of NETs. This is a presentation from a NET Specialist (who some of you may know) presenting to a “GI Malignancies” conference. This is therefore not only awareness of NETs, it’s also some good education for non NET GI experts who may only know the very basics. Useful for patients too! I met Dr Strosberg in Barcelona (ENETS 2017) and thanked him for his presentational and scientific paper output which I often use in my articles.
The classification picture is good as it explains the different facets of NETs and how NETs are classified and categorised in a general way – not seen it done this way before. Slightly out of date as it does not adequately convey the possibility of a well differentiated high grade recently classified by the World Health Organisation – read more here.
Amazingly it is delivered without using the word ‘carcinoid’ other than in reference to syndrome, indicating it can be done and is something also being reflected in all my posts to ensure they are up to date with the latest nomenclature. It’s also a good example for GI doctors as this branch of medicine is often involved in NET diagnostics and surveillance.
Excellent update of all the trials which have introduced treatments in the last decade.
Great update and worth the 30 minutes it takes to watch – you can view it CLICK HERE.
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.
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
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.
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
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.
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.
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.
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
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
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
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.
Conclusions: In PNETS, multi-omic profiling through the KYT program identified targetable alterations in several key pathways. Outcome data will be explored.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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 Gradingwhich has incorporated latest thinking in revised grade 3 classification
Seung Tae Kim
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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
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.
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.
New delivery system for Lanreotide – solution remains the same
Somatostatin Analogues are the ‘workhorse’ treatments for those living with NETs, particularly where certain syndromes are involved. So not just for classic NETs with Carcinoid Syndrome but also for treating insulinoma, gastrinoma, glucagonoma and VIPoma (all types of pNETs) and others. They are most effective if the NETs express somatostatin receptors.
Somatostatin is actually a naturally occurring hormone produced by the hypothalamus and some other tissues such as the pancreas and the gastrointestinal tract. However, it can only handle the normal release of hormones. When NET syndromes occur, the naturally occurring somatostatin is unable to cope. The word ‘analogue’ in the simplest of terms, means ‘manufactured’ and a somatostatin analogue is made to be able to cope with the excess secretion (in most cases).
Although there is hidden complexity, the concept of the drug is fairly simple. It can inhibit insulin, glucagon, serotonin, VIP, it can slow down bowel motility and increase absorption of fluid from the gut. It also has an inhibitory effect on growth hormone release from the pituitary gland (thus why it’s also used to treat a condition called Acromegaly). You can see why it’s a good treatment for those with NET syndromes, i.e. who suffer from the excess secretions of hormones from their NETs. Clearly there can be side effects as it also inhibits digestive enzymes which can contribute to, or exacerbate, gastro-intestinal malabsorption.
Please note somatostatin analogues are not chemo. There are two major types in use:
Octreotide – or its brand name Sandostatin. It is suffixed by LAR for the ‘long acting release’ version.
Lanreotide – brand name Somatuline (suffixed by ‘Depot’ in North America, ‘Autogel’ elsewhere)
So what’s the difference between the two?
A frequently asked question. Here’s a quick summary:
They are made by two different companies. Novartis manufactures Octreotide and Ipsen manufactures Lanreotide. Octreotide has been around for much longer.
The long-acting versions are made and absorbed very differently. Octreotide has a complex polymer and must be injected in the muscle to absorb properly. Lanreotide instead uses has a novel nanotube structure and is water based (click here to see a video of how this works). It is injected deep-subcutaneously and is therefore easier to absorb and is not greatly impacted if accidentally injected into muscle.
Their delivery systems are mainly via injections but are fundamentally different as you can see from the blog graphic which shows the differences between the long acting release versions. Octreotide long acting requires a pre-mix, whilst Lanreotide comes pre-filled.
The long-acting versions are 60, 90 and 120 mg for Lanreotide and 10, 20 and 30 mg for Octreotide.
Octreotide also has a daily version which is administered subcutaneously.
Octreotide has something called a ‘rescue shot’ which is essentially a top up to tackle breakthrough symptoms. It is a subcutaneous injection.
You can also ‘pump’ Octreotide using a switched on/off continuous infusion subcutaneously.
Other than for lab/trial use, to the best of my knowledge, there is no daily injection, rescue shot or ‘pump’ for Lanreotide that is indicated for patient use.
Whilst both have anti-tumour effects, there are differences in US FDA approval: Octreotide (Sandostatin) is approved for symptom control (not anti-tumor) whereas Lanreotide (Somatuline) is approved for tumour control. However, the US FDA recently added a supplemental approval for syndrome control on the basis that it is proven to reduce the need for short acting somatostatin analogues use – read more here. This supplementary approval followed the ELECT trial – results here.
Injection Administration
Always refer to the patient information leaflet as it is not safe to assume that all healthcare professionals are familiar with the administration. Common issues include (but are not limited to): drug temperature requirements, injection site, pinching vs stretching skin, speed of injection.
Please note a new syringe for Lanreotide will be available in June 2019. Further information will be communicated to healthcare professionals in advance of this, to enable them to inform their patients, whom have been prescribed Lanreotide. In addition, the patient information leaflet included in the packet will have clear instructions for use. There will be a prominent yellow box located on the outer carton of the medicine, alerting healthcare professionals and patients that a new syringe is contained inside. Please note that the medicine is still the same and the formulation and storage conditions have not changed.
Here are some interesting videos showing and explaining their administration:
Administering a Somatuline Depot (Lanreotide) injection:
Administering a Sandostatin LAR (Octreotide) injection:
This link also provides guidance on the “new formulation” Octreotide. Click here.
My own experience only includes daily injections of Octreotide (Sep-Nov 2010) and Lanreotide (Dec 2010 onwards). I’ve also had continuous infusion of Octreotide in preparation for surgical or invasive procedures over the period 2010-2012 (i.e. crisis prevention). You can read about my Lanreotide experience by clicking here. If you are interested in what might be coming downstream, please see my blog entitled ‘Somatostatin Analogues and Delivery Systems in the Pipeline’.
Injection site granulomas (lumps)
The issue of ‘granulomas‘ or ‘injection site granulomas’ seems to figure in both drugs. Gluteal injection site granulomas are a very common finding on CT and plain radiographs. They occur as a result of subcutaneous (i.e. intra-lipomatous) rather than intramuscular injection of drugs, which cause localised fat necrosis, scar formation and dystrophic calcification. But no-one seems to know why they occur with somatostatin analogues.
Personally, I find that they are more conspicuous if the injection is done slightly too high which was my initial experience and they took months to fade. I opted to stand up for the first two injections and I attribute this decision for a slightly too high injection site. I now lie down which is actually recommended for the smaller and thinner patient. Although the lumps have reduced in size, I have not seen a new lump for some time indicating location might have been the cause. They sometimes show up on scans. This is not a new problem and has been highlighted for the last 10 years in academic papers. This particular paper is useful and the conclusion confirms this is not something that should worry patients too much. Read more here
Somatostatin Analogues and raised blood sugar levels
It is well documented that both Octreotide and Lanreotide can elevate blood glucose (sugar) levels. Read more in my article Diabetes – the NET Effect.
I think most people have had a form of medical testing at some point in their life, i.e. the sampling and testing of blood, urine, saliva, stool or body tissue. In a nutshell, the medical staff are just measuring the content of a ‘substance’ and then taking a view whether this is normal or not based on pre-determined ranges. These tests are normally done as a physician’s reaction to symptom presentation or maintenance/surveillance of an existing diagnosed condition. Sometimes, abnormal results will lead to more specialist tests.
In cancer, these tests are frequently called ‘markers’. Most tumour markers are made by normal cells as well as by cancer cells; however, they are produced at much higher levels in cancerous conditions. These substances can be found in the blood, urine, stool, tumour tissue, or other tissues or bodily fluids of some patients with cancer. Most tumour markers are proteins. However, more recently, patterns of gene expression and changes to DNA have also begun to be used as tumour markers. Many different tumour markers have been characterized and are in clinical use. Some are associated with only one type of cancer, whereas others are associated with two or more cancer types. No “universal” tumour marker that can detect any type of cancer has been found.
There are some limitations to the use of tumor markers. Sometimes, noncancerous conditions can cause the levels of certain tumor markers to increase. In addition, not everyone with a particular type of cancer will have a higher level of a tumour marker associated with that cancer. Moreover, tumour markers have not been identified for every type of cancer. Tumour markers are not foolproof and other tests and checks are usually needed to learn more about a possible cancer or recurrence.
I’d also like to talk about a group of associated tests, in particular, hormone levels as these tests are really important to help determine the type of Neuroendocrine Tumour. NETs will sometimes oversecrete hormones and this can give clues to the type. The constraints mentioned above apply to hormone levels and other tests to a certain extent.
What this article will not cover
Routine Testing – the post will not cover routine blood tests (i.e. complete blood count etc). Although they may point to a problem, these tests do not necessarily indicate a particular type of NET without other supporting evidence.
Biopsy Testing – Technically, the Immunohistochemical ‘stains’ used in biopsy testing are tumour markers but I’ll not be discussing that today. I did cover the output of biopsies in my blog on NETs – Stages and Grades.
Genetic Testing. This is very specialised but you may find my Genetics and NETs article is of interest.
Sequencing of marker testing – diagnosis
The sequencing of marker testing may have been different for many patients. In my own experience, I had a biopsy and then the biochemical checks were carried out. So regardless of the results of my marker tests, I was to be diagnosed with NETs. Those with lengthy and difficult diagnostic phases will perhaps have had a different sequence with the biochemical markers providing evidence for further tests to formally diagnose. Markers alone will normally not be enough for a diagnosis but they do, however, feed into the treatment plan and provide a baseline at diagnosis and for tracking going forward.
Interpreting test results – International/National/Regional differences
The use of markers tends to be different on an international basis, e.g. specific marker tests can be developed in-country by independent labs. Testing can also vary in the same country as in-country labs use different commercially available ‘testing kits’. Not all tests are available in all countries.
Reference ranges can be dependent on many factors, including patient age, gender, sample population, and test method, and numeric test results can have different meanings in different laboratories. The lab report containing your test results should include the relevant reference range for your test(s). Please consult your doctor or the laboratory that performed the tests to obtain the reference range if you do not have the lab report. Moreover, the ‘normal’ test range can vary from hospital to hospital, even within the same tests. I suspect clinical staff have their own versions of risk thresholds when dealing with test results. Even when results are just above or below, individual physicians can take their own view in a subjective manner. Testing is best done at the same lab each time if possible.
There’s a great website called LabTestsOnlinewhich can describe each test. It’s peer-reviewed, non-commercial and patient-focused but just please note you should always refer to your own lab ‘normal ranges’ which will be printed on your test results. For these reasons, you will not find reference ranges for the majority of tests described on this web site. The link above will take you to the list of ‘country’ affiliated versions with specific information on a country basis.
Here’s some tips I always give people:
1 – Always try to get your own copy of results (preferably on paper) and track them yourself (I use a spreadsheet).
2 – When comparing results inside patient forums, always add the range and if possible, the unit of measurement (i.e. g/L, mmol/L, umol/L etc etc). Failure to do this can at best confuse, and at worst frighten patients. Compare apples with apples not with pears! (this is why it’s important to know the unit of measure and the reference range in addition to the figure).
3 – Don’t get too excited about rises if the test is still inside the normal range – normal is normal!
4 – Don’t get too excited about rises taking you just outside of normal range – your doctors are looking for bigger spikes.
5. Don’t get too excited about a single test result, your doctors are looking for trends, a single test result is not much to go on.
NET Markers
Although some routine blood markers (complete blood count etc) are useful in NETs, it’s pretty much impossible to cover these in any general detail. I’m going to focus on tumor and hormone associated markers
There are many markers involved with NETs. Some do different jobs and some are just variants measuring the same thing (more or less efficiently). You may also see something called ‘gold standard’ in reference to NET Tumour markers. Although thinking is changing (more on this below) and can vary from country to country, it is generally accepted that Chromogranin A and 5HIAA are the gold standard markers for tumour bulk and tumour functionality respectively. These gold standard tests may not be applicable to every type of NET, particularly 5HIAA. I’m also aware that US doctors are reducing the dependency on CgA and using Pancreastatin instead (although many are measuring both).
NETs are known to be heterogeneous in nature (i.e. consisting of or composed of dissimilarelements;nothaving a uniformqualitythroughout). Whilst some markers can be used widely, it follows that there are many very specialist marker tests for individual types of NET. I think this applies to 3 broad categories of NETs: Tumours known to potentially oversecrete Serotonin and and perhaps others (mainly midgut), Pancreatic NETs (or pNETs) secreting various hormones by type; and other less common types and/or syndromes which might be considered by some to be even more complex than the former two and in some cases there are big overlaps.
Another interesting thing about NET markers is that an undiagnosed patient may undergo several specialist tests to eliminate the many possibilities that are being presented as vague and common symptoms. Sometimes this is necessary to eliminate or ‘home in’ on a tumour type or syndrome/hormone involved (it’s that jigsaw thing again!).
Markers too can be divided into broad categories, those measuring how much tumour is in your body and its growth potential and those measuring how functional (or not) those tumours are. The latter can probably be expanded to measure/assess excess hormone secretion and syndromes.
The Anatomy
Certain tests can be anatomy related so to add context and to prevent big repetitive lists when using the terms ‘foregut’, ‘midgut’ and ‘hindgut’, you may find this graphic useful.
Markers for measuring Tumour bulk or load/growth prediction
Chromogranin (plasma/blood test)
Chromogranin is an acidic protein released along with catecholamines from chromaffin cells and nerve terminals. This statement alone might explain why it is a good marker to use with NETs. Depending on the test kit being used, you may see test results for Chromogranin A (CgA) and Chromogranin B (CgB) – the inclusion of CgB tends to be confined to Europe. There is also mention of Chromogranin C (CgC) in places but I’ve never heard of this being used in conjunction with NETs.
One of the disadvantages of CgA is that the results can be skewed by those taking Proton Pump Inhibitors(PPIs). Many NET patients are taking PPIs to treat GERD (….and Zollinger-Ellison Syndrome). In the long-term, this has the result of increasing gastrin levels which can lead to an increase of CgA in the blood including for some months after discontinuing. CgB is said not be as influenced by the use of PPI as CgA. In addition to the issue with PPIs, CgA levels may also be elevated in other illnesses including severe hypertension and renal insufficiency. CgB is also said to be more sensitive to Pheochromocytoma.
Elevated CgA is a constant and somewhat excitable discussion point on patient forums and not just because of the lack of unit of measurement use I discussed above. Some people get quite excited about a single test result. I refer to Dr Woltering et al (ISI Book) where it clearly states that changes in CgA levels of more than 25% over baseline are considered significant and a trend in serial CgA levels over time has been proven to be a useful predictor of tumour growth (i.e. a single test result with an insignificant rise may not be important on its own). Dr Woltering also gives good advice on marker tests when he says “normal is normal” (i.e. an increased result which is still in range is normal).
Here is a nice graphic explaining what else could be the cause of elevated CgA:
CgA appears to be a widely used tumour marker and is effective in most NETs (foregut, midgut and hindgut). It is also sensitive to Pheochromocytoma, particularly when correlated with a 131I-MIBG scan. Interestingly Chromogranin can also be used in the immunohistochemical staining of NET biopsy samples (along with other methods).
As for my own experience, my CgA was only elevated at diagnosis, remained elevated after intestinal surgery but returned to normal after liver surgery (indicating the effect of liver tumour bulk on results). It also spiked out of range when some growth in a distant left axillary node was reported in Jan 2012. Following a lymphadenectomy, it returned to normal again and has remained in range to this day. It has been a good predictor of tumour bulk for me and I’m currently tested every 6 months.
Pancreastatin
In effect, this marker does the same job as CgA. Interestingly, Pancreastatin is actually a fragment of the CgA molecule. There have been many studies (mainly in the US) indicating this is a more efficient marker than CgA, and not only because it is not influenced by the use of PPI. It has also been suggested that it’s more sensitive than CgA and therefore capable of detecting early increases in tumour burden. It has also been suggested it can be an indication of tumour ‘activity’ (whatever that means). It is widely used in the US and some physicians will use it in preference to CgA (…..although from what I read, CgA also seems to be tested alongside). I’m starting to see this mentioned in the UK.
Neurokinin A (NKA)
This is not a well publicised test. However, it is something used in USA but I’d like to hear from others to validate its use elsewhere. In a nutshell, this test, which only applies to well differentiated midgut NETs, appears to have some prognostic indication. I discovered this test in the ISI NET Guidance and it’s backed up by a study authored by names such as Woltering, O’Dorisio, Vinik, et al. This is not a one-off test but one designed to be taken serially, i.e. a number of consecutive tests. These authors believe that NKA can also aid in the early identification of patients with more aggressive tumors, allowing for better clinical management of these patients. NKA is sometimes called Substance K.
Neuron-Specific Enolase (NSE)
In patients with suspected NET who have no clear elevations in the primary tumor markers used to diagnose these conditions, an elevated serum NSE level supports the clinical suspicion.
Markers for measuring Tumour functionality/hormone/peptide levels
So far, I’ve covered basic tumor markers which have a tumor bulk and/or prognostic indication. This section is a slightly more complex area and many more tests are involved. There’s often a correlation between CgA/Pancreastatin and these type of markers in many patients i.e. a serial high level of CgA might indicate a high level of tumour bulk and therefore increased production of a hormone in patients with a syndrome or oversecreting tumor. However, it frequently does not work out like that, particularly when dealing with non-functioning tumours.
The type of marker for this element of NET diagnosis and surveillance will vary depending on the type of NET and its location (to a certain extent). Like tumour bulk/growth, there might be different options or test variants on an international basis. There are too many to list here, so I’ll only cover the most common.
Serotonin Secreting Tumors
There are a few markers in use for measuring the functionality of this grouping of tumours. This tumour group has a tendency to secrete excess amounts of the hormone Serotoninalthough it differs depending on the area of the primary. For example, hindgut tumours tend to secret lower levels than foregut and midgut and therefore this test may present within range. Please also note there may be other hormones of note involved. The antiquated and misleading term ‘Carcinoid’ is sometimes used as a descriptor for these tumours and more and more NET scientific organisations and specialists are now avoiding use of this term.
Lug the Jug
5HIAA. 5HIAA is a metabolite of Serotonin thus why it’s a useful thing to measure to assess functionality in this grouping of tumours. 5HIAA is actually the ‘gold standard’ test for functioning serotonin secreting tumours. It’s a key measure of the effects of carcinoid syndrome and the risk of succumbing to carcinoid heart disease. However, there are two methods of testing: Urine and Plasma. The latter is mainly used in USA but other countries are now looking at implementing the plasma version (in fact I’m now tested in both at my local hospital in UK). The rather obvious key difference between the two is practicality. With the 24 hour urine, there are two key issues: 1. The logistics (i.e. lug the jug). 2. Fasting for up to 3 days prior to the test (4 if you count the day of the test). There are numerous variations on the fasting theme but most labs tend to say not to eat at least the following foods that contain high levels of serotonin producing amines: avocados, bananas, chocolate, kiwi fruit, pineapple, plums, tomatoes, and walnuts. Some lists contain additional items. With the plasma version, the fasting period is reduced to 8 hours. There are also medicinal limitations including drugs that can also alter 5-HIAA urine values, such as acetanilide, phenacetin, glyceryl guaiacolate (found in many cough syrups), methocarbamol, and reserpine. Drugs that can decrease urinary 5-HIAA levels include heparin, isoniazid, levodopa, monoamine oxidase inhibitors, methenamine, methyldopa, phenothiazines, and tricyclic antidepressants. Patients should talk to their doctor before decreasing or discontinuing any medications.
As for my own experience, my 5HIAA (urine) was elevated at diagnosis only returning to normal after removal of my primary and commencement of Lanreotide. It has been a good measure of tumour functionality for me and I’m currently tested every 6 months.
Other tests for the tumour subgroup include but not limited to:
Serum Serotonin (5-HydroxyTryptamine; 5-HT). Firstly let’s deconflict between 5HIAA above and the serotonin (5-HT) blood test. 5HIAA is a metabolite of serotonin but the serotonin test is a measure of pure serotonin in the blood. Morning specimens are preferred and this is a fasting test (10-12 hours). There is always debate on forums about Serum Serotonin results. I have Dr Liu on record as saying “a high serotonin level measured in the blood in isolation really isn’t that dangerous. It’s the 5HIAA (a breakdown product of serotonin, which is easily measured in the blood and urine) that is considered to be more indicative of persistent elevated hormone. It’s this test that is most closely related to the carcinoid heart disease”.
Substance P. A substance associated with foregut and midgut tumours. It is a vasoactive protein that can cause wheezing, diarrhea, tachycardia, flushing
Histamines – Usually associated with foregut tumors. Appears to be involved in patchy rashes and flushing. The advice in the ISI NET book is no anti-histamine medication to be taken for 48 hours prior to blood draw.
Gastric NETs (Stomach)
Testing will be different depending on the Type:
Type 1 – Typical Low Grade, tends to be caused by atrophic gastritis.
Type 2 – Atypical Intermediate Grade and tends to be caused by gastrin secreting tumours. Type 2 normally needs a check for MEN1/Zollinger-Ellison Syndrome.
Type 3 – Tend to be larger and more aggressive tumours.
The key makers are CgA and Gastrin although Gastrin may not be elevated in Type 3. Gastrin ph is useful to differentiate between Type 1 and Type 2. 5HIAA can be considered but Carcinoid Syndrome is rare in Gastric NETs.
NETs of the Pancreas (pNETs)
There are many different types of cells in the pancreas
pNETs can be very difficult to diagnose and not only because they share some presentational similarities to their exocrine counterparts. Some pNETs actually comprise tumours arising in the upper part of the duodenum (small intestine) close to the Pancreas. Moreover, more than half of pNETs are non-functional which increases the difficulty in suspecting and then finding the tumours. However, where there is clinical presentation or suspicion, these symptoms can lead to the appropriate testing to support the output of scans. The fasting gut profile mentioned above can be useful in identifying the offending hormones when the type of NET is not yet known.
Gut Hormones (Glucagon, Gastrin, VIP, Somatostatin, Pancreatic Polypeptide)
A gut hormone screen is used for the diagnosis of a variety of endocrine tumours of the pancreas area. Analysis includes gastrin, VIP, somatostatin, pancreatic polypeptide, and glucagon, but there may be others depending on processes used by your ordering specialist or hospital.
Notes:
1. You may see this referred to as a ‘Fasting Gut Profile’ or a ‘Fasting Gut Hormone Profile’.
2. The individual hormones measured seem to differ between hospital labs.
3. The fasting conditions also vary between hospitals and labs but all agree the conditions are critical to the most accurate results. Always ask for instructions if you’re offered this test.
The gastrin test is usually requested to help detect high levels of gastrin and stomach acid. It is used to help diagnose gastrin-producing tumours called gastrinomas, Zollinger-Ellison (ZE) syndrome, and hyperplasia of G-cells, specialised cells in the stomach that produce gastrin. It may be measured to screen for the presence of multiple endocrine neoplasia type I (MEN) It may be used if a person has abdominal pain, diarrhoea, and recurrent peptic ulcers. A gastrin test may also be requested to look for recurrence of disease following surgical removal of a gastrinoma.
Vasoactive intestinal peptide (VIP) measurement is required for diagnosis of pancreatic tumour or a ganglioneuroma which secretes VIP. Administration of VIP to animals causes hyperglycaemia, inhibition of gastric acid, secretion of pancreatic bicarbonate and of small intestinal juice, and a lowering of systemic blood pressure with skin flush. These features are seen in patients with a tumour of this type which is secreting VIP.
Glucagon is measured for preoperative diagnosis of a glucagon-producing tumour of the pancreas in patients with diabetes and a characteristic skin rash (necrolytic migratory erythema).
Pancreatic polypeptide (PP) production is most commonly associated with tumours producing vasoactive intestinal polypeptide and with carcinoid syndrome and, less commonly, with insulinomas and gastrinomas.
When secreted by endocrine tumours, somatostatin appears to produce symptoms similar to those seen on pharmacological administration, i.e. steatorrhoea, diabetes mellitus and gall stones.
There are several types of pNETs, each with their own syndrome or hormone issue. When they are suspected due to the presentational symptoms, the markers that could be used are listed below. These types of tumours are complex and can be related to one or more syndromes. A patient may be tested using multiple markers to include or exclude these. Depending on other factors, some physicians may recommend additional marker testing in addition to the most common types below.
Somatostatinoma – Somatostatin (plasma somatostatin like immunoreactivity)
PPoma – Pancreatic Polypeptide (PP)
Other NETs/Syndromes
Pheochromocytoma/Paraganglioma – Adrenaline-producing tumours. Plasma and urine catecholamines, plasma free total metanephrines, urine total metanephrines, vanillylmandelic acid (VMA)
Medullary Thyroid Cancer. Medullary thyroid cancer (MTC) starts as a growth of abnormal cancer cells within the thyroid – the parafollicular C cells. In the hereditary form of medullary thyroid cancer (~20% of cases, often called Familial MTC or FMTC), the growth of these cells is due to a mutation in the RET gene which was inherited. This mutated gene may first produce a premalignant condition called C cell hyperplasia. The parafollicular C cells of the thyroid begin to have unregulated growth. In the inherited forms of medullary thyroid cancer, the growing C cells may form a bump or nodule in any portion of the thyroid gland. Unlike papillary and follicular thyroid cancers, which arise from thyroid hormone-producing cells, medullary thyroid cancer originates in the parafollicular cells (also called C cells) of the thyroid. These cancer cells make a different hormone called calcitonin, which has nothing to do with the control of metabolism in the way thyroid hormone does. The other test often seen in MTC is Carcinoembryonic Antigen (CEA). CEA is a protein that is usually found in the blood at a very low level but might rise in certain cancers, such as medullary thyroid cancer. There is no direct relationship between serum calcitonin levels and extent of medullary thyroid cancer. However, trending serum calcitonin and CEA levels can be a useful tool for doctors to consider in determining the pace of change of a patient’s medullary cancer.
[please note there are extremely rare occurrences of elevated calcitonin from places outside the thyroid – read more here.
Parathyroid– Parathyroid hormone (PTH), Serum Calcium. Parathyroid hormone (PTH) is secreted from four parathyroid glands, which are small glands in the neck, located behind the thyroid gland. Parathyroid hormone regulates calcium levels in the blood, largely by increasing the levels when they are too low. A primary problem in the parathyroid glands, producing too much parathyroid hormone causes raised calcium levels in the blood (hypercalcaemia – primary hyperparathyroidism). You may also be offered an additional test called Parathyroid Hormone-Related Peptide (PTHrP). They would probably also measure Serum Calcium in combination with these type of tests. The parathyroid is one of the ‘3 p’ locations often connected to Multiple Endocrine Neoplasia – MEN 1 – see MEN below.
HPA AXIS – It’s important to note something called the HPA axis when discussing pituitary hormones as there is a natural and important connection and rhythm between the Hypothalamus, Pituitary and the Adrenal glands.
Adrenocorticotropic hormone (ACTH) is made in the corticotroph cells of the anterior pituitary gland. It’s production is stimulated by receiving corticotrophin releasing hormone (CRH) from the Hypothalamus. ACTH is secreted in several intermittent pulses during the day into the bloodstream and transported around the body. Like cortisol (see below), levels of ACTH are generally high in the morning when we wake up and fall throughout the day. This is called a diurnal rhythm. Once ACTH reaches the adrenal glands, it binds on to receptors causing the adrenal glands to secrete more cortisol, resulting in higher levels of cortisol in the blood. It also increases production of the chemical compounds that trigger an increase in other hormones such as adrenaline and noradrenaline. If too much is released, The effects of too much ACTH are mainly due to the increase in cortisol levels which result. Higher than normal levels of ACTH may be due to:
Cushing’s disease – this is the most common cause of increased ACTH. It is caused by a tumor in the pituitary gland (PitNET), which produces excess amounts of ACTH. (Please note, Cushing’s disease is just one of the numerous causes of Cushing’s syndrome). It is likely that a Cortisol test will also be ordered if Cushing’s is suspected.
Cortisol
This is a steroid hormone, one of the glucocorticoids, made in the cortex of the adrenal glands and then released into the blood, which transports it all round the body. Almost every cell contains receptors for cortisol and so cortisol can have lots of different actions depending on which sort of cells it is acting upon. These effects include controlling the body’s blood sugar levels and thus regulating metabolism acting as an anti-inflammatory, influencing memory formation, controlling salt and water balance, influencing blood pressure. Blood levels of cortisol vary dramatically, but generally are high in the morning when we wake up, and then fall throughout the day. This is called a diurnal rhythm. In people who work at night, this pattern is reversed, so the timing of cortisol release is clearly linked to daily activity patterns. In addition, in response to stress, extra cortisol is released to help the body to respond appropriately. Too much cortisol over a prolonged period of time can lead to Cushing’s syndrome. Cortisol oversecretion can be associated with Adrenal Cortical Carcinoma (ACC) which can sometimes be grouped within the NET family.
Other hormones related to ACC include:
Androgens (e.g. Testosterone) – increased facial and body hair, particularly females. Deepened voice in females.
Estrogen – early signs of puberty in children, enlarged breast tissue in males.
Aldosterone – weight gain, high blood pressure.
Adrenal Insufficiency (Addison’s Disease) occurs when the adrenal glands do not produce enough of the hormone cortisol and in some cases, the hormone aldosterone. For this reason, the disease is sometimes called chronic adrenal insufficiency, or hypocortisolism.
A tumour outside the pituitary gland, producing ACTH (also called ectopic ACTH). With NETs, this is normally a pNET, Lung/Bronchial NET or Pheochromocytoma.
Multiple Endocrine Neoplasia (MEN). Please note MEN is a group of distinct syndrome not a tumor. Complex area and tends to be multiple instances of some of the tumours above. For a breakdown of MEN types and locations, check out my MEN blog ‘Running in the Family’
Carcinoid Heart Disease(CHD) (Hedinger syndrome)I’m not really talking directly about a tumour here but thought it would be useful to include a blood test called NT-proBNP. I’ve left a link to my CHD article in the paragraph heading for those who wish to learn more about CHD in general. For those not offered an annual Echocardiogram or are ‘non-syndromic’ there is a screening test that can give an indication of any heart issue which might then need further checks.
The Future – Molecular Markers?
This is testing using DNA and genes. Exciting but complex – check out this article which involved some NETs.
Tumour Markers and Hormone levels – complex subject!
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!
Define Diarrhea
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
A team of researchers from Case Western Reserve University School of Medicine have used high-powered microscopes for the first time to view serotonin activating its receptor
Background
I’d never heard of Serotonin until I was diagnosed with Neuroendocrine Cancer in 2010. It is frequently discussed, often with contrasting views from the respondents. One common assumption/question is that it is responsible for many things that can go wrong with Neuroendocrine Cancer patients who have serotonin-producing tumours. “It’s the hormones” is an easy assumption to make or an easy answer to give in response to a complex set of circumstances. It’s difficult to get a definitive answer and the science behind the behaviour of our hormones isn’t really 100% tied down.
You may see serotonin referred to as a ‘neurotransmitter’, a ‘chemical’ and a ‘hormone’ – this is complex but it is my understanding that it can add context in respect the role/location of the serotonin, e.g. chemical and hormone are essentially synonymous and are endocrine related whereas neurotransmitter is concerned with the nervous system (the neuro in neuroendocrine) and the brain (more on this below). Consequently, I’ll keep this as basic as I can (author’s note on completion – it was not easy!).
Serotonin and NETs
One thing which is widely accepted and agreed…… Serotonin is definitely involved in Neuroendocrine Tumours, in particular, those resulting in carcinoid syndrome which can manifest as a number of symptoms including but not limited to flushing and diarrhea. Although serotonin is one of the main ‘hormones’ released in excess by certain NETs (mainly midgut), it is not thought to be the main culprit behind some of the symptoms produced by Carcinoid Syndrome. For example, flushing, the most common symptom (and a cardinal one) is thought to be caused by a number of hormones/peptides – too many to list but the main ones are histamine (particularly foregut), tachykinins (Substance P), bradykinins, prostaglandins …….. and I’m sure serotonin’s in there too! It does, however, appear to be massively guilty in causing carcinoid syndrome diarrhoea, desmoplasia, and carcinoid heart issues.
Where does Serotonin come from?
Serotonin’s technical name is 5-hydroxyltryptamine (5-HT). It is converted from 5-Hydrotryptophan (5-HTP) which is also known as oxitriptan. 5-HTP is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of serotonin (…..and melatonin) from tryptophan. Tryptophan is interesting as that brings in one of the missing pieces of the jigsaw – food! Tryptophan cannot be manufactured in the body, it must be brought in via diet. There is no serotonin in food, it is only manufactured in the body.
Tryptophan in food enters the body and serotonin is created by a biochemical conversion process which combines tryptophan (essentially a protein) with tryptophan hydroxylase (TPH), a chemical reactor. I suspect other substances might be involved in that process. There are two forms of tryptophan hydroxylase – TPH1 and TPH2, which are encoded on two independent genes. TPH1 is linked to peripheral serotonin while TPH2 is related to brain serotonin.
While serotonin cannot cross the blood-brain barrier, tryptophan can, and almost all of it is converted to serotonin. Just to emphasise that NET dietitians do not say to avoid foods containing tryptophan other than at the time of marker testing (see below andnutrition Blog 4).
Serotonin Inhibitors
The introduction of Somatostatin analogues (SSAs) such as Octreotide and Lanreotide, help reduce the secretion of “tumour-derived serotonin” by binding to its receptors on the outside of the cell. If you ever wondered why receptors are important, please check out my blog on this subject (click here).
I mentioned tryptophan hydroxylase (TPH) above and that is actually very interesting as this is how Telotristat Ethyl (XERMELO) is able to help with the symptoms of Carcinoid Syndrome diarrhea (not adequately controlled by SSAs) or where patients are unable to be treated by somatostatin analogues for whatever reason. It’s a potent inhibitor of TPH which will disrupt the manufacturing of tumour-derived serotonin. There is also evidence that it can help reduce the effects or halt the growth of the fibrosis leading to carcinoid heart disease. Slight digression but useful to aid/enhance understanding at this point. Read about Telotristat Ethyl here.
Serotonin and the Brain
There is constant discussion and assumption that serotonin-producing tumours are somehow causing depression, anxiety and rage. Not as simple as that, it’s way more complicated. Certain NETs can overproduce serotonin in the gut but the issues concerning depression and anxiety are normally associated with low levels of serotonin in the brain.
“Cancer anger” is a normal response to fear, despair and grief – a range of feelings which cancer brings into our lives. It can show as frustration, irritability, emotional withdrawal or aggression. You can feel it whether you have been diagnosed or you are a relative or friend. Cancer anger can happen at any stage of the illness, even years after treatment.
I know many people with cancer who suffer from depression, anxiety and rage but they do not have serotonin-producing tumours. What they do have is a life threatening and/or life changing condition which is bound to have an effect on mind as well as body. Serotonin is a natural substance found in the body and not just there to service NETs. If you didn’t have any, you wouldn’t be able to get out of bed according to one of my ‘favs’ Dr Gene Woltering.
Serotonin is separately manufactured in the brain (~10%) and in the gastrointestinal tract (~90%). The serotonin in the brain must be manufactured in the brain, it cannot be directly increased or reduced external to the brain, i.e. it cannot be directly reinforced by gut serotonin (peripheral serotonin). It follows that ‘brain serotonin’ and ‘gut serotonin’ are held in separate stores, they are manufactured in those stores and remain in those stores – there is no cross-pollination. This is managed by something called the blood-brain-barrier (BBB). Therefore, excess serotonin from NETs does not infiltrate the brain. As low-level of ‘brain serotonin’ is often linked to depression, it also follows that it’s possible to have high levels of serotonin in the gut but low levels in the brain.
My simple way of thinking about such things as outlined above, is that low levels of tryptophan in the brain might be contributing to low levels of serotonin in the brain. To clarify that, I researched the reasons why there could be low serotonin in the brain.
First, let’s dismiss any connection that the type of anti-depressant is called Selective serotonin reuptake inhibitors (SSRIs) is involved. It’s thought that SSRIs work by increasing serotonin levels in the brain. Serotonin is a neurotransmitter (a messenger chemical that carries signals between nerve cells in the brain). We already discussed that it’s thought to have a good influence on mood, emotion and sleep. After carrying a message, serotonin is usually reabsorbed by the nerve cells (known as “reuptake”). SSRIs work by blocking (“inhibiting”) reuptake, meaning more serotonin is available to pass further messages between nearby nerve cells. So tryptophan or peripheral serotonin are not really involved.
It would be too simplistic to say that depression and related mental health conditions are caused by low serotonin levels (in the brain), but a rise in serotonin levels (in the brain) can improve symptoms and make people more responsive to other types of treatment, such as Cognitive Behaviour Therapy (CBT).
It should also be noted that the precursor to serotonin, tryptophan, does pass through the BBB and it is therefore possible that tryptophan depletion can lead to less availability in the brain for the manufacture of brain serotonin. Tryptophan depletion can be caused by dietary restrictions (i.e. lack of tryptophan foods) and also by the effects of certain types of tumours as excess serotonin is made leading to less availability of tryptophan. Both could lead to low serotonin in the brain as less tryptophan gets there.
Measuring Serotonin levels
Measuring levels of serotonin is important in both diagnosis and management of certain NETs – although it’s probably sensible to test all potential NET patients during diagnosis when the type of tumour is not yet known. Testing for tumour markers will differ between countries and within countries but the most common standard for testing Serotonin appears to be 5-HIAA (5-hydroxyindoleacetic acid) either via a 24-hour urine test or via a plasma version (mainly used in USA but now creeping into UK). 5-HIAA is the output (metabolite) of 5-HT (Serotonin). Not to be confused with the less reliable ‘serum serotonin’ which is a different test.
Another frequently asked question about serotonin tests is whether they are testing the amount in the brain or the gut. The answer is …… they are testing the levels in the blood. Furthermore, if you are measuring serotonin as an indicator for Carcinoid Syndrome, it has to be remembered that the majority of serotonin is in the gut, so even if serotonin levels in the brain were being measured alongside the gut levels, I don’t believe it would influence the result in any significant way (but I have no science to back that up). It also has to be remembered that serum serotonin and 5HIAA are not absolute tests, they are not 100% sensitive, they are simply indicators of a potential problem. There are methods of measuring brain serotonin but it is very complex and beyond the purposes of this article. However, I would just add that it is the reuptake of Serotonin in the brain (plus some other stuff) that can cause depression, not the actual level or amount in the brain.
I intentionally did not mention the other common test (Chromogranin A) or other markers as they are measuring different things but you can read about in my Testing for Markers blog.
Since my diagnosis, I seem to have been in a perpetual learning phase! What not to do, what not to eat, what not to read! However, a couple of years ago, I came across a list of ‘E’ words (5 of them) which is a handy reminder for Carcinoid Syndrome patients, particularly those whose symptoms are not under control. When I say “carcinoid syndrome” in this article, I only mean the syndrome that is caused by what was once called “Carcinoid Tumors”, i.e. mainly serotonin secreting types but include tumours which are well differentiated found in the small intestine, appendiceal, rectal, lung, and one or two other less common places.
There are many variations of this list but this is my take! I suspect some of this also applies to other types of NETs and other NET Syndromes.
On analysis of this list, it struck me that I was aware of the issues and their potential effects and I’m certain there is science to substantiate the content. These E’s are apparently the most common ‘triggers’ for Carcinoid Syndrome. Clearly, they are not going to have the same effect on every patient e.g. I have the occasional drink of ‘Ethanol’ and I always enjoy it, I go for long exhausting walks and I always feel great after. I had dental treatment without any precautions before I was aware of the risks …….. nothing happened! Before I was treated, stressful meetings at work would make me flush though! As for eating – well that’s another couple of blog’s worth! (see the Diarrhea Jigsaw and Nutrition Blog 4 – Food for Thought)
The 5 Es are, however, very important, as a severe attack of Carcinoid Syndrome symptoms could be debilitating and life-threatening and I’m fairly certain the list was compiled with this in mind. Some people are more affected by Carcinoid Syndrome and this is not necessarily related to the extent or aggressiveness of their disease. Some people just react differently. An extremely severe attack of Carcinoid Syndrome can also be known as a ‘Carcinoid Crisis’ which is very dangerous on the operating table due to the effects of anaesthetics – thus why many NET patients may be infused with somatostatin analogues (usually Octreotide) prior to and during surgery or other medical procedures. There’s a lot of excitement generated around the term ‘Carcinoid Crisis’but it is generally uncommon.
I’m not saying the 5Es should be ignored but NET Cancer is complex and most things need to be read in the correct context. What works for some may not work for others. There can also be confusion surrounding the source of symptoms, i.e. are they syndrome or something else? This is why I believe NET patients need to answer some key questions when considering the risks associated with the 5 E’s:
Are you currently syndromic? If you are, then the 5 ‘E’ list is probably very good advice but interpreting the advice in the correct context remains important.
Are your syndrome related biochemistry results normal (e.g. 5HIAA)? Normal readings (in range) tend to mean the syndrome is under control and many people who were diagnosed with a syndrome may actually be non-syndromic following treatment.
Have you had treatment or are having treatment likely to produce side effects which might be confused with Carcinoid syndrome? For example, surgery can be the long term cause of diarrhea and other issues. Despite the role of somatostatin analogues, these could also be the root cause of certain reactions.
Do you have any other illnesses? If yes, do these other illnesses produce effects similar to carcinoid syndrome? e.g. asthma, diabetes, rosacea, thyroid disorders, vitamin & mineral deficiencies, malabsorption, gut bacterial imbalance. Sorting out the symptoms can be a jigsaw with a missing piece sometimes.
The vagaries of this disease will no doubt throw up some exceptions and additions. There will be patients who have no syndrome but have elevated biochemistry and vice versa! Additionally, there will be patients who have had surgery and/or are being treated with somatostatin analogues but will still be syndromic in varying degrees of severity.
The so-called ‘5 Es’ are as follows:
Epinephrine: This was a new piece of information for me and I only discovered this as a potential problem when I started monitoring some of the USA Facebook forums. This does not appear to be that well-known in UK. Epinephrine (commonly known as adrenaline) is often used in dentistry mixed with a local anaesthetic. I won’t risk this, so I’ve instructed my Dentist to place a note on my record asking for epinephrine not be used (and clearly I’ll remind them each visit!). According to NET guru Dr Woltering, plain novocaine, carbocaine or plain marcaine are preferred. You should also check that your anaesthetist for any procedure you may be undergoing is aware of your carcinoid syndrome. However, the danger is not just with dentistry work. Any anaesthesia is risky. Check out my post ‘carcinoid crisis’.
For those who have standby ‘Epi Pens’, I did read the following statement on the Carcinoid Cancer Foundation website: “ …….. one exception is the administration of epinephrine in the case of an allergic anaphylactic reaction (i.e. a bee sting), so it cannot be avoided in this case, just make sure that Octreotide (Sandostatin) is also available“. This advice is also extremely relevant to Pheochromocytoma and Paraganglioma patients who may be a high risk of intraoperative hypertensive crisis.
Eating: This is very individual. Certain foods or large meals can be difficult, particularly if you have had any gastrointestinal surgeries. I keep a personal diary trying to identify things that upset my system. I try to find some balance between what I know is good for me and also what I know I enjoy. For example, I found that very large meals do not agree with my ‘new plumbing’. If I eat a lot of sweets, I’ll also suffer …..so I just eat a little – check out my blog post Chocolate – The NET Effect.
Personally speaking, I’m fairly certain the vast majority of my issues are related to my treatment (past and present) rather than being provoked by Carcinoid Syndrome, i.e. if I rush to the toilet after a meal, it’s not syndrome, it’s a reaction of my compromised digestive system. So with this in mind, I try to reduce those things but additionally strike a balance between quality of life and excessive and rigid adherence to some of the guidance out there (see below) – as I said above, interpretation and context is important. My compromised system cannot deal with big meals so I ‘graze’ most of the day and then eat a small to medium-sized meal in the evening. I’ve been doing this for 3 years and reduced my visits by 300% without any special or expensive medication.
In my blog Nutrition Blog 4 – Food for Thought, I’ve linked to authoritative sources on potential diet triggers. I’m not suggesting you cut out all of the foods on these lists (you won’t last long!). Some can indulge in those foods and some cannot. For example, chocolate and caffeine (tea/coffee) are on the lists but I eat/drink those frequently (in moderation) and have no problem. It’s a case of testing things out. I like to describe my eating as ‘The Risk Management of my Quality of Life’. By the way, no-one is suggesting that a NET patient with carcinoid syndrome (and don’t forget this is only one syndrome of many with NETs) should stop eating foods high in the offending amines or are precursors to serotonin (e.g. tryptophan). They do not make tumours grow (a myth) but just make sure you adhere to the dietary restrictions for any 5HIAA test.
Emotions: Stressful situations can cause symptoms to flare up. While it is difficult to avoid all stress (work, home, commuting, etc), it is helpful if you can manage or reduce it. Like eating, this is a very individual area. From personal experience, I know stress can exacerbate carcinoid syndrome. Before I started my treatment, I was regularly flushing in meetings at work (….. think boxing matches!). After my treatment, stress was definitely a factor causing increased bowel motility. I’ve removed a lot of stress from my life and it helps. You may need to be ruthless in managing this aspect of your illness.
Exercise: Exercise is extremely important for overall health and well-being and I know quite a lot of NET Cancer patients who exercise regularly without issues. It can, however, trigger carcinoid syndrome if you overdo it – it is, however, like eating, a very individual thing. I take the view that ‘zero’ exercise might potentially be an even higher risk. Even a walk around the garden or gardening is exercise. When I was at work, I would walk to see people rather than phone them. Sometimes I walk to town rather than drive, it all adds up! I have evidence from my own exercising regime proving in my case that exercise can reduce the knock-on effects of some of the other E’s (emotions and eating) and/or the side effects of treatment – check out my blog entitled Exercise is Medicine. Those who are syndromic and/or have other conditions to manage are probably best to take medical advice on how much exercise they need to do.
Ethanol (alcohol, liquor):Many NET patients have difficulty tolerating wine, beer and spirits (hard liquor). I was never a big drinker so for me it was easy to go almost teetotal. I do have the occasional beer but very infrequently and normally on holiday – I personally don’t get any issues with the odd beer but again this is trial and error. I really enjoy my beer when I celebrate my ‘Cancerversaries‘. Also check out my blog Alcohol – the NET Effect
Summary
I’m sure there could be a 5 A’s to 5 Z’s list of things to avoid but as I said above, this needs to be balanced with what the actual risks for you are and if you’re like me, quality of life. If you read most Facebook closed group or forums, you will always find at least one person is affected by something which affects no-one else. Please note this article is just my own appreciation of these issues and I emphasise once again that everyone has different experiences. I do, however, think it’s important to consider any secondary illnesses, effects of surgery and biochemistry results (or indeed a combination of one or more of these factors). Everything in life involves some kind of risk management and if you are totally risk averse, then you are unlikely to have much of a life (or a diet!).
It’s not easy but my daily diary helps me assess trends and work out what things upset me more than others – I can then reduce or eliminate. You need to tailor your own advice perhaps with the help of a doctor and/or dietician versed in NET Cancer. I also have some related posts on the subject of vitamin and mineral deficiencies, malabsorption and probiotics – check them out as the problems associated with these subjects could potentially look like a worsening of carcinoid syndrome and lead to unnecessary worry and unnecessary treatment.
For most, Carcinoid Syndrome can normally be controlled by the use of debulking surgery and/or somatostatin analogues (Octreotide/Lanreotide). However, there is a new drug called ‘Teloristat Ethyl’ (XERMELO) which looks like it may provide supplementary treatment for patients whose carcinoid syndrome diarrhea is not adequately controlled by somatostatin analogues. It’s an expensive drug and comes with side effects so you need to be sure it’s your syndrome causing the problem before you commit to a prescription.
As most of you will be aware, there are currently two main types of Somatostatin Analogues (SSA) in use for the treatment of mainstream Neuroendocrine Tumours (NETs) – Octreotide and Lanreotide. You can click on the links for information on both of these well-known NET treatments. This post will focus on the not so well known and anything in the pipeline including different delivery systems.
This is my live blog post covering new developments in the area of new Somatostatin Analogues and new delivery systems.
Abstract
As most of you will be aware, there are currently two main types of Somatostatin Analogues (SSA) in use for the treatment of mainstream Neuroendocrine Tumours (NETs) – Octreotide andLanreotide. You can click on the links for information on both of these well-known NET treatments. This post will focus on the not so well known and anything in the pipeline including different delivery systems.
Those who have read the Octreotide/ Lanreotide patient leaflets will know those SSAs are also used in the treatment of a condition known as Acromegaly. You can see why the drug is used for both as they control the release of excess secretions of various substances, a problem that has an effect on both conditions. In the case of Acromegaly, the condition is typically caused by pituitary tumours that oversecrete the growth hormone leading to elevated levels of IGF-1. Like NETs, Octreotide/Lanreotide is currently the mainstay non-surgical treatment for this condition. For those not aware of Acromegaly there is a nice infographic explaining it here.
Delivery methods discussed in this post include: a smaller, faster and easier Octreotide injection, an Octreotide capsule, an Octreotide nasal spray. Other somatostatin analogues includes Pasireotide which has already been approved for Cushing’s Syndrome and Acromegaly (core NET possibilities have been investigated) and a new kid in the pipeline called Veldreotide for Acromegaly but potential additional applications in Cushing’s syndrome and neuroendocrine tumors. Finally for those with an interest in Cushings, a drug currently in phase 3 trials called RECORLEV™ (Levoketoconazole) which is not actually a somatostatin analogue, rather it’s a cortisol synthesis inhibitor.
It’s important to understand that NETs and other conditions including Cushings and Acromegaly, very often share the same hormone inhibiting drugs, thus why any development for these type of drugs is of interest to all physicians and patients in the associated conditions.
It’s also useful to understand that many of these drugs/delivery mechanisms are driven by availability of funding and are subject to the vagaries of the market. One entry on the previous version of this article has been removed as the company manufacturing it went into administration (Solid Dose Injections).
Somatostatin Analogues – New Delivery Methods in the Pipeline
New delivery system for Octreotide LAR – “Q-Octreotide” (MDT201)
MTD201 (Q-Octreotide)
Updated 20 Dec 2018.
An unnamed ‘pharma giant’ has signed a deal with Midatech Pharma Plc that will see it evaluate the latter’s Q-Sphera drug delivery platform. Only a guess from me, but I suspect it’s either Novartis or Ipsen.
Midatech’s Q-Sphera™ is an advanced microencapsulation and polymer-depot sustained release (SR) drug delivery platform produced using a novel and disruptive printing based process, with numerous and distinct advantages over conventional reactor based technologies. From a manufacturing perspective Q-Sphera™ is a precise, scalable, efficient, and environmentally friendly microparticle platform. From a clinical perspective Q-Sphera™ ensures monodispersed microparticles that release active drug compounds into the body in a superior linear tightly controlled and predictable manner over an extended period of time from 1 – 6 months. An injection lasting 6 months sounds very exciting but I have no more detail on the feasibility or likelihood of such a change in frequency with Octreotide or Lanreotide but the press release does mention the possibility, i.e. “Q-Sphera allows drug compounds to be released into the body in a “highly controlled manner” over a prolonged period of time; potentially from a few days to up to six months.”
What’s the main differences?
The current trials are based on the use of Sandostatin LAR (Octreotide) using the Q-Sphera delivery system (previously known as Q-Octreotide). The key aspects of usability are reconstitution and needle size but there is also an inference that less frequent injections could be possible.
Apparently, the delivery method (see picture) is smaller, faster, easier with the possibility of less frequent injections. More to follow when known but in the meantime, please see a useful Video about Q-Octreotide. Apologies for the use of the out of date term ‘carcinoid‘.
New Octreotide Delivery Method – Chiasma Capsule
Octreotide Capsules? Graphic from http://www.chiasmapharma.com/
Updated 14 Dec 2017. Acromegaly appears to be in the lead in terms of new delivery methods. A pharma company called Chiasma is working on an oral version of Octreotide for this condition and they are currently at Phase 3 trials. You can check out the technology here.
Clearly, we want drugs to be safe and the announcement is another reminder of why drugs take so long to be approved. Chiasma’s investigational oral octreotide uses their proprietary TPE® (Transient Permeability Enhancer) technology to facilitate gastrointestinal absorption of the unmodified drug into the bloodstream safely (i.e. it keeps the drug safe until it reaches its destination). Hopefully, the new trial can convince the FDA to finally approve. The trial is currently only Acromegaly based and details are here.
This is potentially an exciting development given that both conditions use the same drugs (Octreotide and Lanreotide injections) so there is always the hope that NETs might be next in line if the capsule version is finally approved. However, still very early days as the company does not anticipate the release of top line date from the Phase 3 trial until 2020.
Intranasal administration of Octreotide Acetate
Nasal Spray Octreotide?
Updated 14 May 2017. Dauntless Pharmaceuticals, Inc., a privately held biopharmaceutical company focused on the development of specialty therapeutics, announced the outcome of a Phase 1 clinical studyto assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of DP1038, a novel formulation of octreotide acetate for intranasal administration, compared to subcutaneous Sandostatin® (octreotide acetate) injection in healthy volunteers. DP1038 (octreotide acetate for intranasal administration) is being developed via the 505(b)(2) regulatory pathway for the treatment of acromegaly and neuroendocrine tumors. DP1038 leverages patented technology for enhanced intranasal absorption developed by Aegis Therapeutics, LLC, a drug delivery and drug formulation company that has successfully licensed its technology to leading pharmaceutical and biopharmaceutical companies whose partners have multiple late stage clinical programs under development. The drug will most likely use an administration system patented by Aegis called Intravail® Aegis Therapeutics LLC announced last year that it has been awarded U.S. Patent No. 9,446,134 providing non-invasive metered nasal spray delivery of Octreotide (click here to view the announcement). The enabling Aegis Intravail formulation technology is broadly applicable to a wide range of small molecule and biotherapeutic drugs to increase non-invasive bioavailability by the oral, nasal, buccal, and sublingual routes and to speed attainment of therapeutic drug levels in cases where a non-invasive (i.e., non-injectable) form of the drug is unavailable or where speed of onset is important. A description of Intravail delivery systems can be found by clicking here.
About the Phase 1 Trial The Phase 1 trial was designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of DP1038, a novel formulation of octreotide acetate for intranasal administration, compared to subcutaneous Sandostatin® (octreotide acetate) Injection in healthy volunteers. In Part 1 of the study, each of 12 subjects received three doses of DP1038 plus 100 micrograms of subcutaneous octreotide acetate in a randomized 4 x 4 Latin square design. DP1038 was well tolerated across all doses and demonstrated a consistent, dose-proportional pharmacokinetic profile with significant nasal bioavailability. In Part 2 of the study, a single dose of DP1038, which was selected to exhibit a similar pharmacokinetic profile to subcutaneous octreotide acetate, was evaluated in 20 subjects in a cross-over design to compare the pharmacodynamic effect to 100 micrograms of subcutaneous octreotide acetate. Subjects were given a GHRH-arginine challenge, a standard test to stimulate growth hormone release, followed by administration of DP1038 or subcutaneous octreotide acetate. DP1038 showed comparable growth hormone suppression to the subcutaneous reference product. The news announcing the output from the Phase 1 clinical trial can be found by clicking here.Clearly, this is very early days and the product would need to go through the normal drug approval and acceptance routes etc. However, a Phase 1 trial using patients is very exciting.
New Somatostatin Analogues in the Pipeline
New Somatostatin Analogue – Pasireotide
Updated 14 Dec 2017. Not really new but I wanted to include it because it’s not very well-known. Pasireotide is also known as Signifor and SOM230.This drug is already in the pipeline but only for Acromegaly and Cushing’s Syndrome. I found it interesting that is able to function as a multireceptor-targeted SSA by binding with high affinity to 4 of the 5 somatostatin receptors (sstrs 1, 2, 3 and 5), with the highest affinity for sstr5, resulting in inhibition of adrenocorticotropic hormone (ACTH) secretion (Octreotide only binds to sstrs 2, 3 and 5). In fact, Signifor represents the first specific treatment for ACTH-secreting pituitary adenomas. Moreover, it is the first approved medical treatment for Cushing’s disease. If you’ve read my blog on NET Syndromes, you will see the connection – both involve pituitary tumours and this drug is designed to cater for scenarios where surgery has not solved the problem or is not an option. Interestingly Novartis describes it as a second generation SSA, inferring that Octreotide is first generation. It comes in short and long acting (LAR) forms with a similar delivery system to Octreotide. It is a US FDA approved orphan drug and is also approved for use in the EU. Novartis has also submitted additional regulatory applications for Signifor LAR worldwide. You can read more by clicking here
However, there have been studies in its use for advanced NETs where Octreotide is not working or has not sufficiently controlled the effects of the syndrome. You can read a full text article about the study results by clicking here (you will recognise some of the authors including Edward M Wolin, Christos Toumpanakis, John Ramage, Kjell Öberg). My interpretation of the trial conclusion is that there does not appear to be any significant advantages of Pasireotide over Octreotide. The attachment also confirmed studies are ongoing including a potential combination treatment of Pasireotide and Everolimus (Afinitor). There does not appear to be a study comparing it to Lanreotide.
Jonathan R. Strosberg, MD, associate professor at H. Lee Moffitt Cancer Center, discussed pasireotide as a potential treatment for patients with neuroendocrine tumors (NETs). He said “Pasireotide is a somatostatin analog similar to octreotide (Sandostatin) and lanreotide (Somatuline). However, pasireotide targets 4 out of the 5 somatostatin receptor subtypes, which may provide it with an advantage over the other 3 agents. Thus far, there has not been enough evidence showing that pasireotide has a progression-free survival benefit over the other 2 therapies. It is also associated with hyperglycemia. Pasireotide may be an appropriate choice for patients in later lines of therapy. In the future, he envisions that patients could be selected for therapy based on their somatostatin receptor profile.”
New Somatostatin Analogue – Veldoreotide (COR-005)
Updated 14 Dec 2017. There is another new drug in the pipeline currently known as Veldoreotide or COR-005 (although I can see the term ‘Somatoprim’ used on other searches). COR-005 is an investigational SSA in phase 2 development for treatment of patients with Acromegaly. Although the page on the manufacturer’s website does not mention NETs, an announcement of its progress has just been made at the Endocrine Society’s annual conference for 2016. The announcement states that the drug has “potential additional applications in Cushing’s syndrome and neuroendocrine tumors”. COR-005 targets somatostatin receptors 2, 4 and 5. Read about the drug here.
COR-005 has received orphan drug designation (only for Acromegaly) in the US and EU. There is not enough data to understand how this might benefit NETs and what the differences would be. Hopefully, an update will be available later which will result in an update to this post.
For those interested in Cushing’s Syndrome, (hypercortisolism or high levels of cortisol), the same manufacturer working on Veldoreotide is also working on a new drug in Phase 3 trials known as RECORLEV™ (Levoketoconazole). Not actually a somatostatin analogue, rather it’s a cortisol synthesis inhibitor
Summary
This information is provided for information only. There is no intent to indicate at this point that these new drugs will eventually be approved for NETs. However, it’s another indication that people are working on new treatments which might end up being available at some stage.
The pipeline for new treatments and methods of delivery continues to grow!
When I was diagnosed, I wasn’t feeling ill. In hindsight, I now know some of the signs were there, I just put up with them. Neuroendocrine Cancer had laid a trap for me and I fell right into it. You see, Neuroendocrine Cancer can be very quiet and unobtrusive. It also plays the ‘long game’ and will sometimes take years before it’s finally discovered. It is very very very sneaky.
Not satisfied with loitering in your small intestine, appendix, lungs, stomach, pancreas and a host of other places, it wants to reach out to your liver, your lymph nodes, your bones, bung you up with fibrosis, and get into your heart where it can cause the most damage. It will also try to get into your head, metaphorically speaking – however, it will also try the physical route.
As it spreads, it can become noisier through growth but also by secreting excess amounts of hormonesand other substances. It knows that tumour growth and these excess hormones and substances will mimic routine illnesses such as IBS, diarrhea, stool changes including steatorrhoea, stomach cramps and bloating, asthma, facial flushing, menopause, weight loss, anaemia, fatigue, tachycardia (fast heart beat), pain, and nausea – a real witch’s brew of symptoms. These may manifest themselves as common endocrine conditions e.g. it can mess with your blood sugar and thyroid levels. These are a few examples, there can be many others – it’s a real witch’s brew of symptoms. Neuroendocrine Cancer thinks this is great because it fools doctors into misdiagnosing you with something else which means it can continue to grow undetected and unfettered, spreading further inside you.
If nothing is done to stop its relentless growth, it will eventually kill.
However, sometimes an inquisitive doctor or nurse upsets its progress by thinking ‘outside the box’. Neuroendocrine Cancer hates when people are aware of its devious nature and hates when people know which tests can be used to find it and which treatments are best to attack it. Inquisitive, proactive and determined patients can also add to this effect and sometimes a bit of luck is involved.
It doesn’t give up easy and tries to work around your treatment. It knows your treatment will come with certain consequences and it will try to exploit this situation by keeping you guessing between cancer activity and these consequences. It really hates observant medical staff and patients, particularly those who understand Neuroendocrine Cancer.
Unfortunately for Neuroendocrine Cancer, there is now more knowledge about its devious activities and the latest statistics indicate it’s starting to be caught earlier. Nonetheless, we cannot afford to become complacent.
Neuroendocrine Cancer hates awareness and it will be extremely happy if you don’t share this post.
Please note a new syringe for Lanreotide will be available in 2019, at least in Ireland and UK which have confirmed dates. However, Ipsen are committed to roll it out to the rest of Europe, US, Canada, Australia and New Zealand by end of 2019 (details to follow) following necessary regulatory approvals.
Further information will be communicated to healthcare professionals in advance of this, to enable them to inform their patients, whom have been prescribed Lanreotide. In addition, the patient information leaflet included in the packet will have clear instructions for use. There will be a prominent yellow box located on the outer carton of the medicine, alerting healthcare professionals and patients that a new syringe is contained inside.
The new pre-filled syringe for Somatuline® Autogel® was the result of several studies, involving patients, their caregivers, nurses and other healthcare professionals, to inform and test enhancements to the existing pre-filled syringe. Notable new features are modified ergonomics and handling, a needle shield removal system, an injection process with plunger support and heightened ease of use. The automatic, built-in safety system, which helps to prevent needle stick injury by locking in place following the administration, has not been changed.
Please note that the medicine is still the same and the formulation and storage conditions have not changed.
Diagram of new injection system for Lanreotide (hopefully actual photo to follow once I get my hands on one)
My Lanreotide Experience
When I was discharged from hospital following major surgery in Nov 2010, I knew I would shortly be commencing long-term monthly ‘somatostatin analogue’ treatment and had assumed Octreotide (Sandostatin LAR) would be the drug of choice. However, my Oncologist prescribed Lanreotide (known in the UK as Somatuline Autogel and elsewhere as Somatuline Depot). Technically this is a hormone therapy (it’s not chemo).
Somatostatin Analogues (Octreotide/Lanreotide) are mainstay treatments for many Neuroendocrine Cancer patients and their introduction is a very significant factor in the improvement of both prognostic outcomes and quality of life. Both drugs are designed to control Carcinoid Syndrome (but can be used selectively in other NET syndromes) and both have anti-tumour effects. Check out my Lanreotide vs Octreotide comparison blog.
Although I didn’t relish the thought of any injection in the ‘rear end’ every 28 days for the rest of my life, I admit to being slightly relieved with his choice. I had been reading about patient experiences with the alternative, mainly the needle length and the occasional problems mixing the drug prior to injection. Although Lanreotide has a similar gauge (thickness), the needle is a good bit shorter and is deep subcutaneous rather than Octreotide LAR’s intramuscular (IM) route. No mixing is required as Lanreotide comes prefilled.
If you’re interested in the science, please be aware that a somatostatin analogue is a synthetic (manufactured) version of a naturally occurring hormone which inhibits the peptides and amines that can be dangerously hypersecreted by certain neuroendocrine tumours.
Following an Octreotide Scan, various areas lit up confirming the output from previous CT scans. It also confirmed new ‘hotspots’ for further investigation. This specialist scan confirmed I probably had working receptors to receive something known as a Somatostatin Analogue to help with combatting the effects of Carcinoid Syndrome (please note that not having working receptors does not mean there is no benefit of receiving somatostatin analogues). I was therefore prescribed daily Octreotide (self-injecting) whilst I was waiting for my first major ‘debulking’ surgery, This treatment did eventually lessen the main effect of the carcinoid syndrome, facial flushing. It wasn’t until after my first surgery that the facial flushing was dramatically reduced. I commenced Lanreotide on 9 Dec 2010 and I haven’t had a facial flush since. It’s worth adding that my Chromogranin A (CgA) blood test (correlated to tumour mass) did not return to normal until after a liver resection 3 months later. My 5HIAA urine test results (mainly correlated to serotonin levels) returned to normal prior to liver surgery in Apr 2011 indicating the Lanreotide was doing its job! Somatostatin Analogue side effects are to be expected and most people seem to have different and/or greater or lesser effects than others. The daily Octreotide did not bother me too much other than some discolouring of the stomach at the injection sites (i.e. black and blue!) ….I’m more observant nowadays, so it’s possible I may not have recorded this experience properly.
If you read the UK patient leafletwhich comes with each injection, you can see a list of potential side effects as long as your arm. Neuroendocrine Cancer comes with many signs, syndromes, symptoms and suspicions, so I always advise caution and some analysis when assigning reasons for problems encountered. For North America, the equivalent instructions can be found here (Somatuline Depot). I don’t know precisely why (……. I do have my suspicions), but I’m always very sceptical about the criteria used to compile the list of side effects for any medicine. In my own mind, I’m fairly certain that people have existing symptoms or new symptoms as a result of coincidental treatment that are erroneously labelled under drugs during trials.
You can also self-inject Lanreotide but I’m not ready for that yet! If you do self inject, please note it the site is “the upper outer part of your thigh”. Check out the Ipsen leaflet here.
I think the injection site is very important and getting this wrong will worsen the side effects. For the Healthcare Professional or trained family member administration, the site should be the superior external quadrant but not of the whole ‘butt’, it means of the left or right buttock that is being used on an alternative basis. If nurses think the whole ‘butt’, they might be tempted to stick it quite close to the ‘intergluteal cleft’ – not advisable!
Although the patient leaflets are very clear on how to administer the drug, once the location is established, I always discuss the following with the Nurse before I receive the ‘dart’:
1. The injection should have been removed from the fridge at least 30 minutes before treatment. However, please note Ipsen clarified in 2019 that the product can be put back in the fridge in the original packaging for later use, provided it has been stored for no longer than 24 hours at below 40 deg C (104 deg F) and the number of ‘temperature excursions’ does not exceed three. If you are taking the drug somewhere to be administered or were waiting on a home visit, this might help with scheduling issues.
2. Don’t pinch the skin, stretch it.
3. Put the needle in fast at 90 degrees, inject the drug slow – 20 seconds is recommended. As the drug is viscous, in any case, there is normally some resistance to a fast release.
4. Do not rub or massage the area after as this action can interfere with the formulation of the drug. This is clearly stated on the drug information leaflet, i.e. ” Apply gentle pressure to the injection site with a dry cotton ball or sterile gauze to prevent any bleeding. Do not rub or massage the injection site after administration”.
My experience with side effects. People have different experiences with side effects and just because a particular side effect is mentioned, does not mean to say that everyone will be troubled – many patients experience little or none. For me, over 7 years, I think I can attribute the following to Lanreotide:
itching but only on the legs below the knees centred on the ankles – and nearly always the right leg. Occasionally, the injection site will itch but only for a day or two. I have a tub of emollient cream (almond oil) on standby which seems to calm it down. Note …… a little bit of me thinks there could be a connection with vitamin/mineral deficiency and perhaps a coincidental occurrence and this problem seems much less of an issue over 7 years later. EDIT- could have been Hypothyroidism – click here.
minor pain at the injection site but this only lasts for an hour or two and I believe this to be associated with the administration of the injection, i.e. if the injection is done properly, I don’t really have this problem except for a second or two as it enters. Once, I had pain for 10 days. In my own experience, the best and least painful injections are those done by trained personnel who are confident.
small lumps form at the injection site which is alternating superior external quadrant of the each buttock. You may occasionally hear these being called ‘granulomas‘ or ‘injection site granulomas’. The issue of ‘injection site granulomas’ seems to figure in both Lanreotide and Octreotide. Gluteal injection site granulomas are a very common finding on CT and plain radiographs. They occur as a result of subcutaneous (i.e. intra-lipomatous) rather than intramuscular injection of drugs, which cause localised fat necrosis, scar formation and dystrophic calcification. But no-one seems to know why they occur with somatostatin analogues. I find that they are more conspicuous if the injection is done slightly too high which was my initial experience and they took months to fade. I opted to stand up for the first two injections and I attribute this decision for a slightly too high injection site. I now lie down which is actually recommended for the smaller and thinner patient. Although the lumps have reduced in size, I have not seen a new lump for some time indicating location might have been the cause. They sometimes show up on scans. This is not a new problem and has been highlighted for the last 10 years in academic papers. This particular paper is useful and the conclusion confirms this is not something that should worry patients too much. Read more here
fatigue normally within 24-48 hours of the injection but this is not consistent. Not even sure it can be classed as proper fatigue but it’s a ‘you need to sit down and fall asleep‘ feeling! When this occurs, it normally only lasts for 1 day before the normal energy levels return. Again, like the itching, this appears to be less of an issue today.
malabsorption. although the side effects of gastro-intestinal (GI) surgery and gallbladder removal can cause malabsorption issues leading to steatorrhea (basically the inability to digest fat properly); somatostatin analogues can cause or exacerbate existing steatorrhea, as they inhibit the production of digestive/pancreatic enzymes which aid fat digestion. Most months, I notice a marked but short-term increase in this problem normally within 48-72 hours of the injection.
elevated blood glucose. This is a new issue in 2018 but has been brewing for a year or two. The patient information leaflet for Lanreotide (and for Octreotide) clearly states that this is a potential side effect and also asks those who are already diabetic, to consult their doctor about monitoring doses of diabetic medicine. I’m working with my doctors to keep my blood glucose down to avoid becoming diabetic. Please read this article covering the connections between NETs and Diabetes
A few years ago, there was some ‘talk’ that somatostatin analogues were also able to stunt or reverse the growth of certain neuroendocrine tumours. Has this been the case for me? Possibly. I’ve had regular CT scans every 3-6 months and since two bouts of major surgery in 2010/2011, I’ve also had 3 x Octreoscans over the same period. I did once spend a day analysing 5 years of scan results looking for variations in size and concluded that there was a stable trend and potentially a fading of one or two of my largest liver tumours. I was reminded these two types of scans were not really precise enough to detect small millimetre increases or decreases and as there were other factors at play, there was little commitment to make this declaration. However, I did note in the summary of theCLARINETstudy, Lanreotide was associated with prolonged progression-free survival among patients with advanced, grade 1 or 2 (Ki-67 <10%) enteropancreatic, somatostatin receptor–positive neuroendocrine tumours with prior stable disease, irrespective of the hepatic tumour volume. In terms of its anti-proliferative effects, aninterim report from the CLARINET extension studysuggested longer-term Lanreotide treatment is well tolerated with ‘anti-tumour’ effects in patients with progressive disease. The final CLARINET open label extension studyreport additionally provided evidence for long-term PFS benefits of Lanreotide Autogel 120 mg in patients with indolent pancreatic and intestinal NETs.
There’s currently a trial ongoing in relation to Lanreotide and Lung NETs – read by clicking here.
I have my ups and downs and I do feel quite well most of the time. Most people tell me I look quite well too – lucky they can’t see my insides! Over the last 7 years, I’ve made some fairly significant adjustments to cope with my condition and maintain a reasonable quality of life – my monthly injection of Lanreotide is no doubt playing a big part.
Finally, please spend 5 minutes watching this fascinating video from Ipsen. It explains in easy terms how Lanreotide works. It also has a useful summary of the side effects at the end. Click here to watch the video.
I’ve just been enrolled onto a new service called HomeZone whereby the injection is now administered at my home via an Ipsen provided and funded nurse. Read here to see if you can also take advantage of this service.
THE SOMATULINE ‘RESERVOIR’ FORMING IN THE DEEP SUBCUTANEOUS TISSUE
In July 2018, I received my 100th injection of Somatuline Autogel (Lanreotide). I was very grateful to still be here so I thought it was worth a celebratory cake – injection themed!
Neuroendocrine Cancers can sometimes present with one or more vague symptoms which occasionally results in a lengthy diagnostic phase for some. Sure, there can be issues with doctor experience and knowledge that can add to the problem. However, some people do present with multiple vague and confusing symptoms and some people have comorbidities which have similar symptoms. Textbook diagnostics just don’t make sense, sometimes even when the doctor suspects Neuroendocrine Cancer i.e. classic symptoms of ‘something’ but with negative markers for NETs. Clearly those are extreme cases and just like other complex diseases, many diagnoses of Neuroendocrine Cancer can be extremely challenging. Even for an experienced doctor, it can be a difficult jigsaw!
Most types of Neuroendocrine Cancer can be accompanied by a ‘syndrome’ i.e. the tumours are ‘functional’ and this is normally (but not always) associated with metastatic disease. At this point it’s also worthwhile saying that some Neuroendocrine Cancers can be ‘silent’ (non-functional) for years before any symptoms show and it’s normally only when they metastasize, that these clinical syndromes come to life. Ironically, the manifestation of the disease with a syndrome can occasionally turn out to be a life saver albeit the cancer is normally incurable at this stage – but still treatable.
The most common type of Neuroendocrine Cancer can often present as a collection of symptoms known as Carcinoid Syndrome and the most common of these is flushing with approximately 84% frequency. Others symptoms include (but are not limited to) diarrhoea, heart palpitations, stomach cramps and general abdominal pain/discomfort, shortness of breath, wheezing. You can see the scope for confusion and misdiagnosis. You may find my blog on the ‘5 E’s of Carcinoid Syndrome’ useful.
When you look at these general Carcinoid Syndrome symptoms, flushing seems to be the one that stands out as a ‘cardinal sign’ whereas many others are vague and easily confused with common/regular illnesses. However, the flushing is reported to be different from most people’s perceptions of a ‘flush’. The Carcinoid flush is almost always ‘dry’. To quote my ‘amazing yellow book‘ (co-authored by Woltering, Vinik, O’Dorisio et al), “…. a good rule of thumb is if the flushing is wet (accompanied by sweating), it is due to a cause other than Carcinoid”. Dr James Yao, another well known NETs guru also raises this distinction by stating…. “The facial flushing of carcinoid syndrome is usually a dry flushing, and not associated with sweating like other kinds of flushing. The flushing is often a symptom that others notice before patients do. They may not feel it themselves.”
Additionally, from the same source, there appears to be at least two varieties of flushing in Carcinoid Syndrome related to two different anatomical regions of the primary tumour (again a useful guide from my amazing yellow book):
What to Look For in Flushing – Distinguishing Signs and Symptoms
There are two varieties of flushing in carcinoid syndrome:
1. Midgut: The flush usually is faint pink to red in color and involves the face and upper trunk as far as the nipple line. The flush is initially provoked by alcohol and food containing tyramine (e.g., blue cheese, chocolate, aged or cured sausage, red wine). With time, the flush may occur spontaneously and without provocation. It usually lasts only a few minutes and may occur many times per day. It generally does not leave permanent discoloration.
2. Foregut tumors: The flush often is more intense, of longer duration, and purplish in hue. It is frequently followed by telangiectasia and involves not only the upper trunk but may also affect the limbs. The limbs may become acrocyanotic, and the appearance of the nose resembles that of rhinophyma. The skin of the face often thickens, and assumes leonine facies resembling that seen in leprosy and acromegaly.
Another source for flush descriptions comes from a paid article written by well known NET Endocrinologist – Kjell Öberg.
Four different types of flushing have been described in the literature.
Endocrinology: Adult and Pediatric – 7th Edition 2016.
The first type is the diffuse, erythematous flush, usually affecting the face, neck, and upper chest (i.e., normal flushing area). This flush is commonly of short duration, lasting from 1 to 5 minutes, and is related to early stages of malignant midgut NETs.
The second type is violaceous flush, which affects the same areas of the body and has roughly the same time course or sometimes lasts a little longer. These patients also may have facial telangiectasia. This flush is related to the later stages of malignant midgut NETs and is normally not felt by the patients because they have become accustomed to the flushing reaction.
The third type is prolonged flushing, lasting for hours up to several days. It sometimes involves the whole body and is associated with profuse lacrimation, swelling of the salivary glands, hypotension, and facial edema. These symptoms are usually associated with malignant bronchial carcinoids.
Finally, the fourth type of flushing reaction is bright red, patchy flushing, which is seen in patients with chronic atrophic gastritis and ECLomas (derived from enterochromaffin-like cells) of the gastric mucosa with evidence of increased histamine production.
Differential diagnoses for flushing?
The facial flushing associated with NETs should be distinguished from other causes of flushes. The carcinoid syndrome flush is provoked by spicy food, alcohol, and physical and psychological stress, and it is often worse in the morning. Patients with idiopathic flushes usually have a long history of flushing, starting rather early in life and sometimes with a family history without occurrence of a tumor. Menopausal flushes usually involve the whole body and might be related to release of calcitonin gene–related peptide (CGRP) with transient vasodilation, a so-called dry flush. Another type of menopausal symptom is the wet flush, which includes epinephrine-induced sweating. Proposed mediators of flushing in menopause are CGRP, histamine, prostaglandins, serotonin, lysyl-bradykinin, and substance P. Estrogen is known to have an impact on the production and release of different signaling substances such as noradrenaline and β-endorphin. Low estrogen levels cause lower β-endorphin activity, which in turn enhances the release of gonadotropin-releasing hormone (GnRH), which gives rise to high luteinizing hormone (LH)levels. Postmenopausal women in whom a true carcinoid syndrome is developing can tell the difference between the two types of flushes. Sometimes patients with medullary thyroid carcinoma have brief flushes provoked by alcohol. In patients with watery diarrhea, hypokalemia, achlorhydria syndrome (WDHA; vasoactive intestinal peptide [VIP]omas), a purple-red constant flushing of the whole body may develop. This flushing reaction is related to the vasodilator effects of VIP. Flushes seen in mastocytosis are related to release of histamine from mast cell granules. Mastocytosis is a rare disease of mast cell proliferation that occurs both cutaneously and systemically.
So it’s clear from our experts that the flushing symptom has many potential triggers and can be attributed to the secretion of excess hormones associated with Neuroendocrine Tumours. It’s also clear that the symptom is not just associated with carcinoid syndrome. Although many people focus on serotonin as the main culprit, there appears to be significant evidence to suggest that other hormones may be playing a bigger part with this symptom, e.g. histamine (particularly foregut), tachykinins (Substance P), bradykinins, and prostaglandins.
If you study the online forums, there are frequent questions about flushing, particularly from those looking for a diagnosis and are suspecting Carcinoid Syndrome due to a flushing symptom. However…… even flushing cannot always be attributed to a NET, particularly if it’s the only symptom being presented.
This is a very useful table taken from my amazing yellow book which gives the tests required to determine the potential source of a flushing (differential diagnosis). I strongly suspect this is not an exact science (…..is anything in medicine?) but it’s extremely useful. Personally I would have included Rosacea :-). The referenced article “>Endocrinology: Adult and Pediatric – 7th Edition 2016 by Öberg, Grosssman et al, generally agrees with this list but adds WHDA Syndrome (a pNET called VIPoma), food, drugs, ethanol and idiopathic. It also generalises Neurologic disorders (see more below).
Öberg, Grosssman, et al list the following drugs that can cause flushes:
Bromocriptine
Tamoxifen
Nicotinic Acid
Opiates
Calcium channel blockers
Ketoconazole
Chlorpromazine
Cephalosporin
Öberg, Grosssman, et al list the following foods that can cause flushes:
Spicy food
Glutamate
Sodium nitrate
Sulfites
Hot beverages
Öberg, Grosssman, et al also list the following neurologic disorders that can cause flushes:
Anxiety
Migraine
Parkinson’s disease
Spinal cord lesions
Brain tumors
Clearly these lists are those that can cause a flush but not everyone will experience this. For example, when I was syndromic with flushing, I never had any issues with hot beverages.
My own experience with flushing brings back some memories and it emphasises something I say a lot – the patient has a big part to play in their own diagnosis. Please check out this 90 second video about how I did not play my part! I was experiencing a mild and innocuous flushing sensation for some months before I was diagnosed with metastatic Neuroendocrine Cancer. Even though I knew it was weird and something I hadn’t experienced before, I totally ignored it. I failed to mention it at any of my routine GP appointments or my annual asthma clinic. I failed to mention it to my specialist who was investigating a GP/PCP diagnosis of Iron Deficiency Anemia/weight loss. After a CT scan, the specialist appeared to be scratching his head ….. at that point he knew I had cancer but he also knew it was unusual. I suddenly mentioned the flushing and ‘bingo’. It was the face of a man who had just found a missing piece of a jigsaw and he correctly predicted the output from my subsequent liver biopsy.
For the next few months, I was keeping my condition private at work but it was sometimes difficult to disguise the flushing. At least one person thought my blood pressure was going up! Fortunately, my flushing disappeared after treatment.
I’ll complete this post with an interesting summary from an online forum post in which I was participating. There was a general discussion about the severity of ‘syndrome symptoms’ including triggers and I was staggered to read that people were experiencing flushing whilst carrying out routine day-to-day tasks. I’m so happy I don’t flush when I eat one square of chocolate (that would be a complete disaster!). The one which caught my attention was the simple act of washing hair. Whilst I initially raised my eyebrows and laughed, it did make me think back to the last flush I experienced (and touch wood it was the last …..). Following my diagnosis, I commenced daily injections of Octreotide. These injections reduced the flushing but it didn’t eliminate it. However, after my ‘debulking’ surgery in Nov 2010, my flushing disappeared. However, I do remember this small flush coming out of nowhere whilst I was recovering in hospital after that surgery. I was cleaning my teeth and I do vividly remember this minor task taking some effort!
I haven’t had a flush since and if this symptom comes back, I’ll know I have a new problem to contend with.
I also found myself smiling at the fact that flushing is connected with the toilet and a type of red warm feeling in the upper torso – the two main symptoms of the Carcinoid Syndrome associated with the most common type of Neuroendocrine Cancer. “Please flush after use” – erm…yes sure but actually – no thanks
In the past couple of years, I’ve read so many stories about the quite natural act of using a toilet (…..some more repeatable than others). I think if there was a ‘Bachelor of Science degree in Toiletry’, I might pass with First Class Honours.
I jest clearly but it’s strange that such a routine activity for most can actually become quite scientific in the world of Neuroendocrine Cancer and other ailments which might be described in some scenarios as invisible illnesses.
I also found myself smiling at the fact that flushing is connected with the toilet and a type of red warm feeling in the upper torso – the two main symptoms of the Carcinoid Syndromeassociated with the most common type of Neuroendocrine Cancer. “Please flush after use”– erm…yes sure but actually – no thanks 🙂
You’re kidding me!
When I read about some of the issues others deal with, I think I’m one of the luckier Neuroendocrine Cancer patients regarding these type of issues. I’m in reasonable condition considering the extent of my disease and my subsequent treatment. I put up with a number of irritants but I don’t seem to suffer as much as some appear to do. That said, I think I sometimes downplay my own issues though, I’m well known for ‘not frightening the horses’.
One thing that does worry me is the occasional stomach cramp. Hopefully, I’m not tempting fate as they seem to be vastly reduced in the past 3 years. They can sometimes be very painful and debilitating – normally resolved by going to the toilet (and hopefully one is close!). Handy if I’m in the house, not so handy if I’m on a plane, in town or anywhere where toilets are not in abundance. I did write a blog on this subject following a very painful episode on my Hadrian’s Wall 6 day adventure – ‘My stomach cramps my style’.
As I’ve had intestinal surgery, Bowel obstructions are a potential worry. To date, pain and sluggishness have always been just a bout of constipation. Read my article here. You can carry a card for the bowel obstruction risk courtesy of NET Patient Foundation – these guys have a card for most stuff.
I don’t suffer from ‘carcinoid syndrome induced diarrhea’ but long flights are one of the few times I take Loperamide (Imodium). For long drives and trips to town, I’m simply reliant on toilet availability. Normally, I just wander into hotels and restaurants and help myself. Sometimes I find only the disabled toilet is available and when it’s urgent I have no qualms about using it. Some of them are locked and you have to get a key – again I have no qualms about asking for access despite my outwardly healthy look – nobody has argued yet! If sufficiently urgent, I’m even prepared to ask to use the staff toilets in shops etc. I do have a card in my wallet, which again, I obtained from my friends in the NET Patient Foundation. I’ve not yet had to use it in anger. I also noticed that Macmillan are now doing something similar.
On the subject of urgent visits to the toilet. I recently wrote a blog about a lady with inflammatory bowel disease (IBD) and I suspect in a worse condition than most Neuroendocrine Cancer patients. She too looks outwardly healthy but this illness is clearly a major disability. I’d like to think this type of incident is not that common but her response to it was magnificent and it apparently went viral. Just goes to show that with invisible illnesses ‘Things are not always how they seem‘. The letter is brilliant.
For those who are interested, NET Patient Foundation also do a Carcinoid Crisis at risk emergency card to keep in your wallet/purse so that doctors can be forewarned of the aversion to anaesthetics etc. Mine is in my wallet at all times just in case.
what I mainly remember was my wife Chris holding my hand which gave me a great deal of much-needed comfort and security
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It was 10th November 2010 just after midnight. I gradually woke up after a marathon 9 hoursurgery – the first of what was to be several visits to an operating theatre. The last thing I remembered before going ‘under’ was the voices of the surgical staff. When I woke up, I remember it being dark and I appeared to be constrained and pinned down by the dozen or so tubes going in and out of my weak and battered body. I can still remember the feeling today, it was like I was pinned to the bed and I was completely vulnerable and helpless. However, what I mainly remember was my wife Chris holding my hand which gave me a great deal of much-needed comfort and security.
The build up to this day began on 26 July 2010 when I was given the news that I had metastaticNeuroendocrine Tumours and that the prognosis without any treatment wasn’t too good making the decision to have treatment a lot easier. I told my Oncologist to ‘crack on’ with whatever treatment would be required.
However, it wasn’t that easy and as I was yet to find out, Neuroendocrine Cancer isn’t a simple disease. I first had to undergo a plethora of other tests including specialist scans, blood and urine tests. The specialist scans (crucially) confirmed my tumours were ‘avid’ to a something called a ‘somatostatin analogue’. The scan also confirmed I had more tumours than initially thought. This was key to working out my treatment plan as I now had a grading, staging and I had the right tumour ‘receptors’ to assist along the way.
When I initially presented in May 2010, I hadn’t realised for some months that I was showing symptoms of one of the Neuroendocrine Tumour syndromes (in my case carcinoid syndrome‘. This was mainly facial flushing but thinking back, there was some diarrheaalbeit infrequent. The subsequent specialist blood and urine tests (CgA and 5HIAA respectively) were way out of range confirming both the diagnosis of tumour bulk and tumour activity respectively. The tumour activity (or function) is one thing which makes NETs different from most cancers and is caused by excessive secretion of specific hormonesapplicable to the primary location of the tumour. Thus why I had to be established on a ‘somatostatin analogue’ which is designed to inhibit the excessive secretion. I self-injected Octreotide daily for 2 months until the flushing was under control. When Neuroendocrine Tumours cause carcinoid syndrome, there is a risk of a phenomenon known as ‘Carcinoid Crisis’. This is the immediate onset of debilitating and life-threatening symptoms that can be triggered by a number of events including anaesthesia. As an additional precaution to prevent such complications, I was admitted on the 8th November 2010 in order to have an ‘Octreotide soak’ (Octreotide on a drip) prior to the surgery on 9th November 2010.
As is normal for such procedures, I had therisksexplained to me. There seemed to be a lot of risks on the list and my surgeon, Mr Neil Pearce, carefully explained each one. Death was on the list but I was happy to hear he had a 100% record on his ‘table’. Trust is an extremely important word when you’re in this situation.
As a snub to cancer, I refused the offer of a wheelchair and chose to walk to the operating theatre at around 2.30pm. So together with my ‘drip fed’ Octreotide trolley and wearing my surgical stockings and gown (carefully fastened at the rear!), I wandered down to the operating theatre with my escorting nurse.
The 9-hour operation was designed to debulk what was described as “extensive intra-abdominal neuroendocrine disease”. The operation comprised the removal of 3 feet of small intestine at the terminal ileum plus a right hemicolectomy, a mesenteric root dissection taking out the nodes on the superior mesenteric artery and a mesenteric vein reconstruction. With the assistance of a vascular surgeon, my NET surgeon also dissected out a dense fibrotic retro-peritoneal reaction which had encircled my aorta and cava below the level of the superior mesenteric artery. Phew! Thank goodness I was asleep 🙂
In those days, I had no idea that 10th November was NET Cancer Day. Some 8 years later I not only celebrate the fact that I woke up on this date after my first major surgery but that I have also woken up to the idea and inspiration behind NET Cancer Day in terms of an awareness window of opportunity.
However, on the basis that you can never have enough awareness windows, for me EVERY DAY IS NET CANCER DAY and via my own social media channels, I’m making sure everyone knows!
Thanks for listening
Ronny
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Until I was diagnosed with metastatic Neuroendocrine Cancer, I didn’t have a clue about hormones – it’s one of those things you just take for granted. However, hormones are vital to human health (male and female) and it’s only when things go wrong you suddenly appreciate how important they are ……..like a lot of other things in life I suppose! The presence of over-secreting hormones (often called peptides throughout) is useful to aid diagnosis albeit it often means the tumours have metastasized. It’s also a frequent indication that the person has an associated NET syndrome.
This is a really complex area and to understand the hormone problems associated with Neuroendocrine Cancer, you need to have a basic knowledge of the endocrine and neuroendocrine systems. I’ve no intention of explaining that (!) – other than the following high level summary:
Glands in the endocrine system use the bloodstream to monitor the body’s internal environment and to communicate with each other through substances called hormones, which are released into the bloodstream. Endocrine glands include; Pituitary, Hypothalmus, Thymus, Pineal, Testes, Ovaries Thyroid, Adrenal, Parathyroid, Pancreas.
A Hormone is a chemical that is made by specialist cells, usually within an endocrine gland, and it is released into the bloodstream to send a message to another part of the body. It is often referred to as a ‘chemical messenger’. In the human body, hormones are used for two types of communication. The first is for communication between two endocrine glands, where one gland releases a hormone which stimulates another target gland to change the levels of hormones that it is releasing. The second is between an endocrine gland and a target organ, for example when the pancreas releases insulin which causes muscle and fat cells to take up glucose from the bloodstream. Hormones affect many physiological activities including growth, metabolism, appetite, puberty and fertility.
The Endocrine system. The complex interplay between the glands, hormones and other target organs is referred to as the endocrine system.
The Neuroendocrine System. The diffuse neuroendocrine system is made up of neuroendocrine cells scattered throughout the body. These cells receive neuronal input and, as a consequence of this input, release hormones to the blood. In this way they bring about an integration between the nervous system and the endocrine system (i.e. Neuroendocrine). A complex area but one example of what this means is the adrenal gland releasing adrenaline to the blood when the body prepares for the ‘fight or flight’ response in times of stress, ie, for vigorous and/or sudden action.
Hormones – the NET Effect
At least one or more hormones will be involved at various sites and even within certain syndromes, the dominant and offending hormone may differ between anatomical tumour sites. For example, NETs of the small intestine, lung or appendix (and one or two other places) may overproduce serotonin and other hormones which can cause a characteristic collection of symptoms currently called carcinoid syndrome. The key symptoms are flushing,diarrhea and general abdominal pain, loss of appetite, fast heart rate and shortness of breath and wheezing. The main symptom for me was facial flushing and this was instrumental in my eventual diagnosis. The fact that I was syndromic at the point of diagnosis made it easier to discover, albeit the trigger for the investigation was a fairly innocuous event. Other types of NETs are also affected by the overproduction of hormones including Insulinomas, Gastrinomas, Glucagonomas, VIPomas, Somatostatinomas, and others. These can cause their own syndromes and are not part of carcinoid syndrome as some organisations incorrectly state. For more on NET syndromes – Read Here.
So are hormones horrible?
Absolutely not, they are essential to the normal function of the human body. For example if you didn’t have any of the hormone Serotonin in your system, you would become extremely ill. On the other hand, if your glands start secreting too much of certain hormones, your body could become dysfunctional and in some scenarios, this situation could become life threatening. So hormones are good as long as the balance is correct. NET patients with an oversecreting tumor may be classed as “functional”.
Functional tumors make extra amounts of hormones, such as gastrin, insulin, and glucagon, that cause signs and symptoms.
Nonfunctional tumors do not make extra amounts of hormones. Signs and symptoms are caused by the tumor as it spreads and grows. Many NET patients are deemed to be “non-functioning” with normal hormone levels. It’s also accurate to say that many can move from one stage to the other.
Location Location Location
It’s accurate to say that the type and amount of hormone secretion differs between locations or sites of the functional tumor and this can also create different effects. The division of NETs into larger anatomical regions appears to differ depending on where you look but they all look something likes this:
Foregut NETs: In the respiratory tract, thymus, stomach, duodenum, and pancreas. This group mostly lack the enzyme aromatic amino decarboxylase that converts 5-HTP (5-Hydroxytryptophan – a precursor to serotonin) to serotonin (5-HT); such tumours tend to produce 5-HTP and histamine instead of serotonin. The Pancreas is a particularly prominent endocrine organ and can produce a number of different syndromes each with their associated hormone oversecretion – although many can be non-functional (at least to begin with). Lung NETs rarely produce serotonin, but may instead secrete histamine causing an ‘atypical’ carcinoid syndrome with generalized flushing, diarrhea, periorbital oedema, lacrimation and asthma. They may also produce adrenocorticotropic hormone (ATCH) or corticotropin-releasing factor (CRP), resulting in an ectopic Cushing’s syndrome. Please note the respiratory tract and thymus are not really anatomically pure ‘Foregut’ – but in NETs, grouped there for convenience.
Midgut NETs: In the small intestine, appendix, and ascending colon. For example, serotonin secreting tumors tend to be associated with carcinoid syndrome which tends to be associated with midgut NETs and this is normally the case. Many texts will also tell you that a syndrome only occurs at a metastatic stage. Both are a good rule of thumb but both are technically incorrect. For example, ovarian NETs can have a form of carcinoid syndrome without liver metastasis (tends to be described as atypical carcinoid syndrome). It’s also possible to see serotonin secreting tumors in places such as the pancreas (although what you would call that type of NET is open for debate).
Hindgut NETs (transverse, descending colon and rectum) cannot convert tryptophan to serotonin and other metabolites and therefore rarely cause carcinoid syndrome even if they metastasise to the liver.
Less Common Locations – there are quite a few less common NET locations which may involve less common hormones – some are covered below including the key glands contributing to NETs.
Unknown Primary? – One clue to finding the primary might be by isolating an offending hormone causing symptoms.
The key NET hormones
Serotonin
I used the example of Serotoninabove because it is the most cited problem with NET Cancer although it does tend to be most prevalent in midgut tumors. Serotonin is a monoamine neurotransmitter synthesized from Tryptophan, one of the eight essential amino acids (defined as those that cannot be made in the body and therefore must be obtained from food or supplements). About 90% of serotonin produced in the body is found in the enterochromaffin cells of the gastrointestinal (GI) tract where it is used mainly to regulate intestinal movements amongst other functions. The remainder is synthesized in the central nervous system where it mainly regulates mood, appetite, and sleep. Please note there is no transfer of serotonin across the blood-brain barrier.
Alterations in tryptophan metabolism may account for many symptoms that accompany carcinoid syndrome. Serotonin in particular is the most likely cause of many features of carcinoid syndrome as it stimulates intestinal motility and secretion and inhibits intestinal absorption. Serotonin may also stimulate fibroblast growth and fibrogenesis and may thus account for peritoneal and valvular fibrosis encountered in such tumours; serotonin, however, it is said not to be associated with flushing. The diversion of tryptophan to serotonin may lead to tryptophan deficiency as it becomes unavailable for nicotinic acid synthesis, and is associated with reduced protein synthesis and hypoalbuminaemia; this may lead to the development of pellagra (skin rash, glossitis, stomatitis, confusion/dementia).
Serotonin is also thought to be responsible for ‘right sided’ heart disease (Carcinoid Heart Disease). It is thought that high levels of serotonin in the blood stream damages the heart, leading to lesions which cause fibrosis, particularly of the heart valves. This generally affects the right side of the heart when liver metastases are present. The left side of the heart is usually not affected because the lungs can break down serotonin. Right sided heart failure symptoms include swelling (edema) in the extremities and enlargement of the heart.
Whilst serotonin can be measured directly in the blood, it’s said to be more accurate to measure 5HIAA (the output of serotonin) via blood or urine, the latter is said to be the most accurate.
Tachykinins
Tackykinins include Substance P, Neurokinin A, Neuropeptide K and others. They are active in the enterochromaffin cells of the GI tract but can also be found in lung, appendiceal and ovarian NETs, and also in Medullary Thyroid Carcinoma and Pheochromocytomas. They are thought to be involved in flushing and diarrhea in midgut NETs. The most common tachykinin is Substance P, which is a potent vasodilator (substances which open up blood vessels). Telangiectasias are collections of tiny blood vessels which can develop superficially on the faces of people who have had NETs for several years. They are most commonly found on the nose or upper lip and are purplish in color. They are thought to be due to chronic vasodilatation.
Histamine
Histamine is a hormone that is chemically similar to the hormones serotonin, epinephrine, and norepinephrine. After being made, the hormone is stored in a number of cells (e.g., mast cells, basophils, enterochromaffin cells). Normally, there is a low level of histamine circulating in the body. However (and as we all know!), the release of histamine can be triggered by an event such as an insect bite. Histamine causes the inconvenient redness, swelling and itching associated with the bite. For those with severe allergies, the sudden and more generalized release of histamine can be fatal (e.g., anaphylactic shock). Mast cell histamine has an important role in the reaction of the immune system to the presence of a compound to which the body has developed an allergy. When released from mast cells in a reaction to a material to which the immune system is allergic, the hormone causes blood vessels to increase in diameter (e.g., vasodilation) and to become more permeable to the passage of fluid across the vessel wall. These effects are apparent as a runny nose, sneezing, and watery eyes. Other symptoms can include itching, burning and swelling in the skin, headaches, plugged sinuses, stomach cramps, and diarrhea. Histamine can also be released into the lungs, where it causes the air passages to become constricted rather than dilated. This response occurs in an attempt to keep the offending allergenic particles from being inhaled. Unfortunately, this also makes breathing difficult. An example of such an effect of histamine occurs in asthma. Histamine has also been shown to function as a neurotransmitter (a chemical that facilitates the transmission of impulses from one neural cell to an adjacent neural cell).
In cases of an extreme allergic reaction, adrenaline is administered to eliminate histamine from the body. For minor allergic reactions, symptoms can sometimes be lessened by the use of antihistamines that block the binding of histamine to a receptor molecule. Histamine is thought to be involved with certain types and locations of NET, including Lung and foregut NETs where they can cause pulmonary obstruction, atypical flush and hormone syndromes.
Histamine, another amine produced by certain NETs (particularly foregut), may be associated with an atypical flushing and pruritus; increased histamine production may account for the increased frequency of duodenal ulcers observed in these tumours.
Kallikrein
Kallikrein is a potent vasodilator and may account for the flushing and increased intestinal mobility.
Prostaglandins
Although prostaglandins are overproduced in midgut tumours, their role in the development of the symptoms of carcinoid syndrome is not well established but triggering peristalsis is mentioned in some texts.
Bradykinin
Bradykinin acts as a blood vessel dilator. Dilation of blood vessels can lead to a rapid heartbeat (tachycardia) and a drop in blood pressure (hypotension). Dilation of blood vessels may also be partly responsible for the flushing associated with carcinoid syndrome.
Gastrin
Gastrin is a hormone that is produced by ‘G’ cells in the lining of the stomach and upper small intestine. During a meal, gastrin stimulates the stomach to release gastric acid. This allows the stomach to break down proteins swallowed as food and absorb certain vitamins. It also acts as a disinfectant and kills most of the bacteria that enter the stomach with food, minimising the risk of infection within the gut. Gastrin also stimulates growth of the stomach lining and increases the muscle contractions of the gut to aid digestion. Excess gastrin could indicate a NET known as a Gastric NET (stomach) or a pNET known as Gastrinoma (see pancreatic hormones below).
Endocrine Organs
Thyroid Gland
Calcitonin is a hormone that is produced in humans by the parafollicular cells (commonly known as C-cells) of the thyroid gland. Calcitonin is involved in helping to regulate levels of calcium and phosphate in the blood, opposing the action of parathyroid hormone. This means that it acts to reduce calcium levels in the blood. This hormone tends to involve Medullary Thyroid Carcinoma and Hyperparathyroidism in connection to those with Multiple Endocrine Neoplasia. Worth also pointing out the existence of Calcitonin Gene-Related Peptide (CGRP) which is a member of the calcitonin family of peptides and a potent vasodilator. Please note that hypothyroidism is often a side effect of NETs or treatment for NETs – please click here to read about the connection.
Pituitary Gland
HPA AXIS – It’s important to note something called the HPA axis when discussing pituitary hormones as there is a natural and important connection and rhythm between the Hypothalamus, Pituitary and the Adrenal glands. However, I’m only covering the pituitary and adrenal due to their strong connection with NETs.
Adrenocorticotropic hormone (ATCH) is made in the corticotroph cells of the anterior pituitary gland. It’s production is stimulated by receiving corticotrophin releasing hormone (CRH) from the Hypothalamus. ATCH is secreted in several intermittent pulses during the day into the bloodstream and transported around the body. Like cortisol (see below), levels of ATCH are generally high in the morning when we wake up and fall throughout the day. This is called a diurnal rhythm. Once ACTH reaches the adrenal glands, it binds on to receptors causing the adrenal glands to secrete more cortisol, resulting in higher levels of cortisol in the blood. It also increases production of the chemical compounds that trigger an increase in other hormones such as adrenaline and noradrenaline. If too much is released, The effects of too much ATCH are mainly due to the increase in cortisol levels which result. Higher than normal levels of ATCH may be due to:
Cushing’s disease – this is the most common cause of increased ATCH. It is caused by a tumor in the pituitary gland (PitNET), which produces excess amounts of ATCH. (Please note, Cushing’s disease is just one of the numerous causes of Cushing’s syndrome). It is likely that a Cortisol test will also be ordered if Cushing’s is suspected.
A tumour outside the pituitary gland, producing ATCH is known as an ectopic ATCH. With NETs, this is normally a pNET, Lung/Bronchial/Pulmonary NET or Pheochromocytoma.
Adrenal Glands
Adrenaline and Noradrenline
These are two separate but related hormones and neurotransmitters, known as the ‘Catecholamines’. They are produced in the medulla of the adrenal glands and in some neurons of the central nervous system. They are released into the bloodstream and serve as chemical mediators, and also convey the nerve impulses to various organs. Adrenaline has many different actions depending on the type of cells it is acting upon. However, the overall effect of adrenaline is to prepare the body for the ‘fight or flight’ response in times of stress, i.e. for vigorous and/or sudden action. Key actions of adrenaline include increasing the heart rate, increasing blood pressure, expanding the air passages of the lungs, enlarging the pupil in the eye, redistributing blood to the muscles and altering the body’s metabolism, so as to maximise blood glucose levels (primarily for the brain). A closely related hormone, noradrenaline, is released mainly from the nerve endings of the sympathetic nervous system (as well as in relatively small amounts from the adrenal medulla). There is a continuous low-level of activity of the sympathetic nervous system resulting in release of noradrenaline into the circulation, but adrenaline release is only increased at times of acute stress. These hormones are normally related to adrenal and extra adrenal NETs such as Pheochromocytoma and Paraganglioma. Like serotonin secreting tumours, adrenal secreting tumours convert the offending hormone into something which comes out in urine. In fact, this is measured (amongst other tests) by 24 hour urine test very similar to 5HIAA (with its own diet and drug restrictions). It’s known as 24-hour urinary catacholamines and metanephrines. Worth noting that adrenaline is also known as Epinephrine (one of the 5 E’s of Carcinoid Syndrome).
Cortisol
This is a steroid hormone, one of the glucocorticoids, made in the cortex of the adrenal glands and then released into the blood, which transports it all round the body. Almost every cell contains receptors for cortisol and so cortisol can have lots of different actions depending on which sort of cells it is acting upon. These effects include controlling the body’s blood sugar levels and thus regulating metabolism acting as an anti-inflammatory, influencing memory formation, controlling salt and water balance, influencing blood pressure. Blood levels of cortisol vary dramatically, but generally are high in the morning when we wake up, and then fall throughout the day. This is called a diurnal rhythm. In people who work at night, this pattern is reversed, so the timing of cortisol release is clearly linked to daily activity patterns. In addition, in response to stress, extra cortisol is released to help the body to respond appropriately. Too much cortisol over a prolonged period of time can lead to Cushing’s syndrome. Cortisol oversecretion can be associated with Adrenal Cortical Carcinoma (ACC) which can sometimes be grouped within the NET family.
Other hormones related to ACC include:
Androgens (e.g. Testosterone) – increased facial and body hair, particularly females. Deepened voice in females.
Estrogen – early signs of puberty in children, enlarged breast tissue in males.
Aldosterone – weight gain, high blood pressure.
Adrenal Insufficiency (Addison’s Disease) occurs when the adrenal glands do not produce enough of the hormone cortisol and in some cases, the hormone aldosterone. For this reason, the disease is sometimes called chronic adrenal insufficiency, or hypocortisolism.
Parathyroid
Parathyroid hormone (PTH) is secreted from four parathyroid glands, which are small glands in the neck, located behind the thyroid gland. Parathyroid hormone regulates calcium levels in the blood, largely by increasing the levels when they are too low. A primary problem in the parathyroid glands, producing too much parathyroid hormone causes raised calcium levels in the blood (hypercalcaemia – primary hyperparathyroidism). You may also be offered an additional test called Parathyroid Hormone-Related Peptide (PTHrP). They would probably also measure Serum Calcium in combination with these type of tests. The parathyroid is one of the ‘3 p’ locations often connected to Multiple Endocrine Neoplasia – MEN 1
Pancreatic Hormones (Syndromes)
Pancreatic neuroendocrine tumors form in hormone-making cells of the pancreas. You may see these described as ‘Islet Cells’ or ‘Islets of Langerhans’ after the scientist who discovered them. Pancreatic NETs may also be functional or non-functional:
Functional tumors make extra amounts of hormones, such as gastrin, insulin, and glucagon, that cause signs and symptoms.
Nonfunctional tumors do not make extra amounts of hormones. Signs and symptoms are caused by the tumor as it spreads and grows.
There are different kinds of functional pancreatic NETs. Pancreatic NETs make different kinds of hormones such as gastrin, insulin, and glucagon. Functional pancreatic NETs include the following:
Gastrinoma: A tumor that forms in cells that make gastrin. Gastrin is a hormone that causes the stomach to release an acid that helps digest food. Both gastrin and stomach acid are increased by gastrinomas. When increased stomach acid, stomach ulcers, and diarrhea are caused by a tumor that makes gastrin, it is called Zollinger-Ellison syndrome. A gastrinoma usually forms in the head of the pancreas and sometimes forms in the small intestine. Most gastrinomas are malignant (cancer).
Insulinoma: A tumor that forms in cells that make insulin. Insulin is a hormone that controls the amount of glucose (sugar) in the blood. It moves glucose into the cells, where it can be used by the body for energy. Insulinomas are usually slow-growing tumors that rarely spread. An insulinoma forms in the head, body, or tail of the pancreas. Insulinomas are usually benign (not cancer).
Glucagonoma: A tumor that forms in cells that make glucagon. Glucagon is a hormone that increases the amount of glucose in the blood. It causes the liver to break down glycogen. Too much glucagon causes hyperglycemia (high blood sugar). A glucagonoma usually forms in the tail of the pancreas. Most glucagonomas are malignant (cancer).
Pancreatic Polypeptide (PPoma). A pancreatic polypeptide is a polypeptide hormone secreted by the pancreatic polypeptide (PP) cells of the islets of Langerhans in the endocrine portion of the pancreas. Its release is triggered in humans by protein-rich meals, fasting, exercise, and acute hypoglycemia and is inhibited by somatostatin and intravenous glucose. The exact biological role of pancreatic polypeptide remains uncertain. Excess PP could indicate a pNET known as PPoma.
Other types of tumors: There are other rare types of functional pancreatic NETs that make hormones, including hormones that control the balance of sugar, salt, and water in the body. These tumors include:
VIPomas, which make vasoactive intestinal peptide. VIPoma may also be called Verner-Morrison syndrome, pancreatic cholera syndrome, or the WDHA syndrome (Watery Diarrhea, Hypokalemia (low potassium)and Achlorhydria).
Somatostatinomas, which make somatostatin. Somatostatin is a hormone produced by many tissues in the body, principally in the nervous and digestive systems. It regulates a wide variety of physiological functions and inhibits the secretion of other hormones, the activity of the gastrointestinal tract and the rapid reproduction of normal and tumour cells. Somatostatin may also act as a neurotransmitter in the nervous system.
Having certain syndromes can increase the risk of pancreatic NETs.
Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Multiple endocrine neoplasia type 1 (MEN1) syndrome is a risk factor for pancreatic NETs.
Signs and symptoms of pancreatic NETs
Signs or symptoms can be caused by the growth of the tumor and/or by hormones the tumor makes or by other conditions. Some tumors may not cause signs or symptoms. Check with your doctor if you have any of these problems.
Signs and symptoms of a non-functional pancreatic NET
A non-functional pancreatic NET may grow for a long time without causing signs or symptoms. It may grow large or spread to other parts of the body before it causes signs or symptoms, such as:
Diarrhea.
Indigestion.
A lump in the abdomen.
Pain in the abdomen or back.
Yellowing of the skin and whites of the eyes.
Signs and symptoms of a functional pancreatic NET
The signs and symptoms of a functional pancreatic NET depend on the type of hormone being made.
Too much gastrin may cause:
Stomach ulcers that keep coming back.
Pain in the abdomen, which may spread to the back. The pain may come and go and it may go away after taking an antacid.
The flow of stomach contents back into the esophagus (gastroesophageal reflux).
Diarrhea.
Too much insulin may cause:
Low blood sugar. This can cause blurred vision, headache, and feeling lightheaded, tired, weak, shaky, nervous, irritable, sweaty, confused, or hungry.
Fast heartbeat.
Too much glucagon may cause:
Skin rash on the face, stomach, or legs.
High blood sugar. This can cause headaches, frequent urination, dry skin and mouth, or feeling hungry, thirsty, tired, or weak.
Blood clots. Blood clots in the lung can cause shortness of breath, cough, or pain in the chest. Blood clots in the arm or leg can cause pain, swelling, warmth, or redness of the arm or leg.
Diarrhea.
Weight loss for no known reason.
Sore tongue or sores at the corners of the mouth.
Too much vasoactive intestinal peptide (VIP) may cause:
Very large amounts of watery diarrhea.
Dehydration. This can cause feeling thirsty, making less urine, dry skin and mouth, headaches, dizziness, or feeling tired.
Low potassium level in the blood. This can cause muscle weakness, aching, or cramps, numbness and tingling, frequent urination, fast heartbeat, and feeling confused or thirsty.
Cramps or pain in the abdomen.
Facial flushing.
Weight loss for no known reason.
Too much somatostatin may cause:
High blood sugar. This can cause headaches, frequent urination, dry skin and mouth, or feeling hungry, thirsty, tired, or weak.
Diarrhea.
Steatorrhea (very foul-smelling stool that floats).
Gallstones.
Yellowing of the skin and whites of the eyes.
Weight loss for no known reason.
Too much pancreatic polypeptide may cause:
belly pain.
an enlarged liver.
Testing hormones
Clearly the presenting symptoms will give doctors a clue to the oversecreting hormone (see list above). Excessive secretions or high levels of hormones and other substances can be measured in a number of ways. For example:
Well known tests for the most common types of NET include 5-Hydroxyindoleacetic Acid (5-HIAA) 24 hour urine test which is also measured by a blood draw. Note: -tumor markers can be measured simultaneously e.g. Chromogranin A (CgA) blood test and/or Pancreastatin as there can very often be a correlation between tumour mass and tumour secreting activity. CgA / Pancreastatin is a blood test which measures a protein found in many NET tumour cells. These marker tests are normally associated with tumour mass rather than tumour functionality.
By measuring the level of 5-HIAA in the urine or blood, healthcare providers can calculate the amount of serotonin in the body (5-HIAA is a by-product of serotonin). 5-HIAA test is the most common biochemical test for carcinoid syndrome or the degree of how ‘functional’ tumours are. If you’ve understood the text above, you can now see why there are dietary and drug restrictions in place prior to the test.
Pancreatic Hormone testing. There are other tests for other hormones and there is a common test which measured the main hormones seen in NETs. It may be called different things in different countries, but in UK, it’s known as a ‘Fasting Gut Hormone Profile‘.
Scratching the surface here so for a comprehensive list of marker tests for NETs, have aread here.
Treatment for Over-secreting Hormones
Of course, reducing tumour bulk through surgery and other treatment modalities, should technically reduce over-secretion (I suspect that doesn’t work for all). Other treatments may have the dual effect of reducing tumour burden and the effects of hormone oversecretions.
One of the key treatment breakthroughs for many NET cancer patients, is the use of ‘Somatostatin Analogues’ mainly branded as Octreotide (Sandostatin) or Lanreotide (Somatuline). People tend to associate these drugs with serotonin related secretions and tumours but they are in actual fact useful for many others including the pancreatic NETs listed above. Patients will normally be prescribed these drugs if they are displaying these symptoms but some people may be more avid to the drug than others and this may influence future use and dosages. This is another complex area but I’ll try to describe the importance here in basic terms. Somatostatin is a naturally occurring protein in the human body. It is an inhibitor of various hormones secreted from the endocrine system (some of which were listed above) and it binds with high affinity to the five somatostatin receptors found on secretory endocrine cells. NETs have membranes covered with receptors for somatostatin. However, the naturally occurring Somatostatin has limited clinical use due to its short half-life (<3 min). Therefore, specific somatostatin analogues (synthetic versions) have been developed that bind to tumours and block hormone release. Thus why Octreotide and Lanreotide do a good job of slowing down hormone production, including many of the gut hormones controlling emptying of the stomach and bowel. It also slows down the release of hormones made by the pancreas, including insulin and digestive enzymes – so there can be side effects including fat malabsorption.
The recent introduction of Telotristat Ethyl(XERMELO) is interesting as that inhibits a precursor to serotonin and reduces diarrhea in those patients where it is not adequately controlled by somatostatin analogues.
Other than the effects of curative or cytoreductive surgery, some NETs may have very specialist drugs for inhibiting the less common hormone types. This is not an exhaustive list.
Worth also noting that oversecreting hormones can contribute to a phenomenon known as Carcinoid Crisis – read more here. For catacholamine secreting tumors (Pheochromocytoma/Paraganglioma), this may be known as Intraoperative Hypertensive Crisis
Sorry about the long article – it’s complex and you should always consult your specialist about issues involving hormones, testing for hormones and treating any low or high scores.
One of the most discussed and debated Cancer issues is late diagnosis. Cyberspace is full of disturbing stories and many different cancers are involved. Some cancers are much more difficult to diagnose than others and this increases the need for more awareness and education campaigns.
Under-diagnosed or Under-reported?
Like many other Cancers, Neuroendocrine Cancer (known as Neuroendocrine Tumors or NETs) is one of a number of ‘difficult to diagnose’ conditions with some of its variants more difficult than others. It’s a less common form of cancer but with a fast rising incidence rate, possibly the fastest rising incidence rate of all cancers. In fact, its fast rising incidence rate has been a positive in some ways, contributing to awareness and the introduction of new treatments. In some respects, the incidence rate increase is due to people knowing more about it (…… particularly medical staff), diagnostic tools have improved; and critically …….. the correct ICD codes are being applied by physicians to enable accurate cancer incidence data (although this is probably still far from being 100% accurate in favour of NETs). In short, it’s been under-diagnosed and under-reported for decades.
Consequently, it’s not as ‘rare’ as we have been consistently told. For example, in UK, the latest figures from Public Health England indicate an annual incidence rate of 9/100,000 – to put that into perspective, one patient every 2 hours and above the rare threshold of 5/100,000. In USA, the latest SEER database figures indicate that the prevalence figure extrapolated to 2017 has accelerated beyond 200,000 (i.e. not rare). Eminent NET specialists in USA are saying it’s not rare and one centre is even suggesting there are 200,000 undiagnosed cases in that country, also adding that the autopsy rate of (so-called) ‘carcinoid‘ finds is four times higher than the documented diagnosis figure.
A review of autopsy cases in Australia found that 0.05% had undiagnosed Pheochromocytoma / Paraganglioma. I’m sure I could find more if I kept researching ……..spoiler alert – it isn’t a rare cancer. Even the results from the largest and latest data analysis are said to have understated the true figures.
Is patient and patient advocate organisation reported data accurate?
Statistics indicate that many patients are initially diagnosed with something else and it occasionally takes some time to be formally diagnosed with NETs. However, it’s wrong to suggest this happens to most NET patients. I’ve heard many stories from many people who have had a speedy diagnosis, even those where the cancer had advanced silently to a metastatic stage (I myself am in that category). Unfortunately these don’t tend to be mentioned a lot on social media and they don’t tend to be the people who complete questionnaires for NET patient surveys. Another oddity in survey data is that you can still see several specialists within a short period of time and have an excellent diagnostic experience – it’s the time that is important not the number of people you see in between. It’s also a myth to suggest that you only need to see one doctor to be diagnosed with any cancer. The fourth person I saw officially told me I had cancer but the gap was only 2 months (half of that was my own procrastination). This happens with many cancers, NETs is not special in this regard.
The problem with some of the NET Cancer survey statistics is that the reach is nearly always drawn from a limited audience and therefore the data can be skewed, particularly when the target collection is in the main from patient forums or groups where the ratio of problematic diagnoses is high. Offering these patients a ‘platform’ disguised as a survey is like ‘situating the appreciation’. On certain forums, it can be like pushing at an open door. This is why I currently have little faith in NET patient surveys. It’s a difficult area but we need a new model for capturing the whole spectrum of patient opinion. One positive statement from the recent SEER database study mentioned above…… the increase in incidence is partly due to earlier diagnosis. Clearly there’s more work to be done but it helps to dispel the myth that every NET patient was misdiagnosed for years. No medical corroboration is done, i.e. if a patient says they were misdiagosed, that doesn’t mean that’s an accurate statement from a medical perspective. I have it on good authority that some people who were diagnosed with IBS actually did have IBS, but it was masking the NET, the same is probably true for other symptoms/conditions. PCP/GP guidelines for diagnosing IBS clearly need updating.
Sure, some people will be misdiagnosed and that is no different to many difficult to diagnose conditions. But to suggest this is the most common outcome is way off beam. There are thousands of incidental diagnoses of NETs when checking for other issues – these don’t make good headlines though thus why we don’t hear much about it. Only a very small percentage of NET patients are on forums so it’s not a good measure of how many people got a quick diagnosis vs the opposite. Only a very small percentage of people are on the mailing lists for NET Advocate organisations, so in reaction to patient surveys put out by NET advocate organisations, who will also use patient forums to disseminate, neither are those a good measure of who got a quick diagnosis and the opposite. Ergo, NET patients surveys are always wrong.
So how did I fare with my own diagnosis? I’ve always thought myself luckier than many. I suspect the best I could have hoped for was diagnosis about 20 months prior to ‘D-Day in July 2010. My problem at the time was so vague that I could see myself there wasn’t much justification for expensive tests (i.e. scans). Moreover, by the time I got to see a specialist in 2008, the problem had settled and I was content. Even my second referral to specialists in May 2010 was random as I hadn’t initially intended to say I’d lost a ‘few pounds’ in weight whilst at a routine clinic. Fortunately, I had a pretty thorough and professional nurse who made me have a blood test ‘just to be sure’. My GP immediately referred me to a specialist. The referral specialist was pretty much on the ball. He was looking at a (then) 55-year-old fit and healthy looking male presenting with low haemoglobin – boom! CT scans, ultrasounds, blood tests, the works – except he could not pin down the exact cancer type until I mentioned facial flushing. Eureka, he knew and correctly predicted the results of the forthcoming liver biopsy. It must be said that even if he didn’t know or hadn’t heard of Neuroendocrine Cancer, the biopsy was key to finding out but the scan was the trigger. However, the damage was done and I now live with an incurable metastatic cancer. And I believe the damage was done back at my first issue in 2008. Despite this, I still feel lucky because I’m not dead. I do often wonder what would have happened had I not had that initial blood test. Check out this video of me explaining my diagnosis.
Luck plays a part, so does patient intransigence.
Sometimes with Cancer, you need a bit of luck and I never really think of my diagnosis as late, just unlucky to begin with (not helped by my own indifference to illness) and then geographically lucky as the diagnostic ball starting rolling. It had silently metastasized and perhaps that’s just how the cookie crumbles with silent illnesses in the absence of a whole population screening programme. I’m fairly certain future detection and screening will help find most cancers/conditions earlier as technology and science progresses – but we are not there yet.
I am contacted almost daily from someone who is experiencing flushing and diarrhea but they have not been diagnosed with NETs. Many are quite up to date on the condition but lack any clinical evidence of NETs. It’s not cancer is not really a diagnosis so I feel for these guys who just need a diagnosis of something. If you are reading this and think you may have NETs, read this articlewhere I offer you some advice.
You don’t actually need to be a NET specialist to trigger a diagnosis of a NET
I was helped by three other things:
The nurse who sent me for a ‘just to be sure‘ blood test was not a NET expert but she was doing her job in a thorough manner and triggered my eventual diagnosis.
The GP was not a NET expert but he analysed the blood results, considered my healthy outlook; and then used his instincts and training to send me to a specialist (i.e. he was suspicious of ‘something’).
The investigating specialist was aware of NET Cancer but although he knew I had cancer, he was not suspecting NETs until I said I was having occasional flushing (something I hadn’t mentioned to the nurse or the GP). But he was suspecting ‘something’ and in the end, he did detectsomething through scans and then confirmed it through a biopsy.
Should we expect every single doctor wherever they are, and whatever their experience, to be able to diagnose a NET at first visit?
‘If you don’t suspect it – you won’t detect it’ is a great NET cliché – but simply not practical to expect at primary care and IMHO almost impossible. There are 200 different cancer types and some have a bunch of sub-types. And at primary care level, you can add another 10,000 non-cancer conditions. It’s impossible for anyone to know everything about every single condition, let alone every single cancer BUT ……. a referral for something else can very often be a trigger for a diagnosis of Cancer. In fact, I suspect this is a very frequent scenario which often fails to make the patient survey data. A picture of your insides is key, regardless of what your physician is suspecting. If you can see it, you can normally detect it.
In short, you don’t really need to suspect NETs to detect it. Awareness is really important but it needs to be realistic to be taken seriously.
……if your Doctors don’t suspect something, they won’t detect anything!
Ronny Allan
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When planning to walk Hadrian’s Wall in the north of England in 2014, I carried out a number of risk assessments (as all good Project Managers do!). In true ‘Donald Rumsfeld style’, I considered all the ‘known unknowns’ and the ‘unknown unknowns’ 🙂 Anybody who doesn’t is either reckless or supremely confident (the latter can sometimes be the same as the former……).
As a Cancer patient, there were some issues I had to consider which might not have made the list for most walkers covering this sort of distance and this type of terrain. One of the issues I occasionally experience is stomach cramps, not that frequent but problematic and quite painful when they occur. If you’ve had abdominal surgery, you might be having to deal with issue. Many Neuroendocrine Tumour (NET) patients also suffer these cramps, often due to something called ‘Carcinoid Syndrome’ or simply as a side effect of treatment. This syndrome has symptoms including (amongst others):
Dizziness due to blood pressure that may go up or down – this can be triggered by having an anaesthetic.
For me, it was mainly the flushing – in fact this was instrumental in confirming my diagnosis. However, in hindsight some other issues might have been masked by routine/’run of the mill’ illnesses a couple of years prior to being diagnosed with Cancer.
I’m not particularly ‘syndromic’ at the moment due to my monthly treatment and debulking surgery. However, I do occasionally have to deal with ‘stomach cramps’ (a term which tends to mean the whole abdominal area). Fortunately, they are not that frequent. I might not have a stomach cramp for weeks and then suffer a couple of times in a single week. Consequently, after each attack, I study my activities, my medicine and my diet trying to figure out if there is anything I can avoid to prevent this happening. I now maintain a daily diary to assist. Footnote from 2018, I don’t seem to have them as regular as I used to.
I think most people will have experienced stomach cramps at some point in their lives and those who have will agree it’s not nice. I’ve had some really painful episodes in the last 2 years and as is usually the case, it’s helped by visiting the toilet/bathroom. Getting there can be painful as I sometimes find any movement exacerbates the pain with the worst attacks.
You can now see why I listed this as a key risk in walking the 84 miles of Hadrian’s Wall! You might be excused for thinking there shouldn’t be a problem with all that countryside available? Add the openness of the area; add the constant stream of walkers in both directions and the sum = not much privacy! As an ex-soldier and a male, I’m used to using ‘natural’ toilets or at best temporary structures. I ‘googled’ to check the availability of toilets along Hadrian’s Wall to find they are few and far between.
I do have a special card which I keep in my wallet but it’s not much use out in the hills! I’ve actually never had to use this card ‘in anger’ but I came very close to using it on Day 5 of this 6 day walk. I was suffering quite a lot of pain for a good mile or so on the outskirts of Carlisle which was semi-urban. I walked past a dozen houses but my pride would not let me use the card – silly boy! There was no way I was going to do a ‘Paula Radcliffe’. Things were coming to a head as we approached a bridge with a small copse over a tributary of the River Eden. At last some cover!
Chromogranin is an acidic protein released along with catecholamines from chromaffin cells and nerve terminals. This statement alone might explain why it is a good marker to use with NETs. Depending on the test kit being used, you may see test results for Chromogranin A (CgA) and Chromogranin B (CgB) – the inclusion of CgB tends to be confined to Europe. There is also mention of Chromogranin C (CgC) in places but I’ve never heard of this being used in conjunction with NETs.
