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.
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.
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.
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.
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.
Edit 10 Jan 2019: RadioMedix and Curium Announce FDA Fast Track Designation For 64Cu-Dotatate. Read more byclicking here.
Curium and RadioMedix Inc. announce an exclusive agreement to develop and commercialize 64Cu-Dotatate, an investigational positron emission tomography (PET) diagnostic agent for patients with Neuroendocrine Tumors (NETs). RadioMedix is currently engaged in Phase III clinical trials of the agent and expects to file a New Drug Application with the Food and Drug Administration in 2019. This partnership builds on the initial development work conducted by RadioMedix and will benefit from Curium’s regulatory, manufacturing, distribution, and commercial expertise. The radionuclide is not new, it’s been in use for some time, mainly in Denmark.
64Cu is a PET isotope that can be produced at a central location in quantities to meet the commercial needs of hospitals and imaging centers without the supply limitations of nuclear generator-based PET isotopes,” said Ebrahim Delpassand, MD, CEO of RadioMedix. “Once approved, 64Cu-Dotatate will be available to patients in medical centers with PET capability across the country. This will address the shortage or lack of availability of somatostatin analogue PET agents that we are currently experiencing in many parts of the U.S.”
Ga68 PET Shortages explained
This statement is in relation to the current shortage of Ga68 PET radionuclide. For those not aware, the Society of Nuclear Medicine and Molecular Imaging (SNMMI) has written a letter to the FDA about ongoing shortages of generators that produce gallium-68 (Ga-68), a radioisotope used regularly in medical imaging. The letter—available here.
The letter explains that Ga-68 is currently used to produce NETSPOT from Advanced Accelerator Applications (a Novartis company), which was approved in June 2016 to help treat neuroendocrine tumors (NETs) in adult and pediatric patients using PET. NETSPOT, however, is only approved using specific generators. And those generators are only approved for either 400 uses or one year, whichever comes first. This has led to shortages throughout the United States.
SNMMI notes some possible remedies for this shortage. For instance, “a temporary exemption to the 400-elution limit would have a major impact on NETSPOT capacity for patients,” according to the letter. In addition, using a wider variety of generators to produce NETSPOT or using cyclotron-produced gallium chloride are two other methods that could improve production in a relatively short amount of time. “Further discussion with the manufacturers is necessary,” the authors added.
Read more about Ga68 PET and its use in Neuroendocrine Cancer – click here. Worth also noting that RadioMedix is also involved in a number of NET related initiatives including:
1. Trials for a new type of PRRT called ‘Targeted Alpha-emitter Therapy (TAT) – I’ve written about this previously. Read my article here.
2. An exclusive distributor for the TM Isotopen Technologien München AG (ITM) PRRT product currently in trial. I wrote about this here.
How does 64Cu-Dotatate compare with Ga68 PET and Octreotide Scans?
To learn more about previous studies on 64Cu-Dotatate, here’s 2 articles published in the Journal of Nuclear Medicine which are a head to head comparison of 64Cu-Dotatate with Ga68 Dotatoc and with 111 Indium Octreotide (Octreoscan).
Conclusion: 64Cu-DOTATATE has advantages over 68Ga-DOTATOC in the detection of lesions in NET patients. Although patient-based sensitivity was the same for 64Cu-DOTATATE and 68Ga-DOTATOC in this cohort, significantly more lesions were detected by 64Cu-DOTATATE. Furthermore, the shelf life of more than 24 h and the scanning window of at least 3 h make 64Cu-DOTATATE favorable and easy to use in the clinical setting.
Conclusion: With these results, we demonstrate that 64Cu-DOTATATE is far superior to 111In-DTPA-OC in diagnostic performance in NET patients. Therefore, we do not hesitate to recommend implementation of 64Cu-DOTATATE as a replacement for 111In-DTPA-OC.
The shortage of Ga68 PET radionuclide caused by limitations of the generators in use is unfortunate. Reading the SNMMI letter, I think progress can be made downstream. However, the introduction of a new scanning agent could be useful as long as the trials prove its safety and efficiently and is comparable to current tools. There is no news of any plans to extend this potential new radionuclide outside the US but I suspect that would change following an FDA approval.
When I was offered my very first Ga68 PET/CT at a 6 monthly surveillance meeting in May 2018, I was both excited and apprehensive. Let me explain below why I had a mix of emotions.
I was diagnosed in 2010 with metastatic NETs clearly showing on CT scan, the staging was confirmed via an Octreotide Scan which in addition pointed out two further deposits above the diaphragm (one of which has since been dealt with). In addition to routine surveillance via CT scan, I had two further Octreotide Scans in 2011 and 2013 following 3 surgeries, these confirmed the surveillance CT findings of remnant disease. The third scan in 2013 highlighted an additional lesion in my thyroid (still under a watch and wait regime, biopsy inconclusive but read on….).
To date, my 6 monthly CT scans seem to have been adequate surveillancecover and all my tumour and hormone markers remain normal. I’m reasonably fit and well for a 62-year-old.
Then I ventured into the unknown
I wrote a comprehensive post about the Ga68 PET entitled “…. Into the unknown” – so named because that is how I felt at the time. It’s well-known that the Ga68 is a far superior nuclear scan to the elderly Octreotide type, showing much greater detail with the advantage of providing better predictions of PRRT success if required downstream. It has been a game changer for many and if you look below and inside my article, you will see statistics indicating just how it can ‘change the game’ in somatostatin receptor positive Neuroendocrine Cancer diagnostics and treatment.
The excitement of the Ga68 PET
I was going to get the latest ‘tech’ and thought it could be useful confirmation of what I already knew. I also felt lucky to get one, they are limited in UK and there has to be a clinical need to get access. I was excited because it might just rubber stamp the stability I’ve enjoyed for the past 5 or so years since my last surgery in 2012.
The apprehension of the Ga68 PET
I also felt apprehensive because of the ‘unknown’ factor with cancer, i.e. what is there lurking in my body that no-one knows about, and which might never harm me but this scan will light it up demanding attention. I was also apprehensive in case this more detailed scan found something potentially dangerous. As we know, NETs are mostly slow-growing but always sneaky. Of course, any new tumours found may not actually be new, they were just not seen until the Ga68 PET was able to uncover them. How annoying!
Was Ga68 PET a game changer for me?
Yes, I believe so. I’m now in the ‘bone met club’ and although that single metastasis has probably been there for some time, it’s not a ‘label‘ I was keen to add to my portfolio. It’s brought more light onto my thyroid issue and continues to indicate some issues above the diaphragm including what looks like a new issue around my left pectoral and lights up an existing issue in the clavicle lymph nodes (first pointed out via Octreotide scan in 2010).
It also formed part of an investigation into progression of my retroperitoneal fibrosis (initially diagnosed 2010 but potential growth spotted on recent surveillance CT). I may now need surgery to prevent kidney/bladder issues and/or radiation therapy to tackle the root cause (the latter is ruled out for now – Nov 2018)
It would appear I’m no longer a boring stable patient
The Ga68 PET Scan confirmed:
Bone Metastases. Report indicates “intense focal uptake“. It always amazes me that people can be thankful for having an extra tumour. I’m thankful I only have a single bone metastasis (right rib number 11). I had read so many stories of those who got their first Ga68 PET and came back with multiple bone metastases. I’ll accept one and add to my NET CV. I have no symptoms of this bone metastasis and it will now be monitored going forward. I’m annoyed that I don’t know how long it’s been there though!
Confirmation and better understanding of the following:
Thyroid lesion There is some uptake showing. A 2014 Biopsy of this lesion was inconclusive and actual 2018 Ga68 PET report infers physiological uptake. I’m already diagnosed hypothyroidism, possibly connected. (Edit – on ultrasound in Jan 2019, looks slightly smaller than previous check).
Left Supraclavicular Fossa (SCF) Nodes lighting up “intense uptake“. I’ve had an exploratory biopsy of the SCF nodes, 5 nodes removed negative. Nothing is ‘pathologically enlarged’ in this area. Monitored every 6 months on CT, annually on ultrasound. I had 9 nodes removed from the left axillary in 2012, 5 tested positive for NETs and this area did not light up. This whole area on the left above the diaphragm continues to be controversial. My surgeon once said I had an unusual disposition of tumours. (Edit: Nothing sinister or worryingly enlarged showing on Jan 2019 ultrasound – measuring 6mm).
Report also highlights left subpectoral lymph nodes which is new. The subpectoral area is very interesting as from my quick research, they are closer to the left axillary (armpit) nodes than they are to the SCF nodesI’m hoping to get an ultrasound of these in January at my annual thyroid clinic (Edit: nothing sinister showing on ultrasound in Jan 2019).
My known liver metastases lit up (remnant from liver surgery 2011) – not marked as intense though. The figure of 3 seems to figure highly throughout my surveillance scans although the PET report said “multiple” and predominately right-sided which fits.
Retroperitoneal area. This has been a problem area for me since diagnosis and some lymph nodes are identified (intense word not used). This area has been highlighted on my 3 octreotide scans to date and was first highlighted in my diagnosis trigger scan due to fibrosis (desmoplasia) which was surrounding the aorta and inferior venous cava, some pretty important blood vessels. I wrote an article on the issue very recently – you can read by clicking here. So this scan confirms there are potentially active lymph nodes in this area, perhaps contributing to further growth of the fibrosis threatening important vessels – read below.
I have learned so much about desmoplasia in the last week that I now fully understand why I had to have radical surgery to try to remove as much of the fibrosis as possible from the aortic area. You can read more about this in my article. Desmoplasia via fibrosis is still very much of an unknown and mystery condition in NETs.
I now know that my fibrosis is classed as clinically significant and according to the Uppsala study of over 800 patients inside my article, I’m in 5% of those affected in this way (2% if you calculate it using just the retroperitoneal area).
It appears this problem has come back with new fibrosis or growth of existing fibrosis threatening to impinge on blood vessels related to the kidneys and also my ureters (kidney to bladder urine flow).
I didn’t expect this particular problem – it was a bit of a shock. This is not a straightforward surgery. My hormone markers have been normal for 7 years and this just emphasises the importance of scans in surveillance.
Conventional Imaging is still important though
There’s still quite a lot of hype surrounding the Ga68 PET scan and I get this. However, it does not replace conventional imaging (CI) such as CT and MRI scans which still have their place in routine surveillance and also in diagnostics where they are normally at least the trigger for ‘something is wrong’. For the vast majority, a CT/MRI scan will find tumours and be able to measure reductions and progress in regular surveillance regimes. There are actually recommended usages for the Ga68 PET scan here. For example, it is not recommended for routine surveillance in place of CI.
In fact, the retroperitoneal fibrosishas appeared on every CT scan since diagnosis but the changes were highlighted on my most recent standalone CT and it triggered the Ga68 PET (although my new Oncologist did say I was due a revised nuclear scan). It’s not a ‘functional’ issue (although it is caused by functional tumours). In fact the fibrosis is not mentioned on the Ga68 PET because it is not lighting up – but the lymph nodes surrounding it are mentioned and they are under suspicious as being active.
Read a summary of all conventional scans and nuclear scans by clicking here.
I’ve since has meetings with my Oncologist and Surgeon and a treatment plan is underway. My surgeon explained it all in his wonderfully articulate and brilliant surgical mind. Fortunately it’s not really urgent but pre-emptive treatment will be required at some point as the consequences of kidney/bladder function are quite severe. It’s also possible that PRRT will be considered as a way to treat the tumours responsible for new and renewed growth of the fibrosis. I will keep my blog updated as things progress.
My game has changed, that’s for sure. I’m now entering a new phase and I’m waiting on details of my revised surveillance regime. However, at least my medical team and I now know what WE are dealing with and the risks vs benefits are currently being assessed. I’m heavily involved in that.
Cancer is a growth industry …literally! More people are being diagnosed than ever before. Fortunately, more people are surviving than ever before. This is against a backdrop of better awareness, better screening in the big population cancers, and to a certain extent better diagnostic tools, all of which is leading to earlier diagnosis.
So how does this affect Neuroendocrine Cancer?
According to the latest SEER database figures for Neuroendocrine Cancer, one reason for the 7 fold increase in incidence rates since the 1970s is all of those things above including better diagnostics. This has led to a revised set of epidemiological information in many countries that have made the effort to accurately update their cancer registries and there are consistent reports of incidence rates way beyond the recognised rare thresholds. Another piece of good news is that the increase in NET incidence is also due to earlier diagnosis. To sum that up – NETs is also a growth industry.
Combined with more awareness and education (including the important pathologists), more NETs than ever are being found, and many found earlier. However, it’s not party time yet because there remains far too many misdiagnoses due to the low population of the disease and the difficulty in diagnosing it. I want to focus on scanning (thus the title of the article). Whilst there are really important factors involved in a diagnosis, such as tumor and hormone markers, and biopsies (tissue is the issue), a scan is very frequently what triggers many deeper investigations to unearth a NET, i.e. if you can see it, you can normally detect it (whatever the ‘it’ is). And I include the widespread availability and increasing advances in endoscopy/ultrasounds/cameras which have also been instrumental in picking up many Gastrointestinal NETs.
The Gallium 68 PET Scan
There’s a lot of excitement about the Gallium 68 PET Scan since it was approved by the US FDA. It’s not new though and has been in use in several countries for some time. It’s a ‘nuclear scan’ and can often form part of what is known as a ‘Theranostic Pair’ (i.e. in conjunction with a therapy – read more here).
What does it do?
It comprises two main components – a PET scanning machine, and the use of a diagnostic imaging agent which is injected into the person undergoing the scan. Most machines have an inbuilt CT which forms part of the scan. The agent is a somatostatin analogue labeled radionuclide (Gallium 68) and basically the PET will then be used to see where the peptide/radionuclide mix ‘loiters’ (i.e. where there are concentrations of somatostatin receptors (SSTR) normally indicating ‘focal intense abnormality‘ of the type that is regularly found with NETs.
Imaging Agents. There are different agent variants, namely, DOTATATE, DOTATOC and DOTANOC. In USA, you may sometimes see this referred as NETSPOT which is more of a commercial label for the agent (NETSPOT is a DOTATATE). Ga68 PET or SSTR PET are common descriptors for the entire process regardless of the compound. Clearly the scan works best for those with ‘somatostatin receptor positive’ tumours.
These newer agents have several benefits over the elderly In111-pentetreotide (Octreotide scan), including improved detection sensitivity, improved patient convenience due to the 2-3 hour length of the study (compared to 2 or 3 days with Octreoscan), decreased radiation dose, decreased biliary excretion due to earlier imaging after radiotracer administration, and the ability to quantify uptake. The quantification of the uptake can help decide whether a patient is suitable for radionuclide therapy such as PRRT. Eventually, all Octreotide scans should be replaced with SSTR PET but it will take some time (and money).
Octreoscan vs Ga68 PET
To confirm the advantages of SSTR PET over Octreotide scans, a study comprising 1,561 patients reported a change in tumour management occurred in over a third of patients after SSTR PET/CT even when performed after an Octreotide scan. Worth pointing out that SSTR PET is replacing the ageing Octreotide scan and not conventional imaging (CI). You can see the recommended scenarios for use of SSTR PET in this article published by the Journal of Nuclear Medicine. The slide below is interesting, although it was a small study. However, you can see the treatment changes as a result of a Ga68 PET are quite striking.
Any pitfalls with Ga68 PET Scan?
When you look at the study data above, it looks like an excellent addition to the diagnostic and surveillance toolkit for NETs. However, one of the challenges with modern scanning equipment and techniques is the ability to correctly interpret the results – in my opinion, this is almost as important as the efficiency of the machines and radionuclides. This requirement has been acknowledged in many articles and I particularly like this technical paper from a very experienced nuclear medicine physician Professor Michael Hofman from the Centre for Cancer Imaging at the Peter MacCallum Cancer in Melbourne. I had a chat with Professor Hofman who added that this is a very sensitive scan, so often picks up “new” disease, which isn’t really new, just never identifiable on standard imaging. However, there’s an excellent section on pitfalls in interpretation and I’m quoting an abstract below.
“Although GaTate PET/CT is a highly sensitive and specific technique for NETs, the attending physician or radiologist must be aware of various physiologic and other pathologic processes in which cellular expression of SSTR can result in interpretative error. Most of these processes demonstrate low-intensity and/or nonfocal uptake, in contrast with the focal intense abnormality encountered in NETs. Causes of interpretative pitfalls include prominent pancreatic uncinate process activity, inflammation, osteoblastic activity (degenerative bone disease, fracture, vertebral hemangioma), splenunculi or splenosis, and benign meningioma.”
“The highest-intensity physiologic uptake of GaTate is seen in the spleen, followed by the adrenal glands, kidneys, and pituitary gland”
It follows that failure to interpret nuclear scans alongside the patient’s clinical history can sometimes result in two big issues for patients:
1. Unnecessary worry when ‘something’ shows up which is actually a false positive.
2. Something which leads to irreversible treatment when it is was not required.
Just imagine something which is 40 times better than current PET scan technology? That’s what the scientists are working on now. Here’s an example called “EXPLORER“. You can update yourself here. The issue of interpretation will be even more difficult when the new generation of scans appear. There’s an excellent article from Cancer Research UK talking about the modern phenomenon called ‘overdiagnosis’ – readhere
Lanreotide and Octreotide and timing the scan?
From the same technical document referred above, here’s an extract (updated to include Lanreotide). “Uptake at physiologic and pathologic sites may change in patients who undergo concomitant short- or long-acting somatostatin analog therapy, which competes with the radiotracer for bioavailability. We generally discontinue short-acting octreotide for 12–24 hours and perform imaging in the week before the next dose of long-acting Octreotide/*Lanreotide, which is typically administered monthly“. More evidence behind the reason behind this issue can be found here. *added by the author for completeness.
Having my first Ga68 PET Scan after 8 years of living with NETs?
When I was offered my very first Ga68 PET/CT at my recent 6 monthly surveillance meeting, I was both excited and apprehensive. I was diagnosed in 2010 and my staging was confirmed via an Octreotide Scan pointing out two further deposits (one of which has since been dealt with). I’ve had two further Octreotide Scans in 2011 and 2013 following 3 surgeries. The third scan in 2013 highlighted my thyroid lesion – still under a watch and wait regime. So far, my 6 monthly CT scans seemed to be adequate surveillance cover and my markers remain normal.
I’m apprehensive because of the ‘unknown’ factor with cancer – what is there lurking in my body that no-one knows about and which might never harm me.
I’m excited because it might just confirm that there is nothing new to worry about.
However, I’m both excited (morbidly) and apprehensive because the scan might find something potentially dangerous. As we know, NETs are mostly slow growing but always sneaky. That said, at least I will know and my medical team will know and be able to assess the risk and decide on a course of action.
Doing the Scan
On 5th June 2018, I attended a very experienced Ga68 PET establishment called Guys Cancer Centre in London. I arrived and was immediately taken under the wing of the nuclear medicine guys who asked me fairly in depth questions about my clinical background. They then inserted a cannula ready for the injection of the radiolabelled tracer. I was then installed in the ‘hot room’ where they injected the radionuclide tracer through the cannula and then I had to remain in the hot room for 1 hour to let the tracer circulate. After 1 hour, I was taken to the PET scanner and it took around 30-35 minutes. Following that I was allowed to leave for home. It was an extremely easy experience and a significant improvement on doing the 3 day Octreotide scan.
I recently wrote a blog called Neuroendocrine Cancer – Exciting Times Ahead! I wrote that on a day I was feeling particularly positive and at the time, I wanted to share that positivity with you. I genuinely believe there’s a lot of great things happening. Don’t get me wrong, there’s a lot still to be done, particularly in the area of diagnosis and quality of life after being diagnosed. However, this is a really great message from a well-known NET expert.
In an interview with OncLive, Jonathan R. Strosberg, MD, associate professor at the H. Lee Moffitt Cancer Center in Florida, discussed his presentation on NETs at a recent 2016 Symposium, and shed light on the progress that has been made in this treatment landscape.
OncLive: Please highlight some of the main points from your presentation.
Strosberg: The question I was asked to address is whether we’re making progress in the management of NETs, and I think the answer is unequivocally yes. Prior to 2009, there were no positive published phase III trials.
Since then, there have been 8 trials, 7 of which have reached their primary endpoints. So it’s been a decade of significant improvement. And even though none of these studies were powered to look at overall survival as an endpoint, we’re certainly seeing evidence of improvement in outcomes.
OncLive: What are some of the pivotal agents that you feel have impacted the paradigm in the past several years?
Strosberg: The first group is the somatostatin analogs. We use them to control hormonal symptoms like carcinoid syndrome, but with the CLARINET study, we now know that they substantially inhibit tumor growth.
The next significant drug we use in this disease is everolimus (Afinitor), an oral mTOR inhibitor, which is now approved in several indications based on positive phase III studies. The first was in pancreatic NETs and subsequently, based on the RADIANT-4 trial, it was also approved in lung and gastrointestinal NETs. So that was an important advance.
The next important category of treatment is radiolabeled somatostatin analogs, otherwise known as peptide receptor radiotherapy. The one that’s been tested in a phase III trial is lutetium dotatate, also known as Lutathera. It was tested in patients with progressive midgut NETs and showed a very substantial 79% improvement in progression-free survival, and a very strong trend toward improvement in overall survival, which we hope will be confirmed upon final analysis.
OncLive: Are we getting better at diagnosing and managing the treatment of NETs?
Strosberg: Certainly. I think pathologists are better at making the diagnosis of a NET, rather than just calling a cancer pancreatic cancer or colorectal cancer. They’re recognizing the neuroendocrine aspects of the disease, and doing the appropriate immunohistochemical staining.
We also have better diagnostic tools. We used to rely primarily on octreoscan, and in many cases we still do, but there is a new diagnostic scan called Gallium-68 dotatate scan, also known as Netspot, which has substantially improved sensitivity and specificity. It’s not yet widely available, but it is FDA approved and hopefully will enable better diagnosis as well as staging in the coming years.
And, with the increase in number of phase III studies, we’re developing evidence-based guidelines, which will hopefully lead to more standardization, although knowing how to sequence these new drugs is still quite challenging.
OncLive: With sequencing, what are the main questions that we’re still trying to answer?
Strosberg: If we take, for example, NETs of the midgut, beyond first-line somatostatin analogs, physicians and patients often face decisions regarding where to proceed next, and for some patients with liver-dominant disease, liver-directed therapies are still an option.
For others, everolimus is a systemic option, and then hopefully lutetium dotatate will be an option based on approval of the drug, which is currently pending. Knowing how to choose among those 3 options is going to be a challenge, and I think there will be debates. Hopefully, clinical trials that compare one agent to another can help doctors make that choice. It’s even more complicated for pancreatic NETs. Beyond somatostatin analogs, we have about 5 choices—we have everolimus, sunitinib (Sutent), cytotoxic chemotherapy, liver-directed therapy, and peptide receptor radiotherapy. It’s even more challenging in that area.
OncLive: Are there any other ongoing clinical trials with some of these agents that you’re particularly excited about?
Strosberg: There’s a trial that is slated to take place in Europe which will compare lutetium dotatate with everolimus in advanced pancreatic NETs, and I think that’s going to be a very important trial that will help us get some information on both sequencing of these drugs, as well as the efficacy of Lutathera in the pancreatic NET population, based on well-run prospective clinical trials. I’m particularly looking forward to that trial.
OncLive: Looking to the future, what are some of the immediate challenges you hope to tackle with NETs?
Strosberg: One area of particular need is poorly differentiated neuroendocrine carcinomas. That’s a field that’s traditionally been understudied. There have been very few prospective clinical trials looking at this particular population, and we’re hoping that will change in the near future. There are a number of trials taking place looking at immunotherapy drugs. If these agents work anywhere in the neuroendocrine sphere, they are more likely to work in poorly differentiated or high-grade tumors, in my opinion, given the mutational profile of these cancers. So that’s something I’m particularly looking forward to being able to offer these patients something other than the cisplatin/etoposide combination that goes back decades, and is of short-lasting duration.
See more at: http://www.onclive.com/publications/oncology-live/2016/vol-17-no-24/expert-discusses-recent-progress-in-net-management#sthash.ypkilX2A.dpuf
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I spend a lot of time talking about the most common forms of Neuroendocrine Tumours (NETs), but what about the less well-known types? As part of my commitment to all types of NETs, I’d like to shine a light on two less common tumour types known as Pheochromocytomas and Paragangliomas – incidence rate approximately 8 per million per year. They are normally grouped together and the definitions below will confirm why. If you think it’s difficult to diagnose a mainstream NET, this particular sub-type is a real challenge.
So, let’s get definitions out of the way:
Pheochromocytomas (Pheo for short)
Pheochromocytomas are tumours of the adrenal gland that produce excess adrenaline. They arise from the central portion of the adrenal gland, which is called the adrenal medulla (the remainder of the gland is known as the cortex which performs a different role and can be associated with a different tumour type). The adrenal medulla is responsible for the normal production of adrenaline, which our body requires to help maintain blood pressure and to help cope with stressful situations. The adrenal glands are situated on top of the kidneys (i.e. there are two). Adrenaline is also called ‘epinephrine’ which is curiously one of the 5 E’s of Carcinoid Syndrome.
Paragangliomas (Para for short)
Paragangliomas are tumours that grow in cells of the ‘peripheral’ nervous system (i.e. the nerves outside the brain and spinal cord). Like Pheochromocytomas, they can release excess adrenaline. There can be confusion between the two types of tumour as Paragangliomas are often described as extra-adrenal Pheochromocytomas (i.e. a Pheo external to the adrenal gland).
Going forward, I’m going to talk about both using the single term of ‘Pheochromocytoma’ in the context of an adrenaline secreting tumour but may refer to Paraganglioma where there might be a difference other than anatomical location.
Pheochromocytomas are often referred to as the “ten percent tumour” because as a rule of thumb they do many things about ten percent of the time. However, these figures are slowly changing, so this label is gradually becoming less apparent. The following is a fairly exhaustive list of these characteristics:
A few facts about Pheochromocytomas
As much as 1 in 3 are Malignant but most have undetermined biologic potential. A recent document issued by the World Health Organisation (WHO) stated that “Paragangliomas should not be termed benign”.
Around 10% of Pheochromocytomas are Bilateral (i.e. found in both adrenal glands: 90% arise in just one of the two adrenal glands)
Around 10% are Extra-Adrenal (found within nervous tissue outside of the adrenal glands … i.e. 10% are Paragangliomas)
Around 10% are found in Children (i.e. 90% in adults)
Up to 30% are Familial potentially rising to 50% for metastatic cases and Multiple Endocrine Neoplasia (MEN) involvement.
The recurrence rate is around 16%, i.e. about 1 in 6 patients have a tumor that comes back after surgery. Tumors that come back also have the potential to be malignant. If you have pheo or para and have surgery to remove it, be sure to continue to check in with your doctor to monitor for any returning tumors.
Present with a stroke (10% of these tumours are found after the patient has a stroke)
The classic symptoms of Pheochromocytomas are those attributable to excess adrenaline production. Often these patients will have recurring episodes of sweating, headache, and a feeling of high anxiety.
Headaches (severe)(one of the classic triad, see below)
Excess sweating (generalized)(one of the classic triad, see below)
Racing heart (tachycardia and palpitations)(one of the classic triad, see below)
Anxiety and nervousness
Nervous shaking (tremors)
Pain in the lower chest or upper abdomen
Nausea (with or without vomiting)
According to the ISI Book on NETs (Woltering, Vinik, O’Dorisio, et al), Pheochromocytomas present with a classic triad of symptoms and signs: headache, palpitations and sweating. This symptom complex has a high specificity and sensitivity (>90%) for the diagnosis of Pheochromocytomas. The figure is much lower in individual symptom presentations (palpitations 50%, sweating 30%, headaches 20%). In addition to correctly diagnosing from these symptoms, Pheochromocytomas may also be found incidentally during a surgical procedure even after a diagnosis of an ‘adrenal incidentaloma’
Markers. Like serotoninsecreting tumours, adrenal secreting tumours convert the offending hormone into something which comes out in urine. In fact, this is measured 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. This test is designed to measure production of the different types of adrenaline compounds that the adrenal glands make. Since the body gets rid of these hormones in the urine, we simply collect a patient’s urine for 24 hours to determine if they are over-produced. Like 5HIAA, there is also a plasma (blood draw) version of the test. According to the ISI Book on NETs, there is also an additional test called ‘Vanillylmandelic Acid (VMA). This reference also indicates the most sensitive test is plasma free total metanephrines. Also read more here.
Genetics. The familial connection with Pheo/Para is complex. Up to 13 genes have been identified including NF1, RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2(SDH5), TMEM127, MAXm EPAS1, FH, MDH2. Read more here (very recent update)
Scans. Other than the usual range of scanners, ultrasound, CT/MRI, all of which may be used to find evidence of something, the other scan of note is called MIBG. This is a nuclear scan similar in concept to the Octreotide Scan given to many NET patients (in fact some Pheo patients my get an Octreotide scan if they have somatostatin receptors). The key differences with MIBG is the liquid radioactive material mix which is called iodine-123-meta-iodobenzylguanidine or 131-meta-iodobenzylguanidine (this is where the acronym MIBG originates). Together with the markers above, the results will drive treatment. Depending on availability, the latest PET scans may also be available potentially offering greater detail and accuracy i.e. 18F-FDOPA, 18F-FDG and Ga68. Read more on scans here.
This statement and diagram was provided by Dr Mark Lewis who is an Oncologist and MEN patient. “The algorithm for working up a hyperadrenergic state is attached (and was developed by Dr. Young at Mayo Clinic). It outlines the most reliable testing for a pheo or Paraganglioma”
Additional Factors and Considerations
This is an awareness post so I’m not covering treatment options in any detail except to say that surgery if often used to remove as much tumour as possible. Somatostatin Analogues may also be used in certain scenarios in addition to other hormone suppression or symptom controlling drugs. That said, Pheo/Para patients may be interested in a PRRT trial exclusively for Pheo/Para – read more here (see section entitled – “What about Pheo/Para”)
The adrenal cortex mentioned above is actually the site for Adrenocortical Carcinoma (ACC) – this is a totally different cancer.
Pheochromocytomas are probably difficult to diagnose (you only have to look at the symptoms to see that). The differential diagnoses (i.e. potential misdiagnoses) are: hyperthyroidism, hypoglycaemia, mastocytosis, carcinoid syndrome, menopause, heart failure, arrhythmias, migraine, epilepsy, porphyria lead poisoning, panic attacks and fictitious disorders such as the use of cocaine and benzedrine.
Many Pheochromocytoma patients will also be affected by Multiple Endocrine Neoplasia (MEN), in particular MEN2 (there are some wide-ranging percentage figures online for this aspect). There can also be an association with Von Hippel-Lindau (VHL) syndrome and lesscommonly with Neurofibromatosis type 1.
Given the nature of the hormones involved with Pheochromocytomas, there is a risk of intraoperative hypertensive crises. This is similar in some ways to Carcinoid Crisis but needs careful consideration by those involved in any invasive procedure.
Newly Approved Drug – AZEDRA
On 30th July 2018, Progenics Pharmaceuticals Announces FDA Approval for AZEDRA® (iobenguane I 131) to Treat Unresectable, Locally Advanced or Metastatic Pheochromocytoma or Paraganglioma – read more by clicking here.
Pheochromocytomas are very complex involving many of the challenges found in the more abundant and common types of NETs. To underscore this statement, please see this case studywhere one patient was misdiagnosed with psychiatric problems for 13 years before being correctly diagnosed with a metastatic Pheochromocytoma.
This is an extremely basic overview offered as an awareness message about the lesser known types of NETs. I refer you to my disclaimer. If you wish to learn more about Pheochromocytomas and Paragangliomas, check out the links below.
Scanning is a key diagnostic support and surveillance tool for any cancer. Even though you have elevated bloods or urine (….or not), a picture of your insides is really like a thousand words…. and each picture has a story behind it. Scanning can be a game changer in the hunt for tumours and although scans do not normally confirm the cancer type and grade, they certainly help with that piece of detective work and are key in the staging of the cancer.
When I read stories of people in a difficult diagnosis, I always find myself saying ‘a scan might resolve this’ and I always suggest people should try to get one. Even in the case of a story about late diagnosis or a misdiagnosis, I find myself thinking ‘if only they had done a scan earlier’. Despite what you read on NET forums, a CT scan will be able to find some evidence of tumour activity in 90-95% of cases. However, some are cunningly small or hiding and it can be like trying to find a needle in a haystack.
However, scans are not an exact science…..not yet! Apart from human error, sometimes tumours are too small to see and/or there are issues with ‘pickup’ (i.e. with NETs, nuclear scans need efficient somatostatin receptors). The differences between scan types are more quality (sensitivity) related as new technologies are introduced.
As for my own experience, I was very lucky. I managed to get a referral to a specialist early on in my diagnosis phase. He looked at the referral notes and said “what are you doing this afternoon“. I replied “whatever you want me to do“. He didn’t know I had cancer but his instincts led him to believe he needed to see inside my body, he wanted to scan me. The scan results were pretty clear – I had a metastatic Cancer and further checks were now needed to ascertain exactly what it was. So I took my seat on the roller coaster. Medicine is not an exact science (not yet anyway) but here’s something I believe is a very common occurrence in all cancers – If your doctors don’t suspect something, they won’t detect anything.
There’s frequent discussion about the best types of scans for different types of NETs and which is best for different parts of the anatomy. There’s also different views on the subject (including in the medical community), However, a few well known facts can be gleaned from authoritative NET sources:
Computed Topography (CT)
CT scans are often the initial imaging study for a patient presenting with signs or symptoms suggestive of many cancers including NET. These studies are most useful for disease staging and surgical planning as they provide excellent anatomic detail of the tumors themselves and surrounding structures. Primary NETs (GI and lung NETs) and their metastases are generally hyperenhancing with IV contrast and are best seen in the arterial phase of a triple phase CT scan.
In primary NETs, the average sensitivity of a CT scan is 73%. CT scans have even better sensitivity in detecting NET metastases, as they demonstrate 80% sensitivity for liver metastases (but see MRI below) and 75% sensitivity for other metastases (non-liver). This modality is also useful when the primary tumor site is unknown. In one single-institution retrospective study, it was the most common study ordered to look for an unknown primary tumor site and was able to uncover the primary in 95% of cases.
Magnetic resonance imaging (MRI)
MRI is the best conventional study to detail liver metastases in NETs. It is not as useful as CT for the detection of primary small bowel lesions or their associated lymphadenopathy, but is good for the detection of primary pancreatic NETs. A study comparing MRI, CT and standard somatostatin receptor-based imaging (OctreoScan) reported 95.2% sensitivity for MRI, 78.5% sensitivity for CT and 49.3% sensitivity for the OctreoScan in detecting hepatic metastases. MRI also detected significantly more liver lesions than the other two modalities.
You may see something called Magnetic Resonance Cholangiopancreatography (MRCP). Magnetic resonance cholangiopancreatography (MRCP) is a special type of magnetic resonance imaging (MRI) exam that produces detailed images of the hepatobiliary and pancreatic systems, including the liver, gallbladder, bile ducts, pancreas and pancreatic duct.
The primary role of conventional ultrasound in neuroendocrine disease is detection of liver metastases and estimation of total liver tumor burden. This technique has the advantages of near-universal availability, intraoperative utility, minimal expense and lack of radiation. Most examinations are performed without contrast, which limits their sensitivity (compared with CT and MRI). I know in my own situation, US was used as a quick check following identification of multiple liver metastasis during a CT scan. I’ve also had US used to monitor distant lymph nodes in the neck area but always in conjunction with the most recent CT scan output.
Endoscopic Ultrasound (EUS)
With increased access to endoscopy, NETs in the stomach, duodenum, and rectum are increasingly incidentally detected on upper endoscopy and colonoscopy. Patients are frequently asymptomatic without any symptoms referable to the a NET (i.e. non-functional). EUS has also been used to survey patients at increased risk of developing pancreatic NETs. For example, patients with multiple endocrine neoplasia (MEN). They are also frequently used in conjunction with biopsies using fine needle aspiration (FNA) guided by EUS.
18-Fluoro-Deoxy-Glucose PET (FDG PET) is used to detect malignancy for a variety of tumor types. Unfortunately, its utility has not been borne out in NETs, as the majority of NETs tend to be relatively metabolically inactive and fail to take up the tracer well. However, high-grade NETs are more likely to demonstrate avid uptake of 18FDG, giving these scans utility in identifying tumors likely to display more aggressive behavior.
The use of Fluoro-18-L-Dihydroxyphenylalanine (18F-FDOPA) in PET was developed in the 80’s for the visualisation of the dopaminergic system in patients with degenerative disorders, such as Parkinson’s Disease and related disorders. The ﬁrst publication on the use of 18F-FDOPA PET for brain imaging was in 1983, which was followed by many others on the use of 18F-FDOPA PET for the diagnosis of Parkinson’s disease. Years later, in 1999 the ﬁrst publication on the use of 18F-FDOPA PET for imaging of neuroendocrine tumour appeared. The value of 18F-FDOPA PET has now been proven for the diagnosis and staging of many neuroendocrine tumours, brain tumours and congenital hyperinsulinaemia of infants.
18F-FDOPA is accurate for studying well differentiated tumours. However the difficult and expensive synthesis have limited its clinical employment. It currently can be successfully used for imaging tumours with variable to low expression of somatostatin receptors (SSTR) such as Medullary Thyroid Carcinoma, Neuroblastoma, Pheochromocytoma), and others that cannot be accurately studied with Somatostatin SSTR scans such as the OctreoScan (Somatostatin Receptor Scintigraphy (SRS)), which uses the ligand 111In-DPTA-D-Phe-1-octreotide or the newer 68Ga DOTA-peptides.
Radioiodinated (123I) metaiodobenzylguanidine (MIBG) is an analog of norepinephrine that is used to image catecholamine-secreting NETs such as pheochromocytomas, paragangliomas and glomus tumors. It can also be used to look for Neuroblastoma in children. In patients with functional pheochromocytomas or paragangliomas, this modality has a sensitivity of 90% and positive predictive value of 100%. However, it has limited use in Gastrointestinal (GI) NETs, as this modality was positive in only 49.1% of patients. In the same cohort of patients, OctreoScan was positive in 91.2%. As an imaging tool, this study is best used to confirm a diagnosis of pheochromocytoma or paraganglioma and define the extent of metastatic disease in these tumors. (Note – the Ga68 PET is rising in prominence though). Its most practical use in GI NETs may be to determine whether patients with metastases may benefit from treatment with 131I-MIBG (a form of radiotherapy).
Somatostatin receptor-based imaging techniques
Somatostatin is an endogenous peptide that is secreted by neuroendocrine cells, activated immune cells and inflammatory cells. It affects its antiproliferative and antisecretory functions by binding to one of five types of somatostatin receptors (SSTR1- SSTR5). These are G-protein coupled receptors and are normally distributed in the brain, pituitary, pancreas, thyroid, spleen, kidney, gastrointestinal tract, vasculature, peripheral nervous system and on immune cells. Expression of SSTRs is highest on well-differentiated NETs. Somatostatin receptor type 2 is the most highly expressed subtype, followed by SSTRs 1 and 5, SSTR3 and SSTR4.
It must be noted that even the most modern scans are not an exact science. Radionuclide scans are like conventional imaging, they can be subject to physiological uptake or false positives, i.e. they can indicate suspicious looking ‘glows’ which mimic tumours. This article explains it better than I can – click here.
The ubiquity of SSTRs on NET cell surfaces makes them ideal targets for treatment (e.g. Somatostatin Analogues (Octreotide/Lanreotide) and PRRT), but also for imaging. There are two primary types of somatostatin receptor-based imaging available:
The most common (currently) is the OctreoScan or Somatostatin Receptor Scintigraphy (SRS), which uses the ligand 111In-DPTA-D-Phe-1-octreotide and binds primarily to SSTR2 and SSTR5. In its original form, it provided a planar, full body image. In modern practice, this image is fused with single photon emission computed tomography (SPECT) and CT. This takes advantage of the specificity of the OctreoScan and the anatomic detail provided by SPECT/CT, improving OctreoScan’s diagnostic accuracy. These improvements have been shown to alter the management in approximately 15% of cases, compared with just OctreoScan images. In primary tumors, the OctreoScan’s sensitivity ranges from 35 to 80%, with its performance for unknown primary tumors dipping beneath the lower end of that range (24%). Its ability to detect the primary is limited by the size but not SSTR2 expression, as tumors less than 2 cm are significantly more likely not to localize but do not have significantly different SSTR2 expression than their larger counterparts.
Ga68 PET (or SSTR PET in general)
The newest somatostatin receptor-based imaging modality, although it has been around for some time, particularly in Europe. The most common of these labeled analogs are 68Ga-DOTATOC, 68Ga-DOTANOC and 68Ga-DOTATATE. They may be known collectively as ‘SSTR-PET’. Additionally, the DOTATATE version may often be referred to as NETSPOT in USA but technically that is just the commercial name for the radionuclide mix.
These peptides are easier and cheaper to synthesize than standard octreotide-analog based ligands, boast single time point image acquisition compared to 2 or 3 days with Octreoscan. Its superior spatial resolution derives from the fact that it measures the radiation from two photons coincidentally. SPECT, in comparison, measures the gamma radiation emitted from one photon directly. This results in different limitations of detection – millimeters for 68Ga-PET compared with 1 cm or more for SPECT. There are a few choices of ligands with this type of imaging, but the differences lie primarily in their SSTR affinities – all of the ligands bind with great affinity to SSTR2 and SSTR5. 68Ga-DOTANOC also binds to SSTR3. Despite these differences, no single 68Ga ligand has stood out as the clear choice for use in NETs. As with standard somatostatin receptor-based imaging, these 68Ga-PET studies are fused with CT to improve anatomic localization.
Comparison studies between 68Ga-PET and standard imaging techniques (CT, OctreoScan) have universally demonstrated the superiority of 68Ga-PET in detection of NET primary tumors and metastases. Two early studies compared 68Ga-DOTATOC to standard somatostatin imaging (SRS)-SPECT and CT. Buchmann et al. reported that 68Ga-DOTATOC detected more than 279 NET lesions in 27 patients with histologically proven NETs, whereas SRS-SPECT detected only 157. The greatest number of lesions were detected in the liver. 68Ga-DOTATOC found more than 152 hepatic lesions, while SRS-SPECT found only 105, resulting in a 66% concordance rate between the two modalities. The concordance for abdominal lymph nodes was worse at 40.1%. Cleary these advantages are going to impact on treatment plans, some needing to be altered. In addition, 68Ga-DOTA PET imaging can be used to determine which patients might benefit from use of Somatostatin Analogues (Octreotide/Lanreotide) and PRRT – you can read more about this integrated and potentially personalised treatment in my article on ‘Theranostics‘ – click here.
It’s worth pointing out that SSTR PET is replacing previous types of radionuclide scans, mainly Octreoscan (Indium 111) and is not replacing conventional imaging (CI) such as CT and MRI etc. Whilst SSTR-PET has demonstrated better sensitivity and specificity than CI and In-111, there are specific instances in which SSTR-PET is clearly preferred: at initial diagnosis, when selecting patients for PRRT, and for localization of unknown primaries. For patients in which the tumor is readily seen on CI, SSTR-PET is not needed for routine monitoring. The Journal of Nuclear Medicine has just published “Appropriate Use Criteria for Somatostatin Receptor PETImaging in Neuroendocrine Tumors” which gives guidance on it’s use – issued by the Society of Nuclear Medicine and Molecular Imaging (SNMMI).
Taking the camera inside and directly to the Tumour
Of course there are other ways to “see it” via several types of Endoscopy procedures – taking the camera to the tumour. Read my article about this by clicking here
A look to the future of PET Scans
Just imagine something which is 40 times better than current PET scan technology? That’s what the scientists are working on now. Here’s an example called “EXPLORER“. Clearly there are more answers required in order to see if this is suitable for use with NETs (i.e. will it work with our radionuclide tracers etc) but it is very exciting and like something out of Star Trek. A little bit of me is worried about ‘overdiagnosis’ so interpretation of something that detailed will be very important to avoid unnecessary worry. Read more here and there is a later update here. Check out this cool video of the 3D images:
Scanning is a key diagnostic and surveillance tool for any cancer. Even though you have elevated bloods or urine (….or not), a picture of your insides is really like a thousand words…. and each picture has a story behind it. Scanning can be a game changer in the hunt for tumours and although scans can’t (yet) confirm the cancer type and grade, they certainly help with that piece of detective work and are key in the staging of the cancer.
When I read stories of people in a difficult diagnosis, I always find myself saying ‘a scan might resolve this’ and I always suggest people should try to get one. Even in the case of a story about late diagnosis or a misdiagnosis, I find myself thinking ‘if only they had done a scan earlier’. Despite what you read on NET forums, a CT scan will normally find some evidence of most tumour activity.
However, scans are not an exact science…..not yet! Apart from human error, sometimes tumours are too small to see and/or there are issues with ‘pickup’ (i.e. with NETs, nuclear scans need efficient somatostatin receptors). However, technology is improving all the time and you can read about this in my blog Neuroendocrine Cancer – Exciting times Ahead.
As for my own experience, I was very lucky. I managed to get a referral to a specialist early on in my diagnosis phase. He looked at the referral notes and said “what are you doing this afternoon”. I replied “whatever you want me to do”. He wanted to scan me. He didn’t know I had cancer but his instincts led him to believe he needed to see inside my body. The scan results were pretty clear – I had a metastatic Cancer and further checks were now needed to ascertain exactly what it was. So I took my seat on the rollercoaster. Here’s something I always say I believe is so much better than the impractical early diagnosis messages that seem to pervade our community: If your doctors don’t suspect something, they won’t detect anything and I believe this is a very frequent outcome of many diagnoses for many cancers (not just NETs).
There’s frequent discussion about the best types of scans for different types of NETs and even for different parts of the anatomy. This is correct and there’s also different views on the subject (including in the medical community), However, a few well known facts that can be gleaned from authortative NET sources. I found this useful video summary from the NET Patient Foundation describing the different scans for NET Cancer and what to expect. Worth a look.
Sooner we can all get access to the latest radionuclide scans the better!
In the last 12-24 months, there seems to have been announcement after announcement of new and/or upgraded/enhanced diagnostics and treatment types for Neuroendocrine Cancer. Scans, radionuclide therapies, combination therapies, somatostatin analogues, biological therapies, etc. Some of the announcements are just expansions of existing therapies having been approved in new (but significant) regions. Compared to some other cancers, even those which hit the headlines often, we appear to be doing not too badly. However, the pressure needs to stay on, all patients need access to the best diagnostics and treatments for them; and at the requisite time.There’s even more in the pipeline and I’m hoping to continue to bring you news of new stuff as I have been doing for the last year.
Some of these new diagnostics and treatments will benefit eligible patients who are in diagnosis/newly diagnosed and also those living with the disease. As we’re now in our awareness month, let’s recap:
Many NET Patients will undergo a nuclear scan to confirm CT results and/or to detect further neuroendocrine activity. Basically, a nuclear substance is mixed with a somatostatin analogue, injected into the patient who is then scanned using a 360-degree gamma camera. As gamma cameras are designed to show up radioactive activity; and as Neuroendocrine Tumour cells will bind to the somatostatin analogue, it follows that the pictures provided will show where Neuroendocrine tumours are located. Many people will have had an ‘Octreotide’ Scan (or more formally – Somatostatin Receptor Scintigraphy) which is still the gold standard in many areas. The latest generation of nuclear scans is based on the platform of the Gallium (Ga) 68 PET Scan. The principles of how the scan works is essentially as described above except that the more efficient radioactive/peptide mix and better scan definition, means a much better picture providing more detail (see example below). It’s important to note that positive somatostatin receptors are necessary for both scans to be effective. Europe and a few other areas have been using the Ga-68 PET scans for some time (although they are still limited in availability by sparse deployment). The latest excitement surrounding this new scan is because they are currently being rolled out in USA. Read about the US FDA approval here. You may hear this scan being labelled as ‘NETSPOT’ in USA but this is technically the name for the preparation radiopharmaceutical kit for the scan which includes a single-dose injection of the organic peptide and the radionuclide material. Take a look at a comparison of both scans here:
This slide from a recent NET Research Foundation conference confirms the power of more detailed scanning.
Peptide Receptor Radionuclide Therapy (PRRT)
Similar to above, this treatment has been in use in Europe and other places for some time but is also to be formally deployed in USA if, as is expected, the US FDA approval is positive at the end of this year (Read here). In the most basic terms, this is a treatment whereby a peptide is mixed with a radionuclide and is drip fed over a number of treatments (normally up to 4 spaced out over a year). The concept of delivery of the ‘payload’ to the tumours is actually very similar to the preparation for a radionuclide scan as described above, the key difference is the dosage and length of exposure whilst the tumours are attacked. Once again, receptors are important. The NETTER series of trials showed good results and this is an excellent addition to the portfolio for those patients who are eligible for this treatment. Fingers crossed for the US FDA announcement due by the end of this year. Also fingers crossed that PRRT returns to the NHS England & Wales portfolio of available treatments next year. The Carcinoid Cancer Foundation has an excellent summary of PRRT here.
PRRT and Chemo Combo
Whilst on this subject, I also want to highlight the innovative use of combo therapies in Australia where they are combining PRRT and Chemo (PRCRT). I blogged about this here:
Somatostatin Analogues and their Delivery Systems
Somatostatin analogues are a mainstay treatment for many NET Patients. These drugs target NET cell receptors which has the effect of inhibiting release of certain hormones which are responsible for some of the ‘syndromic’ effects of the disease. Again, receptors are important for the efficacy of this treatment. You can read the ‘geeky’ stuff on how they work here. These drugs mainly comprise Octreotide (provided by Novartis) and Lanreotide (provided by Ipsen). The latter has been around in Europe for 10 years and was introduced to North America earlier this year. Octreotide has been around for much longer, almost 17 years. When you consider these peptides have also been used to support nuclear scans that can detect the presence of tumours; and that studies have shown they also have an anti-tumour effect, they really are an important treatment for many NET Patients. I’ve blogged about new somatostatin analogues in the pipeline and you can read this here. This blog also contains information about new delivery systems including the use of oral capsules and nasal sprays (…….. very early days though).
Treatment for Carcinoid Syndrome
For maintenance and quality of life, the release of a Telotristat Ethyl for Carcinoid Syndrome is an exciting development as is the first new treatment for Carcinoid Syndrome in 17 years. This is a drug which is taken orally and inhibits the secretion of serotonin which causes some of the symptoms of the syndrome including diarrhea. It must be emphasised it’s only for treating diarrhea caused by syndrome and might not be effective for diarrhea caused by other factors including surgery. Read about how it works and its target patient group in my blog here.
The announcement of a clinical trial for the Oncolytic Virus (an Immunotherapy treatment)specifically for Neuroendocrine Tumours is also very exciting and offers a lot of hope. Click the photo for the last progress update.
Earlier this year, AFINITOR became the first treatment approved for progressive, non-functional NETs of lung origin, and one of very few options available for progressive, non-functional GI NET, representing a shift in the treatment paradigm for these cancers. It’s been around for some time in trials (the RADIANT series) and is also used to treat breast and kidney cancer. It’s manufactured by Novartis (of Octreotide fame). It has some varying side effects but these appear to be tolerable for most and as with any cancer drug, they need to weighed against the benefits they bring.
In technical terms, AFINITOR is a type of drug known as an ‘mTOR’ inhibitor (it’s not a chemo as frequently stated on NET patient forums). Taken in tablet form, it works by blocking the mTOR protein. In doing so, AFINITOR helps to slow blood vessels from feeding oxygen and nutrients to the tumour.
Check out Novartis Afinitor website for more detailed information. There’s an excellent update about AFINITOR rom NET expert Dr James Yao here. The US FDA approval can be found here.
………. and relax! Wow, I’ve surprised myself by collating and revising the last 12-24 months. Dr James Yao also agrees – check out his upbeat message in the attached2 page summary. You may also like another upbeat message from Dr Jonathan Strosberg by clicking here.
Neuroendocrine Cancer – who’d have thought it? ….. a bit of a dark horse.
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When I was diagnosed with metastatic Neuroendocrine Cancer on 26 July 2010, I just wanted them to hurry up and fix my body so I could get back to normal. That’s what happens to cancer patients with distant metastases is it not? My expectations of what should happen turned out to be wildly inaccurate and in hindsight, I was also wildly naive. You see, with Neuroendocrine Cancer, particularly well-differentiated, low or medium grade tumours, it sometimes doesn’t work as fast as you would think.
The complexity of the condition needs some consideration as the physicians work up a treatment plan. I’m quite happy and content they took their time, rather than rush into the wrong decisions. If you think about it, this is an advantage with low and medium grade NETs……you normally have some time.
Here’s a very short video discussing this during a patient video shoot: Click here.
I had a confirmed biopsy result following some incidental CT scans and other tests. However, they now needed further checks and marker tests to work out the extent of the disease. So the timeline leading up to major surgery ended up like this:
Diagnosis: 26 July 2010. Grade 2 Small Intestine NET with distant metastasis (Stage 4)
Chromogranin A and 5HIAA: submitted 28 July. Results received 13 Aug – both elevated, indicating and confirming tumour bulk and function status respectively
Octreotide Scan: 17-19 August. Report issued 24 August – confirmed CT plus additional distant hotshots. Also confirmed my tumour receptors were avid to somatostatin analogues.
Daily Octreotide Injections: Started 9 September to control syndrome (derisk surgery)
Referred to NET Multi-Disciplinary Team (MDT): 15 September – they now had sufficient data to form a treatment plan.
Holiday: Late September (it was booked and I felt OK, why not!)
Further MDT assessment: 1- 7 October
Bland Liver Embolisation: 19 October
First Surgery: 9 November – to remove primary and debulk local and regional spread.
You can read the rest of my treatment background here.
So it took 75 days from diagnosis to opening me up to remove the first batch of tumours. With reasonably slow-growing tumours, that isn’t really a long time when you consider they had probably been growing inside me for several years. I’m sure others waited even longer.
Sometimes rushing straight into the operating theatre isn’t really the best option. I’m still here!
Don’t understand Somatostatin Receptors? Join the club! I got my head around the term ‘Somatostatin’ and ‘Somatostatin Analogues’ some time ago but the term ‘Somatostatin Receptor’ (SSTR) is still a bit of a mystery and it’s come to the top of my list of things to study. SSTRs do come up in conversation quite often and I’m fed up of nodding sagely hoping it will eventually become clear! On analysis it looks like a technical subject – and therefore a challenge 🙂
I’ve taken a logical approach working from ‘Somatostatin’ to ‘Somatostatin Analogue’ before commencing on the ‘receptor’ bit. It is intentionally brief and (hopefully) simplistic!
It’s important to understand this hormone and then why your ‘butt dart’ is generically called a ‘Somatostatin Analogue’.
Some Neuroendocrine Tumours secrete hormones and peptides that cause distinct clinical syndromes, including amongst others, carcinoid syndrome. Somatostatin is a naturally occurring hormone and a known inhibitor of some of these NET related hormones and peptides that can be over secreted and cause syndromes. For example, somatostatin from the hypothalamus inhibits the pituitary gland’s secretion of growth hormone (GH) and Thyroid Stimulating Hormone (TSH). In addition, somatostatin is produced in the pancreas and inhibits the secretion of other pancreatic hormones such as insulin and glucagon. However, the naturally produced Somatostatin does not have the lifespan to have any effect on Neuroendocrine Tumours which are over secreting these hormones and peptides. ……. cue manufactured versions that can!
Somatostatin Analogue (SSA)
These are manufactured versions of Somatostatin known as Somatostatin Analogues. These are designed to have a lasting effect to inhibit for much longer and therefore reduce the symptoms caused by the over secretion (i.e. the syndrome). Examples of Somatostatin Analogue include Octreotide (Sandostatin), Lanreotide (Somatuline) and Pasireotide (Signifor).
So how do Somatostatin Analogues actually work?
For the inhibition to work effectively, there needs to be a route into the over secreting tumours, normally via short or long acting injections or even intravenously. On the tumour cells, there are currently 5 known sub-types of ‘Somatostatin Receptors’ (SSTR) which are ‘expressed’ by most NETs. These are known as SSTR1 through to SSTR5. The naturally occurring hormone Somatostatin attempts to bind with all 5 but as above, it lacks the lifespan to make any impact to inhibit sufficiently in cases of overecretion. However, SSAs can overcome this with the longer lifespan. They can successfully in most cases bind with these receptors to inhibit the hormones and peptides causing the problems, particularly SSTR2 with modest affinity to SSTR5. Clearly it’s therefore advantageous to target SSTR2.
The subtypes expressed by NETs are variable and the efficiency of different SSAs in binding to each SSTR subtype also varies. For example the table below lists the variability of Somatostatin Receptor efficiency in different types of NET. Interesting to note that non-functional NETs might not have efficient SSTRs but SSAs will still try to bind to them albeit it might not work or have a lesser effect.
Somatostatin receptors are found in high numbers on the surface of NET’s. Most receptors are in the inactive state (based on something called the phosphorylation status). Traditionally, agents such as dotatate have only bound to activated receptors on the surface. Scientists are looking at ways to bind to inactive receptors to increase therapy success (for example see clinical trial OPS 201)
Table 1 – Somatostatin receptor subtypes in neuroendocrine tumours (mRNA) (See Copyright)
This table above clearly shows the variability of SSTRs when binding with different types of NETs. It follows that manufacturers of SSAs will be using this data in the formulation of their drugs. If you now look at the table below, you can see how efficiently the 3 well-known SSAs inhibit NETs on each SSTR.
Table 2 – Somatostatin receptor subtype-binding affinity of somatostatin analogues (See Copyright)
You can see from the data why Octreotide and Lanreotide target SSTR2 and to a lesser extent SSTR5 but Pasireotide (Signifor or SOM-230) is interesting as it appears to have affinity for SSTRs 1-3 and 5, probably why it has been approved for Cushing’s Disease (ATCH producing). However, to date, 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. You may find this video interesting as the doctor is suggesting it could be used by NET patients in certain scenarios.
What about SSA labelled diagnostics?
The same principles apply. For example, an Octreotide Scan (actually known as ‘Somatostatin Receptor’ Scintigraphy (SRS)) works by taking pictures using a gamma camera which is designed to see radiation from a ‘tracer’. The tracer in question is a radio labelled with an Octreotide variant (such as pentetreotide) which will bind to somatostatin receptors on the surface of the tumour cells In the simplest of terms, this shows up where NETs are. The same principles apply to Ga 68 PET scans which are more advanced and more sensitive than SRS.
What about SSA labelled therapies?
With (say) Peptide Receptor Radiotherapy (PRRT), there is a similar binding mechanism going on. In PRRT, Octreotide or a variant, is combined with a therapeutic dose of the radionuclides, e.g. Yttrium 90 (Y-90) and Lutetium 177 (Lu-177). It binds with the SSTRs on the tumour cells and the therapeutic dose attacks the tumour having been brought there by the binding effect. Simple isn’t it?
Do Somatostatin Receptors work for everyone?
Unfortunately not. Some people have more sensitive receptors than others and the figure of 80% appears to be the most common statistic indicating one-fifth of all NET patients may not be able to respond correctly to SSA treatment or get the right results from Octreoscans/Ga 68 PET and/or PRRT. However, that needs to be taken into context and probably applies to midgut NETs measured against SSTR2 – the tables above tend to confirm this figure. During my research, I did read that higher than normal doses of SSAs may have some effect on those with less sensitive SSTRs. Also, SSAs seem to work much better with well-differentiatedtumours.
How do I know if my Somatostatin Receptors work?
When I was completing my NET checks after diagnosis, my Oncologist declared I was “Octreotide avid” shortly after my Octreoscan was compared with my CT. I’m guessing that is a simple and crude test and how most people find out they have working receptors. I also suspect that if your syndrome symptoms are abated somewhat by SSA injections, then you there is a good chance your SSTRs are working normally. I also suspect those who show clear signs of tumour on CT but not on Octreoscan or Ga 68 PET, could have a receptor issue.
The advent of modern PET scanning (e.g. Ga68) has meant more accurate methods of working out if someone has the right receptors for PRRT through analysis of something known as standardized uptake values (SUV).
A more modern approach is to use a ‘Theranostic Pair” where the same radiolabelled tracer is used with the advantage that the diagnostic element can predict suitability for the therapy component – read more here
Somatostatin Receptor Research – Interest Point
I was please to see a piece of research ongoing to look at the issues with lack of somatostatin receptors. The research is looking at novel imaging agents for NETs which do not have working receptors. Read more here.
I hope this gives you a very basic outline of why Somatostatin Receptors are important to support the diagnosis and treatment of NETs.
Preclinical and clinical studies have indicated that somatostatin receptor (SSTR)expressing tumors demonstrate higher uptake of radiolabeled SSTR antagonists than of the currently approved SSTR agonist versions. See clinical trial OPS 201 for an example of the next generation of somatostatin receptor based theranostics where the use of a somatostatin antagonists.
From day 1 of my diagnosis, I knew my liver was going to need some attention but I had always known that total removal of all tumours would not be possible. This critical organ did in fact produce the biopsy confirming Neuroendocrine Cancer. The early scans indicated multiple liver lesions and an Octreotide scan reported several quite avid isotope activity.
However, as you can see from my clinical history, they first stabilised my syndrome via daily Octreotide so my tumours were subdued ready for major surgery ’round 1′ which took place Nov 2010 – I wrote about this as Part 1 and Part 2 stories. As we are talking about my liver, it’s worth noting that a bland Liver Embolization was carried out prior to ’round 1′ as there was an option to look at the liver whilst I was ‘open’. However, after 9 hours sorting out my other areas, there was insufficient time.
My surgeon (Mr Neil Pearce) promised me a hard year so after 4 months ‘rest’, I was brought back in for major liver surgery (round 2) which took place on 12 Apr 2011. The ‘luck’ word has to be mentioned again because my local NET MDT was led by Mr Pearce who just happened to be one of UK’s top GI surgeons and one of the pioneers of Laparoscopic surgery – that is what I was to receive. In the end, I had a right hepatectomy and a metastasectomy which was calculated to be approximately 66% of my liver removed. Thank goodness it grows back!
The operation went well lasting 6 hours although it could have been shorter. Mr Pearce unfortunately had to spend a quarter of this time picking through ‘dense right sided abdominal adhesions’ caused by ’round 1′. My liver metastasis was described as significant on inspection and around 90% of the tumours were removed during this procedure leaving around half a dozen sub-centimetre deposits. Interestingly he said my pattern of disease was more conspicious on intra-abdominal ultrasound than it had been on previous scans. You can see from the post picture, the type of instruments used in laparoscopic surgery and the fact that they pump air into the abdomen to give sufficient space to operate.
I recovered quickly after only 5 days in hospital and was back at work in 3 weeks. My Chromogranin A finally returned to normal readings recognising the reduction in tumour bulk. My 5HIAA was already back in normal after ’round 1′ and subsequent commencement of Lanreotide. For those who have not had a liver laparoscopic procedure, the healing time is much quicker and you only have limited scarring. I had 3 ‘stab wounds’ (that’s my name for the marks!) across the area of my liver and then a 3 inch scar at the base of my abdomen which was used to remove the ‘bits’ of resected liver.
A follow-up chemo-embolization or TACE (Trans Arterial Chemo embolization) was scheduled a few weeks after the liver surgery which was looking to target the remnant liver tumours. However, this had to be aborted following some routing issues caused by ’round 1′ surgery.
I still have some residual (but stable) disease on my liver but there has been no progression in these 6 years. It’s no secret that debulking or cyto-reductive surgery can be of benefit even to those with advanced or metastatic well differentiated Neuroendocrine disease. I remain thankful for the care and attention I received in the months after my diagnosis.
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 surgeryin 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 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 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.
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.
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!
It’s that time again, every 6 months I need some checks. I’ve done the specialist blood test (Chromogranin A – CgA) and the 24 hour urine (5HIAA) and am waiting on my CT scan appointment. It’s also time for my annual Echocardiogram. I then see my Consultant and he delivers the news. Happy days 🙂
I positively look forward to my tests and I cannot wait to get into that scanner! ‘Scanxiety’ isn’t in my dictionary. Why? Because testing is one thing that’s going to keep me alive for as long as possible. If I don’t get regularly tested, then one day I might just ‘keel over’ because something wasn’t spotted early enough. Even in the event of ‘not so good news’, I still see that as a positive because it means the testing is working and an investigation or further testing can be put into place to find the problem – and the sooner the better. Where’s that scanner, get me in it!
One of the most common posts on NET Cancer forum sites is to express personal concerns or worries about upcoming appointments or waiting on the test results. Thinking back to my own countless appointments either for testing, treatment or for receiving results, I appear to be consistently pragmatic in my approach.
The test results will be what the test results will be. Worrying about them is not going to change them!
Bring it on!
You may enjoy my article “Living with Neuroendocrine Cancer – 7 tips for conquering fear”. Read here
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). Please note the respiratory tract and thymus are not really ‘Foregut’ but 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, in the bronchus or ovary you 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
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.
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 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 is a potent vasodilator and may account for the flushing and increased intestinal mobility.
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 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 responsible for the flushing associated with carcinoid syndrome.
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).
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.
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.
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).
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 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 nonfunctional:
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:
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).
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.
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.
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.
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.
Steatorrhea (very foul-smelling stool that floats).
Yellowing of the skin and whites of the eyes.
Weight loss for no known reason.
Too much pancretic polypeptide may cause:
an enlarged liver.
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 simultanously 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.