Crinetics Pharmaceuticals, Inc. (Nasdaq: CRNX), a clinical stage pharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for endocrine diseases and endocrine-related tumors, today announced the initiation of a Phase 1, double-blind, randomized, placebo-controlled, single and multiple-dose study to evaluate the safety, pharmacokinetics, and pharmacodynamics of CRN01941 in healthy volunteers.
What is CRN01941?
It’s an oral nonpeptide somatostatin receptor subtype 2 (sst2) biased agonist* designed for the treatment of neuroendocrine tumors (NETs) that originate from neuroendocrine cells commonly found in the gut, lung, or pancreas. From the detail contained in the clinical trials document (see below), it appears to involve a capsule. I’m guessing that the use of terms such as ‘non-peptide’ means that it may not be the same as a somatostatin analogue, but the method of operation appear to be similar in that it wants to bind to somatostatin receptor 2 (SST2). I will bring more technical detail once I have it. * chemical that binds to a receptor and activates the receptor to produce a biological response.
This trial launch follows other products including a similar capsule based somatostatin receptor product for treating Acromegaly called CRN00808, currently undergoing two Phase 2 clinical trials. The company is also developing oral nonpeptide somatostatin agonists for hyperinsulinism, as well as oral nonpeptide ACTH antagonists for the treatment of Cushing’s disease.
On the basis that the CRN00808 Phase 2 trial for Acromegaly is using patients previously treated with somatostatin analog based treatment regimens, I suspect this drug is designed for the same market as Sandostatin LAR/Octreotide and Somatuline (Lanreotide). For more information, please visit www.crinetics.com.
The Phase 1 Clinical Trial of CRN01941 for NETs
The trial is initially only based in Perth Western Australia, it is not yet known if there are any plans to expand locations in subsequent phases or parts of the trial. It also appears they are trialling the use of a capsule based drug and another delivery method as yet unknown, the clinical trial only mentions “Oral Solution” so it isn’t an injection. Read more at ClinicalTrials.gov using the identifier NCT03936166.
This is not the first somatostatin receptor based product in the pipeline, please also check out my article about Somatostatin Analogues and Delivery Mechanisms in the pipeline – click here.
My chest infection is now settled, as too is the excitement and apprehension behind my first ever Ga68 PET – the outcome of that is still a work in progress. Earlier this year, my thyroid ‘lesion’ on watch and wait was given a ‘damping down’ with the prescription of a thyroid hormone supplement but I await a re-ignition of that small bush fire downstream.
Bubbling behind the scenes and clamoring for attention is the spiking of my blood glucose test results and I was very recently declared ‘at risk’ for diabetes One of my followers entitled a post in my group with “The hits keep coming” in reference to encountering yet another problem in the journey with Neuroendocrine Cancer. I now know how she feels, this issue is a bit of a ‘left fielder’. However, having analysed the situation and spoken to several doctors, I can now put pen to paper.
Neuroendocrine Cancer is not a household name (…… I’m working on that) but diabetes certainly is. The World Health Organisation reports that the number of adults living with diabetes has almost quadrupled since 1980 to 422 million adults. In USA, estimates from CDC stated around 10 million people diagnosed with diabetes with a further 84 million in pre-diabetes state (at risk). In UK around 3.7 million people have diabetes with about 4 times that amount ‘at risk’. It’s a growth industry (…….. but so is NETs – in the last 40 years, the incidence of NETs is rising at a faster rate than diabetes, a disease which some writers have described as an epidemic).
With those numbers, it follows that many NET patients will be diabetic before diagnosis, some will succumb to diabetes whether they have NETs or not, and some may have an increased risk of succumbing due to their treatment. Some may even be pushed into diabetes as a direct result of their NET type or treatment. It’s important to understand diabetes in order to understand why certain types of NET and certain treatments could have an involvement.
The Pancreas
For understanding of this article, it’s worth noting the pancreas has two main functions: an exocrine function that helps in digestion and an endocrine function that regulates blood sugar. I have talked about the exocrine function in relationship to Neuroendocrine Cancer at length – check out this article on Pancreatic Enzyme Replacement Therapy. In this article, I now want to cover the issues with the endocrine function and blood sugar. First a short primer on diabetes – it is necessarily brief for the purposes of this article.
Diabetes Primer
TypeS OF DIABETES
Type 1 and Type 2 Diabetes are fairly well-known. There’s actually more than two types, but these are the most common. Type 2 is the most prevalent with around 90% of diabetes cases. When you’ve got Type 1 diabetes, you can’t make any insulin at all. If you’ve got Type 2 diabetes, the insulin you make either can’t work effectively, or you can’t produce enough of it. Additional types may come up in the subsequent discussion.
What is the problem?
What all types of diabetes have in common is that they cause people to have too much glucose (sugar) in their blood. But we all need some glucose. It’s what gives us our energy. We get glucose when our bodies break down the carbohydrates that we eat or drink. And that glucose is released into our blood. We also need a hormone called insulin. It’s made by our pancreas, and it’s insulin that allows the glucose in our blood to enter our cells and fuel our bodies.
If you don’t have diabetes, your pancreas senses when glucose has entered your bloodstream and releases the right amount of insulin, so the glucose can get into your cells. But if you have diabetes, this system doesn’t work properly. Diabetes is associated by being overweight but there isn’t a 100% correlation with that. However, when an individual becomes overweight, there is an increase in free fatty acids in the blood stream which may contribute to reduced insulin sensitivity in the tissues, leading to increased glucose levels in blood.
Symptoms and diagnosis of Diabetes
Different people develop different symptoms. In diabetes, because glucose can’t get into your cells, it begins to build up in your blood. And too much glucose in your blood causes a lot of different problems. To begin with it leads to diabetes symptoms, like having to wee a lot (particularly at night), being incredibly thirsty, and feeling very tired. You may also lose weight, get infections like thrush or suffer from blurred vision and slow healing wounds.
I see these symptoms mentioned very frequently and normally people are trying to associate them with NETs and/or the treatment for NETs.
Diabetes diagnosis is normally triggered diagnosed based on blood tests such as fasting Blood Glucose (snapshot) and/or Glycated Hemoglobin (A1C) or HbA1C.
Complications
Over a long period of time, high glucose levels in your blood can seriously damage your heart, your eyes, your feet and your kidneys. These are known as the complications of diabetes.
But with the right treatment and care, people can live a healthy life. And there’s much less risk that someone will experience these complications.
What are the direct connections with Diabetes and NETs?
It’s not surprising that diabetes is mostly associated with Neuroendocrine Tumors of the Pancreas but there are other areas of risk for other types of NETs including to those who are existing diabetics – see below.
Surgery
The main types of surgery for Neuroendocrine Tumors of the Pancreas are Distal Pancreatectomy (tail), Sub-total pancreatectomy (central/tail), Classic Whipple (pancreaticoduodenectomy – head and/or neck of pancreas), Total pancreatectomy (remove the entire pancreas) or an Enucleation (scooping out the tumour with having to remove too much surrounding tissue). From the PERT article link above (exocrine function), you can see why some people need this treatment to offset issues of reduced production of pancreatic enzymes. The same issue can develop with a reduced endocrine function leading to the development of diabetes.
NET Syndromes
The different types of functional pancreatic NETs often called syndromes in their own right due to their secretory role. One might think that Insulinomas are connected to diabetes issues but this hormonal syndrome is actually associated with low blood sugar (hypoglycemia), although low blood sugar can turn out to be a complication of diabetes treatment.
A NET syndrome known as Glucagonoma (a type of functional pancreatic NET) is associated with high blood glucose levels. About 5-10% of pancreatic neuroendocrine tumors are Glucagonomas, tumors that produce an inappropriate abundance of the hormone glucagon. Glucagon balances the effects of insulin by regulating the amount of sugar in your blood. If you have too much glucagon, your cells don’t store sugar and instead sugar stays in your bloodstream. Glucagonoma therefore leads to diabetes-like symptoms (amongst other symptoms). In fact Glucagonoma is sometimes called the 4D syndrome – consists of diabetes, dermatitis, deep venous thrombosis (DVT), and depression.
Another functional pancreatic NET known as Somatostatinoma is prone to developing insulin resistance. Somatostatinomas produce excessive amounts of somatostatin which interferes with the insulin/glucagon function and could therefore lead to diabetes.
Diabetes caused by cancer or cancer treatment
Worth noting that this type of diabetes is sometimes known as ‘Pancreatogenic diabetes’ and this is actually classified by the American Diabetes Association and by the World Health Organization as type 3c diabetes mellitus (T3cDM) and refers to diabetes due to impairment in pancreatic endocrine function due to acute cancer and cancer treatment (and several other conditions). The texts tend to point to cancers (and other conditions) of the pancreas rather than system wide. Prevalence data on T3cDM are scarce because of insufficient research in this area and challenges with accurate diabetes classification in clinical practice. (Authors note: Slightly confusing as many text say that type 3 diabetes is proposed for insulin resistance in the brain (diabetes associated with Alzheimer’s disease). There’s another term for a complete removal of the entire pancreas – Pancreoprivic Diabetes
Other treatment risks
Somatostatin Analogues (e.g. Octreotide and Lanreotide) are common drugs used to control NET Syndromes and are also said to have an anti-tumor effect. They are known to inhibit several hormones including glucagon and insulin and consequently may interfere with blood glucose levels. The leaflets for both drugs clearly state this side effect with a warning that diabetics who have been prescribed the drug, should inform their doctors so that dosages can be adjusted if necessary. The side effects lists also indicates high and low blood glucose symptoms indicating it can cause both low and high blood glucose (hypoglycemia and hyperglycemia). For those who are pre-diabetic or close to pre-diabetic status, there is a possibility that the drug may push blood tests into diabetic ranges. Afinitor (Everolimus). The patient information for Afinitor (Everolimus) clearly states “Increased blood sugar and fat (cholesterol and triglycerides) levels in blood: Your health care provider should do blood tests to check your fasting blood sugar, cholesterol and triglyceride levels in the blood before you start treatment with AFINITOR and during treatment with AFINITOR” Sutent (Sunitinib). The patient information for Sutent (Sinitinib) clearly states that low blood sugar (hypoglycemia) is a potential side effect. It also advises that low blood sugar with SUTENT may be worse in patients who have diabetes and take anti-diabetic medicines. Your healthcare provider should check your blood sugar levels regularly during treatment with SUTENT and may need to adjust the dose of your anti-diabetic medicines.
In rare cases, certain NETs may produce too much Adrenocorticotropic hormone (ACTH), a substance that causes the adrenal glands to make too much cortisol and other hormones. This is often associated with Cushing’s syndrome. Cortisol increases our blood pressure and blood glucose levels with can lead to diabetes as a result of untreated Cushing’s syndrome.
Summary
I think it’s sensible for all NET patients, particularly those with involvement as per above and who are showing the signs of hypoglycemia and hyperglycemia, to be checked regularly for blood glucose and if necessary HbA1c. Many patient information leaflets for the common NET treatments also indicate this is necessary. Always tell your prescribing doctors if you are a diabetic or about any history of low or high blood glucose before treatment for NETs.
My brush with Diabetes (as at Jan 2019)
My blood glucose levels started to climb slightly in 2016 but HbA1c remained normal. However, an HbA1c test in early 2018 put me into pre-diabetic range (44 mmoL/moL). I explained some of the above article to my GP who is corresponding with a diabetes expert at secondary care – the expert suggested that I need to be monitored carefully as weight loss is not necessarily the best response. I have kept my NET team up to date.
At the time of updating, two separate and sequential HbA1c tests (3 month interval) came back normal at 36 mmoL/moL. I’m pragmatic enough to know that I do not need to lose weight as one of the aims of reducing my blood glucose and HbA1c levels (something emphasised by the above mentioned diabetes specialist).
I even got on my bike to do a little bit more exercise just in case!
At this point, I cannot yet say if this is the beginning of progressive Type II diabetes or if my medication is causing these spikes in my blood glucose and HbA1c. Judging by 2 x normal HbA1c, looks like the somatostatin analogue (Lanreotide in my case) may caused a spike to a pre-diabetes score. I will keep you posted.
Summary – if you are noticing these symptoms, get your blood sugar checked (with acknowledgement to Dr Pantalone from Cleveland Clinic)
1. You’re making more trips to the bathroom
Having to go to the bathroom more than normal, particularly at night, is a sign that your blood sugar might be out of whack.
Dr. Pantalone says one of his patients came in for a diagnosis after a family member noticed that he was using the bathroom during each commercial break when they watched TV.
2. You’re getting frequent urinary or yeast infections
When your blood sugar is high and your kidneys can’t filter it well enough, sugar ends up in the urine. More sugar in a warm, moist environment can cause urinary tract and yeast infections, especially in women.
3. You’re losing weight without trying
If you have diabetes, your body isn’t able to use glucose (sugar) as effectively for its energy. Instead, your body will start burning fat stores, and you may experience unexpected weight loss.
4. Your vision is getting worse
High sugar levels can distort the lenses in your eyes, worsening your vision. Changes in your eyeglass prescription or vision are sometimes a sign of diabetes.
5. You’re feeling fatigued or exhausted
Several underlying causes of fatigue may relate to diabetes/high sugar levels, including dehydration (from frequent urination, which can disrupt sleep) and kidney damage.
This feeling of exhaustion is often persistent and can interfere with your daily activities, says Dr Pantalone.
6. You’re noticing skin discoloration
Something that Dr. Pantalone often sees in patients before a diabetes diagnosis is dark skin in the neck folds and over the knuckles. Insulin resistance can cause this condition, known as acanthosis nigricans.
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).
PET/CT (left) and PET (right) scans of patient with intestinal NET and multiple metastases. More lesions are seen in intestinal region with 64Cu-DOTATATE than with 68Ga-DOTATOC.
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.
Multiple small liver metastases (>10), peritoneal solitary tumor mass, and 3 lymph node metastases shown on 64Cu-DOTATATE PET/CT in patient with pancreatic NET. No foci were detected by 111In-DTPA-OC SPECT (Precedence scanner). All findings on PET were confirmed to be true-positive. (A) 111In-DTPA-OC planar images. (B) 64Cu-DOTATATE maximum-intensity-projection image with arrows pointing at liver and lymph node metastases. Insert is fused PET/CT of peritoneal solitary tumor mass. (C) Axial CT and SPECT of liver. (D) Axial CT and PET of liver revealing several small liver metastases.
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.
Summary
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.
From other posts, you’ll be aware of the thyroid lesion (now 17x19mm) which I’ve been tracking since 2013. The surveillance has included routine thyroid blood tests, mainly TSH, T3 and 4. Due to trends in TSH and T4, it’s been suggested I’m borderline hypothyroidism. I’m out of range in TSH (elevated) but the T4 is currently at the lower end of the normal range. On 20 March 2018, following an Endocrine appointment, I was put on a trial dose of 50mcg of Levothyroxine to counter the downwards trend in results indicating hypothyroidism. Levothyroxine is essentially a thyroid hormone (thyroxine) replacement. One month after taking these drugs, my thyroid blood levels are now normal for the first time in 4 years (since there are records of test results – it might be longer).
The NET Connection?
To put things into context, hypothyroidism is an extremely common condition and the main treatment is administration of thyroid hormone replacement therapy (i.e. Lewvothyroxine). This is in the top 5 of the most commonly prescribed medication in USA and UK.
However, there are connections with NETs. Firstly there is one type of cancer known as Medullary Thyroid Cancer (MTC) and it also has a familial version known as Familial MTC or FMTC.
There are also connections between regular Neuroendocrine Tumours (NETs) and the thyroid. It can often be a site for metastasis, something I have not yet written off given it lights up on nuclear scanning – although my biopsy was inconclusive. You can see a summary of the connections and my own thyroid issue in more detail in my article “Troublesome Thyroids”. Please note the parathyroid glands are beyond the scope of this article.
Thyroid Function – the Lanreotide/Octreotide connection
Before I continue talking about hypothyroidism, here’s something not very well-known: Somatostatin analogues might cause a “slight decrease in Thyroid function”(a quote from the Lanreotide patient leaflet). The Octreotide patient leaflet also states “Underactive thyroid gland (hypothyroidism)” as a side effect. Many sources indicate that thyroid function should be monitored when on long-term use of somatostatin analogues. It’s also possible and totally feasible that many NET patients will have thyroid issues totally unrelated to their NETs. Remember, NET patients can get regular illnesses too!
What is Hypothyroidism?
Hypothyroidism is a condition in which your thyroid gland doesn’t produce enough of thyroxine. This leads to an underactive thyroid. It seldom causes symptoms in the early stages, but over time, untreated hypothyroidism can cause a number of health problems, such as obesity, joint pain, infertility and heart disease. Both men and women can have an underactive thyroid, although it’s more common in women. In the UK, it affects 15 in every 1,000 women and 1 in 1,000 men. Children can also develop an underactive thyroid.
What causes Hypothyroidism?
Autoimmune thyroid disease sometimes called Hashimoto’s thyroiditis
Radioactive iodine or surgery to correct hyperthyroidism or cancer
Over-treatment of hyperthyroidism with anti-thyroid drugs
Some medicines
A malfunction of the pituitary gland
What are the symptoms of Hypothyroidism?
The signs and symptoms of hypothyroidism vary, depending on the severity of the hormone deficiency. But in general, any problems you have tend to develop slowly, often over a number of years. At first, you may barely notice the symptoms of hypothyroidism, such as fatigue and weight gain, or you may simply attribute them to getting older. But as your metabolism continues to slow, you may develop more-obvious signs and symptoms. Hypothyroidism signs. Below are major symptoms associated with hypothyroidism:
Fatigue
Weakness
Weight gain or difficulty losing weight (despite reduced food intake)
Coarse, dry hair and dry skin
Hair loss
Sensitivity to cold
Muscle cramps and aches
Constipation
Depression
Irritability
Memory loss
Abnormal menstrual cycles
Decreased libido
Slowed speech (severe cases)
Jaundice (severe cases)
Increase in tongue size (severe cases)
Check out this excellent short video from WebMD – click here or the picture below. It’s based on USA but most of it is relevant globally.
You don’t have to encounter every one of these symptoms to be diagnosed with hypothyroidism. Every patient’s experience with the disorder is different. While you may notice that your skin and hair have become dry and rough, another patient may be plagued more by fatigue and depression.
When hypothyroidism isn’t treated, signs and symptoms can gradually become more severe. Constant stimulation of your thyroid gland to release more hormones may lead to an enlarged thyroid (goiter). In addition, you may become more forgetful, your thought processes may slow, or you may feel depressed.
Now ….. some of these symptoms look very familiar to me and they also look very familiar to some of the comments I see on patient forums related to somatostatin analogues and some of the NET syndromes – that jigsaw thing again. I guess it’s possible that people are borderline hypothyroidism prior to taking somatostatin analogues and the drug pushes them out of range (similar to what it’s known to do with blood glucose levels and diabetes). I’m not suggesting a direct clinical link in all cases but what I am suggesting is that perhaps some of the answers might be found in checking Thyroid hormone levels.
What are the Thyroid Hormone tests for Hypothyroidism?
A high thyroid stimulating hormone (TSH) level with a low thyroxine (T4) level indicates hypothyroidism. Rarely, hypothyroidism can occur when both the TSH and T4 are low. A slightly raised TSH with a normal T4 is called subclinical, mild, or borderline hypothyroidism. Subclinical hypothyroidism can develop into clinical or overt hypothyroidism
Routine ‘Thyroid blood tests’ from your doctor will confirm whether or not you have a thyroid disorder. I now test for TSH (thyroid-stimulating hormone), T4 every 6 months. Mostly in range but recently TSH is spiking out of range and T4 is consistently at the lower end of normal range.
Can hypothyroidism be treated?
Yes. A synthetic version of thyroxine taken daily as prescribed. e.g. Levothyroxine tablets
OK that’s Hypothyroidism – what is Hyperthyroidism?
Hyperthyroidism is a condition where the thyroid gland produces too much thyroid hormone for the body’s needs. It is also known as an overactive thyroid or thyrotoxicosis. An overactive thyroid can affect anyone, but it’s about 10 times more common in women than men and it typically starts between 20 and 40 years of age.
Hyper – means “over -“
Hypo – means “under -“
The terms “hyperthyroid” and “thyrotoxic” are interchangeable
Causes
Graves’ disease – the most common cause
A toxic nodular goitre (a goitre is an enlarged thyroid gland)
A solitary toxic thyroid adenoma (an adenoma is a clump of cells)
Thyroiditis (infection or inflammation of the thyroid gland) which is temporary
Common Symptoms
A speeding up of mental and physical processes of the whole body, such as
weight loss, despite an increased appetite
palpitations / rapid pulse
sweating and heat intolerance
tiredness and weak muscles
nervousness, irritability and shakiness
mood swings or aggressive behaviour
looseness of the bowels
warm, moist hands
thirst
passing larger than usual amounts of urine
itchiness
an enlarged thyroid gland
If the cause is Graves’ disease, you may also have ‘thyroid eye disease’. Smokers are up to eight times more likely to develop thyroid eye disease than non-smokers.
Diagnosis
By a physical examination and blood tests
A low thyroid stimulating hormone (TSH) level with a high thyroxine (T4) level indicate hyperthyroidism
Treatment Options
Antithyroid drugs
Surgery to remove all or part of the thyroid gland
Radioactive iodine to destroy most of the thyroid tissue
Research sources used to compile this post:
1. Lanreotide Patient Leaflet.
2. Octreotide Patient Leaflet.
3. British Thyroid Foundation. (particularly how to interpret Thyroid results – click here) – always check the unit of measure when comparing blood result ranges)
If you want to strike up a friendly conversion with a Brit, ask him or her about the weather – we’re really famous for our weather conversations and they normally focus on rain or clouds! However, despite the famous British ‘reserve’ and ‘stiff upper lip’, they also frequently talk about being ‘under the weather’, a phrase meaning slightly unwell or in low spirits.
I find myself smiling at some of the conversations I hear in medical establishment waiting rooms, particularly the potentially long wait for blood tests. Here, conversations bypass the weather and focus on being under the weather! I thought I was a regular when I started to recognise people in the queue (line!) and their pill conversations. Statements such as “Yes, I just started a ‘blue chap’ ” (medical names are sometimes hard to pronounce). Normally followed by “I’m on that one too and I take it along with my yellow and white chaps“. Some people seem to be taking a veritable rainbow of ‘chaps’. Strangely, some people appear to be quite proud of how many ‘chaps’ they take. I tend to maintain the traditional British reserve and a stiff upper lip in waiting rooms, so I keep quiet (actually I’m just happy to be inside away from the weather!).
I might join in one day and I wonder if they would be impressed with my tally of chaps? I have a funny feeling my tally of drugs is nothing compared to some of you guys and hope you will comment to prove me right! I don’t think I’m proud to give you my list but here’s my ‘chaps’, some prescription, some over the counter:
Apixaban (Eliquis). To prevent a recurrence of pulmonary emboli (PE). Unfortunately, I had PE after my big surgery in 2010. 2 per day.
Pancreatic Enzyme Replacement Therapy (Creon). Recently added, anything between 6 and 12 per day depending on what I eat. Check out this article on PERT. Check out this article on Malabsorption with references to NET dietitians.
Multi-Vitamin (50+ age). I’ve actually been taking these since a few years before diagnosis in 2010. NET patients can be at risk of vitamin and mineral deficiencies. Check out this article on the issues and with references to NET dietitians.
Vitamin B Complex. This was added in 2013 to mainly tackle low B12 (despite my multi-vit containing 400% RDA) and it seemed to help with fatigue. Read more here.
Vitamin D3. This was also added in 2013 to tackle low Vit D levels (again, despite my multi-vit containing 200% RDA). 10µg (400iu). D3 is normally the recommended form of Vitamin D to take, easiest to absorb and more natural. Vitamin D3 is also known as cholecalciferol. Many people who do not live in sunny countries are probably deficient or borderline already.
Probiotic. This was also added in 2013 to try to offset some of the abdominal issues that many NET patients seem to have. I take a 5 billion dose and it seems to help. Check out this article with references to NET dietitians.
Omega 3. This is also something I had been taking since before my diagnosis. I think I took it for a couple of reasons, my diet did not really include foodstuffs containing Omega 3 and I was experiencing some joint pain in my hands. I just never stopped taking it. Dose size 1000mg.
Lanreotide (Somatuline Autogel). An injection rather than a pill/capsule. Quite a big chap! You can read all about my relationship with Lanreotide by clicking here.
Levothyroxine. One 50mcg tablet each morning. My blood tests are indicating hypothyroidism – check out my whole thyroid story by clicking here. All NET patients need to keep an eye on thyroid levels. Read why here.
Seretide and Ventolin. These are asthma drugs, a preventer and a reliever respectively. I hardly ever take the latter nowadays. I had mild asthma as a child, it went at 16 and came back at 35. I take 2 puffs of Seretide night and day. Seems to help. Ventolin seems to be only required if I have a cold or flu thing going on.
Of course, most people have lots of other stuff in the ‘medicine box’ ready for ad hoc issues as they arise (pain killers, imodium, cough mixture, anti-histamines, indigestion, etc etc). I could go on forever.
Please always consult your specialists or dietitian about the requirements for drugs and supplements. You may not actually need them. I only take my supplements after very careful consideration, in reaction to low blood vitamin/mineral tests and listening to what ‘NET aware’ dietitians say (you’ll find references in some of the articles above).
Warning: You should always think carefully about over the counter stuff (including online) as there’s a lot of ‘scammers’ out there selling counterfeit supplements. Always buy from a reputable source. With supplements, remember in most countries they are not regulated in the same way as medicines so it’s worthwhile checking they are compliant with regional food supplements directives. The supplements provider I use is actually approved by the Medicines and Healthcare Products Regulatory Agency (MHRA) covering UK. I’m sure there will be similar approval organisations where you live. Also be careful of some claims about the miracle cure of certain food supplements. There are plenty sites with fake health news online (check out my article on this – click here).
You should be clear why you take supplements and try to consult with a specialist or dietitian for advice.
Finally, don’t forget to take your chaps, they should help you keep well!
After 7 years of avoiding pancreatic enzyme replacement therapy (PERT), I finally asked for some on a trial basis at the end of 2017. To be honest, for some time, I thought they were really only needed in the NET world for those with pancreatic issues (pNETs). I’ve always known I’ve had some digestive issues related to malabsorption. However, I’m not losing weight – this has been stable for some years (but see below). Plus my key vitamin levels (B12 and D) are in range. However, I had been struggling with a lot of bloating issues, thus the trial. You know me, I like to research and analyse such things! I’ve actually written about a lot of these issues in my Nutrition series ….. so this is now ‘Article Number 5’.
Crash Course.We eat food, but our digestive system doesn’t absorb food, it absorbs nutrients. Food has to be broken down from things like steak and broccoli into its nutrient pieces: amino acids (from proteins), fatty acids and cholesterol (from fats), and simple sugars (from carbohydrates), as well as vitamins, minerals, and a variety of other plant and animal compounds. Digestive enzymes, primarily produced in the pancreas and small intestine, break down our food into nutrients so that our bodies can absorb them.
Background
Some of the common symptoms of NETs are gas, bloating, cramping and abdominal pain and the root cause of these issues can sometimes be as a result of insufficient ‘digestive’ enzymes. They are primarily produced in the pancreas (an exocrine function) and the small intestine but also in the saliva glands and the stomach. This post will focus on pancreas and to a certain extent, the small intestine. There are actually some key tell-tale signs of a pancreatic enzyme deficiency, such as steatorrhoea which is described as an excess of fat in faeces, the stool may float due to trapped air, the stool can be pale in colour, may be foul-smelling, and you may also notice droplets of oil or a ‘slick’ in the toilet pan. Steatorrhoea is mainly (but not always) due to malabsorption of fat from the diet and this can actually be caused or made worse by somatostatin analogues which are known to inhibit the supply of pancreatic enzymes. Of course if fat is not being absorbed, then the key nutrients your body needs to function properly might not be either. The signs from that might not be so noticeable but can be even more problematic over time. Please see Article 1.
Those who have had surgery, in particular, in GI tract/digestive system, are at risk of malabsorption; as are those prescribed somatostatin analogues (Lanreotide/Octreotide) as these drugs can inhibit digestive enzymes, causing or adding to the malabsorption effect. For those who need to read more, see Article 2.
One way to combat these issues when they are caused by pancreatic insufficiency is with Pancreatic Enzyme Replacement Therapy (PERT) which can mimic the normal digestive process. However, this is not the whole story as there could be numerous reasons for these issues, perhaps even some which are unrelated to NETs. If you are in doubt about whether you suffer from malabsorption and/or any form of digestive enzyme insufficiency, you should consult your doctors.
Pancreatic Enzyme Replacement Therapy
Many NET patients succumb to malabsorption due to pancreatic insufficiency and are prescribed Pancreatic Enzyme Replacement Therapy, or PERT for short. There are various brands available (e.g. Creon®, Nutrizym®, Pancrease HL® or Pancrex®). Most are in capsule form in various doses.
How does PERT work? Most people experiencing the issues above are going to benefit from a multiple-enzyme replacement which tend to include the key ones such as:
lipase which break down fats (e.g from many different foods)
amylase which breaks down starchy carbohydrates (e.g. potatoes, bread, rice, pasta, cereals, fruits, fibre, etc).
The dose sizes tend to be based on the amount of lipase, i.e. a 25,000 strength would mean 25,000 units of lipase and (normally) a lesser amount of amylase and protease. The entire mix of enzymes may be given a name, e.g. ‘Pancreatin’ or ‘Pancrealipase’. You will be given a number of capsules to be used from your prescribing doctor.
The pancreatic enzyme capsule is swallowed along with food and digests food as they pass through the gut. If your capsules contain an enteric coat or enteric coated granules (delayed release), they should not be affected by stomach acid. The replacement enzymes will help to break down food allowing the nutrients to be absorbed beyond the stomach (i.e. in the small intestine). Do not be alarmed at the dose sizes, a healthy pancreas will release about 720,000 lipase units during every meal!
Frequently Asked Questions (FAQ)
When I first started taking the supplements, I thought of numerous questions, many of which I could not find definitive answers to! Different sites say different (and contradictory) things. Clearly, you should always consult your prescribing doctor and the medicine patient information leaflet. That said, I found the patient information leaflet which came with the capsules is just not detailed enough for an inquisitive patient such as myself!
I always like to refer to best practice which is why I’ve consulted one of the top NET Dietitians, Tara Whyand of Royal Free London. She agreed to an online Q&A session on 28 Feb 2018. This took place on my private Facebook group click here or search Facebook for this group “Neuroendocrine Cancer – Ronny Allan’s Group“. Join, answer some simple questions and then your application will be processed.
The output from the online with with Tara Whyand is below:
Thanks for attending the online event. Here is a tidy summary of the many comments. I hope this is also useful for those who were unable to attend.
Why would I need PERT and are there any tests that can be done to validate this?
“Somatostatin analogues, pancreatic surgery, pancreatitis and cystic fibrosis can cause exocrine pancreatic insufficiency (EPI). This means that the pancreas does not produce enough enzymes to break down food. It results in fatty loose stools called steatorrhoea.
Patients who have exocrine pancreatic insufficiency (EPI) require PERT (pancreatic enzyme replacement therapy) to break down food (fat, protein and carbohydrate). There are many brands of pancreatic enzymes, the most commonly used are Creon and Nutrizyme. Both have different dose levels to choose from.
The fecal elastase test was traditionally used to test the function of the pancreas, although it may not be that useful in NETs. This is because a NET team in Wales found that some NET patients who reported steatorrhoea had a false negative result.
Steatorrhoea may also be a result of bile acid malabsorption and small intestinal bacterial overgrowth which can co-exist and are common especially after surgery. They can both be tested for at a hospital.”
Supplementary Questions:
1a. Would the treatment be different for both EPI and bile acid malabsorption? If not how different?
“Yes BAM requires bile acid sequestrants rather than PERT”.
1b. would this be something you would take in general to help overall digestion and absorption of nutrients?
“No only if you have reasons for EPI to occur”.
PERT dosage. Is there a set dosage for all patients or does it depend on type of NET or surgery? And can I overdose on PERT?
“It depends on what you eat. PERT dose is normally tailored on fat content (the more fat you have, the more enzymes you need), but patients who have had a total pancreatectomy will have to have PERT for all food and drink (apart from water) as carbohydrate and protein needs to be broken down too.”
Supplementary Questions
2a. “What about when taking medication such as Cholesteramine or pills in the morning and evening. Do I need to take it to absorb these?”
“see question 5”.
2b. I had a total pancreatectomy and was told I do not need PERT for fruit and veg?
“there’s carbs in all fruit and veg and often fat and protein too, so no different really.”
Some sources say to take the capsules at the beginning of a meal, some say it’s also at the end of a meal is also OK. How critical is this?
“You must always take the capsules at the beginning of the meal and if the meal goes on longer than ~30 minutes, or there are several courses, you will need to have another capsule/tablet/scoop of enzymes. If you don’t, food will pass by the pancreas undigested and ‘malabsorption occurs. This leads to fatty stools (steatorrhoea), fat soluble vitamin deficiency and weight loss. Unbroken down food can also feed bacteria and you can develop small intestinal bacterial overgrowth as a result.”
Supplementary Questions
3a. so if my oncologist says to take four capsules per meal, then I should take all four at the same time?
“see question 11”
3b. if you have had a total gastrectomy (total removal of the stomach), is there a different procedure for taking PERT? I am on Creon and have heard that perhaps I need to open up the capsules as I can not break down the gelatin casing. Not sure if this is true or not.
“See question 11”
What is a meal? Is it multiple courses, or is there a strategy for each individual course? What about snacks? (i.e. a single biscuit with a cup of tea)
“The standard starting dose for snacks: 22-25,000 units lipase, titrating up when symptoms have not resolved. Most people end up taking 44,000-50,000 for snacks.
For main meals start on 44,000/50,000 and most people will need 66,000-100,000 units lipase/meal for the long term.”
Supplementary Questions:
4a. I have to eat multiple small meals a day (like every 3 hours, so 7 to 8 small meals). Is there a limit on the amount of Creon I can take in a day?
“see question 11”
4b. What is a snack?
“No official definition. Something with a little fat and maybe 50-200kcals.
Are there any problems taking PERT at the same time as other drugs? e.g. I like to take my vitamin supplements with food. And it’s recommended that some drugs be taken with food.
“PERT only breaks down food, but it is important to take your PERT to ensure food and drugs are absorbed. If you do not take you PERT with the meal, it is likely that food and drugs will rush through your bowel without being absorbed. There is no problem taking vitamins and minerals with food and PERT.
Supplementary Questions:
5a. I take a probiotic also, when is best time to take this, before, during or after food?
“Timing doesn’t matter”
I heard PERT is a porcine produce but I’m a vegan? Is there anything else for me?
“There are no other recommended products, and you should only have prescription PERT’s. This is for safety and reliability. Other off the shelf enzymes are unlikely to work.
Pigs are not slaughtered for PERT, they are slaughtered for meat and enzymes are a by-product if that makes anyone feel more comfortable with the idea.”
I heard PERT is a porcine produce but my religion does not allow me to eat such produces. Is there anything else for me?
“PERT are only sourced from a pigs pancreas but Jewish and Muslim patients have been granted approval to take the enzymes on medical grounds from their religious leaders because there is no alternative.”
Some doctors are prescribing PPIs along with PERT claiming that they help the PERT do the job. Do you have a view on this and are there any general diet tips to support the job of PERT without resorting to other drugs?
“Yes if you have had a whipples operation or you have acid reflux you must take an anti-acid (proton-pump inhibitor-PPI) drug to reduce the acid level. If left untreated it can cause ulcers, and when they bleed it can sometimes lead to a life threatening situation. PERT are gastro-resistant-they do not work in too high an acid environment. Sometimes a PPI / H2 blocker can decrease the acid level and allow the PERT to work better. There is no other reliable way of reducing stomach acid.
Note: Ronny Allan input that there is information published about the over-subscribing of PPI for long term use. Additionally that some NET specialists are suggesting a preference for H2 Blockers rather than PPI for NET Patients. H2 Receptor Blockers include Nizatidine (Axid), Famotidine (Pepcid, Pepcid AC), Cimetidine (Tagamet, Tagamet HB), Ranitidine (Zantac). The exceptions would be for PPI therapy necessary for Barrett’s Esophagus and Zollinger Ellison Syndrome (Gastrinoma). Read my article on PPIs by clicking here.
Supplementary Questions:
8a. I had a whipples two and a half years ago and have recently stopped taking omperazole as I didn’t seem to need them. Do you think I should still be taking something to reduce acid level anyway?
“yep think you should be on Ranitadine or a PPI long term.”
8b. Is it possible to suffer from excess acid without even knowing it? I also take probiotics, is it possible they could be minimising any excess acid? Also, I seem to be able to eat whatever I want without consequence but am worried now in case I am doing wrong and storing up trouble for myself.
“yes you can have silent reflux but after a total pancreatectomy you needs lots of adjustments and insulin dosing advice.”
9. How will I know the PERT is working for me? And are there any tests to validate this?
“You will know if your PERT is working well if your symptoms improve – i.e. you get normal (mid brown and formed) stools.
Patients taking enough PERT will not become fat soluble vitamin deficient or lose weight in the long term.
You could do a fecal elastase test (if stools are not liquid), but this is not a very reliable test especially for patients with NETs.
If symptoms do not resolve entirely, there may be a co-existing cause of malabsorption e.g. bile acid malabsorption or small intestinal bacterial overgrowth.”
Supplementary Questions:
9a. With regards to Question 9, how would you know if you have bile acid malabsorption or SIBO? Can you be tested for those?
“If PERT doesn’t resolve things, SIBO testing is another thing to look at using a lactulose drink and hydrogen breath test. If the NET is in the terminal ileum, bile acid malabsorption (BAM) is likely. The test is a SeHCAT scan and treatment usually Questran or Colesevelam.
If I need to stop taking PERT, do I just stop or do I need to taper off consumption over time?
“No, just stop. But only do so if it has caused a side effect and report the reaction to the doctor and pharmaceutical company. If you don’t think they are working, speak with a specialist Dietitian and you may need a PPI or H2 blocker or change brand/dose.”
If someone has had a total gastrectomy, can they take Creon? If so, do they need to open up the pill to remove the gelatin to help the enzymes to work?
“They are to be taken as normally directed. You can open capsules but only into an acidic fruit juice (a pH of 4.5 or below) and swallow immediately. It could be argued that PERT will work most easily in patients having a gastrectomy as you cannot get too high a stomach acid level without stomach P-cells. By the way, shouldn’t be any gelatin in the prescribed PERT”
Supplementary Questions:
11a. Are there any problems with taking too much in a day? I have to have 7 to 8 meals (minimum). I am losing weight. Take with every snack and meal?
“You can overdose – for Creon this is 6000 units lipase per kg of body weight. If you are still losing weight, PERT is not working or something else is the cause of malabsorption”
SUPPLEMENTARY QUESTIONS AT THE END
12A. My steatorrhoea only occurs once/twice a month. Is PERT indicated if steatorrhoea is not chronic?
“Yes, probably need to take all month as steatorrhoea is only a sign of extreme malabsorption, small amounts of malabsorption aren’t noticeable visibly but will reflect in weight and blood vitamin levels.”
12B. I do not need Creon as I am a Lung NET; although I have had my gall bladder removed.
“May need PERT if on somatostatin analogues. Some people take a bile acid sequestrants after gall bladder removal. PERT won’t work for that.”
Summary
I’ve always known about issues such as steatorrhoea and vitamin/mineral deficiency. My weight is fine but very happy to trial PERT to see the differences. I made a mistake of starting the capsules on Dec 23rd just before Christmas – it made for an interesting week! Early days so far but I’m getting used to taking them (and remembering to take them ….). Still seeing signs of steatorrhoea but am tracking this against diet. Not seeing any change to stool frequency. I would appear to be belching more though! I will keep this post live as I learn more.
You may wish to see the output from an online chat I carried out, the link is above.
UPDATE 1st Feb 2019. After 1 year, I’m not sure if there has been any difference to signs of malabsorption with Creon, although the supplement did help with weight gain in the period Oct – Dec 2018 after a dose increase. I had lost weight earlier in 2018 due to a bad chest infection and was having trouble regaining it. Despite the success with the weight gain, that is no long an issue, so I commenced a 3 month trial of Nutrizym to see any change in intermittent but frequent steatorrhea, which potentially indicates a continuing malabsorption issue.
This is an excellent and positive video based overview of where we are with the Management of NETs. This is a presentation from a NET Specialist (who some of you may know) presenting to a “GI Malignancies” conference. This is therefore not only awareness of NETs, it’s also some good education for non NET GI experts who may only know the very basics. Useful for patients too! I met Dr Strosberg in Barcelona (ENETS 2017) and thanked him for his presentational and scientific paper output which I often use in my articles.
The classification picture is good as it explains the different facets of NETs and how NETs are classified and categorised in a general way – not seen it done this way before. Slightly out of date as it does not adequately convey the possibility of a well differentiated high grade recently classified by the World Health Organisation – read more here.
Amazingly it is delivered without using the word ‘carcinoid’ other than in reference to syndrome, indicating it can be done and is something also being reflected in all my posts to ensure they are up to date with the latest nomenclature. It’s also a good example for GI doctors as this branch of medicine is often involved in NET diagnostics and surveillance.
Excellent update of all the trials which have introduced treatments in the last decade.
Great update and worth the 30 minutes it takes to watch – you can view it CLICK HERE.
On the heels of the approval of PRRT in USA and whilst we all wait on positive national announcements of PRRTapproval in UK and elsewhere, here’s news of a new PRRT compound undergoing a phase 3 clinical trial. Isotopen Technologien München AG (ITM), a specialized radiopharmaceutical company, today announced the enrolment of the first patient recruited in Europe for the COMPETE phase III clinical trial at theUniversity Hospital Marburg, Germany. The CEO of ITM said “This marks the starting point of COMPETE in Europe, whereby we expect a rapid increase in the number of recruits.” I actually met these guys at ENETS 2018 – sounds great.
What is the COMPETE trial?
COMPETE is led as an international pivotal multi-center phase III clinical trial evaluating the efficacy and safety of (no-carrier-added) n.c.a.177Lu-Edotreotide (Solucin®) and the trial is comparing it to Everolimus (Afinitor). The trial runs until Dec 2020. The enrolment requires patients with inoperable, progressive, somatostatin-receptor positive neuroendocrine tumors of gastroenteric or pancreatic origin (GEP-NET). The primary endpoint is progression-free survival (PFS). The study will be conducted predominantly in Europe, North America, South Africa and Australia. The first patient to be enrolled and treated was in Australia. The clinical trial document (see references below) indicates its for non-functional GI tumours but for non-functional and functional pNETs. The list of locations can also be found in the clinical trial document. The usual inclusion/exclusion rules apply but the most notable would appear to be an exclusion for those with prior exposure to any PRRT or mTor inhibitor such as Everolimus (Afinitor).
What is 177Lu-Edotreotide (Solucin®) ?
The compound under investigation, Solucin®, is known as a Targeted Radionuclide Therapy (TRT) agent, which consists of the targeting molecule Edotreotide, an octreotide-derived somatostatin analogue and ITM´s EndolucinBeta® (no-carrier-added Lutetium-177). EndolucinBeta® is a synthetic, low-energy beta-emitting isotope of Lutetium, a recently EMA approved pharmaceutical precursor. The radiopharmaceutical Solucin® is administered as an intravenous infusion, specifically targeting and destroying the tumor cells with ionizing radiation. Solucin® received an Orphan Designation (EMA/OD/196/13) for the treatment of GEP-NET, based on early clinical experience, which has demonstrated a substantial clinical benefit with increased PFS and quality of life.
From ITM’s website … “Edotreotide contains DOTA which functions as a chelator for radioisotopes and TOC, a synthetic Somatostatin receptor ligand” (chelator and ligand are just fancy names for ‘bonding’ or ‘binding’). “The compound Edotreotide binds with high affinity Somatostatin receptors and retains both its receptor binding properties and its physiological function when labeled with 177Lu. Somatostatin receptors are predominantly overexpressed by neuroendocrine tumors. 177Lu-Edotreotide, upon binding to Somastotatin receptors in vivo is internalized and retained by tumor cells.”
“Compared to 90Y-Edotreotide, 177Lu-Edotreotide Targeted Radionuclide Therapy in NET was found to be less haematotoxic and associated with a longer median overall survival. That was highly significant for patients with low tumor uptake as well as for patients with extra hepatic and solitary metastases. In a retrospective Phase II trial 177Lu-Edotreotide showed a low uptake/dose delivered to normal organs and very high tumor-to-kidney ratio.”
Other Spin offs from ITM
Interestingly the company is also working on a ‘theranostic pair’ for imaging and treating bone metastases – see graphic below. It does not say whether this includes NET bone metastases but I don’t see why not given the connection with Solucin. However, please note this is some years away from fruition.
I quite like the Facebook memory thing. This morning I got a reminder of a post I made from 7 years ago whilst I was in hospital recovering from my 9 Nov surgery. It had taken 12 days for me to feel strong enough to venture onto social media with a simple message “I’m feeling perkier”. For those not familiar with English localisms, it just means lively, spirited, bright, sunny, cheerful, animated, upbeat, buoyant, bubbly, cheery, bouncy, genial, jaunty, chirpy, sprightly, vivacious, in fine fettle, full of beans, bright-eyed and bushy-tailed. I guess I met some of these descriptors most of the time! I had gotten through the worst and the light at the end of the tunnel was now a faint glimmer.
I’ve recently had a ton of ‘7 years ago cancerversaries’ and there’s still a few to go! I’m currently being reminded of an issue that started just after my initial treatment and by coincidence (perhaps?) the commencement of my Lanreotide (Somatuline Autogel). Itching! However, for me, it’s mainly the right leg below the knee (go figure!). Much less frequently on my arms and sides. I know many people have the same issue but no-one ever seems to find out why – I guess it’s that Neuroendocrine jigsaw thing again?
Initially, I put the issue down to Lanreotide, as this is mentioned in the side effect list on the drug instructions. The initial connection was made because it seemed to be happening immediately after my monthly ‘dart’. A really annoying itch mostly around my ankles and which had to be scratched! An application of a general emollient cream for a few days seemed to do the trick and after a week it was gone (until the next injection …..). However, after a few years, I sensed the issue was drifting away from the injection cycle and adopting a different and more random pattern. I’m also suspicious of a nutritional connection and checking my article Nutrition for NETs -Vitamins and Mineral Challenges, I can see Vit B3 (Niacin) and Vit E are mentioned in regards skin issues. I’d be confused if this was an issue today as I now take plenty supplements to offset GI malabsorption. However, I probably wasn’t taking sufficient between surgery and 2013 as I lacked the knowledge to do so at the time. So nutritional deficiency remains a possibility or at least an added complication. The most recent outbreak has unusually gone on for the last 4 weeks.
I also seem to have had an eczema type issue in my right ear and mild rosacea for more than 7 years (pre diagnosis). As you can imagine my ‘inner detective’ is working overtime! One thing is clear – this itchy leg issue has plagued me for 7 years.
I know that many people have real issues with rashes and skin itching, I’ve seen this so many times with some people describing it as severe. Clearly when this is the case, a doctor’s intervention is generally required. I’ve seen the following connections to NETs and skin issues:
Glucagonoma – a type of functioning pNET can often come with dermatological issues.
Mastocytosis – interesting this site recommends marker testing to rule out Gastronomas (Zollinger-Ellison Syndrome), Carcinoid Syndrome and Pheochromocytoma
Of course there is a Neuroendocrine Carcinoma of the skin known as Merkel Cell Carcinoma – more of a skin lesion effect than regular dermatological issues.
Edit: 2019. Winter in UK has made my itching seem worse, perhaps the cold weather plays a factor. Maybe I just currently have what many people have – dry flaky skin and the onset of winter probably isn’t helping?
ASCO (American Society of Clinical Oncology) is one of the biggest cancer conferences in the world normally bringing together more than 30,000 oncology professionals from around the world to discuss state-of-the-art treatment modalities, new therapies, and ongoing controversies in the field. As Neuroendorine Tumors is on a roll in terms of new treatments and continued research, we appear to be well represented with over 20 ‘extracts’ submitted for review and display. This is fairly complex stuff but much of it will be familiar to many. I’ve filtered and extracted all the Neuroendocrine stuff into one list providing you with an easy to peruse table of contents, complete with relevant linkages if you need to read more. For many the extract title and conclusion will be sufficiently educational or at least prompt you to click the link to investigate further. Remember, these are extracts so do not contain all the details of the research or study. However, some are linked to bigger trials and linkages are shown where relevant. I’ve also linked to some of my blog posts to add context and detail.
I’m hoping to capture any presentations or other output from the meeting which appears to be relevant and this will follow after the meeting. I will also be actively tweeting any output from the live event (for many cancers, not just NETs).
There’s something for everyone here – I hope it’s useful.
Conclusions: Objective response to PRRT defines a subset of patients with markedly improved PFS. SUVave 21.6 defines a threshold below which patients have a poor response to PRRT. This threshold should be taken forward into prospective study.
Check out my recent blog discussing ‘Theranostic pairing” – click here
Conclusions: The duration of SSA use was positively associated with QoL benefit among CS patients. This may be explained by long-term effectiveness of SSAs or selection bias favoring patients with more indolent disease. Future studies will be needed to distinguish between these possibilities.
Conclusions: The incidence of weight gain was dose-related on TE and was greater than that on pbo. It was possibly related to a reduction in diarrhea severity, and it may be a relevant aspect of TE efficacy among patients with functioning metastatic NETs. Clinical trial information: NCT01677910
Conclusions: A pre-PRRT analysis of circulating NET genes, the predictive quotient index comprising “omic” analysis and grading, is validated to predict the efficacy of PRRT therapy in GEP and lung NETs.
Conclusions: CAPTEM shows activity in neuroendocrine tumor of unknown primary. Currently FDA approved treatment options for grade I and grade II GI NETs includes somatostatin analogs and everolimus. Both of which are cytostatic and of limited use in case of visceral crisis or bulky disease where disease shrinkage is required. CAPTEM should be considered for grade II NETS of unknown primary.
Conclusions: This is the first multi-center study in Mexico. Which reflects the clinical characteristics of the NET_GET. The results differ in their epidemiology from that reported in other countries. However, the clinical and therapeutic results are very similar.
Conclusions: These data suggest that serotonin is secreted by nonfunctioning tumors, but does not reach the threshold required for clinical carcinoid symptoms. Monitoring 5HIAA and CgA may be useful during LAN treatment of nonfunctional GEP NETs. Clinical trial information: NCT00353496
Conclusions: CLARINET OLE suggests sustained antitumor effects with LAN 120 mg in enteropancreatic NETs irrespective of tumor origin, and suggests benefits with LAN as early treatment. Clinical trial information: NCT00842348
Conclusions: Pts showed improvement in CS symptoms of flushing and diarrhea and reduction in 5HIAA levels with LAN treatment, indicating efficacy of LAN regardless of prior OCT use. Transition from OCT to LAN was well tolerated among prior OCT pts in ELECT. Clinical trial information: NCT00774930
Conclusions: These findings highlight the utility of molecular classification to identify distinct NET tumor types/subtypes to improve diagnostic precision and treatment decision-making. In addition, significant differences in the distribution of molecular diagnoses of NET subtype by age and gender were identified.
Conclusions: In PNETS, multi-omic profiling through the KYT program identified targetable alterations in several key pathways. Outcome data will be explored.
Conclusions: In this poor prognosis G3 NET cohort of whom 77% had received prior chemotherapy, a median OS of 18 months from start of PRRT is encouraging and warrants further study. PRRT is a promising treatment option for patients with G3 NET with high somatostatin-receptor expression selected by SSRI.
Conclusions: Occurrence of documented carcinoid crisis was low in this high-risk population. However, a significant proportion of patients developed hemodynamic instability, suggesting that carcinoid crisis is a spectrum diagnosis and may be clinically under-recognized. Use of octreotide was not associated with risk of carcinoid crisis or hemodynamic instability; however, this analysis was limited by our modest sample size at a single institution. There remains a need to establish an objective definition of carcinoid crisis and to inform standardization of periprocedural use of octreotide for at-risk patients.
Conclusions: By assessing patients with GI NET from two independent US claim databases, this study suggested that patients diagnosed with CS were 2-3 times more likely to be diagnosed with liver disorder, enlargement of lymph nodes, or abdominal mass, than those without CS during the one year prior to CS diagnosis. Future studies using patient medical charts are warranted to validate and interpret the findings. These findings, when validated, may aid physicians to diagnose CS patients earlier.
Conclusions: Radiological progression within 12 months of completion of PRRT is associated with a worse outcome in terms of OS. Patients with greater liver involvement and highest CgA levels are more likely to progress within 12 months of treatment completion. Earlier treatment with PRRT in patients with radiological progression not meeting RECIST criteria may need to be considered. There may be a greater survival benefit if PRRT is given prior to the development of large volume disease.
Conclusions: To the best of our knowledge, this is the first population-based study to examine potentially relevant pre-existing symptoms, resource utilization and healthcare costs before NET diagnosis. NET patients were more likely to have certain conditions and incurred higher resource utilizations and costs in the year preceding diagnosis of NET.
Conclusions: This population-based study showed that elderly NET pts have significantly different prevalence of co-morbidities compared to non-cancer controls. The impact of these conditions on survival and therapeutic decisions is being evaluated.
Conclusions: In patients with SBNET with liver metastasis, higher tumor grade and post-operative chemotherapy increased risk of death. However, resection of the primary tumor along with liver metastasis improves the 5-year OS with complete cytoreduction providing the most benefit.
Role of 92 gene cancer classifier assay in neuroendocrine tumor of unknown primary. | 2017 ASCO Annual Meeting Abstracts
Conclusions: Tissue type ID was able to identify a primary site in NETs of unknown primary in majority (94.7%) of cases. The result had direct implication in management of patients with regards to FDA approved treatment options in 13/38 patients (pNETs, merkel cell and pheochromocytoma).
Conclusions: Radical loco-regional surgery for primary tumours combined with PRRT provides a novel, highly efficacious approach in metastasised NET. The NETest accurately measures the effectiveness of treatment.
Conclusions: Grade 3 GEP-NECs could be morphologically classified into well and poorly differentiated NETs. Additionally, among grade 3 GEP-NECs, there was a significant difference in ranges of Ki67 index between well and poorly differentiated NECs. Higher levels ( > 60%) of Ki67 index might be a predictive marker for efficacy of EP as a standard regimen in grade 3 GEP-NECs.
Check out my blog post on Gradingwhich has incorporated latest thinking in revised grade 3 classification
Seung Tae Kim
e15686
Theranostic trial of well differentiated neuroendocrine tumors (NETs) with somatostatin antagonists 68Ga-OPS202 and 177Lu-OPS201.
Conclusions: In this trial of heavily treated NETs, preliminary data are promising for the use of 68Ga-OPS202/177Lu-OPS201 as a theranostic combination for imaging and therapy. Additional studies are planned to determine an optimal therapeutic dose and schedule. Clinical trial information: NCT02609737
Conclusions: SREs in NEN patients with BM were not uncommon, especially in patients with grade 3 NEN and osteolytic metastases. Application of ART did not significantly alter median OS or TTSRE, no subgroup with a benefit of ART could be identified. The use of ART in NEN should be questioned and evaluated prospectively.
Conclusions: Rhenium Re 188 P2045, a radiolabeled somatostatin analog, may be used to both identify and treat lung cancer tumors. The ability to image and dose patients with the same targeted molecule enables a personalized medicine approach and this highly targeted patient therapy may significantly improve treatment of tumors that over express somatostatin receptor.
What is Peptide Receptor Radionuclide Therapy (PRRT)?
For those who are still not sure what it’s all about. This is a non-surgical treatment which is normally administered intravenously. It’s based on the use of somatostatin receptors to attract a ‘radiopeptide’. The radiopeptide is a combination of a somatostatin analogue and a radioactive material. As we already know, somatostatin analogues (i.e. Lanreotide/Octreotide) are a NET cell targeting drug, so when combined with radioactivity, it binds with the NET cells and delivers a high dose of targeted radiation to the cancer while preserving healthy tissue. In general, patients tend to receive up to 4 sessions spaced apart by at least 2 months.
PRRT will not work on all NETs and not everyone will suited to this treatment. In general, for this treatment to be more successful, you must have somatostatin receptors in your tumors. Success rates are not 100% – it should not be considered a cure or ‘magic bullet’. However, the results are said to be pretty good. The NETTER-1 trial data which has led to formal approval in Europe, USA and other areas, can be found here.
LATEST ON EXPANDED NETTER-1 TRIAL DATA. “Novartis has announced presentation of a new analysis of Lutathera (lutetium Lu 177 dotatate) NETTER-1 data at the 2018 European Society for Medical Oncology (ESMO) congress examining the impact of Lutathera treatment on patients with low, medium or high liver tumor burden. The data show that Lutathera treatment results in significant improvement in progression free survival (PFS) regardless of the extent of baseline liver tumor burden (LTB), elevated alkaline phosphatase (ALP) liver enzyme or presence of large (>30mm diameter) lesion in patients with progressive midgut neuroendocrine tumors (NETs) compared to octreotide LAR alone.”
Read the latest news on the NETTER-2 trial here. This is designed to look at the benefits of using PRRT on Grade 2 and Grade 3 patients as a first line treatment.
THERANOSTICS
Understanding the terminology is half the battle in understanding the latest developments. I’ve included Ga-68 PET scans within this section (or in more general terms Somatostatin Receptor PET (SSTR PET)) as the term ‘Theranostics‘ is becoming a commonly used theme. Theranostics is a joining of the words diagnostics and therapy.
LUTATHERA is the radionuclide ‘mix’ for use in Peptide Radio Therapy Treatment (PRRT). You may also see this drug called ‘Lutetium’ or ‘Lu-177 dotatate’, or just ‘Lu-177’ on its own. Yttrium 90 (Y-90) is a radionuclide also used in PRRT.
NETSPOT (USA) or SOMAKIT TOC (Europe) is not PRRT but it is the commercial names for the radiopeptide used in Gallium 68 (Ga-68) PET diagnostic scans.
Together they form a ‘theranostic pair’. Theranostics is apt as together (NETSPOT / SOMAKIT TOC and Lutathera), both target NETs expressing the same somatostatin receptor, with Lutathera intended to kill tumor cells by emitting a different kind of low-energy, short-range radiation than that of the diagnostic version.
Moreover, thanks to the theranostic approach that nuclear medicine allows, Novartis/AAA’s NETSPOT/SomaKit TOC products will be able to determine when Lutathera is the appropriate treatment.
Of course, this therapy has been in use in Europe and some other places for some time but to be honest, they have been on a limited scale and never formally approved by national drug agencies. Despite its extensive use, the EU approval in 2017 was actually the very first approval of PRRT anywhere in the world. For example, in UK, it was used for some time for those in need but was removed from routine availability through a ‘slush fund’ formally known as the Cancer Drugs Fund – to cut a long story short, the funding source was cut off, although there are still ways of obtaining the treatment pending formal acceptance by the NHS (certain criteria apply).
In the meantime, I constantly see stories of patients travelling to Switzerland, Germany, Netherlands, Sweden, Great Britain and others; mostly at their own cost. However, it does indicate one thing, there is a huge unmet need in that many patients do not have access to the best treatments in their own country. I see this daily through many private messages.
What about Grade 3 (High Grade) Neoplasms?
The main treatment for Grade 3 is chemotherapy, particularly poorly differentiated. PRRT tends to work better with efficient somatostatin receptors (i.e. somatostatin receptor-positive tumors). The European approval wording only covers Grades 1 and 2. The US FDA approval indicates “somatostatin receptor-positive tumors”. It’s also worth noting that with Grade 3, working somatostatin receptors are more likely to exist in Grade 3 well differentiated NETs, particularly in the lower Ki-67 readings (less than 55%). However, there’s an interesting study from Australia which might be useful to read – check out the abstracthere (note the full version is not available free).
2019 Updated data for Grade 3 Neuroendocrine Neoplasms:
“Compared to studies evaluating the efficacy of chemotherapy for NEN patients with a Ki-67 index less than or equal to 55 percent, PRRT has a longer overall survival rate–22 months versus 14 months,” the researchers pointed out. “These results suggest that PRRT, rather than chemotherapy, may be a superior first-line therapeutic option in selected patients with a high level of SSTR expression and a Ki-67 index of less than or equal to 55%.” Read more here.
Merkel Cell Carcinoma. Although not indicated for this type of Neuroendocrine Neoplasm, there is evidence to suggest that this skin Neuroendocrine Carcinoma does express somatostatin receptors. Read more here.
This article discusses the efficacy of PRRT in Pheo/para – click here. There’s actually still a trial for Pheochromocytoma/Paraganglioma (Pheo/Para). It is known that Pheo/Para can have somatostatin receptor tumors so a useful trial. The aim of the trial is to assess the safety and tolerability. You can read about the trial here.
Where can I get PRRT?
Where can I get PRRT?
Regional Updates
The aim of this section is to update on a regional basis in order to inform an international community of followers and readers.
Background
I wanted a place to review what is happening globally given my following. In many countries, however, I’m dependent on feedback from patients in those countries. Please note this is not intended to be a 100% complete breakdown on everything about PRRT or PRRT centres – it’s a summary. It should be clear from below but please bear that in mind when reading.
This section of this article will cover each region, indicating where PRRT can be obtained (as far as I know). It is not designed to indicate whether this is through public or private facilities (this will depend to too many factors beyond the reach of this article). Please note this is not intended to be a 100% complete breakdown on every single PRRT centre – it’s a summary. This actually should be clear from below but please bear that in mind when reading.
UNITED KINGDOM
On 29 August 2018. National Institute for Health Care Excellence (NICE) England has formally published that Lutetium (177Lu) oxodotreotide, within its marketing authorisation, is an option for treating unresectable or metastatic, progressive, well-differentiated (grade 1 or grade 2), somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours (NETs) in adults. CLICK HERE to read the approval. Currently available in the following NHS locations:
London – at least 2 locations – Royal Free, Guys and St Thomas
Liverpool – The Royal
Manchester – The Christie
Sheffield – Weston Park
Bristol – Bristol Oncology Centre
Newcastle – Freeman Hospital
Coventry – University Hospital
Anecdotal mention of Leicester but waiting to hear confirmation.
On 9 July 2018. The Scottish Medicines Consortium (NICE equivalent) has approved lutetium 177Lu (Lutathera) for patients in NHS Scotland. Good news for Scotland once their hospitals have the capability to deliver. Scottish patients would then not need to travel to England for the NHS Scotland funded treatment. Read more here.
It is funded in Wales and Northern Ireland but is currently administered in England with inter NHS budget transfers.
Canada
On 7th Feb 2019, Health Canada approved Lutathera™ (lutetium (177Lu) oxodotreotide) for the treatment of unresectable (not removable by surgery) or metastatic, well-differentiated, somatostatin receptor-positive (expressing the somatostatin receptor) gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in adults with progressive disease. The treatment was previously available on a trial basis. Read more here.
Site update to follow but the following trial locations may be up and running first:
Juravinski Hamilton
LHSC London
PMCC Toronto
Sunnybrooke Toronto
Cross Cancer Institute, Edmonton
USA
PRRT was approved in USA on 26 Jan 2018.The approval is for the treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults. CLICK HERE.
The extended access program (trial) is no longer offered but these locations should be ahead of the game in terms of provision, notwithstanding insurance and provision of sufficient nuclear material.
In the meantime, known USA sites offering routine “live site” insurance based PRRT treatment are as follows – please note information has been gleaned from US patients due to no other consolidated source of this information being readily available. It’s possible some patients got mixed up between trial locations and live locations so let me know of any omissions or additions/corrections – thanks in advance.
DRAFT – NOT YET COMPLETE – (as at 16 May 2019)
STATE
LOCATION
Due in Service?
CONTACT DETAILS
Arizona
Banner
Now
Dr Boris Naraev
California
UCSF Medical Center Mission Bay San Francisco
Now
tbc
California – Antioch
Kaiser Permanente Antioch Medical Center
Now
tbc
California
Cedars Sinai Medical Center LA
now
tbc
California
Stanford Medical Center
Now
tbc
California
Kaiser Permanente Los Angeles Medical Center
Now
tbc
California
Hoag Hospital Newport Beach
Now
tbc
California
UCLA Health
Now
tbc
California
Kaiser Santa Clara Medical Center
Now
tbc
California
City of Hope LA
Now
tbc
California
San Diego
Now
tbc
Connecticut
Yale New Haven Medical Center
Now
tbc
Connecticut
Hartford Hospital
Now
Salner, Andrew, MD
Radiation Oncology
Colorado
Rocky Mountain Cancer Center Denver
Now
Dr Eric Liu
Colorado
University of Colorado UC Health Denver
Now
tbc
Florida
Moffat Tampa
Now
Dr Strosberg
Florida
University of Miami
Now
tbc
Florida
Mayo Jacksonville
Now
tbc
Florida
Winter Park, Florida Radiation Oncology Orlando
Now
David Diamond MD
Florida
Orlando Health
Now
tbc
Georgia
CCTA Newnan, Atlanta
Now
Dr. Phan
Hawaii
Queen’s Medical Center
Now
Dr. Marc Coel
Idaho
Mountain States Tumor Institute at St. Luke’s Hospital, Boise
Now
Idaho
Eastern Idaho Regional Medical Center, Idaho Falls, Idaho
Now
Illinois
Rush University Chicago
Now
Illinois
Northwestern Chicago
now
tbc
Illinois
The University of Chicago Medicine
now
Xavier M. Keutgen, MD
Illinois
Loyola University Medical Center Maywood
now
tbc
Illinois
CTCA Chicago
now
tbc
Indiana
Indiana University Health
now
tbc
Iowa
University of Iowa
now
Dr T O’Dorisio
Kansas
University of Kansas Medical Center Fairway
now
tbc
Kentucky
University of Kentucky, Markey Cancer Center
now
tbc
Louisiana
Ochsner
now
tbc
Maryland
John Hopkins Baltimore
now
tbc
Massachusetts
Dana Farber Boston
Now
tbc
Massachusetts
Massachusetts General Hospital
Now
tbc
Michigan
Ann Arbor
Now
tbc
Michigan
Detroit – Karmanos Cancer Center
Now
tbc
Minnesota
Mayo Rochester
Now
Dr. Thor Halfdanarson
Minnesota
University of Minnesota Health
Now
tbc
Missouri
Sara Canon Cancer Center Kansas City
Now
tbc
Missouri
Siteman Cancer Center St. Louis/Barnes Jewish Hospital St. Louis
Now
tbc
Nebraska
CHI Bergan
Now
Dr Samuel Mehr
Nebraska
Nebraska Cancer Specialists Omaha
Now
Dr Samuel Mehr
New York
Lenox Hill NYC
Now
tbc
New York
Sloan Kettering
Now
tbc
New York
Stony Brook University Cancer Center Long Island
Now
Nurse Navigator, Patty Zirpoli, RN
New York
Roswell Park Buffalo
Now
Dr Iyer
New York
Mount Sinai
Now
tbc
New York
NYU Langone
Now
tbc
North Carolina
Dukes Durham
Now
tbc
Ohio
The James, Columbus
Now
Dr Shah
Oregon
Oregon Health & Science University (OHSU)
Now
tbc
Pennsylvania
UPMC Pittsburgh
Now
tbc
Pennsylvania
Fox Chase Philadelphia
Now
Dr Paul Engstrom
Rhode Island
Rhode Island Hospital Providence
Now
Dr Paul Engstrom
South Dakota
Sanford in Sioux Falls
now
tbc
Tennessee
Vanderbilt Nashville
Now
tbc
Texas
MD Anderson Houston
Now
tbc
Texas
Excel Diagnostics Houston
Now
tbc
Texas
CHI St Lukes Houston
Now
tbc
Texas
BAMC San Antonio(VA) Houston
Now
tbc
Utah
Huntsman Cancer Institute, Salt Lake City
Now
tbc
Vermont
University of Vermont Medical Center
Now
Jay Kikut, MD, Director of Nuclear Medicine and PET
Virginia
Carilion Clinic Roanoke
Now
tbc
Washington (State)
Virginia Mason Seattle
Now
Dr. Hagen Kennecke
Washington (DC)
VMedStar Georgetown University Hospital
Now
tbc
West Virginia
VMU Cancer Institute Morgantown
Now
Shalu Pahuja, M.D
Wisconsin
UW Health Madison, Carbone Cancer Center
Now
Noelle K. LoConte, MD Specialty: Medical Oncology Primary Location: UW Carbone Cancer Center (608) 265-1700 (800) 323-8942
Wisconsin
Froedtert Milwaukee
Now
Dr Thomas
Europe (excluding UK which is listed above)
The European Medicines Agency (EMA) “market authorisation” received a positive indication on 20th July followed by EC approval on 29 Sep 2017. The positive indication reads “Lutathera is indicated for the treatment of unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours (GEP NETs) in adults”. Of Course, the decision to fund the drug will be with national approval organisations. Whilst I’m sure there are many more, these well-known centres have been making PRRT available for some years (but please note there are others):
Denmark – ‘Rigshospitalet’ since 2009. They have treated around 250 patients- and given 800 treatments.Netherlands – Rotterdam Treatment Centre – click here
Slovenia –Ljubljana, University medical Centre Ljubljana
Sweden – Department of Endocrine Oncology Uppsala University Hospital – click here
Switzerland – University Hospital Basel, Radiology & Nuclear Medicine Clinic – click here
I’d be interested to hear from countries in Europe with their full list of centres or a link to it.
Australia
Australia seems to be ahead of the game or that is what I sense when I read output from there. There’s a good section on the Australian effort – click here.
New Zealand
These guys have had to fight to get some progress on the provision of PRRT. Currently New Zealanders have to go to Melbourne Australia for treatment – almost 50 New Zealanders with NETs are currently raising tens of thousands of dollars to pay for treatment in Australia because the life-prolonging treatment isn’t available locally. But this could change in 2018. Unicorn Foundation New Zealand announced that Pharmac, the New Zealand government agency that decides which pharmaceuticals, have said that PRRT will be funded for patients with medium priority for the treatment of unresectable or metastatic, well-differentiated NETs (irrespective of primary site) that express somatostatin receptors.
Lebanon – The American Hospital of Beirut – Dr Ali Shamseddine “We have started using Lu-177 here in Lebanon. So far, we have treated 3 patients, with good response. The operational cost is much less than in Europe”.
India – Mahatma Gandhi Cancer Hospital, Visakhapatnam. Recently started radionuclide therapy. Although only currently available privately, some patients have been sponsored by the companies that they work for. Point of contact is Dr. K. Raghava Kashyap. I’ve been assured by CNETS India that many locations have PRRT capability – contact them direct please. Also – TATA Memorial Hospital Mumbai (waiting time is long, but cost is low: $200) and there are private clinics in Pune (cost is $1500) and Bengaluru (cost is around $6000). (Info from Russian patient group).
Kuwait – Kuwait Cancer Control Center (KCCC) – read article here.
There’s a lot of inaccurate and out of date information out there. Some is just a lack of understanding, often with a combination of patient forum myth spreading. Some can only be described as propaganda.
Myth 1: All Neuroendocrine Tumours are benign
Not true. By any scientific definition, the word ‘tumour’ means ‘an abnormal mass of tissue that results when cells divide more than they should or do not die when they should. Tumours may be benign (not cancerous), or malignant (cancerous)’. Sure, some NETs will be benign. However, The World Health Organisation (WHO) 2010 classification for digestive system is based on the concept that all NETs have malignant potential, and has therefore abandoned the division into benign and malignant NETs and tumours of uncertain malignant potential. This has been reinforced in the 2017 update to include clarification for other endocrine organ types of NET including Pheochromocytoma. Read more here. The word ‘Carcinoid’ is inextricably linked with this issue – read here why we need to stop using the term to help fight the benign myth.
Myth 2: Neuroendocrine Tumours is a terminal condition
Not true. By any definition of the word terminal in a medical diagnostic context, most NET patients have a good prognostic outlook, even those with metastatic and incurable variants of the disease. Read more here.
Graphic courtesy of Ellie McDowell
Myth 3: Carcinoid is another word for Neuroendocrine Tumours
Not true. Carcinoid is a very old term and was phased out years ago. Carcinoid is not mentioned in the latest WHO Classification schemes for Neuroendocrine Neoplasms (a term covering Neuroendocrine Tumours and Neuroendocrine Carcinoma). Unfortunately, the problem is exacerbated by organisations and individuals who still use the word. Also, those who use the following terms:
“Carcinoid Neuroendocrine”,
“Neuroendocrine Carcinoid”,
“Carcinoid and Neuroendocrine”,
“Neuroendocrine and Carcinoid”,
“Carcinoid NETs” or “CNET”
These are all contextually incorrect and misleading terms (not to mention the bad grammar). ENETS, NANETS and NCCN publications are gradually phasing the word out except in relation to Carcinoid Syndrome (and even then there could be easy solutions for this). Read more here and here.
Myth 4: All NET patients get ‘carcinoid syndrome’
Not true. Firstly, many NET cancers are non-functional; and secondly, carcinoid syndrome is only one of a number of “NET Syndromes” associated with the various types of NET. However, the issue is further confused by those who use the word ‘Carcinoid‘ to incorrectly refer to all NETs and use Carcinoid Syndrome to refer to all NET Syndromes. Read more here.
Myth 5: Neuroendocrine Neolasms are rare
Not true. As a collective grouping of cancers, this is no longer accurate. Read more here. Also check out my post about the “Invisible NET Patient Population“.
Myth 6: Steve Jobs had Pancreatic Cancer
Not true. Steve Jobs had a Neuroendocrine Tumour of the Pancreas. Ditto for a few other famous names. Read more here.
The last few years have reminded me that life is fragile
Myth 7: I’m not getting chemotherapy, I must be doing OK?
Not true. For some cancers or some sub-types of cancers, although it remains an option, chemotherapy is not particularly effective, e.g. some types of Neuroendocrine Cancer (NETs). In general, well differentiated NETs do not normally show a high degree of sensitivity to chemotherapy, although some primary locations fare better than others. However, many of the treatments for NET Cancer are somewhat harsh, have long-term consequences, and have no visible effects. NET patients are often said to “look well” but that doesn’t mean they are not struggling behind the scenes or under the surface. Read more here. P.S. Afinitor (Everolimus), Sutent (Sunitinib) are not chemo – Read more here.
Myth 8: All diarrhea is caused by carcinoid syndrome
Not true. It could be one of the other syndromes or tumor types or a side effect of your treatment. Check out this post.
Myth 9: Neuroendocrine Tumours is a ‘good cancer’
Not true. Simply, no cancer is good. Some are statistically worse than others in prognostic terms, that’s true…… but living with NETs is very often not a walk in the park. However, no one cancer is better to get than any other – they’re all bad. Read more here.
Myth 10: Every NET Patient was misdiagnosed for years
Not true. Many NET Patients are correctly diagnosed early on in their investigation and in a reasonable time. This myth is perpetuated because of two things: firstly, on forums, the ratio of long-term misdiagnosis is high creating a false perception; and secondly, the method of capturing patient surveys is not extensive enough – again creating a false perception. In fact, the latest and largest database analysis from US indicates earlier diagnosis is improving, with more and more NETs being picked up at an early stage. Read more here.
Myth 11: Somatostatin Analogues are a type of Chemotherapy
Not true. Somatostatin Analogues (e.g. Octreotide and Lanreotide) are not chemotherapy, they are hormone inhibiting drugs. They are more biotherapy. As the drugs latch onto somatostatin receptors, they are more targeted than systemic. For the record, Everolimus (Afinitor) and Sunitinib (Sutent) are not chemotherapy either. Read more here.
Myth 12: Stuart Scott (ESPN) and Audrey Hepburn had Neuroendocrine Cancer.
Not true. This is a common misunderstanding within the community. They both had Pseudomyxoma Peritonei (PMP). Read more about PMP here.
Myth 13: I’ve been diagnosed with Neuroendocrine Tumours – my life is over
Not true. Many patients live a very long time and lead fairly normal lives with the right treatment and support. It’s difficult but I try not to use ‘I can’t’ too much. Read more here.
Myth 14: There are only a handful of Neuroendocrine specialists in the world
Not true. There are many specialists in many countries. Get links to specialists by clicking here
Myth 15: The Ga68 PET scan is replacing the CT and MRI scan in routine surveillance for all NET Patients
Not true. It is actually replacing the Octreotide Scan for particular purposes, or will eventually. Read more by clicking here.
Myth 16: All NET Patients are Zebras
Not true. They are in fact human beings and we should treat them as such. Please don’t call me a zebra, I and many others don’t appreciate it. Please don’t use the term on my social media sites, the comment or post will be removed. Sorry but I refuse to perpetuate this outdated dogma. Read why here:
Myth 17: Multiple Endocrine Neoplasia (MEN) is a type of Neuroendocrine Tumour
Not true. Multiple Endocrine Neoplasia are syndromes and inherited disorders not tumours. You can actually have MEN and not have any tumours. However, these disorders can put people at more risk of developing Neuroendocrine or Endocrine Tumours. Read morehere
Myth 18: Palliative Care means end of life or hospice care
Not true. Palliative care is specialized medical care that focuses on providing patients relief from pain and other symptoms of a serious illness. A multidisciplinary care team aims to improve quality of life for people who have serious or life-threatening illnesses, no matter the diagnosis or stage of disease. Read more here
Myth 19: Serotonin is found in foods
Not true. Serotonin is manufactured in the body. Read more here
Myth 20: NETs cannot be cured
Not true. If caught early enough, some NETs can be treated with curative intent (totally resected with margins) with little or no further follow up. It says this in ENETS and NANETS publications which are authored by our top specialists. If we can’t believe them, who can we believe? Read more here.
Myth 21: Pancreatic Enzyme Replacement Therapy (Creon etc) is only for pancreatic patients
Not true. It’s for any patient who is exhibiting exocrine pancreatic insufficiency. Read more here.
Myth 22: High Grade NETs are Carcinomas
Not entirely true. Grade 3 (high grade) comprises well differentiated tumours and poorly differentiated tumours. Only poorly differentiated tumour are carcinomas. Read more here.
More to follow no doubt
For general cancer myths and the dangers of fake health news, please see my ARTICLE HERE
Thanks for reading
Ronny
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OPINION. Date of Article March 2017. In the last 24 months, there seems to have been announcement after announcement of new and/or upgraded/enhanced diagnostics and treatment types for Neuroendocrine Cancer. Increased availability of radionuclide scans, increased availability of radionuclide therapies, combination therapies, increased availability of somatostatin analogues, biological therapies, enhanced surgical and minimally invasive techniques, new oral drugs for carcinoid syndrome, more trials including immunotherapy. Admittedly, some of the announcements are just expansions of existing therapies having been approved in new 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, regardless of where they live, need access to the best diagnostics and treatments for them; and at the requisite time. This alone is one very big unmet need in a whole range of countries still lacking.
The ‘War on Cancer’ forgot about Neuroendocrine
The ‘war on cancer’ has been around for the last 50 years, it’s still being waged. There are now more ‘fronts’ and it’s taking longer than thought to find the ‘cure’. Despite this 50 year war, it seems like there’s only been a war on Neuroendocrine Cancer for the last 10 of those years. I guess they were focused on the big cancers and/or the seemingly impossible ‘universal cure’. Prior to that, for NETs, there is only evidence of some skirmishes, more like guerrilla warfare. Now we have a developed nuclear capability! I believe the turning point was the SEER database work carried out by Dr James Yao in 2004 who confirmed the incidence had grown by 400% in 3 decades, i.e. confirming it was no longer rare. The rise of both incidence and prevalence was then amplified in the follow on ‘2012’ study (Desari et al) which confirmed a 640% increase in 40 years.
Let’s not forget about the consequences of cancer
It is true that half of people diagnosed with cancer now survive for at least ten years. Many live for years with cancer, on ‘watch and wait’ or going through various treatments and tests; their future remaining uncertain. For this group, and even for those whose treatment has successfully removed or shrunk their tumour, the struggle with the consequences and late effects of cancer and its treatment can last for years. Many Neuroendocrine Cancer patients fit into this category.
There’s a lot of work going on within all cancer communities to address the unmet needs of cancer patients who are now living with cancer rather than dying of it. Clearly we need this type of support in the NET world. The issue has been discussed at ENETS for the last two years and I was pleased to have asked the very first question about this particular unmet need, emphasising we need more support for those living with Neuroendocrine Cancer, including research into their common issues. I’ve yet to see any concrete output from the two year’s worth of campaigning.
The first question to the first ever joint patient-physician symposium
Unmet Needs for NETs
So, there’s a lot of treatments for many types of Neuroendocrine Cancer out there, just not everyone has access to them – therefore an unmet need at the international level. Others are earlier diagnosis, access to multi-disciplinary teams (MDT), ability to access quality information at diagnosis and beyond including clinical trials, funding, accurate national registries to improve statistics and more treatments fot some of the less common types. One area where I feel there is a huge unmet need is in the area of patient support following diagnosis. Although some countries are more advanced than others in this area, even in the so-called advanced countries, there are huge gaps in provision of long-term support for those living with Neuroendocrine Cancer. For example, physicians need to focus more on:
Late diagnosis. People will be dealing from the effects of late diagnosis which has resulted in metastatic disease – and some people will have been fighting misdiagnosed illnesses for years. That takes its toll.
Consequences of Surgery. People will have had surgery which in many cases is life changing – various bits of the gut (gastrointestinal tract) are now missing, lungs are now missing – many other locationswill have been excised or partly excised. These bits of our anatomy were there for a purpose and QoL takes a hit when they are chopped out.
Inoperable Tumours and Syndromes. People will be dealing with remnant and/or inoperable tumours which may or may not be producing an associated NET syndrome (some of the symptoms can be rather debilitating in the worst cases)
Consequences of Non-surgical Treatment. Additionally, people will be dealing with the side effects of multi-modal non surgical treatments, such as somatostatin analogue hormone therapy (Octreotide/Lanreotide), chemotherapy, biological therapy (mTOR inhibitors) (i.e. Everolimus (Afinitor)), biological therapy (protein kinase inhibitors (i.e. Sunitinib (Sutent)), radionuclide therapy (i.e. PRRT). Whilst it’s great there are a wide range of therapies, they all come with side effects.
Secondary Illnesses and Comorbidities. Some people will have gained secondary illnesses in part due to the original cancer or treatment – e.g. somatostatin analogue hormone therapy can have a side effect of increasing blood sugar to diabetic levels. There are many other examples.
Finances. NET Cancer can be an expensive cancer to treat and this is exacerbated by the length of time the treatment lasts. A highly prevalent cancer, treatment is for life. It follows that NET Cancer is an ‘expensive’ cancer to have. Whilst most people have access to free public services or private insurance, many people will still end up out-of-pocket due to their cancer.
Emotional Aspects. Many NET patients are kept under surveillance for the remainder of their lives. With that comes the constant worry that the cancer progresses, tumours get bigger, new tumours show up, treatments are denied (i.e. PRRT in the UK). It’s no surprise that anxiety and depression can affect many patients in these situations. To some extent, there can be a knock-on effect to close family members and carers where applicable.
As I said in my question to the panel, even if you found a cure for NETs tomorrow, it will not replace the bits of my GI tract excised as part of my treatment. For many people, even ‘beating’ cancer might not feel much like a ‘win’. It’s a two-way street though – we need to work with our doctors, trying to change lifestyles to cope better with some of these issues. This is why it’s really important to complete patient surveys. However, my point is this: more research into some of these issues (e.g. nutrition, optimum drug dosage, secondary effects) and earlier patient support to help understand and act on these issues, would be good starters. I think some centres are doing elements of this type of support but we need a guideline generating in national and international groupings so that that others can be persuaded to formally introduce it.
“Adding life to years is as important as adding years to life”
Thanks for listening
Ronny
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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
Thanks for reading
Ronny
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Courtesy of Pashtoon Kasi MD on Twitter https://twitter.com/pashtoonkasi/status/1078675398601396224
Theranostics is a joining of the words therapeutics and diagnostics. You may also see it conveyed as ‘Theragnostics’ and these terms are interchangeable. The basic aim of theranotistics is to find and then destroy the ‘bad guys‘. With Neuroendocrine Cancer, finding the tumours (the bad guys) can often be a challenge – they can be small and/or difficult to find – they are sometimes expert at camouflage. Moreover, once found, they can then be difficult to treat (destroy), as they can often prove resistant to conventional cancer drugs and many are inoperable due to sheer quantity, spread and positioning. When they are found and identified, it’s also really helpful to know from the intelligence gathered, how successful the destroy (therapeutic) part of the mission might be.
The nuclear scan uses the same targetin agent as the therapy, therefore if you cancer lights up on the nuclear scan, then the therapy will find its way to the cancer and hopefully work well. That is the beauty of theranostic pairing, i.e. the use of the same agent in the diagnostics – the ability to find, estimate likely success criteria and then hopefully destroy – or at least reduce the capability of the tumours and extend life.
A great example of an approved Theranostic Pairin Neuroendocrine Cancer, is the combination of the Somatostatin Receptor based Ga68 PET scan using NETSPOT or SomaKit TOC™ (US/Europe respectively) and Peptide Receptor Radiotherapy (PRRT) using Lutathera which both target NETs expressing the same somatostatin receptor, with PRRT intended to kill tumor cells by emitting a different kind of low-energy, short-range radiation than that of the diagnostic version. As mentioned above, the Ga68 PET scan can give a reasonably indication of therapeutic success using PRRT based on measurements taken during the scan (too complex for this article).
Nuclear medicine makes it possible by using the same molecular targeting compound to create diagnostic and therapeutic drugs, which work as theranostic pairings. Advanced Accelerator Applications’ theranostic platform is based on radiolabelling a single targeting molecule with either gallium Ga-68 for diagnostic use or lutetium Lu-177 for therapeutic use. AAA’s pipeline now includes several theranostic drug pairings for oncology indications including prostate and breast cancer; and gastrointestinal stromal tumors (GIST).
Newer imaging agents targeting somatostatin receptors (SSTR) labelled with 68 Ga have been developed, namely, DOTATATE, DOTATOC and DOTANOC. They are collectively referred to as SSTR PET.
The main difference among these three tracers (DOTA-TOC, DOTA-NOC, and DOTA-TATE) is their variable affinity to SSTR subtypes. All of them can bind to SSTR2 and SSTR5, while only DOTA-NOC shows good affinity for SSTR3.
These agents have several benefits over In111-pentetreotide (Octreotide scan), including improved detection sensitivity, improved patient convenience due to the 2 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 PRRT. Eventually, all Octreotide scans should be replaced with SSTR 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
Ga68 PET scans have been in many locations for some time. Current excitement is focused on USA locations with Ga68 PET (NETSPOT) only recently approved (DOTATATE). Other countries/scan centres may use one of the other types of imaging agent.
Read much more about this scan in my detailed article on Ga68 PET here.
So SSTR PETs above have the ability to find and estimate likely success criteria for therapy. We are now in a position to move on to ‘THERApy’ – e.g. Peptide Receptor Radiotherapy or PRRT.
THERANOSTICS – DESTROY
click on picture to watch video
Lutathera® (note the ‘THERA’ which makes up the brand name)
Definitions:
Europe Approval: LUTATHERA®(lutetium (177Lu) Oxodotreotide) is indicated for the treatment of unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours (GEPNETs) in adults.
USA Approval: LUTATHERA® (lutetium Lu 177 dotatate) is indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut and hindgut neuroendocrine tumors in adults.
For commercial purposes, the drug may be slightly different on a regional basis. For all intents and purposes it does the same job.
PRRT with LUTATHERA®
LUTATHERA® solution for infusion is a ‘radiolabelled somatostatin analog (SSA)’ comprised of a radionuclide (Lutetium-177) and a peptide (differs between Europe and USA)
The relevant SSA binds with high affinity to the somatostatin receptors (SSTR) overexpressed in malignant neuroendocrine cells such as the ones found in GEP-NETs.
Lutetium-177 is a β particle emitting radionuclide, with a mean penetration range of 0.67 millimetres in tissue (maximum penetration range of 2.2 mm) which is sufficient to kill targeted tumour cells with a limited effect on neighbouring normal cells.
The affinity for SSTRs and the specificity of binding ensures a high level of specificity in the delivery of radiation to the tumour. Before starting treatment with LUTATHERA®, imaging must confirm the presence of these receptors in tumour tissues.
As an example of how the drug is administered, please watch this short video from the European site:
Video courtesy of Advanced Accelerator Applications Please see the following post for a summary of PRRT activity worldwide. Please note this linked article is not designed to contain a list of every single location or country available – please bear that in mind when you read it – CLICK HERE
I’m very grateful to the team at Advanced Accelerator Applications (a Novartis Company) for allowing me to use their site for graphics and videos.
In another ‘theranostic’ development, check out my article on the Satoreotide trial (Ops 201/202) from Ipsen (of Lanreotide fame) – click here to read – the trial is recruiting.
Welcome to my second ‘community’ newsletter, the monthly summary of NET news in Dec 2016, views and ICYMI (in case you missed it!).
December was a particularly special month. For the previous 3 months, I had been busily working behind the scenes and on my various social media presences to put on a good show for the 2016 WEGO Health Activist Awards. This paid off and I won the Best in Show ‘Community’ category in addition to being shortlisted as one of 5 finalists in the blog category. The community award was special because it means we all won the award as a part of this ‘Community’. I’ve picked up a whole new bunch of friends outside the NET world bringing much-needed exposure to NET Cancer. I had a quiet week resting before I resumed normal activity and then a sprint finish at the end of the month took me over the magic 10,000 blog hits figure (and even more on Facebook). Stick with me because I really need your help and support and anyone else you know who can assist. The WEGO awards brought a significant increase in twitter followers.
Blogging
A quiet month in terms of numbers of blogs. Due to the vagaries of Facebook inner workings, some of these may not have even shown on your timeline. So, ICYMI …….here’s a summary with links:
First in a series of ‘spotlight on ……’ posts – this one on Pheochromocytomas and Paragangliomas. Read here.
I shared an inspiration message with you – one that I received from an old friend. Read ‘Keep your light burning’ which had a great response.
Confused about the difference between Lanreotide and Octreotide? This blog will help – it got a really good response and you can read it here. I also received lots of questions about the individual drugs which was great and shows the importance of this subject to patients out there.
Other News in Dec
New Audiences for NET Cancer. From Day 1, I said it was my aim to find new audiences for NETS rather than just share stuff within our own community. Two new openings in Dec to report:
The exposure during the build up to the 2016 WEGO Health Activist Awardswhere I made the final in two categories continued into Dec culminating in the award win (you can listen to the announcement live here). I also featured in a radio show just before the announcement and you can listen to it here (start at 40.30).
I’m ‘extremely’ active on twitter and I find a lot of my research stuff there. I also use it to support other conditions and it’s mostly returned (i.e. others help with NET awareness). There is so much on twitter that I could swamp the community Facebook site so I started a twitter newsletter via an app called Nuzzel which seeks out stuff I normally like. You can sign up for this newsletter here as I wont be posting it every day. Click this link and sign up if you think this is something you’d be interested in receiving.
Blog Milestone. My blog tipped over 200,000 views in Dec and it’s already accelerating toward a quarter of a million. Thanks – keep sharing!
Facebook Milestone. My Facebook page was 2 years old in Dec 🙂 Please recommend this page to anyone you think would be interested.
Invite or recommend my page please – let’s grow awareness!
Figures
Facebook – 3726. This is a key outlet for my blog – please encourage others to like my page(if you’d like to know how to use your Facebook to invite others to my page – let me know, I can provide you with a step by step approach)Please also join my 2017 awareness campaign event here (select ‘Going’)
New delivery system for Lanreotide – solution remains the same
Somatostatin Analogues are the ‘workhorse’ treatments for those living with NETs, particularly where certain syndromes are involved. So not just for classic NETs with Carcinoid Syndrome but also for treating insulinoma, gastrinoma, glucagonoma and VIPoma (all types of pNETs) and others. They are most effective if the NETs express somatostatin receptors. They also have an anti-tumour effect but more of a slowing down of growth rather than a killing or reduction of tumour size – but there are always outliers where such effects are displayed.
Somatostatin is actually a naturally occurring hormone produced by the hypothalamus and some other tissues such as the pancreas and the gastrointestinal tract. However, it can only handle the normal release of hormones. When NET syndromes occur, the naturally occurring somatostatin is unable to cope. The word ‘analogue’ in the simplest of terms, means ‘manufactured’ and a somatostatin analogue is made to be able to cope with the excess secretion (in most cases).
Although there is hidden complexity, the concept of the drug is fairly simple. It can inhibit insulin, glucagon, serotonin, VIP, it can slow down bowel motility and increase absorption of fluid from the gut. It also has an inhibitory effect on growth hormone release from the pituitary gland (thus why it’s also used to treat a condition called Acromegaly). You can see why it’s a good treatment for those with NET syndromes, i.e. who suffer from the excess secretions of hormones from their NETs. Clearly there can be side effects as it also inhibits digestive enzymes which can contribute to, or exacerbate, gastro-intestinal malabsorption.
Please note somatostatin analogues are not chemo. There are two major types in use:
Octreotide – or its brand name Sandostatin. It is suffixed by LAR for the ‘long acting release’ version.
Lanreotide – brand name Somatuline (suffixed by ‘Depot’ in North America, ‘Autogel’ elsewhere)
So what’s the difference between the two?
A frequently asked question. Here’s a quick summary:
They are made by two different companies. Novartis manufactures Octreotide and Ipsen manufactures Lanreotide. Octreotide has been around for much longer.
The long-acting versions are made and absorbed very differently. Octreotide has a complex polymer and must be injected in the muscle to absorb properly. Lanreotide instead uses has a novel nanotube structure and is water based (click here to see a video of how this works). It is injected deep-subcutaneously and is therefore easier to absorb and is not greatly impacted if accidentally injected into muscle.
Their delivery systems are mainly via injections but are fundamentally different as you can see from the blog graphic which shows the differences between the long acting release versions. Octreotide long acting requires a pre-mix, whilst Lanreotide comes pre-filled.
The long-acting versions are 60, 90 and 120 mg for Lanreotide and 10, 20 and 30 mg for Octreotide.
Octreotide also has a daily version which is administered subcutaneously.
Octreotide has something called a ‘rescue shot’ which is essentially a top up to tackle breakthrough symptoms. It is a subcutaneous injection.
You can also ‘pump’ Octreotide using a switched on/off continuous infusion subcutaneously.
Other than for lab/trial use, to the best of my knowledge, there is no daily injection, rescue shot or ‘pump’ for Lanreotide that is indicated for patient use.
Whilst both have anti-tumour effects, there are differences in US FDA approval: Octreotide (Sandostatin) is approved for symptom control (not anti-tumor) whereas Lanreotide (Somatuline) is approved for tumour control. However, the US FDA recently added a supplemental approval for syndrome control on the basis that it is proven to reduce the need for short acting somatostatin analogues use – read more here. This supplementary approval followed the ELECT trial – results here.
Injection Administration
Always refer to the patient information leaflet as it is not safe to assume that all healthcare professionals are familiar with the administration. Common issues include (but are not limited to): drug temperature requirements, injection site, pinching vs stretching skin, speed of injection.
Please note a new syringe for Lanreotide will be available in June 2019. Further information will be communicated to healthcare professionals in advance of this, to enable them to inform their patients, whom have been prescribed Lanreotide. In addition, the patient information leaflet included in the packet will have clear instructions for use. There will be a prominent yellow box located on the outer carton of the medicine, alerting healthcare professionals and patients that a new syringe is contained inside. Please note that the medicine is still the same and the formulation and storage conditions have not changed.
Here are some interesting videos showing and explaining their administration:
Administering a Somatuline Depot (Lanreotide) injection:
Administering a Sandostatin LAR (Octreotide) injection:
This link also provides guidance on the “new formulation” Octreotide. Click here.
My own experience only includes daily injections of Octreotide (Sep-Nov 2010) and Lanreotide (Dec 2010 onwards). I’ve also had continuous infusion of Octreotide in preparation for surgical or invasive procedures over the period 2010-2012 (i.e. crisis prevention). You can read about my Lanreotide experience by clicking here. If you are interested in what might be coming downstream, please see my blog entitled ‘Somatostatin Analogues and Delivery Systems in the Pipeline’.
Injection site granulomas (lumps)
The issue of ‘granulomas‘ or ‘injection site granulomas’ seems to figure in both drugs. Gluteal injection site granulomas are a very common finding on CT and plain radiographs. They occur as a result of subcutaneous (i.e. intra-lipomatous) rather than intramuscular injection of drugs, which cause localised fat necrosis, scar formation and dystrophic calcification. But no-one seems to know why they occur with somatostatin analogues.
Personally, I find that they are more conspicuous if the injection is done slightly too high which was my initial experience and they took months to fade. I opted to stand up for the first two injections and I attribute this decision for a slightly too high injection site. I now lie down which is actually recommended for the smaller and thinner patient. Although the lumps have reduced in size, I have not seen a new lump for some time indicating location might have been the cause. They sometimes show up on scans. This is not a new problem and has been highlighted for the last 10 years in academic papers. This particular paper is useful and the conclusion confirms this is not something that should worry patients too much. Read more here
Somatostatin Analogues and raised blood sugar levels
It is well documented that both Octreotide and Lanreotide can elevate blood glucose (sugar) levels. Read more in my article Diabetes – the NET Effect.
I’m continually seeing certain drugs for treatment of Neuroendocrine Tumours (NETs) described as chemotherapy. I think there must be some confusion with more modern drugs which are more targeted and work in a different way to Chemotherapy.
I researched several sites and they all tend to provide a summary of chemotherapy which is worded like this: Chemotherapy means:
a treatment of cancer by using anti-cancer medicines called cytotoxic drugs. Cytotoxic medicines are poisonous (toxic) to cancer cells. They kill cancer cells or stop them from multiplying. Different cytotoxic medicines do this in different ways. However, they all tend to work by interfering with some aspect of how the cells divide and multiply. Two or more cytotoxic medicines are often used in a course of chemotherapy, each with a different way of working. This may give a better chance of success than using only one. There are many different cytotoxic medicines used in the treatment of cancer. In each case the one (or ones) chosen will depend on the type and stage of your cancer. Interestingly, there are several statements along the lines of ‘Cytotoxic medicines work best in cancers where the cancer cells are rapidly dividing and multiplying’, a key issue with lower grade NETs.
Well known chemotherapy treatments for NETs include (but are not limited to): Capecitabine (Xeloda), Temozolomide (Temodal), Fluorouracil (5-FU), Oxaliplatin (Eloxatin) Cisplatin, Etoposide (Etopophos, Vepesid), Carboplatin, Streptozotocin (Zanosar). Some of these may be given as a combination treatment, e.g. CAPecitabine and TEMozolomide (CAPTEM).
In the past, any medication used to treat cancer was regarded as chemotherapy. However, over the last 20 years, new types of medication that work in a different way to chemotherapy have been introduced. Many of these new types of medication are known as targeted therapies. This is because they’re designed to target and disrupt one or more of the biological processes that cancerous cells use to grow and reproduce. They are classed as biological therapy. In contrast, chemotherapy medications are mostly systemic in nature and designed to have a poisonous effect on cancerous cells, thus the term ‘cytotoxic’.
The following well known NETs treatment are not really chemotherapy and describing them in this way is not only misleading but may actually cause alarm to other patients. Furthermore, if you check any authoritative NET Cancer specialist or advocate organisation; any general and authoritative cancer site or the manufacturer’s websites; you will not see the drugs below listed within the term chemotherapy.
Somatostatin Analogues e.g. Sandostatin (Octreotide), Somatuline (Lanreotide). Although these drugs have an anti-cancer effect for some, they are in fact hormone inhibitors and are therefore a hormone therapy.
Everolimus (Afinitor). This is a targeted biological therapy or more accurate a mammalian target of rapamycin (mTOR) inhibitor. It is a type of treatment called a signal transduction inhibitor. Signal transduction inhibitors stop some of the signals within cells that make them grow and divide. Everolimus stops a particular protein called mTOR from working properly. mTOR controls other proteins that trigger cancer cells to grow. So everolimus helps to stop the cancer growing or may slow it down.
Sunitinib (Sutent). This is a targeted biological therapy or more accurate a protein (or tyrosine) kinase inhibitor. Protein kinase is a type of chemical messenger (an enzyme) that plays a part in the growth of cancer cells. Sunitinib blocks the protein kinase to stop the cancer growing. It can stop the growth of a tumour or shrink it down.
I can only speculate why some of the confusion exists but I do have some personal experience I can quote too. Firstly I believe it could be easier for some people to describe the new agents as ‘chemotherapy’ rather than explain things such as somatostatin analogues, ‘mammalian target of rapamycin (mTOR) inhibitors’, protein kinase inhibitor or angiogenesis inhibitors. Another reason could be that health insurance companies do not have the correct database structures in place on their IT systems and therefore need to ‘pigeon hole’ drugs into the closest category they can see. Often this is chemotherapy and this only adds to the confusion. In the days when I had health insurance, my Lanreotide injections were coded as chemotherapy on all my bills. I challenged it and this is how they explained the issue.
When you’ve been diagnosed with cancer at an incurable stage, certain words start to mean more. Take ‘palliative’ for example. Before I was diagnosed I had always associated the word ‘palliative’ with someone who had a terminal disease and this type of care was to make the final days/weeks as comfortable as possible. So it was a bit of a shock to find out in 2010 that my treatment was palliative in nature. However, I’m still not dead and I’m still receiving palliative care. Go figure! The answer is simple – the cancer story is changing. What was once feared as a death sentence is now an illness that many people survive. As survival rates increase, so too will the number of people living with the legacy of cancer and its treatment.
What is palliative care?
Some people with incurable cancer will continue to receive treatment to keep the cancer at bay and that treatment is by definition, palliative. In fact, palliative care can be given at any time during an illness. It’s not just for treatment of the cancer, it’s also to help with the effects of that treatment, i.e. the consequences of cancer. It also encompasses things such as emotional and other practical support.
In the most general terms and while it clearly can go into some detail and long lists, palliative care can be defined as follows:
Cancer and its treatment often cause side effects. Relieving a person’s symptoms and side effects is an important part of cancer care. This approach is called symptom management, supportive care, or palliative care. Palliative care is any treatment that focuses on reducing symptoms, improving quality of life, and supporting patients and their families. Any person, regardless of age or type and stage of cancer, may receive palliative care.
I looked at a few sites and many of them confirm the above. However, there appears to be even more sites where it is still heavily associated and inextricably linked with end of life or hospice care where you may come into contact with the term palliative care specialist. Whilst it’s not wrong to make that association, more work needs to be done to cater for the growing numbers of ‘incurable but treatable’ who are not ‘terminal’ and still need this type of support, in some ways like you would with a chronic condition. I also sense a push in certain areas to emphasise the meaning of palliative care to include a much broader definition than is currently in most people’s minds. This needs much more publicity. I’m not saying that ‘palliative’ does not include ‘hospice care’ but I’m not intending to cover that aspect in this blog which is aimed as those with incurable but treatable cancers.
My palliative care experience
When I was diagnosed with metastatic Neuroendocrine Tumours (NETs) in 2010, I quickly accepted the fact that any treatment I would receive would not be curative. I also quickly accepted that if I didn’t have any treatment, I would probably die. The words used were ‘debulking’ and ‘cytoreductive’, more technical sounding but essentially meaning the same thing as palliative. Debulking means removing as much tumour as possible in order to increase the chance that perhaps other treatments can be of some help. Cytoreductive means the same thing but generally extends the ‘debulking’ activity to other modes of treatment (e.g. chemotherapy/radiotherapy).
NETs is one of a number of cancers for which ‘debulking’ and ‘cytoreductive’ therapies can in many cases confer some survival advantage. In fact if you read ENETS or NANETS guidance for advanced NETs, you will frequently see the statement that cytoreductive surgery should be considered if greater than 90% of metastatic tumour burden can be safely resected or ablated. NETs, particularly with distant metastases, can come with a ‘syndrome’ and some of the symptoms can be rather debilitating for many patients. These syndromes are a result of tumours secreting excess amounts of hormonesand the types vary from patient to patient and from NET type to NET type. It follows that if surgical debulking reduces the amount of tumours, then it should normally decrease the effects of the associated syndrome. In fact, one letter from a specialist did describe my surgery in symptom palliation terms. I can confirm this is about right as my hormone marker 5HIAA remained elevated after surgery to remove my primary and local tumours, but did not return to normal until after my liver surgery.
However, there are a number of other treatments that can be considered ‘palliative’ in a metastatic or advanced environment. Getting rid of tumours is always the optimum treatment for any cancer but just as surgical debulking can reduce the amount of cancer, other non-surgical modalities such as liver embolization or ablation can have the effect of reducing the symptoms of the cancer and therefore providing relief to the patient. Somatostatin Analogues (Octreotide/Lanreotide) are another good example of palliative care. Although they might have an anti-tumour effect for some, they mostly work by reducing or inhibiting the secretion of excess hormones which contribute to the various NET syndromes. ‘Symptom control’ is as defined above, palliative care.
I’m already looking forward to my next palliative care appointment.
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:
Scans
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:
Octreoscan output vs Gallium 68 PET output
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.
Oncolytic Virus
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.
Everolimus (Afinitor)
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.
Summary
………. 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.
Thanks for reading
Ronny
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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. My expectations of speed turned out to be wildly inaccurate and in hindsight, I was also wildly naive. You see, with Neuroendocrine Cancer, particularly well-differentiated, low or medium grade tumours, it sometimes doesn’t work as fast as you would think and there are good reasons for that.
The complexity of the condition needs some consideration as the physicians work up a treatment plan. I’m quite happy and content they took their time, rather than rush into the wrong decisions. If you think about it, this is an advantage with low and medium grade NETs……you normally have some time to get the ducks in a line (and there are some pretty important ducks in that line).
Here’s a very short video discussing this during a patient video shoot: Click here.
I had a confirmed biopsy result following some incidental CT scans and other tests. However, they now needed further checks and marker tests to work out the extent of the disease. So the timeline leading up to major surgery ended up like this:
Diagnosis: 26 July 2010. Met with Oncologist. Grade 2 Small Intestine NET with distant metastasis (Stage 4)
Chromogranin A and 5HIAA: submitted 28 July. Results received 13 August – both elevated, indicating and confirming tumour bulk and function status respectively
Octreotide Scan:17-19 August. Report issued 24 August – confirmed CT plus additional distant hotshots. Also confirmed my tumour receptors were avid to somatostatin analogues.
Daily Octreotide Injections: Started 9 September to control syndrome (derisk surgery)
Referred to NET Multi-Disciplinary Team (MDT): 15 September – they now had sufficient data to form a treatment plan.
Holiday: Late September (it was booked and I felt OK, why not!)
Further MDT assessment and consultations: 1- 7 October
Bland Liver Embolisation: 19 October
First Surgery: 9 November – to remove primary and debulk local and regional spread.
You can read the rest of my treatment background here.
So it took 75 days from diagnosis to opening me up to remove the first batch of tumours. With reasonably slow-growing tumours, that isn’t really a long time when you consider they had probably been growing inside me for several years. I’m sure others waited even longer.
Sometimes rushing straight into the operating theatre isn’t really the best option. I’m still here!
Diarrhea can be a symptom of many conditions but it is particularly key in Neuroendocrine Tumour (NET) Syndromesand types, in particular, Carcinoid Syndrome but also in those associated with various other NET types such as VIPoma, PPoma, Gastrinoma, Somatostatinoma, Medullary Thyroid Carcinoma.
Secondly, it can be a key consequence (side effect) of the treatment for Neuroendocrine Tumours and Carcinomas, in particular following surgery where various bits of the gastrointestinal tract are excised to remove and/or debulk tumour load.
There are other reasons that might be causing or contributing, including (but not limited to) endocrine problems such as hyperthryoidism, mastocytosis or Addison’s disease (which may be secondary illnesses in those with NETs). It’s also possible that ‘non-sydromic’ issues such as stress and diet are contributing. It could be caused by other things such as Irritable Bowel Syndrome (IBS). Yes, believe it or not, NET Patients can get normal diarrhea causing diseases too!
Define Diarrhea
I want to give a general definition of diarrhea as there are many variants out there. In general, they all tend to agree that diarrhea is having more frequent, loose and watery stools. Three or more stools per day seems to be the generally accepted threshold, although some sites don’t put a figure on it. It’s not pleasant and just about everyone on the planet will suffer it at some point in their life, perhaps with repeated episodes. Normally it’s related to some kind of bug, or something you’ve eaten and will only last a few days before it settles (acute diarrhea). Diarrhea lasting more than a couple of weeks is considered chronic and some people will require medical care to treat it. It can also be caused by anxiety, a food allergy/intolerance or as a side effect of medicine. Pharmacists and GPs will be seeing many patients with this common ailment every single day of business.
Diarrhea induced by a Syndrome
When you consider the explanation above, it’s not really surprising that diarrhea related symptoms can delay a diagnosis of Neuroendocrine Cancer (and most likely other cancers too, e.g. pancreatic cancer, bowel cancer). For example, diarrhea is the second most common symptom of Carcinoid Syndrome (Flushing is actually the most common) and is caused mainly by the oversecretion of the hormone Serotonin from the tumours. Please note diarrhea in other types of syndromes or NETs may be caused by other hormones, for example it may also be caused by excess calcitonin in the case of Medullary Thyroid Carcinoma or VIP in the case of a functional pNET known as VIPoma. I’ve heard stories of people being told they have IBS or something similar for years before they received what is now a late diagnosis and at an advanced cancer stage. This is only one of the reasons why NETs is not an easy condition to diagnose, although it is possible that some people actually had IBS and it was masking the NET. Even after treatment to remove or reduce tumours, many people will remain syndromic and need assistance and treatment to combat diarrhea induced by a NET syndrome (see below).
Diarrhea as a Consequence (Side effect) of Treatment for Neuroendocrine Cancer and Other Conditions
All cancer treatments can have consequences and Neuroendocrine Cancer is definitely no exception here. For example, if they chop out several feet of small intestine, a chunk of your large intestine, chunks (or all) of your stomach or your pancreas, your gallbladder and bits of your liver, this is going to have an effect on the efficiency of your ‘waste disposal system’. One effect is that it will now work faster! Another is that the less effective ‘plumbing’ may not be as efficient as it was before. There are also knock-on effects which may create additional issues with the digestive system including but not limited to; Malabsorption and SIBO. I recommend you read my posts on Malabsorption and SIBO.
Surgery can often be the root cause of diarrhea. A shorter gut for example, means shorter transit times presenting as increased frequency of bowel movements. Another example is the lack of terminal ileum can induce Bile Acids Malabsorption (BAM) (sometimes known as Bile Salts Malabsorption) in degrees of severity based on size of resection. Lack of a gallbladder (common with NETs) can also complicate. Bile Acids are produced in the liver and have major roles in the absorption of lipids in the small intestine. Following a terminal ileum resection which includes a right hemicolectomy, there is a risk that excess Bile Acids will leak into the large intestine (colon) via the anastomosis (the new joint between small and large intestines). This leakage can lead to increased motility, shortening the colonic transit time, and so producing watery diarrhea (or exacerbating an existing condition). Although this condition can be treated using bile acid sequestrants (i.e. Questran), it can be difficult to pinpoint it as the cause.
Surgery of the pancreas can also produce effects such as exocrine pancreatic insufficiency which can lead to a malabsorption condition known as steatorrhea which may be confused with diarrhea (although some texts call it a type of diarrhea). It isn’t really diarrhea but it may look like it given the presentation of the faeces and patients may suffer both diarrhea and steatorrhea concurrently. Patients will recognise it in their stools which may be floating, foul-smelling, greasy (oily) and frothy looking. Treatment options will mainly include the use of Pancreatic Enzyme Replacement Therapy or PERT for short (Creon etc).
Many non-surgical treatments can also cause diarrhea, including but not limited to; somatostatin analogues (see below), chemotherapy, biological targeted therapy (e.g. Everolimus, Sunitinib), radiotherapy.
Somatostatin analogues are an interesting one as they are designed to inhibit secretion of particular hormones and peptides by binding to the receptors found on Neuroendocrine tumour cells. This has the knock-on effect of inhibiting digestive/pancreatic enzymes which are necessary to break down the fat in our foods leading to Malabsorption of important nutrients. This may worsen the steatorrhea in pancreatic NET patients but also lead to steatorrhea in others with non-pancreatic locations who have been prescribed these drugs.
Other conditions may actually be the cause of the diarrhea or the treatment for those conditions. For example, it is possible that people actually do have Irritable Bowel Syndrome (IBS). Treatment therapy for common conditions may also be contributing, for example the use of Proton Pump Inhibitors for acid reflux.
Treatment for Syndrome Induced Diarrhea
Like many other NET patients, I’m on a 28 day injection of somatostatin analogues (in my case Lanreotide). Both Octreotide and Lanreotide are designed to reduce the effects of NET syndromes and therefore can often make a difference to syndrome induced diarrhea. These drugs also have anti-tumour effect and so even if you are not syndromic or they do not halt or adequately control syndrome induced diarrhea, they are still a valuable contribution to NET treatment.
Some syndromic patients find they still have diarrhea despite somatostatin analogues and they end up having ‘rescue shots’ or pumps for relief (both of these methods tend to be Octreotide based). (Hopefully they are not getting confused between diarrhea caused by the non-syndrome effects – see above). Some have more frequent injections of the long acting versions of somatostatin analogues which has the effect of increasing the dosage. There’s a new drug available for those whose carcinoid syndrome induced diarrhea is not adequately controlled or perhaps they are unable to have somatostatin analogues as a treatment. Telotristat Ethylworks by inhibiting tryptophan hydroxylase (TPH), a chemical reactor involved in the manufacture of serotonin, which is the main cause of syndrome induced diarrhea. It was approved by the US FDA in February 2017, EU areas in September 2017, and is on the way to being approved elsewhere. Read about this drug here.
Sorting out the symptoms – post diagnosis
I like to describe this as the Neuroendocrine Cancer jigsaw. It’s a really difficult one and sometimes you cannot find a piece, or the pieces won’t fit. However, metaphorically speaking, the missing piece might be a NET specialist presentation, a comment, statement or view from another patient, a link to an article from a reputable source, or even something you do to improve your lot – there might even be trial and error involved. It might even be this blog post!
How do you work out whether diarrhea is caused by a hormone producing tumour or by the side effects of treatments? There’s no easy answer to this as both might be contributing. One crude but logical way is to just accept that if you have normal hormonemarkers, for example 5HIAA (there could be more for other tumour/syndrome types), and you’re not really experiencing any of the other classic symptoms, then your syndrome might be under control due to your treatment (e.g. debulking surgery and/or somatostatin analogues, or another drug). My Oncologist labels me as ‘non-syndromic’ – something which I agree with. I’m 99.999999% sure my issues are as a result of the treatment I’ve had and am receiving.
This disease is so individual and there are many factors involved including the type of syndrome/NET, patient comorbidities and secondary illnesses, consequences of the surgery or treatments performed, side effects of drugs – all of which is intermingled with suspicion and coincidence – it’s that jigsaw again! I always like to look in more detail to understand why certain things might be better than others, I always challenge the ‘status quo’ looking to find a better ‘normal’. I really do think there are different strategies for syndrome induced diarrhea and that which is a result of treatment or a side effect of treatment. There’s also different prices, with inhibitors costing thousands, whilst classic anti-diarrhea treatments are just a few pennies. Adjustments to diets are free!
When I was discharged from hospital after the removal of my small intestinal primary, I was in the toilet A LOT (I was actually in the toilet a lot before I was discharged – check out my primary surgery blogs here) . My surgeon did say it would take months to get back to ‘normal’ – he was right and it did eventually settle – although my new ‘toilet normal’ was soft and loose and several times daily. My previously elevated CgA and 5HIAA were eventually back to normal and my flushing had disappeared. I didn’t have too many issues with diarrhea before diagnosis. Deduction: my issues are most likely not syndrome induced.
I read that many people find basic ‘Loperamide’ (Imodium) helps and I tend to agree with that if you are non syndromic and just need that little bit of help. I decided long time ago I would not become ‘hooked’ and only really take it for two purposes: 1) if I have a bad patch and 2) if I’m going on a long journey (i.e. on a plane perhaps). I estimate I’ve used 4 packets in as many years. Loperamide decreases the activity which causes intestinal motility (peristalsis). This has the effect of increasing the time material stays in the intestine therefore allowing more water to be absorbed from the fecal matter. Ideal for those with a shorter bowel due to surgery and advice from a medical professional is always advisable. To reduce the risk of malabsorption induced diarrhea and steatorrhoea, both of which can lead to loss of valuable nutrients, the use of Pancreatic Enzyme Replacement Therapy (PERT) might need to be introduced as required by your NET specialist.
Have a look at Enterade – the results from trials look good.
Clearly, I cannot offer any professional medical advice on coping with diarrhea, I can only discuss my own situation and what I found worked for me. Don’t forget, like many diseases, what works for one, might not work for another. However, I did tackle my problems following the advice of an experienced dietitian who specialises in NET Cancer. That said, I was ‘sleep walking’ for over 2 years thinking my issues were just part of the way things were after my treatment. I was wrong about that!
As for my own strategy, here’s things that helped me:
made some changes to diet(they were not huge changes),
maintained a diary to help with monitoring progress or setbacks,
hydration is also important (….still working on that one).
started taking PERT (Creon) on 23 Dec 2017 (changed to Nutrizym Feb 2019) but looks reasonably positive so far.
With no fancy and expensive drugs, I’ve gone from 6-8 visits to 1-2 visits (as a daily average, it’s actually 1.5). This didn’t happen overnight though, it took a lot of time and patience. All of this doesn’t mean to say I don’t have issues from time to time …… because I do!
In summary, I think it’s important that people be sure what is actually causing their diarrhea after diagnosis so that the right advice and the optimum treatment can be given.
Listen to Dr Wolin talking about this particular jigsaw puzzle – click here
Also see a nice article that come out of NANETS 2017 – click here
Of course, some people sometimes have the opposite effect but that’s in another blog here – Constipation
CT and G68 PET fused showing somatostatin receptor pick up
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!
Somatostatin
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.
Somatostatin Receptors
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 (Strosberg) 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.
Summary
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.
Since my diagnosis, I seem to have been in a perpetual learning phase! What not to do, what not to eat, what not to read! However, early on in my experience, I came across a list of ‘E’ words (5 of them) which is a handy reminder for Carcinoid Syndrome patients, particularly those whose symptoms are not under control. When I say “carcinoid syndrome” in this article, I only mean the syndrome that is caused by what was once called “Carcinoid Tumors”, i.e. mainly serotonin secreting types but include tumours which are well differentiated found in the small intestine, appendiceal, rectal, lung, and one or two other less common places. There are many variations of this list but this is my take! I suspect some of this also applies to other types of NETs and other NET Syndromes.
On analysis of this list, it struck me that I was aware of the issues and their potential effects and I’m certain there is science to substantiate the content. These E’s are apparently the most common ‘triggers’ for Carcinoid Syndrome. Clearly, they are not going to have the same effect on every patient e.g. I have the occasional drink of ‘Ethanol’ and I always enjoy it, I go for long exhausting walks as ‘Exercise’ and I always feel great after. I had dental treatment using ‘Epinephrine’ without any precautions before I was aware of the risks …….. nothing happened! Before I was treated, stressful meetings (‘Emotions’) at work would make me flush though! As for ‘Eating’ – well that’s another couple of blog’s worth! Worth noting that many people without carcinoid syndrome will have reactions to eating but there are specifics that might need some attention in someone with carcinoid syndrome and elevated 5HIAA levels.
The 5 Es are, however, not something to be totally ignored. In extreme scenarios, a severe attack of Carcinoid Syndrome symptoms could be debilitating and life-threatening and I’m fairly certain the list was compiled with this in mind. Some people are more affected by Carcinoid Syndrome and this is not necessarily related to the extent or aggressiveness of their disease. Some people just react differently. An extremely severe attack of Carcinoid Syndrome can also be known as a ‘Carcinoid Crisis’ which is very dangerous, mostly on the operating table due to the effects of anaesthetics – thus why many NET patients may be infused with somatostatin analogues (usually Octreotide) prior to, during, and for a period after surgery or other medical procedures. There’s a lot of excitement generated around the term ‘Carcinoid Crisis’ but it is very uncommon.
I’m not saying the 5 Es should be ignored but NETs are a complex disease and most things need to be read in the correct context. What works for some may not work for others. There can also be confusion surrounding the source of symptoms, i.e. are they syndrome or something else? This is why I believe NET patients need to answer some key questions when considering the risks associated with the 5 E’s:
Are you currently syndromic? If you are, then the 5 ‘E’ list is probably very good advice but interpreting the advice in the correct context remains important.
Are your syndrome related biochemistry results normal (e.g. 5HIAA)? Normal readings (in range) tend to mean the syndrome is under control and many people who were diagnosed with a syndrome may actually be non-syndromic following treatment.
Have you had treatment or are having treatment likely to produce side effects which might be confused with Carcinoid syndrome? For example, surgery can be the long term cause of diarrhea and other issues. Despite the role of somatostatin analogues, these could also be the root cause of certain reactions.
Do you have any other illnesses? If yes, do these other illnesses produce effects similar to carcinoid syndrome? e.g. asthma, diabetes, rosacea, thyroid disorders, vitamin & mineral deficiencies, malabsorption, gut bacterial imbalance. Sorting out the symptoms can be a jigsaw with a missing piece sometimes.
The vagaries of this disease will no doubt throw up some exceptions and additions. There will be patients who have no syndrome but have elevated biochemistry and vice versa. Additionally, there will be patients who have had surgery and/or are being treated with somatostatin analogues but will still be syndromic in varying degrees of severity.
The so-called ‘5 Es’ are as follows:
Epinephrine: This was a new piece of information for me and I only discovered this as a potential problem when I started monitoring some of the USA Facebook forums. This does not appear to be that well-known in UK.
Epinephrine (commonly known as adrenaline) is often used in dentistry mixed with a local anaesthetic. I won’t risk this, so I’ve instructed my Dentist to place a note on my record asking for epinephrine not be used (and clearly I’ll remind them each visit!). According to NET guru Dr Woltering, plain novocaine, carbocaine or plain marcaine are preferred. According to a dental source on my site (also a patient):
“4% Citanest Plain Dental (Prilocaine Hyrocholride Injection) is also safe and Epinephrine Free. It isn’t as profound of a numbness and may need reapplying during a procedure. It is the common alternative here in the USA.
4% Articaine without Epinephrine is also available and is known to work better on Mandibular Blocks. Again this is commonly used in the USA. It’s important to know what to ask for, not just ‘Epinephrine free’. Bring this up at your dental exam appointment, so that they will be sure to have it in stock. If you are unfamiliar with the office, schedule your appointment after they confirm that the proper local is in stock. Never use the term Novacaine as the generic term for dental anesthetic, this hasn’t been used in the USA for decades. Allergic reactions to Novacaine were too common. Lidocaine and Septocaine are the drug of choice. However, Lidocaine will always have Epinephrine. Where as, Septocaine (articaine) has versions with Ephedrine and without”.
Always check that your anaesthetist for any procedure you may be undergoing is aware of your carcinoid syndrome.
However, the danger is not just with dentistry work. Any anaesthesia is risky. Check out my post ‘carcinoid crisis’.
For those who have standby ‘Epi Pens’, I did read the following statement on the Carcinoid Cancer Foundation website: “ …….. one exception is the administration of epinephrine in the case of an allergic anaphylactic reaction (i.e. a bee sting), so it cannot be avoided in this case, just make sure that Octreotide (Sandostatin) is also available“. This advice is also extremely relevant to Pheochromocytoma and Paraganglioma patients who may be a high risk of “intraoperative hypertensive crisis”.
Eating: This is very individual. Certain foods or large meals can be difficult, particularly if you have had any gastrointestinal surgeries. I keep a personal diary trying to identify things that upset my system. I try to find some balance between what I know is good for me and also what I know I enjoy. For example, I found that very large meals do not agree with my ‘new plumbing’. If I eat a lot of sweets, I’ll also suffer …..so I just eat a little – check out my article Chocolate – The NET Effect.
Personally speaking, I’m fairly certain the vast majority of my issues are related to my treatment (past and present) rather than being provoked by Carcinoid Syndrome, i.e. if I rush to the toilet after a meal, it’s not syndrome, it’s a reaction of my compromised digestive system. So with this in mind, I try to reduce those things but additionally strike a balance between quality of life and excessive and rigid adherence to some of the guidance out there (see below) – as I said above, interpretation and context is important. My compromised system cannot deal with big meals so I ‘graze’ most of the day and then eat a small to medium-sized meal in the evening. I’ve been doing this since 2014 and reduced my visits by 300% without any special or expensive medication.
In my blog Nutrition Blog 4 – Food for Thought, I’ve linked to authoritative sources on potential diet triggers. I’m not suggesting you cut out all of the foods on these lists (you won’t last long!). Some can indulge in those foods and some cannot. For example, chocolate and caffeine (tea/coffee) are on the lists but I eat/drink those frequently (in moderation) and have no problem. It’s a case of testing things out. I like to describe my eating as ‘The Risk Management of my Quality of Life’. By the way, no-one is suggesting that a NET patient with carcinoid syndrome (and don’t forget this is only one syndrome of many with NETs) should stop eating foods high in the offending amines or are precursors to serotonin (e.g. tryptophan). They do not make tumours grow (a myth) but just make sure you adhere to the dietary restrictions for any 5HIAA test.
Emotions: Stressful situations can cause symptoms to flare up. While it is difficult to avoid all stress (work, home, commuting, etc), it is helpful if you can manage or reduce it. Like eating, this is a very individual area. From personal experience, I know stress can exacerbate carcinoid syndrome. Before I started my treatment, I was regularly flushing in meetings at work (….. think boxing matches!). After my treatment, stress was definitely a factor causing increased bowel motility. I’ve removed a lot of stress from my life and it helps. You may need to be ruthless in managing this aspect of your illness.
Exercise: Exercise is extremely important for overall health and well-being and I know quite a lot of NET Cancer patients who exercise regularly without issues. It can, however, trigger carcinoid syndrome if you overdo it – it is, however, like eating, a very individual thing. I take the view that ‘zero’ exercise might potentially be an even higher risk. Even a walk around the garden or gardening is exercise. When I was at work, I would walk to see people rather than phone them. Sometimes I walk to town rather than drive, it all adds up! I have evidence from my own exercising regime proving in my case that exercise can reduce the knock-on effects of some of the other E’s (emotions and eating) and/or the side effects of treatment – check out my blog entitled Exercise is Medicine. Those who are syndromic and/or have other conditions to manage are probably best to take medical advice on how much exercise they need to do.
Ethanol (alcohol, liquor):Many NET patients have difficulty tolerating wine, beer and spirits (hard liquor). I was never a big drinker so for me it was easy to go almost teetotal. I do have the occasional beer but very infrequently and normally on holiday – I personally don’t get any issues with the odd beer but again this is trial and error. I really enjoy my beer when I celebrate my ‘Cancerversaries‘. Also check out my blog Alcohol – the NET Effect
Summary
I’m sure there could be a 5 A’s to 5 Z’s list of things to avoid but as I said above, this needs to be balanced with what the actual risks for you are and if you’re like me, quality of life. If you read most Facebook closed group or forums, you will always find at least one person is affected by something which affects no-one else. Please note this article is just my own appreciation of these issues and I emphasise once again that everyone has different experiences. I do, however, think it’s important to consider any secondary illnesses, effects of surgery and biochemistry results (or indeed a combination of one or more of these factors). Everything in life involves some kind of risk management and if you are totally risk averse, then you are unlikely to have much of a life (or a diet!).
It’s not easy but my daily diary helps me assess trends and work out what things upset me more than others – I can then reduce or eliminate. You need to tailor your own advice perhaps with the help of a doctor and/or dietician versed in NET Cancer. I also have some related posts on the subject of vitamin and mineral deficiencies, malabsorption and probiotics – check them out as the problems associated with these subjects could potentially look like a worsening of carcinoid syndrome and lead to unnecessary worry and unnecessary treatment.
For most, Carcinoid Syndrome can normally be controlled by the use of debulking surgery and/or somatostatin analogues (Octreotide/Lanreotide). However, there is a new drug called ‘Teloristat Ethyl’ (XERMELO) which looks like it may provide supplementary treatment for patients whose carcinoid syndrome diarrhea is not adequately controlled by somatostatin analogues. It’s an expensive drug and comes with side effects so you need to be sure it’s your syndrome causing the problem before you commit to a prescription.
The majority of Neuroendocrine Tumours (NETs) are slow-growing (well differentiated). However, many tumours can be silent (non-functioning) for some years before they start to ‘function’ and inform you of their presence. Even then, it may take some time to work out the real cause as thesymptoms can mimic regular ailments. Moreover, in most cases, the appearance of a functional tumour normally indicates the disease has metastasized and could now be incurable. Some tumours will grow and metastasize without syndromes, i.e. they are non-functional. These may become functional at some point in the future.
However, with most slow-growing NETs, this does not mean terminalas there are various treatment options even at Stage IV. In fact, NETs are one example wheresurgery at the metastatic stage can often provide prognostic advantages denied in other more aggressive types of cancer at the same stage. However, it’s true to say that many NET patients regardless of tumour type or grade and stageof tumour, need to live with quality of life (QoL) challenges.
I sense a change of thinking about people living longer with cancer and the reasons are fairly obvious. Due to better diagnostics and treatment (including for NETs), more people are now living with their cancer; and as a species were are actually living longer. Add the two together and you can see why the big charity organisations are now saying that one in two people will develop cancer at some point in their lives. Ergo – as we live longer we are more likely to come into contact with cancer on the basis that age is a big factor whether someone gets it or not. Now that sounds pessimistic but this needs to be put into context. For example, in UK today, more than one in three (35%) of those people who die having had a cancer diagnosis will now die from other causes. This is up from one in five (21%) 20 years ago. By 2020 this will improve further to almost four in 10 people (38%). This means the number of people who get cancer but die from another cause has doubled over the past 20 years. According to Macmillan Cancer, the cancer story is changing. What was once feared as a death sentence is now an illness that many people survive. A small bit of research indicates this type of thinking is becoming more apparent in other countries too. As survival rates increase, so too will the number of people living with the legacy of cancer and its treatment.
HOWEVER!
Although more people are living with cancer rather than dying from it, quality of life must be a factor going forward. Any quality of life campaign fits nicely into the existing challenges faced by many Neuroendocrine Cancer patients who need support well beyond their diagnosis and treatment and for some time.
I consider these campaigns additional help in fighting our corner. And of course we need help because for many NET patients there will be no remission, there will be no cure. Cancer patients need more support after a cancer diagnosis. NET patients are effectively already in this position and have been for some time. We have been at the forefront of a group of people living with cancer and needing close support and surveillance. For example:
Late diagnosis. People will be dealing from the effects of late diagnosis which has resulted in metastatic disease – and some people will have been fighting misdiagnosed illnesses for years. That takes its toll.
Consequences of Surgery. People will have had surgery which in many cases is life changing – various bits of the gut (gastrointestinal tract) are now missing, lungs are now missing – many other locationswill have been excised or partly excised. These bits of our anatomy were there for a reason and QoL takes a hit when they are chopped out. Many patients succumb to gastrointestinal malabsorption.
Inoperable Tumours and Syndromes. People will be dealing with remnant and/or inoperable tumours which may or may not be producing an associated NET syndrome (some of the symptoms can be rather debilitating in the worst cases)
Consequences of Non-surgical Treatment. Additionally, people will be dealing with the side effects of multi-modal non surgical treatments, such as somatostatin analogue hormone therapy (Octreotide/Lanreotide), chemotherapy, biological therapy (mTOR inhibitors) (i.e. Everolimus (Afinitor)), biological therapy (protein kinase inhibitors (i.e. Sunitinib (Sutent)), radionuclide therapy (i.e. PRRT). Whilst it’s great there are a wide range of therapies, they all come with side effects.
Secondary Illnesses and Comorbidities. Some people will have gained secondary illnesses in part due to the original cancer or treatment – i.e. somatostatin analogue hormone therapy can have a side effect of increasing blood sugar to diabetic levels and reduce thyroid function. There are many other examples.
Finances. NET Cancer can be an expensive cancer to treat and this is exacerbated by the length of time the treatment lasts. Whilst people have access to free public services or private insurance, many people will end up out-of-pocket due to their cancer. Over time, this adds up.
Emotional Aspects. Many NET patients are kept under surveillance for the remainder of their lives. With that comes the constant worrythat the cancer progresses, tumours get bigger, new tumours show up, treatments are denied (i.e. PRRT in the UK). It’s no surprise that anxiety and depression can affect many patients in these situations. To some extent, there can be a knock-on effect to close family members and carers/caregivers where applicable.
Living with Neuroendocrine Cancer is not easy – it takes guts (both metaphorically and literally).
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