The Invisible NET Patient Population 

The Invisible NET Patinet Population

OPINION

 

I found some of the quotes from the recent NET SEER Database study (Dasari et al) very interesting.  The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program is a comprehensive source of population-based information initiated in 1973 that is updated annually. Although the study is US-based, it represents the largest study of Neuroendocrine Tumors (NETs) ever recorded and is therefore a good guide to what might be found beyond USA. In fact, other national declarations of incidence and prevalence of NETs seem to bear these statistics out, i.e incidence rates of 7-8/100,000 …… almost 7 times the rate recorded in the 1970s. If you want to understand the factors behind this massive increase, I covered this extensively in my post “Neuroendocrine Tumors – not as rare as you think“.  In this article, I looked at USA and beyond. Those who are regular readers of my articles will already know I’ve been ‘banging on’ about this for a few years. Other organisations and individuals (including NET specialists) are now indicating these tumors are not rare, some vindication for my aforementioned ‘banging on’.  This is now a serious disease with some serious statistics behind it and we need a new way of doing things.

 There are two further quotes which I’d like to focus on in this article:

1. From the NET SEER Database study published 2017:

…… many cases of NETs may not have been reported to cancer registries unless considered malignant…… it is likely that we have underestimated their true incidence and prevalence” – i.e. the slide here:

SEER 2012 Underestimated

2. From Dana Farber (Kulke, Chan):

“Estimated more than 200,000 undiagnosed cases in the US” – this slide here:

dana-farber-200000

…. But what do these quotes actually mean?  Here’s my take:

Underestimating the true incidence and prevalence of NETs

I studied the latest SEER NET study, formally titled “Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States” (authored by Arvind Dasari, MD, MS; Chan Shen, PhD; Daniel Halperin, MD; et al). From this document, I can see the authors were aware of the well-known faults in cancer registries worldwide and the effect this has on the true incidence and prevalence of Neuroendocrine Cancer.  These issues, which are a worldwide problem, include the incorrect registration of Neuroendocrine Cancer as other types based on the anatomical location of the primary tumor.  At this point, you may wish to check out my post “The Human Anatomy of Neuroendocrine Cancer” which provides some real life examples of the confusion between primary Neuroendocrine location and other cancers. That said, things are definitely improving because the latest SEER data shows a marked increase in the incidence of High Grade Neuroendocrine Carcinomas (NEC), an area where this issue is prevalent. A similar increase in NEC was also illustrated in the UK’s figures from Public Health England (PHE) in 2016 (click here) indicating that cancer registries are getting better and not before time, although it has to be said this only came about due to a major intervention by NET Patient Foundation and others. Through this work, it’s becoming clear that the incidence of all NETs in UK is around 8 to 9 per 100.000 (rare threshold <=5).

But there’s another issue impacting whether a diagnosis is actually entered on a cancer registry or not.  Unfortunately, there are members of the medical community who still see well differentiated NETs as benign tumors, ‘not a proper cancer’ and still use ancient terminology ………  ‘Carcinoid’.  The WHO 2010 classification for NETs was based on the concept that all NETs have malignant potential. Here’s a quote from the UKINETS Guidelines in 2011 (Ramage, Caplin, Meyer, Grossman, et al).

Tumours should be classified according to the WHO 2010 classification (Bosman FT, Carneiro F, Hruban RH, et al. WHO Classification of Tumours of the Digestive System. Lyon: IARC, 2010). This classification is fundamentally different from the WHO 2000 classification scheme, as it no longer combines stage related information with the two-tiered system of well and poorly differentiated NETs. The WHO 2010 classification is based on the concept that all NETs have malignant potential, and has therefore abandoned the division into benign and malignant NETs and tumours of uncertain malignant potential.

The guidance in WHO 2017 for Endocrine Organs reinforces this statement.

The undiagnosed NET patient population

From above, you can see why the incidence (and therefore the prevalence) of our disease has almost definitely been underestimated.  However, that’s not the end of my story……..

A number of statements are clear about Neuroendocrine Tumors:

  • Low/Intermediate grade well differentiated tumors are known to have been growing slowly over a number of years before discovery or accurate diagnosis occurs,
  • They can be difficult to diagnose,
  • They are not that well-known amongst the general medical population,
  • Many people are initially misdiagnosed with another condition, with some this will result in late presentation with metastatic disease.
  • Many NETs are found during autopsies.

The living undiagnosed. It’s worth pointing out that one of the conclusions made by the recent SEER NET study is that the increase in incidence and prevalence can be attributed to a number of factors including earlier diagnosis.  This is of course excellent news.  Also worth noting that another conclusion of the study is that we are all living longer, reflecting improvements in therapies.  This is also great news and is a factor in increased prevalence figures. However, it seems obvious that there are hundreds of thousands of people out there still be diagnosed who have tumors silently growing inside them and who are in a loop of referrals between primary and secondary care awaiting a proper diagnosis. See the Dana Farber slide above.  Please help these people by sharing this article – you never know who it will reach – Diagnosing the Undiagnosed.

The dead undiagnosed? The true incidence of NETs may be much higher owing to the lack of diagnosis until after death.  For example:

  • In USA, a respected NET specialist stated that the autopsy find for (excuse the outdated terminology…….) ‘carcinoid‘ is 4 times the recorded diagnosis rate (based on the known incidence rate at the time, this is 8 per 100,000).
  • In Australia, one study claimed that 0.05% of all autopsies found a Pheochromocytoma or Paraganglioma. “
  • The Mayo Clinic experience shows that in up to 50% of cases of pheochromocytoma, the correct diagnosis is made at autopsy (ergo the incidence rate could be double what is published).
  • Here is an article claiming that former US President Dwight D Eisenhower had a biopsy confirming he had a Pheochromocytoma.  Click here.
  • A Hong Kong study indicated that 1% of all autopsies discovered an ‘Islet Cell’ tumour (i.e. a Pancreatic NET or pNET).
  • In one series, (excuse the outdated terminology…….) ‘carcinoid’ tumors were found in 1.22% of 16,294 autopsies in Malmö, Sweden, 90% of which were incidental findings.

It’s possible that many of these people showed no NET symptoms during their life but …… it’s equally possible that many of these people had NET symptoms but just put up with it and/or had been diagnosed with something else, and then died without a correct diagnosis.  There is no evidence that any investigation follow ups were done so this possibility remains.

The potential for even more undiagnosed. To add to the underdiagnoses of NETs issue, is this most amazing piece of research published in 2018 – Pan-cancer molecular classes transcending tumor lineage across 32 cancer types, multiple data platforms, and over 10,000 cases.  It was published in the American Association of Cancer Research (AACR) journal ‘Clinical Cancer Research and authored by Chad Creighton et al. D.  This was a pan-cancer piece of research which indicated that Neuroendocrine disease may be more prevalent than anyone has ever thought.  There’s a summary article here which I suggest you read fully.  The rather explosive extract is as follows:

We expected that about 1 percent of

Are you undiagnosed but suspect NETs?

Check out my advice by clicking here.

Summary

I suspect there’s an invisible patient population for many conditions but the slow-growing and relatively quiet nature of Neuroendocrine Cancer means there could be a significant undiagnosed burden walking around, looking for a diagnosis, putting up with symptoms and being treated for other conditions. I see people on forums looking for clues, social media can sometimes be helpful here. That said, I do get the feeling some do not have NETs, regardless of the symptoms they associate with the disease, but I guess many of them will go on to be formally diagnosed with something. I’m contacted by many ‘undiagnosed’ people on my own blog and supporting Facebook sites (mostly privately) and I can tell you that’s a tough gig.  I only hope I’ve given them some useful ideas about where to look or what to ask/suggest.

I feel earlier diagnosis reported in the SEER study is partly due to increased awareness, particularly in the medical world. I would also suggest that it has improved in the general population due to the explosion of social media information dissemination. It’s also accurate to say that improvements in diagnostic capabilities is also playing its part in pushing up incidence rates, just as improved therapies have pushed up prevalence rates, something emphasised by Dasari (et al) in the most recent study.  Things are improving but there is so much more to do.

The issues caused by inefficient registries together with ‘the undiagnosed’, combine to suggest there is a large invisible NET patient population out there ……. we just need to find them!  

Thanks to NET Patient Foundation for featuring this article here.

NET Patient Foundation logo

Neuroendocrine Tumor Drug Clinical Trial – Cabozantinib (includes news on Pheochromoctyoma and Paraganglioma)

What is Cabozantinib?

Cabozantinib is an oral drug which works by blocking the growth of new blood vessels that feed a tumour. In addition to blocking the formation of new blood cells in tumours, Cabozantinib also blocks pathways that may be responsible for allowing cancers cells to become resistant to other “anti-angiogenic” drugs. It is a type of drug called a growth blocker.  Cabozantinib has been studied or is already in research studies as a possible treatment for various types of cancer, including prostate cancer, ovarian cancer, brain cancer, thyroid cancer, lung cancer, and kidney cancer. During my research, I found that it has a connection to Medullary Thyroid Cancer (MTC) which is a type of Neuroendocrine Cancer, frequently associated with Multiple Endocrine Neoplasia (MEN).  Cabozantinib, under the brand name of ‘Cometriq’ was approved by the FDA in 2012 for use in MTC.  Read more about Cometriq here.  It’s also been approved by the FDA for advanced renal cell carcinoma (RCC) (branded as Cabometyx). I also discovered that there is an exclusive licensing Agreement with the manufacturers (Elelixis) and Ipsen (of Lanreotide fame) to commercialize and develop Cabozantinib in regions outside the United States, Canada and Japan

Growth blockers are a type of biological therapy and include tyrosine kinase inhibitors, proteasome inhibitors, mTOR inhibitors, PI3K inhibitors, histone deacetylase inhibitors and hedgehog pathway blockers.  Cabozantinib is a tyrosine kinase inhibitor (TKI).  They block chemical messengers (enzymes) called tyrosine kinases.  Tyrosine kinases help to send growth signals in cells so blocking them stop the cell growing and dividing.  Some TKIs can block more than one tyrosine kinase and these are known as multi-TKIs.

cabozantinib-picture
Example action of Cabozantinib

So Capozantinib is a tyrosine kinase inhibitor and is therefore a biological therapy and growth blocker just like Everolimus (Afinitor) and Sunitinib (Sutent) – some texts describe thelattero two as chemotherapy but this is just not accurate.

Very technical process but in the simplest of terms, Cabozantinib is designed to disrupt the actions of VEGF (a growth factor) and MET (a growth factor receptor) which promote spread of cancerous cells through the growth of new blood vessels.  Whilst we are on this subject, please note Everolimus (Afinitor) is an mTOR inhibitor and Sunitinib (Sutent) is a tyrosine kinase inhibitor. Many people think these drugs are a type of chemo – that is incorrect, these are targeted biological therapies.  See more on this by clicking here.

What is the current trial status of Capozantinib?

A Phase III trial is now recruiting entitled Cabozantinib S-malate in Treating Patients With Neuroendocrine Tumors Previously Treated With Everolimus That Are Locally Advanced, Metastatic, or Cannot Be Removed by Surgery”. 

The trial has 172 locations across the US (see link below). The primary study (final data) is scheduled Jan 1st 2021.

You can read the trial documentation by clicking here.

Progress report

  1. Poster submission for 2017 Gastrointestinal Cancer Symposium
  2. Onc Live output from the 2017 Gastrointestinal Cancer Symposium
  3. Output from NANETS 2017
  4. A funded piece of research by the NET Research Foundation – check it out herelooks like they are trying to figure out what patients might benefit from Cabozantinib using biomarker data to predict response.
  5. Dr Jennifer Chan speaking in 2018 about the drug potential.  (Apologies for the use of the out of date term ‘Carcinoid‘).
  6. Phase 3 Clinical Trial Document – click here

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UPDATED 2018 – There’s also another trial looking at unresectable metastatic Pheochromocytomas and Paragangliomas

A Phase 2 Study to Evaluate the Effects of Cabozantinib in Patients with Unresectable Metastatic Pheochromocytomas and Paragangliomas 

This part is from an article collaboration between MedPage Today® and the American Association of Clinical Endocrinologists

BOSTON — Cabozantinib (Cabometyx) may benefit patients with malignant pheochromocytomas and paragangliomas, according to results of a phase II trial presented here.

Patients receiving cabozantinib (Cometriq) treatment experienced notable tumor shrinkage in the lymph nodes, liver, and lung metastases, according to Camilo Jimenez, MD, of the MD Anderson Cancer Center in Houston, and colleagues.

Additionally, progression-free survival significantly increased after treated to 12.1 months (range 0.9-28) compared with just 3.2 months prior to treatment, they reported at the American Association of Clinical Endocrinologists (AACE) annual meeting.

Cabozantinib treatment was also tied to an improvement in blood pressure and performance status, as well as remission of diabetes among these patients.

“Malignant pheochromocytomas and paragangliomas are frequently characterized by an excessive secretion of catecholamines. [Patients] have a large tumor burden and they have a decreased overall survival,” explained Jimenez. “Tumors are frequently very vascular and frequently associated with bone metastases. In fact, up to 20% of patients who have malignancy of pheochromocytomas and paragangliomas may have predominant bone metastases.”

He added that “an interesting aspect of this tumor is that C-MET receptor mutation have been found in occasional patients with malignant pheochromocytomas and paragangliomas.”

Cabozantinib is an anti-angiogenic tyrosine kinase inhibitor, which also targets RET, MET, and AXL. It is approved for metastatic medullary thyroid cancer, and was more recently approved for first-line treatment of advanced renal cell carcinoma.

“MET pathway is also involved in the development of bone metastases. In fact, cabozantinib is a very effective medications for patients who have bone metastases in the context of cancer of different origins,” Jimenez said.

In order to be eligible for the trial, patients with confirmed pheochromocytoma or paraganglioma had to be ineligible for curative surgery, have ≥3 months life expectancy, no risk for perforation or fistula, and adequate organ functioning. Prior to cabozantinib initiation, patients could not receive chemotherapy or biologic agents within 6 weeks, radiation within 4 weeks, or MIBG within 6 months.

Following histological confirmation of disease progression >1 year according to RECIST 1.1, the trial included 14 patients with measurable disease and eight patients with predominant/exclusive bone metastases. Fifteen patients subsequently enrolled into the trial, six of whom had germline mutations of the SDHB gene.

All participants were all started at an initial daily dose of 60 mg of cabozantinib, which was subsequently reduced down to between 40 to 20 mg due to toxicity in 13 patients based on tolerance.

The majority of these patients with measurable disease experienced some level of disease response. Six patients reported a partial response, defined as over a 30% reduction, while three patients achieved moderate response, marked by a 15%-30% reduction. Five of the patients with predominant bone metastases reported disease stabilization, according to results of an FDG-PET scan. One patient experienced disease progression while on treatment.

Overall, cabozantinib was generally well-tolerated without any grade 4 or 5 treatment-related adverse events reported. Some of the most common adverse events reported included grade mild dysgeusia, hand and foot syndrome, mucositis, fatigue, weight loss, and hypertension, according to the authors.

  • Primary Source – American Association of Clinical Endocrinologists meeting – AACE 2018; Abstract 142. attended my Medscape writers

You can see the Pheo/Para clinical trial document by clicking here.

————————————–

Summary

I generated this blog article to add value rather than just post the outputs for your own perusal.  I hope you find it useful.

Please note that taking part in a clinical trial is a big decision and must be considered carefully in conjunction with your specialists if necessary.  This article is not suggesting this trial is right for you.  Please check the inclusion and exclusion criteria in the trials document carefully. (Pheo/Para patients see other clinical trial link above)

Neuroendocrine Neoplasms (NEN) – benign vs malignant

Kunz His belief these tumors did not metastisize

OPINION:

One of the most controversial aspects of Neuroendocrine Neoplasms, in particular low grade Neuroendocrine Tumours (NETs), is the ‘benign vs malignant’ question.  It’s been widely debated and it frequently patrols the various patient forums and other social media platforms. It raises emotions and it triggers many responses ….. at least from those willing to engage in the conversation. At best, this issue can cause confusion, at worst, it might contradict what new patients have been told by their physicians (….or not been told). I don’t believe it’s an exact science and can be challenging for a NET specialist let alone a doctor who is not familiar with the disease.

NANETS Guidance talks about the ‘…heterogeneous clinical presentations and varying degrees of aggressiveness‘ and ‘…there are many aspects to the treatment of neuroendocrine tumours that remain unclear and controversial‘.  I’m sure the ‘benign vs malignant’ issue plays a part in these statements.

In another example, ENETS Guidance discusses (e.g.) Small Intestine Tumours (Si-NETs) stating that they ‘derive from serotonin-producing enterochromaffin cells. The biology of these tumors is different from other NENs of the digestive tract, characterized by a low proliferation rate [the vast majority are grade 1 (G1) and G2], they are often indolent’.  However, they then go on to say that ‘Si-NETs are often discovered at an advanced disease stage – regional disease (36%) and distant metastasis (48%) are present‘.  It follows that the term ‘indolent‘ does not mean they are not dangerous and can be ignored and written off as ‘benign’. This presents a huge challenge to physicians when deciding whether to cut or not to cut.

Definitions

To fully understand this issue, I studied some basic (but very widely accepted) definitions of cancer.  I also need to bring the ‘C’ word into the equation (Carcinoid), because the history of these tumours is frequently where a lot of the confusion lies.  The use of the out of date term by both patients, patient advocates and doctors exacerbates the issue given that it decodes to ‘carcinoma like‘ which infers it is not a proper cancer.  See more below.

Let’s look at these definitions provided by the National Cancer Institute.  Please note I could have selected a number of organisations but in general, they all tend to agree with these definitions give or take a few words. These definitions help with understanding as there can be an associated ‘tumour’ vs ‘cancer’ debate too.

Cancer – Cancer is the name given to a collection of related diseases. In all types of cancer, some of the body’s cells begin to divide without stopping and spread into surrounding tissues. There are more than 100 types of cancer which are usually named for the organs or tissues where the cancers form.  However, they also may be described by the type of cell that formed them.

Author’s note: The last sentence is important for Neuroendocrine Tumour awareness (i.e. Neuroendocrine Tumour of the Pancreas rather than Pancreatic Cancer).

Carcinoma – Carcinomas are the most common grouping of cancer types. They are formed by epithelial cells, which are the cells that cover the inside and outside surfaces of the body. There are many types of epithelial cells, which often have a column-like shape when viewed under a microscope.

Author’s note: By definition, Carcinomas are malignant, i.e. they are without question malignant cancers. Poorly differentiated Neuroendocrine Neoplasms are deemed to be a ‘Neuroendocrine Carcinoma’ according to the most recent World Health Organisation (WHO) classification of Neuroendocrine Tumours (2017) and ENETS 2016 Guidance. You will have heard of some of the types of Carcinoma such as ‘Adenocarcinoma’ (incidentally, the term ‘Adeno’ simply means ‘gland’). It follows that Grade 3 Neuroendocrine Carcinomas (NEC) are beyond the scope of this discussion.

Malignant – Cancerous. Malignant cells can invade and destroy nearby tissue and spread to other parts of the body.

Benign – Not cancerous. Benign tumors may grow larger but do not spread to other parts of the body.

Author’s Note: This is a key definition because there are people out there who think that low grade NETs are not cancer. 

Tumour (Tumor) – An abnormal mass of tissue that results when cells divide more than they should or do not die when they should. Tumors may be benign (not cancerous), or malignant (cancerous). Also called Neoplasm.

Author’s Note: Neoplasm is an interesting term as this is what is frequently used by ENETS and NANETS in their technical documentation, sometimes to cover all Neuroendocrine types of cancer (Tumor and Carcinoma). It follows that a malignant tumour is Cancer. The term “Malignant Neuroendocrine Tumour” is the same as saying “Neuroendocrine Cancer”

Neuroendocrine Tumours – Benign or Malignant?

Definitions out of the way, I have studied the ENETSUKINETS and NANETS guidance both of which are based on internationally recognised classification schemes (i.e. the World Health Organisation (WHO)).

In older versions of the WHO classification schemes (1980 and 2000), the words ‘benign’ and ‘uncertain behaviour’ were used for Grades 1 and 2. However, the 2010 edition, the classification is fundamentally different (as is the recent 2017 publication).  Firstly, it separated out grade and stage for the first time (stage would now be covered by internationally accepted staging systems such as TNM – Tumour, (Lymph) Nodes, Metastasis). Additionally, and this is key to the benign vs malignant discussion, the WHO 2010 classification is based on the concept that all NETs have malignant potential.  Here’s a quote from the UKINETS 2011 Guidelines (Ramage, Caplin, Meyer, Grossman, et al).

Tumours should be classified according to the WHO 2010 classification (Bosman FT, Carneiro F, Hruban RH, et al. WHO Classification of Tumours of the Digestive System. Lyon: IARC, 2010). This classification is fundamentally different from the WHO 2000 classification scheme, as it no longer combines stage related information with the two-tiered system of well and poorly differentiated NETs. The WHO 2010 classification is based on the concept that all NETs have malignant potential, and has therefore abandoned the division into benign and malignant NETs and tumours of uncertain malignant potential.

The guidance in 2017 WHO reinforces this statement to include endocrine organs, including the pancreas and adrenal glands.

The C Word (Carcinoid) – part of the problem?

History lesson – Carcinoid tumours were first identified as a specific, distinct type of growth in the mid-1800’s, and the name “karzinoide” was first applied in 1907 by German pathlogist Siegfried Oberndorfer in Europe in an attempt to designate these tumors as midway between carcinomas (cancers) and adenomas (benign tumors).

The word ‘Carcinoid’ originates from the term ‘Carcinoma-like’.  ‘CARCIN’ is a truncation of Carcinoma. ‘OID’ is a suffix used in medical parlance meaning ‘resembling’ or ‘like’.  This is why many people think that Carcinoid is not a proper cancer.

The situation is made even more confusing by those who use the term “Carcinoid and Neuroendocrine Tumors” inferring that it is a separate disease from the widely accepted and correct term ‘Neuroendocrine Tumor’ or Neuroendocrine Neoplasm.  A separate discussion on this subject can be found in this post here. I encourage you to stop using the term ‘Carcinoid’ which is just perpetuating the problem. 

Kunz His belief these tumors did not metastisize

How are NENs Classified?

If you read any NET support website it will normally begin by stating that Neuroendocrine Tumours constitute a heterogeneous group of tumours. This means they are a wide-ranging group of different types of tumours.  However, the latest WHO classification scheme uses the terms ‘Neuroendocrine Tumour’ for well differentiated Grade 1 (low-grade), Grade 2 (Intermediate Grade) and Grade 3 (High Grade) NET; and ‘Neuroendocrine Carcinoma’ (NEC) for  poorly differentiated tumours which are by default grade 3 or high grade. They also use the term ‘Neoplasm’ to encompass all types of NET and NEC. So Grade 1 is a low-grade malignancy and so on (i.e any grade of NET is a malignant tumour).  You may benefit from reading my blog article on Staging and Grading of NETs as this is also a poorly understood area.

Can some NETs be Benign?

By any accepted definition of cancer terms, a tumour can be non-cancerous (benign) or cancerous (malignant).  This is correct for any cancer type. For example, the word is used in the 2016 version of Inter Science Institute publication on Neuroendocrine Tumors, a document I frequently reference in my blog.  For example, I’ve seen statements such as “These tumors are most commonly benign (90%)” in relation to Insulinoma (a type of Pancreatic NET or pNET). Ditto for Pheochromocytoma (an adrenal gland NET).  Adrenal and Pituitary ‘adenomas’ are by definition benign (adenoma is the benign version of Adenocarcinoma).  And I note that there is a ‘benign’ code option for every single NET listed in the WHO International Classification of Diseases (ICD) system.

The ‘BUT‘ is this – all WHO classification systems are based on the concept that NETs always have malignant potential.  The WHO 2017 classification update confirmed this thinking by adding endocrine organs including the pancreas and adrenal glands.

don't worry it's benign widescreen

Can Tumours be Malignant or become Malignant?

Using the definition above, if a tumour invades and destroy nearby tissue and spread to other parts of the body, then it’s malignant (i.e  Cancer). However, there’s a reason why the WHO declared in 2010 that all NETs have malignant potential (as amplified in WHO 2017). It may not happen or it may happen slowly over time but as Dr Richard Warner says, “they don’t all fulfill their malignant potential, but they all have that possible outcome”.  Thus why ongoing surveillance is important after any diagnosis of Neuroendocrine Tumour of any grade or at any stage.  Dr Lowell Anthony, a NET Specialist from the University of Kentucky explains this much better than I can – CLICK HERE to hear his two-minute video clip.  This issue even caused confusion with doctors, some of whom still think a Stage 4 NET is still benign. Not only is this very insensitive to the patient concerned but it also goes against all the definitions of ‘benign’ and ‘malignant’ that exist in authoritative texts.

Summary

This was a difficult piece of research. I do believe there are scenarios where NETs will be benign and probably never cause the person any real harm (e.g. many are found on autopsies). I  suspect this is the same for many cancers. However, based on the above text and the stories of people who have presented for a second time but with metastatic disease, use of the word ‘benign’ is probably best used with great care.

I would certainly (at least) raise an eyebrow if someone said to anyone with any NET tumour, “you don’t need any treatment or surveillance for a NET”; or “it has been cured and no further treatment or surveillance is required”.  Particularly if they are not a NET specialist or a recognised NET Centre.

Remember, I’m not a medical professional, so if you are in any doubt as to the status of your NET, you should discuss this directly with your specialist.  A good place to start is evidence of your Grade, Differentiation, Primary Site Location and Stage.

You may be interested in reading these associated posts:

Carcinoid vs Neuroendocrine

Neuroendocrine Neoplasms – Grading and Staging (WHO 2017)

Incurable vs Terminal

10 Questions for your doctor

Thanks for reading

Ronny

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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

Ronny Allan is an award winning patient leader and advocate for Neuroendocrine Cancer.


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Telotristat Ethyl (XERMELO®) – an oral treatment for Carcinoid Syndrome Diarrhea not adequately controlled by Somatostatin Analogues

Telotristat Ethyl is an extremely significant introduction to the treatment of Carcinoid Syndrome diarrhea. It’s the first addition to the standard of care in more than 16 years and the first time an oral syndrome treatment has been developed.  The drug was previously known as Telotristat Etiprate but was changed to Ethyl in Oct 2016. ‘Etiprate’ was previously a truncation of ‘ethyl hippurate’.  The brand name is XERMELO® 

UPDATE MARCH 2018 

The March 2018 issue of Clinical Therapeutics provides the first report of the effects of XERMELO on changes in weight in patients with neuroendocrine tumors (NETs) and carcinoid syndrome that participated in the TELESTAR study. You have to remember that XERMELO is approved for those with carcinoid syndrome diarrhea not adequately controlled by somatostatin analogues (author’s note – i.e not for diarrhea caused by (say) side effects of surgery).

Of the 120 patients with weight data available, up to 32.5% of patients treated with XERMELO experienced significant, dose-dependent weight gain (≥3% from baseline). Only 5.1% of patients on placebo experienced weight gain. Importantly, patients with weight gain experienced improvement in carcinoid syndrome control, as seen in reduction of bowel movement frequency and in parameters of nutritional status associated with positive changes in patient-reported outcomes compared with patients with stable weight or weight loss. Those patients also experienced reduced u5-HIAA levels. Patients with weight gain also experienced fewer serious adverse events than patients with stable weight or weight loss.

(see link below)

Who is the drug for?

The drug may be of benefit to those whose carcinoid syndrome diarrhea is not adequately controlled by somatostatin analogues (Octreotide/Lanreotide). It doesn’t replace somatostatin analogues – it is an additional treatment alongside (although I have heard of patients in the US being subscribed who are not receiving somatostatin analogue treatment)

Where is it currently approved?

The US FDA approved the drug 28 February 2017.

On 19 September 2017,the European Commission approved Xermelo® (telotristat ethyl) for the treatment of carcinoid syndrome diarrhea in patients inadequately controlled by somatostatin analogue therapy after the scientific committee of the EMA (known as Committee for Medicinal Products for Human Use (CHMP)) adopted a positive opinion recommending the approval of Xermelo® (telotristat ethyl) 250 mg three times a day for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analogue (SSA) therapy in adults inadequately controlled by SSA therapy. The Ipsen press release is here.  Clearly some action will be required in EC national countries before the drug becomes available through the appropriate healthcare systems.


On 17 Oct 2018, Health Canada announced approval for Canadian NET patients – click here.

For all other countries please note that Ipsen will pursue a worldwide regulatory plan for marketing authorisation submissions in the territories in which it operates. Once approved, Ipsen will be distributing the drug in all countries less USA and Japan where Lexicon retains the rights. Outside USA and Europe will be constrained by national approval timelines.

How does it work?

In the simplest of terms, the drug is an inhibitor of the enzyme tryptophan hydroxylase (TPH).  TPH is the rate-limiting enzyme in serotonin synthesis which converts tryptophan (an essential amino acid which comes from diet) to 5-hydroxytryptophan, which is subsequently converted to serotonin, one of the main causes of carcinoid syndrome effects including carcinoid heart disease.  The trial data indicates that Telotristat ethyl significantly reduced the frequency of bowel movements. Furthermore, it was also associated with “significantly reduced levels of urinary 5-HIAA“, a marker for systemic serotonin levels, which are typically elevated in severe carcinoid syndrome.  Essentially it works by reducing the manufacture of Serotonin so it’s it may not have any effect on diarrhea not caused by syndrome (i.e. post surgery etc).

telotristat-etiprate-clinical-trial-serotonin-as-a-key-driver-of-carcinoid-syndrome

Resources for your perusal:

  • You can read more about the trial data in a summary by Dr Matthew Kulke (Dana Farber) by CLICKING HERE (latest review from 2017 ASCO).
  • There is also an excellent summary in video form by Dr Lowell Anthony (University of Kentucky) by CLICKING HERE. (“any reduction in diarrhea is meaningful“).
  • The detailed output from the trial (results) can be found by CLICKING HERE.
  • Great 2016 article from ASCO (American Society of Clinical Oncologists) can be found by CLICKING HERE.
  • FDA Approval.  CLICK HERE
  • Lex Pharma press release on approval.  CLICK HERE
  • EU Approval (Ipsen Press Release).  CLICK HERE
  • The manufacturer Lex Pharma have established a dedicated site – CLICK HERE
  • 2018 revised clinical data – CLICK HERE

 

Serotonin Video with myself and Dr Mike Morse

I made a video in 2019 with Dr Mike Morse sponsored by Lexicon Pharmaceuticals, Inc.  It’s all about Carcinoid Syndrome with a slant towards hormones, in particular Serotonin. Entitled “Likely Suspects: How Hormones May Lead to Carcinoid Syndrome – What People Living With Carcinoid Syndrome Need to Know”

You need to register to watch although some of you will already be registered and just need an email to login to see the this webcast. The one I’m featured in is the latest in a series on the subject and I’d like to break the record for views please! Please help me achieve this 💙 I would also love to get your feedback and sincerely hope you will find the time to listen in.  Please also find the time to complete the survey at the end.  Thanks

Click on the link here: www.CarcinoidWebcast.com

Don’t forget to press the play button and ensure your sound is turned up, particularly on mobile devices.

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Thanks for reading

Ronny

I’m also active on Facebook.  Like my page for even more news.  I’m also building up this site here: Ronny Allan

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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

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