ASCO 2017 – Let’s talk about NETs #ASCO17

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.

68Ga-DOTATATE PET/CT to predict response to peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumours (NETs).  

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

Rohini Sharma 4093
A multicohort phase II study of durvalumab plus tremelimumab for the treatment of patients (PTS) with advanced neuroendocrine neoplasms (NENs) of gastroenteropancreatic (GEP) or lung origin (the DUNE trial-GETNE1601-).

News of a trial – no conclusion included.  However, see trial data NCT03095274

Ignacio Matos Garcia TPS4146
Association between duration of somatostatin analogs (SSAs) use and quality of life in patients with carcinoid syndrome in the United States based on the FACT-G instrument.

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.

Daniel M. Halperin e15693
Association of weight change with telotristat ethyl in the treatment of carcinoid syndrome.

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

See my blog post Telotristat Ethyl

Martin O Weickert e15692
Blood measurements of neuroendocrine tumor (NET) transcripts and gene cluster analysis to predict efficacy of peptide radioreceptor therapy.

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.

Lisa Bodei 4091
Capecitabine and temozolomide (CAPTEM) in neuroendocrine tumor of unknown primary.

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.

Aman Chauhan e15691
Clinical and epidemiological features in 495 gastroenteropancreatic neuroendocrine patients in Mexico.

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.

Rafael Medrano Guzman e15687
Effect of lanreotide depot (LAN) on 5-hydroxyindoleacetic acid (5HIAA) and chromogranin A (CgA) in gastroenteropancreatic neuroendocrine (GEP NET) tumors: Correlation with tumor response and progression-free survival (PFS) from the phase III CLARINET study.

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

Alexandria T. Phan 4095
Final progression-free survival (PFS) analyses for lanreotide autogel/depot 120 mg in metastatic enteropancreatic neuroendocrine tumors (NETs): The CLARINET extension study.

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

Edward M. Wolin 4089
Lanreotide depot (LAN) for symptomatic control of carcinoid syndrome (CS) in neuroendocrine tumor (NET) patients previously responsive to octreotide (OCT): Subanalysis of patient-reported symptoms from the phase III elect study.

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

Check out my blog post about Lanreotide and Lanreotide vs Octreotide

George A. Fisher 4088
Molecular classification of neuroendocrine tumors: Clinical experience with the 92-gene assay in >24,000 cases.

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.

Andrew Eugene Hendifar e15700
Multi-omic molecular profiling of pancreatic neuroendocrine tumors.

Conclusions: In PNETS, multi-omic profiling through the KYT program identified targetable alterations in several key pathways. Outcome data will be explored.

Rishi Patel e15685
Outcomes of peptide receptor radionuclide therapy (PRRT) in metastatic grade 3 neuroendocrine tumors (NETs).

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.

Mei Sim Lung e15694
Periprocedural management of patients undergoing liver resection or liver-directed therapy for neuroendocrine tumor metastases.

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.

See my blog on “Carcinoid Crisis” 

Daniel Kwon e15689
Predictive factors of carcinoid syndrome among patients with gastrointestinal neuroendocrine tumors (GI NETs).

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.

Beilei Cai e15690
Predictors of outcome in patients treated with peptide radio-labelled receptor target therapy (PRRT).

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.

Dalvinder Mandair 4090
Pre-existing symptoms, resource utilization, and healthcare costs prior to diagnosis of neuroendocrine tumors: A SEER-Medicare database study.

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.

Chan Shen 4092
Prevalence of co-morbidities in elderly patients with distant stage neuroendocrine tumors.

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.

A. Dasari e15699
Prognostic factors influencing survival in small bowel neuroendocrine tumors with liver metastasis.

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.

Nicholas Manguso e15688
Role of 92 gene cancer classifier assay in neuroendocrine tumor of unknown primary.

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).

Aman Chauhan e15696
Surgery in combination with peptide receptor radionuclide therapy is effective in metastatic neuroendocrine tumors and is definable by blood gene transcript analysis.

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.

Andreja Frilling e15697
The impact of pathologic differentiation (well/ poorly) and the degree of Ki-67 index in patients with metastatic WHO grade 3 GEP-NECs.

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 Grading which 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

Diane Lauren Reidy 4094
Use of antiresorptive therapy (ART) and skeletal-related events (SREs) in patients with bone metastases of neuroendocrine neoplasms (NEN).

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.

Leonidas Apostolidis 4096
Targeted radiopeptide therapy Re188-P2045 to treat neuroendocrine lung cancer

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.

Christopher Peter Adams, Wasif M. Saif e20016

Thanks for reading

Ronny
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Neuroendocrine Cancer – Hormones

HormonesNET 2018

Until I was diagnosed with metastatic Neuroendocrine Cancer, I didn’t have a clue about hormones – it’s one of those things you just take for granted. However, hormones are vital to human health (male and female) and it’s only when things go wrong you suddenly appreciate how important they are ……..like a lot of other things in life I suppose! The presence of over-secreting hormones (often called peptides throughout) is useful to aid diagnosis albeit it often means the tumours have metastasized. It’s also a frequent indication that the person has an associated NET syndrome.

This is a really complex area and to understand the hormone problems associated with Neuroendocrine Cancer, you need to have a basic knowledge of the endocrine and neuroendocrine systems.  I’ve no intention of explaining that (!) – other than the following high level summary:

  • Glands in the endocrine system use the bloodstream to monitor the body’s internal environment and to communicate with each other through substances called hormones, which are released into the bloodstream.  Endocrine glands include; Pituitary, Hypothalmus, Thymus, Pineal, Testes, Ovaries Thyroid, Adrenal, Parathyroid, Pancreas.
  • A Hormone is a chemical that is made by specialist cells, usually within an endocrine gland, and it is released into the bloodstream to send a message to another part of the body. It is often referred to as a ‘chemical messenger’. In the human body, hormones are used for two types of communication. The first is for communication between two endocrine glands, where one gland releases a hormone which stimulates another target gland to change the levels of hormones that it is releasing. The second is between an endocrine gland and a target organ, for example when the pancreas releases insulin which causes muscle and fat cells to take up glucose from the bloodstream. Hormones affect many physiological activities including growth, metabolism, appetite, puberty and fertility.
  • The Endocrine system. The complex interplay between the glands, hormones and other target organs is referred to as the endocrine system.
  • The Neuroendocrine System. The diffuse neuroendocrine system is made up of neuroendocrine cells scattered throughout the body.  These cells receive neuronal input and, as a consequence of this input, release hormones to the blood. In this way they bring about an integration between the nervous system and the endocrine system (i.e. Neuroendocrine).  A complex area but one example of what this means is the adrenal gland releasing adrenaline to the blood when the body prepares for the ‘fight or flight’ response in times of stress, ie, for vigorous and/or sudden action.

Hormones – The NET Effect

Hormones – the NET Effect

At least one or more hormones will be involved at various sites and even within certain syndromes, the dominant and offending hormone may differ between anatomical tumour sites. For example, NETs of the small intestine, lung or appendix (and one or two other places) may overproduce serotonin and other hormones which can cause a characteristic collection of symptoms currently called carcinoid syndrome.   The key symptoms are flushing, diarrhea and general abdominal pain, loss of appetite, fast heart rate and shortness of breath and wheezing. The main symptom for me was facial flushing and this was instrumental in my eventual diagnosis. The fact that I was syndromic at the point of diagnosis made it easier to discover, albeit the trigger for the investigation was a fairly innocuous event.  Other types of NETs are also affected by the overproduction of hormones including Insulinomas, Gastrinomas, Glucagonomas, VIPomas, Somatostatinomas, and others.  These can cause their own syndromes and are not part of carcinoid syndrome as some organisations incorrectly state. For more on NET syndromes – Read Here.

So are hormones horrible? 

Absolutely not, they are essential to the normal function of the human body.  For example if you didn’t have any of the hormone Serotonin in your system, you would become extremely ill.  On the other hand, if your glands start secreting too much of certain hormones, your body could become dysfunctional and in some scenarios, this situation could become life threatening.  So hormones are good as long as the balance is correct. NET patients with an oversecreting tumor may be classed as “functional”.

  • Functional tumors make extra amounts of hormones, such as gastrin, insulin, and glucagon, that cause signs and symptoms.
  • Nonfunctional tumors do not make extra amounts of hormones. Signs and symptoms are caused by the tumor as it spreads and grows. Many NET patients are deemed to be “non-functioning” with normal hormone levels. It’s also accurate to say that many can move from one stage to the other.

Location Location Location

It’s accurate to say that the type and amount of hormone secretion differs between locations or sites of the functional tumor and this can also create different effects.  The division of NETs into larger anatomical regions appears to differ depending on where you look but they all look something likes this:

Foregut NETs: In the respiratory tract, thymus, stomach, duodenum, and pancreas. This group mostly lack the enzyme aromatic amino decarboxylase that converts 5-HTP (5-Hydroxytryptophan – a precursor to serotonin) to serotonin (5-HT); such tumours tend to produce 5-HTP and histamine instead of serotonin.  The Pancreas is a particularly prominent endocrine organ and can produce a number of different syndromes each with their associated hormone oversecretion – although many can be non-functional (at least to begin with). Please note the respiratory tract and thymus are not really ‘Foregut’ but grouped there for convenience. 

Midgut NETs: In the small intestine, appendix, and ascending colon. For example, serotonin secreting tumors tend to be associated with carcinoid syndrome which tends to be associated with midgut NETs and this is normally the case. Many texts will also tell you that a syndrome only occurs at a metastatic stage.  Both are a good rule of thumb but both are technically incorrect. For example, in the bronchus or ovary you can have a form of carcinoid syndrome without liver metastasis (tends to be described as atypical carcinoid syndrome). It’s also possible to see serotonin secreting tumors in places such as the pancreas (although what you would call that type of NET is open for debate).

Hindgut NETs (transverse, descending colon and rectum) cannot convert tryptophan to serotonin and other metabolites and therefore rarely cause carcinoid syndrome even if they metastasise to the liver.

Less Common Locations – there are quite a few less common NET locations which may involve less common hormones – some are covered below including the key glands contributing to NETs.

Unknown Primary? –  One clue to finding the primary might be by isolating an offending hormone causing symptoms.

The key NET hormones

Serotonin

I used the example of Serotonin above because it is the most cited problem with NET Cancer although it does tend to be most prevalent in midgut tumors. Serotonin is a monoamine neurotransmitter synthesized from Tryptophan, one of the eight essential amino acids (defined as those that cannot be made in the body and therefore must be obtained from food or supplements). About 90% of serotonin produced in the body is found in the enterochromaffin cells of the gastrointestinal (GI) tract where it is used mainly to regulate intestinal movements amongst other functions. The remainder is synthesized in the central nervous system where it mainly regulates mood, appetite, and sleep. Please note there is no transfer of serotonin across the blood-brain barrier.

Alterations in tryptophan metabolism may account for many symptoms that accompany carcinoid syndrome. Serotonin in particular is the most likely cause of many features of carcinoid syndrome as it stimulates intestinal motility and secretion and inhibits intestinal absorption. Serotonin may also stimulate fibroblast growth and fibrogenesis and may thus account for peritoneal and valvular fibrosis encountered in such tumours; serotonin, however, it is said not to be associated with flushing. The diversion of tryptophan to serotonin may lead to tryptophan deficiency as it becomes unavailable for nicotinic acid synthesis, and is associated with reduced protein synthesis and hypoalbuminaemia; this may lead to the development of pellagra (skin rash, glossitis, stomatitis, confusion/dementia).

Serotonin is also thought to be responsible for ‘right sided’ heart disease (Carcinoid Heart Disease). It is thought that high levels of serotonin in the blood stream damages the heart, leading to lesions which cause fibrosis, particularly of the heart valves. This generally affects the right side of the heart when liver metastases are present. The left side of the heart is usually not affected because the lungs can break down serotonin. Right sided heart failure symptoms include swelling (edema) in the extremities and enlargement of the heart.

Whilst serotonin can be measured directly in the blood, it’s said to be more accurate to measure 5HIAA (the output of serotonin) via blood or urine.

Tachykinins

Tackykinins include Substance P, Neurokinin A, Neuropeptide K and others. They are active in the enterochromaffin cells of the GI tract but can also be found in lung, appendiceal and ovarian NETs, and also in Medullary Thyroid Carcinoma and Pheochromocytomas. They are thought to be involved in flushing and diarrhea in midgut NETs. The most common tachykinin is Substance P, which is a potent vasodilator (substances which open up blood vessels). Telangiectasias are collections of tiny blood vessels which can develop superficially on the faces of people who have had NETs for several years. They are most commonly found on the nose or upper lip and are purplish in color. They are thought to be due to chronic vasodilatation.

Histamine

Histamine is a hormone that is chemically similar to the hormones serotonin, epinephrine, and norepinephrine. After being made, the hormone is stored in a number of cells (e.g., mast cells, basophils, enterochromaffin cells). Normally, there is a low level of histamine circulating in the body. However (and as we all know!), the release of histamine can be triggered by an event such as an insect bite. Histamine causes the inconvenient redness, swelling and itching associated with the bite. For those with severe allergies, the sudden and more generalized release of histamine can be fatal (e.g., anaphylactic shock). Mast cell histamine has an important role in the reaction of the immune system to the presence of a compound to which the body has developed an allergy. When released from mast cells in a reaction to a material to which the immune system is allergic, the hormone causes blood vessels to increase in diameter (e.g., vasodilation) and to become more permeable to the passage of fluid across the vessel wall. These effects are apparent as a runny nose, sneezing, and watery eyes. Other symptoms can include itching, burning and swelling in the skin, headaches, plugged sinuses, stomach cramps, and diarrhea. Histamine can also be released into the lungs, where it causes the air passages to become constricted rather than dilated. This response occurs in an attempt to keep the offending allergenic particles from being inhaled. Unfortunately, this also makes breathing difficult. An example of such an effect of histamine occurs in asthma. Histamine has also been shown to function as a neurotransmitter (a chemical that facilitates the transmission of impulses from one neural cell to an adjacent neural cell).

In cases of an extreme allergic reaction, adrenaline is administered to eliminate histamine from the body. For minor allergic reactions, symptoms can sometimes be lessened by the use of antihistamines that block the binding of histamine to a receptor molecule.  Histamine is thought to be involved with certain types and locations of NET, including Lung and foregut NETs where they can cause pulmonary obstruction, atypical flush and hormone syndromes.

Histamine, another amine produced by certain NETs (particularly foregut), may be associated with an atypical flushing and pruritus; increased histamine production may account for the increased frequency of duodenal ulcers observed in these tumours.

Kallikrein

Kallikrein is a potent vasodilator and may account for the flushing and increased intestinal mobility.

Prostaglandins

Although prostaglandins are overproduced in midgut tumours, their role in the development of the symptoms of carcinoid syndrome is not well established but triggering peristalsis is mentioned in some texts.

Bradykinin

Bradykinin acts as a blood vessel dilator. Dilation of blood vessels can lead to a rapid heartbeat (tachycardia) and a drop in blood pressure (hypotension). Dilation of blood vessels may also be responsible for the flushing associated with carcinoid syndrome.

Gastrin

Gastrin is a hormone that is produced by ‘G’ cells in the lining of the stomach and upper small intestine. During a meal, gastrin stimulates the stomach to release gastric acid. This allows the stomach to break down proteins swallowed as food and absorb certain vitamins. It also acts as a disinfectant and kills most of the bacteria that enter the stomach with food, minimising the risk of infection within the gut. Gastrin also stimulates growth of the stomach lining and increases the muscle contractions of the gut to aid digestion. Excess gastrin could indicate a NET known as a Gastric NET (stomach) or a pNET known as Gastrinoma (see pancreatic hormones below).

Endocrine Organs

Thyroid Gland

Calcitonin is a hormone that is produced in humans by the parafollicular cells (commonly known as C-cells) of the thyroid gland. Calcitonin is involved in helping to regulate levels of calcium and phosphate in the blood, opposing the action of parathyroid hormone. This means that it acts to reduce calcium levels in the blood. This hormone tends to involve Medullary Thyroid Carcinoma and Hyperparathyroidism in connection to those with Multiple Endocrine Neoplasia. Worth also pointing out the existence of Calcitonin Gene-Related Peptide (CGRP) which is a member of the calcitonin family of peptides and a potent vasodilator.  Please note that hypothyroidism is often a side effect of NETs or treatment for NETs – please click here to read about the connection.

Pituitary Gland

HPA AXIS – It’s important to note something called the HPA axis when discussing pituitary hormones as there is a natural and important connection and rhythm between the Hypothalamus, Pituitary and the Adrenal glands. However, I’m only covering the pituitary and adrenal due to their strong connection with NETs.

Adrenocorticotropic hormone (ATCH) is made in the corticotroph cells of the anterior pituitary gland. It’s production is stimulated by receiving corticotrophin releasing hormone (CRH) from the Hypothalamus. ATCH is secreted in several intermittent pulses during the day into the bloodstream and transported around the body. Like cortisol (see below), levels of ATCH are generally high in the morning when we wake up and fall throughout the day. This is called a diurnal rhythm. Once ACTH reaches the adrenal glands, it binds on to receptors causing the adrenal glands to secrete more cortisol, resulting in higher levels of cortisol in the blood. It also increases production of the chemical compounds that trigger an increase in other hormones such as adrenaline and noradrenaline. If too much is released, The effects of too much ATCH are mainly due to the increase in cortisol levels which result. Higher than normal levels of ATCH may be due to:

Cushing’s disease – this is the most common cause of increased ATCH. It is caused by a tumor in the pituitary gland (PitNET), which produces excess amounts of ATCH. (Please note, Cushing’s disease is just one of the numerous causes of Cushing’s syndrome). It is likely that a Cortisol test will also be ordered if Cushing’s is suspected.

A tumour outside the pituitary gland, producing ATCH is known as an ectopic ATCH. With NETs, this is normally a pNET, Lung/Bronchial/Pulmonary NET or Pheochromocytoma.

Adrenal Glands

Adrenaline and Noradrenline

These are two separate but related hormones and neurotransmitters, known as the ‘Catecholamines’. They are produced in the medulla of the adrenal glands and in some neurons of the central nervous system. They are released into the bloodstream and serve as chemical mediators, and also convey the nerve impulses to various organs. Adrenaline has many different actions depending on the type of cells it is acting upon.  However, the overall effect of adrenaline is to prepare the body for the ‘fight or flight’ response in times of stress, i.e. for vigorous and/or sudden action. Key actions of adrenaline include increasing the heart rate, increasing blood pressure, expanding the air passages of the lungs, enlarging the pupil in the eye, redistributing blood to the muscles and altering the body’s metabolism, so as to maximise blood glucose levels (primarily for the brain). A closely related hormone, noradrenaline, is released mainly from the nerve endings of the sympathetic nervous system (as well as in relatively small amounts from the adrenal medulla). There is a continuous low-level of activity of the sympathetic nervous system resulting in release of noradrenaline into the circulation, but adrenaline release is only increased at times of acute stress.  These hormones are normally related to adrenal and extra adrenal NETs such as Pheochromocytoma and Paraganglioma.  Like serotonin secreting tumours, adrenal secreting tumours convert the offending hormone into something which comes out in urine. In fact, this is measured (amongst other tests) by 24 hour urine test very similar to 5HIAA (with its own diet and drug restrictions).  It’s known as 24-hour urinary catacholamines and metanephrines.  Worth noting that adrenaline is also known as Epinephrine (one of the 5 E’s of Carcinoid Syndrome).

Cortisol

This is a steroid hormone, one of the glucocorticoids, made in the cortex of the adrenal glands and then released into the blood, which transports it all round the body. Almost every cell contains receptors for cortisol and so cortisol can have lots of different actions depending on which sort of cells it is acting upon. These effects include controlling the body’s blood sugar levels and thus regulating metabolism acting as an anti-inflammatory, influencing memory formation, controlling salt and water balance, influencing blood pressure. Blood levels of cortisol vary dramatically, but generally are high in the morning when we wake up, and then fall throughout the day. This is called a diurnal rhythm. In people who work at night, this pattern is reversed, so the timing of cortisol release is clearly linked to daily activity patterns. In addition, in response to stress, extra cortisol is released to help the body to respond appropriately. Too much cortisol over a prolonged period of time can lead to Cushing’s syndrome.  Cortisol oversecretion can be associated with Adrenal Cortical Carcinoma (ACC) which can sometimes be grouped within the NET family.

Other hormones related to ACC include:

Androgens (e.g. Testosterone) – increased facial and body hair, particularly females. Deepened voice in females.

Estrogen – early signs of puberty in children, enlarged breast tissue in males.

Aldosterone – weight gain, high blood pressure.

Adrenal Insufficiency (Addison’s Disease) occurs when the adrenal glands do not produce enough of the hormone cortisol and in some cases, the hormone aldosterone. For this reason, the disease is sometimes called chronic adrenal insufficiency, or hypocortisolism.

Parathyroid

Parathyroid hormone (PTH) is secreted from four parathyroid glands, which are small glands in the neck, located behind the thyroid gland. Parathyroid hormone regulates calcium levels in the blood, largely by increasing the levels when they are too low.  A primary problem in the parathyroid glands, producing too much parathyroid hormone causes raised calcium levels in the blood (hypercalcaemia – primary hyperparathyroidism). You may also be offered an additional test called Parathyroid Hormone-Related Peptide (PTHrP). They would probably also measure Serum Calcium in combination with these type of tests. The parathyroid is one of the ‘3 p’ locations often connected to Multiple Endocrine Neoplasia – MEN 1

Pancreatic Hormones (Syndromes)

Pancreatic neuroendocrine tumors form in hormone-making cells of the pancreas. You may see these described as ‘Islet Cells’ or ‘Islets of Langerhans’ after the scientist who discovered them. Pancreatic NETs may also be functional or nonfunctional:

  • Functional tumors make extra amounts of hormones, such as gastrin, insulin, and glucagon, that cause signs and symptoms.
  • Nonfunctional tumors do not make extra amounts of hormones. Signs and symptoms are caused by the tumor as it spreads and grows.

There are different kinds of functional pancreatic NETs. Pancreatic NETs make different kinds of hormones such as gastrin, insulin, and glucagon. Functional pancreatic NETs include the following:

  • Gastrinoma: A tumor that forms in cells that make gastrin. Gastrin is a hormone that causes the stomach to release an acid that helps digest food. Both gastrin and stomach acid are increased by gastrinomas. When increased stomach acid, stomach ulcers, and diarrhea are caused by a tumor that makes gastrin, it is called Zollinger-Ellison syndrome. A gastrinoma usually forms in the head of the pancreas and sometimes forms in the small intestine. Most gastrinomas are malignant (cancer).
  • Insulinoma: A tumor that forms in cells that make insulin. Insulin is a hormone that controls the amount of glucose (sugar) in the blood. It moves glucose into the cells, where it can be used by the body for energy. Insulinomas are usually slow-growing tumors that rarely spread. An insulinoma forms in the head, body, or tail of the pancreas. Insulinomas are usually benign (not cancer).
  • Glucagonoma: A tumor that forms in cells that make glucagon. Glucagon is a hormone that increases the amount of glucose in the blood. It causes the liver to break down glycogen. Too much glucagon causes hyperglycemia (high blood sugar). A glucagonoma usually forms in the tail of the pancreas. Most glucagonomas are malignant (cancer).
  • Pancreatic Polypeptide (PPoma). A pancreatic polypeptide is a polypeptide hormone secreted by the pancreatic polypeptide (PP) cells of the islets of Langerhans in the endocrine portion of the pancreas. Its release is triggered in humans by protein-rich meals, fasting, exercise, and acute hypoglycemia and is inhibited by somatostatin and intravenous glucose. The exact biological role of pancreatic polypeptide remains uncertain. Excess PP could indicate a pNET known as PPoma.
  • Other types of tumors: There are other rare types of functional pancreatic NETs that make hormones, including hormones that control the balance of sugar, salt, and water in the body. These tumors include:
    • VIPomas, which make vasoactive intestinal peptide. VIPoma may also be called Verner-Morrison syndrome, pancreatic cholera syndrome, or the WDHA syndrome (Watery Diarrhea, Hypokalemia (low potassium)and Achlorhydria).
    • Somatostatinomas, which make somatostatin. Somatostatin is a hormone produced by many tissues in the body, principally in the nervous and digestive systems. It regulates a wide variety of physiological functions and inhibits the secretion of other hormones, the activity of the gastrointestinal tract and the rapid reproduction of normal and tumour cells. Somatostatin may also act as a neurotransmitter in the nervous system.

The pancreas is one of the ‘3 p’ locations often connected to Multiple Endocrine Neoplasia – MEN 1

Having certain syndromes can increase the risk of pancreatic NETs.

Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Multiple endocrine neoplasia type 1 (MEN1) syndrome is a risk factor for pancreatic NETs.

Signs and symptoms of pancreatic NETs

Signs or symptoms can be caused by the growth of the tumor and/or by hormones the tumor makes or by other conditions. Some tumors may not cause signs or symptoms. Check with your doctor if you have any of these problems.

Signs and symptoms of a non-functional pancreatic NET

A non-functional pancreatic NET may grow for a long time without causing signs or symptoms. It may grow large or spread to other parts of the body before it causes signs or symptoms, such as:

  • Diarrhea.
  • Indigestion.
  • A lump in the abdomen.
  • Pain in the abdomen or back.
  • Yellowing of the skin and whites of the eyes.

Signs and symptoms of a functional pancreatic NET

The signs and symptoms of a functional pancreatic NET depend on the type of hormone being made.

Too much gastrin may cause:

  • Stomach ulcers that keep coming back.
  • Pain in the abdomen, which may spread to the back. The pain may come and go and it may go away after taking an antacid.
  • The flow of stomach contents back into the esophagus (gastroesophageal reflux).
  • Diarrhea.

Too much insulin may cause:

  • Low blood sugar. This can cause blurred vision, headache, and feeling lightheaded, tired, weak, shaky, nervous, irritable, sweaty, confused, or hungry.
  • Fast heartbeat.

Too much glucagon may cause:

  • Skin rash on the face, stomach, or legs.
  • High blood sugar. This can cause headaches, frequent urination, dry skin and mouth, or feeling hungry, thirsty, tired, or weak.
  • Blood clots. Blood clots in the lung can cause shortness of breath, cough, or pain in the chest. Blood clots in the arm or leg can cause pain, swelling, warmth, or redness of the arm or leg.
  • Diarrhea.
  • Weight loss for no known reason.
  • Sore tongue or sores at the corners of the mouth.

Too much vasoactive intestinal peptide (VIP) may cause:

  • Very large amounts of watery diarrhea.
  • Dehydration. This can cause feeling thirsty, making less urine, dry skin and mouth, headaches, dizziness, or feeling tired.
  • Low potassium level in the blood. This can cause muscle weakness, aching, or cramps, numbness and tingling, frequent urination, fast heartbeat, and feeling confused or thirsty.
  • Cramps or pain in the abdomen.
  • Facial flushing.
  • Weight loss for no known reason.

Too much somatostatin may cause:

  • High blood sugar. This can cause headaches, frequent urination, dry skin and mouth, or feeling hungry, thirsty, tired, or weak.
  • Diarrhea.
  • Steatorrhea (very foul-smelling stool that floats).
  • Gallstones.
  • Yellowing of the skin and whites of the eyes.
  • Weight loss for no known reason.

Too much pancretic polypeptide may cause:

  • belly pain.
  • an enlarged liver.

Testing hormones

Clearly the presenting symptoms will give doctors a clue to the oversecreting hormone (see list above). Excessive secretions or high levels of hormones and other substances can be measured in a number of ways. For example:

Well known tests for the most common types of NET include 5-Hydroxyindoleacetic Acid (5-HIAA) 24 hour urine test which is also measured by a blood draw. Note: – tumor markers can be measured simultanously e.g. Chromogranin A (CgA) blood test and/or Pancreastatin as there can very often be a correlation between tumour mass and tumour secreting activity. CgA / Pancreastatin is a blood test which measures a protein found in many NET tumour cells. These marker tests are normally associated with tumour mass rather than tumour functionality.

By measuring the level of 5-HIAA in the urine or blood, healthcare providers can calculate the amount of serotonin in the body (5-HIAA is a by-product of serotonin).  5-HIAA test is the most common biochemical test for carcinoid syndrome or the degree of how ‘functional’ tumours are.  If you’ve understood the text above, you can now see why there are dietary and drug restrictions in place prior to the test.

Pancreatic Hormone testing. There are other tests for other hormones and there is a common test which measured the main hormones seen in NETs. It may be called different things in different countries, but in UK, it’s known as a ‘Fasting Gut Hormone Profile‘.

Scratching the surface here so for a comprehensive list of marker tests for NETs, have a read here.

Treatment for Over-secreting Hormones

Of course, reducing tumour bulk through surgery and other treatment modalities, should technically reduce over-secretion (I suspect that doesn’t work for all).  Other treatments may have the dual effect of reducing tumour burden and the effects of hormone oversecretions.

One of the key treatment breakthroughs for many NET cancer patients, is the use of ‘Somatostatin Analogues’ mainly branded as Octreotide (Sandostatin) or Lanreotide (Somatuline). People tend to associate these drugs with serotonin related secretions and tumours but they are in actual fact useful for many others including the pancreatic NETs listed above.  Patients will normally be prescribed these drugs if they are displaying these symptoms but some people may be more avid to the drug than others and this may influence future use and dosages. This is another complex area but I’ll try to describe the importance here in basic terms. Somatostatin is a naturally occurring protein in the human body. It is an inhibitor of various hormones secreted from the endocrine system (some of which were listed above) and it binds with high affinity to the five somatostatin receptors found on secretory endocrine cells. NETs have membranes covered with receptors for somatostatin. However, the naturally occurring Somatostatin has limited clinical use due to its short half-life (<3 min). Therefore, specific somatostatin analogues (synthetic versions) have been developed that bind to tumours and block hormone release. Thus why Octreotide and Lanreotide do a good job of slowing down hormone production, including many of the gut hormones controlling emptying of the stomach and bowel.  It also slows down the release of hormones made by the pancreas, including insulin and digestive enzymes – so there can be side effects including fat malabsorption.

The recent introduction of Telotristat Ethyl (XERMELO) is interesting as that inhibits a precursor to serotonin and reduces diarrhea in those patients where it is not adequately controlled by somatostatin analogues.

Other than the effects of curative or cytoreductive surgery, some NETs may have very specialist drugs for inhibiting the less common hormone types.  This is not an exhaustive list.

Worth also noting that oversecreting hormones can contribute to a phenomenon known as Carcinoid Crisis – read more here.  For catacholamine secreting tumors (Pheochromocytoma/Paraganglioma), this may be known as Intraoperative Hypertensive Crisis

Sorry about the long article – it’s complex and you should always consult your specialist about issues involving hormones, testing for hormones and treating any low or high scores.

Thanks for reading

Ronny

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