An interesting trial from Provectus Biopharmaceuticals Inc. Phase 1 results were presented at the American Society of Clinical Oncology (ASCO) 2019 Annual Meeting, held in Chicago, IL from May 31-June 4, 2019
In an ogoing Phase 1 clinical trial of single agent PV-10 for the treatment of symptomatic neuroendocrine tumors (NET) metastatic to the liver. Intralesional injection of oncolytic immunotherapy PV-10 can yield immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells. PV-10 clinical development includes cutaneous melanoma, hepatocellular carcinoma, and metastatic liver cancers such as uveal melanoma in single-agent and combination therapy settings.
What is PV-10?
Described above as “Oncolytic Immunotherapy” but elsewhere as “Ablative Immunotherapy”, the latter indicates the method of administering the therapy i.e. tumour ablation. It’s more well known for trials in treating Melanoma where tumour ablation (albeit subcutaneous) is more common as a treatment.
Scientific Description: PV-10 causes acute oncolytic destruction of injected tumors, releasing damage associated molecular pattern molecules (DAMPs) and tumor antigens that initiate an immunologic cascade where local response by the innate immune system facilitates systemic anti-tumor immunity by the adaptive immune system. The DAMP release-mediated adaptive immune response activates lymphocytes, including CD8+ T cells, CD4+ T cells, and NKT cells, based on clinical and preclinical experience in multiple tumor types. T cell function can be further augmented by combining PV-10 with immune checkpoint inhibition. Sometimes it’s known as its short name “Rose Bengal“.
What is ‘Rose Bengal’?
It’s actually a 135 year old chemical stain, originally discovered in 1882, and for more than half a century used as a dye in cancer diagnosis.
Rose Bengal, in a 10% solution known as PV-10, has displayed greatest promise in the treatment of melanoma, where it was shown in an 80-patient Phase II trial to achieve a complete response rate in 50% of patients’ tumours and an overall response in 71%. A bystander effect was also seen in untreated lesions, suggesting a positive immune response, although it was more effective when all lesions were injected with PV-10.
Scientific Description: PV-10’s active pharmaceutical ingredient is rose bengal disodium (RB) (4,5,6,7-tetrachloro-2’,4’,5’,7’-tetraiodofluorescein disodium salt), a small molecule halogenated xanthene. PV-10 drug product is a bright rose red solution containing 10% w/v RB in 0.9% saline for injection, which is supplied in single-use glass vials containing 5 mL (to deliver) of solution and administered without dilution to solid tumors via intratumoral injection.
What is the trial doing and where is the trial located?
This single-center Phase 1 study is being conducted at The Queen Elizabeth Hospital in Adelaide, Australia to evaluate the potential safety, tolerability, and preliminary efficacy of PV-10 in metastatic NET patients (NCT02693067). The primary endpoint for the trial is safety, and secondary endpoints include objective response rate (ORR) of injected target and measurable bystander lesions, target lesion somatostatin receptor expression, and biochemical response. Six patients in the first cohort each received one percutaneously-administered injection of PV-10 to one target lesion per treatment cycle. Patients in the second cohort can receive PV-10 injection of multiple lesions per cycle (2 of 6 patients in the second cohort have received at least one cycle of PV-10 thus far).
Results of Cohort 1 as follows:
Cohort 1 has fully enrolled, with 4 of 6 subjects male, median age 65yrs, range 47-72. Primary sites were: small bowel 3, pancreas 2, caecal 1; grade: Gd1 = 5, Gd2 = 1. All patients received prior Somatostatin Analogues (SSA) and PRRT. Median CgA was 645 (range 30-2819). To date 1 subject has received 4 PV-10 treatment cycles, 1 has received 2 cycles, and 4 have received a single cycle. Toxicity has been acceptable, including pain post procedure, carcinoid flare and nausea. LFT’s have remained stable. Overall QOL score was stable for 5 of 6 subjects. ORR in injected lesions is 50% (progression in 1 subject), with overall disease control of 84%. CgA response: 5 stable, 1 progression. One subject with “carcinoid pellagra” had rash resolution. Response follow-up is ongoing and additional efficacy and functional data will be presented. Hepatic IL PV-10 elicited no safety concerns with encouraging evidence of both local and systemic disease control. Enrolment to Cohort 2 is underway
When reading articles in the mainstream media, found in medical publications; and even listening to doctors speak about my disease, it’s clear that the focus is on the term “Neuroendocrine Tumours” or NET for short. Many websites of advocate foundation organisations and specialist scientific organisations, all still use the term “NET” in their naming. I too am guilty of having a large Facebook site falling into this category. It’s little wonder that those with high grade disease can often feel like the forgotten patient group. Clearly all the aforementioned organisations support all patients regardless of grade, but it’s true to say that the naming and general use of terminology continues to fall behind. It’s also true that the term NET remains applicable to the majority of patients and that many use it as a convenience when they actually mean all types including Neuroendocrine Carcinoma. Nonetheless, context remains an important part of overall understanding and inclusivity – words and acronyms matter.
However, High grade or Grade 3 is no longer just Neuroendocrine Carcinoma (NEC). Things have changed since 2017.
What are Neuroendocrine Neoplasms?
Neuroendocrine neoplasms (NENs) are without doubt a heterogeneous (i.e. diverse) bunch of tumours with a common phenotype (i.e. the physical appearance or biochemical characteristic). However, there are two fundamentally different groups of NENs: well-differentiated, low-proliferating NENs, called neuroendocrine tumours (NETs), and poorly differentiated, highly proliferating NENs, called neuroendocrine carcinomas (NECs). The difference between well and poorly differentiated has been described as a ‘dichotomy’, most likely due to the origin from different neuroendocrine progenitor cells (i.e. source cells). Should the term Neuroendocrine Neoplasm be used more? Yes, probably. But should we perhaps also ask if ENETS and NANETS will change their names to ENENS and NANENS?
This revised classification is not recent as many are currently suggesting. These changes were covered in my Staging and Grading article produced in early 2017 and confirmed Neuroendocrine Neoplasms (or NENs) was the overarching term for all types of neuroendocrine disease. See graphic below.
Traditionally, any proliferation score over 20% on the Ki-67 proliferation index (or over 20 mitoses/10 HPF on the Mitotic Index) would have been deemed a Neuroendocrine Carcinoma. However, in the pancreas, NETs and NECs may overlap in their proliferation index, making the distinction between them difficult and leading to treatment uncertainties.
In 2017, the Endocrine ‘Blue Book’ of cancer classification systems introduced a new pancreatic NET category based on a Grade 3 tumour which is well differentiated (i.e. cancer cells look more like normal cells and tend to grow and spread more slowly). While all classifications for all NENs recognise the existence of the two major groups (NET and NEC), there are proposals to develop common NEN classification across all the ‘Blue Books’ and future versions will reflect these changes. The most interesting change will be in the Lung classification because high grade NENs can be small cell or large cell and it’s probably the most controversial grouping.
Interestingly, ENETS guidelines already use the term across the board in their 2016 series (i.e. in advance of the 2017 changes). These changes are part influenced by the results of the NORDIC NEC study which showed that although patients with a Ki67 <55% were less responsive to platinum-based chemotherapy (i.e. drug names ending in ‘platin’ such as Cisplatin, Carboplatin, Oxaliplatin), they had a longer survival, and concluded that not all NEC should be considered as one single disease entity. Also worth noting that the NORDIC NEC study covered many different areas of the anatomy, not just the pancreas. Some of the rationale for the division of grade 3 into well differentiated NETs and poorly differentiated carcinomas is that some grade 3 tumours which are classified into this category according to the Ki67 index percentage, have been recognised to behave more like grade 2 NETs rather than aggressive carcinomas. The inference is that there could be treatment and prognostic significance if a patient is a Grade 3 NET.
MANEC vs MiNEN
Added for completeness. This mixed and rare neoplasm type has traditionally been related to NEC but in 2017 the nomenclature change to a new term was necessary to reflect the fact that some of the tumours involved were not carcinomas or adenocarcinomas but rather were well differentiated tumours or even adenomas (i.e. benign). Previously known as Mixed AdenoNeuroendocrine Carcinoma (MANEC), they were renamed to Mixed Neuroendocrine Non-Neuroendocrine Neoplasms (MiNEN).
MiNEN are neoplasms with two distinct neuroendocrine and non-neuroendocrine cell populations. They can be morphologically classified into three entities: collision, composite, and amphicrine MiNEN. Currently, both components composing a MiNEN must represent at least 30% of the whole tumour. Diagnosis of MiNEN is usually facilitated by the presence of at least one well-differentiated component which may be the Neuroendocrine or Non-Neuroendocrine component. However, the two components may be difficult to identify with conventional morphological techniques, particularly when they are poorly differentiated, and their identification may require additional immunohistochemical techniques. MiNEN usually originate from organs that contain neuroendocrine cells and in which “classical” NENs are known to develop, such as pancreas, appendix, colon, and to a lesser degree small intestine. Other locations in my source document includes Oesophagus, Stomach, Bilary Tract and Gallbladder, Duodenum and Ampulla of Vater and Rectum.
NEC vs NET
Having researched widely, I believe there are 8 key differences between NET and NEC:
Grade – NEC is only Grade 3, NETs can be Grade 1, 2 or 3.
Differentiation – all NETs are well differentiated, NECs are poorly differentiated. Important difference at Grade 3.
Aggressiveness – Most NETs tend to be indolent or slow growing while NECs tend to be aggressive and faster growing. However, Ki67 and/or mitotic count is an aggressiveness measurement tool. Genetic profiles can also be a guide but this is beyond the purposes of this article but may be explored in subsequent parts. It follows that NECs normally have a worse prognosis in comparison to NETs.
Hormone Secretion – NETs can produce peptide hormones that may be associated with hormonal syndromes. NECs usually fail to express hormones or produce hormonal syndromes.
Somatostatin Receptors – A NET is much more likely to express somatostatin receptors which can influence treatments such as somatostatin analogues and peptide receptor radiotherapy (PRRT)
Hereditary Syndromes – NETs are much more likely to be associated with hereditary syndromes such as Multiple Endocrine Neoplasia (MEN).
Platinum Based Chemotherapy – NETs are less likely to show a good response to platinum based chemotherapy which can often be the first line treatment for NEC.
Primary Locations – can be vastly different in terms of commonality and therefore provide clues to investigators. Common locations for NEC include: Lung, Esophagus, Colon, Urogential Organs and Skin – with the exception of Lung, these are very rare locations in NETs. Conversely, rare/very rare locations for NEC but common in NET include: Rectal, Small Intestine, Appendix, Stomach, Pancreas.
I intend to cover more on Grade 3 tumours going forward and a ‘Part 2’ article will follow covering treatment differences, genetic profiles and unmet needs.
In addition to my own knowledge gained over the years of researching and writing, the following resources were key in establishing the facts used in compiling this article:
1. Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P, et al: Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol 2013; 24: 152–160
2. de Mestier L, Cros J, Neuzillet C, Hentic O, Egal A, Muller N, Bouché O, Cadiot G, Ruszniewski P, Couvelard A, Hammel P: Digestive System Mixed Neuroendocrine-Non-Neuroendocrine Neoplasms. Neuroendocrinology 2017;105:412-425. doi: 10.1159/000475527
3. Koppel G: Neuroendocrine Neoplasms: Dichotomy, Origin and Classifications. Visc Med 2017;33:324-330. doi: 10.1159/000481390
4. Rindi G, Klimstra DS, Abedi-Ardekani B, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol. 2018;31(12):1770–1786. doi:10.1038/s41379-018-0110-y
I once wrote a post about patient stories, in particular the ones I receive in my private messages. The headline was “The shock effect never wears off“. But none have been more shocking than the one I received early in 2019. (edit: After posting this article, I heard of a few similar cases).
This is a story about someone who is a private person but felt the need to reach out to me about their diagnostic experience. This person wanted to talk about it, but in private and I was happy to listen. I was so moved by this story, I persuaded this person to let me tell it here whilst retaining their anonymity. Hence referral going forward as ‘Patient E’. I just felt that someone somewhere might learn something very important.
The Story of ‘Patient E’
In December 2018, Patient E was told ‘Stage 4 Pancreatic Cancer’ and had 10 months to live. Chemo was to be attempted in January in an effort to extend life but in the meantime was told to spend Christmas for the last time with the family, a spouse and 3 young children. On 2nd January, Patient E was then told (with apologies) it was actually a ‘Neuroendocrine Tumour with a pancreatic primary’. The only good thing about this story so far, is that they told the children nothing over Christmas. “Why worry happy little people” was the bit of the story which brought out my tears.
Initially I was quite angry this could happen to anyone but I was then calmed by Patient E who now had fresh hope and optimism, perhaps realising that there were possibilities for many more years with the family.
The Story of ‘Patient F’
In March of 2017 I was having bad indigestion and since I already had two cardiac stents went to a local hospital to make sure I wasn’t having cardiac issues. They found a mass on the pancreas and metastasis to the liver. I saw a surgeon a couple of days later and he told me it was inoperable, adding that I should pretty much get my affairs in order. A biopsy was then carried out confirming it was neuroendocrine and we were thrilled. I then received a call a couple of days later, saying they had it wrong, it was not neuroendocrine and they wanted to start chemo ASAP! I then received a further call a few days later, saying they were not sure and needed to do more tests. We then went a different hospital where two different surgeons said that it was inoperable. One oncologist said she did not know; and another thought it might be a combination of the two. At this point. they sent my slides to a NET specialist hospital for their opinion, coincidentally we had already scheduled an appointment there. When we walked into this appointment, the NET Specialist greeted us with a big smile and hug, saying that that both she and the surgeon had reviewed my slides; and that it was definitely neuroendocrine – they could operate. Two weeks later the surgeon removed the mass from my pancreas and my spleen. He said that it was probably there for years and looked like it was ready to burst. I was unbelievably lucky.
So why do these things happen? Apart from the serious communications lapse by the hospitals, this is another example of the problems we as a community face with the anatomical approach many doctors take with cancer, with some even describing a pancreatic Neuroendocrine Tumour as a type of Pancreatic Cancer (this happens with other parts of the anatomy too).
Patients E and F are not alone, I once wrote a story about rock star Wilko Johnson (of Dr Feelgood fame) who was given a very similar prognosis. However, Wilko was in the later stages of his life and decided instead of undergoing gruelling chemotherapy, he would forego any treatment and tour with his band in the final 12 months of his life and …….. make an album with Roger Daltrey of The Who. It wasn’t until someone enquired why he wasn’t dead after 12 months, that they re-checked and changed the diagnosis to Neuroendocrine Tumour with a pancreatic primary. Read the whole story here.
I wonder how many other times this has happened.
Neuroendocrine Tumours with a pancreatic primary (pNET) is a totally different cancer to Pancreatic Cancer. With Pancreatic Cancer, most people die, quite the opposite with pNETs where most people live. Read more about the main differences here.
I’m grateful to Patients E and F for contacting me to let me know that my blog and my other support sites have been helpful in the transition from despair to hope since finding out the correct diagnosis. I do hope Patients E and F will keep me updated.
On 8th July 2010, I was sat in front of a secondary care consultant, his speciality was colorectal. I asked specifically for this consultant for two reasons, firstly, he carried out a colonoscopy some 20 months previously which turned out to be negative. Secondly, my GP had referred me to the iron deficiency anaemia clinic, and they wanted to do ….. a colonoscopy. I changed that plan because this “non-issue” was dragging on; quite frankly I wanted it to be resolved quickly, and I wanted it to be resolved in my favour – after all, I wasn’t actually ill!
Rewind two months, I had an incidental set of blood tests ordered by a nurse following a routine visit to my local medical centre (……. “I think I’ve lost a bit of weight“). My haemoglobin was low (even lower on repeat testing). The GP compared my results to someone in their eighties with malnutrition. In hindsight, I should have been alarmed by that statement but instead I went on holiday to Barbados. Apparently low haemoglobin is a sign of iron deficiency anaemia. I suspected it would pass, either my blood results would revert to normal naturally, or they would after a prescription for some pills. That’s what normally happens, isn’t it? I was so indifferent to the issue, I even delayed the blood tests by three weeks.
Back to 8th July 2010 ….I hadn’t really given him many clues but within minutes of chatting with the secondary care consultant (who was armed with the results of the negative colonoscopy test), he said “what are you doing this afternoon“. I had no hesitation in saying “whatever you want me to do“. I’m still not getting it as I saw this as a chance to get an all clear, get some pills, get back to normal. To cut a long story short, the results confirmed I had a metastatic cancer. If you can see it, you can detect it. The scan didn’t confirm which type of cancer so further checks were planned.
Following the scan results, I had a dozen other tests to narrow it down to Neuroendocrine Cancer (eventually confirmed by biopsy). During these 2 weeks of tests, I finally confessed for the first time that I had been experiencing facial flushing and intermittent diarrhea. In those days, I wasn’t really in tune with my body.
I had been sitting on a beach in Barbados sipping piña coladas with my wife and neither of us had any inkling that I had a serious life threatening illness and that it had been growing inside of me for some years. Slow but sneaky? You betcha. They did some damage too – check out my treatment summary here.
I remain thankful to all those involved in the triggering of my ‘incidental’ diagnosis. The Nurse who ordered the ‘just to be sure’ blood tests, the GP who immediately referred me to secondary care (increased my chances of being diagnosed with cancer), the secondary care specialist who was instrumental in getting to the bottom of the problem in double-quick time.
My intransigence, denial and withholding vital symptoms from the doctors didn’t really help – there’s a lesson for all there.
I’ve posted extensively about Oncolytic virus trials, focused on the ongoing Neuroendocrine Cancer trial in Uppsala Sweden. I wanted to incorporate this information into a single article ready for future news, whilst at the same time updating you on further developments in the field of Oncolytic Viruses for Neuroendocrine Cancer. The excitement of the Uppsala work has dampened in recent years, not helped by the fact that one of the first patients unfortunately died. In the absence of any news, I suspect there has been no real progress and/or the funding has run out.
What exactly are Oncolytic Viruses?
Oncolytic Viruses infects and breaks down cancer cells but not normal cells. Oncolytic viruses can occur naturally or can be made in the laboratory by changing other viruses. Certain oncolytic viruses are being studied in the treatment of cancer. Some scientists say they are another type of immunotherapy whilst others say it’s too early to classify as such. The good news is that Neuroendocrine Cancer seems to figure in this work with two of these viruses apparently working on mice to date. Listed below are two active projects involving NETs, one directly and one indirectly.
I’ll briefly describe what’s happening and then you can link to my Facebook article if you need more background.
The trial is called AdVince after Vince Hamilton who funded it. Unfortunately he died before he saw any output but his forward thinking and benevolence lives on and might hopefully help NET patients in the longer term. It’s quite a small trial and is being conducted in Uppsala University Sweden, a famous European NET Centre of Excellence and where many people from across the world attend to take advantage of PRRT availability and experience and is home to famous NET specialist Kjell Öberg, MD, PhD, a professor of endocrine oncology.
A Swedish man (Jan-Erik Jannsson) was the first to get the virus to their cancer (NETs) using a genetically modified virus.
Unfortunately, I was given the news from a source close to the trial that Jan died last year of pneumonia. I have no evidence to suggest his death is in anyway connected to the trial but I’m told he was an ill man prior to the trial commencing. I have therefore dedicated this post to him. RIP Jan.
The initial data presented by the trial indicated that AdVince can be safely evaluated in a phase I/IIa clinical trial for patients with liver-dominant NET. The last I heard from the trial is that they are trying to recruit a further 12 patients to Phase IIa (the trial document allows for up to 36).
Read more background on my Facebook post here: Click here
The trial document on Clinical Trials Website: Click here
This is an oncolytic viral therapy currently in phase III and phase Ib/II clinical trials for use against primary liver (Hepatocellular Carcinoma) and Colorectal cancers, respectively. Pexa-Vec is a weakened (or attenuated) virus that is based on a vaccine used in the eradication of smallpox. The modified virus is injected directly into the cancer tumour, to grow inside these rapidly growing cancer cells and hopefully kill them.
According to the Colorectal Clinical Trial, the aim of the study is to evaluate whether the anti-tumor immunity induced by Pexa-Vec oncolytic viral therapy can be enhanced by immune checkpoint inhibition i.e. they are testing it in conjunction with Immunotherapy drugs (in the case of Colorectal, Durvalumab, and a combination of Durvalumab and Tremelimumab).
The Hepatocellular Carcinoma trial (Phocus) is at Phase III where the sponsors are evaluating Pexa-Vec to determine if it can slow the progression of advanced liver cancer and improve quality of life. I can other trials appearing such as this one for Colorectal Cancer and this one for any solid tumour type.
The work is a collaboration forged between University of California San Francisco (UCSF) vascular researcher Donald McDonald, MD, PhD, and researchers at San Francisco-based biotech SillaJen Biotherapeutics Inc. (formerly Jennerex Biotherapeutics, Inc.), a subsidiary of SillaJen, Inc., headquartered in Korea.
So what’s the Neuroendocrine Connection with Pexa-Vec?
As part of the research, McDonald’s lab injected it intravenously into mice genetically modified to develop pancreatic neuroendocrine cancer. They found that the virus failed to infect healthy organs or make the animals ill, but succeeded in infecting blood vessels within tumors. These initial infections caused the vessels to leak and expose the tumor cells to the virus. In these experiments, the virus managed to infect and destroy only a small proportion of tumor cells directly, the researchers found, but within five days of the initial infection, the rest of the tumor began to be killed by a powerful immune reaction. Live human trials have commenced in 2018 and the “patient 1” is a pancreatic NET patient. Read more here. Interestingly they added Keytruda (an immunotherapy) to the mix. It’s only been four months since ‘Patient 1’ (Tamara) began the trial, but a mid-treatment CT scan was said to be “promising”. I will keep this article live and bring you updates as I receive them.
Clearly it’s still early days in the Oncolytic Virus field with minimum breakthrough in terms of success on humans. In terms of the Neuroendocrine connection, it is exciting that two programmes are showing results (albeit in mice). We wait to hear from Uppsala on how the human test of AdVince is coming along. My agents are scanning the internet every day looking for any comment.
If you want to learn more about Oncolytic Viruses in general – there’s a great summary here.
These are my top performing posts for 2017 – comprising one eighth of my entire hits for the year. My blog hits for 2017 almost reached a quarter of a million, double that of 2016 which was double that of 2015. A chunk of these figures can be attributed to most of these articles. Please share to maintain the momentum.
Top 6 posts for 2017 (Click on each article title to read)
“Cured” – In cancer, this word can evoke a number of emotions. Interestingly, not all these emotions will be as positive as you might think. If you want to spark a heated debate on a Neuroendocrine Cancer patient forum, just mention that you’ve been cured.
I’ve been living with Neuroendocrine Cancer for 8 years so I must be cured, right? Unfortunately not as straightforward as this, and I’m guessing this is the case for many cancers. Doctors clearly need to be careful when saying the word “cured‘ even if there is a small likelihood that a cancer will recur. There’s plenty of ‘conservative’ and alternative terms that can be used, such as ‘stable’, ‘no evidence of disease (NED)’, ‘in remission’ or ‘complete response’. However, I don’t see the latter two much in Neuroendocrine disease circles.
So with all these ‘ifs’ and ‘buts’, what exactly is a cure?
Answering this question isn’t a simple case of ‘yes’ or ‘no’, because it depends on the way that the term ‘cancer’ is defined. It should actually be viewed as an umbrella term for a collection of hundreds of different diseases. They all share the fundamental characteristic of rogue cells growing out of control, but each type of cancer, and each person’s individual cancer, is unique and comes with its own set of challenges.
That’s why it’s very unlikely that there will be one single cure that can wipe out all cancers. That doesn’t mean individual cases of cancer can’t be cured. Many cancers in fact already can be. Scientists aren’t actually on the hunt for a ‘silver bullet’ against all cancers, Quite the opposite. The more scientists get to know each type of cancer inside and out, the greater the chance of finding new ways to tackle these diseases so that more people can survive. Thanks to a much deeper understanding of cell biology and genetics, there exist today a growing number of targeted therapies that have been designed at a molecular level to recognise particular features specific of cancer cells. Along with chemotherapy, surgery and radiotherapy, these treatments—used singly and in combination—have led to a slow, but steady, increase in survival rates. You can definitely count Neuroendocrine Cancer in that category.
Cancer is seen today less as a disease of specific organs, and more as one of molecular mechanisms caused by the mutation of specific genes. The implication of this shift in thinking is that the best treatment for, say, colorectal cancer may turn out to be designed and approved for use against tumors in an entirely different part of the body, such as the breast. We’re certainly seeing that with certain targeted therapies and more recently with Immunotherapy.
Surely a cure is more possible if cancer is diagnosed earlier?
To a certain extent this is true for many types of cancer, not just for NETs. In fact the same scientists did say ….”We detect those attacks when they’re still early, before the cancers have widely spread, at a time when they can still be cured simply by surgery or perhaps surgery and adjuvant therapy, which always works better on smaller tumors.”.
What about Neuroendocrine Tumors (NETs)? Clearly I’m not qualified to make such statements except to say that I am of the opinion that earlier diagnosis is better for any curative scenario. When you read NET guidelines (ENETS/NANETS etc), the word ‘cure’ and ‘curative’ is mentioned in relation to surgery. Bearing in mind that our most expert NET specialists are involved in the drafting of these guidelines, perhaps we should pause and think before dismissing these claims. Having checked ENETS publications, I can see it’s related to certain conditions and factors such as localisation within the organ, tumour size, good resection margins, and a suitable follow-up surveillance.
Clearly with advanced disease, the cancer becomes incurable but treatment for many being palliative to reduce tumor bulk and reduce any symptoms and/or syndrome effects. Despite this, the outlook for metastatic NETs at the lower grades is good. While we’re talking about palliative care, do not confuse this with end of life, that is only one end of the palliative spectrum. It can and is used at the earliest stage of cancer.
Immunotherapy will eventually cure cancer, right?
Immunotherapy will play a huge part in cancer treatment in the future, that we know. But to suggest that it’s a cure is probably overstating its current success. Neuroendocrine Cancer has not been forgotten – you can read more about Neuroendocrine Cancer and Immunotherapy here.
I heard the Oncolytic Virus at Uppsala is a cure for NETs?
There is currently no scientific evidence that the Oncolytic Virus (AdVince) can cure humans with Neuroendocrine Cancer. So far it has only been proven in destroying neuroendocrine tumours in mice. The Oncolytic Viruses developed in Uppsala are now being evaluated in phase I clinical trials for neuroendocrine cancer. If you’re not up to speed with this trial, read more here – Oncolytic Virus Uppsala
Isn’t prevention better than a cure?
This old adage is still relevant BUT latest thinking would indicate it is not applicable to all cancers. Scientists claim that 66% of cancer is simply a form of ‘bad luck’ and if the claim is accurate, it follows that many cancers are simply inevitable. The thinking suggests that random errors occurring during DNA replication in normal stem cells are a major contributing factor in cancer development confirming that “bad luck” explains a far greater number of cancers than do hereditary and environmental factors. This scientific thinking is a tad controversial so it’s worth remembering that even if, as this study suggests, most individual cancer mutations are due to random chance, the researchers also admit that the cancers they cause may still be preventable. It’s complex!
The newspapers are always talking about breakthroughs and cures for cancer?
Newspapers looking for a good headline will use words such as ‘cure’. Sadly, headlines are generally written by sub-editors who scan the article and look to find a ‘reader-oriented angle’ for the heading. They either can’t or don’t have time to understand what’s actually being said. Unfortunately this then leads to people sharing what is now a misleading article without a thought for the impact on those who are worried about the fact they have cancer and whether it can be cured or not. There’s also a lot of fake health news out there – check out my article series about the problems with the internet and ‘Miracle Cures’.
To cure, they must know the cause?
To a certain extent, that’s very accurate. Have you ever wondered what caused your NETs? I did ponder this question in an article here. The only known cause of NETs is currently the proportion of patients with heredity syndromes – see my article of Genetics and Neuroendocrine Cancer. Interestingly, the NET Research Foundation recently awarded funding to look at the causes of Small Intestine (SI) NETs (one of the most common types). A scientific collaboration between UCL, Dana-Farber Cancer Institute, UCSF Medical Centre and the UCL Cancer Institute / Royal Free Hospital London. The team’s approach has the potential to identify inherited, somatic (non-inherited) genetic, epigenetic and infectious causes of SI-NETs. The research is questioning whether SI-NETs are caused by DNA changes in later life or by aberrant genes inherited at birth; environmental influences or infectious agents – or is it a combination of all these factors? Very exciting. Read more here.
What would a cure mean to those living with NETs?
This is something that has crossed my mind, even though I don’t believe it will happen in my lifetime. I guess it would be good to get rid of the known remnant tumors left behind from my treatment (and any micrometastases currently not detectable). However, many NET patients are living with the consequences of cancer and its treatment, including surgery, chemotherapy, biological therapy, somatostatin analogues, radionuclide therapy, liver directed therapy, and others. Many of these effects would remain – let’s face it, a cure is not going to give me back bits of my small and large intestine, liver and an army of lymph nodes. So support for those living with NETs would need to remain despite a cure.
The emotional aspect of the word ‘cured’ seems to be an issue across many cancers and it’s certainly very controversial in NET circles. The world has still not cured the many cancers that exist. But over the next five to ten years the era of personalised medicine could see enormous progress in making cancer survivable. I think both doctors and patients need to take a pragmatic view on the ‘cured’ word and to end this article I wanted to share an interesting quote I found whilst researching.
For the first few years after my diagnosis, I avoided using the word ‘survivor’ in relation to my incurable cancer. It just didn’t seem to sit right despite the fact I’m a ‘glass half full’ kind of guy.
However …….. I was studying the term ‘Survivorship’ and found it also applies to those living with incurable and long term cancer. This piece of research totally changed my thinking. The slides above were provided by National Cancer Survivors Day (which seems to have turned rather international) – well done NCSD.Org – you should check out the site and sign up for their newsletter
What is ‘Survivorship’?
The definition differs slightly between national cancer advocate organisations but it would appear it also means “Living with, through, and beyond cancer“ which is a UK term. According to these definitions, cancer survivorship begins at diagnosis and includes people who continue to have treatment over the long-term, to either reduce the risk of recurrence or to manage chronic disease. It follows that those with incurable Cancers such as my own (Neuroendocrine) should be included under the term ‘Survivorship’.
Times are changing
I think it’s useful to look at overall statistics for survivorship to contextualise why the word ‘survivor’ might actually be more apt than it was 20 years ago. For example, in the UK, more than one in three people (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 will have doubled over the past 20 years. I’m seeing similar reports from USA too where, for example, the number of cancer survivors is predicted to rise by a third by 2026 (15 million to 20 million). Almost half of the current survivors are aged 70+. In another example, the US National Cancer Institute (NCI) is predicting:
‘Silver Tsunami’ of Cancer Survivors in the next quarter century (read here).
There is also a very recent article which confirms this thinking, let me quote a bit of it: The cancer death rate has dropped by 23 percent since 1991, with some even larger gains in types of cancer that used to be extremely lethal. This means there are more and more patients like Thornton who are neither dying from cancer nor defeating it entirely. Instead, they’re learning to live with it. Full article here.
Of course, it must not be forgotten that many people will need support to maintain a decent quality of life and be supported with ongoing and long-term treatment. These are both challenges global health systems need to face with rising cancer prevalence. And both of these challenges will greatly affect my own type of cancer – Neuroendocrine. This is why I’m a very strong advocate for more focus on some of these support type issues and unmet needs, and the resources to deliver them.
So does that mean I’m a Survivor?
My research indicates this can be a very individual thing. I guess ‘survivor’ does not appeal to all people who simply have a ‘history of cancer’; and most likely for different reasons. For those with incurable or long-term cancers, some people might not think of themselves as a survivor, but more as someone who is “living with cancer.” Some may feel like they’re living but not surviving. I get that and it potentially resonates with my reluctance to use the ‘S’ word for a short period after my diagnosis. Thinking this topic through has made me compare where I was at diagnosis and where I am now. Also, I’ve considered what I’ve been able to do and what I have plans to do, despite my condition. I’ve done so much, been to so many places since I was diagnosed, and got plans to do much more, I must be surviving! Perhaps the words “I got this” was my subconscious thought in the picture I’ve used below?
And this picture which always gets a tremendous response every time I post it:
Here’s a great quote I found in relation to the term ‘survivor’:
“You may not like the word, or you may feel that it does not apply to you, but the word “survivor” helps many people think about embracing their lives beyond their illness”.
You may sometimes feel like you’re not surviving but if you’re reading this then you most definitely must be?
Until I was diagnosed with metastatic Neuroendocrine Cancer, I didn’t have a clue about hormones – it’s one of those things you just take for granted. However, hormones are vital to human health (male and female) and it’s only when things go wrong you suddenly appreciate how important they are ……..like a lot of other things in life I suppose! The presence of over-secreting hormones (often called peptides throughout) is useful to aid diagnosis albeit it often means the tumours have metastasized. It’s also a frequent indication that the person has an associated NET syndrome.
This is a really complex area and to understand the hormone problems associated with Neuroendocrine Cancer, you need to have a basic knowledge of the endocrine and neuroendocrine systems. I’ve no intention of explaining that (!) – other than the following high level summary:
Glands in the endocrine system use the bloodstream to monitor the body’s internal environment and to communicate with each other through substances called hormones, which are released into the bloodstream. Endocrine glands include; Pituitary, Hypothalmus, Thymus, Pineal, Testes, Ovaries Thyroid, Adrenal, Parathyroid, Pancreas.
A Hormone is a chemical that is made by specialist cells, usually within an endocrine gland, and it is released into the bloodstream to send a message to another part of the body. It is often referred to as a ‘chemical messenger’. In the human body, hormones are used for two types of communication. The first is for communication between two endocrine glands, where one gland releases a hormone which stimulates another target gland to change the levels of hormones that it is releasing. The second is between an endocrine gland and a target organ, for example when the pancreas releases insulin which causes muscle and fat cells to take up glucose from the bloodstream. Hormones affect many physiological activities including growth, metabolism, appetite, puberty and fertility.
The Endocrine system. The complex interplay between the glands, hormones and other target organs is referred to as the endocrine system.
The Neuroendocrine System. The diffuse neuroendocrine system is made up of neuroendocrine cells scattered throughout the body. These cells receive neuronal input and, as a consequence of this input, release hormones to the blood. In this way they bring about an integration between the nervous system and the endocrine system (i.e. Neuroendocrine). A complex area but one example of what this means is the adrenal gland releasing adrenaline to the blood when the body prepares for the ‘fight or flight’ response in times of stress, ie, for vigorous and/or sudden action.
Hormones – the NET Effect
At least one or more hormones will be involved at various sites and even within certain syndromes, the dominant and offending hormone may differ between anatomical tumour sites. For example, NETs of the small intestine 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), (see below for more detail). It’s also possible to see predominantly serotonin secreting tumors in places such as the pancreas (although what you would call that type of NET is open for debate).
Lung NETs rarely produce serotonin, but may instead secrete histamine causing an ‘atypical’ carcinoid syndrome with generalized flushing, diarrhea, periorbital oedema, lacrimation and asthma. They may also produce adrenocorticotropic hormone (ATCH) or corticotropin-releasing factor (CRP), resulting in an ectopic Cushing’s syndrome. Please note the respiratory tract and thymus are not really anatomically pure ‘Foregut’ – but in NETs, grouped there for convenience.
Gastric (Stomach) NETs. Gastrin is the main hormone but there can also be histamine producing an atypical carcinoid syndrome effect.
Midgut NETs: In the small intestine, appendix, and ascending colon. For example, serotonin secreting tumors tend to be associated with carcinoid syndrome which tends to be associated with midgut NETs and this is normally the case. Many texts will also tell you that a syndrome only occurs at a metastatic stage. Both are a good rule of thumb but both are technically incorrect. For example, ovarian NETs can have a form of carcinoid syndrome without liver metastasis (tends to be described as atypical carcinoid syndrome).
Hindgut NETs (transverse, descending colon and rectum) cannot convert tryptophan to serotonin and other metabolites and therefore rarely cause carcinoid syndrome even if they metastasise to the liver.
Less Common Locations – there are quite a few less common NET locations which may involve less common hormones – some are covered below including the key glands contributing to NETs.
Unknown Primary? – One clue to finding the primary might be by isolating an offending hormone causing symptoms.
The key NET hormones
I used the example of Serotoninabove because it is the most cited problem with NET Cancer although it does tend to be most prevalent in midgut tumors. Serotonin is a monoamine neurotransmitter synthesized from Tryptophan, one of the eight essential amino acids (defined as those that cannot be made in the body and therefore must be obtained from food or supplements). About 90% of serotonin produced in the body is found in the enterochromaffin cells of the gastrointestinal (GI) tract where it is used mainly to regulate intestinal movements amongst other functions. The remainder is synthesized in the central nervous system where it mainly regulates mood, appetite, and sleep. Please note there is no transfer of serotonin across the blood-brain barrier.
Alterations in tryptophan metabolism may account for many symptoms that accompany carcinoid syndrome. Serotonin in particular is the most likely cause of many features of carcinoid syndrome as it stimulates intestinal motility and secretion and inhibits intestinal absorption. Serotonin may also stimulate fibroblast growth and fibrogenesis and may thus account for peritoneal and valvular fibrosis encountered in such tumours; serotonin, however, it is said not to be associated with flushing. The diversion of tryptophan to serotonin may lead to tryptophan deficiency as it becomes unavailable for nicotinic acid synthesis, and is associated with reduced protein synthesis and hypoalbuminaemia; this may lead to the development of pellagra (skin rash, glossitis, stomatitis, confusion/dementia).
Serotonin is also thought to be responsible for ‘right sided’ heart disease (Carcinoid Heart Disease). It is thought that high levels of serotonin in the blood stream damages the heart, leading to lesions which cause fibrosis, particularly of the heart valves. This generally affects the right side of the heart when liver metastases are present. The left side of the heart is usually not affected because the lungs can break down serotonin. Right sided heart failure symptoms include swelling (edema) in the extremities and enlargement of the heart.
Whilst serotonin can be measured directly in the blood, it’s said to be more accurate to measure 5HIAA (the output of serotonin) via blood or urine, the latter is said to be the most accurate.
Tackykinins include Substance P, Neurokinin A, Neuropeptide K and others. They are active in the enterochromaffin cells of the GI tract but can also be found in lung, appendiceal and ovarian NETs, and also in Medullary Thyroid Carcinoma and Pheochromocytomas. They are thought to be involved in flushing and diarrhea in midgut NETs. The most common tachykinin is Substance P, which is a potent vasodilator (substances which open up blood vessels). Telangiectasias are collections of tiny blood vessels which can develop superficially on the faces of people who have had NETs for several years. They are most commonly found on the nose or upper lip and are purplish in color. They are thought to be due to chronic vasodilatation.
Histamine is a hormone that is chemically similar to the hormones serotonin, epinephrine, and norepinephrine. After being made, the hormone is stored in a number of cells (e.g., mast cells, basophils, enterochromaffin cells). Normally, there is a low level of histamine circulating in the body. However (and as we all know!), the release of histamine can be triggered by an event such as an insect bite. Histamine causes the inconvenient redness, swelling and itching associated with the bite. For those with severe allergies, the sudden and more generalized release of histamine can be fatal (e.g., anaphylactic shock). Mast cell histamine has an important role in the reaction of the immune system to the presence of a compound to which the body has developed an allergy. When released from mast cells in a reaction to a material to which the immune system is allergic, the hormone causes blood vessels to increase in diameter (e.g., vasodilation) and to become more permeable to the passage of fluid across the vessel wall. These effects are apparent as a runny nose, sneezing, and watery eyes. Other symptoms can include itching, burning and swelling in the skin, headaches, plugged sinuses, stomach cramps, and diarrhea. Histamine can also be released into the lungs, where it causes the air passages to become constricted rather than dilated. This response occurs in an attempt to keep the offending allergenic particles from being inhaled. Unfortunately, this also makes breathing difficult. An example of such an effect of histamine occurs in asthma. Histamine has also been shown to function as a neurotransmitter (a chemical that facilitates the transmission of impulses from one neural cell to an adjacent neural cell).
In cases of an extreme allergic reaction, adrenaline is administered to eliminate histamine from the body. For minor allergic reactions, symptoms can sometimes be lessened by the use of antihistamines that block the binding of histamine to a receptor molecule. Histamine is thought to be involved with certain types and locations of NET, including Lung and foregut NETs where they can cause pulmonary obstruction, atypical flush and hormone syndromes.
Histamine, another amine produced by certain NETs (particularly foregut), may be associated with an atypical flushing and pruritus; increased histamine production may account for the increased frequency of duodenal ulcers observed in these tumours.
Kallikrein is a potent vasodilator and may account for the flushing and increased intestinal mobility.
Although prostaglandins are overproduced in midgut tumours, their role in the development of the symptoms of carcinoid syndrome is not well established but triggering peristalsis is mentioned in some texts.
Bradykinin acts as a blood vessel dilator. Dilation of blood vessels can lead to a rapid heartbeat (tachycardia) and a drop in blood pressure (hypotension). Dilation of blood vessels may also be partly responsible for the flushing associated with carcinoid syndrome.
Gastrin is a hormone that is produced by ‘G’ cells in the lining of the stomach and upper small intestine. During a meal, gastrin stimulates the stomach to release gastric acid. This allows the stomach to break down proteins swallowed as food and absorb certain vitamins. It also acts as a disinfectant and kills most of the bacteria that enter the stomach with food, minimising the risk of infection within the gut. Gastrin also stimulates growth of the stomach lining and increases the muscle contractions of the gut to aid digestion. Excess gastrin could indicate a NET known as a Gastric NET (stomach) or a pNET known as Gastrinoma (see pancreatic hormones below).
Calcitonin is a hormone that is produced in humans by the parafollicular cells (commonly known as C-cells) of the thyroid gland. Calcitonin is involved in helping to regulate levels of calcium and phosphate in the blood, opposing the action of parathyroid hormone. This means that it acts to reduce calcium levels in the blood. This hormone tends to involve Medullary Thyroid Carcinoma and Hyperparathyroidism in connection to those with Multiple Endocrine Neoplasia. Worth also pointing out the existence of Calcitonin Gene-Related Peptide (CGRP) which is a member of the calcitonin family of peptides and a potent vasodilator. Please note that hypothyroidism is often a side effect of NETs or treatment for NETs – please click here to read about the connection.
HPA AXIS – It’s important to note something called the HPA axis when discussing pituitary hormones as there is a natural and important connection and rhythm between the Hypothalamus, Pituitary and the Adrenal glands. However, I’m only covering the pituitary and adrenal due to their strong connection with NETs.
Adrenocorticotropic hormone (ATCH) is made in the corticotroph cells of the anterior pituitary gland. It’s production is stimulated by receiving corticotrophin releasing hormone (CRH) from the Hypothalamus. ATCH is secreted in several intermittent pulses during the day into the bloodstream and transported around the body. Like cortisol (see below), levels of ATCH are generally high in the morning when we wake up and fall throughout the day. This is called a diurnal rhythm. Once ACTH reaches the adrenal glands, it binds on to receptors causing the adrenal glands to secrete more cortisol, resulting in higher levels of cortisol in the blood. It also increases production of the chemical compounds that trigger an increase in other hormones such as adrenaline and noradrenaline. If too much is released, The effects of too much ATCH are mainly due to the increase in cortisol levels which result. Higher than normal levels of ATCH may be due to:
Cushing’s disease – this is the most common cause of increased ATCH. It is caused by a tumor in the pituitary gland (PitNET), which produces excess amounts of ATCH. (Please note, Cushing’s disease is just one of the numerous causes of Cushing’s syndrome). It is likely that a Cortisol test will also be ordered if Cushing’s is suspected.
A tumour outside the pituitary gland, producing ATCH is known as an ectopic ATCH. With NETs, this is normally a pNET, Lung/Bronchial/Pulmonary NET or Pheochromocytoma.
Adrenaline and Noradrenline
These are two separate but related hormones and neurotransmitters, known as the ‘Catecholamines’. They are produced in the medulla of the adrenal glands and in some neurons of the central nervous system. They are released into the bloodstream and serve as chemical mediators, and also convey the nerve impulses to various organs. Adrenaline has many different actions depending on the type of cells it is acting upon. However, the overall effect of adrenaline is to prepare the body for the ‘fight or flight’ response in times of stress, i.e. for vigorous and/or sudden action. Key actions of adrenaline include increasing the heart rate, increasing blood pressure, expanding the air passages of the lungs, enlarging the pupil in the eye, redistributing blood to the muscles and altering the body’s metabolism, so as to maximise blood glucose levels (primarily for the brain). A closely related hormone, noradrenaline, is released mainly from the nerve endings of the sympathetic nervous system (as well as in relatively small amounts from the adrenal medulla). There is a continuous low-level of activity of the sympathetic nervous system resulting in release of noradrenaline into the circulation, but adrenaline release is only increased at times of acute stress. These hormones are normally related to adrenal and extra adrenal NETs such as Pheochromocytoma and Paraganglioma. Like serotonin secreting tumours, adrenal secreting tumours convert the offending hormone into something which comes out in urine. In fact, this is measured (amongst other tests) by 24 hour urine test very similar to 5HIAA (with its own diet and drug restrictions). It’s known as 24-hour urinary catacholamines and metanephrines. Worth noting that adrenaline is also known as Epinephrine (one of the 5 E’s of Carcinoid Syndrome).
This is a steroid hormone, one of the glucocorticoids, made in the cortex of the adrenal glands and then released into the blood, which transports it all round the body. Almost every cell contains receptors for cortisol and so cortisol can have lots of different actions depending on which sort of cells it is acting upon. These effects include controlling the body’s blood sugar levels and thus regulating metabolism acting as an anti-inflammatory, influencing memory formation, controlling salt and water balance, influencing blood pressure. Blood levels of cortisol vary dramatically, but generally are high in the morning when we wake up, and then fall throughout the day. This is called a diurnal rhythm. In people who work at night, this pattern is reversed, so the timing of cortisol release is clearly linked to daily activity patterns. In addition, in response to stress, extra cortisol is released to help the body to respond appropriately. Too much cortisol over a prolonged period of time can lead to Cushing’s syndrome. Cortisol oversecretion can be associated with Adrenal Cortical Carcinoma (ACC) which can sometimes be grouped within the NET family.
Other hormones related to ACC include:
Androgens (e.g. Testosterone) – increased facial and body hair, particularly females. Deepened voice in females.
Estrogen – early signs of puberty in children, enlarged breast tissue in males.
Aldosterone – weight gain, high blood pressure.
Adrenal Insufficiency (Addison’s Disease) occurs when the adrenal glands do not produce enough of the hormone cortisol and in some cases, the hormone aldosterone. For this reason, the disease is sometimes called chronic adrenal insufficiency, or hypocortisolism.
Parathyroid hormone (PTH) is secreted from four parathyroid glands, which are small glands in the neck, located behind the thyroid gland. Parathyroid hormone regulates calcium levels in the blood, largely by increasing the levels when they are too low. A primary problem in the parathyroid glands, producing too much parathyroid hormone causes raised calcium levels in the blood (hypercalcaemia – primary hyperparathyroidism). You may also be offered an additional test called Parathyroid Hormone-Related Peptide (PTHrP). They would probably also measure Serum Calcium in combination with these type of tests. The parathyroid is one of the ‘3 p’ locations often connected to Multiple Endocrine Neoplasia – MEN 1
Pancreatic Hormones (Syndromes)
Pancreatic neuroendocrine tumors form in hormone-making cells of the pancreas. You may see these described as ‘Islet Cells’ or ‘Islets of Langerhans’ after the scientist who discovered them. Pancreatic NETs may also be functional or non-functional:
Functional tumors make extra amounts of hormones, such as gastrin, insulin, and glucagon, that cause signs and symptoms.
Nonfunctional tumors do not make extra amounts of hormones. Signs and symptoms are caused by the tumor as it spreads and grows.
There are different kinds of functional pancreatic NETs. Pancreatic NETs make different kinds of hormones such as gastrin, insulin, and glucagon. Functional pancreatic NETs include the following:
Gastrinoma: A tumor that forms in cells that make gastrin. Gastrin is a hormone that causes the stomach to release an acid that helps digest food. Both gastrin and stomach acid are increased by gastrinomas. When increased stomach acid, stomach ulcers, and diarrhea are caused by a tumor that makes gastrin, it is called Zollinger-Ellison syndrome. A gastrinoma usually forms in the head of the pancreas and sometimes forms in the small intestine. Most gastrinomas are malignant (cancer).
Insulinoma: A tumor that forms in cells that make insulin. Insulin is a hormone that controls the amount of glucose (sugar) in the blood. It moves glucose into the cells, where it can be used by the body for energy. Insulinomas are usually slow-growing tumors that rarely spread. An insulinoma forms in the head, body, or tail of the pancreas. Insulinomas are usually benign (not cancer).
Glucagonoma: A tumor that forms in cells that make glucagon. Glucagon is a hormone that increases the amount of glucose in the blood. It causes the liver to break down glycogen. Too much glucagon causes hyperglycemia (high blood sugar). A glucagonoma usually forms in the tail of the pancreas. Most glucagonomas are malignant (cancer).
Pancreatic Polypeptide (PPoma). A pancreatic polypeptide is a polypeptide hormone secreted by the pancreatic polypeptide (PP) cells of the islets of Langerhans in the endocrine portion of the pancreas. Its release is triggered in humans by protein-rich meals, fasting, exercise, and acute hypoglycemia and is inhibited by somatostatin and intravenous glucose. The exact biological role of pancreatic polypeptide remains uncertain. Excess PP could indicate a pNET known as PPoma.
Other types of tumors: There are other rare types of functional pancreatic NETs that make hormones, including hormones that control the balance of sugar, salt, and water in the body. These tumors include:
VIPomas, which make vasoactive intestinal peptide. VIPoma may also be called Verner-Morrison syndrome, pancreatic cholera syndrome, or the WDHA syndrome (Watery Diarrhea, Hypokalemia (low potassium)and Achlorhydria).
Somatostatinomas, which make somatostatin. Somatostatin is a hormone produced by many tissues in the body, principally in the nervous and digestive systems. It regulates a wide variety of physiological functions and inhibits the secretion of other hormones, the activity of the gastrointestinal tract and the rapid reproduction of normal and tumour cells. Somatostatin may also act as a neurotransmitter in the nervous system.
Having certain syndromes can increase the risk of pancreatic NETs.
Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Multiple endocrine neoplasia type 1 (MEN1) syndrome is a risk factor for pancreatic NETs.
Signs and symptoms of pancreatic NETs
Signs or symptoms can be caused by the growth of the tumor and/or by hormones the tumor makes or by other conditions. Some tumors may not cause signs or symptoms. Check with your doctor if you have any of these problems.
Signs and symptoms of a non-functional pancreatic NET
A non-functional pancreatic NET may grow for a long time without causing signs or symptoms. It may grow large or spread to other parts of the body before it causes signs or symptoms, such as:
A lump in the abdomen.
Pain in the abdomen or back.
Yellowing of the skin and whites of the eyes.
Signs and symptoms of a functional pancreatic NET
The signs and symptoms of a functional pancreatic NET depend on the type of hormone being made.
Too much gastrin may cause:
Stomach ulcers that keep coming back.
Pain in the abdomen, which may spread to the back. The pain may come and go and it may go away after taking an antacid.
The flow of stomach contents back into the esophagus (gastroesophageal reflux).
Too much insulin may cause:
Low blood sugar. This can cause blurred vision, headache, and feeling lightheaded, tired, weak, shaky, nervous, irritable, sweaty, confused, or hungry.
Too much glucagon may cause:
Skin rash on the face, stomach, or legs.
High blood sugar. This can cause headaches, frequent urination, dry skin and mouth, or feeling hungry, thirsty, tired, or weak.
Blood clots. Blood clots in the lung can cause shortness of breath, cough, or pain in the chest. Blood clots in the arm or leg can cause pain, swelling, warmth, or redness of the arm or leg.
Weight loss for no known reason.
Sore tongue or sores at the corners of the mouth.
Too much vasoactive intestinal peptide (VIP) may cause:
Very large amounts of watery diarrhea.
Dehydration. This can cause feeling thirsty, making less urine, dry skin and mouth, headaches, dizziness, or feeling tired.
Low potassium level in the blood. This can cause muscle weakness, aching, or cramps, numbness and tingling, frequent urination, fast heartbeat, and feeling confused or thirsty.
Cramps or pain in the abdomen.
Weight loss for no known reason.
Too much somatostatin may cause:
High blood sugar. This can cause headaches, frequent urination, dry skin and mouth, or feeling hungry, thirsty, tired, or weak.
Steatorrhea (very foul-smelling stool that floats).
Yellowing of the skin and whites of the eyes.
Weight loss for no known reason.
Too much pancreatic polypeptide may cause:
an enlarged liver.
Clearly the presenting symptoms will give doctors a clue to the oversecreting hormone (see list above). Excessive secretions or high levels of hormones and other substances can be measured in a number of ways. For example:
Well known tests for the most common types of NET include 5-Hydroxyindoleacetic Acid (5-HIAA) 24 hour urine test which is also measured by a blood draw. Note: -tumor markers can be measured simultaneously e.g. Chromogranin A (CgA) blood test and/or Pancreastatin as there can very often be a correlation between tumour mass and tumour secreting activity. CgA / Pancreastatin is a blood test which measures a protein found in many NET tumour cells. These marker tests are normally associated with tumour mass rather than tumour functionality.
By measuring the level of 5-HIAA in the urine or blood, healthcare providers can calculate the amount of serotonin in the body (5-HIAA is a by-product of serotonin). 5-HIAA test is the most common biochemical test for carcinoid syndrome or the degree of how ‘functional’ tumours are. If you’ve understood the text above, you can now see why there are dietary and drug restrictions in place prior to the test.
Pancreatic Hormone testing. There are other tests for other hormones and there is a common test which measured the main hormones seen in NETs. It may be called different things in different countries, but in UK, it’s known as a ‘Fasting Gut Hormone Profile‘.
Scratching the surface here so for a comprehensive list of marker tests for NETs, have aread here.
Treatment for Over-secreting Hormones
Of course, reducing tumour bulk through surgery and other treatment modalities, should technically reduce over-secretion (I suspect that doesn’t work for all). Other treatments may have the dual effect of reducing tumour burden and the effects of hormone oversecretions.
One of the key treatment breakthroughs for many NET cancer patients, is the use of ‘Somatostatin Analogues’ mainly branded as Octreotide (Sandostatin) or Lanreotide (Somatuline). People tend to associate these drugs with serotonin related secretions and tumours but they are in actual fact useful for many others including the pancreatic NETs listed above. Patients will normally be prescribed these drugs if they are displaying these symptoms but some people may be more avid to the drug than others and this may influence future use and dosages. This is another complex area but I’ll try to describe the importance here in basic terms. Somatostatin is a naturally occurring protein in the human body. It is an inhibitor of various hormones secreted from the endocrine system (some of which were listed above) and it binds with high affinity to the five somatostatin receptors found on secretory endocrine cells. NETs have membranes covered with receptors for somatostatin. However, the naturally occurring Somatostatin has limited clinical use due to its short half-life (<3 min). Therefore, specific somatostatin analogues (synthetic versions) have been developed that bind to tumours and block hormone release. Thus why Octreotide and Lanreotide do a good job of slowing down hormone production, including many of the gut hormones controlling emptying of the stomach and bowel. It also slows down the release of hormones made by the pancreas, including insulin and digestive enzymes – so there can be side effects including fat malabsorption.
The recent introduction of Telotristat Ethyl(XERMELO) is interesting as that inhibits a precursor to serotonin and reduces diarrhea in those patients where it is not adequately controlled by somatostatin analogues.
Other than the effects of curative or cytoreductive surgery, some NETs may have very specialist drugs for inhibiting the less common hormone types. This is not an exhaustive list.
Worth also noting that oversecreting hormones can contribute to a phenomenon (currently) 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.