In my article ‘Ever wonder what caused your NET’, I concluded that currently, the only known scientifically explained causes for NETs were hereditary/genetic in nature. This is mostly associated with those who have MEN syndromes (yes, they are a syndrome not a type of tumour) and a few other less common types of NET including Pheochomocytoma/Paraganglioma (Pheo/Para) and Medullary Thyroid Carcinoma (MTC) (the familial version of MTC is often referred to as FMTC). However, please note this does not mean that all those diagnosed with pancreatic, parathyroid, pituarity, Pheo/Para and MTC tumours, will have any hereditary or genetic conditions, many will simply be sporadic tumors.
In recent years, it has become increasingly apparent that a number of Neuroendocrine tumours arise as a result of germline genetic mutations and are inherited in an autosomal dominant pattern. The number of genes implicated is increasing.
Apparently, 5-10% of Gastroenteropancreatic NETs (GEP NETs) are estimated to have a hereditary background. Hereditary syndromes associated with these include Multiple Endocrine Neoplasia (MEN), Von Hippel Lindau (VHL), Neurofibromatosis Type 1 (NF1), Tuberous Sclerosis (TS) and others. People who have a genetic condition may present with the tumors (perhaps along with an associated functional hormone syndrome) and so the genetic condition if there is one, may not be known at this point.
Overview of genes with recurrent mutations in NETs and their distribution accordingly to anatomical location. Please note the percentages on the above diagram may differ depending on where you look). Citation: European Journal of Endocrinology 174, 6; 10.1530/EJE-15-0972
How will I know if I am affected?
Some people do worry about this, often because of what they find on the internet including inside patient forums. I suspect some people already know via family connections and as an example (there are many), I guess if you have 2 tumors found in (say) parathyroid and pancreas, it should at least raise a suspicion for MEN1 and be investigated.
Many people say how do I know, how do I check and this is obviously a delicate subject. Of course, your first port of call should be your NET specialist if you suspect or know of any connection.
Thus why I was interested in a paper published in Springer Link – titled “When should genetic testing be performed in patients with neuroendocrine tumours.” When reading, you’ll find it’s actually much more than that! Check it out here:
When should genetic testing be performed in patients with neuroendocrine tumours?
In this review, the authors examined the features which may lead a clinician to suspect that a patient may have an inherited cause of a NET and they outlined which underlying conditions should be suspected. They also discussed what type of screening may be appropriate in a variety of situations. If there is a way to identify which patients are likely to have a germline mutation, this would enable clinicians to counsel patients adequately about their future disease risk, and allows for earlier detection of at-risk patients through family screening. There’s a couple of minor errors in the text but I’ve contacted the authors who also agreed they should have included the pituitary.
The authors focused on presentations of NETs of the gastrointestinal system, chromaffin cell tumours (Pheochromocytoma and Paraganglioma) and Medullary Thyroid Carcinoma. Pituitary tumors (normally associated with MEN1), were not considered in scope for the review. Interesting thought, the review includes news of a move by endocrinologists to reclassify ‘Pituitary Adenomas’ as Pituitary NETs (PitNETs). Read the abstract here. This would appear to be in line with a gradual shift from the benign nomenclature associated with certain NETs to the ‘malignant’ potential of these type of tumors. The abbreviation is also in line with others, e.g. pNET, SiNET, etc. A useful reminder that we must stop using the term ‘Carcinoid‘ as this is regressing this extremely useful initiative to highlight the malignant potential of all NETs.
There also appears to be some linkage to the study looking at the possibility of familial Small Intestine NETs (SiNETs). You can read more about a US registered trial here (with apologies for use of the now defunct term ‘Carcinoid‘).
This is a complex subject and the text above is very basic. If you wish to dig further, the quoted reference is a good read. Just to emphasise, it’s aim is to provide advice about when to recommend genetic testing for NETs, and in doing so provides some useful reference information. Please also note they are finding new genetic links all the time so there could be some omissions of recently discovered genes but the article remains good enough as a primer on the subject. It’s broken down into 4 distinct tumor groupings:
3. Pheochromocytoma/ParagangliomaThe familial connection with Pheo/Para is complex. Up to 13 genes have been identified including NF1, RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2(SDH5), TMEM127, MAXm EPAS1, FH, MDH2. Read more here (recent update). The NIH also have a useful section – click here.
Welcome to my monthly ‘Community’ newsletter. This is June 2017’s monthly summary of Ronny Allan’s Community news, views and ICYMI (in case you missed it!).
NET News
The following news items may be of interest:
NETs in the UK National News. Great publicity. Featuring NET Patient Foundation. Click here.
Immunotherapy. Merkel Cell Carcinoma is already benefiting from an FDA approved drug with another pending. Check out this link.
Awareness. Giovanni from LACNETS generates awareness in her local area – I have no doubt that awareness saves lives. Read here.
Lanreotide. Ipsen announces approval in Japan for treating NETs. Click here.
NET Cancer Blog Activity
June was a slower month in ‘new’ blogging terms mainly due to holiday but even during this holiday, I’m being invited to external projects and a continuing flow of private messages. I’m still suffering with back pain but patiently waiting to see a physiotherapist. However, despite a low month for brand new blogs, I still managed for the first time to break through the monthly blog view figure of 20000. ……..Thank you all so much, a lot of this was down to your support for some scheduled posts whilst I was on holiday ♥
I continue to receive a steady flow of private contacts, mainly from patients seeking information. I don’t have an issue with private contact but please note my disclaimer. Please also note that I cannot accept telephone calls on a one to one basis. The number of non-patients contacting me for other reasons (mainly to help with something) continues to grow and this is producing some great publicity and awareness.
I’ve been nominated for the 2017 WEGO Health Awards in three categories so far, Blog, Patient Leader Hero and Lifetime Achievement. If you remember last year, I made it to the final in two categories of Blog and Community and won the latter. The nominations period ends on 7th July and I’ll let you know how you can vote for me. A vote for me is a vote for Neuroendocrine Cancer awareness.
BREAKING NEWS (…ish). I’ve been accepted as a ‘Cure Today’ contributor which means my articles will get a wider distribution than they do now. I’ve not contributed yet but clearly they will be posted on all my social media outlets for you to read. You can see my profile here: http://www.curetoday.com/community/contributors
New (or significantly updated) Blogs Published
Due to the vagaries of Facebook inner workings, some of these may not have even shown on your Facebook timeline. So, ICYMI …….here’s a summary with links:
New Audiences for NET Cancer. From Day 1, I said it was my aim to find new audiences for NETS rather than just share stuff within our own community.
I’m ‘extremely’ active on twitter and I find a lot of my research stuff there. I also use it to support other conditions and it’s mostly returned (i.e. others help with NET awareness and are made aware of NETs in the process). There is so much on twitter that I could swamp the community Facebook site so I started a twitter newsletter via an app called Nuzzel which seeks out stuff I normally like. Click this link and sign up if you think this is something you’d be interested in receiving. Currently 239 subscribers – up 25% on last month.
I continue to be featured by ‘external’ organisations such as WEGO and my PODCAST is reaching new audiences – click here. Other irons are in the fire but unable to bring you firm news just yet.
I’m proud to be a ‘Community Champion’ on the Macmillan Cancer Support Forum helping outliers from the NET community there. I’ll be reporting more on this in the coming weeks. This is the biggest cancer support organisation in the UK.
I’ve been accepted as a ‘Cure Today’ contributor which means my articles will get a wider distribution than they do now. I’ve not contributed yet but clearly they will be posted on all my social media outlets for you to read. Click hereto read more.
Speaking Engagements
On 7 July, I’ve been invited to speak for 10 minutes at the PLANETS patient conferencein Southampton. This is special for me as it’s where my major treatments took place and some of my medical team will be there.
On 5th October, I’ve been invited to speak for around an hour at the Cardiff (South Wales) NET Patient meeting (moved from July due to forecast low attendance) Things are starting to happen in this area and I already know Dr Mo Khan who is a NET specialist working hard on behalf of patients. I’m really looking forward to visiting and talking to this group.
Writing and other types of Engagement (external)
On 12 July, I’ve been invited to speak to Ipsen (UK). Still setting up this short notice meeting, details to follow in a separate post. Additionally, I was interviewed by a health reporter and separately by a health consultant. I’m not at liberty to provide details yet but if anything is published in the public domain, I will of course publish it on my social media channels.
Remember …….
Social Media and Stats
Blog Milestone. In June, I tipped over 310000 views! Thank you all so much ♥ Keep sharing! On track for 400000 by end of the year.
Facebook Milestone. I’m aiming for 5000 followers by year-end and this is on track. The Facebook page is now my biggest outlet for awareness and education so please please please recommend this page to anyone you think would be interested.
Instagram
I’m expanding into Instagram to see how that goes. I’ve amassed over 200 followers to date. Initially, I’ll just be posting pictures of things that inspire me, mostly scenic photos of places I’ve been or want to go! You can follow me here: Click here to go to my Instagram page
Figures
Facebook – 4806. This is a key outlet for my blog – please encourage others to like my page(if you’d like to know how to use your Facebook to invite others to my page – let me know, I can provide you with a step by step approach). Please also join my 2017 awareness campaign event here (select ‘Going’)
Where did June 2017 Blog views come from? – Top 10 countries: Germany on the up (wunderbar). And thanks to USA!
For interest. the 10 Ten Facebook followers by Country – Germany still sneaking up (wunderbar wieder). Interestingly Canada always reads more than Australia despite fewer followers.
WOW! – that’s an amazing amount of awareness and hopefully, support for others. However, I cannot do this without you guys liking, commenting and sharing! The likes give me motivation, the comments (and private messages) give me inspiration (or at least a chance to explain further) and the sharing gives me a bigger platform. A bigger platform generates more awareness.
Thanks for your great support in June. Onwards and upwards!
Thanks for reading
Ronny
Hey, I’m also active on Facebook. Like my page for even more news.
“A combination of two common immunotherapy drugs shrinks rare, aggressive neuroendocrine tumors, according to new research results presented at the American Association for Cancer Research Annual Meeting 2019, held March 29-April 3 in Atlanta“. See below under section: – Nivolumab (Opdiva) and Ipilimumab (Yervoy) in Treating Patients With High Grade Neuroendocrine Carcinoma
Immunotherapy for Neuroendocrine Neoplasms
There’s a lot of Immunotherapy stuff out there! However, I also wanted to break it down and perhaps see if I can pick up the what, when, why, where and how in regards to Neuroendocrine Cancer. It’s really difficult, not least because the picture is not clear and there is no general roadmap printed, let alone one for Neuroendocrine disease. Immunotherapy for NETs was discussed at ENETS 2017 in Barcelona. The presentation that sticks out was one given by Dr Matthew Kulke, a well-known NET Specialist in Boston. My reaction to the presentation was one of ‘expectation management’ and caution i.e. it’s too soon to know if we will get any success and when we will get it. He also hinted that it’s more likely that any success will first be seen in poorly differentiated high-grade Neuroendocrine Carcinoma (NEC). Dr Jonathan Strosberg also said similar in a post here. In fact, from below you will see that grade 3 poorly differentiated is where the bulk of trial activity is (…..but read on, there is some action around plain old well differentiated NETs). You will also see that there are disappointing results so far with single agent Keytruda.
Retain hope but just be cautious with some of the hype surrounding Immunotherapy
Immunotherapy is exciting, but we also need to be aware of the risks of taking the brakes off the immune system. We have seen and heard more and more stories about people with grim cancer diagnoses who became cancer-free after treatment with immunotherapy. This offers hope to those with cancer, but we need to be cautious when discussing immunotherapy. This treatment method is still new, and the cancer community is still learning about how it affects the body. An unfettered immune system may end up attacking healthy, functioning parts of a person’s body, causing unpredictable side effects that may be life-threatening EVEN if not treated early.
For those considering a trial, I think it’s worth spending some time reading this article from Cancer.NET – Doctor Approved Patient Information from the American Society of Clinical Oncology – “What You Need to Know About Immunotherapy Side Effects“.
For Neuroendocrine Neoplasms, only Neuroendocrine Carcinoma of the skin (Merkel Cell Carcinoma) and Small Cell Lung Cancer (SCLC) has an approved drug (see below). Anything else is currently an experimental scenario (clinical trial). Before launching into what is out for with an interest in NET and NEC, it’s worth pointing out that Immunotherapy is not for everyone, does not work for everyone, and has side effects for everyone.
Let’s start with Pembrolizumab (Keytruda)?
‘Pembrolizumab’ is more famously known as ‘Keytruda‘. This drug crops up everywhere and it has connections to many different cancers. Before I talk about this trial called PLANET, it’s very useful to take a quick look at the history of Keytruda which was only really made famous after former US President Jimmy Carter was treated with it for metastatic melanoma. There was a lot of media hype surrounding what made his treatment successful as he was also given radiation for his brain tumours and his large liver tumour was removed by surgery. However, putting the hype and conjecture to one side, Keytruda’s CV is pretty impressive. Pembrolizumab (Keytruda) is currently approved to treat certain scenarios in Hodgkin lymphoma, Melanoma, Non-small cell lung cancer (NSCLC), Squamous cell carcinoma of the head and neck, Urothelial carcinoma, Microsatellite instability-high (MSI-H) related cancers (a very interesting development as it’s the US FDA’s very first approval on a tissue/site agnostic basis).
However, despite this excelent record, it’s worth also noting that NANETS 2018 reported limited use of Keytruda (see below) as a single agent to treat high grade Neuroendocrine Neoplasms.
Other approvals are anticipated.
So what about Neuroendocrine Neoplasms?
Approvals:
FDA granted accelerated approval to Avelumab (BAVENCIO) for the treatment of patients 12 years and older with metastatic Merkel cell carcinoma (MCC). MCC is a Neuroendocrine Carcinoma of the skin. Avelumab is a programmed death-ligand 1 (PD-L1) blocking human IgG1 lambda monoclonal antibody. This is the first FDA-approved product to treat this type of cancer – CLICK HERE for more information.
In Aug 2018, the FDA granted Nivolumab (OPDIVO) accelerated approval for third-line treatment of metastatic small cell lung cancer (a type of Neuroendocrine Carcinoma. Read more – click here.
In Dec 2018, US FDA approves pembrolizumab for adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). Click here.
On March 18, 2019, the FDA approved Atezolizumab (TECENTRIQ) in combination with carboplatin and etoposide, for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). Click here.
This trial is interesting. Nivolumab (Opdiva) and Ipilimumab (Yervoy) in Treating Patients With High Grade Neuroendocrine Carcinoma It’s a multiple cancer setup and includes several of the less common NET/NEC types including ‘Lung Carcinoid’, ‘Anal NEC’, ‘Gastic NEC’, ‘Pancreatic NEC’ ‘Esophageal NEC. Interesting because this is the drug combo that NEC patient Danielle Tindle has moved onto after Keytruda didn’t really work in the medium to long-term (see the Danielle Tindle story below). Looking at the list in the trial document, I’m thinking they might mean high-grade Lung Neuroendocrine rather than ‘carcinoid’. I could be wrong. It’s currently recruiting.
Update from 2019 AACR Annual Meeting.
The immune checkpoint inhibitor combination of nivolumab (Opdivo) and ipilimumab (Yervoy) induced a greater than 40% response rate and was well tolerated in patients with high-grade neuroendocrine carcinoma, according to findings from the phase II DART trial presented at the 2019 AACR Annual Meeting.
“DART is the first NCI-funded rare tumor immunotherapy basket study which we think is unique in its design scale,” lead author Sandip Patel MD, an associate professor of medicine at the University of California San Diego School of Medicine, said in a press briefing at the meeting. “We’re studying over 37 rare tumor types [using the] combination of ipilimumab plus nivolumab. The neuroendocrine cohort, the nonpancreatic cohort, had promising signs of benefit—[particularly] in patients with high-grade neuroendocrine carcinoma—independent to primary site,” added Patel.
I also have some evidence of the use of Pembrolizumab (Keytruda) by an Australian high-grade thymus patient – I posted something here (Danielle Tindle)
PDR001 (Spartalizamab) – see below.
UPDATE from NANETS 2018. “A preliminary trial of checkpoint blockade for neuroendocrine tumors (NETs) produced little evidence of activity, according to data reported here. Only one of 21 patients with high-grade NETs responded to treatment with pembrolizumab (Keytruda). Three others had stable disease. The trial had an objective response threshold of 5% as the definition of clinically interesting, as reported at the North American Neuroendocrine Tumor Society annual symposium. “Pembrolizumab, though generally well tolerated, showed limited activity as a single agent in high-grade neuroendocrine neoplasms (NENs) in this study,” Arvind Dasari, MD, of MD Anderson Cancer Center in Houston, and colleagues concluded.” More info.
Update from Gastrointestinal Tumor symposium 2019. “Disappointing results for single agent pembrolizumab (Keytruda) in well differentiated NET. Response Rate 3.7%. Not a viable option. Listen to Dr Jonathan Strosberg describe the poor results. Click here.
SPARTALIZUMAB (PDR001)
This is an interesting trial sponsored by Novartis (of Octreotide fame). PDR001 (anti-PD-1) is an investigational immunotherapy being developed by Novartis to treat both solid tumors and lymphomas (cancers of the blood). It is currently being trialled on many cancers including Neuroendocrine Neoplasms both well and poorly differentiated. Click here:Clinical Trial SPARTALIZUMAB – Immunotherapy for Neuroendocrine Neoplasms (PDR001)
NET Research Foundation
Please also see the wonderful work done by NET Research Foundation who are using their funds to explore the use of Immunotherapy in NETs – check out their update by clicking here.
But what about just plain old well differentiated low or moderate grade NETs?
I found the following:
Pembrolizumab (Keytruda) in combination with Lanreotide
According to the trial documentation, it’s for patients with non-resectable, recurrent, or metastatic well or moderately (sic) differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). i.e. most of us. It is recruiting. You can read about the PLANET trial by clicking here. Make sure you fully check the inclusion and exclusion criteria. Please note the incorrect reference to ‘moderately differentiated’ – this is no longer used in the grading classification for Neuroendocrine Neoplasms.
Study of Pembrolizumab in Participants With Advanced Solid Tumors (MK-3475-028/KEYNOTE-28) – NCT03054806 and another called ‘A Clinical Trial of Pembrolizumab (MK-3475) Evaluating Predictive Biomarkers in Subjects With Advanced Solid Tumors’ (KEYNOTE 158) NCT02628067
From Gastrointestinal Tumor symposium 2019. “Disappointing results for single agent pembrolizumab in Well Differentiated NET. Response Rate 3.7%. Not a viable option. Listen to Dr Jonathan Strosberg describe the poor results. Click here.
Study for the Evaluation of Pembrorolizumab (MK-3475) in Patients with Rare Tumors (Experimental: Paraganglioma-Pheochromocytoma Group)
It is not known if this part of the trial is affected by the results above in Keynote-28. This study is recruiting at MD Andersen Houston Texas. Read more here.
PDR001 (Spartalizamab) -a Novartis drug – read about this trial click here.
Atezolizumab and Bevacizumab in Solid Tumors
In 2016, US FDA approved Atezolizumab (TECENTRIQ) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC). Bevacizumab (also known as AVISTAN) is a well known drug already used to treat many cancers. Avastin is not actually Immunotherapy but is a tumor-starving (anti-angiogenic) therapy, i.e. its purpose is to prevent the growth of new blood vessels …. ergo this is a combo treatment using an Immunotherapy drug and an anti-angiogenic drug.
Criteria:
Well differentiated Neuroendocrine tumors, Grade 1 or grade 2 according to reviewing pathologist
Progressive disease over the preceding 12 months
Any number of prior therapies
Patients using a somatostatin analogue for symptom control must be on stable doses for 56 days prior to enrolment.
According to the trial documenation, there are two ‘baskets’ of types: Pancreatic NET (pNET) and “extrapancreatic” (i.e. beyond or not in the pancreas) including typical or atypical Lung NETs. Merkel Cell Carcinoma (a type of Neuroendocrine Carcinoma of the skin) is also included in the trial. You can read about this trial by clicking here. Make sure you fully check the inclusion and exclusion criteria. Again, within the trial documentation, please note the incorrect reference to ‘moderately differentiated’ – this is no longer used in the grading classification for Neuroendocrine Neoplasms.
By the way, what exactly does Immunotherapy do?
For those still wondering what cancer immunotherapy actually is, this is the most basic description I could find!
Immunotherapy – Hype or Hope?
I mentioned above that there was a lot of hype surrounding Keytruda and other immunotherapy treatments. You may therefore enjoy this CNN article about the hype and hope aspect, it was given considerable sharing at ASCO17 – read the article by clicking here
If you’re on an Immunotherapy trial not listed here, please let me now so I can update the post. Thanks in advance.
What is Peptide Receptor Radionuclide Therapy (PRRT)?
For those who are still not sure what it’s all about. This is a non-surgical treatment which is normally administered intravenously. It’s based on the use of somatostatin receptors to attract a ‘radiopeptide’. The radiopeptide is a combination of a somatostatin analogue and a radioactive material. As we already know, somatostatin analogues (i.e. Lanreotide/Octreotide) are a NET cell targeting drug, so when combined with radioactivity, it binds with the NET cells and delivers a high dose of targeted radiation to the cancer while preserving healthy tissue. In general, patients tend to receive up to 4 sessions spaced apart by at least 2 months.
PRRT will not work on all NETs and not everyone will suited to this treatment. In general, for this treatment to be more successful, you must have somatostatin receptors in your tumors. Success rates are not 100% – it should not be considered a cure or ‘magic bullet’. However, the results are said to be pretty good. The NETTER-1 trial data which has led to formal approval in Europe, USA and other areas, can be found here.
LATEST ON EXPANDED NETTER-1 TRIAL DATA. “Novartis has announced presentation of a new analysis of Lutathera (lutetium Lu 177 dotatate) NETTER-1 data at the 2018 European Society for Medical Oncology (ESMO) congress examining the impact of Lutathera treatment on patients with low, medium or high liver tumor burden. The data show that Lutathera treatment results in significant improvement in progression free survival (PFS) regardless of the extent of baseline liver tumor burden (LTB), elevated alkaline phosphatase (ALP) liver enzyme or presence of large (>30mm diameter) lesion in patients with progressive midgut neuroendocrine tumors (NETs) compared to octreotide LAR alone.”
Read the latest news on the NETTER-2 trial here. This is designed to look at the benefits of using PRRT on Grade 2 and Grade 3 patients as a first line treatment.
THERANOSTICS
Understanding the terminology is half the battle in understanding the latest developments. I’ve included Ga-68 PET scans within this section (or in more general terms Somatostatin Receptor PET (SSTR PET)) as the term ‘Theranostics‘ is becoming a commonly used theme. Theranostics is a joining of the words diagnostics and therapy.
LUTATHERA is the radionuclide ‘mix’ for use in Peptide Radio Therapy Treatment (PRRT). You may also see this drug called ‘Lutetium’ or ‘Lu-177 dotatate’, or just ‘Lu-177’ on its own. Yttrium 90 (Y-90) is a radionuclide also used in PRRT.
NETSPOT (USA) or SOMAKIT TOC (Europe) is not PRRT but it is the commercial names for the radiopeptide used in Gallium 68 (Ga-68) PET diagnostic scans.
Together they form a ‘theranostic pair’. Theranostics is apt as together (NETSPOT / SOMAKIT TOC and Lutathera), both target NETs expressing the same somatostatin receptor, with Lutathera intended to kill tumor cells by emitting a different kind of low-energy, short-range radiation than that of the diagnostic version.
Moreover, thanks to the theranostic approach that nuclear medicine allows, Novartis/AAA’s NETSPOT/SomaKit TOC products will be able to determine when Lutathera is the appropriate treatment.
Of course, this therapy has been in use in Europe and some other places for some time but to be honest, they have been on a limited scale and never formally approved by national drug agencies. Despite its extensive use, the EU approval in 2017 was actually the very first approval of PRRT anywhere in the world. For example, in UK, it was used for some time for those in need but was removed from routine availability through a ‘slush fund’ formally known as the Cancer Drugs Fund – to cut a long story short, the funding source was cut off, although there are still ways of obtaining the treatment pending formal acceptance by the NHS (certain criteria apply).
In the meantime, I constantly see stories of patients travelling to Switzerland, Germany, Netherlands, Sweden, Great Britain and others; mostly at their own cost. However, it does indicate one thing, there is a huge unmet need in that many patients do not have access to the best treatments in their own country. I see this daily through many private messages.
What about Grade 3 (High Grade) Neoplasms?
The main treatment for Grade 3 is chemotherapy, particularly poorly differentiated. PRRT tends to work better with efficient somatostatin receptors (i.e. somatostatin receptor-positive tumors). The European approval wording only covers Grades 1 and 2. The US FDA approval indicates “somatostatin receptor-positive tumors”. It’s also worth noting that with Grade 3, working somatostatin receptors are more likely to exist in Grade 3 well differentiated NETs, particularly in the lower Ki-67 readings (less than 55%). However, there’s an interesting study from Australia which might be useful to read – check out the abstracthere (note the full version is not available free).
2019 Updated data for Grade 3 Neuroendocrine Neoplasms:
“Compared to studies evaluating the efficacy of chemotherapy for NEN patients with a Ki-67 index less than or equal to 55 percent, PRRT has a longer overall survival rate–22 months versus 14 months,” the researchers pointed out. “These results suggest that PRRT, rather than chemotherapy, may be a superior first-line therapeutic option in selected patients with a high level of SSTR expression and a Ki-67 index of less than or equal to 55%.” Read more here.
Merkel Cell Carcinoma. Although not indicated for this type of Neuroendocrine Neoplasm, there is evidence to suggest that this skin Neuroendocrine Carcinoma does express somatostatin receptors. Read more here.
This article discusses the efficacy of PRRT in Pheo/para – click here. There’s actually still a trial for Pheochromocytoma/Paraganglioma (Pheo/Para). It is known that Pheo/Para can have somatostatin receptor tumors so a useful trial. The aim of the trial is to assess the safety and tolerability. You can read about the trial here.
Where can I get PRRT?
Where can I get PRRT?
Regional Updates
The aim of this section is to update on a regional basis in order to inform an international community of followers and readers.
Background
I wanted a place to review what is happening globally given my following. In many countries, however, I’m dependent on feedback from patients in those countries. Please note this is not intended to be a 100% complete breakdown on everything about PRRT or PRRT centres – it’s a summary. It should be clear from below but please bear that in mind when reading.
This section of this article will cover each region, indicating where PRRT can be obtained (as far as I know). It is not designed to indicate whether this is through public or private facilities (this will depend to too many factors beyond the reach of this article). Please note this is not intended to be a 100% complete breakdown on every single PRRT centre – it’s a summary. This actually should be clear from below but please bear that in mind when reading.
UNITED KINGDOM
On 29 August 2018. National Institute for Health Care Excellence (NICE) England has formally published that Lutetium (177Lu) oxodotreotide, within its marketing authorisation, is an option for treating unresectable or metastatic, progressive, well-differentiated (grade 1 or grade 2), somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours (NETs) in adults. CLICK HERE to read the approval. Currently available in the following NHS locations:
London – at least 2 locations – Royal Free, Guys and St Thomas
Liverpool – The Royal
Manchester – The Christie
Sheffield – Weston Park
Bristol – Bristol Oncology Centre
Newcastle – Freeman Hospital
Coventry – University Hospital
Anecdotal mention of Leicester but waiting to hear confirmation.
On 9 July 2018. The Scottish Medicines Consortium (NICE equivalent) has approved lutetium 177Lu (Lutathera) for patients in NHS Scotland. Good news for Scotland once their hospitals have the capability to deliver. Scottish patients would then not need to travel to England for the NHS Scotland funded treatment. Read more here.
It is funded in Wales and Northern Ireland but is currently administered in England with inter NHS budget transfers.
Canada
On 7th Feb 2019, Health Canada approved Lutathera™ (lutetium (177Lu) oxodotreotide) for the treatment of unresectable (not removable by surgery) or metastatic, well-differentiated, somatostatin receptor-positive (expressing the somatostatin receptor) gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in adults with progressive disease. The treatment was previously available on a trial basis. Read more here.
Site update to follow but the following trial locations may be up and running first:
Juravinski Hamilton
LHSC London
PMCC Toronto
Sunnybrooke Toronto
Cross Cancer Institute, Edmonton
USA
PRRT was approved in USA on 26 Jan 2018.The approval is for the treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults. CLICK HERE.
The extended access program (trial) is no longer offered but these locations should be ahead of the game in terms of provision, notwithstanding insurance and provision of sufficient nuclear material.
In the meantime, known USA sites offering routine “live site” insurance based PRRT treatment are as follows – please note information has been gleaned from US patients due to no other consolidated source of this information being readily available. It’s possible some patients got mixed up between trial locations and live locations so let me know of any omissions or additions/corrections – thanks in advance.
DRAFT – NOT YET COMPLETE – (as at 16 May 2019)
STATE
LOCATION
Due in Service?
CONTACT DETAILS
Arizona
Banner
Now
Dr Boris Naraev
California
UCSF Medical Center Mission Bay San Francisco
Now
tbc
California – Antioch
Kaiser Permanente Antioch Medical Center
Now
tbc
California
Cedars Sinai Medical Center LA
now
tbc
California
Stanford Medical Center
Now
tbc
California
Kaiser Permanente Los Angeles Medical Center
Now
tbc
California
Hoag Hospital Newport Beach
Now
tbc
California
UCLA Health
Now
tbc
California
Kaiser Santa Clara Medical Center
Now
tbc
California
City of Hope LA
Now
tbc
California
San Diego
Now
tbc
Connecticut
Yale New Haven Medical Center
Now
tbc
Connecticut
Hartford Hospital
Now
Salner, Andrew, MD
Radiation Oncology
Colorado
Rocky Mountain Cancer Center Denver
Now
Dr Eric Liu
Colorado
University of Colorado UC Health Denver
Now
tbc
Florida
Moffat Tampa
Now
Dr Strosberg
Florida
University of Miami
Now
tbc
Florida
Mayo Jacksonville
Now
tbc
Florida
Winter Park, Florida Radiation Oncology Orlando
Now
David Diamond MD
Florida
Orlando Health
Now
tbc
Georgia
CCTA Newnan, Atlanta
Now
Dr. Phan
Hawaii
Queen’s Medical Center
Now
Dr. Marc Coel
Idaho
Mountain States Tumor Institute at St. Luke’s Hospital, Boise
Now
Idaho
Eastern Idaho Regional Medical Center, Idaho Falls, Idaho
Now
Illinois
Rush University Chicago
Now
Illinois
Northwestern Chicago
now
tbc
Illinois
The University of Chicago Medicine
now
Xavier M. Keutgen, MD
Illinois
Loyola University Medical Center Maywood
now
tbc
Illinois
CTCA Chicago
now
tbc
Indiana
Indiana University Health
now
tbc
Iowa
University of Iowa
now
Dr T O’Dorisio
Kansas
University of Kansas Medical Center Fairway
now
tbc
Kentucky
University of Kentucky, Markey Cancer Center
now
tbc
Louisiana
Ochsner
now
tbc
Maryland
John Hopkins Baltimore
now
tbc
Massachusetts
Dana Farber Boston
Now
tbc
Massachusetts
Massachusetts General Hospital
Now
tbc
Michigan
Ann Arbor
Now
tbc
Michigan
Detroit – Karmanos Cancer Center
Now
tbc
Minnesota
Mayo Rochester
Now
Dr. Thor Halfdanarson
Minnesota
University of Minnesota Health
Now
tbc
Missouri
Sara Canon Cancer Center Kansas City
Now
tbc
Missouri
Siteman Cancer Center St. Louis/Barnes Jewish Hospital St. Louis
Now
tbc
Nebraska
CHI Bergan
Now
Dr Samuel Mehr
Nebraska
Nebraska Cancer Specialists Omaha
Now
Dr Samuel Mehr
New York
Lenox Hill NYC
Now
tbc
New York
Sloan Kettering
Now
tbc
New York
Stony Brook University Cancer Center Long Island
Now
Nurse Navigator, Patty Zirpoli, RN
New York
Roswell Park Buffalo
Now
Dr Iyer
New York
Mount Sinai
Now
tbc
New York
NYU Langone
Now
tbc
North Carolina
Dukes Durham
Now
tbc
Ohio
The James, Columbus
Now
Dr Shah
Oregon
Oregon Health & Science University (OHSU)
Now
tbc
Pennsylvania
UPMC Pittsburgh
Now
tbc
Pennsylvania
Fox Chase Philadelphia
Now
Dr Paul Engstrom
Rhode Island
Rhode Island Hospital Providence
Now
Dr Paul Engstrom
South Dakota
Sanford in Sioux Falls
now
tbc
Tennessee
Vanderbilt Nashville
Now
tbc
Texas
MD Anderson Houston
Now
tbc
Texas
Excel Diagnostics Houston
Now
tbc
Texas
CHI St Lukes Houston
Now
tbc
Texas
BAMC San Antonio(VA) Houston
Now
tbc
Utah
Huntsman Cancer Institute, Salt Lake City
Now
tbc
Vermont
University of Vermont Medical Center
Now
Jay Kikut, MD, Director of Nuclear Medicine and PET
Virginia
Carilion Clinic Roanoke
Now
tbc
Washington (State)
Virginia Mason Seattle
Now
Dr. Hagen Kennecke
Washington (DC)
VMedStar Georgetown University Hospital
Now
tbc
West Virginia
VMU Cancer Institute Morgantown
Now
Shalu Pahuja, M.D
Wisconsin
UW Health Madison, Carbone Cancer Center
Now
Noelle K. LoConte, MD Specialty: Medical Oncology Primary Location: UW Carbone Cancer Center (608) 265-1700 (800) 323-8942
Wisconsin
Froedtert Milwaukee
Now
Dr Thomas
Europe (excluding UK which is listed above)
The European Medicines Agency (EMA) “market authorisation” received a positive indication on 20th July followed by EC approval on 29 Sep 2017. The positive indication reads “Lutathera is indicated for the treatment of unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours (GEP NETs) in adults”. Of Course, the decision to fund the drug will be with national approval organisations. Whilst I’m sure there are many more, these well-known centres have been making PRRT available for some years (but please note there are others):
Denmark – ‘Rigshospitalet’ since 2009. They have treated around 250 patients- and given 800 treatments.Netherlands – Rotterdam Treatment Centre – click here
Slovenia –Ljubljana, University medical Centre Ljubljana
Sweden – Department of Endocrine Oncology Uppsala University Hospital – click here
Switzerland – University Hospital Basel, Radiology & Nuclear Medicine Clinic – click here
I’d be interested to hear from countries in Europe with their full list of centres or a link to it.
Australia
Australia seems to be ahead of the game or that is what I sense when I read output from there. There’s a good section on the Australian effort – click here.
New Zealand
These guys have had to fight to get some progress on the provision of PRRT. Currently New Zealanders have to go to Melbourne Australia for treatment – almost 50 New Zealanders with NETs are currently raising tens of thousands of dollars to pay for treatment in Australia because the life-prolonging treatment isn’t available locally. But this could change in 2018. Unicorn Foundation New Zealand announced that Pharmac, the New Zealand government agency that decides which pharmaceuticals, have said that PRRT will be funded for patients with medium priority for the treatment of unresectable or metastatic, well-differentiated NETs (irrespective of primary site) that express somatostatin receptors.
Lebanon – The American Hospital of Beirut – Dr Ali Shamseddine “We have started using Lu-177 here in Lebanon. So far, we have treated 3 patients, with good response. The operational cost is much less than in Europe”.
India – Mahatma Gandhi Cancer Hospital, Visakhapatnam. Recently started radionuclide therapy. Although only currently available privately, some patients have been sponsored by the companies that they work for. Point of contact is Dr. K. Raghava Kashyap. I’ve been assured by CNETS India that many locations have PRRT capability – contact them direct please. Also – TATA Memorial Hospital Mumbai (waiting time is long, but cost is low: $200) and there are private clinics in Pune (cost is $1500) and Bengaluru (cost is around $6000). (Info from Russian patient group).
Kuwait – Kuwait Cancer Control Center (KCCC) – read article here.
Cabozantinib is an oral drug which works by blocking the growth of new blood vessels that feed a tumour. In addition to blocking the formation of new blood cells in tumours, Cabozantinib also blocks pathways that may be responsible for allowing cancers cells to become resistant to other “anti-angiogenic” drugs. It is a type of drug called a growth blocker. Cabozantinib has been studied or is already in research studies as a possible treatment for various types of cancer, including prostate cancer, ovarian cancer, brain cancer, thyroid cancer, lung cancer, and kidney cancer. During my research, I found that it has a connection to Medullary Thyroid Cancer (MTC) which is a type of Neuroendocrine Cancer, frequently associated with Multiple Endocrine Neoplasia (MEN). Cabozantinib, under the brand name of ‘Cometriq’ was approved by the FDA in 2012 for use in MTC. Read more about Cometriq here. It’s also been approved by the FDA for advanced renal cell carcinoma (RCC) (branded as Cabometyx). I also discovered that there is an exclusive licensing Agreement with the manufacturers (Elelixis) and Ipsen (of Lanreotide fame) to commercialize and develop Cabozantinib in regions outside the United States, Canada and Japan
Growth blockers are a type of biological therapy and include tyrosine kinase inhibitors, proteasome inhibitors, mTOR inhibitors, PI3K inhibitors, histone deacetylase inhibitors and hedgehog pathway blockers. Cabozantinib is a tyrosine kinase inhibitor (TKI). They block chemical messengers (enzymes) called tyrosine kinases. Tyrosine kinases help to send growth signals in cells so blocking them stop the cell growing and dividing. Some TKIs can block more than one tyrosine kinase and these are known as multi-TKIs.
Example action of Cabozantinib
So Capozantinib is a tyrosine kinase inhibitor and is therefore a biological therapy and growth blocker just like Everolimus (Afinitor) and Sunitinib (Sutent) – some texts describe thelattero two as chemotherapy but this is just not accurate.
Very technical process but in the simplest of terms, Cabozantinib is designed to disrupt the actions of VEGF (a growth factor) and MET (a growth factor receptor) which promote spread of cancerous cells through the growth of new blood vessels. Whilst we are on this subject, please note Everolimus (Afinitor) is an mTOR inhibitor and Sunitinib (Sutent) is a tyrosine kinase inhibitor. Many people think these drugs are a type of chemo – that is incorrect, these are targeted biological therapies. See more on this by clicking here.
What is the current trial status of Capozantinib?
A Phase III trial is now recruiting entitled “Cabozantinib S-malate in Treating Patients With Neuroendocrine Tumors Previously Treated With Everolimus That Are Locally Advanced, Metastatic, or Cannot Be Removed by Surgery”.
The trial has 172 locations across the US (see link below). The primary study (final data) is scheduled Jan 1st 2021.
You can read the trial documentation by clicking here.
A funded piece of research by the NET Research Foundation – check it out here – looks like they are trying to figure out what patients might benefit from Cabozantinib using biomarker data to predict response.
BOSTON — Cabozantinib (Cabometyx) may benefit patients with malignant pheochromocytomas and paragangliomas, according to results of a phase II trial presented here.
Patients receiving cabozantinib (Cometriq) treatment experienced notable tumor shrinkage in the lymph nodes, liver, and lung metastases, according to Camilo Jimenez, MD, of the MD Anderson Cancer Center in Houston, and colleagues.
Additionally, progression-free survival significantly increased after treated to 12.1 months (range 0.9-28) compared with just 3.2 months prior to treatment, they reported at the American Association of Clinical Endocrinologists (AACE) annual meeting.
Cabozantinib treatment was also tied to an improvement in blood pressure and performance status, as well as remission of diabetes among these patients.
“Malignant pheochromocytomas and paragangliomas are frequently characterized by an excessive secretion of catecholamines. [Patients] have a large tumor burden and they have a decreased overall survival,” explained Jimenez. “Tumors are frequently very vascular and frequently associated with bone metastases. In fact, up to 20% of patients who have malignancy of pheochromocytomas and paragangliomas may have predominant bone metastases.”
He added that “an interesting aspect of this tumor is that C-MET receptor mutation have been found in occasional patients with malignant pheochromocytomas and paragangliomas.”
Cabozantinib is an anti-angiogenic tyrosine kinase inhibitor, which also targets RET, MET, and AXL. It is approved for metastatic medullary thyroid cancer, and was more recently approved for first-line treatment of advanced renal cell carcinoma.
“MET pathway is also involved in the development of bone metastases. In fact, cabozantinib is a very effective medications for patients who have bone metastases in the context of cancer of different origins,” Jimenez said.
In order to be eligible for the trial, patients with confirmed pheochromocytoma or paraganglioma had to be ineligible for curative surgery, have ≥3 months life expectancy, no risk for perforation or fistula, and adequate organ functioning. Prior to cabozantinib initiation, patients could not receive chemotherapy or biologic agents within 6 weeks, radiation within 4 weeks, or MIBG within 6 months.
Following histological confirmation of disease progression >1 year according to RECIST 1.1, the trial included 14 patients with measurable disease and eight patients with predominant/exclusive bone metastases. Fifteen patients subsequently enrolled into the trial, six of whom had germline mutations of the SDHB gene.
All participants were all started at an initial daily dose of 60 mg of cabozantinib, which was subsequently reduced down to between 40 to 20 mg due to toxicity in 13 patients based on tolerance.
The majority of these patients with measurable disease experienced some level of disease response. Six patients reported a partial response, defined as over a 30% reduction, while three patients achieved moderate response, marked by a 15%-30% reduction. Five of the patients with predominant bone metastases reported disease stabilization, according to results of an FDG-PET scan. One patient experienced disease progression while on treatment.
Overall, cabozantinib was generally well-tolerated without any grade 4 or 5 treatment-related adverse events reported. Some of the most common adverse events reported included grade mild dysgeusia, hand and foot syndrome, mucositis, fatigue, weight loss, and hypertension, according to the authors.
Primary Source – American Association of Clinical Endocrinologists meeting – AACE 2018; Abstract 142. attended my Medscape writers
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Summary
I generated this blog article to add value rather than just post the outputs for your own perusal. I hope you find it useful.
Please note that taking part in a clinical trial is a big decision and must be considered carefully in conjunction with your specialists if necessary. This article is not suggesting this trial is right for you. Please check the inclusion and exclusion criteria in the trials document carefully. (Pheo/Para patients see other clinical trial link above)
Courtesy of Pashtoon Kasi MD on Twitter https://twitter.com/pashtoonkasi/status/1078675398601396224
Theranostics is a joining of the words therapeutics and diagnostics. You may also see it conveyed as ‘Theragnostics’ and these terms are interchangeable. The basic aim of theranotistics is to find and then destroy the ‘bad guys‘. With Neuroendocrine Cancer, finding the tumours (the bad guys) can often be a challenge – they can be small and/or difficult to find – they are sometimes expert at camouflage. Moreover, once found, they can then be difficult to treat (destroy), as they can often prove resistant to conventional cancer drugs and many are inoperable due to sheer quantity, spread and positioning. When they are found and identified, it’s also really helpful to know from the intelligence gathered, how successful the destroy (therapeutic) part of the mission might be.
The nuclear scan uses the same targetin agent as the therapy, therefore if you cancer lights up on the nuclear scan, then the therapy will find its way to the cancer and hopefully work well. That is the beauty of theranostic pairing, i.e. the use of the same agent in the diagnostics – the ability to find, estimate likely success criteria and then hopefully destroy – or at least reduce the capability of the tumours and extend life.
A great example of an approved Theranostic Pairin Neuroendocrine Cancer, is the combination of the Somatostatin Receptor based Ga68 PET scan using NETSPOT or SomaKit TOC™ (US/Europe respectively) and Peptide Receptor Radiotherapy (PRRT) using Lutathera which both target NETs expressing the same somatostatin receptor, with PRRT intended to kill tumor cells by emitting a different kind of low-energy, short-range radiation than that of the diagnostic version. As mentioned above, the Ga68 PET scan can give a reasonably indication of therapeutic success using PRRT based on measurements taken during the scan (too complex for this article).
Nuclear medicine makes it possible by using the same molecular targeting compound to create diagnostic and therapeutic drugs, which work as theranostic pairings. Advanced Accelerator Applications’ theranostic platform is based on radiolabelling a single targeting molecule with either gallium Ga-68 for diagnostic use or lutetium Lu-177 for therapeutic use. AAA’s pipeline now includes several theranostic drug pairings for oncology indications including prostate and breast cancer; and gastrointestinal stromal tumors (GIST).
Newer imaging agents targeting somatostatin receptors (SSTR) labelled with 68 Ga have been developed, namely, DOTATATE, DOTATOC and DOTANOC. They are collectively referred to as SSTR PET.
The main difference among these three tracers (DOTA-TOC, DOTA-NOC, and DOTA-TATE) is their variable affinity to SSTR subtypes. All of them can bind to SSTR2 and SSTR5, while only DOTA-NOC shows good affinity for SSTR3.
These agents have several benefits over In111-pentetreotide (Octreotide scan), including improved detection sensitivity, improved patient convenience due to the 2 hour length of the study (compared to 2 or 3 days with Octreoscan), decreased radiation dose, decreased biliary excretion due to earlier imaging after radiotracer administration, and the ability to quantify uptake. The quantification of the uptake can help decide whether a patient is suitable for PRRT. Eventually, all Octreotide scans should be replaced with SSTR PET. To confirm the advantages of SSTR PET over Octreotide scans, a study comprising 1,561 patients reported a change in tumour management occurred in over a third of patients after SSTR PET/CT even when performed after an Octreotide scan. Worth pointing out that SSTR PET is replacing the ageing Octreotide scan and not conventional imaging (CI). You can see the recommended scenarios for use of SSTR PET in this article published by the Journal of Nuclear Medicine
Ga68 PET scans have been in many locations for some time. Current excitement is focused on USA locations with Ga68 PET (NETSPOT) only recently approved (DOTATATE). Other countries/scan centres may use one of the other types of imaging agent.
Read much more about this scan in my detailed article on Ga68 PET here.
So SSTR PETs above have the ability to find and estimate likely success criteria for therapy. We are now in a position to move on to ‘THERApy’ – e.g. Peptide Receptor Radiotherapy or PRRT.
THERANOSTICS – DESTROY
click on picture to watch video
Lutathera® (note the ‘THERA’ which makes up the brand name)
Definitions:
Europe Approval: LUTATHERA®(lutetium (177Lu) Oxodotreotide) is indicated for the treatment of unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours (GEPNETs) in adults.
USA Approval: LUTATHERA® (lutetium Lu 177 dotatate) is indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut and hindgut neuroendocrine tumors in adults.
For commercial purposes, the drug may be slightly different on a regional basis. For all intents and purposes it does the same job.
PRRT with LUTATHERA®
LUTATHERA® solution for infusion is a ‘radiolabelled somatostatin analog (SSA)’ comprised of a radionuclide (Lutetium-177) and a peptide (differs between Europe and USA)
The relevant SSA binds with high affinity to the somatostatin receptors (SSTR) overexpressed in malignant neuroendocrine cells such as the ones found in GEP-NETs.
Lutetium-177 is a β particle emitting radionuclide, with a mean penetration range of 0.67 millimetres in tissue (maximum penetration range of 2.2 mm) which is sufficient to kill targeted tumour cells with a limited effect on neighbouring normal cells.
The affinity for SSTRs and the specificity of binding ensures a high level of specificity in the delivery of radiation to the tumour. Before starting treatment with LUTATHERA®, imaging must confirm the presence of these receptors in tumour tissues.
As an example of how the drug is administered, please watch this short video from the European site:
Video courtesy of Advanced Accelerator Applications Please see the following post for a summary of PRRT activity worldwide. Please note this linked article is not designed to contain a list of every single location or country available – please bear that in mind when you read it – CLICK HERE
I’m very grateful to the team at Advanced Accelerator Applications (a Novartis Company) for allowing me to use their site for graphics and videos.
In another ‘theranostic’ development, check out my article on the Satoreotide trial (Ops 201/202) from Ipsen (of Lanreotide fame) – click here to read – the trial is recruiting.
Scanning is a key diagnostic support and surveillance tool for any cancer. Even though you have elevated bloods or urine (….or not), a picture of your insides is really like a thousand words…. and each picture has a story behind it. Scanning can be a game changer in the hunt for tumours and although scans do not normally confirm the cancer type and grade, they certainly help with that piece of detective work and are key in the staging of the cancer.
When I read stories of people in a difficult diagnosis, I always find myself saying ‘a scan might resolve this’ and I always suggest people should try to get one. Even in the case of a story about late diagnosis or a misdiagnosis, I find myself thinking ‘if only they had done a scan earlier’. Despite what you read on NET forums, a CT scan will be able to find some evidence of tumour activity in 90-95% of cases. However, some are cunningly small or hiding and it can be like trying to find a needle in a haystack.
However, scans are not an exact science…..not yet! Apart from human error, sometimes tumours are too small to see and/or there are issues with ‘pickup’ (i.e. with NETs, nuclear scans need efficient somatostatin receptors). The differences between scan types are more quality (sensitivity) related as new technologies are introduced.
As for my own experience, I was very lucky. I managed to get a referral to a specialist early on in my diagnosis phase. He looked at the referral notes and said “what are you doing this afternoon“. I replied “whatever you want me to do“. He didn’t know I had cancer but his instincts led him to believe he needed to see inside my body, he wanted to scan me. The scan results were pretty clear – I had a metastatic Cancer and further checks were now needed to ascertain exactly what it was. So I took my seat on the roller coaster. Medicine is not an exact science (not yet anyway) but here’s something I believe is a very common occurrence in all cancers – If your doctors don’t suspect something, they won’t detect anything.
There’s frequent discussion about the best types of scans for different types of NETs and which is best for different parts of the anatomy. There’s also different views on the subject (including in the medical community), However, a few well known facts can be gleaned from authoritative NET sources:
Conventional Imaging
Computed Topography (CT)
CT scans are often the initial imaging study for a patient presenting with signs or symptoms suggestive of many cancers including NET. These studies are most useful for disease staging and surgical planning as they provide excellent anatomic detail of the tumors themselves and surrounding structures. Primary NETs (GI and lung NETs) and their metastases are generally hyperenhancing with IV contrast and are best seen in the arterial phase of a triple phase CT scan.
In primary NETs, the average sensitivity of a CT scan is 73%. CT scans have even better sensitivity in detecting NET metastases, as they demonstrate 80% sensitivity for liver metastases (but see MRI below) and 75% sensitivity for other metastases (non-liver). This modality is also useful when the primary tumor site is unknown. In one single-institution retrospective study, it was the most common study ordered to look for an unknown primary tumor site and was able to uncover the primary in 95% of cases.
Magnetic resonance imaging (MRI)
MRI is the best conventional study to detail liver metastases in NETs. It is not as useful as CT for the detection of primary small bowel lesions or their associated lymphadenopathy, but is good for the detection of primary pancreatic NETs. A study comparing MRI, CT and standard somatostatin receptor-based imaging (OctreoScan) reported 95.2% sensitivity for MRI, 78.5% sensitivity for CT and 49.3% sensitivity for the OctreoScan in detecting hepatic metastases. MRI also detected significantly more liver lesions than the other two modalities.
You may see something called Magnetic Resonance Cholangiopancreatography (MRCP). Magnetic resonance cholangiopancreatography (MRCP) is a special type of magnetic resonance imaging (MRI) exam that produces detailed images of the hepatobiliary and pancreatic systems, including the liver, gallbladder, bile ducts, pancreas and pancreatic duct.
Ultrasound (US)
The primary role of conventional ultrasound in neuroendocrine disease is detection of liver metastases and estimation of total liver tumor burden. This technique has the advantages of near-universal availability, intraoperative utility, minimal expense and lack of radiation. Most examinations are performed without contrast, which limits their sensitivity (compared with CT and MRI). I know in my own situation, US was used as a quick check following identification of multiple liver metastasis during a CT scan. I’ve also had US used to monitor distant lymph nodes in the neck area but always in conjunction with the most recent CT scan output.
Endoscopic Ultrasound (EUS)
With increased access to endoscopy, NETs in the stomach, duodenum, and rectum are increasingly incidentally detected on upper endoscopy and colonoscopy. Patients are frequently asymptomatic without any symptoms referable to the a NET (i.e. non-functional). EUS has also been used to survey patients at increased risk of developing pancreatic NETs. For example, patients with multiple endocrine neoplasia (MEN). They are also frequently used in conjunction with biopsies using fine needle aspiration (FNA) guided by EUS.
Somatostatin receptor-based imaging techniques
Graphic courtesy of Advanced Accelerator Applications
Somatostatin is an endogenous peptide that is secreted by neuroendocrine cells, activated immune cells and inflammatory cells. It affects its antiproliferative and antisecretory functions by binding to one of five types of somatostatin receptors (SSTR1- SSTR5). These are G-protein coupled receptors and are normally distributed in the brain, pituitary, pancreas, thyroid, spleen, kidney, gastrointestinal tract, vasculature, peripheral nervous system and on immune cells. Expression of SSTRs is highest on well-differentiated NETs. Somatostatin receptor type 2 is the most highly expressed subtype, followed by SSTRs 1 and 5, SSTR3 and SSTR4.
It must be noted that even the most modern scans are not an exact science. Radionuclide scans are like conventional imaging, they can be subject to physiological uptake or false positives, i.e. they can indicate suspicious looking ‘glows’ which mimic tumours. This article explains it better than I can – click here.
The ubiquity of SSTRs on NET cell surfaces makes them ideal targets for treatment (e.g. Somatostatin Analogues (Octreotide/Lanreotide) and PRRT), but also for imaging. There are two primary types of somatostatin receptor-based imaging available:
Octreoscan – In111 based
The most common (currently) is the OctreoScan or Somatostatin Receptor Scintigraphy (SRS), which uses the ligand 111In-DPTA-D-Phe-1-octreotide and binds primarily to SSTR2 and SSTR5. In its original form, it provided a planar, full body image. In modern practice, this image is fused with single photon emission computed tomography (SPECT) and CT. This takes advantage of the specificity of the OctreoScan and the anatomic detail provided by SPECT/CT, improving OctreoScan’s diagnostic accuracy. These improvements have been shown to alter the management in approximately 15% of cases, compared with just OctreoScan images. In primary tumors, the OctreoScan’s sensitivity ranges from 35 to 80%, with its performance for unknown primary tumors dipping beneath the lower end of that range (24%). Its ability to detect the primary is limited by the size but not SSTR2 expression, as tumors less than 2 cm are significantly more likely not to localize but do not have significantly different SSTR2 expression than their larger counterparts.
Octreoscan – Tc99m based
In one study, it was shown that sensitivity and negative predictive
values of Tc-99m-Octreotide scan is significantly higher than that of CT
and MRI. Using Tc-99m instead of In-111 had several advantages that
include better availability, cheaper and higher quality images. In
addition, to less radiation exposure to both patients and nuclear
medicine personnel. In the absence of Ga68 PET, this could prove a reliable alternative. Please note this scan is completed in a single day vs In111 Octreotide time of 2-3 days.
Ga68 PET (or SSTR PET in general)
The newest somatostatin receptor-based imaging modality, although it has been around for some time, particularly in Europe. The most common of these labeled analogs are 68Ga-DOTATOC, 68Ga-DOTANOC and 68Ga-DOTATATE. They may be known collectively as ‘SSTR-PET’. Additionally, the DOTATATE version may often be referred to as NETSPOT in USA but technically that is just the commercial name for the radionuclide mix.
These peptides are easier and cheaper to synthesize than standard octreotide-analog based ligands, boast single time point image acquisition compared to 2 or 3 days with Octreoscan. Its superior spatial resolution derives from the fact that it measures the radiation from two photons coincidentally. SPECT, in comparison, measures the gamma radiation emitted from one photon directly. This results in different limitations of detection – millimeters for 68Ga-PET compared with 1 cm or more for SPECT. There are a few choices of ligands with this type of imaging, but the differences lie primarily in their SSTR affinities – all of the ligands bind with great affinity to SSTR2 and SSTR5. 68Ga-DOTANOC also binds to SSTR3. Despite these differences, no single 68Ga ligand has stood out as the clear choice for use in NETs. As with standard somatostatin receptor-based imaging, these 68Ga-PET studies are fused with CT to improve anatomic localization.
Comparison studies between 68Ga-PET and standard imaging techniques (CT, OctreoScan) have universally demonstrated the superiority of 68Ga-PET in detection of NET primary tumors and metastases. Two early studies compared 68Ga-DOTATOC to standard somatostatin imaging (SRS)-SPECT and CT. Buchmann et al. reported that 68Ga-DOTATOC detected more than 279 NET lesions in 27 patients with histologically proven NETs, whereas SRS-SPECT detected only 157. The greatest number of lesions were detected in the liver. 68Ga-DOTATOC found more than 152 hepatic lesions, while SRS-SPECT found only 105, resulting in a 66% concordance rate between the two modalities. The concordance for abdominal lymph nodes was worse at 40.1%. Cleary these advantages are going to impact on treatment plans, some needing to be altered. In addition, 68Ga-DOTA PET imaging can be used to determine which patients might benefit from use of Somatostatin Analogues (Octreotide/Lanreotide) and PRRT – you can read more about this integrated and potentially personalised treatment in my article on ‘Theranostics‘ – click here.
It’s worth pointing out that SSTR PET is replacing previous types of radionuclide scans, mainly Octreoscan (Indium 111) and is not replacing conventional imaging (CI) such as CT and MRI etc. Whilst SSTR-PET has demonstrated better sensitivity and specificity than CI and In-111, there are specific instances in which SSTR-PET is clearly preferred: at initial diagnosis, when selecting patients for PRRT, and for localization of unknown primaries. For patients in which the tumor is readily seen on CI, SSTR-PET is not needed for routine monitoring. The Journal of Nuclear Medicine has just published “Appropriate Use Criteria for Somatostatin Receptor PETImaging in Neuroendocrine Tumors” which gives guidance on it’s use – issued by the Society of Nuclear Medicine and Molecular Imaging (SNMMI).
Other PET Scans
18FDG PET
18-Fluoro-Deoxy-Glucose PET (FDG PET) is used to detect malignancy for a variety of tumor types. Unfortunately, its utility has not been borne out in NETs, as the majority of NETs tend to be relatively metabolically inactive and fail to take up the tracer well. However, high-grade NETs are more likely to demonstrate avid uptake of 18FDG, giving these scans utility in identifying tumors likely to display more aggressive behavior.
18F-FDOPA PET
The use of Fluoro-18-L-Dihydroxyphenylalanine (18F-FDOPA) in PET was developed in the 80’s for the visualisation of the dopaminergic system in patients with degenerative disorders, such as Parkinson’s Disease and related disorders. The first publication on the use of 18F-FDOPA PET for brain imaging was in 1983, which was followed by many others on the use of 18F-FDOPA PET for the diagnosis of Parkinson’s disease. Years later, in 1999 the first publication on the use of 18F-FDOPA PET for imaging of neuroendocrine tumour appeared. The value of 18F-FDOPA PET has now been proven for the diagnosis and staging of many neuroendocrine tumours, brain tumours and congenital hyperinsulinaemia of infants.
18F-FDOPA is accurate for studying well differentiated tumours. However the difficult and expensive synthesis have limited its clinical employment. It currently can be successfully used for imaging tumours with variable to low expression of somatostatin receptors (SSTR) such as Medullary Thyroid Carcinoma, Neuroblastoma, Pheochromocytoma), and others that cannot be accurately studied with Somatostatin SSTR scans such as the OctreoScan (Somatostatin Receptor Scintigraphy (SRS)), which uses the ligand 111In-DPTA-D-Phe-1-octreotide or the newer 68Ga DOTA-peptides. Read more about the use of 18F-FDOPA in ‘endocrine tumours’ here. Please bear in mind that more recent Ga68 PET studies may supersede some of the data mentioned. If in doubt ask your specialist.
I-MIBG
Radioiodinated (123I) metaiodobenzylguanidine (MIBG) is an analog of norepinephrine that is used to image catecholamine-secreting NETs such as pheochromocytomas, paragangliomas and glomus tumors. It can also be used to look for Neuroblastoma in children. In patients with functional pheochromocytomas or paragangliomas, this modality has a sensitivity of 90% and positive predictive value of 100%. However, it has limited use in Gastrointestinal (GI) NETs, as this modality was positive in only 49.1% of patients. In the same cohort of patients, OctreoScan was positive in 91.2%. As an imaging tool, this study is best used to confirm a diagnosis of pheochromocytoma or paraganglioma and define the extent of metastatic disease in these tumors. (Note – the Ga68 PET is rising in prominence though). Its most practical use in GI NETs may be to determine whether patients with metastases may benefit from treatment with 131I-MIBG (a form of radiotherapy). Please bear in mind that more recent Ga68 PET studies may supersede some of the data mentioned. If in doubt ask your specialist.
Miscellaneous Scans
Parathyroid Scan – Sestamibi
Sestamibi scanning is the preferred way in which to localize diseased parathyroid glands prior to an operation. This parathyroid scan was invented in the early 1990’s and now is widely available. Sestamibi is a small protein which is labeled with the radio-pharmaceutical technetium99 (Tc99m). This very mild and safe radioactive agent is injected into the veins of a patient with hyperparathyroidism (parathyroid disease) and is absorbed by the overactive parathyroid gland. Since normal parathyroid glands are inactive when there is high calcium in the bloodstream, they do not take up the radioactive particles. When a gamma camera is placed over the patient’s neck an accurate picture will show the overactive gland. Only the overactive parathyroid gland shows up…a very accurate test.
The Sestamibi scan will display the hyperactive gland which is causing hyperparathyroidism in about 90 percent (90% sensitivity) of all patients. If the Sestamibi does show the hyperactive gland it is almost always correct (98-100% specificity). It takes approximately two hours to perform the Sestamibi scan after it has been injected. Pictures of the neck and chest are usually taken immediately after the injection and again in 1.75 to 2.0 hours (shown above). Newer techniques allow for more complete two and three dimensional images to be obtained of a patient’s neck. This technique is called SPECT scanning (Single Proton Emission Computerized Tomography) but it is usually not necessary.
Skeletal Scintigraphy (bone scan)
Quite often, bone metastases in NETs will be found via conventional imaging or special to NET nuclear scans such as Ga68 PET or MIBG. However, a bone scan can often find them or confirm findings of scans looking for NETs.
Skeletal scintigraphy is a special type of nuclear medicine procedure that uses small amounts of radioactive material to diagnose and assess the severity of a variety of bone diseases and conditions, including fractures, infection, and cancer.
Nuclear medicine imaging procedures are non-invasive and — with the exception of intravenous injections — usually painless medical tests that help physicians diagnose and evaluate medical conditions. These imaging scans use radioactive materials called radiopharmaceuticals or radiotracers. Radioactive energy emitted from the radiotracer is detected by a special camera or imaging device that produces pictures of the bones called scintigrams. Abnormalities are indicated by areas of abnormal bone that take up more or less of the radiopharmaceutical which appear brighter or darker than normal bone on the scintigram.
Because nuclear medicine procedures are able to image the functions of the body at the molecular level, they offer the potential to identify disease in its earliest stages as well as a patient’s response to therapeutic interventions. In fact, a bone scan can often find bone abnormalities much earlier than a regular x-ray exam.
Taking the camera inside and directly to the Tumour
Of course there are other ways to “see it” via several types of Endoscopy procedures – taking the camera to the tumour. Read my article about this by clicking here
A look to the future of PET Scans
Just imagine something which is 40 times better than current PET scan technology? That’s what the scientists are working on now. Here’s an example called “EXPLORER“. Clearly there are more answers required in order to see if this is suitable for use with NETs (i.e. will it work with our radionuclide tracers etc) but it is very exciting and like something out of Star Trek. A little bit of me is worried about ‘overdiagnosis’ so interpretation of something that detailed will be very important to avoid unnecessary worry. Read more here and there is a later update here. Check out this cool video of the 3D images:
6. Useful video from NET Research Foundation about which scans to use for which job. CLICK HERE to watch.
7. Useful video summary from the NET Patient Foundation describing the different scans for NET Cancer and what to expect. Worth a look. CLICK HERE for the scan video
Sooner we can ALL get access to the latest radionuclide scans the better – this is currently an unmet need in many countries.
If you are any doubt about which type of scan is best for you and their availability, please consult your specialist.
Please Share this post for Neuroendocrine Cancer awareness and to help another patient
Scanning is a key diagnostic and surveillance tool for any cancer. Even though you have elevated bloods or urine (….or not), a picture of your insides is really like a thousand words…. and each picture has a story behind it. Scanning can be a game changer in the hunt for tumours and although scans can’t (yet) confirm the cancer type and grade, they certainly help with that piece of detective work and are key in the staging of the cancer.
When I read stories of people in a difficult diagnosis, I always find myself saying ‘a scan might resolve this’ and I always suggest people should try to get one. Even in the case of a story about late diagnosis or a misdiagnosis, I find myself thinking ‘if only they had done a scan earlier’. Despite what you read on NET forums, a CT scan will normally find some evidence of most tumour activity.
However, scans are not an exact science…..not yet! Apart from human error, sometimes tumours are too small to see and/or there are issues with ‘pickup’ (i.e. with NETs, nuclear scans need efficient somatostatin receptors). However, technology is improving all the time and you can read about this in my blog Neuroendocrine Cancer – Exciting times Ahead.
As for my own experience, I was very lucky. I managed to get a referral to a specialist early on in my diagnosis phase. He looked at the referral notes and said “what are you doing this afternoon”. I replied “whatever you want me to do”. He wanted to scan me. He didn’t know I had cancer but his instincts led him to believe he needed to see inside my body. The scan results were pretty clear – I had a metastatic Cancer and further checks were now needed to ascertain exactly what it was. So I took my seat on the rollercoaster. Here’s something I always say I believe is so much better than the impractical early diagnosis messages that seem to pervade our community: If your doctors don’t suspect something, they won’t detect anything and I believe this is a very frequent outcome of many diagnoses for many cancers (not just NETs).
There’s frequent discussion about the best types of scans for different types of NETs and even for different parts of the anatomy. This is correct and there’s also different views on the subject (including in the medical community), However, a few well known facts that can be gleaned from authortative NET sources. I found this useful video summary from the NET Patient Foundation describing the different scans for NET Cancer and what to expect. Worth a look.
Sooner we can all get access to the latest radionuclide scans the better!
Since my diagnosis, I seem to have been in a perpetual learning phase! What not to do, what not to eat, what not to read! However, early on in my experience, I came across a list of ‘E’ words (5 of them) which is a handy reminder for Carcinoid Syndrome patients, particularly those whose symptoms are not under control. When I say “carcinoid syndrome” in this article, I only mean the syndrome that is caused by what was once called “Carcinoid Tumors”, i.e. mainly serotonin secreting types but include tumours which are well differentiated found in the small intestine, appendiceal, rectal, lung, and one or two other less common places. There are many variations of this list but this is my take! I suspect some of this also applies to other types of NETs and other NET Syndromes.
On analysis of this list, it struck me that I was aware of the issues and their potential effects and I’m certain there is science to substantiate the content. These E’s are apparently the most common ‘triggers’ for Carcinoid Syndrome. Clearly, they are not going to have the same effect on every patient e.g. I have the occasional drink of ‘Ethanol’ and I always enjoy it, I go for long exhausting walks as ‘Exercise’ and I always feel great after. I had dental treatment using ‘Epinephrine’ without any precautions before I was aware of the risks …….. nothing happened! Before I was treated, stressful meetings (‘Emotions’) at work would make me flush though! As for ‘Eating’ – well that’s another couple of blog’s worth! Worth noting that many people without carcinoid syndrome will have reactions to eating but there are specifics that might need some attention in someone with carcinoid syndrome and elevated 5HIAA levels.
The 5 Es are, however, not something to be totally ignored. In extreme scenarios, a severe attack of Carcinoid Syndrome symptoms could be debilitating and life-threatening and I’m fairly certain the list was compiled with this in mind. Some people are more affected by Carcinoid Syndrome and this is not necessarily related to the extent or aggressiveness of their disease. Some people just react differently. An extremely severe attack of Carcinoid Syndrome can also be known as a ‘Carcinoid Crisis’ which is very dangerous, mostly on the operating table due to the effects of anaesthetics – thus why many NET patients may be infused with somatostatin analogues (usually Octreotide) prior to, during, and for a period after surgery or other medical procedures. There’s a lot of excitement generated around the term ‘Carcinoid Crisis’ but it is very uncommon.
I’m not saying the 5 Es should be ignored but NETs are a complex disease and most things need to be read in the correct context. What works for some may not work for others. There can also be confusion surrounding the source of symptoms, i.e. are they syndrome or something else? This is why I believe NET patients need to answer some key questions when considering the risks associated with the 5 E’s:
Are you currently syndromic? If you are, then the 5 ‘E’ list is probably very good advice but interpreting the advice in the correct context remains important.
Are your syndrome related biochemistry results normal (e.g. 5HIAA)? Normal readings (in range) tend to mean the syndrome is under control and many people who were diagnosed with a syndrome may actually be non-syndromic following treatment.
Have you had treatment or are having treatment likely to produce side effects which might be confused with Carcinoid syndrome? For example, surgery can be the long term cause of diarrhea and other issues. Despite the role of somatostatin analogues, these could also be the root cause of certain reactions.
Do you have any other illnesses? If yes, do these other illnesses produce effects similar to carcinoid syndrome? e.g. asthma, diabetes, rosacea, thyroid disorders, vitamin & mineral deficiencies, malabsorption, gut bacterial imbalance. Sorting out the symptoms can be a jigsaw with a missing piece sometimes.
The vagaries of this disease will no doubt throw up some exceptions and additions. There will be patients who have no syndrome but have elevated biochemistry and vice versa. Additionally, there will be patients who have had surgery and/or are being treated with somatostatin analogues but will still be syndromic in varying degrees of severity.
The so-called ‘5 Es’ are as follows:
Epinephrine: This was a new piece of information for me and I only discovered this as a potential problem when I started monitoring some of the USA Facebook forums. This does not appear to be that well-known in UK.
Epinephrine (commonly known as adrenaline) is often used in dentistry mixed with a local anaesthetic. I won’t risk this, so I’ve instructed my Dentist to place a note on my record asking for epinephrine not be used (and clearly I’ll remind them each visit!). According to NET guru Dr Woltering, plain novocaine, carbocaine or plain marcaine are preferred. According to a dental source on my site (also a patient):
“4% Citanest Plain Dental (Prilocaine Hyrocholride Injection) is also safe and Epinephrine Free. It isn’t as profound of a numbness and may need reapplying during a procedure. It is the common alternative here in the USA.
4% Articaine without Epinephrine is also available and is known to work better on Mandibular Blocks. Again this is commonly used in the USA. It’s important to know what to ask for, not just ‘Epinephrine free’. Bring this up at your dental exam appointment, so that they will be sure to have it in stock. If you are unfamiliar with the office, schedule your appointment after they confirm that the proper local is in stock. Never use the term Novacaine as the generic term for dental anesthetic, this hasn’t been used in the USA for decades. Allergic reactions to Novacaine were too common. Lidocaine and Septocaine are the drug of choice. However, Lidocaine will always have Epinephrine. Where as, Septocaine (articaine) has versions with Ephedrine and without”.
Always check that your anaesthetist for any procedure you may be undergoing is aware of your carcinoid syndrome.
However, the danger is not just with dentistry work. Any anaesthesia is risky. Check out my post ‘carcinoid crisis’.
For those who have standby ‘Epi Pens’, I did read the following statement on the Carcinoid Cancer Foundation website: “ …….. one exception is the administration of epinephrine in the case of an allergic anaphylactic reaction (i.e. a bee sting), so it cannot be avoided in this case, just make sure that Octreotide (Sandostatin) is also available“. This advice is also extremely relevant to Pheochromocytoma and Paraganglioma patients who may be a high risk of “intraoperative hypertensive crisis”.
Eating: This is very individual. Certain foods or large meals can be difficult, particularly if you have had any gastrointestinal surgeries. I keep a personal diary trying to identify things that upset my system. I try to find some balance between what I know is good for me and also what I know I enjoy. For example, I found that very large meals do not agree with my ‘new plumbing’. If I eat a lot of sweets, I’ll also suffer …..so I just eat a little – check out my article Chocolate – The NET Effect.
Personally speaking, I’m fairly certain the vast majority of my issues are related to my treatment (past and present) rather than being provoked by Carcinoid Syndrome, i.e. if I rush to the toilet after a meal, it’s not syndrome, it’s a reaction of my compromised digestive system. So with this in mind, I try to reduce those things but additionally strike a balance between quality of life and excessive and rigid adherence to some of the guidance out there (see below) – as I said above, interpretation and context is important. My compromised system cannot deal with big meals so I ‘graze’ most of the day and then eat a small to medium-sized meal in the evening. I’ve been doing this since 2014 and reduced my visits by 300% without any special or expensive medication.
In my blog Nutrition Blog 4 – Food for Thought, I’ve linked to authoritative sources on potential diet triggers. I’m not suggesting you cut out all of the foods on these lists (you won’t last long!). Some can indulge in those foods and some cannot. For example, chocolate and caffeine (tea/coffee) are on the lists but I eat/drink those frequently (in moderation) and have no problem. It’s a case of testing things out. I like to describe my eating as ‘The Risk Management of my Quality of Life’. By the way, no-one is suggesting that a NET patient with carcinoid syndrome (and don’t forget this is only one syndrome of many with NETs) should stop eating foods high in the offending amines or are precursors to serotonin (e.g. tryptophan). They do not make tumours grow (a myth) but just make sure you adhere to the dietary restrictions for any 5HIAA test.
Emotions: Stressful situations can cause symptoms to flare up. While it is difficult to avoid all stress (work, home, commuting, etc), it is helpful if you can manage or reduce it. Like eating, this is a very individual area. From personal experience, I know stress can exacerbate carcinoid syndrome. Before I started my treatment, I was regularly flushing in meetings at work (….. think boxing matches!). After my treatment, stress was definitely a factor causing increased bowel motility. I’ve removed a lot of stress from my life and it helps. You may need to be ruthless in managing this aspect of your illness.
Exercise: Exercise is extremely important for overall health and well-being and I know quite a lot of NET Cancer patients who exercise regularly without issues. It can, however, trigger carcinoid syndrome if you overdo it – it is, however, like eating, a very individual thing. I take the view that ‘zero’ exercise might potentially be an even higher risk. Even a walk around the garden or gardening is exercise. When I was at work, I would walk to see people rather than phone them. Sometimes I walk to town rather than drive, it all adds up! I have evidence from my own exercising regime proving in my case that exercise can reduce the knock-on effects of some of the other E’s (emotions and eating) and/or the side effects of treatment – check out my blog entitled Exercise is Medicine. Those who are syndromic and/or have other conditions to manage are probably best to take medical advice on how much exercise they need to do.
Ethanol (alcohol, liquor):Many NET patients have difficulty tolerating wine, beer and spirits (hard liquor). I was never a big drinker so for me it was easy to go almost teetotal. I do have the occasional beer but very infrequently and normally on holiday – I personally don’t get any issues with the odd beer but again this is trial and error. I really enjoy my beer when I celebrate my ‘Cancerversaries‘. Also check out my blog Alcohol – the NET Effect
Summary
I’m sure there could be a 5 A’s to 5 Z’s list of things to avoid but as I said above, this needs to be balanced with what the actual risks for you are and if you’re like me, quality of life. If you read most Facebook closed group or forums, you will always find at least one person is affected by something which affects no-one else. Please note this article is just my own appreciation of these issues and I emphasise once again that everyone has different experiences. I do, however, think it’s important to consider any secondary illnesses, effects of surgery and biochemistry results (or indeed a combination of one or more of these factors). Everything in life involves some kind of risk management and if you are totally risk averse, then you are unlikely to have much of a life (or a diet!).
It’s not easy but my daily diary helps me assess trends and work out what things upset me more than others – I can then reduce or eliminate. You need to tailor your own advice perhaps with the help of a doctor and/or dietician versed in NET Cancer. I also have some related posts on the subject of vitamin and mineral deficiencies, malabsorption and probiotics – check them out as the problems associated with these subjects could potentially look like a worsening of carcinoid syndrome and lead to unnecessary worry and unnecessary treatment.
For most, Carcinoid Syndrome can normally be controlled by the use of debulking surgery and/or somatostatin analogues (Octreotide/Lanreotide). However, there is a new drug called ‘Teloristat Ethyl’ (XERMELO) which looks like it may provide supplementary treatment for patients whose carcinoid syndrome diarrhea is not adequately controlled by somatostatin analogues. It’s an expensive drug and comes with side effects so you need to be sure it’s your syndrome causing the problem before you commit to a prescription.
We all know that Neuroendocrine Tumours (NETs) and their syndromes are complex but there is even more complexity to be found in a group of related disorders known as Multiple Endocrine Neoplasia (MEN). I recommend all NET patients should try to understand the basics of MEN and vice versa, particularly as both conditions seem to come with a plethora of endocrine related effects.
Overview
MEN patients will normally have a tumour in at least two endocrine glands – thus the terms ‘Multiple’ and ‘Endocrine’ (tumours can also develop in other organs and tissues). Neoplasia is just another name for tumour and these can be non-cancerous (benign) or cancerous (malignant) with the potential to metastasize.
MEN syndromes can comprise varying combinations of tumours and many will be aware of the tumour risks from family knowledge. So putting the heredity aspects to one side, it’s potentially an extremely challenging surveillance and subsequent diagnostic scenario if (and when) these risks are realised. To add to the complexity, some of the associated tumours can be sporadic (non hereditary) classic Neuroendocrine Tumours in various locations.
MEN Types
MEN is actually an umbrella term for a number of types (syndromes) of the disease – MEN1, MEN2a and 2b (2b was formerly MEN3). There’s a new kid on the block called MEN4 which is extremely rare.
In the most basic of terms regarding the relationship with tumours:
MEN1 seems to be centred on tumours of the parathyroid glands, the pituitary gland, and the pancreas (the 3 P’s).
MEN2a mainly focuses on medullary thyroid carcinoma, pheochromocytoma, parathyroid hyperplasia or adenomas (causing hyperparathyroidism), and occasionally cutaneous lichen amyloidosis.
MEN2b medullary thyroid carcinoma, pheochromocytoma, multiple mucosal neuromas and intestinal ganglioneuromas, and often a marfanoid habitus and other skeletal abnormalities.
MEN4 – A relatively new MEN variant and related to the CDKN1B gene, similar to MEN1 but normally only 2 of the 3 Ps, parathyroid and pituitary. Also referred to as MENX Possible association with tumors of the adrenals, kidneys, and reproductive organs.
What is particularly distinctive with MEN is that they are inherited disorders (familial). That means that they can be passed down in families, with each child of an affected parent having a 1 in 2 or 50% risk of inheritance. Consequently genetic screening/testing is normally undertaken in established MEN families and those at risk of MEN.
Associated Issues
You may also have heard of other rare NETs with a familial aspect, in particular Pheochromocytomas (adrenal gland tumours) and Paragangliomas (outside the adrenal gland), Not all are inherited and I mention them because of the connection with MEN2a and 2b.
I’m grateful to my friend and MEN patient Linda Hageman for supporting my blog activities and also for allowing me to join the AMEN support group to learn more. This is one of the friendliest and well run support groups I’ve seen. On this site, you will find Dr Mark Lewis, an Oncologist and MEN patient who supports Linda (who is a Nurse) with a ‘Ask the Doctor’ section on their website.
There are other organisations including one specifically for Pheochromocytomasand I’m grateful to Jennifer Shepard for featuring my nutrition blog series.
One of the curious things about Neuroendocrine Cancer (NETs going forward) is that it can very often exhibit one or more vague symptoms collectively known as a ‘syndrome’. Syndrome is an apt word to describe these complications as the most general meaning in medical terms is a group of symptoms that together are characteristic of a specific disorder or disease”. Having a syndrome can often be the difference between having a ‘functional’ condition or a non-functional’ condition – see more below.
This frequently makes Neuroendocrine Cancer very difficult to diagnose quickly. It’s a very devious disease.
It’s not all about Carcinoid Syndrome!
Most people think of Carcinoid Syndrome when they discuss NETs. Anyone suggesting that all NET patients get carcinoid syndrome or that all symptoms of NETs are caused by carcinoid syndrome, is WAY off the mark. Firstly, not everyone will have a ‘syndrome’ in addition to their tumours – the percentage is actually well below 50%. Secondly, there are in actual fact, several associated syndromes depending on the anatomical location and type of NET. As an example of one syndrome, statistics vary from source to source but it is estimated that around a 30-45% of all ‘midgut’ patients will present with metastatic disease and around a third of those (∼10-15% of all midgut) will exhibit Carcinoid Syndrome indicating their tumours are ‘functional’ (secreting excess hormones, particularly serotonin). It follows that Carcinoid Syndrome itself is not that common and it could be the same with other types of NET (even though it can appear more prevalent on forums).
Diagnostic Challenges in NETs (this graphic only covers so-called Carcinoid Syndrome). Inner segments are the key symptoms, outer segments are some of the potential misdiagnosis/delayed diagnosis. Graphic courtesy of Modlin IM, Kidd M, Latich I, et al. Current status of gastrointestinal carcinoids. Gastroenterology 2005; 128: 1717-1751
Functional / Non-Functional
These tumours and associated syndromes are treatable for most but the difficult part can be arriving at a diagnosis. Moreover, without a syndrome, some of these tumours can be silently growing and as they grow slowly, the ‘silence’ can go on for some years. Even with a syndrome, the root cause can remain disguised as the symptoms are similar to many day-to-day illnesses, again the reason for the title of this blog. Curiously, the lack of a syndrome can sometimes lead to an even later presentation and the consequences that arise (i.e. no signs to aid a diagnosis). In fact a large proportion of Pancreatic NETs are non-functional at diagnosis. There can be the odd exception but in general terms, NETs are either functional (with a syndrome) or non-functional (no syndrome). It’s also possible that patients can move from one state to another.
It’s useful to know about the range of tumor markers and hormone markers – read more here
Syndrome and Tumors – ‘Chicken or Egg’ ?
I’m always confused when someone says they have been diagnosed with a Syndrome rather than a NET type. You normally need a tumor to produce the symptoms of a syndrome.
The exception might be hereditary syndromes e.g. MEN. MEN syndromes are genetic conditions. This means that the cancer risk and other features of MEN can be passed from generation to generation in a family. A mutation (alteration) in the various MEN genes gives a person an increased risk of developing endocrine/neuroendocrine tumors and other symptoms of MEN. It’s also possible that the tumors will be discovered first. It’s complex!
Major NET Syndromes
(information mainly taken from the ISI Book on NETs with a cross-reference from ENETS and UKINETS Guidelines)
TheISI Book on Neuroendocrine Tumors 2016(Woltering et al) confirms there are a number of syndromes associated directly and indirectly with NETs and are described as individual syndromes according to their secretory hormones and peptides. The reference publication expands on this list to aid diagnoses by including common presentations, associated tumour types and locations and the offending secreting hormones. You can see why Neuroendocrine Cancer is a diagnostic challenge!
Carcinoid – a syndrome connected with (mainly) serotonin secreting tumours in certain locations (mainly small intestine, lung, stomach, appendix, rectum). The key symptoms include diarrhoea, flushing of the skin (particularly the face), stomach cramping, heart problems such as palpitations, and wheezing. The syndrome is actually caused by the release of a number of hormones, in particular Serotonin, Bradykinin, Tachykinin (Substance P), Histamine, and Prostaglandins.
(there’s also a very rare instance of pancreatic based tumours producing carcinoid syndrome effects – according to ENETs less than 1% of all tumours associated with carcinoid syndrome)
Whipple’s Triad – Whipple’s Triad is the classic description of insulinoma which includes symptoms of hypoglycemia with a low blood glucose concentration relieved by the ingestion of glucose. These tumours can be located anywhere within the pancreas in the 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. Some of these tumours will be associated with MEN1 syndrome.
Zollinger-Ellinson Syndrome. A tumour that forms in cells that make gastrin and can be known as a Gastrinoma. 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. This is a condition in which one or more tumours form in the pancreas, the upper part of the duodenum or the stomach (these organs are very close and tightly packed together). These tumours secrete large amounts of the hormone gastrin, which causes your stomach to produce too much acid. The excess acid can lead to peptic ulcers, in addition to diarrhea and other symptoms. Associated with Gastrinoma (pNET) and Gastric NETs. Some of these tumours may be associated with MEN1 syndrome.
Werner-Morrison Syndrome. Vasoactive Intestinal Peptide (VIP) is secreted thus the pNET term – VIPoma – Sometimes the syndrome is referred as WDHA – Watery Diarrhea, Hypokalemia (potassium deficiency), and Achlorhydria (absence of hydrochloric acid in gastric secretions). Sometimes known as Pancreatic Cholera. Some of these tumours may be associated with MEN1 syndrome
Glucagonoma. A tumour that forms in cells that make 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) rendering most patients diabetic. A glucagonoma usually forms in the tail of the pancreas. Some of these tumours may be associated with MEN1 syndrome. See also Sweet’s Syndrome below. Sometimes known as the 4D syndrome – Dermatological, Diabetes, DVT, Depression.
Somatostatinomais a very rare type of NET, with an incidence of one in 40 million persons. These tumours produce excess somatostatin arise from the delta cells in the pancreas, although these cells can also be present in duodenal/jejunum tissue where around 44% of these tumours occur. Somatostatin is a naturally occurring peptide that inhibits the function of almost all gut hormones (author’s note – this fact should give you an appreciation of how somatostatin analogues tackle associated syndromes whilst giving you certain side effects as a result!)
Pancreatic Polypeptide (PP) – PPoma. A complicated one and not too much information (even in the ISI book or ENETS Guidelines). However, it’s the third most common type of islet cell tumour (i.e. pNET). The function of pancreatic polypeptide is not completely understood. Patients present with weight loss, jaundice, and abdominal pain. The diagnosis is confirmed by pancreatic polypeptide levels > 300 pg/ml. Some of these tumours may be associated with MEN1 syndrome.
Hedinger Syndrome – the technical name for Carcinoid Heart Disease and an ideal replacement term now that Carcinoid is being phased out.
Cushing’s – also known as hypercortisolism. A collection of symptoms caused by very high levels of a hormone called cortisol in the body. In Cushing’s disease, oversecretion of pituitary ACTH induces bilateral adrenal hyperplasia. This results in excess production of cortisol, adrenal androgens, and 11-deoxycorticosterone. Cushing’s disease, a subset of Cushing’s syndrome, is due to a pituitary corticotroph adenoma and results in a partial resistance to the suppression of ACTH by cortisol so that secretion is unrestrained. In contrast, causes of Cushing’s syndrome may include the following:
• Adrenal adenoma or carcinoma arise spontaneously. ACTH levels are undetectable.
• Non-pituitary (ectopic) tumours produce ACTH. They most frequently originate in the thorax and are highly aggressive small cell carcinomas of the lung or slow- growing bronchial or thymic carcinoid tumours. Some produce corticotropin- releasing hormone (CRH) instead, which stimulates pituitary ACTH secretion and can therefore mimic a pituitary tumour.
• Other causes include NETs of the gastric, pancreatic, and intestinal organs; Pheochromocytomas, and MCT.
The hallmark of Cushing’s syndrome is that ACTH levels are partially resistant to suppression with dexamethasone, even at very high doses. Some MEN patients with pituitary tumours may have Cushing’s Syndrome. AdrenoCorticoTropic Hormone (ACTH) releasing tumours are somerimes known as ACTHoma.
Sweet’s – Dermatitis/rash associated with Glucagonomas. Not to be confused with Pellagra (B3 deficiency)
Neuroendocrine / Endocrine tumors can be seen in several inherited familial syndromes, including but not limited to:
MEN1 – Mainly involved the 3 Ps, Pituitary, Pancreas and Parathyroid. The pituitary tumours are primarily Prolactinomas, the pancreatic tumours are mainly PPomas, Gastrinomas and Insulinoma. Many also have association with Zollinger-Ellinson syndrome (ZES). Sometimes known as Wermer Syndrome. Associated with the MEN1 gene.
MEN2A– associated with the RET gene, can result in Medullary Thyroid Carcinoma, Pheochromocytoma, and overactive parathyroid glands characterised by a high calcium level.
MEN2B. An inherited disorder characterised by the certain development of Medullary Thyroid Carcinoma, plus the possible development of pheochromocytomas and characteristic tumours (mucosal neuromas) of the lips, tongue and bowels. Parathyroid disease is extremely rare in MEN2B. Also connected with the RET gene.
MEN4. A relatively new MEN variant and related to the CDKN1B gene. Similar to MEN1 but normally only 2 of the 3 Ps, parathyroid and pituitary; and potentially other places.
Succinate dehydrogenase (SDH) is an enzyme which is important for the metabolic function of mitochondria. Patients with mutations of these genes have increased risk of pheochromocytomas, paragangliomas, stomach tumors and kidney tumors.
SDHx mutations (SDHA, SDHB, SDHC, and SDHD) can present as Pheochromocytomas/Paragangliomas and other non-NET conditions. If this interests you see site http://www.SDHcancer.org
Von Hippel-Lindau (VHL) – not an exclusively NET syndrome. VHL is a rare disorder caused by a faulty gene. It is named after the two doctors who first described the disease, and affects about one in 35,000 people. Tumours develop in one or more parts of the body. Many of these tumours involve the abnormal growth of blood vessels in parts of the body which are particularly rich in blood vessels. Areas most frequently affected are the eyes, the back of the brain (cerebellum), the spinal cord, the kidneys, the adrenal glands and the pancreas. People are affected differently, even within the same family. The only VHL tumour which tends to run in families affects the adrenal glands (Pheochromocytoma). Different VHL features tend to develop at different ages. The eye angiomas often develop in childhood. Others, including tumours found in the cerebellum, spinal cord or adrenal glands (Haemangioblastomas and Pheochromocytomas) can develop from late childhood onwards. The kidney tumours are usually the last things that develop, from the mid-twenties onwards. Most VHL related tumours are benign.
Summary
As for my own experience of syndromes, I did once show symptoms of the most common NET syndrome (currently known as Carcinoid syndrome) where the key symptoms include diarrhoea, flushing of the skin (particularly the face), stomach cramping, heart problems such as palpitations, and wheezing. You can see why those symptoms are frequently and easily confused with other conditions. If you have a similar diagnosis, you may benefit from looking at something known as The 5 E’swhich is a useful list of things to be wary of.
I did have issues for a year or two in 2010 leading up to diagnosis and until my treatment was underway. I was experiencing flushing and infrequent bouts of diarrhea but I totally ignored it (hear me talk about this). However, it ended up being instrumental in my diagnosis albeit some good luck was involved in getting to that point. My twist of fate which involved a low hemoglobin score led me to a scan and ‘bingo’. I had a ‘gastrointestinal blip’ some 18 months previously but that proved colonoscopy negative. Despite my distant and metastatic tumour disposition and seemingly late diagnosis, I’m current non-syndromic due to “early” intervention and good treatment. However, my ongoing treatment continues to play its part.
For many,the vague and routine symptoms generated by a syndrome contribute to the fact that NET Cancer is frequently misdiagnosed with some people suffering from the side effects for many years before a correct diagnosis is made.
There are many other less known syndromes that appear to be directly or indirectly connected with Neuroendocrine Tumours and I may update this post if I discover they are more prevalent than I think. Please let me know if you’ve been told you have a NET related syndrome not listed.
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
Serotonin
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.
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 partly 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 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:
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 pancreatic 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 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.
