We’ve all heard the age-old question about the chicken and the egg? Scientists claimed to have ‘cracked’ the riddle of whether the chicken or the egg came first. The answer, they say, is the chicken. Researchers found that the formation of egg shells relies on a protein found only in a chicken’s ovaries. Therefore, an egg can exist only if it has been inside a chicken. There you have it!
On a similar subject, I’m often confused when someone says they have been diagnosed with ‘Carcinoid Syndrome’and not one of associated ‘Neuroendocrine Tumours’. So which comes first? I guess it’s the way you look at it. In terms of presentation, the syndrome might look like it comes first, particularly in cases of metastatic/advanced disease or other complex scenarios. Alternatively, a tumour may be found in an asymptomatic patient, quite often incidentally. However, on the basis that the widely accepted definition of Neuroendocrine Tumours would indicate that a syndrome is secondary to tumour growth, then the tumour must be the chicken.
I sometimes wonder what patients are told by their physicians….. or perhaps by their insurance companies (more on the latter below). That said, I did see some anecdotal evidence about one person who was diagnosed with Carcinoid Syndrome despite the lack of any evidence of tumours or their markers. This might just be a case of providing a clinical diagnosis in order to justify somatostatin analogue treatment but it does seem unusual given that scientifically speaking, Carcinoid Syndrome can only be caused by a particular type of NET.
I have a little bit of experience with this confusion and it still annoys me today. Shortly after my diagnosis, I had to fill out an online form for my health insurance. The drop down menu did not have an entry for Neuroendocrine ‘anything’ but I spotted Carcinoid only to find it was actually Carcinoid Syndrome. By this stage I had passed the first level of NET knowledge and was therefore suspicious of the insurance company list. I called them and they said it was a recognised condition and I should not worry. Whilst that statement might be correct, I did tell them it was not a cancer per se but an accompanying syndrome caused by the cancer. I added that I was concerned about my eligibility for cancer cover treatment and didn’t want to put an incorrect statement on the online form. However, they persisted and assured me it would be fine on that selection. On the basis it was really the only option I could select, I selected and submitted. I did get my cover sorted. However, it’s now clear to me that their database was totally out of date. A similar thing happened when I was prescribed Octreotide and then Lanreotide, the only ‘treatment type’ they could find on their database was ‘chemotherapy‘ – again their system was out of date. I’m told by someone in the know, that individual insurance companies are not responsible for this list, they all get it from a central place – I’d love to pay that central place a visit!
I quickly thought about all the other NET Syndromes for their ‘chicken and egg’ status! Pancreatic NET (pNET) Syndromes must all be ‘chicken’ given the tumour definition and the secretion of the offending hormones that cause these other syndromes e.g. Insulin, Gastrin, Glucagon, Pancreatic Polypeptide (PP), Vasoactive Intestinal Peptide (VIP) and Somatostatin, etc.
All of that said, the exception might be hereditary syndromes e.g. MEN (yes it is a syndrome, not a tumor type). 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 as you will see in my article entitled “Genetics and Neuroendocrine Tumors”.
One of the most controversial aspects of Neuroendocrine Tumours (NETs) is the ‘benign vs malignant’ question. It’s been widely debated and it frequently patrols the various patient forums and other social media platforms. It raises emotions and it triggers many responses ….. at least from those willing to engage in the conversation. At best, this issue can cause confusion, at worst, it might contradict what new patients have been told by their physicians (….or not been told). I don’t believe it’s an exact science and can be challenging for a NET specialist let alone a doctor who is not familiar with the disease.
NANETS Guidance talks about the ‘…heterogeneous clinical presentations and varying degrees of aggressiveness‘ and ‘…there are many aspects to the treatment of neuroendocrine tumours that remain unclear and controversial‘. I’m sure the ‘benign vs malignant’ issue plays a part in these statements.
In another example, ENETS Guidance discusses (e.g.) Small Intestine Tumours (Si-NETs) stating that they ‘derive from serotonin-producing enterochromaffin cells. The biology of these tumors is different from other NENs of the digestive tract, characterized by a low proliferation rate [the vast majority are grade 1 (G1) and G2], they are often indolent’. However, they then go on to say that ‘Si-NETs are often discovered at an advanced disease stage – regional disease (36%) and distant metastasis (48%) are present‘. It follows that the term ‘indolent‘ does not mean they are not dangerous and can be ignored and written off as ‘benign’. This presents a huge challenge to physicians when deciding whether to cut or not to cut.
To fully understand this issue, I studied some basic (but very widely accepted) definitions of cancer. I also need to bring the ‘C’ word into the equation (Carcinoid), because the history of these tumours is frequently where a lot of the confusion lies. The use of the out of date term ‘Carcinoid’ exacerbates the issue given that it decodes to ‘carcinoma like‘ which infers it is not a proper cancer. See more below.
Let’s look at these definitions provided by the National Cancer Institute. Please note I could have selected a number of organisations but in general, they all tend to agree with these definitions give or take a few words. These definitions help with understanding as there can be an associated ‘tumour’ vs ‘cancer’ debate too.
Cancer – Cancer is the name given to a collection of related diseases. In all types of cancer, some of the body’s cells begin to divide without stopping and spread into surrounding tissues. There are more than 100 types of cancer which are usually named for the organs or tissues where the cancers form. However, they also may be described by the type of cell that formed them.
Author’s note: The last sentence is important for Neuroendocrine Tumour awareness (i.e. Neuroendocrine Tumour of the Pancreas rather than Pancreatic Cancer).
Carcinoma – Carcinomas are the most common grouping of cancer types. They are formed by epithelial cells, which are the cells that cover the inside and outside surfaces of the body. There are many types of epithelial cells, which often have a column-like shape when viewed under a microscope.
Author’s note: By definition, Carcinomas are malignant, i.e. they are cancers. High Grade (Grade 3) poorly differentiated “NETs” are deemed to be a ‘Carcinoma’ according to the most recent World Health Organisation (WHO) classification of Neuroendocrine Tumours (2017) and ENETS 2016 Guidance. You will have heard of some of the types of Carcinoma such as ‘Adenocarcinoma’ (incidentally, the term ‘Adeno’ simply means ‘gland’). It follows that Grade 3 Neuroendocrine Carcinomas are beyond the scope of this discussion.
Malignant – Cancerous. Malignant cells can invade and destroy nearby tissue and spread to other parts of the body.
Benign – Not cancerous. Benign tumors may grow larger but do not spread to other parts of the body.
Author’s Note: This is a key definition because there are people out there who think that low grade NETs are not cancer.
Tumour (Tumor) – An abnormal mass of tissue that results when cells divide more than they should or do not die when they should. Tumors may be benign (not cancerous), or malignant (cancerous). Also called Neoplasm.
Author’s Note: Neoplasm is an interesting term as this is what is frequently used by ENETS and NANETS in their technical documentation, sometimes to cover all Neuroendocrine types of cancer (Tumor and Carcinoma). It follows that a malignant tumour is Cancer. The term “Malignant Neuroendocrine Tumour” is the same as saying “Neuroendocrine Cancer”
Neuroendocrine Tumours – Benign or Malignant?
Definitions out of the way, I have studied the ENETS, UKINETS and NANETS guidance both of which are based on internationally recognised classification schemes (i.e. the World Health Organisation (WHO)).
In older versions of the WHO classification schemes (1980 and 2000), the words ‘benign’ and ‘uncertain behaviour’ were used for Grades 1 and 2. However, the 2010 edition, the classification is fundamentally different (as is the recent 2017 publication). Firstly, it separated out grade and stage for the first time (stage would now be covered by internationally accepted staging systems such as TNM – Tumour, (Lymph) Nodes, Metastasis). Additionally, and this is key to the benign vs malignant discussion, the WHO 2010 classification is based on the concept that all NETs have malignant potential. Here’s a quote from the UKINETS 2011 Guidelines (Ramage, Caplin, Meyer, Grossman, et al).
Tumours should be classified according to the WHO 2010 classification (Bosman FT, Carneiro F, Hruban RH, et al. WHO Classification of Tumours of the Digestive System. Lyon: IARC, 2010). This classification is fundamentally different from the WHO 2000 classification scheme, as it no longer combines stage related information with the two-tiered system of well and poorly differentiated NETs. The WHO 2010 classification is based on the concept that all NETs have malignant potential, and has therefore abandoned the division into benign and malignant NETs and tumours of uncertain malignant potential.
The guidance in 2017 WHO reinforces this statement to include endocrine organs, including the pancreas and adrenal glands.
History lesson – Carcinoid tumours were first identified as a specific, distinct type of growth in the mid-1800’s, and the name “karzinoide” was first applied in 1907 by German pathlogist Siegfried Oberndorfer in Europe in an attempt to designate these tumors as midway between carcinomas (cancers) and adenomas (benign tumors).
The word ‘Carcinoid’ originates from the term ‘Carcinoma-like’. ‘CARCIN’ is a truncation of Carcinoma. ‘OID’ is a suffix used in medical parlance meaning ‘resembling’ or ‘like’. This is why many people think that Carcinoid is not a proper cancer.
The situation is made even more confusing by those who use the term “Carcinoid and Neuroendocrine Tumors” inferring that it is a separate disease from the widely accepted and correct term ‘Neuroendocrine Tumor’ or Neuroendocrine Neoplasm. A separate discussion on this subject can be found in this post here. I encourage you to stop using the term ‘Carcinoid’ which is just perpetuating the problem.
How are NETs Classified?
If you read any NET support website it will normally begin by stating that Neuroendocrine Tumours constitute a heterogeneous group of tumours. This means they are a wide-ranging group of different types of tumours. However, the latest WHO classification scheme uses the terms ‘Neuroendocrine Tumour’ for well differentiated Grade 1 (low-grade), Grade 2 (Intermediate Grade) and Grade 3 (High Grade) NET; and ‘Neuroendocrine Carcinoma’ for Grade 3 (High Grade) poorly differentiated tumours. They also use the term ‘Neoplasm’ to encompass all types of NET and NEC. So Grade 1 is a low-grade malignancy and so on (i.e any grade of NET is a malignant tumour). You may benefit from reading my blog article on Staging and Grading of NETs as this is also a poorly understood area.
Can some Tumours be Benign?
By any accepted definition of cancer terms, a tumour can be non-cancerous (benign) or cancerous (malignant). This is correct for any cancer type. For example, the word is used in the 2016 version of Inter Science Institute publication on Neuroendocrine Tumors, a document I frequently reference in my blog. For example, I’ve seen statements such as “These tumors are most commonly benign (90%)” in relation to Insulinoma (a type of Pancreatic NET or pNET). Ditto for Pheochromocytoma (an adrenal gland NET). Adrenal and Pituitary ‘adenomas’ are by definition benign (adenoma is the benign version of Adenocarcinoma). And I note that there is a ‘benign’ code option for every single NET listed in the WHO International Classification of Diseases (ICD) system.
The ‘BUT’ is this – all WHO classification systems are based on the concept that all NETs have malignant potential. The WHO 2017 classification update confirmed this thinking by adding endocrine organs including the pancreas and adrenal glands.
Can Tumours be Malignant or become Malignant?
Using the definition above, if a tumour invades and destroy nearby tissue and spread to other parts of the body, then it’s malignant (i.e Cancer). However, there’s a reason why the WHO declared in 2010 that all NETs have malignant potential (as amplified in WHO 2017). It may not happen or it may happen slowly over time but as Dr Richard Warner says, “they don’t all fulfill their malignant potential, but they all have that possible outcome”. Thus why ongoing surveillance is important after any diagnosis of Neuroendocrine Tumour of any grade or at any stage. Dr Lowell Anthony, a NET Specialist from the University of Kentucky explains this much better than I can – CLICK HEREto hear his two-minute video clip.
This was a difficult piece of research. I do believe there are scenarios where NETs will be benign and probably never cause the person any real harm (e.g. many are found on autopsies). I suspect this is the same for many cancers. However, based on the above text and the stories of people who have presented for a second time but with metastatic disease, use of the word ‘benign’ is probably best used with great care.
I would certainly (at least) raise an eyebrow if someone said to anyone with any NET tumour, “you don’t need any treatment or surveillance for a NET”; or “it has been cured and no further treatment or surveillance is required”. Particularly if they are not a NET specialist or a recognised NET Centre.
Just a note to say Happy Thanksgiving to my friends in USA or who may be celebrating it elsewhere. I am so thankful for the support I get from the US who make up the biggest proportion of subscribers to my blog and associated Facebook page. So I’m thinking of y’all today!
Now …….. I hate to stereotype but I guess a lot of you might be eating turkey today? No Thanksgiving is complete without a turkey at the table (… so I’m told!). And also a nap right after it’s eaten….. right?
As you know I like to analyse such things …… Apparently, the meat has a bad reputation for making eaters sleepy, but is there really science to back that up? My google alerts feed increases around this time of the year due to the connection of turkey with the word ‘serotonin’. So for me, this is very educational. Those who read my blog article on the ‘S’ word may remember that tryptophan is one of the bodies amino acids and is partly responsible for the manufacture of Serotonin in our system. Turkey is said to be high in tryptophan although most say it is no higher than many other meats. I’ve also heard the stories about how eating too much turkey makes you sleepy. Melatonin is said to be the hormone which helps with sleep regulation and is manufactured from Serotonin (which is manufactured from tryptophan). However, the articles I read, (one was from the New York Times and one from Time Magazine) both confirm this is not exactly correct with one describing the turkey/sleepy connection as a “common myth” mainly due to the other food and drink consumed at the same time as the turkey In any case, what’s wrong with an afternoon or evening nap after a traditional meal?
For those worried about eating too much tryptophan, don’t be, all NET nutritionists say you should not be concerned about this and the only food restrictions that apply are right before the 5HIAA test as directed by your local specialist.
Actually I read that turkey is a really healthy meat to eat, it’s low in fat, full of protein and other nutrients including the important B vitamins that NET patients might be at risk of deficiency (B3 and B12). Note to self …… eat more turkey!
Enjoy your Thanksgiving! It’s OK to have a nap too ……
On a personal note, I’m also very thankful to still be here after 8 years!
I’m continually seeing certain drugs for treatment of Neuroendocrine Tumours (NETs) described as chemotherapy. I think there must be some confusion with more modern drugs which are more targeted and work in a different way to Chemotherapy.
I researched several sites and they all tend to provide a summary of chemotherapy which is worded like this: Chemotherapy means:
a treatment of cancer by using anti-cancer medicines called cytotoxic drugs. Cytotoxic medicines are poisonous (toxic) to cancer cells. They kill cancer cells or stop them from multiplying. Different cytotoxic medicines do this in different ways. However, they all tend to work by interfering with some aspect of how the cells divide and multiply. Two or more cytotoxic medicines are often used in a course of chemotherapy, each with a different way of working. This may give a better chance of success than using only one. There are many different cytotoxic medicines used in the treatment of cancer. In each case the one (or ones) chosen will depend on the type and stage of your cancer. Interestingly, there are several statements along the lines of ‘Cytotoxic medicines work best in cancers where the cancer cells are rapidly dividing and multiplying’, a key issue with lower grade NETs.
Well known chemotherapy treatments for NETs include (but are not limited to): Capecitabine (Xeloda), Temozolomide (Temodal), Fluorouracil (5-FU), Oxaliplatin (Eloxatin) Cisplatin, Etoposide (Etopophos, Vepesid), Carboplatin, Streptozotocin (Zanosar). Some of these may be given as a combination treatment, e.g. CAPecitabine and TEMozolomide (CAPTEM).
In the past, any medication used to treat cancer was regarded as chemotherapy. However, over the last 20 years, new types of medication that work in a different way to chemotherapy have been introduced. Many of these new types of medication are known as targeted therapies. This is because they’re designed to target and disrupt one or more of the biological processes that cancerous cells use to grow and reproduce. They are classed as biological therapy. In contrast, chemotherapy medications are mostly systemic in nature and designed to have a poisonous effect on cancerous cells, thus the term ‘cytotoxic’.
The following well known NETs treatment are not really chemotherapy and describing them in this way is not only misleading but may actually cause alarm to other patients. Furthermore, if you check any authoritative NET Cancer specialist or advocate organisation; any general and authoritative cancer site or the manufacturer’s websites; you will not see the drugs below listed within the term chemotherapy.
Somatostatin Analogues e.g. Sandostatin (Octreotide), Somatuline (Lanreotide). Although these drugs have an anti-cancer effect for some, they are in fact hormone inhibitors and are therefore a hormone therapy.
Everolimus (Afinitor). This is a targeted biological therapy or more accurate a mammalian target of rapamycin (mTOR) inhibitor. It is a type of treatment called a signal transduction inhibitor. Signal transduction inhibitors stop some of the signals within cells that make them grow and divide. Everolimus stops a particular protein called mTOR from working properly. mTOR controls other proteins that trigger cancer cells to grow. So everolimus helps to stop the cancer growing or may slow it down.
Sunitinib (Sutent). This is a targeted biological therapy or more accurate a protein (or tyrosine) kinase inhibitor. Protein kinase is a type of chemical messenger (an enzyme) that plays a part in the growth of cancer cells. Sunitinib blocks the protein kinase to stop the cancer growing. It can stop the growth of a tumour or shrink it down.
I can only speculate why some of the confusion exists but I do have some personal experience I can quote too. Firstly I believe it could be easier for some people to describe the new agents as ‘chemotherapy’ rather than explain things such as somatostatin analogues, ‘mammalian target of rapamycin (mTOR) inhibitors’, protein kinase inhibitor or angiogenesis inhibitors. Another reason could be that health insurance companies do not have the correct database structures in place on their IT systems and therefore need to ‘pigeon hole’ drugs into the closest category they can see. Often this is chemotherapy and this only adds to the confusion. In the days when I had health insurance, my Lanreotide injections were coded as chemotherapy on all my bills. I challenged it and this is how they explained the issue.
When you’ve been diagnosed with cancer at an incurable stage, certain words start to mean more. Take ‘palliative’ for example. Before I was diagnosed I had always associated the word ‘palliative’ with someone who had a terminal disease and this type of care was to make the final days/weeks as comfortable as possible. So it was a bit of a shock to find out in 2010 that my treatment was palliative in nature. However, I’m still not dead and I’m still receiving palliative care. Go figure! The answer is simple – the cancer story is changing. What was once feared as a death sentence is now an illness that many people survive. As survival rates increase, so too will the number of people living with the legacy of cancer and its treatment.
What is palliative care?
Some people with incurable cancer will continue to receive treatment to keep the cancer at bay and that treatment is by definition, palliative. In fact, palliative care can be given at any time during an illness. It’s not just for treatment of the cancer, it’s also to help with the effects of that treatment, i.e. the consequences of cancer. It also encompasses things such as emotional and other practical support.
In the most general terms and while it clearly can go into some detail and long lists, palliative care can be defined as follows:
Cancer and its treatment often cause side effects. Relieving a person’s symptoms and side effects is an important part of cancer care. This approach is called symptom management, supportive care, or palliative care. Palliative care is any treatment that focuses on reducing symptoms, improving quality of life, and supporting patients and their families. Any person, regardless of age or type and stage of cancer, may receive palliative care.
I looked at a few sites and many of them confirm the above. However, there appears to be even more sites where it is still heavily associated and inextricably linked with end of life or hospice care where you may come into contact with the term palliative care specialist. Whilst it’s not wrong to make that association, more work needs to be done to cater for the growing numbers of ‘incurable but treatable’ who are not ‘terminal’ and still need this type of support, in some ways like you would with a chronic condition. I also sense a push in certain areas to emphasise the meaning of palliative care to include a much broader definition than is currently in most people’s minds. This needs much more publicity. I’m not saying that ‘palliative’ does not include ‘hospice care’ but I’m not intending to cover that aspect in this blog which is aimed as those with incurable but treatable cancers.
My palliative care experience
When I was diagnosed with metastatic Neuroendocrine Tumours (NETs) in 2010, I quickly accepted the fact that any treatment I would receive would not be curative. I also quickly accepted that if I didn’t have any treatment, I would probably die. The words used were ‘debulking’ and ‘cytoreductive’, more technical sounding but essentially meaning the same thing as palliative. Debulking means removing as much tumour as possible in order to increase the chance that perhaps other treatments can be of some help. Cytoreductive means the same thing but generally extends the ‘debulking’ activity to other modes of treatment (e.g. chemotherapy/radiotherapy).
NETs is one of a number of cancers for which ‘debulking’ and ‘cytoreductive’ therapies can in many cases confer some survival advantage. In fact if you read ENETS or NANETS guidance for advanced NETs, you will frequently see the statement that cytoreductive surgery should be considered if greater than 90% of metastatic tumour burden can be safely resected or ablated. NETs, particularly with distant metastases, can come with a ‘syndrome’ and some of the symptoms can be rather debilitating for many patients. These syndromes are a result of tumours secreting excess amounts of hormonesand the types vary from patient to patient and from NET type to NET type. It follows that if surgical debulking reduces the amount of tumours, then it should normally decrease the effects of the associated syndrome. In fact, one letter from a specialist did describe my surgery in symptom palliation terms. I can confirm this is about right as my hormone marker 5HIAA remained elevated after surgery to remove my primary and local tumours, but did not return to normal until after my liver surgery.
However, there are a number of other treatments that can be considered ‘palliative’ in a metastatic or advanced environment. Getting rid of tumours is always the optimum treatment for any cancer but just as surgical debulking can reduce the amount of cancer, other non-surgical modalities such as liver embolization or ablation can have the effect of reducing the symptoms of the cancer and therefore providing relief to the patient. Somatostatin Analogues (Octreotide/Lanreotide) are another good example of palliative care. Although they might have an anti-tumour effect for some, they mostly work by reducing or inhibiting the secretion of excess hormones which contribute to the various NET syndromes. ‘Symptom control’ is as defined above, palliative care.
I’m already looking forward to my next palliative care appointment.
If there’s a word which is synonymous with cancer, it’s chemotherapy. It’s what most people have in their mind when they are talking to a cancer patient…… ‘have you had chemotherapy‘ or ‘when do you start chemotherapy‘.
I was nonchalantly asked by a friend some time ago ‘how did you get on with chemotherapy’ – he was surprised to hear I hadn’t had it despite my widespread disease. Cue – lengthy explanation! I wasn’t annoyed by the question, I just think people automatically assume every cancer patient has to undergo some form of systemic chemotherapy. If you read any newspaper article about cancer, they do nothing to dispel that myth, as many articles contain a story about a cancer patient with no hair.
Sure, chemotherapy is not the nicest treatment to receive and it does have pretty awful side effects for most. I watched my daughter-in-law go through 3 or 4 months of this treatment where she was literally confined to a combination of her bedroom and her bathroom. And it did shock me to see her without hair. I would never want anyone to go through that and it really brings it home when it happens to a close member of your family.
Despite its bad press in regards toxicity and it’s awful side effects, chemotherapy is widely used in many cancers. Statistics show that it does work for many patients (….. my daughter-in-law is still here looking after two of my four grandsons and my son still has a wife ♥). However, I suspect it has a limited future as more efficient and less toxic drugs and delivery systems come online downstream. Immunotherapy is often touted as a replacement for chemotherapy but this may be a while yet. So for now, millions of cancer patients worldwide will continue to be prescribed chemotherapy as part of their treatment regime.
However, for some cancers, chemotherapy is not particularly effective. Neuroendocrine Cancer (NETs) is one such cancer. In general, NETs do not show a high degree of sensitivity to chemotherapy. For example, it’s often inadequate for the treatment of well-differentiated tumours with a low proliferation index but can be more effective in particular anatomical locations. The one exception is for high grade tumours (known as Neuroendocrine Carcinoma if poorly differentiated) where chemotherapy is much more likely to feature. I’m not saying that the lower grades will never receive chemotherapy – that door is always left open for those with progressive cancer who perhaps have run out of treatment options. Putting Grade 3 to one side, I’ve heard people say that NETs is the ‘good‘ cancer or the ‘good looking’ cancer often citing the chemotherapy thing as some justification. That is of course a stupid thing to say. I accept that not everyone will lose their hair and not every chemo will cause hair loss.
Here’s the rub. Many other treatments come with pretty challenging side effects. Moreover, the side effects and the consequences of these other treatments can last for some time, and for many, a lifetime. For example with NETs:
Surgery can be pretty extensive, in some cases radical and life changing. Many cancer patients receive surgery for NETs which is still the only real ‘curative’ treatment, although for most, it’s cytoreductive or palliative in nature. If you lose bits of your small intestine, large intestine, liver, spleen, cecum and appendix, gallbladder, stomach, rectum, lungs, pancreas, thyroid, parathyroids, pituitary gland, adrenal gland, thymus gland, ovaries, oesophagus (…….I could go on), this comes with various side effects which can present some quality of life issues. There can be huge consequences of having this treatment.
Other ‘consequences’ of cancer surgery include (but are not limited to), pulmonary emboli (blood clots), lymphedema, short bowel syndrome, gastrointestinal malabsorption, diabetes.
Somatostatin Analogues do a great job but they do add to some of the effects of surgery (mainly malabsorption).
Even the so-called ‘silver bullet’ treatment Peptide Receptor Radio Nuclide Therapy (PRRT) can have pretty severe side effects and presents some risk to kidneys and bone marrow as a long term consequence.
I’ve not had chemotherapy and I would rather avoid it if I can. However, as I’ve hinted above, there are other harsh (….perhaps harsher?) treatments out there. Moreover, whilst hair normally grows back, your small intestines, lungs and pancreas won’t. Many people will have to live for the rest of their life with the consequences of their cancer and its treatment.
It sometimes appears that every other cancer article involves someone undergoing chemotherapy. I just wish someone would write an article about my lack of terminal ileum and ascending colon, the malabsorption issues as a consequence of that, my missing mesenteric lymph nodes, my retroperitoneal fibrosis, not forgetting to mention my diseased liver, my left axillary lymph nodes (and the mild lymphedema I now have after their removal), my left supraclavicular lymph nodes, my suspect thyroid lesion and my hypothyroidism which may be due to that, my small lung nodule and my pulmonary emboli which after nearly 6 years of daily injections means my abdomen looks and feels like I’ve done 12 rounds with Mike Tyson. However, it just wouldn’t be a good picture nor would it be as powerful as one of a person with no hair. Just saying!
I’ve made no secret of the fact that I don’t believe Neuroendocrine Cancer is rare and you can read why in some detail in my article Neuroendocrine Cancer – not as rare as you think. Better diagnostic technology, greater awareness and better recording of the correct disease in national cancer registries.
The latest figures for Public Health England (covering ~90% of UK), indicate there are now 4800 diagnoses of NETs every year, i.e. more people than ever are being diagnosed, It is calculated from an incidence rate of 9/100,000 (using the 2011 census for England of 53,000,000) The new figures do not include Lung Neuroendocrine Carcinomas (LCNEC and SCLC) – so it is understated. This would appear to debunk the myth that the condition is rare given that the incidence rate has now gone beyond the threshold to be considered rare in Europe (5/100,000).
You can read the Public Health England (PHE) paper by visiting the NET Patient Foundation site here.
To put this diagnostic data into perspective:
4800 newly diagnosed NETs a year in England alone
= 400 a month
= 92 a week
= 13 a day
= 1 every 1.84 hrs
And in USA …
The UK is not alone in recording major increases taking the incidence and prevalence beyond the threshold of rare disease categorisation. The very latest SEER figures for USA confirmed the disease is no longer rare in 2017, particularly as the annual incidence rate is now 23,000 in that country (circa 5 every 2 hours).
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:
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.
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.
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.
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.
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).
Somatostatin receptor-based imaging techniques
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).
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.
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:
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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!
In the last 12-24 months, there seems to have been announcement after announcement of new and/or upgraded/enhanced diagnostics and treatment types for Neuroendocrine Cancer. Scans, radionuclide therapies, combination therapies, somatostatin analogues, biological therapies, etc. Some of the announcements are just expansions of existing therapies having been approved in new (but significant) regions. Compared to some other cancers, even those which hit the headlines often, we appear to be doing not too badly. However, the pressure needs to stay on, all patients need access to the best diagnostics and treatments for them; and at the requisite time.There’s even more in the pipeline and I’m hoping to continue to bring you news of new stuff as I have been doing for the last year.
Some of these new diagnostics and treatments will benefit eligible patients who are in diagnosis/newly diagnosed and also those living with the disease. As we’re now in our awareness month, let’s recap:
Many NET Patients will undergo a nuclear scan to confirm CT results and/or to detect further neuroendocrine activity. Basically, a nuclear substance is mixed with a somatostatin analogue, injected into the patient who is then scanned using a 360-degree gamma camera. As gamma cameras are designed to show up radioactive activity; and as Neuroendocrine Tumour cells will bind to the somatostatin analogue, it follows that the pictures provided will show where Neuroendocrine tumours are located. Many people will have had an ‘Octreotide’ Scan (or more formally – Somatostatin Receptor Scintigraphy) which is still the gold standard in many areas. The latest generation of nuclear scans is based on the platform of the Gallium (Ga) 68 PET Scan. The principles of how the scan works is essentially as described above except that the more efficient radioactive/peptide mix and better scan definition, means a much better picture providing more detail (see example below). It’s important to note that positive somatostatin receptors are necessary for both scans to be effective. Europe and a few other areas have been using the Ga-68 PET scans for some time (although they are still limited in availability by sparse deployment). The latest excitement surrounding this new scan is because they are currently being rolled out in USA. Read about the US FDA approval here. You may hear this scan being labelled as ‘NETSPOT’ in USA but this is technically the name for the preparation radiopharmaceutical kit for the scan which includes a single-dose injection of the organic peptide and the radionuclide material. Take a look at a comparison of both scans here:
This slide from a recent NET Research Foundation conference confirms the power of more detailed scanning.
Peptide Receptor Radionuclide Therapy (PRRT)
Similar to above, this treatment has been in use in Europe and other places for some time but is also to be formally deployed in USA if, as is expected, the US FDA approval is positive at the end of this year (Read here). In the most basic terms, this is a treatment whereby a peptide is mixed with a radionuclide and is drip fed over a number of treatments (normally up to 4 spaced out over a year). The concept of delivery of the ‘payload’ to the tumours is actually very similar to the preparation for a radionuclide scan as described above, the key difference is the dosage and length of exposure whilst the tumours are attacked. Once again, receptors are important. The NETTER series of trials showed good results and this is an excellent addition to the portfolio for those patients who are eligible for this treatment. Fingers crossed for the US FDA announcement due by the end of this year. Also fingers crossed that PRRT returns to the NHS England & Wales portfolio of available treatments next year. The Carcinoid Cancer Foundation has an excellent summary of PRRT here.
PRRT and Chemo Combo
Whilst on this subject, I also want to highlight the innovative use of combo therapies in Australia where they are combining PRRT and Chemo (PRCRT). I blogged about this here:
Somatostatin Analogues and their Delivery Systems
Somatostatin analogues are a mainstay treatment for many NET Patients. These drugs target NET cell receptors which has the effect of inhibiting release of certain hormones which are responsible for some of the ‘syndromic’ effects of the disease. Again, receptors are important for the efficacy of this treatment. You can read the ‘geeky’ stuff on how they work here. These drugs mainly comprise Octreotide (provided by Novartis) and Lanreotide (provided by Ipsen). The latter has been around in Europe for 10 years and was introduced to North America earlier this year. Octreotide has been around for much longer, almost 17 years. When you consider these peptides have also been used to support nuclear scans that can detect the presence of tumours; and that studies have shown they also have an anti-tumour effect, they really are an important treatment for many NET Patients. I’ve blogged about new somatostatin analogues in the pipeline and you can read this here. This blog also contains information about new delivery systems including the use of oral capsules and nasal sprays (…….. very early days though).
Treatment for Carcinoid Syndrome
For maintenance and quality of life, the release of a Telotristat Ethyl for Carcinoid Syndrome is an exciting development as is the first new treatment for Carcinoid Syndrome in 17 years. This is a drug which is taken orally and inhibits the secretion of serotonin which causes some of the symptoms of the syndrome including diarrhea. It must be emphasised it’s only for treating diarrhea caused by syndrome and might not be effective for diarrhea caused by other factors including surgery. Read about how it works and its target patient group in my blog here.
The announcement of a clinical trial for the Oncolytic Virus (an Immunotherapy treatment)specifically for Neuroendocrine Tumours is also very exciting and offers a lot of hope. Click the photo for the last progress update.
Earlier this year, AFINITOR became the first treatment approved for progressive, non-functional NETs of lung origin, and one of very few options available for progressive, non-functional GI NET, representing a shift in the treatment paradigm for these cancers. It’s been around for some time in trials (the RADIANT series) and is also used to treat breast and kidney cancer. It’s manufactured by Novartis (of Octreotide fame). It has some varying side effects but these appear to be tolerable for most and as with any cancer drug, they need to weighed against the benefits they bring.
In technical terms, AFINITOR is a type of drug known as an ‘mTOR’ inhibitor (it’s not a chemo as frequently stated on NET patient forums). Taken in tablet form, it works by blocking the mTOR protein. In doing so, AFINITOR helps to slow blood vessels from feeding oxygen and nutrients to the tumour.
Check out Novartis Afinitor website for more detailed information. There’s an excellent update about AFINITOR rom NET expert Dr James Yao here. The US FDA approval can be found here.
………. and relax! Wow, I’ve surprised myself by collating and revising the last 12-24 months. Dr James Yao also agrees – check out his upbeat message in the attached2 page summary. You may also like another upbeat message from Dr Jonathan Strosberg by clicking here.
Neuroendocrine Cancer – who’d have thought it? ….. a bit of a dark horse.
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