Recent Progress in NET Management – Positive presentation from Jonathan R Strosberg MD

jonathan-strosbergI recently wrote a blog called Neuroendocrine Cancer – Exciting Times Ahead! I wrote that on a day I was feeling particularly positive and at the time, I wanted to share that positivity with you. I genuinely believe there’s a lot of great things happening. Don’t get me wrong, there’s a lot still to be done, particularly in the area of diagnosis and quality of life after being diagnosed. However, this is a really great message from a well-known NET expert.

In an interview with OncLive, Jonathan R. Strosberg, MD, associate professor at the H. Lee Moffitt Cancer Center in Florida, discussed his presentation on NETs at a recent 2016 Symposium, and shed light on the progress that has been made in this treatment landscape.

OncLive: Please highlight some of the main points from your presentation.

Strosberg: The question I was asked to address is whether we’re making progress in the management of NETs, and I think the answer is unequivocally yes. Prior to 2009, there were no positive published phase III trials.

Since then, there have been 8 trials, 7 of which have reached their primary endpoints. So it’s been a decade of significant improvement. And even though none of these studies were powered to look at overall survival as an endpoint, we’re certainly seeing evidence of improvement in outcomes.

OncLive: What are some of the pivotal agents that you feel have impacted the paradigm in the past several years?

Strosberg: The first group is the somatostatin analogs. We use them to control hormonal symptoms like carcinoid syndrome, but with the CLARINET study, we now know that they substantially inhibit tumor growth.

The next significant drug we use in this disease is everolimus (Afinitor), an oral mTOR inhibitor, which is now approved in several indications based on positive phase III studies. The first was in pancreatic NETs and subsequently, based on the RADIANT-4 trial, it was also approved in lung and gastrointestinal NETs. So that was an important advance.

The next important category of treatment is radiolabeled somatostatin analogs, otherwise known as peptide receptor radiotherapy. The one that’s been tested in a phase III trial is lutetium dotatate, also known as Lutathera. It was tested in patients with progressive midgut NETs and showed a very substantial 79% improvement in progression-free survival, and a very strong trend toward improvement in overall survival, which we hope will be confirmed upon final analysis.

OncLive: Are we getting better at diagnosing and managing the treatment of NETs?

Strosberg: Certainly. I think pathologists are better at making the diagnosis of a NET, rather than just calling a cancer pancreatic cancer or colorectal cancer. They’re recognizing the neuroendocrine aspects of the disease, and doing the appropriate immunohistochemical staining.

We also have better diagnostic tools. We used to rely primarily on octreoscan, and in many cases we still do, but there is a new diagnostic scan called Gallium-68 dotatate scan, also known as Netspot, which has substantially improved sensitivity and specificity. It’s not yet widely available, but it is FDA approved and hopefully will enable better diagnosis as well as staging in the coming years.

And, with the increase in number of phase III studies, we’re developing evidence-based guidelines, which will hopefully lead to more standardization, although knowing how to sequence these new drugs is still quite challenging.

OncLive: With sequencing, what are the main questions that we’re still trying to answer?

Strosberg: If we take, for example, NETs of the midgut, beyond first-line somatostatin analogs, physicians and patients often face decisions regarding where to proceed next, and for some patients with liver-dominant disease, liver-directed therapies are still an option.

For others, everolimus is a systemic option, and then hopefully lutetium dotatate will be an option based on approval of the drug, which is currently pending. Knowing how to choose among those 3 options is going to be a challenge, and I think there will be debates. Hopefully, clinical trials that compare one agent to another can help doctors make that choice. It’s even more complicated for pancreatic NETs. Beyond somatostatin analogs, we have about 5 choices—we have everolimus, sunitinib (Sutent), cytotoxic chemotherapy, liver-directed therapy, and peptide receptor radiotherapy. It’s even more challenging in that area.

OncLive: Are there any other ongoing clinical trials with some of these agents that you’re particularly excited about?

Strosberg: There’s a trial that is slated to take place in Europe which will compare lutetium dotatate with everolimus in advanced pancreatic NETs, and I think that’s going to be a very important trial that will help us get some information on both sequencing of these drugs, as well as the efficacy of Lutathera in the pancreatic NET population, based on well-run prospective clinical trials. I’m particularly looking forward to that trial.

OncLive: Looking to the future, what are some of the immediate challenges you hope to tackle with NETs?

Strosberg: One area of particular need is poorly differentiated neuroendocrine carcinomas. That’s a field that’s traditionally been understudied. There have been very few prospective clinical trials looking at this particular population, and we’re hoping that will change in the near future. There are a number of trials taking place looking at immunotherapy drugs. If these agents work anywhere in the neuroendocrine sphere, they are more likely to work in poorly differentiated or high-grade tumors, in my opinion, given the mutational profile of these cancers. So that’s something I’m particularly looking forward to being able to offer these patients something other than the cisplatin/etoposide combination that goes back decades, and is of short-lasting duration.

See more at: http://www.onclive.com/publications/oncology-live/2016/vol-17-no-24/expert-discusses-recent-progress-in-net-management#sthash.ypkilX2A.dpuf

Thanks for reading

Ronny

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Neuroendocrine Tumours – benign vs malignant

Kunz His belief these tumors did not metastisize

OPINION:

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.

Definitions

To fully understand this issue, I studied some basic (but very widely accepted) definitions of cancer.  I also need to bring the ‘C’ word into the equation (Carcinoid), because the history of these tumours is frequently where a lot of the confusion lies.  The use of the out of date term ‘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 ENETSUKINETS and NANETS guidance both of which are based on internationally recognised classification schemes (i.e. the World Health Organisation (WHO)).

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

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

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

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

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

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

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

Kunz His belief these tumors did not metastisize

How are 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.

don't worry it's benign widescreen

Can Tumours be Malignant or become Malignant?

Using the definition above, if a tumour invades and destroy nearby tissue and spread to other parts of the body, then it’s malignant (i.e  Cancer). However, there’s a reason why the WHO declared in 2010 that all NETs have malignant potential (as amplified in WHO 2017). It may not happen or it may happen slowly over time but as Dr Richard Warner says, “they don’t all fulfill their malignant potential, but they all have that possible outcome”.  Thus why ongoing surveillance is important after any diagnosis of Neuroendocrine Tumour of any grade or at any stage.  Dr Lowell Anthony, a NET Specialist from the University of Kentucky explains this much better than I can – CLICK HERE to hear his two-minute video clip.

Summary

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

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

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

You may be interested in reading these associated posts:

Carcinoid vs Neuroendocrine

Neuroendocrine Neoplasms – Grading and Staging (WHO 2017)

Incurable vs Terminal

10 Questions for your doctor

Thanks for listening

Ronny

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Neuroendocrine Cancer – Incurable is not untreatable

Incurable is not untreatable

OPINION. When I was being officially told I had an advanced and incurable cancer, I did what most people seem to do on films/TV ….. I asked “how long do I have“.  The Oncologist said ” … perhaps just months“.  That must have been quite a shock because for a few moments after that, I heard nothing – my brain was clearly still trying to process those words – I wasn’t even feeling unwell! The really important bit I missed was him go on to say “…but with the right treatment, you should be able to live for a lot longer”.  Fortunately, my wife Chris heard it all and I was refocused.  “OK Doc – let’s go” I said.  Always take someone with you to take notes at important meetings with Oncologists!

I continue to see quite a few posts and articles about death and dying and I noticed some patients were using the word ‘terminal‘ to describe Neuroendocrine Cancer, despite in some cases, having been diagnosed some years ago, despite in most cases in reference to well differentiated diagnoses. This label is not just confined to use within Facebook forums, I’ve also seen this on wider social media including twitter, blogs and newspaper items. For some, this appears to be the prognosis given to them by their doctors. I find this surprising. However, I’m much less surprised to see many comments on forums from people who had been told the worst by their doctors but were still alive and kicking WAY beyond those worst case prognostic statements, including the higher grade cases.

Definitions are important so what does ‘terminal cancer’ actually mean? 

I’m conscious there are legal ramifications with the definitions (wills, life insurance, disability etc) and that these may differ on an international/federal basis.  I therefore intentionally confined my searching to a couple of ‘big hitter’ and ‘authoritative’ sites:

Cancer Research UK defines terminal as “When cancer is described as terminal it means that it cannot be cured and is likely to cause death within a limited period of time. The amount of time is difficult to predict but it could be weeks to several months”.

The American Cancer Society defines terminal as “an irreversible condition (it cannot be cured) that in the near future will result in death or a state of permanent unconsciousness from which you are unlikely to recover. In most states, a terminal illness is legally defined as one in which the patient will die shortly whether or not medical treatment is given.”

Can terminal as defined above be applied to Neuroendocrine Cancer? 

I’m sure it can, e.g. with very advanced and very aggressive disease and for any grade when taking into account the condition of the patient and other factors (secondary illnesses/comorbidities, refusal of treatment etc). Clearly, that is a terrible situation.  I’m also conscious that some people do eventually die because of this disease or its consequences and that is also terrible.

How long is a piece of string?

I think with most Neuroendocrine Cancer patients, “how long do I have” can be a tough question to answer. Thinking back to my own situation, although it was an obvious question to ask my Oncologist, I can see it might have caught him unawares.  I suspect he was erring on the side of caution as I don’t believe he had formulated my treatment plan ….. i.e. my case had not yet been looked at by a Multi-Disciplinary Team (MDT), a bit like a ‘Tumor Board’.  I had already been confirmed Grade 2 (via liver biopsy) and my CT scans were indicating widespread disease.  I was yet to have an Octreotide scan and the conventional biochemical markers (CgA and 5HIAA).  I suspect, faced with my question, he went for the worst case, based on the statistics he had access to at the time. What I now know is that, in the year of my diagnosis, the median survival was 33 months in patients with advanced Grade 1/Grade 2 NETs with distant metastasis.  These statistics are certainly better today but my Oncologist was probably on the right track.  However, at no time did he use the word ‘terminal’.

The Cancer story is changing

What I also found during my research is that as more and more people in the UK are now living with cancer (all cancer) rather than dying from it, there is a new class of patients emerging – Macmillan UK call this “treatable but not curable” and I believe this is very relevant to Neuroendocrine Cancer.  I touched on this in an awareness blog entitled “Living with Neuroendocrine Cancer – it takes guts“.  You will find some data in this blog about a major increase in the amount of people with cancer who eventually die of something else (…… basically it has doubled). For many, Cancer is no longer a death sentence.  I do accept that it can be difficult to live with certain cancers and this is also covered in my “it takes guts” blog linked above.

Survivorship and Hope

You can find numerous examples of long-term survivors of advanced Neuroendocrine Tumours on the ‘airwaves’, many with a relatively good quality of life (QoL).  I don’t normally pay much attention to prognostic data, I take my lead from the huge number of patients living a long time with Neuroendocrine Cancer.  However, I was particularly interested to read a set of USA statistics from NOLA (Boudreaux, Woltering et al) which said “Our survival of stage IV midgut NET patients that we performed surgical debulking on was published in the Journal of the American College of Surgeons in 2014. It showed our 5, 10 and 20-year survival rates were 87%, 77% & 41% respectively. It’s also worth noting the comparison with the 2004 SEER database analysis which listed the 5 & 10 year SEER survival at 54% and 30% respectively”.  Clearly, the NOLA figures are guidelines (and only for midgut) but they do seem to reflect my previous statement about seeking out positives rather than dwelling on the negatives.  The SEER 2012 figures are much better than the 2004 versions stating “Survival for all NETs has improved over time, especially for distant-stage gastrointestinal NETs and pancreatic NETs in particular, reflecting improvement in therapies.

Exciting times ahead

On the subject of therapy improvement, there has been a plethora of new treatments coming online and more entering and progressing through the approvals pipeline.  Check out my article entitled Exciting Times Ahead Also listen to a NET Expert along the same lines.  PRRT is making a real difference.

Summary

Following my diagnosis in 2010, I went on to receive really good treatment and it continues to this day with Lanreotide backed up by a rigorous surveillance regime (and this is backed up by my own advocacy!).  However, I have totally accepted the fact that I have metastatic Neuroendocrine Cancer and that it cannot be cured.  By the way, I intentionally used ‘metastatic‘ rather than Stage IV.  Mention of Stage IV can set off alarm bells and send the wrong message to the recipient. I don’t believe Stage IV has the same ‘red flag’ meaning for well-differentiated NETs as it does with more aggressive cancers of the same stage. Given what I know now, I would certainly challenge any doctor who told me I had a ‘terminal disease’ and at the same time told me I had a slow-growing well differentiated Neuroendocrine Cancer.

I now live with this disease (….and it’s consequences) and do not feel like I’m dying of it.  Moreover, I most certainly do not see myself as a ‘terminal’ cancer patient, particularly as I’ve now been living with it since 2010.

I like to focus on how I can live better with it.

Whilst we’re on this subject, please note Palliative Care is not just end of life / hospice care.  That’s another misunderstanding bordering on mythical status. Read more here.

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Graphic courtesy of Ellie McDowell

 

Thanks for reading

Ronny

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Neuroendocrine Neoplasms – Grade and Stage (incorporating WHO 2017 changes)

Grades of Neuroendocrine Tumour

One of the most discussed and sometimes confusing subjects on forums is the staging and grading of Neuroendocrine Neoplasms (NENs). Mixing them up is a common error and so it’s important to understand the difference despite the apparent complexity. If I was to make a list of questions for my specialist/Oncologist at diagnosis, it would include “What is the stage, grade and differentiation of my cancer”.  To enable me to synchronise with the documented guidance, I’m going to use the following WHO 2017 approved terms in this post:

  • Neuroendocrine Neoplasm (NEN) – all types of Neuroendocrine tumour of whatever grade (please note Neoplasm is another word for tumour)
  • Neuroendocrine Tumour (NET) – all well-differentiated tumours (an explanation of differentiation will be provided below)
  • Neuroendocrine Carcinoma (NEC) – all poorly differentiated tumours

NEN Breakdown

Stage vs Grade

In the most basic of terms, stage is the spread or extent of cancer and grade is the aggressiveness of cancer. They are totally different things and an understanding of both is important as they are critical to predict outcome (to a certain extent) and guide therapy. There is no correlation between the two, you can have the lowest grade with the highest stage (actually very common with NETs).

As patients, we deal with many medical specialists during diagnosis and subsequent treatment.  However, we rarely meet the pathologist who plays a critical role in the outcome. Precise diagnosis is what drives patient decisions and treatment. If the pathology is wrong, everything that follows could be incorrect as well.  It’s a very important area.

Grading (aggressiveness)

Grading and Ki67

Antigen KI-67 is a nuclear protein that is associated with and may be necessary for cellular proliferation.  Ki-67 is therefore an excellent marker to determine the growth fraction of a given cell population. The fraction of Ki-67-positive tumour cells (the Ki-67 labeling index) is often correlated with the clinical course of cancer.

Pathologists normally need to count about a thousand cells in order to determine the percentage of cells that are Ki67 positive – thus why you see Ki67 expressed as a percentage. 0% is the lowest, 100% is the highest. Often, they add greater or less than signs depending on the sample involved, i.e. >5% or <5%. There are other measurement systems in place, mainly Mitotic Count.

The ranges for Neuroendocrine Neoplasms (NENs) are divided in to 3 Grades depending what range the Ki67 number lands in. With NENs, the differentiation (well or poorly) is almost as important at grade 3 (high grade).  Grades 1 and 2 are by default well differentiated NETs).

Why is differentiation important?

To fully understand grading, you also need to understand the concept of ‘differentiation’.  In the most basic of terms, ‘differentiation’ refers to the extent to which the cancerous cells resemble their non-cancerous counterparts.  This is an important point for NETs because many low-grade tumour cells can look very similar to normal cells. The differentiation of a NET has an impact on both prognostics and treatment regimes.

NENs fall into one of three grades based on their differentiation and their proliferative rate. The proliferative rate is measured mainly using two methods known as Miotic Count and Ki-67 index, the latter seems to be more frequently used (but see below for Lung NETs). The Ki-67 index can usually be determined, even in cases of small biopsies but Mitotic rate counting requires a moderate amount of tumour tissue (at least 50 HPFs or 10 mm) and may not be feasible for small biopsies.  The Miotic Count method may be preferred or used in addition to Ki-67 for certain Lung NET scenarios as it is said to be more helpful in distinguishing atypical from typical NET (what some might ‘old fashionably’ and incorrectly refer to as Lung Carcinoid tumours), and for small and large cell lung Neuroendocrine Carcinomas (NEC).

Some of you may have heard the term ‘moderately differentiated’ which tended to align with an intermediate grade or Grade 2. However, please note that the term moderately differentiated as a classification was phased out in 2010 by WHO reducing from 3 differentiation levels to 2.  Grade 2 is also defined as well differentiated but based on different proliferative rate (see table). High grade was normally referred to as Neuroendocrine Carcinoma indicating it is a faster growing and more aggressive cancer. However, see below for an important change to high grade classification.

Grading – Key WHO 2017 Changes

WHO Classifications of Cancer are published in something known in medical world as “The Blue Book”.  For NETs, the 2017 version comprises only the “WHO Classification of Tumours of Endocrine Organs”.  Technically this would preclude the digestive system and lung NETs but the leading NET pathologists have submitted a recommendation to normalise all NET Blue Books along the same classification scheme.  Worth also noting that the latest ENETS Guidelines are already using the new grading terms.  Many sites remain out of date so be careful where you look.

Misc Grading Issues

The proliferative rate can be diverse in NENs, so sampling issues can limit the accuracy of grading. More substantial samples of tumour are therefore preferable for grading thus why the Ki-67 index is preferred for biopsies where large amounts of tissue may not be available. The distinction of low-grade from intermediate grade can be challenging when using small samples. A couple of interesting observations about NET grading which I spotted during my research and ‘forum watching’.  You can have multiple primary tumours and these might have different Ki-67 scores.  Additionally, on larger tumours, Ki-67 scores can be different on different parts of the tumour.  And something I know from my own experience, secondary tumours can have different Ki-67 scores than primary – even a different grade.  In my own case, my liver secondary tumours were graded higher than my primary which according to my surgeon is in keeping with a clone of the disease having become more aggressive over time.  Royal Free Hospital NET Centre indicates a person’s grade should be taken from the highest biopsy grade taken. This is a fairly complex area but a recent study published by the US National Institute of Health and many anecdotal comments made by NET specialists indicates that is a fairly common scenario.

 

Summary of Key Changes

The 2017 World Health Organisation (WHO) classification sub-divided Grade 3 into two new entities: a well differentiated high-grade NET and a poorly differentiated high-grade NEC.  There may also be a cut-off point in proliferative rate (i.e. Ki-67) between NET and NEC in relation to potential treatment strategies (55% is mentioned for pNETs but I’m currently investigating). Physicians don’t really have much data to support specific guidelines for treatment so all cases will be personalised.

The Grade 1 to 2 Ki-67 cut-off is changed from 2 to < 3 for clarification purposes.  There was some discussion as to whether it should be <5 but this was not accepted.

Well differentiated High Grade NETs are now recognised.  These are known as a NET rather than a NEC.  Both Grade 3 (NET) and Grade 3 (NEC) have the same biopsy marker cut-offs as per the leading slide but it is thought that a threshold reading of 55% could have some influence on the treatment regime. For example, a well differentiated tumour with a Ki67 of less than 55% might benefit from the same treatment given to Grade 1 or 2 patients, whereas a well differentiated tumour with a Ki67 of more than 55% might benefit from the same treatment given to poorly differentiated NEC. Only a guideline and I suspect this is like many things in NENs, very individual, relies on many factors, so your specialist will drive this accordingly.  You may see these 2 grades listed as Grade 3a for NET and Grade 3b for NEC.

Previously, Pheochromocytoma did not have an official grading regime, i.e. they were just benign or malignant.  Now they are using the same grading system as above.  I’m assuming this is the same for Paraganglioma and I will confirm in due course.  This is an excellent change and a continuation from the WHO 2010 classification where there was great emphasis away from a benign/malignant classification to formal grade levels on the basis that all NETs have malignant potential.

It also introduced a change to the naming of mixed cell tumours from Mixed AdenoNeuroendocrine Carcinoma (MANEC) to Mixed Neuroendocrine Non-Neuroendocrine Neoplasms (MiNEN).  A full explanation of MiNEN will follow but I would suggest the use of the term ‘Neoplasm’ has been chosen rather than ‘Carcinoma’ is because these neoplasms can be well or poorly differentiated.

It’s not possible at this time to acquire copies of the official output but I will keep this blog live.

The source material for the 2017 version of this article.

From leading Pathologist Dr Anthony Gill – Remember this is based on Endocrine Organs only but it will eventually apply to all.   I am awaiting access to free documentation to update this article further – only ones I can currently find are not free!

 

Staging (spread)

Staging is the extent or spread of disease.  Most types of cancer have 4 stages, numbered from 1 to 4 indicating a rising spread as the number is bigger. Often doctors write the stage down in Roman numerals, perhaps this is to stop any confusion between standard numbers used for Grades? So you may see stages written as I, II, III and IV.  In addition to this standard method, there is also an agreed model known as TNM (Primary Tumour, Regional Node, Distant Metastasis) which is essentially a more detailed staging definition when combined with the Stage 1-4 model.  Please note with TNM models, there could be different stage descriptions depending on the location of the primary tumour and similarly different TNM models for different tumour locations.

WHO 2017 changes

WHO 2017 has recommended enhancements to the TNM system mainly the use of additional suffixes indicating the extent of lymph node involvement. Details to follow when I can free access.

The following example shows the stage descriptions for a NET of the small intestine (the others are similar but worded accordingly for that part of the anatomy):

Stage I tumour is less than 1 cm in size and has not spread to the lymph nodes or other parts of the body.

Stage II tumour is greater than 1 cm in size and has started to spread beyond the original location, but has not spread to the lymph nodes or other parts of the body.

Stage III is any size tumour that has spread to nearby areas of the body and also to at least one lymph node.

Stage IV is any size tumour that has spread to one or more lymph nodes and has also spread to other, more distant areas of the body (such as the liver).

It’s also worth pointing out that Stage IV does not necessarily mean a cancer is more dangerous than other cancers of lesser stages.  This is an important point for NETs where Stage 4 can be matched up with a low-grade tumour i.e. Stage 4 for lower grade NETs is very often not the ‘red flag’ it is for other more aggressive cancers.  For example, doctors may surgically remove a Stage IV NET, while surgery might not help a patient with a cancer of a higher grade at such a late stage.

Notes:

  • Sometimes doctors use the letters to further divide the number categories – for example, stage 2A or stage 3B.  This is normally to clarify or provide more detail of the primary tumour size/invasion in conjunction with the TNM model.
  • You may also see something called Stage 0 which is for ‘Carcinoma in situ’. It means that there is a group of abnormal cells in an area of the body. However, the number of abnormal cells is too small to form a tumour and may, therefore, be currently classed as benign.  The World Health Organisation (WHO) system does not appear to recognise Stage 0 for NETs.

The most generic model for TNM staging is below but please note this could be adjusted for particular types of NET.

Primary Tumor (T)
TX: Primary tumor cannot be evaluated
T0: No evidence of primary tumour
Tis: in situ (abnormal cells are present but have not spread to neighbouring tissue; although not cancer, in situ may become cancer and is sometimes called preinvasive cancer)

T1, T2, T3 and T4 is a measure of the size of, and/or invasion/penetration by, the primary tumour and the wording varies between different NET sites. e.g. for a small intestinal NET:

T1 tumour invades mucosa or submucosa and size <=1 cm

T2 tumour invades muscularis propria or size >1 cm

T3 tumour invades subserosa

T4 tumour invades the visceral peritoneum (serosa)/other organs

For any T add (m) for multiple tumours

Regional Lymph Nodes (N)
NX: Regional lymph nodes cannot be evaluated
N0: No regional lymph node involvement
N1: regional lymph node metastasis

Distant Metastasis (M)
MX: Distant metastasis cannot be evaluated
M0: No distant metastasis
M1: Distant metastasis is present

You may occasionally see TNM staging be prefixed by lower case letters.  The most commonly used prefix is ‘p’ simply meaning the grading has been confirmed by pathology.  e.g. pT4 N1 M1

Specialists can combine the Stage to create a TNM – for example:

This slide will be updated when I get access to WHO 2017 or updated AJCC pubication.

Summary

A complex area and I hope I have condensed it sufficiently for you to understand enough for your purposes.  Despite looking very scientific, it is not an exact science. There are many variables as there always are with Neuroendocrine disease.  NENs can be very challenging for a pathologist even an experienced one who may not have encountered NENs before.  However, it is an extremely important part of initial diagnosis and also when needed during surveillance.  It is a vital tool used by Multidisciplinary Teams (MDT) in treatment plans and for prognostic purposes.  If you need to learn further, I recommend this document:

If you are interested in this subject and have one hour to spare, there is a great video here from LACNETS worth watching.

Finally – always make sure you get your pathology results at diagnosis and following any subsequent sampling.

You may benefit from reading these associated posts:

Benign vs Malignant

Incurable vs Terminal

Carcinoid vs Neuroendocrine

10 Questions for your doctor

Looking for a needle in a haystack

Thanks for reading

Ronny

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Chemotherapy for Neuroendocrine Cancer

One of the great things about learning is that it never ends 🙂   I came across this piece of information about how chemotherapy was invented. I had no idea.  It began as a deadly cloud but it eventually ended up as a silver lining for certain cancer patients.  It all began with the development of mustard gas and I’m sure we’ve all seen the awful pictures of solders leading each other from the battlefield having been affected by this ‘deadly cloud‘.  Let’s hope we never have to witness that again.  This weapon was first used 100 years ago this week (note: blog published in Apr 2015) but out of the horror came a ‘silver lining‘ – the idea behind what is now called chemotherapy.

However, the development didn’t really begin until the second world war when two doctors from Yale University (Louis Goodman and Alfred Gilman), conducted animal and then human trials.  Then in 1948, UK scientist Professor Alexander Haddow published a ground breaking piece of research in the journal Nature, showing exactly which bits of the nitrogen mustard molecule were needed to kill cancer cells. Perhaps more importantly, he also found out how to make the chemical less toxic, but with more potent cancer-killing activity. So mustard gas went from the very real battleground of the WWI trenches into the frontline of cancer treatment where it still is today.

You can read more about this on the Cancer Research UK Science Blog

Chemotherapy and Neuroendocrine Cancer

One of the unusual aspects of Neuroendocrine Cancer is that chemotherapy is not normally considered as a ‘standard’ treatment unlike many other cancers. The exception is high grade (Grade 3) where it is often a first and/or second line therapy.  Poorly differentiated Neuroendocrine disease is normally labelled as Neuroendocrine Carcinoma (NEC) but worth pointing out there is now a Grade 3 well differentiated classification known as a ‘Grade 3 NET’ rather than Grade 3 NEC. Depending on Ki67 score, there could be differing treatment options for Grade 3 NET and Grade 3 NEC.  Read more in my article Staging and Grading.

The type of chemo or the combination of different treatments will often depend on the tumour type and anatomical location involved but may include (but 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). many as a combo treatment.  There is a useful article explaining the role of Ki-67 in determining optimal chemotherapy in high grade neuroendocrine tumors.

Horses for Courses – Chemo is sometimes used for well differentiated lower grade NETs. 

Cytotoxic chemotherapy is often inadequate for treatment of Grade 1 and 2 (well differentiated) Neuroendocrine tumours which have a low proliferation index. Chemotherapy does not appear to like their slow cytokinetic growth. However,  it tends to work better on certain parts of the anatomy than others, e.g. pancreatic NETs and Lung NETs.  Of interest is a statistic from NET Research Foundation indicating that 23% of patients who were to be prescribed chemo had their treatment changed to a non-chemo option following a Ga68 PET scan.  Read more here.

For second line therapy (including for well differentiated NETs where other conventional treatments are not working), chemo may be given.  These include (but not limited to) Capecitabine, Temozolomide, Bevacizumab, Xelox, Folfox.  There are other specialist chemos for Mixed Neuroendocrine Non-Neuroendocrine Neoplasms (MiNEN).

Capecitabine plus Temozolomide (CAPTEM for short) is fast becoming the standarad chemotherapy treatment when it is required with certain lower grade NETs.  Dr Robert Fine says the results of the CAPTEM trial showed “tremendous responses in every neuroendocrine tumor”. The treatment elicited a response rate of 45% and a stable disease rate of 52% including those with certain types of NETs and pituitary tumours – types of neuroendocrine tumour that are notoriously ‘chemoresistant’.  You can read more about this here (click here) and you can also listen to Dr Fine enthusiastically talking about this on a short You Tube video clip – (click here).  Clearly it is not going to work for all.

Other CAPTEM Resources:

  • There’s a very interesting report on the use of CAPTEM in NETs – (click here)
  • CAPTEM Trial Document – (click here)

PRRT and Chemo Combo Treatment

In Australia, they’re also using a combo treatment of chemo (CAPTEM) and PRRT – I blogged about this click here.

“Chinese Dumplings”

There’s also a useful surgical technique which includes the use of intra-operative chemo, known as “Chinese Dumplings” – I wrote about this click here.

Chemo Embolisation

My Oncologist did mention Chemotherapy on my initial meeting, that was a shock and realisation I had something serious.  However, that never transpired but I was once scheduled to have a chemo-embolisation (or TACE, Trans-arterial Chemo Embolisation). Clearly TACE is more targeted than conventional and generally systemic chemotherapy techniques. Perhaps that my Oncologist actually meant.  The chemo-embolisation never transpired either (long story).

Chemotherapy vs Targeted Biological Agents and Somatostatin Analogues

I often see people describing Somatostatin Analogues (Lanreotide/Octreotide), Afinitor (Everolimus) and Sutent (Sunitinib) as chemo but that’s isn’t technically correct, and I’ve yet to find a NET Specialist or a NET Specialist Organisation who classifies these drugs as chemo.  See my article “Chemo or not Chemo” (click here).

Future of Chemo?

A lot is written about how much longer chemo will be around.  It gets a bad press – I suspect mainly due to the side effects.  There are suggestions that it will eventually be replaced by Immunotherapy and other treatments downstream.  However, immunotherapy is really still in its infancy and there remains a lack of long term data on success rates and side effects.  I suspect chemo will be around for a while longer, particularly for cancers where it has a track record of curing according to ASCO.  Very recently (June 2018), cancer experts said that chemo will be around for a long time yet – read more here

None of the content of this post should be interpreted as advice or a  recommendation for chemotherapy. If in doubt about suitability for any form of chemo, or the type you have been prescribed, patients should seek the advice of their treating doctor or NET specialist.

Thanks for reading

Ronny

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