ASCO 2017 – Let’s talk about NETs #ASCO17

ASCO (American Society of Clinical Oncology) is one of the biggest cancer conferences in the world normally bringing together more than 30,000 oncology professionals from around the world to discuss state-of-the-art treatment modalities, new therapies, and ongoing controversies in the field.  As Neuroendorine Tumors is on a roll in terms of new treatments and continued research, we appear to be well represented with over 20 ‘extracts’ submitted for review and display.  This is fairly complex stuff but much of it will be familiar to many.  I’ve filtered and extracted all the Neuroendocrine stuff into one list providing you with an easy to peruse table of contents, complete with relevant linkages if you need to read more.  For many the extract title and conclusion will be sufficiently educational or at least prompt you to click the link to investigate further.  Remember, these are extracts so do not contain all the details of the research or study. However, some are linked to bigger trials and linkages are shown where relevant.  I’ve also linked to some of my blog posts to add context and detail.

I’m hoping to capture any presentations or other output from the meeting which appears to be relevant and this will follow after the meeting.  I will also be actively tweeting any output from the live event (for many cancers, not just NETs).

There’s something for everyone here – I hope it’s useful.

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

Conclusions: Objective response to PRRT defines a subset of patients with markedly improved PFS. SUVave 21.6 defines a threshold below which patients have a poor response to PRRT. This threshold should be taken forward into prospective study.

Check out my recent blog discussing ‘Theranostic pairing” – click here

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

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

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

Conclusions: The duration of SSA use was positively associated with QoL benefit among CS patients. This may be explained by long-term effectiveness of SSAs or selection bias favoring patients with more indolent disease. Future studies will be needed to distinguish between these possibilities.

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

Conclusions: The incidence of weight gain was dose-related on TE and was greater than that on pbo. It was possibly related to a reduction in diarrhea severity, and it may be a relevant aspect of TE efficacy among patients with functioning metastatic NETs. Clinical trial information: NCT01677910

See my blog post Telotristat Ethyl

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

Conclusions: A pre-PRRT analysis of circulating NET genes, the predictive quotient index comprising “omic” analysis and grading, is validated to predict the efficacy of PRRT therapy in GEP and lung NETs.

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

Conclusions: CAPTEM shows activity in neuroendocrine tumor of unknown primary. Currently FDA approved treatment options for grade I and grade II GI NETs includes somatostatin analogs and everolimus. Both of which are cytostatic and of limited use in case of visceral crisis or bulky disease where disease shrinkage is required. CAPTEM should be considered for grade II NETS of unknown primary.

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

Conclusions: This is the first multi-center study in Mexico. Which reflects the clinical characteristics of the NET_GET. The results differ in their epidemiology from that reported in other countries. However, the clinical and therapeutic results are very similar.

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

Conclusions: These data suggest that serotonin is secreted by nonfunctioning tumors, but does not reach the threshold required for clinical carcinoid symptoms. Monitoring 5HIAA and CgA may be useful during LAN treatment of nonfunctional GEP NETs. Clinical trial information: NCT00353496

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

Conclusions: CLARINET OLE suggests sustained antitumor effects with LAN 120 mg in enteropancreatic NETs irrespective of tumor origin, and suggests benefits with LAN as early treatment. Clinical trial information: NCT00842348

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

Conclusions: Pts showed improvement in CS symptoms of flushing and diarrhea and reduction in 5HIAA levels with LAN treatment, indicating efficacy of LAN regardless of prior OCT use. Transition from OCT to LAN was well tolerated among prior OCT pts in ELECT. Clinical trial information: NCT00774930

Check out my blog post about Lanreotide and Lanreotide vs Octreotide

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

Conclusions: These findings highlight the utility of molecular classification to identify distinct NET tumor types/subtypes to improve diagnostic precision and treatment decision-making. In addition, significant differences in the distribution of molecular diagnoses of NET subtype by age and gender were identified.

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

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

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

Conclusions: In this poor prognosis G3 NET cohort of whom 77% had received prior chemotherapy, a median OS of 18 months from start of PRRT is encouraging and warrants further study. PRRT is a promising treatment option for patients with G3 NET with high somatostatin-receptor expression selected by SSRI.

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

Conclusions: Occurrence of documented carcinoid crisis was low in this high-risk population. However, a significant proportion of patients developed hemodynamic instability, suggesting that carcinoid crisis is a spectrum diagnosis and may be clinically under-recognized. Use of octreotide was not associated with risk of carcinoid crisis or hemodynamic instability; however, this analysis was limited by our modest sample size at a single institution. There remains a need to establish an objective definition of carcinoid crisis and to inform standardization of periprocedural use of octreotide for at-risk patients.

See my blog on “Carcinoid Crisis” 

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

Conclusions: By assessing patients with GI NET from two independent US claim databases, this study suggested that patients diagnosed with CS were 2-3 times more likely to be diagnosed with liver disorder, enlargement of lymph nodes, or abdominal mass, than those without CS during the one year prior to CS diagnosis. Future studies using patient medical charts are warranted to validate and interpret the findings. These findings, when validated, may aid physicians to diagnose CS patients earlier.

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

Conclusions: Radiological progression within 12 months of completion of PRRT is associated with a worse outcome in terms of OS. Patients with greater liver involvement and highest CgA levels are more likely to progress within 12 months of treatment completion. Earlier treatment with PRRT in patients with radiological progression not meeting RECIST criteria may need to be considered. There may be a greater survival benefit if PRRT is given prior to the development of large volume disease.

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

Conclusions: To the best of our knowledge, this is the first population-based study to examine potentially relevant pre-existing symptoms, resource utilization and healthcare costs before NET diagnosis. NET patients were more likely to have certain conditions and incurred higher resource utilizations and costs in the year preceding diagnosis of NET.

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

Conclusions: This population-based study showed that elderly NET pts have significantly different prevalence of co-morbidities compared to non-cancer controls. The impact of these conditions on survival and therapeutic decisions is being evaluated.

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

Conclusions: In patients with SBNET with liver metastasis, higher tumor grade and post-operative chemotherapy increased risk of death. However, resection of the primary tumor along with liver metastasis improves the 5-year OS with complete cytoreduction providing the most benefit.

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

Role of 92 gene cancer classifier assay in neuroendocrine tumor of unknown primary. | 2017 ASCO Annual Meeting Abstracts

Conclusions: Tissue type ID was able to identify a primary site in NETs of unknown primary in majority (94.7%) of cases. The result had direct implication in management of patients with regards to FDA approved treatment options in 13/38 patients (pNETs, merkel cell and pheochromocytoma).

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

Conclusions: Radical loco-regional surgery for primary tumours combined with PRRT provides a novel, highly efficacious approach in metastasised NET. The NETest accurately measures the effectiveness of treatment.

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

Conclusions: Grade 3 GEP-NECs could be morphologically classified into well and poorly differentiated NETs. Additionally, among grade 3 GEP-NECs, there was a significant difference in ranges of Ki67 index between well and poorly differentiated NECs. Higher levels ( > 60%) of Ki67 index might be a predictive marker for efficacy of EP as a standard regimen in grade 3 GEP-NECs.

Check out my blog post on Grading which has incorporated latest thinking in revised grade 3 classification

Seung Tae Kim e15686
Theranostic trial of well differentiated neuroendocrine tumors (NETs) with somatostatin antagonists 68Ga-OPS202 and 177Lu-OPS201.

Conclusions: In this trial of heavily treated NETs, preliminary data are promising for the use of 68Ga-OPS202/177Lu-OPS201 as a theranostic combination for imaging and therapy. Additional studies are planned to determine an optimal therapeutic dose and schedule. Clinical trial information: NCT02609737

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

Conclusions: SREs in NEN patients with BM were not uncommon, especially in patients with grade 3 NEN and osteolytic metastases. Application of ART did not significantly alter median OS or TTSRE, no subgroup with a benefit of ART could be identified. The use of ART in NEN should be questioned and evaluated prospectively.

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

Conclusions: Rhenium Re 188 P2045, a radiolabeled somatostatin analog, may be used to both identify and treat lung cancer tumors. The ability to image and dose patients with the same targeted molecule enables a personalized medicine approach and this highly targeted patient therapy may significantly improve treatment of tumors that over express somatostatin receptor.

Christopher Peter Adams, Wasif M. Saif e20016

Thanks for reading

Ronny
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Neuroendocrine Tumor Drug Clinical Trial – Cabozantinib (includes news on Pheochromoctyoma and Paraganglioma)

What is Cabozantinib?

Cabozantinib is an oral drug which works by blocking the growth of new blood vessels that feed a tumour. In addition to blocking the formation of new blood cells in tumours, Cabozantinib also blocks pathways that may be responsible for allowing cancers cells to become resistant to other “anti-angiogenic” drugs. It is a type of drug called a growth blocker.  Cabozantinib has been studied or is already in research studies as a possible treatment for various types of cancer, including prostate cancer, ovarian cancer, brain cancer, thyroid cancer, lung cancer, and kidney cancer. During my research, I found that it has a connection to Medullary Thyroid Cancer (MTC) which is a type of Neuroendocrine Cancer, frequently associated with Multiple Endocrine Neoplasia (MEN).  Cabozantinib, under the brand name of ‘Cometriq’ was approved by the FDA in 2012 for use in MTC.  Read more about Cometriq here.  It’s also been approved by the FDA for advanced renal cell carcinoma (RCC) (branded as Cabometyx). I also discovered that there is an exclusive licensing Agreement with the manufacturers (Elelixis) and Ipsen (of Lanreotide fame) to commercialize and develop Cabozantinib in regions outside the United States, Canada and Japan

Growth blockers are a type of biological therapy and include tyrosine kinase inhibitors, proteasome inhibitors, mTOR inhibitors, PI3K inhibitors, histone deacetylase inhibitors and hedgehog pathway blockers.  Cabozantinib is a tyrosine kinase inhibitor (TKI).  They block chemical messengers (enzymes) called tyrosine kinases.  Tyrosine kinases help to send growth signals in cells so blocking them stop the cell growing and dividing.  Some TKIs can block more than one tyrosine kinase and these are known as multi-TKIs.

cabozantinib-picture
Example action of Cabozantinib

So Capozantinib is a tyrosine kinase inhibitor and is therefore a biological therapy and growth blocker just like Everolimus (Afinitor) and Sunitinib (Sutent) – some texts describe thelattero two as chemotherapy but this is just not accurate.

Very technical process but in the simplest of terms, Cabozantinib is designed to disrupt the actions of VEGF (a growth factor) and MET (a growth factor receptor) which promote spread of cancerous cells through the growth of new blood vessels.  Whilst we are on this subject, please note Everolimus (Afinitor) is an mTOR inhibitor and Sunitinib (Sutent) is a tyrosine kinase inhibitor. Many people think these drugs are a type of chemo – that is incorrect, these are targeted biological therapies.  See more on this by clicking here.

What is the current trial status of Capozantinib?

A Phase III trial is now recruiting entitled Cabozantinib S-malate in Treating Patients With Neuroendocrine Tumors Previously Treated With Everolimus That Are Locally Advanced, Metastatic, or Cannot Be Removed by Surgery”. 

The trial has 172 locations across the US (see link below). The primary study (final data) is scheduled Jan 1st 2021.

You can read the trial documentation by clicking here.

Progress report

  1. Poster submission for 2017 Gastrointestinal Cancer Symposium
  2. Onc Live output from the 2017 Gastrointestinal Cancer Symposium
  3. Output from NANETS 2017
  4. A funded piece of research by the NET Research Foundation – check it out herelooks like they are trying to figure out what patients might benefit from Cabozantinib using biomarker data to predict response.
  5. Dr Jennifer Chan speaking in 2018 about the drug potential.  (Apologies for the use of the out of date term ‘Carcinoid‘).
  6. Phase 3 Clinical Trial Document – click here

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UPDATED 2018 – There’s also another trial looking at unresectable metastatic Pheochromocytomas and Paragangliomas

A Phase 2 Study to Evaluate the Effects of Cabozantinib in Patients with Unresectable Metastatic Pheochromocytomas and Paragangliomas 

This part is from an article collaboration between MedPage Today® and the American Association of Clinical Endocrinologists

BOSTON — Cabozantinib (Cabometyx) may benefit patients with malignant pheochromocytomas and paragangliomas, according to results of a phase II trial presented here.

Patients receiving cabozantinib (Cometriq) treatment experienced notable tumor shrinkage in the lymph nodes, liver, and lung metastases, according to Camilo Jimenez, MD, of the MD Anderson Cancer Center in Houston, and colleagues.

Additionally, progression-free survival significantly increased after treated to 12.1 months (range 0.9-28) compared with just 3.2 months prior to treatment, they reported at the American Association of Clinical Endocrinologists (AACE) annual meeting.

Cabozantinib treatment was also tied to an improvement in blood pressure and performance status, as well as remission of diabetes among these patients.

“Malignant pheochromocytomas and paragangliomas are frequently characterized by an excessive secretion of catecholamines. [Patients] have a large tumor burden and they have a decreased overall survival,” explained Jimenez. “Tumors are frequently very vascular and frequently associated with bone metastases. In fact, up to 20% of patients who have malignancy of pheochromocytomas and paragangliomas may have predominant bone metastases.”

He added that “an interesting aspect of this tumor is that C-MET receptor mutation have been found in occasional patients with malignant pheochromocytomas and paragangliomas.”

Cabozantinib is an anti-angiogenic tyrosine kinase inhibitor, which also targets RET, MET, and AXL. It is approved for metastatic medullary thyroid cancer, and was more recently approved for first-line treatment of advanced renal cell carcinoma.

“MET pathway is also involved in the development of bone metastases. In fact, cabozantinib is a very effective medications for patients who have bone metastases in the context of cancer of different origins,” Jimenez said.

In order to be eligible for the trial, patients with confirmed pheochromocytoma or paraganglioma had to be ineligible for curative surgery, have ≥3 months life expectancy, no risk for perforation or fistula, and adequate organ functioning. Prior to cabozantinib initiation, patients could not receive chemotherapy or biologic agents within 6 weeks, radiation within 4 weeks, or MIBG within 6 months.

Following histological confirmation of disease progression >1 year according to RECIST 1.1, the trial included 14 patients with measurable disease and eight patients with predominant/exclusive bone metastases. Fifteen patients subsequently enrolled into the trial, six of whom had germline mutations of the SDHB gene.

All participants were all started at an initial daily dose of 60 mg of cabozantinib, which was subsequently reduced down to between 40 to 20 mg due to toxicity in 13 patients based on tolerance.

The majority of these patients with measurable disease experienced some level of disease response. Six patients reported a partial response, defined as over a 30% reduction, while three patients achieved moderate response, marked by a 15%-30% reduction. Five of the patients with predominant bone metastases reported disease stabilization, according to results of an FDG-PET scan. One patient experienced disease progression while on treatment.

Overall, cabozantinib was generally well-tolerated without any grade 4 or 5 treatment-related adverse events reported. Some of the most common adverse events reported included grade mild dysgeusia, hand and foot syndrome, mucositis, fatigue, weight loss, and hypertension, according to the authors.

  • Primary Source – American Association of Clinical Endocrinologists meeting – AACE 2018; Abstract 142. attended my Medscape writers

You can see the Pheo/Para clinical trial document by clicking here.

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Summary

I generated this blog article to add value rather than just post the outputs for your own perusal.  I hope you find it useful.

Please note that taking part in a clinical trial is a big decision and must be considered carefully in conjunction with your specialists if necessary.  This article is not suggesting this trial is right for you.  Please check the inclusion and exclusion criteria in the trials document carefully. (Pheo/Para patients see other clinical trial link above)

Neuroendocrine Cancer: To cut or not to cut?

surgery
OPINION – nothing in here should be taken as advice from the author. 

On paper, surgery remains the only potentially ‘curative‘ option for Neuroendocrine Tumours (NETs) but there are stage, grade and anatomical constraints to that opinion. Many people get ‘twitchy’ about the ‘C word’ but our most eminent NET specialists use the term frequently including in the major treatment guidelines.

I use the word ‘curative’ with some reservations because for many who are diagnosed at an advanced stage, surgery will not cure but will debulk or cytoreduce as much tumour as possible in order to palliate symptoms and improve quality of life.  This is a big deal because NETs is one of a small number of cancers where debulking surgery can often provide a survival advantage for metastatic cases.  One of the reasons it’s a big deal is because with more aggressive cancers at an advanced stage, surgery just might not be offered. It follows that surgery is most likely adding to the fairly decent NETs survival statistics, including for those with metastatic disease at diagnosis.  More on this below.

That’s a fairly simplistic explanation on behalf of surgery. However, as we all know, nothing in Neuroendocrine Cancer is simple.  There are always a number of factors involved and every decision can in some way be on an individual basis.  There are guidelines for treatment of most types of NETs but ……. they are just that – guidelines.  NET Centres and NET Specialists are encouraged to use these guidelines, for example, a European Centre of Excellence has ENETS Guidelines.  There is a North American equivalent set published by NANETS and NCCN have a decent complementary set.  The UK and Ireland guys (UKINETS) also published a set although many UK centres are ENETS accredited.

Whether to cut or not to cut (or watch and wait then cut if necessary) and the sequencing of treatments is a really difficult issue for NET specialists.  I quite liked watching these two video clips and they cover this issue quite nicely including some interesting abdominal challenges in surgery from known NET Specialists – these short video sessions are highly recommended:

a.  Risk Stratification and Management of NETs – click here

b.  Surgical Considerations for NETs – click here

Surgery can sometimes be a tough call (……to cut or not to cut?)

It is an area where I have some sympathy for physicians and surgeons who sometimes have tough decisions to make. Surgery is risky, particularly where people are presenting in a weak condition, perhaps with very advanced disease, secondary illness and comorbidities.  I also suspect age is a factor (I was surprised to find myself considered ‘young’ at 55).  Physicians and surgeons need to weigh up these risks and the  consequences of the surgery against a ‘watch and wait’ or alternative non-surgical approach.  This would normally be discussed via a ‘Tumor Board’ or Multi-Disciplinary Team (MDT) meeting. However, and although imaging helps, the situation is not really 100% clear until the surgeon ‘gets inside’.  Remember, all physicians and surgeons are bound by the ‘Hippocratic oath’ of “Do no harm“.  Sometimes with NETs, it’s a tough call not only before they go inside but whilst they’re inside.

Surgery should be a carefully considered treatment (…..think before cutting?)

I read many stories from many different parts of the world and I also hear them from people who contact me privately on a daily basis.  Some of them are perplexed why they are not receiving surgery and some are not entirely happy with the surgery they received. Many are perplexed by different advice from different doctors.  I find it very difficult to respond to many. My most frequent answer is “ask your doctor” but I’m normally pretty helpful with the sorts of questions to ask.

One thing which tends to surprise people is speed – or lack of it!  With lower grade NETs, the extent of the tumour (stage), its metastases, histological grade and secretory profile should be determined as far as possible before planning treatment. I like to remind people that in 2010, it took from 26 July to 9 Nov before my body saw a scalpel. With Grade 1/2 well differentiated NETs, you can often get away with that gap.  Sometimes when you are diagnosed with NET, it’s a case of ‘hurry up and wait’.

Back to the guidelines, of course most people will probably fit reasonably well into the relevant guidelines flow chart.  A very generic example here (not for active use please, your area may have an alternative based on availability of treatments etc):

algorithm-ukinets-page-2-gutjnl-2012-january-61-1-6-f2-large
Very generic treatment algorithm UKINETS – Ramage JK, Ahmed A, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine tumours (NETs) Gut 2012;61:6-32.  For example purposes only please.

Timing of Surgery (……to cut now, to cut later?)

Following on from the scenario above, timing of surgery can be another factor in a ‘watch and wait’ situation. I guess this might be something in the back of the minds of more cautious doctors when faced with a rather indolent and very slow growing Neuroendocrine Tumour. For some this can be a sensible thing – ‘kicking butt’ in a surgical context is sometimes the wrong approach. The worry is that if they are not a NET specialist, they may not fully understand the vagaries of neuroendocrine tumor behaviour (i.e. they all have malignant potential – WHO 2010/2017). We’ve all heard the stories of people being told it’s not cancer, right? Please note my article Benign vs Malignant.  However, you may be interested in this post from someone who is one of the most experienced NET surgeons on the planet.  Dr Eric Liu talks quite candidly about the ‘timing’ of surgery suggesting a ‘watch and wait’ approach in certain scenarios.

Of course cutting now might actually be a pre-emptive measure. For example, if physicians can see a growth which is critically placed close to an important structure such as a blood vessel or the bile duct or bowel. Even if the disease cannot be cured, removing the tumour may prevent problems in the future by removing disease from key areas before the vital structure has been damaged or blocked. For example, my surgeon conducted a high risk operation on some desmoplasia (serotonin fibrosis) which had encircled my aorta and cava almost occluding the latter. There’s an excellent surgery pamphlet from NET Patient Foundation and I strongly recommend a read as it’s an experienced surgeon’s approach to surgery with NETs (actually written by my own surgeon Mr Neil Pearce!).  Click here to read it.

One NET centre in USA has published very detailed surgical statistics indicating that surgical cytoreduction in NET patients has low morbidity and mortality rates and results in prolonged survival.  Their conclusion went on to say “We believe that surgical cytoreduction should play a major role in the care of patients with NETs”.  You can read the extract from this document by clicking here.  Authors: Woltering et al.

Was Steve Jobs a smart guy who made a stupid decision when it came to his health? It might seem so, from the broad outlines of what he did in 2003 when a CT scan and other tests found a cancerous tumour in his pancreas. Doctors urged him to have an operation to remove the tumour, but Mr. Jobs put it off and instead tried a vegan diet, juices, herbs, acupuncture and other alternative remedies. Nine months later, the Neuroendocrine Tumour had grown. Only then did he agree to surgery, during which his doctors found the cancer had spread to his liver. The rest is summarised in my article Steve Jobs.

Summary

This is a difficult subject and no one size fits all. Treatment for NETs can be very individual including surgery.  I guess you need to be comfortable with your team. I was lucky, in that I lived close to a NET Centre.  I was referred to their surgical team once my staging and grading were complete and I was stabilised on somatostatin analogues (carcinoid syndrome under control).  I realise it’s difficult for many but I always say to people who make contact, it’s best if you can be seen by a NET centre or an experienced NET specialist – at least be guided by one if not possible or practical.  Personally, I think the surgeon’s experience in dealing with NETs is really important.  But even experienced NET centres/specialists have to make tough calls.

You may benefit from my 10 Questions article which also has links to NET Specialists.

Thanks for reading

Ronny

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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

 

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

I’m also active on Facebook.  Like my page for even more news. Please also support my other site – click here and ‘Like’

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“You must be doing OK, you’ve not had chemotherapy”

chemo

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 look well, I still have all my hair – but you should see my insides!

insides
(you may also like this blog – click above)

I’m not playing ‘Cancer Olympics’ with this post as I wish all cancer patients, regardless of type, regardless of treatment regimes, the very best outcomes.

Thanks for reading

You may also enjoy these similar and related articles:

Things not to say to a cancer patient – click here

Shame on you! – click here

I look well but you should see my insides – click here

Things are not always how they seem – click here

Not every illness is visible – click here

Not the stereotypical picture of sick – click here

An Ode to Invisible Illness – click here

Poker Face or Cancer Card – click here

Thanks for reading

Ronny

I’m also active on Facebook. Like my page for even more news. I’m also building up this site here: Ronny Allan

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Read my Cure Magazine contributions

Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

 

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

Grades of Neuroendocrine Tumour WHO 2017 15 Dec 2017

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.

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 I’m told on good authority from world leading pathologists and from listening to lectures at ENETS 2018, that the classification in the leading picture is to be used for all NENs. 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.

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).

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 less than 55% might benefit from the same treatment given to poorly differentiated NEC. 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 this 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!

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.

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

I’m also active on Facebook. Like my page for even more news. Help me build up my new site here – click here and ‘Like’

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My Diagnosis and Treatment History

Sign up for my twitter newsletter

Check out my Podcast Interview (click and press play)

Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!


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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 different 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 also depend on the type and anatomical location of the High Grade tumour involved but may include (but not limited to) chemos such as Cisplatin, Etoposide, Carboplatin, Paclitaxel, Irinotecan, Folfox, Folfiri, 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

However, cytoxic chemotherapy is often inadequate for treatment of Grade 1 and 2 Neuroendocrine tumours, because these tumours tend to have a well-differentiated histology and low proliferation index – standard chemotherapy does not appear to like their slow cytokinetic growth. Although they tend to work better on certain parts of the anatomy, e.g. pancreatic 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).

Does it work on the lower grade NETs?

Capecitabine plus Temozolomide (CAPTEM for short) is fast becoming a treatment used on certain lower grade NETs.  Dr Robert Fine says the results of the 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 Embolization

My Oncologist did mention Chemotherapy on my initial meeting and I was once scheduled to have a chemo-embolization (or TACE, Trans-arterial Chemo Embolization) but it never occurred due to post surgical routing issues. Clearly TACE is more targeted than conventional and generally systemic chemotherapy techniques.

Chemotherapy vs Targeted Biological Agents

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

If in doubt about suitability for any form of chemo, patients should seek the advice of a NET specialist.

Thanks for reading

Ronny

I’m also active on Facebook.  Like my page for even more news.  I’m also building up this site here: Ronny Allan

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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

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