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 any inference of the ‘C word’ (cure) 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?)
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):
Removal of the primary in metastatic NENs
In 2019, Wiley published a paper where the data indicated that resection of the primary tumor improves survival in patients with gastro‐entero‐pancreatic neuroendocrine neoplasms with liver metastases. This is based on an analysis of the SEER database, the largest collection of NEN related data on incidence and prevalence. Read more here. Note some old terms are used but it is based on historical data, e.g. moderately differentiated is no longer used. Note also figures appears to be a combination of well and poorly differentiated and careful interpretation of prognostic data is required.
In another published paper, there’s data to support the Wiley one above at least in SI NETs and pNETs. The paper from European Journal of Surgical Oncology (EJSO) concluded that …”Meta-analysis demonstrates that palliative resection of primary small intestine (SI-NETs) and pancreatic (pNETs) in the setting of unresectable metastatic disease can increase survival. Although these results should be interpreted with caution due to potential selection and publication bias, the data supports consideration of surgery, particularly in patients with low tumour burdens and good functional status“. It’s only an abstract (the whole data is a subscription article) but read it here.
Removal of Liver Metastases
According to a paper written by several well known surgeons (see below), around half of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have stage IV disease at presentation and the most likely organ to be affected by metastases is the liver. Hepatic involvement and hepatic tumor burden is a key prognostic factor affecting survival of these patients. In this paper, they claim that systemic therapies including sandostatin (PROMID), lanreotide (CLARINET), everolimus (RADIANT 3 and 4), sunitinib and Peptide Receptor Radionuclide Therapy (NETTER-1) have not shown efficacy in reducing liver tumor burden in patients with stage IV GEP-NETs. They concluded that although often overlooked, surgical debulking has been associated with a significant survival advantage in large retrospective studies and in our opinion should remain an important therapeutic option for patients with stage IV GEP-NETs and liver metastases. The paper is only available on subscription but an abstract can be found here. Authors: Keutgen XM, Schadde E, Pommier RF, Halfdanarson TR, Howe JR, Kebebew E.
Pancreatic NETs remain controversial
There’s much debate in the NET specialist community about what to do with small indolent pancreatic NETs (pNETs). You may find snippets of this debate inside some of the references above but this article includes a discussion between physicians about the merits of cutting or not cutting (i.e. watch and wait). Read more here. It comes with a bonus study on pNETs highlighting one of the key problems areas and how it may be solved in the future.
Small Intestine NETs is not routine bowel surgery
Operating in the area of the small intestine is not for the inexperienced and by that I also mean knowledge of NETs and the associated complications. Read more in this post which contains input by world renowned NET experts. Click here or on the photo below.
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.
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.
Steve Jobs was a >smart guy but did he make 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. Just to emphasise this is one very famous example of a case where earlier surgery may have benefited a patient but it still may not apply to you or any other patient you know.
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.
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A person with Neuroendocrine Cancer fell into a hole and couldn’t get out. When a work colleague walked by the person called out for help,