Proton Pump Inhibitors – the NET Effect


Proton pump inhibitors (PPIs) reduce the production of acid by blocking the enzyme in the wall of the stomach that produces acid. Acid is necessary for the formation of most ulcers in the oesophagus, stomach, and duodenum, and the reduction of acid with PPIs prevents ulcers and allows any ulcers that exist in the oesophagus, stomach, and duodenum to heal. PPIs are prescribed to treat acid related conditions such as:

  • Esophageal duodenal and stomach ulcers
  • NSAID-associated ulcer
  • Ulcers
  • Gastroesophageal reflux disease (GERD)
  • Zollinger-Ellison Syndrome – ZES (note this is a syndrome associated with a functioning duodenal or pancreatic NET known as a Gastrinoma)
  • They also are used in combination with antibiotics for eradicating Helicobacter pylori, a bacterium that together with acid causes ulcers of the stomach and duodenum for eradicating H. pylori, a bacterium that together with acid causes ulcers of the stomach and duodenum.

Although this should not be considered a full list applicable to all countries, the drugs tend to be prescribed or purchased under the following names:

  • Aspirin and Omeprazole (Yosprala)
  • Dexlansoprazole (Dexilent, Dexilent Solutab)
  • Esomeprazole (Nexium, Nexium IV, Nexium 24 HR)
  • Esomeprazole magnesium/naproxen (Vimovo)
  • Lansoprazole (Prevacid, Prevacid IV, Prevacid 24-Hour, Zoton FasTab)
  • Omeprazole (Prilosec, Prilosec OTC, Losec, Mepradec)
  • Omeprazole and sodium bicarbonate (Zegerid, Zegerid OTC)
  • Pantoprazole (Protonix, Pantoloc Control)
  • Rabeprazole (Aciphex, Aciphex Sprinkle, Pariet)

PPIs have revolutionized the management of acid-related diseases and there is evidence supporting their superior efficacy and overall safety profile. Unfortunately, it would appear this has possibly led to their overuse and inappropriate use. When used appropriately, the overall benefits significantly outweigh the potential risks in most patients.

One US pharmacist magazine has stated that almost half of all patients taking a PPI do not have a clear indication. It follows that PPIs may not be the appropriate treatment for many people. The American Gastro Journal nicely covers this issue – click here.

What is the connection with NETs?

Millions of people will have been prescribed these drugs for the various reasons listed above and as I said above quoting from a reputable US Pharmacist magazine, perhaps many do not have a clear indication for their use. So this issue is much wider than NETs.

Above, you can see a direct link to duodenal/pancreatic NET syndrome – ZES. However, there is also a known link between the use of PPIs and the effect on the Chromogranin A blood test, the most common tumour marker used in the diagnosis and surveillance of many types of NET. Several studies have concluded that PPIs falsely elevate Chromogranin A – read more here.

Any other risks of using PPIs?

There are several well-known risks of using PPIs in the long-term. However, many drugs have side effects, often the risks of not taking a particular drug can be outweighed by taking it. I will not comment further but leave you with some references to read yourself:

1. From the UK National Health Service (NHS). They took a balanced view adding the risk element I described above. Importantly they stated that PPIs are not usually intended to be taken long-term. Read more here. The British Medical Journal (BMJ) published the study referred to by the NHS here.

2. The NHS also published an article based on the results of a US study. Again, they indicated the study had similar limitations to the one above. Read more here (links to the study contained within).

3. There are literally dozens of similar articles but most seem to point to these two studies. However, it should also be noted that the US FDA has issued safety warnings about long-term use of PPIs. This is covered in the aforementioned US Pharmacist magazine article here.

Are there alternatives to PPIs?

Firstly, you should NEVER stop taking PPIs without speaking to the doctor who prescribed them.

There’s a class of drugs known as Histamine H2 Receptor Antagonists (H2RA) that reduce the amount of acid produced by the cells in the lining of the stomach. They are also commonly called H2 blockers. They include Cimetidine (Tagamet, Tagamet HB), Famotidine (Pepcid, Pepcid AC), Nizatidine (Axid) and Ranitidine (Zantac). Brand names may differ from country to country. From what I read, they are not as powerful as PPIs but for some people they may prove adequate. Read more about H2 blockers here.

So I can just stop taking PPIs and start taking H2 blockers?

NO. As I said above, you should never discontinue a prescription for PPI without talking to your doctor. However …. it’s not common knowledge that suddenly stopping PPIs is not a good idea – you must gradually reduce (i.e. taper off).

Why taper? PPIs block the production of acid in your stomach which can help with the symptoms but that also turns on the release of gastrin. This is not ideal for two reasons according to NOLANETS:

  1. When you try to get off of PPI, the gastrin stimulates acid production and stays elevated, potentially for several months (depending on how long you were on the PPIs). This makes your reflux worse than before and makes getting off of this medication very difficult. Gastrin also stimulates Chromogranin A thus why this can be elevated in patients who have been taking PPIs.
  2. Gastrin also acts like a growth factor and stimulates the growth of ECL cells (enterochromaffin like cells). Clearly this does not happen to everyone on PPIs. However, and as per the NHS advice above, PPIs should not be considered a long-term solution except for conditions for which they are clinically indicated (e.g. Barrett’s oesophagus, Gastrinoma (Zollinger Ellison Syndrome).

What are NET Specialists saying about this?

The best source of information on this seems to be in two main areas:

1. One is NOLANETS (Dr Eugene Woltering et al) who appear to be leading the way on identifying those who may have a clinical indication for use of H2 blockers rather than PPI and this NET Specialist organisation has produced a sheet showing how to taper people off the drug and onto the less risky H2 blockers. Read the NOLANETS “Get off PPIs” Sheet by clicking here. They state that PPI use increases circulating gastrin which in turn increases the amount of acid in the stomach. The increase in gastrin also stimulates the enterochromaffin like cells (ECL) of the stomach to produce Chromogranin A and this explains why it can be elevated in PPI users. The US Pharmacy magazine quoted above, appears to confirm this thinking.

2. The European NET Society (ENETS) discusses the issue in their guidelines but only in relation to Zollinger-Ellison Syndrome (ZES). This is a direct quote from ENETS 2016 Guidance – “The widespread use of PPIs is a major problem for the diagnosis of ZES because these drugs have an extended duration of action (up to one week), they cause hypergastrinemia in 80-100% of all normal subjects, and can confound the diagnosis. Furthermore, if PPIs are abruptly stopped in a true ZES patient, anti-peptic complications can rapidly develop, and therefore some expert groups have recently recommended that the diagnosis of ZES should be established without stopping the PPIs or by attempting to taper the dose. Unfortunately, as suggested in a number of recent papers, in most patients, the diagnosis cannot be easily established without an interruption of the PPIs. Furthermore, a secretin test cannot be used while a patient is taking PPIs because it can result in a false positive test. Other tumour markers such as serum chromogranin A were found to be not reliable for the diagnosis of ZES patients, as up to 30% have normal plasma chromogranin A levels. PPIs also lead to increased chromogranin A levels on their own. It is therefore recommended that if the diagnosis is unclear, the patient should be referred to a centre of excellence and if this is not possible, PPI withdrawal should be cautiously performed (in an asymptomatic patients with no active acid-peptic disease or damage) and with adequate cover by H2 blockers and careful patient monitoring”.

PPIs and PERT

I have anecdotal evidence that people are being prescribed PPIs alongside Pancreatic Enzymes Replacement Therapy (e.g. Creon, Nutrizym etc). While most types of PERT are gastro-resistant, a high acid environment may impair their efficacy. The rationale behind using PPI (or H2 blocker) is to decrease the acid level and allow the PERT to work better. Given the research behind this article, I would certainly challenge the use of PPI alongside long-term use of PERT.

Summary

The aim of this article is not to scare anyone, I’ve been careful with the sources, quotes and facts. Like anything in life (including the medical world), there are risks and knowing about them allows us to manage these risks in conjunction with our doctors and healthcare specialists. If you are concerned about anything you find inside this article, I suggest you speak directly to your doctor/specialist for advice.

Personally speaking, I would like to see more from the NET Specialist community on this issue.

Thanks for reading

Ronny

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Clinical Trial: Lenvatinib Efficacy in Metastatic Neuroendocrine Tumors (TALENT)



Lenvatinib has just completed a Phase 2 trial in Gastrointestinal (GI) and Pancreatic Neuroendocrine Tumours.  The trial was sponsored by Grupo Espanol de Tumores Neuroendocrinos (Spanish NET scientific organisation) and the manufacturers.  A European venture with sites in Austria, Italy, Spain, UK.   Headline: The responses are better than Everolimus (Afinitor) and Sunitinib (Sutent).

What is Lenvatinib?

It is a type of targeted therapy known as a multikinase inhibitor. The brand name is ‘LENVIMA‘. These work by inhibiting multiple intracellular and cell surface kinases, some of which are implicated in tumour growth and metastatic progression of cancer, thus decreasing tumour growth and replication. A range of receptor kinases are involved in these processes, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor (c-KIT), Flt3, fibroblast growth factor receptor (FGFR), which can be hyperactivated during tumour formation and progression.  Tumour growth may be prevented by inhibiting the action of these hyperactivated receptor kinases, and as tumour progression usually involves the action of multiple kinases rather than just one, it is logical to target multiple kinases.

The Lenvantinib mechanism of action is similar to targeted therapy drugs already in use (or in trial) for Neuroendocrine Tumours:

  • Sunitinib (Sutent) – a targeted therapy receptor protein-tyrosine kinase inhibitor.  It inhibits the actions of vascular endothelial growth factor (VEGF) and is an angiogenesis inhibitor (i.e. the development of blood vessels to supply the tumour with nutrients, which they need to grow).  It is a mutlikinase in inhibitor.
  • Everolimus (Afinitor) – a targeted therapy kinase inhibitor that inhibits mammalian target of rapamycin (mTor) kinase, an enzyme required for cell growth and survival. By blocking this enzyme, the medication prevents cell division and, in turn, tumor growth. The medication can also interrupt angiogenesis.
  • Cabozantinib, an oral potent inhibitor of vascular endothelial growth factor receptor 2, MET, and AXL, and currently on trial for Neuroendocrine Cancer.  Click here.

Multikinase inhibitors such as Lenvatinib, may be used to treat advanced kidney cancer as well as other specific types of cancer (in my research I also noted that in addition to kidney cancer, the drug is already approved for liver and thyroid cancers).  Worth also noting that the 3 examples of targeted therapy above are not just in use/in trial for Neuroendocrine Cancer, they are also in use/in trial for others including Renal (Kidney) Cancer, Breast Cancer.  Often more than one single kinase inhibitor can be given as a combo treatment, perhaps in sequence, to tackle multi kinases.

Anything special about Lenvatinib for Neuroendocrine Cancer? 

Recent reports from oncology conferences indicate that Lenvatinib showed significant antitumor activity and a favourable toxicity profile in progressive advanced NETs. This is the highest reported ORR with a targeted agent, confirmed by central radiology assessment in pancreatic NETs and Gastrointestinal (GI) NETs with promising progression free survival (PFS) in a pre-treated population; further evaluation is warranted.

Adverse events were mild to moderate in 90% of patients, the most frequent being fatigue, diarrhea and hypertension.

Lenvatinib showed the highest reported overall response rate (ORR) by central radiology assessment with a targeted agent in advanced NETs:

Average 29.2%

pNETs: 40.4% (95% CI 27.3-54.9),

GI NETs: 18.5% (95% CI 9.7-31.9.

Worth noting that Everolimus and Sunitinib were approved with ORRs much less than these figures.

What’s next? 

Given the responses in comparison to other approved targeted agents, a phase 3 trial should be anticipated.  Studies are “currently ongoing” and “further evaluation warranted”.  I will keep this article live to provide updates.

Reference material used in the compilation of this article:

1. Annals of Oncology – Efficacy of Lenvatinib in patients with advanced pancreatic (panNETs) and gastrointestinal (giNETs) grade 1/2 (G1/G2) neuroendocrine tumors: Results of the international phase II TALENT trial (GETNE 1509) 23 Oct 2018 –  click here.

2. ESMO Congress 2018 – Efficacy of Lenvatinib in patients with advanced pancreatic (panNETs) and gastrointestinal (giNETs) grade 1/2 (G1/G2) neuroendocrine tumors – click here

3. Prime Oncology Slide Show – click here (useful)

4. Clinical Trials Document NCT02678780 – click here

5. Manufactures website – click here.

Thanks for reading

Ronny

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Clinical Trial: Intra-arterial Lu177 (PRRT) for Neuroendocrine Cancer liver metastases (LUTIA)


PRRT INTRA ARTERIAL

 

The treatment of liver metastasis is a common approach following a metastatic diagnosis or discovery of liver metastasis downstream via re-staging. In addition to surgery, there are several liver directed therapies available via embolization techniques. This comes in several flavours:

1. Bland liver embolization – a minimally invasive technique which simply blocks the blood supply to the liver tumours in an attempt to reduce or kill those tumours. Sometimes called Hepatic Arterial Embolization or HAE.

2. Chemotherapy liver embolization – as above but adds in some cytotoxic chemo to the mix. Sometimes called Trans Arterial Chemo Embolization or TACE.

3. Radioembolization is a minimally invasive procedure that combines embolization and radiation therapy to treat liver cancer. Tiny glass or resin beads filled with the radioactive isotope yttrium Y-90 are placed inside the blood vessels that feed a tumour. Often known as Sirtex or SIR-Spheres.

Of course systemic treatment is body-wide and so includes the liver as a target. Systemic treatment includes (but is not limited to) Lu177 (PRRT), Chemotherapy, Targeted Therapies such as Everolimus (Afinitor) and Sunitinib (Sutent). Also included are somatostatin analogues such as Lanreotide and Octreotide.

Sometimes systemic treatment is not fully effective on all metastases and although PRRT response rates are good, often patients still live with the burden of remnant liver tumours once therapy is finished.

Doctors in the Netherlands are looking at a trial using Lu177 (PRRT) as a liver directed therapy. The trial is based at 3 sites in the Netherlands and is titled: Intra-arterial Lutetium-177-dotatate for Treatment of Patients With Neuro-endocrine Tumor Liver Metastases (LUTIA). You can read more about the trial by clicking here.

I will keep this article open for any updates.

Thanks for reading

Ronny

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Clinical Trial SPARTALIZUMAB – Immunotherapy for Neuroendocrine Neoplasms (PDR001)

THUMBNAIL_CarTcell.jpg

PDR001 (anti-PD-1) is an investigational immunotherapy being developed by Novartis to treat both solid tumors and lymphomas (cancers of the blood).  It is currently being trialled on many cancers including Neuroendocrine.  It’s brand name is SPARTLIZUMAB.

How PDR001 works

PDR001 is a type of immunotherapy, meaning that it acts by activating the body’s own immune system to recognize and fight cancer cells. Normally, an immune system cell called T-cells recognizes and kills infected or abnormal cells, including those that are cancerous. To prevent T-cells from accidentally damaging healthy and essential tissues, however several immune system checkpoints exist to inhibit, or block, them from going about this work. One example is the programmed cell death 1 (PD-1) pathway. Healthy cells produce and display a protein called programmed cell death ligand-1 or ligand-2 (PD-L1 or PD-L2) on their surface. These proteins bind to and activate a receptor called PD-1 that is produced by T-cells. When activated, PD-1 sends a message to the T-cells that prevents them from attacking that particular cell. Cancer cells can hijack this system by producing PD-L1 or PD-L2, effectively hiding from T-cells and evade destruction.
PDR001 is an antibody, a protein designed to interact with and block a specific target. It acts by binding to PD-1, blocking it from interacting with both PD-L1 and PD-L2. This binding blocks the PD-1-mediated inactivation of the T-cells, so that they are able to recognize and target cancer cells. This should result in a reduction in tumor growth and size.

PDR001 in clinical trials

PDR001 has been investigated in multiple completed and ongoing clinical trials, both alone and in combination with a wide range of other agents.

Novartis presented results from an ongoing first-in-human Phase 1/2 clinical trial (NCT02404441) of PDR001 at the American Society of Clinical Oncology (ASCO) meeting in 2016. Preliminary trial results suggested that the drug is well-tolerated and safe, with a similar profile to other anti-PD-1 drugs currently being developed. The trial is still recruiting patients with various types of advanced cancer at 43 sites across North America, Europe, and Asia; more information is available by clicking on its identification number.

Novartis then initiated several dozen other Phase 1, 2 and 3 trials, all registered on clinicaltrials.gov, to continue investigating the safety and anti-tumor activity of PDR001 in a wide range of cancer types, and in combination with other investigational and approved therapies. For example, a Phase 3 trial (NCT02967692) is comparing the safety and efficacy of PDR001 to a placebo, in combination with Tafinlar (dabrafenib) and Mekinist (trametinib), as a treatment for advanced melanoma.

What about Neuroendocrine?

A phase 2, multi-center study assessed the efficacy and safety of PDR001 in patients with non-functional well and poorly-differentiated Neuroendocrine Neoplasms.  According to the clinical trial document, the types of NENs covered are:

  • Well-differentiated Non-functional NET of Thoracic Origin
  • Well-differentiated Non-functional NET of Gastrointestinal Origin
  • Well-differentiated Non-functional NET of Pancreatic Origin
  • Poorly-differentiated Gastroenteropancreatic Neuroendocrine Carcinoma

The clinical trial indicates the trial is active but not recruiting but it would look like they have all the patients needed and are currently analysing the trial data so far awaiting the next phase perhaps.  In fact I have discovered two pieces of evidence from the trial sponsors:

pdr001 results conclusion
Annals of Oncology (2018) 29 (suppl_8): viii467-viii478. 10.1093/annonc/mdy293

In another analysis of the results:  “Patients with well-differentiated advanced NETs were eligible if they had progressed on prior therapy, including everolimus, while the GEP-NEC patients were eligible if they had progressed on one line of chemotherapy. All patients in the trial received spartalizumab via a 30-minute infusion once every 4 weeks until disease progression or unacceptable toxicity.

In the full well-differentiated cohort, there were 7 partial responses (7%), and 55% had stable disease, while 31% had progressive disease. The confirmed objective response rate was 7%, and the disease control rate was 63%. In the GEP-NEC cohort, the objective response rate was 5%, and the disease control rate was 19%.

The thoracic NETs patients fared best with spartalizumab, with limited responses seen in the pancreatic and GI NETs groups; responses seemed to be associated with PD-L1 expression. In the thoracic NETs cohort, two of five PD-L1–positive patients had a partial response. PD-L1 positivity was more common in the GEP-NEC cohort; among 14 PD-L1–positive patients in that group, the partial response rate was 43%.

The most common adverse events regardless of cause included abdominal and back pain, anemia, dyspnea, and hypertension.

Kjell Öberg, MD, PhD, of Uppsala University in Sweden, discussed the study for ESMO. “We have hope,” he said. “We see that maybe there are some tumor types that might respond to immunotherapy.” In general, NETs are considered an “immunological desert.” There is usually very low infiltration of immune cells in these tumors, and there are a low number of genetic mutation events.”

You can also listen to two very well known NET experts (Simron Singh and Jonathan Strosberg) talk about this trial and the drug ……. “the highest response rate was seen in atypical lung neuroendocrine tumors. It was approximately 20%, but in most cases was not durable”.  See the remainder of the discussion by clicking here.

You can read more about immunotherapy trials for Neuroendocrine Neoplasms by clicking here. This article includes some advice in interpreting the ‘hype’ that can surround immunotherapy which is still a developing approach to treating cancer.

Thanks for reading

Ronny

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Q-Sphera™ – Next Generation Somatostatin Analogue delivery system?

757z468_1-SG02126-(1)

From my article about the somatostatin analogues and their drug delivery systems pipeline, there has been a very interesting development in a product called Q-Sphera (was previously known as Q-Octreotide).  In a press release today, it was announced that an unnamed ‘pharma giant’ has signed a deal with Midatech Pharma Plc that will see it evaluate the latter’s Q-Sphera drug delivery platform.  Only a guess from me, but I suspect it’s either Novartis or Ipsen (but other possibilities are emerging).

Midatech’s Q-Sphera™ is an advanced microencapsulation and polymer-depot sustained release (SR) drug delivery platform produced using a novel and disruptive printing based process, with numerous and distinct advantages over conventional reactor based technologies. From a manufacturing perspective Q-Sphera™ is a precise, scalable, efficient, and environmentally friendly microparticle platform. From a clinical perspective Q-Sphera™ ensures monodispersed microparticles that release active drug compounds into the body in a superior linear tightly controlled and predictable manner over an extended period of time from 1 – 6 months.  An injection lasting 6 months sounds very exciting but I have no more detail on the feasibility or likelihood of such a change in frequency with Octreotide or Lanreotide but the press release does mention the possibility, i.e. “Q-Sphera allows drug compounds to be released into the body in a “highly controlled manner” over a prolonged period of time; potentially from a few days to up to six months.”

What’s the main differences?

The current trials are based on the use of Sandostatin LAR (Octreotide) using the Q-Sphera delivery system (previously known as Q-Octreotide). The key aspects of usability are reconstitution and needle size but there is also an inference that less frequent injections could be possible.   A comparison of the trial output is as follows:

  • Reconstitution: For Sandostatin LAR (SLAR)™ the procedure to prepare the product for injection is a complex 30 step error prone process, taking up to 40 minutes and, once reconstituted, the product has to be given immediately to prevent solidifying and wastage of the injection. For MTD201™ Q-Octreotide the preparation process is a simple 5 – 7 minute procedure, after which the product is stable up to 2 hours. For the nurse preparing and giving the injection, the short and flexible process of MTD201™ has clear advantages over the all consuming SLAR process™.
  • Needle size: For SLAR, a large 19G needle is prescribed for the injection to prevent blockage, and often an even large 18G needle is required for successful injection. For MTD201 Q-Octreotide the precision microencapsulation technology means that a much smaller 21G needle can be used, and there are no blockages. Other Q-Sphera products use even finer needles as small as 27G. The importance of this is evident from the first-in-human phase I data where MTD201 had lower injection pain – 8% for MTD201 versus 25% for SLAR™, and much lower injection site
    tenderness – 8% for MTD201 versus 83% for SLAR.

This is an exciting development and I will keep this article live with further information as I receive it.

Thanks for reading

Ronny

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Neuroendocrine Cancer: a needle in a haystack


needle in a haystack

It’s no secret that Neuroendocrine Cancer can be difficult to diagnose. Although earlier diagnosis is improving (as reported in the SEER database report issued in 2017), there is still a lot of ground to cover. It’s also no secret that certain cancers are difficult to diagnose (NETs is one) and there are a number of reasons why this happens, including but not limited to: – they grow silently, they often produce vague symptoms which can be mistaken for much more common illnesses, and their complexity is not fully understood.

I wanted to cover two different aspects of the problem of finding NETs. Firstly, in finding the primary tumour so that the type of NET can be properly established – this drives the best treatment regime. Secondly in finding all the tumours, as this establishes the correct and most detailed staging declaration – this drives treatment plans and surveillance regimes that need to be put into place.

Hunting Tumours – Primary vs Secondary

It’s really important to determine which tumours are primary and which are secondary (metastasis). There’s a number of ways to help work this out and knowledge of NETs epidemiology studies can help.

Specialist Knowledge – certain things are known about the behaviour of NETs

Specialists and in particular NET specialists will be aware of the vagaries of NETs in terms of what tumours are normally a primary and which are normally secondary and many of the pitfalls involved in working that out. Many NETs will have metastasized to the liver at diagnosis, so whilst it is not impossible to have a primary liver NET, the vast majority of liver tumours found will be secondary (metastases). NET Specialists are more likely to have the experience than generalists. They know that the varying metastatic potential depending on the primary site clearly indicates differing biology and genetics across sites and they know that NETs are indeed a heterogeneous group of tumours. The differences cannot be explained by whether the NET is situated in the foregut, midgut, or hindgut. For example, Appendiceal NET is known to be less prone to metastasis. This may be due to the high rate of incidental findings during appendectomies, or because the appendix is an immunological organ where malignant cells can therefore be expected to be frequently recognized by the immune system.

The majority of the digestive tract is drained by the portal venous system, explaining the dominance of liver metastases in this group of tumours. This also explains our finding that many nervous system and bone metastases originate from NETs in the lungs. Disseminated tumour cells may directly reach the systemic circulation from the lungs, whereas if originating from the midgut region, they need to first pass both the liver and the lungs.

As an example of this heuristic knowledge, one Swedish study indicated that two-thirds of peritoneal metastases will be attributed to Small Intestine NETs (SI NETs). SI NETs and Pancreatic NETs (pNETs) are the most likely to metastasize. The least likely sites to metastasize are the Appendix and Rectum. The same study indicated that in addition to the common metastatic locations of lymph nodes and liver, Lung NETs are more likely to metastasize to the brain and bone than other types. I believe the findings from this study more or less correlates to other information I’ve had access to and also confirms the technical behaviour paragraph above.

There are many other clues open to those involved in diagnosing a NET:

Patient. Very often the patient plays a big part of determining where the primary and other tumours might be by carefully describing symptoms.

Incidental Finds. NETs are very often found incidentally during trips to the ER/A&E and also during tests for something else. This is particularly the case with Appendiceal NETs and might explain why the average age of a patient is significantly lower in this type of NET.

Blood tests and Hormone Markers. We are not yet in a position where these types of tests can diagnose (but we are moving in that direction). In the case of unknown primaries (CUP), sometimes test results can help to find where some of these cancers started. With NETs, symptomatic patients can often test to confirm an elevated hormone marker which may narrow it down to a specific organ or gland. Read more here.

Scans and Endoscopies. Most cancers of a certain size may show up on conventional scanning such as CT, MRI and Ultrasound. Nuclear scans are now playing a bigger part in finding tumours which betray their location through functional behaviour by lighting up or glowing on these imaging devices. Endoscopies (e.g. gastroscopies, colonoscopies, even gastro intestinal pill cameras can be used) can help but like scans are not foolproof). Generally with NETs, if you can see it, you can detect it. Read more here.

Hereditary Conditions. Around 5-10% of NETs are hereditary in nature, mostly involving the MEN group of syndromes. Many of those people will know they are at risk of developing NETs and their doctors should know the most common locations for primary tumours associated with each gene. So a declared or suspected hereditary syndrome is useful in finding primary tumours if they exist and are proving difficult to find.

Biopsies. “Tissue is the issue”. Pathology can very often give really strong clues as to the type of NET and therefore the likely location of a primary tumour, for example additional tests such as immunostains. Many biopsies will come from secondary cancer (metastases), mostly the liver.  Despite all the potential diagnostic routes above, the place the cancer started is sometimes still not found and this may lead to atypical diagnostic/treatment plans and in certain cases this might even include exploratory biopsies via surgery (invasive/minimally invasive), perhaps combined with opportunistic tumour removal if found during the procedure.

Staging. Simple staging can be given if locations of metastases are known. For example in the case of Liver metastases, the stage is automatically Stage 4. However, the full staging definition relies on knowing distant metastases, loco-regional metastases and the full Tumour/Node/Metastases (TNM) definition (size, spread, etc) cannot be given without a primary. Read more here.

Cancers of Unknown Primary

Cancer is always named for the place where it started, called the primary site. Sometimes doctors can’t tell where a cancer may have started. When cancer is found in one or more places where it seems to have spread, but the site where it started is not known, it is called a cancer of unknown primary (CUP) or an occult primary cancer.

When you look at the ratio of all cancers, the figure for cancers of unknown primary (CUP) is quite startling. Depending on where you look the figure is around 2-10%. That doesn’t seem a lot but when you consider the amount of people diagnosed with cancer, the total figure must be staggering. Interestingly, Cancer Research UK say that 60% of CUP cases are in the over 75s. In another interesting Swedish study, doctors claimed that the rates of metastatic cases were higher with certain NETs than they were in their anatomical counterparts, reinforcing the dangerous and sneaky nature of NETs.

Despite quite advanced scanning and diagnostic testing currently in place, and the extensive knowledge of NET specialists, there can still be reasons for not being able to find the primary tumour:

  • The primary is just too small to be seen and is growing quite slow. Very small cancers might not cause symptoms or be seen on scans. This is a particularly relevant point with NETs.
  • The primary could be hidden in tissue in between different organs causing confusion about the actual primary location.
  • The body’s immune system killed the primary cancer. It’s also possible (but not common) that any secondary cancer (i.e. metastases) is still growing.
  • The tumour has become loose from its primary location and exited the body, e.g. from a wall of the bowel and excreted out in the stool.
  • The primary cancer was removed during surgery for another condition and doctors didn’t know cancer had formed. For example, a uterus with cancer may be removed during a hysterectomy to treat a serious infection.

Summary

I hope this is useful for many NET patients, particularly those who are looking for a diagnosis or looking for a primary tumour.

Neuroendocrine Cancer – at times, it can really be like looking for a needle in a haystack.

Thanks for reading

Ronny

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patients included

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Neuroendocrine Cancer Clinical Trial – Lutetium-177 OPS-201 (Satoreotide)

ops 201

What is Lutetium-177 OPS-201?

This is a ‘next generation’ Peptide receptor radionuclide therapy (PRRT) or more specifically the radiopharmaceutical that binds to both activated and unactivated somatostatin receptors which are upregulated on these tumours. There is far higher binding via this mechanism than standard octreotate. The technical name of the radiopharmaceutical is Satoreotide tetraxetan lutetium-177 (author’s note, I’m guessing but it could be a variant of Lanreotide).  It was once named JR11.

What’s the difference to the current approved therapy? 

Conventional PRRT (e.g. Lutathera, Lu177 Dotatate) is based on a somatostatin receptor ‘agonist’ approach, whereas 177Lu Ops 201 Satoreotide is a receptor ‘Antagonist’.  The differences are quite technical but in the most layman terms , the antagonist has the capability of attaching (binding) to more receptors, including those in a ‘resting’ or ‘inactive’ state, spends more time on the tumor than agonist based therapies. The result is a higher number of receptor binding sites and greater tumor uptake.  In addition it is said to show an improved tumor-to-kidney dose ratio compared to 177Lu-DOTA-TATE.

This would also be reflected in the theranostic use of the drug in Ga68 imaging (i.e. Ga68 Satoreotide).

Useful reading:

This presentation from Theranostics Australia

The Clinical Trial

The clinical trial is named “Study to Evaluate the Safety and Preliminary Efficacy of 177Lu-OPSC001 in NETs”.  The protocol involves 3 cycles 8 weeks apart of intravenous Lu-177 OPS-201. All patients will have baseline Ga-68 octreotate imaging performed.

The treatment is available for all NET patients with a histologically confirmed diagnosis of:

  • unresectable GEP NET (Grade I and Grade II according to WHO classification (2010, Annex 01), functioning and non-functioning).
  • unresectable “typical lung NET” or “atypical lung NET” are acceptable (with the exception of Large Cell Bronchial Neuroendocrine Neoplasms and Small Cell Lung Cancers).
  • malignant, unresectable pheochromocytoma or paraganglioma

Patients who have previously had Lu-177 octreotate (e.g. Lutathera) are not eligible. Patients may have had any other treatment including chemotherapy, radiotherapy or Somatostatin Analogues (e.g. octreotide, landreotide).

There are other inclusion and exclusion criteria to be found within the clinical trial document.  The trial is due to compete in May 2022.

Where is the Trial based?  

At the time of writing and according to the Clinical Trial document, Australia (Melbourne and Perth),  Austria (Vienna), Denmark (Aarhus), Switzerland (Basel), UK (Royal Free London).  Two sites are also listed in France (Nantes and Toulouse) but trial document currently marked as not yet recruiting.

I have anecdotal evidence to suggest one more UK site is possible in 2019, Windsor in UK, a private healthcare provider but it will be open to public and private patients.

What about USA?

I also found an additional trial based in Memorial Sloan Kettering New York designed to take a theranostic approach by using  Satoreotide (JR11) for the pre-treatment imaging, e.g. Ga68 satoreotide (JR11) and the 177Lu version for treatment. The clinical trial document indicates this trial is active but NOT RECRUITING and is entitled “Theranostics of Radiolabeled Somatostatin Antagonists 68Ga-DOTA-JR11 and 177Lu-DOTA-JR11 in Patients With Neuroendocrine Tumors”

Thanks for reading

You may also find these PRRT related articles useful:

PRRT Overview plus locations 

Phase 1 trial of Targeted Alpha-emitter Therapy (TAT) –  212 Pb-AR-RMX

COMPETE trial 177Lu Edotreotide-Solucin

PRRT and Chemo Trial

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!

patients included

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Neuroendocrine Cancer – Short Update from NANETS 2018

NANETS 2018

I would love to go to a NANETS conference but I would need sponsorship or otherwise have to fund my own way there. Seattle sounds like a great place to visit. I would even have been their twitter correspondent had they asked!

I’ve been to the European equivalent twice, they always have theirs in Barcelona it would seem, at least NANETS uses different locations making it more interesting.  It’s a scientific conference for the most part, but I guess some basic stuff is also covered.

However, in the world of instant contact and communications on the internet, together with twitter, one can keep up to speed on what is or has been discussed.  One day, NANETS and ENETS will be sufficiently advanced that we can all watch the presentations from the comfort of our own homes (you heard it here!)

I’ve put together a collection of things I found interesting and offer them here for your perusal and selection via links.

One of the first issues to discuss was the confirmation of the new NANETS management team and board – you will recognise most names here:

Officers (2018 to 2020 Term):

    • Chair: James Howe, MD The University of Iowa Carver College of Medicine
    • Vice Chair: Emily Bergsland, MD The University of California San Francisco School of Medicine
    • Secretary: Jonathan Strosberg, MD Moffitt Cancer Center
    • Treasurer: Pam Kunz, MD Stanford University Medical Center

Board of Directors:

      • Jennifer Chan, MD, MPH (2018-2020) Dana Farber Cancer Institute
      • Thorvardur Halfdanarson, MD (2018-2020) The Mayo Clinic
      • Daniel Halperin, MD (2015-2019) University of Texas MD Anderson Cancer Center
      • Erik Nakakura, MD, Ph.D. Research Committee Board Representative (2018-2020) The University of California San Francisco School of Medicine
      • Rodney Pommier, MD (2018-2020) Oregon Health and Science University
      • Diane Reidy, MD (2015-2019) Memorial Sloan Kettering Cancer Center
      • Simron Singh, MD, Conference Committee Board Representative (2018-2019) Odette Cancer Center at Sunnybrook Health Sciences Center
      • Michael Soulen, MD (2018-2020) The Hospital of the University of Pennsylvania
      • James Yao, MD (2018-2020) University of Texas MD Anderson Cancer Center

Abstract Selection

A selection of poster abstracts below.  There was a lot more but these ones made output on twitter so I guess these were headline acts and probably of interest to patients. The extract texts/short videos I’ve included are probably all that most patients will need but when I have electronic access to the posters, I will update with links if possible and repost for those who would like to see the full detail.

The Value of Genetic Testing in NETs

This cover two posters, one for Neuroendocrine Carcinoma (very interesting) and the other covering Neuroendocrine Tumours (i.e. well differentiated NETs).  Click on the title above or click here.

An Update on Lung NET Guidelines

Some interesting snippets here and an indication that the most comprehensive Lung NET Guidelines are those produced by ENETS by Caplin et al.   Click on the title above or click here.

A Comprehensive Look at Update and Developments in NETs (Dr Thorvardur Haldanasron).

Interesting summary of new stuff in trials. Plus some interesting bits on SI NETs and pNETs.  Click on the title or click here.   There’s also a short video of Dr Haldanasron (slightly different content) – click here.

Sequencing of Lanreotide Can Improve Outcomes in Patients With Advanced GEP-NETs

Interesting trial output looking at the potential benefits of Lanreotide after Octreotide.  Click on the title or click here.

Dr Scott Paulson on Current Challenges in the NETs Treatment Landscape

Interesting and as with many specialist videos I’ve seen, sequencing of treatment remains challenging.  Text and video inside.  Click on the title to see more or click here.

Debating Best First-Line Treatment in Well-Differentiated G3 NENs

As you will know from my staging and grading article, there is now a Grade 3 well differentiated tumour status (called a NET rather than a Neuroendocrine Carcinoma).  However, there is not yet enough data to work out the optimum treatments, which may, in certain circumstances, be different from their poorly differentiated counterparts (Neuroendocrine Carcinoma).  Click on the title above or click here.

Examining the Benefits of Integrative Oncology, Nutrition in NETs

An unmet need – very interesting text.  Click on the title or click here.

Dr Heloisa Soares Discusses the Roles of Somatostatin Analogs in GEP-NETs

Dr Soares discusses the two roles of Somatostatin analogs: treating symptoms related to the tumors and controlling tumor growth.  Complete with video. Click on the title or click here.

Analysis Demonstrates Effectiveness, Patient Satisfaction With Lanreotide in GEP-NETs

Interesting data analysis about Lanreotide.  Click on the title or click here.

Ipsen Presents Data on Somatuline Depot at the North American Neuroendocrine Tumor Society (NANETS) Annual Symposium

Some very interesting stuff in here including comparisons with Octreotide.  Click on the title or click here.

Immunotherapy -Hits, Misses With New Therapies for Neuroendocrine Tumors

You may be prompted for a login, if so, let me know, I will post you the content.  The ‘misses’ is mainly the fact that Keytruda (Pembrolizumab) does not look good as a single agent treatment for high grade NEC. Headline is “Pembrolizumab, though generally well tolerated, showed limited activity as a single agent in high-grade neuroendocrine neoplasms (NENs) in this study,” Arvind Dasari, MD, of MD Anderson Cancer Center in Houston, and colleagues concluded.”  Some other interesting points though.   Click on the title above or 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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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

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Don’t worry, it’s benign!



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). This post will not cover Neuroendocrine Carcinoma which by definition is malignant.

Any definition of the word ‘tumour’ will confirm it can either be benign or malignant. However, and while I’m sure there are benign NETs, the key statement to explain any slow growing or indolent NET is that they all have malignant potential – thus why surveillance and follow up is really important. This is the key factor in the changes found in the 2010 Digestive System World Health Organisation (WHO) classification system from the previous ‘flaky’ version. This reinforcement of the malignant potential of all NETs was duplicated in the recent 2017 Endocrine System equivalent, which is now proposed as a classification scheme for all NETs (see below).

“Carcinoid”

Of course we are not helped by the continued use of the term Carcinoid which decodes to ‘Cancer Like’ – that is potentially regressing the work of those specialists who are trying to undo the last 100 years of complacency in the medical world (and not really the type of awareness we need). The word is gradually being erased from NET nomenclature and the recent 2018 proposal by the International Agency for Research on Cancer (IARC) and WHO NET expert consensus panel to ditch it from the remaining versions of out of date WHO classifications (e.g. Pulmonary/Lung, Pituitary, Head & Neck, Genito-urinary, Adrenal and Paraganglia, Skin), is the final nail in the coffin for Carcinoid. RIP Carcinoid. This also supports our awareness issues with the media reporting the wrong cancer types based on anatomy of the primary tumour. Dear Doctors, Patient Advocates and Patients ….. please stop using the word!

I have lost count of the stories from Neuroendocrine Cancer patients who have been told their tumour was benign but then returned with incurable and metastatic cancer sometime downstream. Clearly there are doctors who do not understand NETs and/or are not aware of the changes in WHO classification schemes since 2010. Sure, some will prove to be ‘benign’ in nature and may not cause many issues but any Ki-67 below 3% is a formal grade of Neuroendocrine Neoplasm. I accept that it’s currently difficult to work out which cases will turn more aggressive and when, thus why surveillance and follow up are really important and also why patients should be seeing doctors who understand NETs. Worth also noting that many slow growing and indolent tumors can still often produce troublesome NET syndromes.

I’ve even heard one patient story where it was claimed a doctor called a metastatic NET case benign! Any definition of ‘benign’ on any respectable cancer site, will include the statement that they do not spread to other parts of the body. The NET Patient world is full of slow growing Grade 1 Stage 4 patients – by definition, they’re all malignant.

Read more detail in these articles as these issues are inextricably linked.

‘Benign vs Malignant’.
‘Carcinoid vs Neuroendocrine’
‘The Invisible NET Patient Population’
‘Staging and Grading’

I’m sure there are scenarios in all cancers where tumours can be benign and will never harm the person but if a Doctor says you have a Neuroendocrine Tumour and not to worry because it’s benign, ask questions.  Start with “how do you know it will never turn malignant” and “what will be done going forward to check”. 

Thanks for listening

Ronny

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