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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Thanks for reading

Ronny

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Neuroendocrine Cancer – Exciting Times Ahead!  

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In the last 12-24 months, there seems to have been announcement after announcement of new and/or upgraded/enhanced diagnostics and treatment types for Neuroendocrine Cancer.  Scans, radionuclide therapies, combination therapies, somatostatin analogues, biological therapies, etc.  Some of the announcements are just expansions of existing therapies having been approved in new (but significant) regions. Compared to some other cancers, even those which hit the headlines often, we appear to be doing not too badly.  However, the pressure needs to stay on, all patients need access to the best diagnostics and treatments for them; and at the requisite time.  There’s even more in the pipeline and I’m hoping to continue to bring you news of new stuff as I have been doing for the last year.

Some of these new diagnostics and treatments will benefit eligible patients who are in diagnosis/newly diagnosed and also those living with the disease. As we’re now in our awareness month, let’s recap:

Scans

Many NET Patients will undergo a nuclear scan to confirm CT results and/or to detect further neuroendocrine activity.  Basically, a nuclear substance is mixed with a somatostatin analogue, injected into the patient who is then scanned using a 360-degree gamma camera.  As gamma cameras are designed to show up radioactive activity; and as Neuroendocrine Tumour cells will bind to the somatostatin analogue, it follows that the pictures provided will show where Neuroendocrine tumours are located.  Many people will have had an ‘Octreotide’ Scan (or more formally – Somatostatin Receptor Scintigraphy) which is still the gold standard in many areas. The latest generation of nuclear scans is based on the platform of the Gallium (Ga) 68 PET Scan. The principles of how the scan works is essentially as described above except that the more efficient radioactive/peptide mix and better scan definition, means a much better picture providing more detail (see example below). It’s important to note that positive somatostatin receptors are necessary for both scans to be effective. Europe and a few other areas have been using the Ga-68 PET scans for some time (although they are still limited in availability by sparse deployment). The latest excitement surrounding this new scan is because they are currently being rolled out in USA.  Read about the US FDA approval here.  You may hear this scan being labelled as ‘NETSPOT’ in USA but this is technically the name for the preparation radiopharmaceutical kit for the scan which includes a single-dose injection of the organic peptide and the radionuclide material. Take a look at a comparison of both scans here:

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Octreoscan output vs Gallium 68 PET output

This slide from a recent NET Research Foundation conference confirms the power of more detailed scanning.

Peptide Receptor Radionuclide Therapy (PRRT)

Similar to above, this treatment has been in use in Europe and other places for some time but is also to be formally deployed in USA if, as is expected, the US FDA approval is positive at the end of this year (Read here).  In the most basic terms, this is a treatment whereby a peptide is mixed with a radionuclide and is drip fed over a number of treatments (normally up to 4 spaced out over a year). The concept of delivery of the ‘payload’ to the tumours is actually very similar to the preparation for a radionuclide scan as described above, the key difference is the dosage and length of exposure whilst the tumours are attacked. Once again, receptors are important. The NETTER series of trials showed good results and this is an excellent addition to the portfolio for those patients who are eligible for this treatment. Fingers crossed for the US FDA announcement due by the end of this year.  Also fingers crossed that PRRT returns to the NHS England & Wales portfolio of available treatments next year.  The Carcinoid Cancer Foundation has an excellent summary of PRRT here.

PRRT and Chemo Combo

Whilst on this subject, I also want to highlight the innovative use of combo therapies in Australia where they are combining PRRT and Chemo (PRCRT).  I blogged about this here:

PRRT CAPTEM

Somatostatin Analogues and their Delivery Systems

Somatostatin analogues are a mainstay treatment for many NET Patients.  These drugs target NET cell receptors which has the effect of inhibiting release of certain hormones which are responsible for some of the ‘syndromic’ effects of the disease.  Again, receptors are important for the efficacy of this treatment.  You can read the ‘geeky’ stuff on how they work here.  These drugs mainly comprise Octreotide (provided by Novartis) and Lanreotide (provided by Ipsen). The latter has been around in Europe for 10 years and was introduced to North America earlier this year.  Octreotide has been around for much longer, almost 17 years.  When you consider these peptides have also been used to support nuclear scans that can detect the presence of tumours; and that studies have shown they also have an anti-tumour effect, they really are an important treatment for many NET Patients.  I’ve blogged about new somatostatin analogues in the pipeline and you can read this here.  This blog also contains information about new delivery systems including the use of oral capsules and nasal sprays (…….. very early days though).

Treatment for Carcinoid Syndrome

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For maintenance and quality of life, the release of a Telotristat Ethyl for Carcinoid Syndrome is an exciting development as is the first new treatment for Carcinoid Syndrome in 17 years.  This is a drug which is taken orally and inhibits the secretion of serotonin which causes some of the symptoms of the syndrome including diarrhea.  It must be emphasised it’s only for treating diarrhea caused by syndrome and might not be effective for diarrhea caused by other factors including surgery.  Read about how it works and its target patient group in my blog here.

Oncolytic Virus

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The announcement of a clinical trial for the Oncolytic Virus (an Immunotherapy treatment) specifically for Neuroendocrine Tumours is also very exciting and offers a lot of hope. Click the photo for the last progress update.  

Everolimus (Afinitor)

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Earlier this year, AFINITOR became the first treatment approved for progressive, non-functional NETs of lung origin, and one of very few options available for progressive, non-functional GI NET, representing a shift in the treatment paradigm for these cancers.  It’s been around for some time in trials (the RADIANT series) and is also used to treat breast and kidney cancer.  It’s manufactured by Novartis (of Octreotide fame).  It has some varying side effects but these appear to be tolerable for most and as with any cancer drug, they need to weighed against the benefits they bring.

In technical terms, AFINITOR is a type of drug known as an ‘mTOR’ inhibitor (it’s not a chemo as frequently stated on NET patient forums).  Taken in tablet form, it works by blocking the mTOR protein. In doing so, AFINITOR helps to slow blood vessels from feeding oxygen and nutrients to the tumour.

Check out Novartis Afinitor website for more detailed information.  There’s an excellent update about AFINITOR rom NET expert Dr James Yao here.  The US FDA approval can be found here.

Summary

………. and relax!   Wow, I’ve surprised myself by collating and revising the last 12-24 months.  Dr James Yao also agrees – check out his upbeat message in the attached 2 page summary.  You may also like another upbeat message from Dr Jonathan Strosberg by clicking here.

Neuroendocrine Cancer – who’d have thought it?  ….. a bit of a dark horse.

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!

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