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Al Musella`s Brain Tumor Blog on SNO2014

Al's Comment:

 This is my thoughts on the exciting news from SNO this week!


Posted on: 11/19/2014

Al’s Brain Tumor Blog:   Update from Society Of Neurooncology Meeting Nov 2014

By Al Musella, DPM  11/19/2014

 

This was an exciting week for brain tumor treatments.  The big news for the week was the announcement that the Optune trial (Optune is the new name for the Novocure Novo-TTF 100a device) was stopped because it was working so well that it would be unethical to withhold treatment in the control group.  Dr Roger Stupp (of the “Stupp Protocol” which is the current standard of care for glioblastomas) made the presentation about the results, showing almost a 50% increase in the 2 year survival rate for newly diagnosed glioblastoma.    This is the first time a non-toxic treatment had a successful phase 3 trial in any cancer.  Dr Stupp said "a new standard of care for patients with GBM has been established", and  "A new cancer treatment modality has been born".  He called it a “paradigm shift”. 

Note that Optune is not yet the current standard of care. Here in the USA that gets determined by the National Comprehensive Cancer Network guidelines, which takes time to update. Hopefully they will update the guidelines soon.

  At first the significance of Dr Stupp saying it was a “paradigm shift” didn’t hit me, but as I thought about it and talked to many of the researchers, I realized that this opens the door to an entire new way of thinking about the brain tumor treatments.

 First – a little history for perspective:   way back in 1980, the  median overall survival for GBMs was 6 months and the 2 year survival rate was only 7.5%.  Studies reported overall survivals of 3 months if there was no treatment,  4 months for those who only had surgery,  9.25 months for patients with surgery and radiation, and 10 months for surgery, radiation and chemotherapy (bcnu, procarbazine, ccnu, vincristine and various combinations).

The next step was the approval of Gliadel Wafer. This is a biodegradable implant that slowly releases chemotherapy at the tumor site. It was approved for recurrent GBM in 1996 and for newly diagnosed gbm in 2003. For newly diagnosed, it showed an increase in overall survival of 2.3 months, from 11.6 months in placebo wafer group to 13.9 in Gliadel group.

Next came Temodar. It was rejected for GBM by the FDA the first time but approved for recurrent anaplastic Astrocytomas in 1999. It was later approved for newly diagnosed gbm in 2005, and when used at the same time as radiation as well as after radiation, added 2.5 months for a total of 14.6 months overall survival.

Avastin was approved in 2009 for recurrent gbm, based on a high response rate as well as a significant increase in patient quality of life but minimal survival advantage. Research is going on now to find out better ways of using it.

And finally, the Novocure Novo-ttf100A system (now called Optune), was approved in 2011 for recurrent gbm, based on significant increase in quality of life but minimal survival advantage for recurrent gbm.   New research just reported a major increase in survival advantage of 3.3 months, to a total of 23.7 months from diagnosis, when Optune is used for newly diagnosed GBM along with the standard treatments.

Quick recap of overall survival for newly diagnosed GBM patients:

No treatment: 3 months

Surgery alone adds one month

Radiation adds 5 months

Chemotherapy (not counting Temodar) adds less than 1 month

Gliadel adds 2.3 months

Temodar adds 2.5 months

Avastin didn’t add much to survival but had other benefits

Optune adds 3.3 months

We went from 6 months average survival in the 1980s to almost 2 years now, and we have a lot more treatment choices.  Just combining these approved treatments may yield big gains.  Gliadel has sort of faded away, mostly because it may make you ineligible for some clinical trials. However, when designing a cocktail approach that excuse is no longer an issue – it can be built into the trials to see how much of an impact it can have. Many patients have tumor progression very quickly even through radiation.  My dad progressed so fast that he couldn’t finish radiation.  Gliadel may buy enough time before the progression starts for all of these other treatments to kick in, which may be another big step forward!

There are also many treatments in clinical trials now, some reporting amazing results – but on small number of patients. And lastly, there are a huge number of treatments that are approved for other diseases that we can use off label – the old chemotherapies, as well as newer targeted treatments and checkpoint inhibitors.

So the challenge now becomes finding a combination of treatments that can quickly make great strides toward the cure.  In the past, the main limit was toxicity – when you add multiple treatments, each of which causes harm to the person, you can quickly cause enough problems that all treatments have to be stopped to let the patient recover.

 The New Paradigm is to include  non-toxic and low toxicity treatments.  Adding Optune to the treatment plan brings NO toxicity concerns (other than treatable skin rashes).  That means that we have more opportunity to add other treatments without hitting the limits of what a patient can take.  There are many treatments that can be added which have minimal toxicity. These are more targeted to a specific pathways or markers on tumor cells and don’t just indiscriminately hurt cells as the other treatments do. For example, the Rindopepimut vaccine added over 3 months to survival for recurrent gbm, with minimal side effects. Hopefully it will be approved by the FDA in the next year or 2 so we can add it to the cocktail.   The DC-Vax and ICT-107 vaccines showed promising results and might also be approved soon.  Other vaccines, such as the CMV / Polio virus vaccines as well as newer vaccines that are customized to the genetic profile of the patient look promising but are further away from approval.  There are also gene therapies (Tocagen) and targeted therapies in the pipeline.

 

The problem is prioritizing which of the countless treatments to add for each patient. This may result in optimized combinations for each patient based on their tumor or it could end up being a master cocktail for all patients. The current structure of our clinical trial system does not easily allow for combinations of novel therapies, low cost off-patent drugs and/ or natural products. The current system can’t pay the high cost of running the traditional trials for a treatment that can't be sold to recoup the investment. There were a few lectures at the SNO meeting last week that talked about these issues and offered some excellent suggestions on how to proceed and speed up the process of testing. I am working on this problem.

 

The biggest catalyst for this process is the Society of Neuro-oncology conference.  It affords an amazing opportunity for networking and making connections.  There was a lot of cooperation – many of the researchers are buying into the concept of this new paradigm.  The brain tumor foundations also played major roles and worked together well. We all get many grant applications – I had over 100 so far this year – which puts us in the position of being able to introduce people working on complementary projects. For example, there was one researcher with a new way to quickly screen many treatment combinations.  I helped identify promising treatments for him to try, then introduced him to the people working on them.

Another problem is that it is very hard to use experimental treatments in a cocktail approach – so we have to fight to speed up the approvals.  The Society of Neuro-Oncology, ABC2, National Brain Tumor Society and the Musella Foundation have been working together on ways to speed up the drug development process, as the “Jumpstarting Brain Tumor Drug Development Coalition”.  Our 2 main initiatives are the Clinical Trial Endpoints Initiative, where we are working with the FDA and other organizations to identify when a new treatment is working or not in more accurate ways, as well as faster and cheaper.  Our other initiative is imaging standardization. We had a meeting at the SNO conference with experts from around the country to help define a standard set of protocols so that MRIs from different scanners can be compared, as well as better define when progression, pseudoprogression, pseudo-response and radiation necrosis occurs.

 

Bottom line:  This is a historic time for the brain tumor community. I think that we are going to see major advances come quickly – over the next few years.  We actually may have all of the components needed now to make the major breakthrough.  There are 2 ways you can help speed up the process:

1.       Money:  2/3 of the research projects that come across my desk do not get funded due to lack of money. Any of them may be the next building block needed for the big breakthrough.  We are trying to create new types of clinical trials, and to fund the trials needed even when there is no profit to be made – such as with repurposed drugs that are already off patent.
Help by making donations, or hosting fundraisers for any of the brain tumor foundations.  There are some big ideas that are not being implemented because we can’t raise the funding for them.

2.       Activism. We have had many meetings with the FDA – and it now appears that they are on our side and want to help speed up the approval process. We came a long way since the FDA rejected Temodar for GBMs. However, when the next treatments come up for approval, we can’t be complacent and need your help when we ask you to sign a petition or write a letter – they really help. Then once approved, Medicare becomes a problem as they have a limited budget and if they approve an expensive treatment for us, they have to cut a different treatment for others.  Brain tumor patients were known for not being organized and putting up a united front.  That just changed. We have to show them we are now a force and have  thousands of people on our side. We have a petition now to help try to get Medicare to pay for Optune.  Go to http://virtualtrials.com/activism.cfm to sign the petition and get 10 of your friends to do the same.  Repeat every time we ask for your help.  These things matter – we used petitions to help Medicare pay for Gliadel, Temodar and Avastin.

 

 

 

     Disclaimers: The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Musella Foundation For Brain Tumor Research & Information, Inc.  
        The following companies are sponsors of the Musella Foundation, but I have never personally received anything of value from any of them:  Arbor Pharmaceuticals (Gliadel), Celldex Therapeutics,  Genetech, Novocure, and Tocagen.

 

 


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