Al Musella, DPM, President, Musella Foundation For Brain Tumor Research & Information, Inc., Hewlett, NY;
Email: musella@virtualtrials.com Phone: 888-295-4740

Q: You direct an established foundation that supports research and information about brain tumors. What would you do if you yourself were diagnosed with a glioblastoma multiforme (GBM)?

A: Now that GBMs are in the news again, I would like to discuss what I would do if it happened to me — an adult in otherwise good shape. There are several choices.

1. Standard of care: Surgery, radiation, Temozolomide. Chance of 5 year survival is about 5%.
2. Standard of care PLUS Optune. Bumps my chance of 5 year survival up to 13% with no added toxicity.
3. Phase 3 Clinical trials: There are only two phase 3 clinical trials for newly diagnosed GBM in the USA. The first, intraoperative radiotherapy may be worth trying, as it is a single application. However, there is only a 50-50 chance of getting the radiation, versus serving as a control. The other is using an off label immunotherapy drug, Nivolumab, which has previously failed as monotherapy, tested against Temozolomide in cases where Temozolomide is known to have little effect (unmethylated MGMT). Half of the patients will get Temozolomide in a situation where it is set up to fail. That is not acceptable to me especially since the Nivolumab is readily available off label outside of the trial without the risk of using an ineffective drug. (And using it off label opens up the possibility of combining with other treatments which may wind up working)
4. Phase 1 or 2 trials: There are about 100 of these trials in the USA. There are many interesting choices here, but we do not have enough data to make an informed decision on which one to try. We do have early results from some phase 1 trials which show results much better than the standard therapies, but it is not likely that any one of these alone will make a big difference in survival for most patients. We do not have the ongoing results of these trials – we only get the results a few months after the trial is over. And while inside the trial, we cannot combine them with other treatments. Many of these trials will exclude you if you use Optune.
5. Off label use of drugs approved for other diseases. There are many choices here and a rational approach might be to select a “cocktail of drugs” based on a genomic analysis of my tumor.
6. Cocktail approach involving experimental and approved treatments. Right now this is impossible or very difficult to obtain. However, if it were possible, this would be my approach. Especially if we had a registry of all of the patients, the treatments they tried and the outcome so we can learn from every patient. A Proposed New FDA Drug Approval Pathway: “Conditional” April 5, 2017 and More Details May 10, 2017

1. Surgery – trying for maximal safe resection, possibly using Gliolan (a dye that helps surgeons see small clusters of GBM cells) to increase chances of maximal resection, and insertion of Gliadel wafer (intraoperative chemo therapy) if the resection cavity is not up against the ventricles (and we are not planning on entering a trial that excludes prior use of Gliadel).
2. Radiation – standard radiation or possibly proton beam radiation. Possibly followed by some type of boost. Possibly try adding a radiation enhancer like Trans Sodium Crocetinate – especially if there is residual tumor.
3. Temozolomide – during and after radiation. Only if the tumor sample has methylated MGMT. If the tumor is unmethylated, I would try to get Val-083 either in a trial or on compassionate use / right to try.
4. Optune. We are put into a very tricky situation here. Many trials will disqualify you if you use Optune, but Optune has the highest survival rates in large trials. So you are being asked to gamble a known doubling of chances of 5 year survival for an unknown experimental treatment that might or might not help, and you might even be assigned to a control group. I would use Optune.
5. There are a few immunotherapies that have shown remarkable results in a minority of patients. A few of the early vaccine trials and the MDNA55 trial have tails of 20% or more of patients living over 5 years and with minimal or no side effects. The early Tocagen trials showed some impressive results. I would try to get one (or maybe 2) of these, and consider adding a checkpoint inhibitor. The polio vaccine trial (PVSRIPO) is getting a lot of hype on “60 minutes” with some very impressive results – but on a small number of patients, and a few serious side effects. I know the first patient in the trial, and she is doing great and tumor free 5 years after the treatment. It is hard to get into, but I would try. [Disclaimer: I am on the patient advisory board of the brain tumor center at Duke, and helped fund the PVSRIPO Trial].

What would you do?
Al Musella’s contact info is included in the author affiliations at the top of this page.
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Smruti Vidwans, PhD, Chief Science Officer at CollabRx

Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Jerald P. Radich, MD, Director of the Molecular Oncology Lab at the Fred Hutchinson Cancer Research Center, and Professor of Medicine at the University of Washington School of Medicine

Q: In March 2016, we published your blog about how to initiate therapy for an adult patient newly diagnosed with chronic myeloid leukemia (CML). As of July 2017, what, if anything, has changed?
A: Two words: Generic imatinib.
The National Comprehensive Cancer Network (NCCN) and its European counterpart, the European Leukemia Network (ELN) are both agnostic in regards to the initial tyrosine kinase inhibitor (TKI) treatment of choice for chronic phase CML.  To review, the more potent “second generation” TKIs (dasatinib and nilotinib) have, compared to the “first generation” TKI imatinib, more efficacy in regards to a lower rate of progression to blast crisis, and deeper molecular responses. Imatinib appears to have a safer long-term toxicity profile, especially in regards to cardiovascular issues. TKI therapy has allowed CML patients to have a near normal life expectancy, and randomized trials show no survival advantage of one TKI over another.  When the second generation TKIs were approved, they were considerably more expensive than imatinib, but by way of some imaginative marketing feats, branded imatinib prescription costs rose to similar levels as the newer TKIs (~$140.000/year). Thus, there is no obvious cost advantage for prescribing the old, reliable imatinib. (Imagine this happening in the auto industry. The 2018 models come out, and last year’s price for the 2017 model suddenly rises to the 2018 version level. Who would buy the outdated model?)
However, in 2016 a generic version of imatinib became available. Costs of this generic were initially very similar to the branded drug, but a second generic was introduced, and costs have predictably begun to fall. A quick internet search finds that branded imatinib will cost roughly $11,000/month, whereas generic imatinib runs from $6-10,000/month. Experience with other generics suggest that these costs should further plummet with the introduction of more generics. In the meantime, you can send your patient to Canada ($9,000/year) or, if more adventuresome, India ($400/year). The extra savings should cover business class flight and a number of fine hotel stays.
The goals of CML treatment are

1. prevent progression to blast phase (since therapy efficacy has not progressed in decades)
2. minimize toxicity
3. in the appropriate patients, get a deep molecular response, as some patients with a deep and lasting molecular response can have their TKI discontinued, and not relapse

Considerations in this latter group are younger patients (especially if they wish to have children), and those patients who actually will consider discontinuation (some don’t if they have had a great response to therapy). Thus, in patients with high-risk chronic phase CML (by Sokal, Hasford, or EUTOS clinical score), or young patients wishing the option of possible discontinuation, the second generation TKIs are a fine choice. For patients with low-risk disease, older, and/or adverse co-morbidities (particularly cardiovascular) imatinib is a solid pick. The availability of generic imatinib makes this an even more attractive option for the majority of newly diagnosed cases.
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Melinda Roberts, Web and Product Development Lead Globiana Inc.

Q: Many people are interested in their own genes and wonder whether they are predisposed to cancer or other maladies.  You recently participated in the “23 and me” testing process. As a well-educated and informed consumer, did you find that service useful? Were the explanations given sufficient? Was it worth the cost and trouble? Have the results changed anything about your life?

A: Last December, my septuagenarian uncle left an urgent voice message for me, setting off several days of phone tag. When we finally connected he asked, “Have you heard of those DNA-based ancestry services? I know you’ve been researching our family tree, so I thought, why not? I did one and found out that we aren’t even Scottish! We’re Irish! My whole life has been a lie!”

Grandpa Tam
I thought of all the time I spent tracing some ancestors to the year 1639 and being frustrated that I couldn’t get more than a hundred years on the paternal side. At least we had documents! I looked at the ship’s manifest marking my grandparents’ emigration from Scotland, our family coat of arms that inspired one son’s semester art project, a photo of my Glaswegian grandfather posing proudly in the Shotts and Dykehead Caledonia Pipe Band in East Calder, and thought, “Well, shoot. I’m going to have to spit in a tube.”

Off to 23andMe.com. I had, of course, heard of these services but thought them cost-prohibitive in light of our richly documented heritage, but now I was a little peeved and suddenly $99 was just fine. In fact, I would go one further and spring for the $199 “Health and Ancestry Service” that promised a comprehensive understanding of my ancestry, traits, and health. What a steal.
Just this month my reports were ready, and they were voluminous. Ancestry: 5 reports. Carrier Status: 42 reports. Genetic Health Risk: 4 reports. Traits: 19 reports (What??). Wellness: 8 Reports, plus an invitation to participate in their “DNA Relatives” program and to continue to share and compare information. They even worked in a little gamification, awarding “insights” for each set of research questions answered. 77 reports worked out to $2.58 a report. This was more than a steal.
What I learned:

• No variant detected for any of the 42 carrier status listed
• No variants detected for Late-onset Alzheimer’s Disease (you’re welcome, kids), Parkinson’s disease, or Hereditary Thrombophilia
• Variant detected for Alpha-1 Anti…Antitryp…Antitrypsin Deficiency, but not likely at risk
• I can detect Asparagus in urine
• I probably don’t have dimples (I do), or a cleft chin
• I probably DO have detached earlobes (check), light freckling (check), wet earwax (I have nothing to compare it to, so likely check), lighter eyes (check) had little baby hair (check), a longer second toe (check), no widow’s peak (check), little or no unibrow (check, thanks to tweezing), and prefer sweet taste over bitter (check), am predisposed to weigh more than average (thanks), unlikely to flush with alcohol (how can I tell? I’m probably drunk), likely to be a deep sleeper (check, until firstborn arrived), and don’t move around much in sleep (if I did, my husband and I would have to sleep in the Coliseum)
• I have 1,258 relatives already in the 23andMe DNA Family! (Good upsell)

The service provides lots of fun graphics, such as the locations of my DNA relatives and migrations of my maternal line (presumably because the guys never asked for directions). Mom, you swung way east before heading north (the shortest route). Good job.

I can’t say I’ve changed anything in my life as a result of these findings, but I am very pleased to be able to tell my children that we are unlikely to face several very traumatic future ailments, and am newly motivated to contribute to their research.
By the way, I am 63% British and Irish. And as I was warned, nothing about Scotland, but of course that is because “Scottish” falls under British. I won’t tell Uncle Dougal.

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Keith Flaherty, MD, Associate Professor of Medicine, Harvard Medical School; Director of Developmental Therapeutics, Cancer Center, Massachusetts General Hospital

Q: A lot has happened in the field of Metastatic Melanoma since March, 2016. In April of 2017, would your reply be any different? If so, in what way, and why?
A: The only change from 2016 to 2017 in terms of treatment options for a young patient with metastatic disease is that the 2016 leaning toward combination CTLA-4/PD1 immunotherapy has come back to PD1 monotherapy versus BRAF/MEK combination therapy. With two-year follow-up data from the BMS 067 trial, there was very little difference in survival (5%) versus the very large difference in risk of severe toxicity. But, PD1 antibody therapy with CTLA-4 antibody therapy as a backup remains a very compelling option for BRAF wild-type patients and BRAF/MEK combination therapy as a first-line or second line therapy for those with a BRAF mutation remains on the menu.

Response from March 2016

Q: What is your basic approach to handling a new young adult patient in good general health who is referred to you with a diagnosis of Malignant Melanoma, metastatic to liver or lung? The primary cutaneous melanoma, 1.5 mm in thickness, was diagnosed in Maine 5 years ago and was of skin on the forearm; treated there by wide resection with clear margins and no lymph node dissection. There was no molecular/genomic testing of the primary.
A: In a case like this, there are a few additional elements of data that I always try to obtain:

1. Brain MRI
2. Serum LDH
3. V600 BRAF mutation status (younger patients are significantly more likely than older patients to have a V600 BRAF mutation), so it’s likely that this patient has one
4. Presence or absence of disease-related symptoms
5. Prior scans that might allow the pace of disease progression to be ascertained (not always possible in a very recently diagnosed patient; but even if 4-6 weeks have passed since the first assessment prior to me seeing the patient, I’ll consider repeating imaging of the lungs and liver to glean the pace of progression.

The factors above go into determining disease burden and pace of disease progression. Presence of brain metastases does not necessarily impact choice of first-line systemic therapy, but certainly informs the need for resection (for single large metastases) or stereotactic radiation for one or several small metastases in parallel with pursuing systemic therapy. The presence of numerous brain metastases would push me to select BRAF/MEK combination therapy if a V600 BRAF mutation were found. Elevated serum LDH, the presence of disease-related symptoms, or evidence of rapid disease progression each push me toward considering of BRAF/MEK combination therapy (presuming BRAF mutant), and certainly two or three of these three factors would force that decision. In the absence of any of these factors, first-line immunotherapy is generally my approach. For most patients that means single-agent PD-1 antibody therapy. But, for young patients who are not deterred by a high rate of severe toxicity and for patients with any of the three “aggressive’ disease warning signs indicated above, I would favor combined CTLA-4/PD-1 antibody therapy. This is based on the higher initial response-rate and short-term ability to control the disease with the combination compared to PD-1 antibody monotherapy. We do not yet know that this combination improves overall survival compared to sequential therapy with PD-1, CTLA-4 and/or BRAF/MEK inhibition. In the absence of that data, I favor PD-1 monotherapy first-line for most patients. If a patient progresses on first-line PD-1 antibody therapy, then I reassess the same warning sign factors as above, now informed by the rate of progression evident on follow-up scans. Modest evidence of progression pushes me to consider CTLA-4 antibody therapy as the second-line approach versus BRAF/MEK combination therapy for more aggressive evidence of disease progression. Recent evidence that the same strategy will soon be an option with MEK inhibitor monotherapy in NRAS mutant melanoma patients. These decision points for selecting first, second and even third line therapy are currently informed by clinical factors. However, we know that each treatment approach can produce years-long remissions as first-line treatment. Thus, it is imperative that we continue to conduct clinical research to develop additional diagnostic methods for identifying those patients predicted to achieve long-term benefit from each of therapies and relay on these for navigating among these multiple treatment options.