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Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Fixed and Variable Factors that Impact a Brain Tumor Patient’s Prognosis

A Q&A with Burt Nabors, MD, Professor and Director of the Division of Neuro-oncology at the University of Alabama, Birmingham, and a member of the Cancer Commons Brain Tumor Advisory Board; bnabors@uabmc.edu

Q: Primary brain gliomas can be devastating, often deadly, malignancies. Obvious prognostic factors include whether they are grade 1, 2, 3, or 4; their extent of growth prior to diagnosis (stage); and their location, such as in the brain stem. What are other key factors that affect prognosis? Some say that the skill of the original surgeon is the most important prognostic factor. Others suggest that the size (case volume) of the initial treating institution is most important. What do you think?

A: An excellent question and one I may try to answer in two ways. The first are the known and well-quantified prognostic factors. The two most powerful are the patient’s age and their performance status. Age is a pretty clear factor and one we cannot alter. We in the neuro-oncology community are seeing increased attention to treatment recommendations based on age, both at the young and older ends of the spectrum. These efforts do appear to provide brain tumor patients in those spaces improved outcomes. However, as a modifiable prognostic factor, age is not one.

A patient’s performance status is, at the core, a measure of how well they retain their station in life and can manage their activities of daily living independently. It most likely reflects the summation of several other factors, such as the location of the tumor, the grade, and the ability of the neurosurgeon to safely resect (remove) tumor. When looking simply at tumor location, we do see improved outcomes for tumors in the non-dominant hemisphere or in more silent regions, such as the frontal or anterior temporal lobes compared to more eloquent or vulnerable brain regions. However, again, the location of the tumor is not modifiable by the individual patient. It is where it is.

As you suggest, another—and modifiable—way to consider this question is to focus on the experience and skill of the neurosurgeon. I would submit the factors that have the greatest impact here are the training environment for the neurosurgeon, the experience and interest of the neurosurgeon in brain cancer, and the volume of the treatment facility. Surgery at centers involved in high volumes of brain tumor surgery with neurosurgeons who are dedicated to advancing the practice of surgical intervention is an important consideration.

The current practice of the neurosurgeon also has a significant impact on patient outcomes. This has been well quantified and published, clearly for high-grade glial tumors such as glioblastoma, but also for lower-grade tumors such as astrocytoma and oligodendroglioma WHO II. This need for a dedicated practice is typically seen in environments that offer pre-operative neurological function mapping, advanced imaging modalities, and intraoperative awake craniotomy with cortical mapping. When this degree of neurosurgical sophistication is available, it is often in settings with multidisciplinary groups, including a research base with an intense interest and focus on brain cancers.

An unfortunate current reality is that, most often, settings with this degree of sophistication are in our larger urban centers, where ease of access for patients living and presenting in a more rural environment can be quite a challenge. Creating opportunities to provide access and equal care to all remains a significant part of the neuro-oncology mission and challenge.

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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.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

The Importance of Brain Tumor-Initiating Cells in Glioblastoma

A Q&A with Anita Hjelmeland, PhD, Associate Professor of Cell, Developmental and Integrative Biology at the University of Alabama Birmingham School of Medicine

Q: The inner workings of malignant gliomas are mysterious to many of us. Why does the prognosis of patients with these tumors remain poor?

A: Glioblastoma is a primary brain tumor that is treated with surgery, radiation, and chemotherapy. While surgical removal of glioblastoma is a goal, glioblastoma cells move into the normal brain where they cannot be removed and where many chemical therapies do not reach. The latter is due to a special wall of blood vessels called the blood-brain barrier that protects the brain from toxins. To overcome these obstacles, researchers are developing ways to identify tumor cells during surgery and break down the blood brain barrier for short periods of time.

Another reason that glioblastoma is difficult to treat involves the body’s defense against invaders—the immune system. The immune system usually will not attack cells it recognizes as “self” (if it does, autoimmune diseases will develop), but special immune cells can recognize and destroy infected self cells that have different proteins on the cell surface than do normal cells. Glioblastoma cells also have different-from-normal proteins that could be targeted by drugs, but glioblastoma cells often block the activity of immune cells. To improve the treatment of glioblastoma, there are clinical trials testing the effects of drugs or viruses that are designed to activate the immune system.

A final reason that glioblastoma cures remain elusive is that tumor cells are not all the same. There are different genetic or mutational features that could lead to resistance to any one targeted therapy. Glioblastoma cells also behave differently depending on their environment: for example, lower oxygen levels can promote resistance to radiation. Furthermore, glioblastoma cells can resemble specialized cells in the brain to differing degrees, reflecting a difference in stem-cell state. To improve our ability to target all tumor cells, researchers seek to identify ways to prevent therapeutic resistance and combine therapies to try to make them more effective.

Q: Your research delves seriously into the role of brain tumor-initiating cells (BTICs). What are BTICs, what do they do, and how might an understanding of them lead to improved therapies? 

A: Glioblastoma cells can look and act more or less like normal stem cells in the brain, the neural stem cells. Neural stem cells are important during development and in brain diseases because they remake themselves, a process called self-renewal, and make specialized (differentiated) brain cells like neurons. Neural stem cells and differentiated brain cells can be distinguished by levels of different proteins called markers, which can also be expressed by glioblastoma cells. Glioblastoma cells with neural stem cell markers and the ability to self-renew or differentiate are called cancer stem cells or glioblastoma stem cells. Human glioblastoma stem cells have a greater capacity to cause tumors to initiate or grow in mice without an immune system: this tumor-initiating ability has led to the alternative name of BTICs.

BTICs can comprise only a small portion of the overall number of tumor cells present but could be especially important to eradicate. BTICs better survive chemo- and radiotherapy, and can live in environments where therapies are less effective. BTICs possess a high capacity to invade and readily move into the normal brain. Therefore, BTICs are believed to be the cells that remain after surgery, radiation or chemotherapy. Any such cells that remain after treatment, as their name denotes, can stimulate glioblastoma to grow anew. Thus, it is imperative that we make strong efforts to understand how to eradicate BTICs along with the more differentiated tumor cells in the hope of extending patient survival. Our ability to ever cure glioblastoma could rest upon that success.

It is important to note that glioblastoma is not alone in harboring tumor-initiating cells. By studying ways to combat BTICs in glioblastoma, progress is likely to be made towards understanding better therapies for other malignancies with such a capacity for therapeutic resistance and recurrence.

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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.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Options to Treat a Glioblastoma

A Q&A with 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—a newly diagnosed GBM in 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 24.9% (if used over 90% of the time) with no added toxicity.
  3. Phase 3 Clinical trials: There are now about nine phase 3 trials for newly diagnosed GBM. Some have impressive phase 1 and phase 2 data. By the time a treatment gets to phase 3, it has shown enough promise in earlier trials that the sponsor is willing to risk a lot of money to test in a phase 3 trial. Most have two big downsides: 1) Most have a control group of patients who receive the old standard of care so that some of the participants do not get the experimental treatment. 2) Most do not allow you to use Optune, so you are trading a known benefit for a chance at an unknown benefit.
  4. Phase 1 or 2 trials: There are about 75 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 are much better than those seen with 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 (under the current system) 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.
  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 tried, and the outcomes so we can learn from every patient.

Getting Access to Experimental Therapies
There are a few pathways to getting experimental therapies. Currently, none are really practical on a large scale. I have tried to get expanded access/compassionate use/right-to-try access on the most promising experimental treatments and it is very hard. Last year, fewer than 1,000 patients were able to get FDA approval to try experimental drugs under the FDA’s expanded access program for all types of cancer. Getting multiple drugs this way for a cocktail is just about impossible. We had high hopes for the Right To Try act which was passed this year, but it turned out not to help at all. Drug companies are not willing to use this pathway for brain tumor patients. However, even if we could get them, without tracking the results, we are not learning and are doomed to repeating the same failures.
Marty Tenenbaum and I previously wrote about our ideas for solving this problem. See https://virtualtrials.com/fda2017.cfm
So – bottom line: What would I do?

  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 chemotherapy) 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. The length of time to use 3. temozolomide is controversial. There is finally a phase 3 trial comparing 6 months versus 12 months of temozolomide, but right now we really do not know which is best. Some doctors use it for as long as needed.
  4. There are a few immunotherapies that have shown remarkable results in a minority of patients. A few of the early vaccine and gene therapy trials have tails of 20% or more of patients living over 5 years and with minimal or no side effects. I would try to get one (or maybe two) of these. The polio vaccine trial (PVSRIPO) is getting a lot of hype on “60 minutes” with some very impressive results on a small number of patients. I know the first patient in the trial, and she is doing great and tumor free 5 years after the treatment. [Disclaimer: I am on the patient advisory board of the brain tumor center at Duke, and helped fund the PVSRIPO Trial].
  5. 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 as I said before, you are being asked to gamble a known benefit for an unknown experimental treatment that might or might not help, and you might even be assigned to a control group. The results with Optune alone are still not good enough. The results shown above were for newly diagnosed GBMs. For recurrent GBMs, they are not nearly as good so it is important to use it early in the course of the disease. Ideally I would combine Optune with one of the immunotherapy treatments in phase 2 or 3, but that is not possible yet. We really need to fix that. Why should I be allowed to die just to appease an archaic tradition of requiring standard phase 2 and 3 trials?

What would you do?
Al Musella’s contact info is included in the author affiliations at the top of this page.
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.