Henry Friedman Discusses the Quagmire of Glioblastoma

Special Topic of Glioblastoma Interview, Janaury 2012

Henry S. Friedman

In our Special Topics analysis of glioblastoma research over the past decade, the work of Dr. Henry Friedman ranks at #6 by total papers and #15 by total cites, based on 89 papers cited a total of 3,894 times. Three of these papers rank among the top 20 papers over the past decade or over the past two years.

In Essential Science IndicatorsSM from Thomson Reuters, his work includes 177 papers, the majority of which are classified in the field of Clinical Medicine, cited a total of 5,003 times between January 1, 2001 and August 31, 2011.

Friedman is Deputy Director of the Preston Robert Tisch Brain Tumor Center at Duke University Medical Center in Durham, North Carolina, where he also serves as the James B. Powell Jr. Professor of Neuro-Oncology, Professor of Pediatrics, Associate Professor of Surgery and Medicine, and Assistant Professor of Pathology.

In the interview below, ScienceWatch.com correspondent Gary Taubes talks with Friedman about his highly cited work as it relates to glioblastoma.


SW: What prompted your initial research in glioblastoma? In other words, how did you get into this line of research?

I was planning originally to be a hematologist. I was working for Frank Oski, one of the leading pediatric hematologists on the planet, and I told him after spending a block of months in a hematology laboratory that I really didn't like it and wanted to do oncology. He said, "God damn it, just another cancer doc. OK, if you're going to that, at least do neuro-oncology, because nobody's doing anything there and if you accomplish anything, you'll be doing things nobody has ever done before."

Then when I got to Duke in 1981 and said I wanted to do neuro-oncology, they put me into the lab of Darrell Bigner, who's the leading neuro-oncology researcher of his generation. I did two and half years of a fellowship essentially in pediatric hematology and oncology, focusing on neuro-oncology. I also did full lab training in neuro-oncology. When I was studying pediatric brain tumors, I did a lot of laboratory work on medulloblastoma and a lot of clinical work on all the pediatric brain tumors. In the mid-1990s, I switched over to adult tumors.

Glioblastoma itself happens to be a grade four malignant glioma, the most aggressive of the gliomas seen in both the adult and pediatric population. When we talk about glioblastoma or GBM or grade-four glioma, we're talking about the same thing. They're all the same tumor.

SW: Your most-cited papers are on a relatively new drug called bevacizumab. What were you reporting in these studies and what does this drug do?

One study that we published had bevacizumab, which is also called Avastin, along with the addition of irinotecan—the two drugs together. Bevacizumab is an active agent in recurrent glioma in adults, but it wasn't clear that there's any benefit to the addition of irinotecan. It may add to the disease control but it's still not clear that it does.

SW: Why has that research been so highly cited?

Henry S. Friedman
The Neuroteam at the Duke Cancer Institute. Photo credit: Duke Photography.

Because that was probably the first paper that really brought Avastin to the world, showing its activity in recurrent glioblastoma. That was a major paper. It was the first paper reporting the results of a clinical trial with bevacizumab in patients with recurrent glioblastoma. It opened up a whole field. There were other papers on the drug, but not from formal trials. That was the first trial that evaluated the regimen in patients with GBM. That's why it's cited so often.

A subsequent paper randomized patients to Avastin or Avastin plus irinotecan, although it was not designed as a comparative study. That paper led to the DFA approval of Avastin in recurrent GBM.

SW: You also have a highly cited paper on IDH1 and IDH2 mutations in glioblastomas. Could you tell us what prompted research and what you found?

I'm not the first or last author on that. So that's not fair for me to be considered the authority on that. I didn't do that research; I merely contributed patients. The IDH1 and IDH2 work was done by Hai Yan, who's the first author, and Darrell Bigner, who is the last author listed on that paper. That was a major discovery, new mutations that had not been seen before in gliomas at all stages—low grade through high grade. It represents a potential new target to go after. It's a good prognostic feature when you have that. But I can't and shouldn't be given credit for the work.

SW: What would you describe as the major advances in glioblastoma research in the last decade?

When we're talking about malignant glioma, the field has moved very slowly. If we stretch the last decade a little bit, to the late 1990s, then temozolomide represents a step in the right direction, a modestly active drug. When you look at therapy of malignant glioma, it's been known for a long time that surgery, major resection, and radiotherapy increases duration of survival but doesn't cure it.

There are two drugs from the 1960s that are approved for malignant glioma, carmustine (BCNU) and procarbazine. There is also Gliadel, which releases BCNU from polymer wafers implanted in the tumor site, temozolomide, and, more recently, Avastin. Lomustine, an oral analogue of BCNU, is also approved. That's it. That's all that's approved as chemotherapy for this disease.

Recently the FDA approved a device, but when devices get approved, they get approved on the basis of efficacy not safety. This particular one is called Novocure—it's a helmet that generates an electric current and the patient wears it 20 hours a day. But that approval is on the basis of safety, not efficacy. I'm not a believer in that therapy.

SW: What are the challenges or obstacles to treating glioblastomas? What makes them such an intractable problem?

"The bottom line, though, is that we do have an ever-increasing cohort of patients, a small minority, who appear to be winning and we can learn from those patients"

They're infiltrative, so they're all over the brain at diagnosis. They are incredibly molecularly diverse; there are so many different pathways that are screwed up, there's no one target you can go after. It's a real quagmire in other words. So you've got infiltrative tumors that are frequently in parts of the brain that can't be resected; they're resistant to almost all chemotherapies and radiotherapy used, and they have so many different genetic abnormalities, that it's hard to imagine any one drug ever having a major impact. Glioblastoma is a cancer nightmare.

SW: Does the epidemiology of the tumor tell you anything that might help attack it?

No. The only proven cause is radiation exposure.

SW: What keeps you from being pessimistic about the future of this research?

I do think we're chipping away at the problem. An ever-increasing small minority of patients appear to be getting cured, although we're not really sure why. So it's not as grim as it was 20 years ago.

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