Treatment Options for Glioblastoma and other Gliomas

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Lawrence Recht, M.D.
Director of Adult Neuro-Oncology
Stanford Cancer Institute

The foundation for glioblastoma treatment includes surgery, radiation and the chemotherapeutic agent, temozolomide. The first step (after patient stabilization) is maximal safe debulking by the surgeon. The key here is “safe”; there is no need to sacrifice function for better survival (since there is no evidence that this improves outcome). Therefore, this may range from a visually total tumor removal to a biopsy (when tumors occur in inaccessible areas).

Once pathologic confirmation is received, standard treatment next involves a combination of involved field radiation (using a dose of approximately 60 Gy to the area of MR enhancement with a 2 cm field extension, a process that takes approximately six weeks) and temozolomide chemotherapy (75 mg/M2 every day for 42 days). We prefer to get this started within a month of radiation, although there is evidence that delays up to six weeks do not impact outcome. Once radiation is finished, a rest period of 2-4 weeks ensues after which patients are restarted on temozolomide, which is administered at a dose of 150 mg/M2 for five days out of 28). Chemotherapy treatment then continues for at least 6 and often 12 months, depending on tolerance).

Avastin (bevacizumab) plays an important role in treatment, although the precise timing of its initiation remains controversial. At Stanford, we generally reserve its usage until time of recurrence, unless patients are requiring high doses of steroids for mass effect (at which time we would start earlier).

Once recurrence occurs, there are no standard treatments (other than Avastin). It is at this point that we tend to offer patients entry into experimental protocols; if they decline or are not eligible, we generally administer a nitrosourea such as CCNU in addition to Avastin. - Recht

Since his own diagnosis of glioblastoma (GBM) in 1995 at age 50, Ben Williams has spent considerable time researching the literature for treatment options, and the following discussion summarizes what he has learned. Most of the information is from medical journals. Some is from information that has been contributed by others to various online brain tumor patient support groups, which he has followed up on, and some is from direct communications by phone or e-mail with various physicians conducting the treatments that are described. References are presented at the end for those who would like their physicians to take this information seriously. Although this discussion is intended to be primarily descriptive of the recent development of new treatment options, it is motivated by his belief that the development of new agents, per se, is likely to fall short of providing effective treatment. What is needed, in addition, is a new approach to treatment that recognizes the power of evolution as the enemy of victims of cancer.

http://virtualtrials.com/pdf/williams2008.pdf

Treatment Name: Chemosensitivity assay for malignant brain tumors

Phase: Other / Approved

Treatment ID#: 961

Age Group: Adult And Pediatric

Min Karnofsky Score: Not Specified

Conditions:

Prior Surgery is Allowed
Prior Radiation is Allowed
Prior Chemotherapy is Allowed
This is a laboratory test, not a trial.

Tumor Types:

Any Malignant Brain Tumor
Glioblastoma Multiforme
Gliosarcoma
Oligodendroglioma High Grade

Comments: A sample of the tumor is sent to the lab for analysis to see which chemotherapy drugs work the best on your specific tumor.

Treatment Type: Surgery

Contact:

Larry Weisenthal MD,PhD
Weisenthal Cancer Group
15140 Transistor Lane
Huntington Beach, CA 92649 USA
Phone: 714-894-0011
E-mail: mail@weisenthal.org
Website: http://weisenthalcancer.com/

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John de Groot, M.D.
MD Anderson Cancer Center

Gliomas. These primary brain tumors arise within the brain, but we don't know the cell of origin.

There are multiple grades of gliomas -- grade II, III and IV, with grade IV being the most malignant.

Grade IV tumors are called glioblastoma. They are the most aggressive and are very infiltrative - they spread into other parts of the brain quickly. Glioblastomas don't metastasize outside of the brain.

Glioblastomas can occur in any lobe of the brain and even the brain stem and cerebellum, but more commonly occur in the frontal and temporal lobes. Below, I've answered some common questions I get about glioblastoma.

1. Are there any known causes or risks factors for glioblastoma?
Glioblastoma are more common in males, persons older than 50, and people of Caucasian or Asian ethnicity. There are a few very rare familial syndromes that are associated with brain tumors. One of the only known risk factors that we have for brain tumors is radiation exposure.

2. What are common symptoms of glioblastoma?

The symptoms for any brain tumor are related to the locations from where the brain tumor originates and the rate of tumor growth. Symptoms can vary widely. Some are silent and only found incidentally when a brain scan is done for another reason.

The most common symptoms include headaches, nausea, vomiting and seizures. Tumors frequently cause subtle personality changes and memory loss or, again, depending on location, muscle weakness and disturbances in speech and language.

3. How is a glioblastoma diagnosed?

Most patients with glioblastoma undergo a CT scan, followed by MRI. The actual pathological diagnosis has to be made at the time of surgery (tissue is removed and examined by a neuropathologist).

4. What are the treatment options for a glioblastoma? And why, typically, is it hard to treat?

The standard treatment for glioblastomas is maximal safe resection (surgery), followed by concurrent radiation and an oral chemotherapy called temolozomide over a 6-week period. Upon completion of radiation, 6-12 cycles of adjuvant temolozomide are given to the patient five days in a row every four weeks.

Glioblastomas are not surgically curable, but there is good evidence that the more tumor that can be removed, the better the prognosis. The radiation and chemotherapy are designed to target the infiltrative component of the glioblastoma and delay tumor progression.

5. What clinical trials are available for glioblastoma?

We have multiple clinical trials for glioblastoma, depending on the disease's stage. We have clinical trials for newly diagnosed patients before they have radiation, as well as newly diagnosed patients after they finish chemotherapy and radiation.

Most of our clinical trials are for patients with recurrent tumor, after failing temolozomide. Unfortunately, the recurrence rate for glioblastomas is near 100%, with an average time to recurrence of six to seven months.

6. What glioblastoma research is being done at MD Anderson?

The Department of Neuro-Oncology and the MD Anderson Brain Tumor Center are looking at new drugs that haven't made it into the clinic yet and drugs that doctors are prescribing, but for other diseases. We're trying to determine whether they'd be effective for glioblastoma.

We're very interested in identifying subgroups of patients that might benefit from a specific drug. I'm very interested in targeting angiogenesis (the process of blood vessel formation), which plays a critical role in the ability for brain tumors to grow quickly.

7. What advice would you give someone who has just been diagnosed with a glioblastoma?

One of the most important things that you can do is to seek care or even a second opinion by people that spend all of their time treating this disease. Glioblastoma is a very complicated disease. There are a lot of nuances to both the diagnosis and the treatment, and you want an expert to help you work through the treatment process.

Also look for a physician who will give you the undivided time and attention you deserve. Your doctor shouldn't be rushing through your visit. I talk to patients about their diagnosis, explain to them all the aspects of the treatment as well as the impact of the tumor on their quality of life. I also spend as much time answering questions as the patient requires.

Source: cancerwise http://www2.mdanderson.org/cancerwise/

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New research from Wake Forest Baptist Medical Center shows that patients suffering from aggressive brain tumors can be effectively treated with smaller radiation fields to spare the rest of the brain and preserve cognition.

"For patients with glioblastoma, we now know we can safely and effectively treat them with smaller radiation fields to spare the rest of their normal brain," said lead investigator Michael D. Chan, M.D., assistant professor of radiation oncology at Wake Forest Baptist. "That's important because it lessens the symptoms from radiation toxicity like tiredness and nausea."

Chan said that a patient's cognition is related to how much normal brain is irradiated so focusing radiation on smaller areas of the brain may help preserve cognition and does not seem to lead to an increase in the likelihood of the tumor recurring. Overall, while long-term survival rates for glioblastoma multiforme patients have not improved by much with treatment advances, the ability to treat with smaller radiation fields preserves cognition and provides the possibility of better quality of life.

Recent research findings from Chan and colleagues appeared online last month ahead of print in the American Journal of Clinical Oncology. While there have been other similar studies, this one is the largest to compare smaller radiation margins to larger ones to document differences in patterns of failure for patients, Chan said. For this retrospective study, records for 161 patients treated at Wake Forest Baptist over the last 10 years were reviewed.

"We decided a few years ago that it would be worthwhile to look at whether using these tighter margins would affect the tumors coming back outside of the radiation field, or tell us if we are barely missing," Chan said. "We are the first to show definitively that people with smaller margins don't do any worse than those with larger margins."

Chan said that in the 1990s, Wake Forest Baptist's Edward G. Shaw, M.D., professor of radiation oncology, was part of a group that pioneered using smaller margins because it was less toxic. Smaller radiation margins around the tumor do not seem to lead to an increase in the tumor returning just outside of the radiation field, Chan said. A smaller radiation field, combined with modern treatment techniques, like newer chemotherapy agents and radiation technologies, provides physicians with more options.

"Treatments have gotten better over time and people with GBM may live longer than they had in the past. Our study found that the margins did not affect where the GBM came back or how long it took it to come back and it did not affect the overall survival," Chan said. "This could potentially be practice changing."

Reference: Co-authors include Anna K. Paulsson, B.S., Kevin P. McMullen, M.D., Ann M. Pfeiffer, Ph.D., William H. Hinson, PhD., William T. Kearns, M.S., Annette J. Johnson, M.D., M.S., Glenn J. Lesser, M.D., Thomas L. Ellis, M.D., Stephen B. Tatter, M.D., Ph.D., Waldemar Debinski, M.D., Ph.D., and Edward G. Shaw, M.D., M.A., all of Wake Forest Baptist.

Citation: Wake Forest Baptist Medical Center. "Researchers Find Smaller Radiation Fields Can Spare Brain When Treating Tumors." Medical News Today. MediLexicon, Intl., 11 Jan. 2013

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The drug bevacizumab, also known by the trade name Avastin, shrinks tumors briefly in patients with an aggressive brain cancer known as glioblastoma multiforme, but then they often grow again and spread throughout the brain for reasons no one previously has understood. Now, Mayo Clinic researchers have found out why this happens. They have also discovered that pairing Avastin with another cancer drug, dasatinib, can stop that lethal spread. Dasatinib (Sprycel) is approved for use in several blood cancers.

The findings, based on an animal study, are detailed in the online issue of PLOS ONE. Based on those results, Mayo Clinic has already conducted a phase I clinical trial testing a combination of Avastin (bevacizumab) and Sprycel (dasatinib) in glioblastoma patients whose other therapies failed. Mayo is now carrying out a randomized phase II study of 100 patients through Alliance for Clinical Trials in Oncology, a clinical trials network supported by the National Cancer Institute.

"We are very encouraged. This finding could potentially benefit many cancer patients," says co-author Panos Z. Anastasiadis, Ph.D., chair of the Department of Cancer Biology at Mayo Clinic in Florida. Working with him were researchers and oncologists from Mayo Clinic campuses in Florida and Minnesota.

The research began after Dr. Anastasiadis, a basic scientist who studies cell adhesion and migration, gave a seminar to a group of oncologists who treat brain tumors. The issue of Avastin-induced invasion was brought up and a collaboration to study it was quickly set up and funded by the Mayo Clinic Specialized Program of Research Excellence (SPORE) grant for brain cancer, one of only four in the country.

The issue of Avastin's induced aggressiveness is not limited to brain cancer, Dr. Anastasiadis says.

"While Avastin offers clear benefit in some patients, oncologists have noted that when cancers of many types recur after use of Avastin, they become aggressive and invasive," he says.

The team discovered that as brain tumors become more aggressive after use of Avastin in mice, the cancers begin inducing a family of kinases known as Src, which then activate proteins found at the edge of brain tumors. These proteins essentially give the tumor cells "legs" upon which to crawl away and find a new source of nutrition, Dr. Anastasiadis says.

"Anti-angiogenesis drugs like Avastin deprive tumor cells of blood nutrients, so the tumors shrink initially, but we believe that this deprivation acts like a switch to turn on proteins that help the cancer cells migrate to other parts of the brain in search of blood," he says. "In short, if Avastin does not allow a tumor to make new blood vessels to feed it, the tumor will move to other existing blood vessels."

The researchers then tested Sprycel, a drug that inhibits Src kinases. They found that while use of Avastin or Sprycel alone did not provide much benefit in mouse models of human glioblastoma, use of both together shrank tumors and blocked any subsequent spread.

"If you block that migration, the cells are forced to stick together and hopefully die by lack of nutrition," Dr. Anastasiadis says.

Researchers next will work to identify which patients benefit the most from this new treatment, which do not, and why.

Reference: The study was funded by National Institutes of Health grants R01CA100467and R01NS069753.

Citation: Mayo Clinic. "Bevacizumab And Dasatinib Combination Shows Promise In Fighting Glioblastoma." Medical News Today. MediLexicon, Intl., 18 Feb. 2013.

http://cancerfocus.org/forum/showthread.php?t=3696

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[Wow! This is blockbuster news! In one study, patients who were expected to benefit the most from Avastin based on "genetic" testing had the worst survival rates.]

(AP) - New research raises fresh questions about which cancer patients benefit from Avastin, a drug that lost its approval for treating breast cancer nearly two years ago.

Avastin did not prolong life when used as a first treatment for people with brain tumors like the one U.S. Sen. Edward Kennedy died of several years ago, two studies found. In one, patients who were expected to benefit the most from Avastin based on genetic testing had the worst survival rates. Side effects also were more common with Avastin.

The drug is approved for treating brain tumors that have recurred for people who already tried chemotherapy or radiation. But that approval was based on studies suggesting it briefly delayed the worsening of the disease. No definitive study shows it helps those patients live longer, either.

Something similar happened with breast cancer: Avastin won the Food and Drug Administration's approval after studies suggested it delayed disease progression. But when later research showed it did not prolong life and brought more side effects, its approval for breast cancer was revoked.

However, many cancer experts say the same thing should not happen now, and that Avastin should retain its approval for brain cancer patients whose disease has recurred.

"I would definitely not want the FDA to take that away from patients," said Dr. Deepa Subramaniam, director of the brain tumor center at Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C. "That's very different from the breast cancer story," where there are many other drugs that can be tried, she said.

She had no role in the new studies, which were discussed Sunday at an American Society of Clinical Oncology conference in Chicago.

Avastin, made by Swiss-based Roche's Genentech unit, acts by depriving tumors of a blood supply. It's also sold for treating certain colon, lung and kidney tumors. Another study discussed Sunday and released previously showed it helped women with advanced cervical cancer live nearly four months longer.

The new brain cancer studies tested it as initial treatment for glioblastoma, the most common and deadly type of tumor. About 10,000 Americans each year are diagnosed with these tumors, which are nearly always incurable.

In one study, 637 patients received standard chemotherapy plus radiation, and half also received Avastin. Both groups lived about 16 months, and those on Avastin had more side effects — mostly low blood counts, blood clots and high blood pressure.

"Our study would strongly suggest that it is not beneficial to do it as front-line treatment but to reserve it as second-line or salvage therapy," said study leader Dr. Mark Gilbert of the University of Texas MD Anderson Cancer Center in Houston. Federal grants and Genentech paid for the study, and Gilbert consults for the company.

More troubling, independent experts said, is that patients who were expected to do the best based on genetic and other tests surprisingly had a worse survival trend — 16 months versus 25 months for others in the study.

New research needs to be done to better define which patients benefit, said Rakesh Jain, a brain tumor expert at Massachusetts General Hospital in Boston.

"We just cannot give these agents to every patient," he said.

A second study that tested Avastin as initial therapy with radiation and the drug Temodar found it did not prolong life, but patients on Avastin went nearly five months longer before their tumors appeared to worsen.

Avastin costs about $43,000 plus doctor infusion charges for a course of treatment for people whose brain tumors have recurred.

Note: Bevacizumab-induced tumor calcifications can be elicited in glioblastoma microspheroid culture and represent massive calcium accumulation death (MCAD) of tumor endothelial cells

http://precedings.nature.com/documents/7069/version/1

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The angiogenesis inhibitor bevacizumab (Avastin) failed to increase overall survival (OS) or statistically significant progression-free survival (PFS) for glioblastoma patients in the frontline setting, according to research led by researchers at The University of Texas MD Anderson Cancer Center.

The study was presented at the American Society of Clinical Oncology 2013 Annual Meeting by Mark Gilbert, M.D., professor in MD Anderson's Department of Neuro-Oncology.

Glioblastoma is both the most common and lethal form of brain cancer. More than 12,000 people will be diagnosed with the disease in 2013, with an average survival rate of less than 18 months, said Gilbert.

Bevacizumab works as a monoclonal antibody against VEGF-A, which is produced by glioblastoma to stimulate blood vessel growth. The angiogenesis inhibitor first showed promise in glioblastoma as clinicians reported positive results treating the disease under approved compassionate use. Numerous institutional studies then found similar results: a 35-40 percent objective response rate, or tumor shrinkage, of more than 50 percent, and a six-month PFS rate in the mid-30 percent, said Gilbert. With those findings, in May, 2009, the FDA granted an accelerated registration of bevacizumab in the second line setting.

However, before this trial, no randomized, double-blind studies with the drug in glioblastoma had been conducted.

"Obviously, glioblastoma is a cancer with too few effective therapies," said Gilbert, who also holds the Blanche Bender Professorship in Cancer Research. "When we launched this study, those in the field of brain cancer - both the scientific and patient communities - were excited. Bevacizumab recently received approval in the second-line (recurrent disease) setting, and we knew some physicians were already giving the drug as a frontline therapy - even with virtually no data to support that decision. It was important from a patient care and regulatory standpoint that we conduct this trial."

The Phase III, international study (RTOG 0825) was a collaboration of three cooperative groups: RTOG, NCCTG and ECOG.

The randomized, double-blind, placebo-controlled study registered 978 and enrolled 637 patients, respectively, all of whom were newly diagnosed with glioblastoma. Participants underwent surgery to resect some or most of the tumor, received the standard of care of chemoradiation with temozolomide, and were randomized to receive either bevacizumab or placebo. The study was designed with two primary endpoints: PFS and OS.

Two distinguishing factors of the study design include: crossover to bevacizumab in the placebo arm at the time of progression, and longitudinal assessment of symptom burden, neurocognitive function and quality of life.

"With the crossover, we could determine the possible overall, or progression free survival benefits that could distinguish the potential benefits of early versus later use of bevacizumab," Gilbert said. "Also, there may be some alternative advantages for delaying progression in the disease. In order to interpret that possible delay in progression, it was important to understand what the quality of the survival of that possible progression free survival interval."

A third distinction: the study was designed to look at the impact of pre-specified molecular markers -- a nine-gene signature expression and MGMT methylation -- to determine if a subgroup that specifically benefited from bevacizumab could be identified.

The researchers found no difference in OS between the bevacizumab and placebo arms, 15.7 and 16.1 months, respectively. PFS did not reach the pre-set level statistical significance -- although longer -- in those taking bevacizumab upfront (10.7 months), compared to in those receiving placebo (7.3 months).

Bevacizumab was associated with a higher rate of toxicities, including hypertension, bleeding, deep vein thrombosis and pulmonary embolism, and gastrointestinal perforation. Those on the therapy also experienced increase rates of symptom burden and neurocognitive decline, as well decreased quality of life, compared to those on placebo.

When looking at the molecular markers, no subgroup of patients that benefitted from bevacizumab could be identified, said Gilbert.

Despite the disappointing findings, Gilbert stressed that the study did not find that bevacizumab had no place in the management of glioblastoma.

"Ultimately, our study showed that bevacizumab has the same benefit whether given early or late and because of the risk of extra toxicity upfront, its used can be reserved as a later treatment for most patients," said Gilbert.

Complementary studies detailing quality of life, symptom burden and molecular findings were presented by MD Anderson faculty at ASCO trade show.

References:

In addition to Gilbert, others on the international study include: Kenneth D. Adalpe, M.D., Paul D. Brown, M.D., Ritsuko Komaki, M.D., Eric Sulman, M.D. Ph.D., and Jeffrey Wefel, all of MD Anderson; James Dignam, Ph.D., and Minhee Won, both of RTOG; Minesh Mehta, M.D., professor, University of Maryland Medical Center; Deborah T. Blumenthal, M.D., Tel Aviv Sourasky Medical Center; Michael A. Vogelbaum, M.D., Ph.D., Cleveland Clinic Foundation; Howard Colman, M.D., Ph.D., Huntsman Cancer Institute; Arnab Chakravarti, M.D., Arthur James Cancer Center; Robert Jeraj, Ph.D., University of Wisconsin; Terri S. Armstrong, Ph.D., University of Texas Health Science Center School of Nursing; Kurt Jaeckle, M.D., Mayo Clinic Florida; David Schiff, M.D., University of Virginia Medical Center; James Atkins, M.D., National Surgical Adjuvant Breast and Bowel Project and SCCC-CCOP; David Brachman, M.D., Arizona Oncology Services Foundation; and Maria Werner-Wasik, M.D., Thomas Jefferson University Hospital.

Gilbert is on Roche's advisory board; Genentech financially supported the 0825 study; it was also supported by NCI U10CA 21661, U10 CA37422.

Citation: University of Texas M. D. Anderson Cancer Center. "No Benefit Offered By Bevacizumab For Newly Diagnosed Glioblastoma." Medical News Today. MediLexicon, Intl., 4 Jun. 2013.

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A heated debate has again developed over the use of Avastin for the treatment of glioblastoma, this time in the front-line setting in combination with chemotherapy in newly diagnosed patients.

Although a previous trial showed some benefit, data presented during a plenary session at the 2013 ASCO trade show showed no clear benefit.

Experts are now divided over what this means for patients.

Controversy surrounding the use of this agent arose in 2010 when the same data on the use of Avastin in recurrent glioblastoma were used to approve it in the United States but reject it in Europe.

The data for newly diagnosed glioblastoma have experts arguing again. Some believe that there is no clear benefit to adding Avastin to chemotherapy in this setting, whereas others disagree.

Ryo Nishikawa, MD, professor and chair of neuro-oncology and neurosurgery at the Comprehensive Cancer Center, International Medical Center at Saitama Medical University in Saitama, Japan, told Medscape Medical News, "For overall survival, we see no difference. Usually, oncologists think that if there is no difference in overall survival, there is no approval. But because survival in glioblastoma is quite limited, 3 or 4 months of progression-free survival is significant for patients," he said.

"Progression-free survival is kind of an arbitrary end point, but overall survival is a solid end point. Approval should be based on a solid end point, we know that. But in glioblastoma, the situation is a bit different," Dr. Nishikawa noted.

The new data come from a placebo-controlled randomized phase 3 study, the RTOG 0825 trial, conducted in 637 neurologically stable patients 18 years or older with newly diagnosed glioblastoma multiforme. All patients had Karnofsky Performance Scale scores of at least 60 and a tumor tissue block larger than 1 cm³.

After surgical resection, patients were randomized to receive standard chemoradiation with temozolomide plus either placebo or Avastin (10 mg/kg every 2 weeks).

The researchers found no statistically significant benefit to Avastin therapy for the 2 primary end points of overall survival and progression-free survival. However, progression-free survival was prolonged. In addition, toxicity increased in the Avastin group.

"We feel that Avastin remains an important therapy for patients with glioblastoma, but the results of this study do not support its front-line use. Rather, it can be reserved as a later treatment," said lead author Mark R. Gilbert, MD, professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston, during a press briefing.

Despite the data demonstrating these limitations, study discussant Howard Fine, MD, director of the Brain Tumor Center and deputy director of the NYU Cancer Institute in New York City, said he feels strongly that Avastin is "the single most important therapeutic agent in glioblastoma since temozolomide, maybe even more so."

It comes down to whether "benefit" is measured in terms of overall survival, progression-free survival, or quality of life, Martin van den Bent, MD, PhD, past chair of the European Organization of Research and Treatment (EORTC) Brain Tumor Group, told Medscape Medical News. That's going to be the critical part of the discussion," he said.

Median overall survival was similar in the Avastin and placebo groups (15.7 vs 16.1 months; P = .21).

A confounding feature of this study was that patients in the placebo group were allowed to cross over to Avastin if their disease progressed, "so there's a chance that the crossover eliminated the survival benefit," Dr. Gilbert explained.

Progression-free survival was prolonged with Avastin, compared with placebo (10.7 vs 7.3 months). However, "even though the P value was 0.007, it did not reach our predetermined definition of significance," he noted.

"We decided that we would weight it more toward overall survival, " he explained. Therefore, the researchers chose a P value of .05 for statistical significance and then divided it between the 2 coprimary outcomes, setting a P value of .046 for overall survival and .004 for progression-free survival — which adds up to .05.

In addition to no survival benefit with Avastin, toxicity was higher, he noted.

Specifically, Avastin was associated with more hypertension than placebo (4.8% vs 1.0%), more deep vein thrombosis/pulmonary embolism (9.9% vs 7.7%), more wound issues (2.3% vs 1.0%), more gastrointestinal perforation (1.3% vs 0.7%), more significant hemorrhage (1.3% vs 1.0%), and more neutropenia (15.1% vs 7.3%).

Secondary analyses, which evaluated the impact of MGMT methylation and a 9-gene signature on treatment outcome, failed to identify any subgroups that benefited from Avastin, he added.

Data for quality of life, symptom burden, and neurocognitive functions were presented in separate studies. On those measurements, patients in the Avastin group generally fared worse than those in the placebo group.

More patients free of progression on imaging showed a decline in these functional domains, said Dr. Gilbert. "Put in the context of the prolongation of progression-free survival, that made the difference. Not only did we not hit the progression-free survival target that was prespecified, we also saw that, over time, a portion of the patients who were progression-free on bevacizumab did not maintain their overall function status."

These RTOG 0825 quality-of-life results are in contrast to those from the AVAglio trial — a similarly designed study, sponsored by Roche, that evaluated the addition of Avastin to standard chemoradiation, said Dr. Fine. Results from AVAglio were reported in a separate study.

Both trials showed no increase in overall survival with Avastin and an increase in progression-free survival by about 3 months; however, the progression-free survival increase was deemed statistically significant in the AVAglio analysis but not in the RTOG study.

However, the quality-of-life data from AVAglio were "strikingly different" than the RTOG data, noted Dr. Fine.

"RTOG showed worsened patient-reported symptom burden and worsening neurocognitive function with Avastin. By contrast, the AVAglio trial showed the exact opposite — improved quality of life, prolonged Karnofsky Performance Scale scores, and reduced doses of steroids," he added.

A possible explanation for this difference is the fact that AVAglio did not evaluate neurocognitive function, which is particularly sensitive to disease progression. Dr. Fine suggested that a decline in neurocognitive function could be masked by the ability of Avastin to stabilize the blood–brain barrier and decrease gadolinium enhancement on MRI scan.

Additionally, radiographic definitions of progression-free survival were different in the two trials.

But the whole issue of defining progression-free survival by radiographic parameters is a particular problem when dealing with Avastin, Dr. van den Bent told Medscape Medical News.

"VEGF inhibitors like Avastin decrease the leakiness of the vessels, making it more difficult to detect progression, he said. "But, is what we are seeing an antitumor effect or are we simply looking at scans that look better because they have less leaky vessels?"

This is where the patient's experience during progression-free survival becomes particularly important, he noted.

"What does the increase in progression-free survival mean?" he said. "If you see an increase in progression-free survival, does that imply that the patient will live in good clinical condition longer? I think it's going to be a heated debate, where we need data and more understanding of the data before we can make any certain statements."

On the basis of the AVAglio trial, and now results from the RTOG-0825 trial, "there does not appear to be a clinical benefit from upfront treatment with Avastin in glioblastoma," said Christina Tsien MD, from the University of Michigan in Ann Arbor, during at a "highlights of the day" session.

She added that Avastin might be of benefit in particular subsets of patients, such as those who cannot undergo resection, but at the moment, there are no biomarkers that would indicate which patients would benefit.

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As for the quality-of-life and symptom end points of the RTOG 0825 trial, Dr. Tsien said she agrees that the effects of Avastin in reducing vascular permeability and edema might lead to a "pseudo response," which looks like a response on imaging, but in fact the tumor is progressing. Conversely, "pseudo progression" is a possibility in the placebo group, where there is no antiangiogenic effect of Avastin; patients might feel worse and imaging might suggest progression, but the tumor could still be responding.

"I remain doubtful about the true antitumor efficacy of Avastin in glioblastoma," said Deepa Subramaniam, MD, director of the brain tumor center at the Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C. "It is certainly a very helpful drug in the symptomatic patient and does improve survival in very specific patient subsets, but I do not think we know what those subsets are, meaning we have no reliable predictive markers for benefit from Avastin. This is true of the role of Avastin in most other solid tumors for which it is approved."

There is a convincing biologic explanation for why the drug would be beneficial in recurrent but not newly diagnosed disease, explained Dr. Fine.

"There are 2 predominant growth patterns within glioblastoma — angiogenic and nonangiogenic," he explained.

At the time of tumor progression, patients have angiogenic-driven tumors. "If you treat them at this time with an antiangiogenic agent, such as Avastin, you could see benefit." This is not likely the case with newly diagnosed disease, he said. In fact, the use of Avastin in newly diagnosed patients could result in a more treatment-resistant recurrence. "If they've had long-term Avastin from the start, then when they recur, it is a nonangiogenic recurrence," which will not respond to Avastin, he explained.

The research was supported by the National Cancer Institute and Genentech. Dr. Gilbert reports serving as a consultant or in an advisory role for Novartis, EMD Serono, Genentech, and Merck; receiving honoraria from Novartis, EMD Serono, Genentech, and Merck; and receiving research funding from GlaxoSmithKline, Genentech, and Merck. RTOG 0825 investigator Michael Vogelbaum, MD, PhD, reports receiving honoraria from Merck. RTOG 0825 investigator Howard Colman, MD, PhD, reports serving as a consultant or in an advisory role for Castle Biosciences and Roche/Genentech. RTOG 0825 investigator Terri Armstrong, PhD, ANP-BD, reports receiving research funding from Genentech. RTOG 0825 investigators Jeffrey Scott Wefel, PhD, and David Schiff, MD, report serving as a consultant or in an advisory role for Genentech. RTOG 0825 investigator Erik Sulman, MD, PhD, reports serving as a consultant or in an advisory role for GlaxoSmithKline, and receiving honoraria from Merck. RTOG 0825 investigator Minesh Mehta, MD, reports serving as a consultant or in an advisory role for Genentech and Merck, owning stock in Accuray, and receiving honoraria from Merck.

Citation: No Benefit to Bevacizumab for Newly Diagnosed Glioblastoma? Medscape. Jun 03, 2013.

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Adding bevacizumab to frontline radiation and temozolomide therapy for glioblastoma produced disappointing results in a double-blind, placebo-controlled phase III trial.

Bevacizumab (Avastin) extended progression-free survival, but did not improve overall survival in the Radiation Therapy Oncology Group (RTOG) 0825 study, and investigators reported that the angiogenesis inhibitor was associated with worse neurocognitve and quality of life outcomes.

Among 637 patients who were randomized, median overall survival reached 16.1 months in those assigned to radiation, temozolomide (Temodar), and placebo, compared with 15.7 months in patients assigned to radiation, temozolomide, and bevacizumab, Dr. Mark R. Gilbert reported in the plenary session at the annual ASCO trade show.

Median progression-free survival reached 10.7 months in the Avastin arm, vs. 7.3 months in the placebo arm, said Dr. Gilbert, professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston. The P value was .0007, but this difference was not statistically significant because of an unusual trial design that split criteria for statistical significance between the two primary outcome measures of overall and progression-free survival. In addition, patients in the Avastin arm had significantly worse neurocognitive and overall symptom scores over time.

“We feel that Avastin remains an important therapy for our patients with glioblastoma, but the results of this study do not support its frontline use. Rather, it can be reserved as a later treatment,” he said at a press briefing prior to his presentation.

Outcomes contrast with Avaglio study

Some results of the publicly funded RTOG 0825 trial run counter to those from the Avaglio study, an industry-sponsored trial whose results were also presented at the trade show.

The Avaglio investigators found that adding Avastin to radiotherapy and Temodar “achieved a clinically meaningful, statistically significant progression-free survival improvement in patients with glioblastoma,” Dr. Warren Mason, a neuro-oncologist at the Princess Margaret Hospital in Toronto, reported at another session.

The Avaglio trial, which ran parallel to RTOG 0825 and was very similar in design, showed a quality of life benefit for patients on Avastin, but did not look at neurocognitive outcomes.

Median progression-free survival in Avaglio reached 10.6 months in 458 patients in its radiation, Temodar, and Avastin arm, vs. 6.2 months in 463 patients in its radiation, Temodar, and placebo arm, and the difference was significant (hazard ratio, 0.64; P less than .0001).

However, as in RTOG 0825, median overall survival was virtually identical in both Avaglio trial arms, at 16.8 and 16.7 months, respectively.

Avastin misses RTOG targets

The RTOG trial enrolled neurologically stable patients with glioblastoma who had a Karnofsky performance score of at least 70 and who had tumor tissue samples available for evaluation. They were randomized to receive standard chemoradiation with Temodar for 3 weeks followed by chemoradiation with Temodar and either Avastin or placebo for 6-12 maintenance cycles.

The treatment type was unblinded at progression, and patients were allowed to cross over, or continue on Avastin. Progression was defined as a greater than 25% increase in tumor area without recent steroid reduction, or worsening of neurologic symptoms.

In a pooled analysis including both study arms, patients with methylation of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) had better median and overall survival than patients with MGMT unmethylated (methylated MGMT is a marker for favorable prognosis). Median overall survival for the MGMT methylated group was 23.2 months, compared with 14.3 months for the unmethylated group (HR in unmethylated tumors, 2.10; P less than .001). Respective median progression-free survival was 14.1 months vs. 8.2 months (HR, 1.67; P less than .001).

(The results of the GLARIUS trial, also reported at this meeting, showed that Avastin combined with irinotecan (Camptosar) in chemoradiation was associated with longer progression-free survival than Temodar chemoradiation in newly diagnosed patients with MGMT-unmethylated glioblastoma. In a preliminary finding from that study, there was a suggestion of an overall survival benefit for the Avastin-Camptosar combination.)

As noted, in RTOG 0825, patients in the Avastin arm scored significantly worse on a clinical trial battery composite of cognitive function (P = .038), on overall symptom interference with daily activity (P less than .001), and on quality of life cognitive function (P less than .009).

In contrast, patients on Avastin in Avaglio had improved quality of life, prolonged preservation of performance scores, and reduced steroid doses compared with controls.

Why the differences?

Dr. Howard A. Fine, director of the brain tumor center at New York University, the invited discussant for RTOG 0825, said that the differences in patient-reported outcomes between the trials may reflect differences in statistical analysis, possibly different analytical methodologies used to query the data, or the lack of neurocognitive data in Avaglio.

Another possibility to account for the worsening neurocognitive function with Avastin is the drug’s documented ability to stabilize the blood-brain barrier and decrease MRI gadolinium enhancement, he said. This could mean that patients experience radiographic occult disease progression that does not show up well on brain scans.

Dr. Gilbert and Dr. Fine commented that theoretically at least, glioblastoma should be an ideal target for angiogenesis inhibitors such as Avastin, because they display a high degree of vascularity, and endothelial proliferation is part of the pathologic definition of the disease.

But although Avastin has been demonstrated to improve response rates and delay progression in recurrent glioblastoma, its relative lack of efficacy in the first line is puzzling, Dr. Fine said.

Potential explanations include the crossover designs of both the RTOG and Avaglio studies, suboptimal delivery of Avastin to the tumor, or the possibility that the vascular endothelial growth factor receptor may not be the best target in glioblastoma.

“Despite these new data demonstrating its limitation, I feel very strongly that Avastin represents the single most important agent in glioblastoma since Temodar, and maybe even more so. Ongoing and future trials will better define how and when it should be optimally used in these patients that have such limited therapeutic options,” Dr. Fine concluded.

The RTOG 0285 study was supported by the National Cancer Institute, with additional support from Genentech. Avaglio was supported by Roche. Dr. Gilbert disclosed consulting for, and receiving honoraria and research support from, Genentech. Dr. Mason disclosed being a consultant/adviser to Hoffman-La Roche. Dr. Fine reported having no relevant financial disclosures.

Citation: Frontline Bevacizumab Fails to Boost Glioblastoma Survival in Key Trials. N. Osterweil IMNG Medical Media, 2013 Jun 03.

[gpawelski]

A novel drug for patients with brain cancer, 2B3-101, has shown preliminary positive results. The Dutch biotech to-BBB has developed Glutathione PEGylated liposomal doxorubicin (2B3-101) and initiated a clinical trial to investigate this new treatment. The Phase I safety results will be presented at the European Cancer Congress 2013 in Amsterdam at the end of September.

"This first clinical trial with 2B3-101 has focused on the safety of this new treatment, yet, promising signs of anti-tumor activity were observed in many of the patients at the higher dose levels tested," says Dr. Dieta Brandsma from the Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital (NKI-AVL).

The preliminary positive results from this clinical trial have warranted further investigation into the efficacy of 2B3-101. Thus, as a next step, four disease groups will be treated in the Phase IIa part of this trial, including patients with recurrent malignant gliomas, and patients with brain metastases from breast cancer, small cell lung cancer or melanomas.

Fredrik Lonnqvist, Chief Medical Officer at to-BBB, adds, "The prognosis for patients with brain cancer is usually poor, and there are very limited treatment options available. Therefore, we are committed to the continued evaluation of 2B3-101, based on the results seen so far."

Results of this first clinical trial with 2B3-101 will be presented at the European Cancer Congress 2013 (ECCO-ESMO-ESTRO) on the 30th of September. The safety of 2B3-101 was investigated both in patients with brain metastases from solid tumors and in patients with recurrent malignant gliomas. Patients that participated in this study were either refractory to standard therapy or unable to receive existing standard therapy. Adverse events reported during the study were all expected, and mainly related to transient bone marrow suppression, skin lesions (hand-foot syndrome) and mild to moderate infusion reactions. No signs of drug-related neurotoxicity and cardiotoxicity were observed. An additional 2B3-101 dose-escalation study in combination with Herceptin® is currently also about to be completed, which will allow inclusion of additional HER2+ breast cancer patients with brain metastases in the Phase IIa part of this trial.

The brain is a well-protected organ. The so-called blood-brain barrier selectively allows nutrients to enter the brain, and keeps harmful substances but also most drugs out of the brain. This makes treatment of brain tumors much more challenging compared to treatment of tumors outside the brain. By use of to-BBB's proprietary G-Technology, the blood-to-brain delivery of drugs is enhanced by using active transport processes at the blood-brain barrier.

The 2B3-101 concept is based on the G-Technology and has previously been evaluated in non-clinical studies with promising results. In these studies, to-BBB has shown that conjugation of glutathione to the tips of pegylated liposomes can provide a five-fold increased delivery of doxorubicin to the brain compared to untargeted liposomes. In addition, treatment with 2B3-101 improved the survival of mice in an experimental model of brain cancer (glioblastoma) by 60%.

Citation: to-BBB. "A potential new treatment option for patients with brain cancer." Medical News Today. MediLexicon, Intl., 27 Sep. 2013.

http://clinicaltrials.gov/show/NCT01386580
http://www.tobbb.com/products/2B3-101