Experts Explore Avenues for Better Brain Tumor Treatment

Daniel M. Keller, PhD

October 23, 2013

VIENNA, Austria — Although many tumors are now successfully treated with modern drugs and better-targeted radiation therapy, primary brain tumors and secondary metastatic ones to the brain still present a major treatment obstacle.

At the recent XXI World Congress of Neurology (WCN), Medscape Medical News spoke with 2 experts who offered their perspectives on what's been tried, where the field stands, and possible avenues to pursue to develop better treatments.

Primary Brain Tumors

Riccardo Soffietti, MD, professor of neuro-oncology at the University Hospital in Torino, Italy, is an expert on primary brain tumors, the most common one of which is glioblastoma multiforme (GBM). He said the past year has been an important one because "we are the end of the history of the first generation of the new antiangiogenic agents."

The idea has been to inhibit new blood vessel formation, starving the tumor of needed nutrients and oxygen. However, Dr. Soffietti says the news has "not been so great."

Clinical trials with the first antiangiogenic agent bevacizumab (Avastin) showed activity in recurrent malignant gliomas after standard treatment with surgery, radiation, and temozolomide, and this indication of second-line use was approved in the United States but not Europe. That led researchers to investigate bevacizumab in newly diagnosed patients. The final results on this first-line use are now in, and they are disappointing, Dr. Soffietti said. Progression-free survival showed a "modest" median advantage of 4 months, but there was no advantage in overall survival, he noted.

There were 2 trials in newly diagnosed glioblastoma, conducted in Europe and the United States, and although they had somewhat different designs, they produced similar results. Dr. Soffietti commented that the manufacturer (Roche/Genentech) is moving ahead to try to gain approval of the drug for newly diagnosed patients on the basis of the modestly better progression-free survival (and in fact, this has been granted in Japan). But he added that, "as a physician, I think on both sides of the Atlantic, we think that bevacizumab is probably better for poor prognostic patients or recurrent patients."

More bad news has come from trials of another antiangiogenic agent, cilengitide, he continued. Phase 2 trials produced small but promising results, but phase 3 trials showed no effect in newly diagnosed patients.

The major problem is that there are no drugs that are active enough on GBM cells, he explained. The cells are heterogeneous, and although a drug may work against some cells, it may miss others. The problem is particularly important with regard to the highly targeted agents, which have been designed to attack a specific cell surface receptor, enzyme, or intracellular signal.

Dr. Soffietti commented that technological advances have improved surgery and radiation therapy, and the use of alkylating agents has been optimized, all of which combined have prolonged median survival in GBM from around 14 to 16 months a decade ago to 20 or 21 months now.

However, in light of the negative results with antiangiogenic agents, it is time to go back to the lab for more preclinical studies on other treatment approaches, he said. "We need for the future to know more regarding the molecular pathways" in order to identify critical steps to try to inhibit" the tumors, he commented, adding: "We have a lot of work to do still."

Treatment strategies will need to be personalized because GBM is not one disease but rather consists of multiple diseases, each with its own molecular defects requiring different molecular approaches. After conventional treatment, more specific drugs are needed. Maybe scientists do not have to go back to the ultimate trigger for a GBM, but if they can discover the cascade of cellular events, that may allow various points for intervention, he suggested.

One recent advance has been the ability to identify patients who may respond better to chemotherapy. The MGMT gene codes for a protein important in DNA repair. Methylation of the gene promoter predicts a better response to temozolomide, with median survival of about 36 months vs about 9 to 12 months for patients with nonmethylated MGMT. This sort of approach therefore allows classifying gliomas into different types and tailoring treatments, Dr. Soffietti commented.

For future clinical trials, Dr. Soffietti says recent results have shown "that not only is survival an important endpoint, especially in incurable disease, but also quality of life is very important." It may have been somewhat neglected in the past, but with improvements in prognoses, the amount of added life should be good life. He said he is trying to impress this point upon drug regulatory authorities so that they consider it in their approval processes.

Finally, he said there is probably better news in some other central nervous system tumor types, such as low-grade gliomas, in which there has been good progress, and in rarer tumors, such as medulloblastomas and ependymomas.

Brain Metastases

Secondary brain tumors — those originating in other tissues and metastasizing to the brain — make up the bulk of brain tumors. They are about 10 times more frequent than primary brain tumors.

Wolfgang Grisold, MD, section head in neuro-oncology at Kaiser Franz Josef Hospital in Vienna, Austria, said that over the past 10 years, the picture of secondary brain tumors has shifted. Tumors that previously were not commonly seen going to the brain, such as intestinal tumors and prostate cancer, now do so more often. He attributes this to modern care "because the patients are treated so well and survive longer."

Neuro-oncologists see these patients, who may present with seizures, changes in mentation, or gait disorders. Some of these changes may be caused directly by the metastases, but they may also result from meningeal carcinomatosis.

There are always 2 important treatment considerations, Dr. Grisold noted. First, "it's not only the brain we are treating. We're treating the patient, and the patient may have various extents of disease progression." The second consideration is whether there is 1 isolated brain metastasis or more.

Problems with drug therapies for brain metastases include the question of whether they are active on the tumor and whether they reach the site in sufficient concentration, he explained. Local necrosis can limit the amount of drug reaching the tumor. The blood-brain barrier is generally not a problem with brain metastases because they have new vessel formation, unlike primary brain tumors.

Antiangiogenic therapies have been tried in some circumstances, and although the concept is interesting, Dr. Grisold said these therapies have not yet progressed very far in clinical trials in secondary brain tumors. Hormonal therapy may be effective for metastases from the breast, he added.

More Targeted Radiation

Many factors determine the best course of treatment. Whole-brain radiation, used more frequently in the past, has late effects, especially as people live longer, Dr. Grisold commented. Avoiding irradiating the hippocampus may help to avoid later dementia or cognitive decline, he noted. Small, shaped radiation beams are good for hitting metastases but not primary brain tumors.

Nonetheless, whole-brain radiation is still used. "It is like a dogma, and this dogma has been around for 20 or 30 years," Dr. Grisold lamented. He said many clinicians are working "on destroying this dogma," but medical practice changes slowly. Better imaging techniques today can detect small metastases, so whole-brain radiation may not be as necessary as previously thought.

Meningeal spread can cause brain and cranial nerve dysfunction and sensory problems. It is seen most frequently with breast cancer. These patients often have prolonged survival, and metastases can occur 5 or even 10 years into the course of the disease, he noted.

A worldwide discussion is ongoing over how to treat meningeal disease, with some groups preferring intrathecal drug administration and others advocating systemic therapy to hit tumor seeding throughout the body. Although cure is not possible at this stage of the disease, treatment can ameliorate symptoms and improve quality of life, he said.

Dr. Grisold cautioned that although treatment guidelines are good and are evidence-based, one must consider them in the context of each patient. For example, if guidelines were developed from studies with mostly younger patients, an elderly person may do better with a variation of the treatment or a different one entirely. He cited a recent Swedish study in Lancet Oncology (2012;13:916-926) showing that elderly patients with newly diagnosed glioblastoma (primary brain tumor) did poorly with standard radiation therapy vs hypofractionated radiation.

For the neuro-oncologist, "palliative care is not just the dying of the patient, but it's the long-term care for the quality of life and for the needs of the patient," he said. Cognitive changes and, for example, speech changes in these patients present special needs.

Whose Quality of Life?

Any cancer exacts a toll on family caregivers, often with depression or anxiety, as well as on the patient. Dr. Grisold noted that the amount of attention given to caregivers varies around the world. He said that good systems are in place for this in the Netherlands, which uses nurses and case managers, and in Italy, which provides home care.

The caregivers often suffer, and traditionally they have been ignored, both during the patient's treatment and after their loved one has died, he commented . Dr. Grisold proposes a sort of debriefing, in which caregivers are given help to overcome any guilt they have about their interaction with the patient, as well as to help them deal with their loss of a sense of duty for caregiving.

Dr. Soffietti and Dr. Grisold have disclosed no relevant financial relationships.

XXI World Congress of Neurology (WCN).

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