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Patients with Low-Grade Gliomas had Longer Progression-Free Survival with Combined Chemotherapy/Radiation Compared with Radiation Alone

ARTICLE IN BRIEF

Figure

PROGRESSION-FREE SURVIVAL, according to treatment group. All hazard ratios for the comparison of radiation therapy alone (RT) or radiation therapy plus PCV in the analyses of progression-free survival are for disease progression or death, and all P values are two-sided. Tick marks indicate censored data. There were too few events among patients without the R132H mutation in the isocitrate dehydrogenase 1 gene (IDH1) to assess the association with treatment.

Overall survival was found to be longer among those who received combination chemotherapy and radiation for grade 2 gliomas than those who received radiotherapy alone.

Patients with low-grade gliomas who received radiation therapy plus six cycles of chemotherapy treatment consisting of procarbazine, lomustine (also called CCNU), and vincristine (PCV) had longer progression-free survival and overall survival rates than patients who received radiation therapy alone, according to a new study published in the April 7 issue of the New England Journal of Medicine.

“Because the rate of progression and death begins to diverge between the radiation only and chemoradiation arms, we have the possibility that some patients on the chemoradiation arm may be cured,” said the lead author Jan Buckner, MD, chair of oncology at Mayo Clinic in Rochester, MN. “We will continue to follow these patients over time to address even longer-term progression-free survival and overall survival. Protocol NO577 is assessing the comparative efficacy of radiation plus PCV versus radiation plus temozolomide in patients with grade 2 or 3 tumors with 1p/19q codeletion, and we would need to encourage clinicians to enroll patients into the trial.”

Dr. Buckner added that his team is working to examine the longer-term impact of treatment on cognitive function, including the impact of alternative methods of radiation therapy delivery, such as proton bean radiation.

The Radiation Therapy Oncology Group (RTOG) randomized 251 patients with grade 2 gliomas from October 1998 through June 2002 — 126 to radiation therapy alone, and 125 to radiation plus PCV — as part of the RTOG 9802 trial. Patients recruited into the phase 3 clinical trial were considered to be high-risk as they were over 40 years of age, and those under the age of 40 had only part of the tumor removed through surgery.

Although grade 2 gliomas constitute just 5 to 10 percent of all brain tumors in adults, progressive neurologic symptoms develop in nearly all patients, and nearly all patients die prematurely, the study authors noted.

The investigators administered radiation therapy at a dose of 54 Gy to patients in 30 fractions of 1.8 Gy each over a period of six weeks. Those randomized to the chemotherapy plus radiation arm of the trial received six cycles of PCV after radiation therapy was completed. Researchers also sent tumor samples to a lab to determine the IDH1 mutational status of the samples.

SURVIVAL RATES

At a median follow-up time of 11.9 years, 67 percent of patients were identified as having tumor progression, and 55 percent of patients had died. Patients who received radiation therapy plus PCV chemotherapy had longer median survival times compared with those in the trial arm who received radiation therapy alone (13.3 versus 7.8 years, respectively; p=0.003). Median progression-free survival time for patients receiving radiation therapy plus PCV chemotherapy versus radiation therapy alone was 10.4 years and 4.0 years, respectively.

For both progression-free survival and overall survival distributions, differences between treatment arms became apparent only after two to four years following randomization. Favorable prognostic variables included the radiotherapy plus PCV arm, oligodendroglioma histology, IDH1 R132H mutation, and younger age, the study authors wrote.

At the 10-year follow-up mark, progression-free survival and overall survival rates for patients who received radiation therapy and PCV chemotherapy were 51 percent versus 21 percent for those who only received radiation. Overall survival rates for those who received combined radiation plus PCV chemotherapy were 60 percent versus 40 percent for those who received radiation therapy alone.

When researchers analyzed survival rates by histologic type of tumor, they found that patients with tumors that had mutation-specific monoclonal antibody IDH1 R132H mutations had significantly longer overall survival rates than did those without the mutation, regardless of the treatment they received (p=0.02). Median survival was 13.1 years (95 percent CI, 10.1 to not reached) among patients with the mutation versus 5.1 years (95 percent CI, 1.9 to 11.5) among those without it.

Among patients with the IDH1 R132H mutation, those who received the combination therapy had longer overall survival than those who received radiation therapy alone (p=0.02).

The number of events among patients without the mutation was too small to determine the association of treatment effect in this subgroup, the study authors noted.

Treatment toxicity was greater in those who received radiation plus PCV chemotherapy and consistent with patients receiving multi-agent chemotherapy regimens. The most common toxicities were fatigue, anorexia, nausea and vomiting, which were mostly grade 1 or 2 in severity with the exception of grade 3 or 4 neutropenia.

In addition, late events attributed to radiation therapy occurred in 245 patients and included toxic effects in the brain in 54 patients. Most of the events were grade 1 or 2 in severity, according to the findings.

The authors concluded that while the amount of treatment benefit from the combined radiation therapy plus chemotherapy was substantial, the toxic effects were greater than those derived from radiation therapy alone and that “patients and their physicians will have to weigh whether the longer survival justifies the more toxic therapeutic approach.”

Other medications released since the trial began are better tolerated, including temozolomide, the study authors noted; in 1999, it was initially indicated for treatment of anaplastic astrocytoma and then in 2005 for treatment of glioblastoma multiforme. Now it is often used as monotherapy for low-grade gliomas.

EXPERTS COMMENT

Lynne P. Taylor, MD, FAAN, director of neuro-oncology at Virginia Mason Medical Center, told Neurology Today that she was encouraged by the findings. “The five-and-a half year increase in median overall survival is huge in a field that usually measures success by two to four months of survival,” she said, adding that progression-free survival at 10 years being 51 percent for combined therapy versus 10 percent for radiation therapy alone is “also a very big quality of life issue, because it means our patients were not only surviving, but doing so with few seizures, cognitive decline, aphasia, etc.”

Dr. Taylor also pointed out that in the group that received radiation therapy plus chemotherapy, 93 percent of the patients received radiation therapy per protocol or an acceptable variation, yet only 56 percent received chemotherapy per protocol. The median number of chemotherapy treatment cycles was three for procarbazine, four for CCNU, and four for vincristine. “This implies to me that the chemotherapy was even more effective than they thought, given the impressive increase in survival and quality of life, despite the fact that they found the treatment regimen somewhat toxic.”

David Schiff, MD, FAAN, professor of neurology and co-director of the Neuro-Oncology Center at the University of Virginia School of Medicine in Charlottesville, agreed. He said there are no comparison data for radiation therapy plus temozolomide versus radiation therapy plus PCV, which would be useful. “In glioblastoma, radiation therapy and temozolomide has led to improvements we don't see with radiation therapy and PCV. But the RTOG 9802 data for PCV are strikingly good,” he said.

Patrick Y. Wen, MD, FAAN, professor of neurology and director of the neuro-oncology program at Dana-Farber/Brigham and Women's Cancer Center, agreed that the findings are “quite important” and that the “net effect of this study is that we will treat brain tumors more aggressively with a combination of PCV and radiation.”

Both Drs. Wen and Schiff pointed to an ongoing clinical trial for anaplastic oligodendroglioma involving radiation therapy and temozolomide versus radiation therapy and PCV. “That data will take years to accrue and for the data to mature, but may suggest which form of chemotherapy is most effective with radiation for low-grade gliomas,” said Dr. Schiff.

The current study was supported by grants from the National Cancer Institute, a grant from the North Center Cancer Treatment Group, and the Ohio State University Comprehensive Cancer Center.

LINK UP FOR MORE INFORMATION:

•. Buckner J, Shaw EG, Pugh SL, et al. Radiation plus procarbazine, CCNU, and vincristine in low-grade gliomas http://www.nejm.org/doi/full/10.1056/NEJMoa1500925. N Engl J Med 2016; 374:1344–1355.