Janis C. Kelly

June 11, 2014

CHICAGO — For the first time, a prospective study has demonstrated a treatment-related increase in survival in patients with grade II glioma, according to long-term data presented here at the 2014 Annual Meeting of the American Society of Clinical Oncology®.

But an expert commentator contends that the treatment regimen used in the study might not be the best combination currently available.

The results come from the RTOG 9802 trial, which has spanned 2 decades.

Grade II gliomas, which constitute 5% to 10% of all primary brain tumors in adults, are relatively indolent. However, nearly all patients eventually develop progressive neurologic symptoms and die prematurely, explained lead author Jan C. Buckner, MD, from the Mayo Clinic in Rochester, Minnesota.

His team evaluated 251 patients with diffuse gliomas, classified as grade II on the basis of World Health Organization criteria. Patients were randomized to radiation therapy alone (54 Gy in 30 fractions) or to radiation therapy followed by 6 cycles of chemotherapy, consisting of procarbazine, CCNU, and vincristine (PCV).

Median overall survival was better with the combination than with radiation therapy alone (7.8 vs 13.3 years).

The 5-year overall survival rate was also better with the combination than with radiation therapy alone (73.0% vs 63.1%), as was the 10-year overall survival rate (60.1% vs 40.1%).

Median follow-up was 11.9 years and, to date, 55% of patients have died.

"With further follow-up and more events, the difference in overall survival is now statistically significant," Dr. Buckner reported. The hazard ratio in favor of the combination is 0.59.

Despite the positive result, there is doubt about the usefulness of the findings.

"RTOG 9802 used a very old regimen. Combination radiation and chemotherapy is now the new standard of care, but it is not clear that PCV is the right regimen," said Michael Prados, MD, from the University of California, San Francisco. PCV has not been tested against the commonly used temozolomide or single-agent nitrosourea.

Nevertheless, Dr. Prados, who spoke at the Highlights of the Day session but was not involved with the study, is enthusiastic.

"This is the first prospective study ever to show an increase in survival with combination treatment in low-grade glioma. It is really a dramatic improvement in the standard of care, and this was our first positive study in a long time," he said.

Another expert was even more effusive.

That is remarkable.

"I don't know of any other tumor type where the addition of chemotherapy has had such a profound extension of survival in a disease we usually think of as chemotherapy-resistant. That is remarkable," said session comoderator Howard Alan Fine, MD, from the Perlmutter Cancer Center in New York City.

Long-term Data Confirm Earlier Findings

These mature data confirm the progression-free survival advantage of radiation therapy plus chemotherapy over radiation therapy alone previously reported by RTOG 9802 investigators (J Clin Oncol. 2012;30:3065-3070).

Dr. Buckner's team found that Cox proportional hazards model for progression-free survival identified treatment and histology as independent prognostic variables. Patients with oligodendroglioma had the best prognosis, followed by those with oligoastrocytoma and those with astrocytoma. Extent of surgery, sex, and baseline neurologic function were not significant factors in progression-free survival.

Prognostic factors for overall survival were similar, except men had worse survival than women.

There was more hematologic toxicity with the combination than with radiation therapy alone, but only 3 patients required red cell transfusions and only 1 required a platelet transfusion.

"Toxicity, although greater with PCV, is acceptable and similar to that seen with many combination chemotherapy regimens commonly in use. Severe cognitive impairment at 5 years, measured by the Mini-Mental State Exam, was infrequent and, compared with baseline, improvement was somewhat more likely than decline," Dr. Buckner reported.

The investigators plan future analyses to assess treatment effect by histologic type and by molecular markers, including 1p/19q codeletion, mutations, and germline polymorphisms.

Dr. Buckner has disclosed no relevant financial relationships. Some of his coauthors report financial relationships with a variety of companies.

2014 Annual Meeting of the American Society of Clinical Oncology (ASCO): Abstract 2000. Presented June 3, 2014.


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