Stunning 7-Year Survival Difference in Brain Tumor Trial

Practice-Changing Results

Nick Mulcahy

January 30, 2012

January 30, 2012 — Long-term results from a brain tumor trial show that a chromosomal abnormality — 1p19q codeletion — plays a crucial role in the outcome of patients with oligodendrogliomas. The trial also demonstrates that codeleted tumors are profoundly chemosensitive.

In the Radiation Therapy Oncology Group (RTOG) 9402 trial, adding chemotherapy to the standard treatment of radiation doubled survival in patients with the codeletion.

Oligodendrogliomas comprise about 10% of all adult primary brain and central nervous system tumors. In this clinical trial, the codeletion was found in just under half of the participants (126 of 286 patients).

"The Radiation Therapy Oncology Group and other participating cooperative groups are to be congratulated for conducting this randomized clinical trial in a rare form of brain tumor, which took many years," said Jeffrey Abrams, MD, associate director of the Cancer Therapy Evaluation Program at the National Cancer Institute (NCI) in Bethesda, Maryland.

"Their persistence and dedication was rewarded, as this genetic abnormality has a powerful effect on survival. The results will change how patients with this disease are treated. This clinical trial also highlights the necessity of collecting tumor tissue for genetic studies to define more precisely the patients who benefit most from specific therapies," he said in a statement.

Practice-Changing Result

The RTOG 9402 trial was designed to compare the effectiveness of radiation therapy with and without chemotherapy in patients who have anaplastic oligodendroglioma. The 286-patient trial involved patients with and without the codeletion.

In a subset analysis, the 59 patients with codeleted tumors who received chemotherapy plus radiotherapy had a median overall survival of 14.7 years, compared with 7.3 years for the 67 patients with codeleted tumors who received radiotherapy alone.

Thus, having the codeletion is the key to gaining a benefit from combination therapy. "The big story is the magnitude of the survival difference for codeleted cases when chemotherapy was added to radiation therapy," said researcher J. Gregory Cairncross, MD, professor and head of Department of Clinical Neurosciences at the University of Calgary in Alberta, Canada, in an email to Medscape Medical News.

Patients without the abnormality received no benefit from chemotherapy plus radiotherapy.

All oligodendroglioma patients with the 1p19q codeletion should now be treated with chemotherapy in addition to the current standard of radiation, said Dr. Cairncross.

This is a practice-changing result, he said.

For oligodendroglioma patients without the codeletion, there is uncertainty on how best to treat beyond the current standard of care, he added. "There is no clear path for these patients, who are now the subject of a new clinical trial, called CATNON," Dr. Cairncross said, referring to the RTOG 0834 trial.

But the optimal treatment for patients with the codeletion is now abundantly clear thanks to the results of RTOG 9402.

Significance of Abnormality

When the trial started in 1994, the significance of the chromosomal abnormality was not known, said Bhupinder Mann, MBBS, senior clinical investigator in the Cancer Therapy Evaluation Program at the NCI.

However, within a couple of years, retrospective studies suggested that the codeletion "was associated with chemosensitivity," he said in an interview with Medscape Medical News. "It's quite well known that these tumors are chemosensitive," he noted. Now, there are data from a randomized clinical trial to demonstrate the effect.

The researchers were able to determine which patients had the 1p19q codeletion because they had tumor tissue samples from more than 90% of participants, Dr. Mann said.

The RTOG 9402 trial, which is now complete, involved 95 centers in North America and the United Kingdom. Patients with aggressive oligodendrogliomas were equally randomized to receive radiotherapy alone or radiotherapy plus chemotherapy, which included procarbazine, lomustine, and vincristine (PCV). Tumor tissue analysis was performed when a majority of patients had been followed for 11 years, according to a press release from the NCI.

For the entire study population, the median overall survival time for patients receiving radiotherapy alone and those receiving radiotherapy plus PCV chemotherapy was similar. But for the subset of patients with 1p19q codeleted tumors, there was a very different result.

The 7-year survival difference found in the patients with codeleted tumors who received PCV chemotherapy plus radiotherapy, compared with the patients with codeleted tumors who received radiotherapy alone, is "remarkable," said Dr. Mann.

The study results have not been presented or published yet, Dr. Mann said. The researchers are in the process of writing an abstract for submission to the American Society of Clinical Oncology for inclusion in the 2012 annual meeting. However, the NCI recently issued a press release with some of the results to publicize the findings.

Testing patients with oligodendrogliomas for the codeletion has been in practice since the late 1990s, said Dr. Cairncross. However, "there has been doubt and uncertainty" about the predictive value of codeletion, he said.

Codeletion Also Dramatically Prognostic

In addition to predicting which patients will benefit from the combination of chemotherapy and radiation, the presence of the codeletion is also prognostic, according to the study results.

The researchers looked at all of the patients with and without the codeletion, regardless of treatment group. Overall, the 126 patients with 1p19q codeleted tumors had a median survival time of 8.7 years, compared with 2.7 years for the 135 patients whose tumors did not carry the 1p19q codeletion.

This finding suggests that patients whose tumors contain the chromosomal abnormality will live substantially longer than patients whose tumors do not, regardless of treatment, according to press materials from the NCI, which sponsored the trial.

More Study Details

Participating patients had histologically proven unifocal or multifocal, supratentorial, or pure or mixed anaplastic oligodendroglioma. For study inclusion, there could be no evidence of spinal drop metastasis or spread to noncontiguous meninges. Tumors could not be located in the posterior fossa (i.e., brainstem or cerebellum), nor were spinal cord tumors allowed. Patients were required to have a Karnofsky performance status of 60% to 100%. Also, patients were not allowed to have had previous chemotherapy or radiation therapy.

Within 2 weeks of randomization to the combination treatment, patients received oral lomustine on day 1, oral procarbazine on days 8 to 21, and intravenous vincristine on days 8 and 29. Treatment continued every 6 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. In the 6 weeks after day 29 of course 4, patients underwent radiotherapy 5 days a week for 5.6 weeks, followed by boost radiotherapy 5 days a week for 1 week.

Within 2 weeks of randomization to radiotherapy alone, patients underwent the same radiotherapy as those in the combination group.

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