Patients with newly diagnosed anaplastic oligodendroglial tumors with chromosome 1p and 19q deletions live dramatically longer lives if PCV chemotherapy is added before or after standard radiation therapy, long-term follow-up from two large, prospective trials shows.*
The survival benefit was not statistically significant in patients without the signature co-deletions, which occur in about 50%-60% of patients with this rare, slow-growing brain tumor.
Median overall survival in the 80 patients harboring the 1p/19q co-deletions was 9.3 years with radiation, but had not been reached in those also treated with PCV chemotherapy (hazard ratio 0.56; P value = .059).
Overall survival was 21 months and 25 months, respectively, among the 236 patients without the co-deletions (HR 0.83; P = .19) in the European Organization for Research and Treatment of Cancer (EORTC) 26951 trial.
“This opens the venue for personalized medicine not based on the histology of the tumor, but the molecular signatures of these tumors,” Dr. Martin van den Bent said at a press conference at the annual meeting of the American Society of Clinical Oncology.
A survival advantage with combination therapy was also seen in patients with MGMT (O6-methylguanine DNA methyltransferase) methylated tumors and IDH (isocitrate dehydrogenase) mutations, but further study will be needed to confirm this, he added.
The most pressing question for clinicians is whether to use the older, more toxic PCV chemotherapy regimen of procarbazine (Matulane), lomustine (CeeNU) and vincristine (Oncovin) for its known survival advantage or to substitute the less toxic, oral alkylating agent temozolomide (Temodar), which has replaced PCV since the phase III trial was launched some 17 years ago.
Dr. van den Bent said in an interview that PCV plus radiation should be the standard of care for anaplastic oligodendroglial (AOD) patients but admits it’s a difficult question to answer because of the toxicity associated with PCV, including weight loss and bone marrow suppression, which he described as mostly asymptomatic. Nearly half or 46% of patients treated with PCV in the trial experienced grade 3 or 4 hematologic toxicity.
He noted, however, that the results were the same regardless of the number of PCV cycles given in the trial, raising the question of how much PCV chemotherapy is actually needed.
“The thing that’s important is that we now know that we get this huge increase in survival with PCV,” he said. “The question for the physicians at home is whether they are willing to trade a certain survival benefit for an unknown survival benefit, and I expect that there will be a lot of discussions in the coming months where this will be one of the primary questions.”
Dr. Mark R. Gilbert, a professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston, who was invited to discuss the plenary abstract, said the previous standard of radiation alone is no longer adequate for patients with AOD tumors with 1p/19q co-deletions, and that the existing data support the first-line treatment of these patients with radiation and chemotherapy.
He added that the optimal chemo-radiation treatment has not been established, with data available on chemotherapy given before or after radiation and the place for temozolomide in this disease yet to be determined.
“If we decide temozolomide has a role, should it be used as we do for grade IV glioma, which is concurrently with radiation followed by adjuvant treatment?” he asked.
EORTC 26951 randomized patients to radiotherapy 59.4 Gy alone or followed by six cycles of lomustine 110 mg/m2 on day 1, procarbazine 60 mg/m2 on day 8-21 and IV vincristine 1.4 mg/m2 on days 8 and 28. The median follow-up was 140 months, with 24% of patients still alive in 2012. In all, 75% of patients who progressed in the radiation arm crossed over to PCV.
In the intent-to-treat population, median overall survival increased from 31 months with radiation alone to 42 months with the addition of PCV chemotherapy (HR 0.75; P = .018). The overall survival benefit was observed despite the crossover treatment (risk reduction 0.75), observed Dr. van den Bent, professor of neuro-oncology at Erasmus University Medical Center, Rotterdam, the Netherlands.
Progression-free survival nearly doubled from 13 months to 24 months with adjuvant PCV (HR 0.66; P = .003).
In patients with the 1p/19q co-deletions, median overall survival was 112 months with radiation alone, but has not been reached in those treated also given chemotherapy (P = .059; relative risk reduction 0.56).
Among those without 1p/19q co-deletions, the addition of PCV delayed progression from a median of 50 months with radiation alone to 157 months, (HR 0.42). In the non-deleted patients, progression was prolonged from 9 months to only 15 months (HR 0.73).
In univariate analysis 1p/19q co-deletions, IDH, and MGMT were all independent prognostic factors for survival (P less than .0001), with only MGMT falling out in multivariate analysis.
Virtually all 1p/19q co-deleted tumors show IDH mutation and virtually all IDH-mutated tumors show MGMT promoter methylation, Dr. van den Bent pointed out. Post-hoc testing revealed IDH mutations in 46% of 178 patients and MGMT methylation in 74% of 183 patients tested.
In a separate presentation at the meeting, North American investigators reported that patients with 1p/19q co-deletions lived twice as long or 14.7 years with PCV chemotherapy followed by radiation, compared with 7.3 years with radiation alone in the phase III, 291-patient Radiation Therapy Oncology Group (RTOG) 9402 trial (HR 0.59; P = .03).
Survival times were not significantly different at 2.6 years and 2.7 years, respectively, in patients without such deletions (HR 0.86; P = .39).
In all, 64% of patients given PCV experienced grade III-IV toxicity, although salvage treatment was more common with radiation only (81% vs. 57%; P = .04).
The overall survival benefit was observed after a median follow-up of 11.3 years, reversing an early analysis in 2006 that showed no overall survival benefit for the combined therapy, according to lead author Dr. J. Gregory Cairncross, professor and head of clinical neurosciences at University of Calgary (Alta.).
Dr. Bruce J. Roth
The same phenomenon was reported in the EORTC cohort.
“It could be because, after 6 or 7 years, the effects of radiation therapy begin to wear off and then the beneficial effects of chemotherapy kick in,” Dr. van den Bent speculated. “We don’t know. It’s a unique phenomenon. I can’t recall having seen this before, but we have two trials showing exactly the same separation of the survival curves after only 6 years.”
Press conference moderator Dr. Bruce J. Roth, an oncology professor at Washington University in St. Louis, said most AOD patients in the United States are treated with radiation after surgery, and that the minority of those who do receive chemotherapy will likely continue to receive temozolomide because of the ease of administration and lower toxicity.
Dr. van den Bent said the ongoing intergroup phase III CATNON trial of concurrent and adjuvant temozolomide in patients with non-1p/19q co-deleted tumors should further define which patients benefit from chemotherapy, but that results will not be available for many years.
Dr. Van den Bent reports consulting with and honoraria from MSD. A co-author reports consulting with MSD and honoraria from GlaxoSmithKline and Roche Diagnostics.
RTOG 9402 was supported by grants from the National Cancer Institute, North Central Cancer Treatment Group, Southwest Oncology Group, Eastern Cooperative Oncology Group and the NCIC Clinical Trials Group.
* This story has been updated and revised on 6/8/2012.