Trial of Chemoradiation for Anaplastic Astrocytoma Ends Early Without Winner

Treatment with radiotherapy and temozolomide led to a median survival of 3.9 years compared with 3.8 years for radiotherapy plus nitrosurea. Progression-free survival (PFS) and time to progression (TTP) also did not differ significantly between treatment groups.

The nitrosurea regimen proved more difficult to tolerate, reflected in a significantly higher rate of grade ≥3 nonhematologic toxicity, and more than one-fourth of patients in the arm discontinued treatment because of intolerable toxicity.

“Molecular correlative studies showed thatIDHmutation andATRXmutation were prognostic factors,” Susan M. Chang, MD, director of neuro-oncology at the University of California, San Francisco, reported at 2015 ASCO Annual Meeting in Chicago. “Further studies are pending.

“The results highlight the importance of molecular and cytogenetic characterization as eligibility and stratification factors for clinical studies.”

Previous studies have shown a survival benefit with adjuvant nitrosurea in patients who have anaplastic glioma. Temozolomide has demonstrated efficacy in recurrent anaplastic glioma and newly diagnosed glioblastoma.

The two agents had not previously been compared with respect to efficacy in newly diagnosed anaplastic astrocytoma, providing a rationale for a randomized clinical trial. Launched in 2002, the trial ended prematurely in 2007 because of slow patient accrual. At the time, 201 patients had been randomized to the two treatment arms.

The trial’s primary objective was to compare overall survival of patients with newly diagnosed anaplastic astrocytoma treated with radiotherapy and either temozolomide or nitrosurea. Secondary objectives included TTP, toxicity, and correlative molecular analyses for the primary endpoint and TTP.

Primary eligibility criteria were newly diagnosed anaplastic astrocytoma or mixed oligoastrocytoma (<25%), Karnofsky performance status of at least 80, and laboratory values within normal limits.

All patients received radiotherapy at a total dose of 59.4 Gy, administered in 1.8 Gy fractions. Patients were randomized to temozolomide 200 mg/m²daily for days 1 to 5 of the first week of radiotherapy and repeated every 28 days for a total of 12 cycles or to nitrosurea in the form of intravenous BCNU 80 mg/m²or oral CCNU 130 mg/m²every 8 weeks for a total of six cycles.

The trial required 454 randomized patients to demonstrate a 33% reduction in the survival hazard with temozolomide. Chang reported data for 196 evaluable patients. Median follow-up was 3.6 years overall and 9.1 years in the 68 patients who remained alive as of October 2014.

Baseline characteristics did not differ significantly between the treatment groups with respect to median age (42-43), KPS, type of surgery (total resection, partial, or biopsy only), or centrally reviewed histology (97%-98% anaplastic astrocytoma).

About 96% of all patients completed the planned radiation protocol. However, 60.4% of patients randomized to temozolomide completed planned therapy versus 21.4% of the nitrosurea group.

Disease progression or death accounted for 28.1% of treatment terminations in the temozolomide arm versus 38.8% in the nitrosurea arm. No patient in the temozolomide group stopped treatment because of side effects or toxicity compared with 27.6% in the nitrosurea group.

Worst nonhematologic toxicity by treatment arm did not differ significantly between treatment arms, as two-thirds of patients had less than grade 3 toxicity. Worst overall toxicity did differ significantly, as 47.9% of the temozolomide arm had grade &ge;3 toxicity versus 75.8% of patients in the nitrosurea group (P<.001).

In addition to the lack of survival difference, the hazard for progression or death was 15% lower in the temozolomide, but the difference did not achieve statistical significance (P= .32).

IDHmutation status was known for 60 patients in the temozolomide arm and 51 patients in the nitrosurea group. A slightly higher proportion of patients assigned to nitrosurea tested positive (49% versus 40%). Patients withIDH-positive tumors had significantly better median overall survival, 7.9 years compared with 2.8 years, representing a 49% reduction in the hazard ratio (P= .006).

ATRXmutation status was known in 31 patients in the temozolomide arm (ATRXpositive in 14 cases) and in 32 patients in the nitrosurea group (also 14 positive). Median survival time was 9.4 years among patients withATRX-positive tumors and 3.9 years for theATRX-negative subgroup (HR = 0.42,P= 0.008).

&ldquo;This is the only prospective, randomized phase III study to assess the efficacy of radiotherapy plus temozolomide versus radiotherapy and nitrosurea in newly diagnosed anaplastic astrocytoma,&rdquo; said Chang. &ldquo;The trial had central review of histology and a long follow-up with central review of progression-free survival.&rdquo;

&ldquo;A limitation of the study is that it did not have a radiotherapy-only arm, which will be definitively addressed in the CATNON study of the role of temozolomide chemotherapy added to radiotherapy,&rdquo; she added. &ldquo;Another limitation is that prospective tissue collection was not mandated, limiting tissue correlative studies.&rdquo;