Improvement in Overall Survival With Addition of Chemotherapy to Radiotherapy in Low-Grade Glioma


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The magnitude of treatment benefit from combined chemotherapy plus radiation therapy is substantial, but the toxic effects are greater than those observed with radiation therapy alone.

—Jan C. Buckner, MD, and colleagues
Jan C. Buckner, MD

Jan C. Buckner, MD

Final results of the RTOG 9802 phase III trial reported in The New England Journal of Medicine by Jan C. Buckner, MD, of Mayo Clinic, Rochester, and colleagues, showed that the addition of chemotherapy with procarbazine, lomustine, and vincristine to radiotherapy significantly prolonged overall survival in patients with low-grade glioma.1 A previous report from the trial showed significantly prolonged progression-free survival with the addition of chemotherapy.2

Study Details

In the trial, 251 patients with grade 2 astrocytoma, oligoastrocytoma, or oligodendroglioma were randomized between 1998 and 2002 to receive radiation therapy alone (n = 126) or followed by six cycles of combination chemotherapy with procarbazine, lomustine, and vincristine (n = 125). Patients who were 18 to 39 years old were eligible if they had undergone subtotal resection or biopsy, and those who were 40 years of age or older were eligible if they had undergone resection of any of the tumor or biopsy. Radiotherapy was given at 54 Gy (30 fractions of 1.8 Gy) over 6 weeks. Chemotherapy was given as six 8-week cycles of oral procarbazine (60 mg/m2/d on days 8 to 21), oral lomustine (110 mg/m2 on day 1), and intravenous vincristine (1.4 mg/m2 on days 8 and 29).

Long-Term Benefit of Chemoradiotherapy in Glioma

  • The addition of chemotherapy to radiotherapy was associated with significantly improved median overall survival in patients with low-grade glioma.
  • Ten-year overall survival with chemotherapy plus radiotherapy vs radiotherapy alone was 60% vs 40%, and 10-year progression-free survival was 51% vs 21%, respectively.

For the chemotherapy and control groups, median age was 41 and 40 years; 52% and 61% were male; 89% and 92% were white; the extent of surgery was biopsy in 48% and 47%, partial resection in 41% and 44%, and total resection in 11% and 9%; histology was astrocytoma in 29% and 23%, oligodendroglioma in 40% and 45%, and oligoastrocytoma in the remainder; and IDH1 R132H mutation was present in 64% and 61%, respectively.

Overall Survival

Median follow-up was 11.9 years, with 55% of patients having died. Median overall survival was 13.3 years among patients who received chemotherapy plus radiotherapy vs 7.8 years among those receiving radiotherapy alone (hazard ratio [HR] = 0.59, P = .003). Benefit was observed in subgroups with oligodendroglioma (HR = 0.43, P = .009), oligoastrocytoma (HR = 0.56, P = .05), astrocytoma (HR = 0.73, P = .31), and IDH1 mutation (HR = 0.42, P = .02). Overall survival was 72% vs 63% at 5 years and 60% vs 40% at 10 years.

Progression-Free Survival

Median progression-free survival was 10.4 vs 4.0 years (HR = 0.50, P < .001). Benefit was observed in subgroups with oligodendroglioma (HR = 0.36, P < .001), oligoastrocytoma (HR = 0.52, P = .02), astrocytoma (HR = 0.58, P = .06), and IDH1 mutation (HR = 0.32, P < .001). Progression-free survival was 61% vs 44% at 5 years and 51% vs 21% at 10 years.

Multivariate analysis showed that radiation therapy plus chemotherapy treatment and oligodendroglioma histology were favorable prognostic factors for both progression-free and overall survival.

Adverse Events

Hematologic adverse events of ≥ grade 3 were more common in the chemotherapy group, including decreased platelets (18%, all grade 3, vs 0%) and neutropenia (44%, 35% grade 3, vs < 1%). Overall, late central nervous system (CNS) toxic effects of radiation of grade ≥ 3 occurred in < 1% of patients.

The investigators concluded: 

The magnitude of treatment benefit from combined chemotherapy plus radiation therapy is substantial, but the toxic effects are greater than those observed with radiation therapy alone. Patients and their physicians will have to weigh whether the longer survival justifies the more toxic therapeutic approach. ■

Disclosure: The study was funded by the National Cancer Institute and others. For full disclosures of the study authors, visit www.nejm.org.

References

1. Buckner JC, Shaw EG, Pugh SL, et al: Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med 374:1344-1355, 2016

2. Shaw EG, Wang M, Coons SW, et al: Randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-grade glioma: Initial results of RTOG 9802. J Clin Oncol 30:3065-3070, 2012.


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