Front-line Systemic Therapy for Anaplastic Glioma

There is emerging evidence to support use of systemic therapy in treatment of newly diagnosed anaplastic glioma. Specifically, fractionated external beam RT with adjuvant or neoadjuvant chemotherapy is now a standard of care for patients with 1p19q co-deleted anaplastic oligodendroglioma and oligoastrocytoma.

Procarbazine, Lomustine and Vincristine (PCV)

The largest trial conducted in patients with malignant glioma showed that adjuvant PCV given at 6-week intervals derived no benefit over RT alone. 1A subsequent meta-analysis of 12 randomised controlled trials of 3004 patients demonstrated a significant increase in survival with use of chemotherapy (HR = 0.85; 95% CI, 0.78 to 0.91; P <0.0001), with an absolute increase in 1-year survival of 6% from 40% to 46%.2This finding was consistent with previous meta-analysis, which showed an increase in 1-year and 2-year survival for patients treated with adjuvant chemotherapy compared to RT alone.3RTOG 9402, a phase III trial of adjuvant PCV in anaplastic oligodendroglioma or anaplastic mixed oligoastrocytoma patients with Karnofsky performance score (KPS) 60, initially failed to demonstrate improved overall survival (OS) in patients receiving adjuvant PCV (PCV followed by RT) compared to RT alone at 3 years.4In addition, 65% of patients in treatment arm experienced grade III or IV toxicity and 1 patient died. Subsequently, a long-term follow-up (median follow-up 11.3 years) reported there remained no difference in median survival by treatment for the entire patient cohort (4.6 years for PCV plus RT vs 4.7 years for RT; HR = 0.79; 95% CI, 0.60 to 1.04; P = 0.1).5Patients with 1p19q co-deleted tumours, however, survived longer than those with non-co-deleted tumours (PCV plus RT: 14.7 vs 2.6 years, HR = 0.36; 95% CI, 0.23 to 0.57; P = 0.001; RT: 7.3 vs 2.7 years, HR = 0.40; 95% CI, 0.27 to 0.60; P = 0.01). Also, the median survival of those with co-deleted tumours treated with adjuvant PCV was twice that of patients receiving RT (14.7 vs 7.3 years; HR = 0.59; 95% CI, 0.37 to 0.95; P = 0.03). For those with non-co-deleted tumours, there was no difference in median survival by treatment arm (2.6 vs 2.7 years; HR = 0.85; 95% CI, 0.58 to 1.23; P = 0.39). In the same period, the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group conducted a prospective phase III study of adjuvant PCV (RT followed by PCV) in age 70 years and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2, and demonstrated significant improved 5-year progression free survival (PFS) (1.9 vs 1.1 years) but not OS when compared to RT alone.5With 12 years followup, median OS was significantly prolonged in the adjuvant PCV arm when compared to RT arm (42.3 vs 30.6 months).6Similar to findings from RTOG 9402, subgroup analysis of a cohort of 76 patients with 1p19q co-deletion from EORTC 26951 trial, showed that treatment with adjuvant PCV resulted in significantly improved median OS compared to RT alone (not reached vs 112 months).6In contrast, the patients without co-deletion showed no difference in survival. It is worth noting that 38% of patients in the chemoradiation arm discontinued adjuvant PCV due to toxicity.7

Temozolomide

Temozolomide is an alkylating agent. Newly diagnosed anaplastic oligodendroglioma has shown response to temozolomide monotherapy.8, 9In addition, benefits of combined chemoradiation with temozolomide in grade III glioma have been extrapolated from phase III trials conducted in glioblastoma patients.10, 11A local retrospective study of 62 patients however failed to show significant difference between patients who received chemoradiation with temozolomide and RT only (PFS: 14.8 vs 16.7 months; OS: 34.1 vs 27.4 months).12Results from 2 ongoing phase III trials, CODEL (ClinicalTrials.gove NCT00887146) and CATNON (NCT00626990) will answer the question of whether chemoradiation with temozolomide is beneficial in patients with newly diagnosed 1p19q-co-deleted and non-1p19q deleted anaplastic gliomas respectively.