Glioblastomas treatment

Surgery plus radiation therapy and chemotherapy.

Surgery plus radiation therapy.

Carmustine-impregnated polymer implanted during initial surgery.

Radiation therapy and concurrent chemotherapy.

Standard therapy is based on a large, multicenter, randomized trial (NCT00006353) conducted by the EORTC and National Cancer Institute of Canada (NCIC). This trial reported a survival benefit with concurrent radiation therapy and temozolomide, compared with radiation therapy alone.[15,16][Level of evidence A1] In this study, 573 patients with glioblastoma were randomly assigned to receive standard radiation to the tumor volume with a 2- to 3-cm margin (60 Gy, 2 Gy per fraction, over 6 weeks) alone or with temozolomide (75 mg/m2 orally per day during radiation therapy for up to 49 days, followed by a 4-week break and then up to six cycles of five daily doses every 28 days at a dose of 150 mg/m2, increasing to 200 mg/m2 after the first cycle).

Standard therapy is based on a large, multicenter, randomized trial (NCT00006353) conducted by the EORTC and National Cancer Institute of Canada (NCIC). This trial reported a survival benefit with concurrent radiation therapy and temozolomide, compared with radiation therapy alone.[15,16][Level of evidence A1] In this study, 573 patients with glioblastoma were randomly assigned to receive standard radiation to the tumor volume with a 2- to 3-cm margin (60 Gy, 2 Gy per fraction, over 6 weeks) alone or with temozolomide (75 mg/m2 orally per day during radiation therapy for up to 49 days, followed by a 4-week break and then up to six cycles of five daily doses every 28 days at a dose of 150 mg/m2, increasing to 200 mg/m2 after the first cycle).

OS was statistically significantly better in the combined radiation therapy–temozolomide group (HRdeath, 0.6; 95% confidence interval [CI], 0.5–0.7; OS rate at 3 years was 16.0% for the radiation therapy–temozolomide group vs. 4.4% in the radiation therapy–alone group).

Standard therapy is based on a large, multicenter, randomized trial (NCT00006353) conducted by the EORTC and National Cancer Institute of Canada (NCIC). This trial reported a survival benefit with concurrent radiation therapy and temozolomide, compared with radiation therapy alone.[15,16][Level of evidence A1] In this study, 573 patients with glioblastoma were randomly assigned to receive standard radiation to the tumor volume with a 2- to 3-cm margin (60 Gy, 2 Gy per fraction, over 6 weeks) alone or with temozolomide (75 mg/m2 orally per day during radiation therapy for up to 49 days, followed by a 4-week break and then up to six cycles of five daily doses every 28 days at a dose of 150 mg/m2, increasing to 200 mg/m2 after the first cycle).

A companion molecular correlation subset study to the EORTC-NCIC trial provided strong evidence that epigenetic silencing of the MGMT DNA-repair gene by promoter DNA methylation was associated with increased OS in patients with newly diagnosed glioblastoma.[13]

Standard therapy is based on a large, multicenter, randomized trial (NCT00006353) conducted by the EORTC and National Cancer Institute of Canada (NCIC). This trial reported a survival benefit with concurrent radiation therapy and temozolomide, compared with radiation therapy alone.[15,16][Level of evidence A1] In this study, 573 patients with glioblastoma were randomly assigned to receive standard radiation to the tumor volume with a 2- to 3-cm margin (60 Gy, 2 Gy per fraction, over 6 weeks) alone or with temozolomide (75 mg/m2 orally per day during radiation therapy for up to 49 days, followed by a 4-week break and then up to six cycles of five daily doses every 28 days at a dose of 150 mg/m2, increasing to 200 mg/m2 after the first cycle). › A companion molecular correlation subset study to the EORTC-NCIC trial provided strong evidence that epigenetic silencing of the MGMT DNA-repair gene by promoter DNA methylation was associated with increased OS in patients with newly diagnosed glioblastoma.[13]

MGMT promoter methylation was an independent favorable prognostic factor (HR, 0.45; 95% CI, 0.32–0.61; log-rank P < .001).

Standard therapy is based on a large, multicenter, randomized trial (NCT00006353) conducted by the EORTC and National Cancer Institute of Canada (NCIC). This trial reported a survival benefit with concurrent radiation therapy and temozolomide, compared with radiation therapy alone.[15,16][Level of evidence A1] In this study, 573 patients with glioblastoma were randomly assigned to receive standard radiation to the tumor volume with a 2- to 3-cm margin (60 Gy, 2 Gy per fraction, over 6 weeks) alone or with temozolomide (75 mg/m2 orally per day during radiation therapy for up to 49 days, followed by a 4-week break and then up to six cycles of five daily doses every 28 days at a dose of 150 mg/m2, increasing to 200 mg/m2 after the first cycle). › A companion molecular correlation subset study to the EORTC-NCIC trial provided strong evidence that epigenetic silencing of the MGMT DNA-repair gene by promoter DNA methylation was associated with increased OS in patients with newly diagnosed glioblastoma.[13]

The median OS for patients with MGMT methylation was 18.2 months (95% CI, 15.5–22.0), compared with 12.2 months (95% CI, 11.4–13.5) for patients without MGMT methylation.

To test whether protracted (dose-dense) temozolomide enhances treatment response in patients with newly diagnosed glioblastoma, a multicenter, randomized, phase III trial conducted by the RTOG, EORTC, and the North Central Cancer Therapy Group, RTOG 0525 (NCT00304031), compared standard adjuvant temozolomide treatment (days 1–5 of a 28-day cycle) with a dose-dense schedule (days 1–21 of a 28-day cycle). All patients were treated with surgery followed by radiation therapy and concurrent daily temozolomide. Patients were then randomly assigned to receive either standard adjuvant temozolomide or dose-dense temozolomide.[14][Level of evidence A1]

To test whether protracted (dose-dense) temozolomide enhances treatment response in patients with newly diagnosed glioblastoma, a multicenter, randomized, phase III trial conducted by the RTOG, EORTC, and the North Central Cancer Therapy Group, RTOG 0525 (NCT00304031), compared standard adjuvant temozolomide treatment (days 1–5 of a 28-day cycle) with a dose-dense schedule (days 1–21 of a 28-day cycle). All patients were treated with surgery followed by radiation therapy and concurrent daily temozolomide. Patients were then randomly assigned to receive either standard adjuvant temozolomide or dose-dense temozolomide.[14][Level of evidence A1]

Among 833 randomly assigned patients, no statistically significant difference between standard and dose-dense temozolomide was observed for median OS (16.6 months for standard temozolomide vs. 14.9 months for dose-dense temozolomide; HR, 1.03; P = .63) or for median PFS (5.5 vs. 6.7 months; HR, 0.87; P = .06).

To test whether protracted (dose-dense) temozolomide enhances treatment response in patients with newly diagnosed glioblastoma, a multicenter, randomized, phase III trial conducted by the RTOG, EORTC, and the North Central Cancer Therapy Group, RTOG 0525 (NCT00304031), compared standard adjuvant temozolomide treatment (days 1–5 of a 28-day cycle) with a dose-dense schedule (days 1–21 of a 28-day cycle). All patients were treated with surgery followed by radiation therapy and concurrent daily temozolomide. Patients were then randomly assigned to receive either standard adjuvant temozolomide or dose-dense temozolomide.[14][Level of evidence A1]

Protracted temozolomide, which depletes intracellular MGMT, was predicted to have greater efficacy in tumors with MGMT-promoter methylation. To test this retrospectively, MGMT status was determined in 86% of randomly assigned patients. No difference in efficacy was observed in either the MGMT-methylated or MGMT-unmethylated subsets. There was no survival advantage for the use of dose-dense temozolomide versus standard-dose temozolomide in newly diagnosed glioblastoma patients, regardless of MGMT status. However, this study confirmed the strong prognostic effect of MGMT methylation because the median OS was 21.2 months (95% CI, 17.9–24.8) for patients with methylation versus 14 months (HR, 1.74; 95% CI, 12.9–14.7; P < .001) for patients without methylation.

To test whether protracted (dose-dense) temozolomide enhances treatment response in patients with newly diagnosed glioblastoma, a multicenter, randomized, phase III trial conducted by the RTOG, EORTC, and the North Central Cancer Therapy Group, RTOG 0525 (NCT00304031), compared standard adjuvant temozolomide treatment (days 1–5 of a 28-day cycle) with a dose-dense schedule (days 1–21 of a 28-day cycle). All patients were treated with surgery followed by radiation therapy and concurrent daily temozolomide. Patients were then randomly assigned to receive either standard adjuvant temozolomide or dose-dense temozolomide.[14][Level of evidence A1]

The efficacy of dose-dense temozolomide for patients who have recurrent glioblastoma, however, is yet to be determined.

RTOG 0825 (NCT00884741): Patients were randomly assigned to receive standard therapy (chemoradiation therapy with temozolomide) or standard therapy plus bevacizumab. OS and PFS were coprimary end points.[17][Level of evidence A1]

RTOG 0825 (NCT00884741): Patients were randomly assigned to receive standard therapy (chemoradiation therapy with temozolomide) or standard therapy plus bevacizumab. OS and PFS were coprimary end points.[17][Level of evidence A1]

Bevacizumab did not improve OS (median OS was 16–17 months for each arm). However, it increased median PFS (10.7 months in the bevacizumab arm vs. 7.3 months in the placebo arm; HR, 0.79; P = .007).

RTOG 0825 (NCT00884741): Patients were randomly assigned to receive standard therapy (chemoradiation therapy with temozolomide) or standard therapy plus bevacizumab. OS and PFS were coprimary end points.[17][Level of evidence A1]

The PFS result in the RTOG 0825 trial did not meet the prespecified significance level (P = .004).

AVAglio (NCT00943826): Patients were randomly assigned to receive standard therapy (chemoradiation therapy with temozolomide) or standard therapy plus bevacizumab. OS and PFS were coprimary end points.[18][Level of evidence A1]

AVAglio (NCT00943826): Patients were randomly assigned to receive standard therapy (chemoradiation therapy with temozolomide) or standard therapy plus bevacizumab. OS and PFS were coprimary end points.[18][Level of evidence A1]

Bevacizumab did not improve OS (median OS was 16–17 months for each arm). However, it increased median PFS (10.6 months in the bevacizumab arm vs. 6.2 months in the placebo arm; HR, 0.64; P < .0001).

AVAglio (NCT00943826): Patients were randomly assigned to receive standard therapy (chemoradiation therapy with temozolomide) or standard therapy plus bevacizumab. OS and PFS were coprimary end points.[18][Level of evidence A1]

The PFS result was statistically significant and associated with clinical benefit because patients who received bevacizumab remained functionally independent longer (9.0 months in the bevacizumab arm vs. 6.0 months in the standard therapy arm) and had a longer time until their Karnofsky Performance status deteriorated (HR, 0.65; P < .0001).

AVAglio (NCT00943826): Patients were randomly assigned to receive standard therapy (chemoradiation therapy with temozolomide) or standard therapy plus bevacizumab. OS and PFS were coprimary end points.[18][Level of evidence A1]

Patients who received bevacizumab also had delayed initiation of corticosteroids (12.3 months vs. 3.7 months; HR, 0.71; P = .002), and more patients were able to discontinue corticosteroids if they were already taking them (66% in the bevacizumab arm vs. 47% in the standard therapy arm).