贝伐珠单抗联合放疗-替莫唑胺治疗新诊断的胶质母细胞瘤。

Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma.

机构信息

From Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Service de Neuro-Oncologie, Centre Hospitaliere Universitaire Timone, Marseille (O.L.C.), UFR de Santé, Médecine et Biologie Humaine, Bobigny (A.F.C.), and Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Avicenne, Service de Neurologie, Université Paris 13 (A.F.C.), and AP-HP, Université Pierre-et-Marie-Curie, Group Hospitalier Pitié-Salpêtrière (K.H.-X.), Paris - all in France; University Hospital of Heidelberg, Department of Neurooncology, and German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany (W.W.); Princess Margaret Hospital, Toronto (W.M.), and McGill University, Montreal (P.K.) - both in Canada; Regional Cancer Center, Stockholm Gotland, Karolinska, Stockholm, and the Department of Radiation Sciences and Oncology, Umeå University, Umeå - both in Sweden (R.H.); the Royal Marsden National Health Service Foundation Trust, Sutton, Surrey, United Kingdom (F.S.); Saitama Medical University, Saitama, Japan (R.N.); Oncology Institute "Ion Chiricuta," Cluj-Napoca, Romania (D.C.); Medical Oncology Department, Azienda Unità Sanitaria Locale, Bologna, Italy (A.A.B.); F. Hoffmann-La Roche, Basel, Switzerland (M.H., L.A.); and University of California, Los Angeles, Los Angeles (T.C.).

出版信息

N Engl J Med. 2014 Feb 20;370(8):709-22. doi: 10.1056/NEJMoa1308345.

DOI:10.1056/NEJMoa1308345

PMID:24552318

Abstract

BACKGROUND

Standard therapy for newly diagnosed glioblastoma is radiotherapy plus temozolomide. In this phase 3 study, we evaluated the effect of the addition of bevacizumab to radiotherapy-temozolomide for the treatment of newly diagnosed glioblastoma.

METHODS

We randomly assigned patients with supratentorial glioblastoma to receive intravenous bevacizumab (10 mg per kilogram of body weight every 2 weeks) or placebo, plus radiotherapy (2 Gy 5 days a week; maximum, 60 Gy) and oral temozolomide (75 mg per square meter of body-surface area per day) for 6 weeks. After a 28-day treatment break, maintenance bevacizumab (10 mg per kilogram intravenously every 2 weeks) or placebo, plus temozolomide (150 to 200 mg per square meter per day for 5 days), was continued for six 4-week cycles, followed by bevacizumab monotherapy (15 mg per kilogram intravenously every 3 weeks) or placebo until the disease progressed or unacceptable toxic effects developed. The coprimary end points were investigator-assessed progression-free survival and overall survival.

RESULTS

A total of 458 patients were assigned to the bevacizumab group, and 463 patients to the placebo group. The median progression-free survival was longer in the bevacizumab group than in the placebo group (10.6 months vs. 6.2 months; stratified hazard ratio for progression or death, 0.64; 95% confidence interval [CI], 0.55 to 0.74; P<0.001). The benefit with respect to progression-free survival was observed across subgroups. Overall survival did not differ significantly between groups (stratified hazard ratio for death, 0.88; 95% CI, 0.76 to 1.02; P=0.10). The respective overall survival rates with bevacizumab and placebo were 72.4% and 66.3% at 1 year (P=0.049) and 33.9% and 30.1% at 2 years (P=0.24). Baseline health-related quality of life and performance status were maintained longer in the bevacizumab group, and the glucocorticoid requirement was lower. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%).

CONCLUSIONS

The addition of bevacizumab to radiotherapy-temozolomide did not improve survival in patients with glioblastoma. Improved progression-free survival and maintenance of baseline quality of life and performance status were observed with bevacizumab; however, the rate of adverse events was higher with bevacizumab than with placebo. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT00943826.).

摘要

背景

新诊断的胶质母细胞瘤的标准疗法是放疗加替莫唑胺。在这项 3 期研究中，我们评估了贝伐珠单抗联合放疗替莫唑胺治疗新诊断的胶质母细胞瘤的效果。

方法

我们将幕上胶质母细胞瘤患者随机分配接受静脉注射贝伐珠单抗（每公斤体重 10 毫克，每两周一次）或安慰剂，联合放疗（每周 5 天，2 Gy；最大剂量 60 Gy）和口服替莫唑胺（每天每平方米体表面积 75 mg）6 周。在 28 天的治疗休息期后，继续使用贝伐珠单抗（每公斤体重静脉注射 10 毫克，每两周一次）或安慰剂，联合替莫唑胺（每天每平方米体表面积 150-200 mg，连用 5 天），进行六个 4 周周期的维持治疗，随后贝伐珠单抗单药治疗（每公斤体重静脉注射 15 mg，每三周一次）或安慰剂，直至疾病进展或出现不可接受的毒性作用。主要终点是研究者评估的无进展生存期和总生存期。

结果

共有 458 名患者被分配到贝伐珠单抗组，463 名患者被分配到安慰剂组。贝伐珠单抗组的无进展生存期长于安慰剂组（10.6 个月比 6.2 个月；分层进展或死亡风险比为 0.64；95%置信区间[CI]为 0.55 至 0.74；P<0.001）。在各亚组中均观察到无进展生存期的获益。两组之间的总生存期无显著差异（分层死亡风险比为 0.88；95%CI 为 0.76 至 1.02；P=0.10）。贝伐珠单抗组和安慰剂组的总生存率分别为 1 年时 72.4%和 66.3%（P=0.049）和 2 年时 33.9%和 30.1%（P=0.24）。贝伐珠单抗组的基线健康相关生活质量和表现状态维持时间更长，且糖皮质激素需求较低。贝伐珠单抗组比安慰剂组有更多的患者发生 3 级或更高级别的不良事件（66.8%比 51.3%）和 3 级或更高级别常与贝伐珠单抗相关的不良事件（32.5%比 15.8%）。