Abstract
Patients with a newly diagnosed glioblastoma multiforme (GBM) have a high risk of recurrent disease with a dismal outcome despite intensive treatment of sequential surgery and chemoradiotherapy with temozolomide (TMZ), followed by TMZ as a single agent. Bevacizumab (BV) may increase response rates to chemotherapy in the recurrent treatment setting of GBM. We hypothesized that a neoadjuvant treatment strategy for patients with newly diagnosed GBM using chemoradiotherapy plus BV would improve resectability and thus survival. We performed a phase II trial of the treatment strategy of BV plus chemoradiation to determine the safety of this combination in patients who had already undergone primary surgery for their GBM.
After a biopsy (6 patients) or a resection (13 patients) of a newly diagnosed GBM, 19 patients received radiotherapy (30 fractions of 2 Gy) in combination with daily TMZ 75 mg/m2 and BV 10 mg/kg on days 1, 14, and 28, followed by 6 monthly cycles of TMZ 150–200 mg/m2 on days 1–5.
The overall response rate was 26%. Three patients had a complete response after resection, and in two patients, a complete response after resection followed by chemoradiation plus BV was seen. No grade 3–4 toxicities were observed during combination treatment. The median progression-free survival was 9.6 months (95% confidence interval [CI]: 4.3–14.4 months). The median overall survival was 16 months (95% CI: 8.1–26.3 months), similar to a matched control group that received standard chemoradiotherapy from our institution.
Combination of bevacizumab with radiotherapy and TMZ is safe and feasible in patients with newly diagnosed GBM, but because of low response rates, this treatment strategy does not favor a neoadjuvant approach.
摘要
研究背景. 新诊断的多形性胶质母细胞瘤（GBM）患者即使接受了先手术，继而替莫唑胺（TMZ）化疗同步放疗，之后 TMZ 单药化疗的强化治疗方案，仍有高复发风险，预后不良。贝伐珠单抗（BV）可以提高化疗方案在复发 GBM 患者中的反应率。我们推测，一种针对新诊断 GBM 患者的新辅助治疗策略（即 TMZ 同步放化疗联合 BV）能提高该患者人群的手术切除率和生存。我们就此开展了一项 II 期临床研究，评价这一联合治疗方案在接受过首次手术切除的 GBM 患者中的安全性。
研究方法. 19 例新诊断 GBM 患者在活检（6 例）和手术切除（13 例）后接受放疗（剂量 2 Gy，30 次分割）联合每天 TMZ 化疗（75 mg/m2），在第 1、14、28 天时加用 BV（10 mg/kg）。此后给予 TMZ 单药治疗（150 ∼ 200 mg/m2，第 1 ∼ 5 天，每 28 天一周期方案，共 6 个周期）。
研究结果. 总体反应率为 26%。3 例患者在手术切除后达到完全缓解， 2 例患者在手术切除继以放化疗联合 BV 治疗后达到完全缓解。联合治疗期间未观察到 3 ∼ 4 级毒性反应。中位无进展生存（PFS）为 9.6 个月[95% 可信区间（CI）4.3 ∼ 14.4 个月]。中位总生存（OS）为 16 个月（95%CI 8.1 ∼ 26.3 月），与匹配的对照组（来自本机构，接受标准放化疗方案的患者）相似。
研究结论. BV 联合 TMZ 同步放化疗方案在新诊断 GBM 患者中是安全可行的，但由于反应率较低，并不支持将其作为该患者人群的新辅助治疗策略。The Oncologist 2015;20:107–108
Discussion
We hypothesized that neoadjuvant treatment strategies for patients with a newly diagnosed GBM using chemoradiotherapy plus bevacizumab may improve resectability and thus survival. However, neoadjuvant treatment is rarely applied for these patients because the most effective way to reduce intracranial pressure is still surgery. Tumor volume itself and the marked brain edema associated with GBM are responsible for elevated intracranial pressure with associated morbidity and mortality. Because of the risk of death through cerebral herniation and the fast growth of the tumor, most GBM patients are currently operated on within 1 or 2 weeks after initial diagnosis.
We hypothesized that BV treatment results in immediate and significant reduction of cerebral edema in patients with GBM and may provide the opportunity to postpone surgical resection while reducing tumor volume through a neoadjuvant strategy, eventually resulting in improved locoregional tumor control and improved survival.
The outcome of patients with GBM may benefit from this strategy with a more radical primary resection that will ultimately reduce the chance of residual disease. Tumor recurrence occurs in 90%–95% close to the resection margin. This is attributed to the findings of increased tumor cell density along the margin, with a sharp drop noted as the distance from the resection cavity increases. In view of this high locoregional tumor recurrence rate, it is worth increasing surgical efficiency to improve locoregional control. Neoadjuvant strategies have been successful at improving margin-free tumor resections and local control in patients with other solid tumors.
Because the addition of bevacizumab to treatment in the recurrent GBM setting leads to an immediate and significant reduction of cerebral edema and tissue hypoxia and normalization of the tumor vasculature, we hypothesized that neoadjuvant BV in combination with chemoradiation would improve the surgical outcome of GBM.
Because of the goal of our feasibility trial, BV administrations were not continued during adjuvant temozolomide cycles.
Analysis of toxicity data from our small group of 19 patients did not reveal any grade 3–4 toxicity during the experimental treatment phase of BV in combination with chemoradiotherapy (Table 1). The experimental treatment was well tolerated and was not complicated by known BV-related side effects, In comparison with the standard treatment for GBM in the European Organization for Research and Treatment of Cancer and National Cancer Institute of Canada (EORTC-NCIC) trial, we found slightly more grade 1–2 side effects but no grade 3–4 side effects. Patient characteristics in our study are comparable to the standard patient characteristics in daily practice and, for example, in the EORTC-NCIC trial. Our findings indicate that limiting the addition of BV to the concomitant treatment phase only is safe and feasible, but because of low response rates, this treatment strategy does not favor a neoadjuvant approach.
Treatment-related toxicity in all 19 patients treated with chemoradiotherapy combined with bevacizumab and adjuvant temozolomide
Treatment-related toxicity in all 19 patients treated with chemoradiotherapy combined with bevacizumab and adjuvant temozolomide
Author disclosures available online.
Access the full results at: vanLinde-14-418.theoncologist.com
Nederlands Trial Register Identifier: CCMO NL20411.018.07 Sponsor(s): No
Principal Investigator: Myra E. van Linde IRB Approved: Yes
