Saran Frank, Chinot Olivier L, Henriksson Roger, Mason Warren, Wick Wolfgang, Cloughesy Timothy, Dhar Sunita, Pozzi Emanuela, Garcia Josep, Nishikawa Ryo
The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK (F.S.); Aix-Marseille University, AP-HM, Service de Neuro-Oncologie, CHU Timone, Marseille, France (O.L.C.); Regional Cancer Center, Stockholm-Gotland, Karolinska University Hospital, Stockholm, Sweden (R.H.); Department of Radiation Sciences and Oncology, Umeå University, Förvaltningshuset, Universitetstorget, Umeå, Sweden (R.H.); Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada (W.M.); University Medical Center and German Cancer Research Center, Heidelberg, Germany (W.W.); University of California, Los Angeles, California, USA (T.C.); Genentech Inc., South San Francisco, California, USA (S.D.); F. Hoffmann-La Roche Ltd, Basel, Switzerland (E.P., J.G.); Saitama Medical University, Saitama, Japan (R.N.).
Neuro Oncol. 2016 Jul;18(7):991-1001. doi: 10.1093/neuonc/nov300. Epub 2016 Jan 24.
The proposed use of bevacizumab with radiotherapy/temozolomide for newly diagnosed glioblastoma raised potential safety concerns. Bevacizumab has been linked with stroke, bleeding events, and wound-healing complications in other tumor types; these events are of particular concern for glioblastoma (highly vascular tumors that are usually resected). Published data on the interaction of bevacizumab with radiotherapy/temozolomide are also limited. We report safety data from a phase III randomized trial (Avastin in Glioblastoma), focusing on these considerations.
Eligible patients received: radiotherapy and temozolomide plus bevacizumab/placebo, 6 cycles; a 4-week treatment break; temozolomide plus bevacizumab/placebo, 6 cycles; and bevacizumab/placebo until progression. Data on adverse events (AEs) were collected throughout.
Bevacizumab-treated patients (n = 461) had a longer median safety follow-up time (12.3 vs 8.5 mo), and a higher proportion completed 6 cycles of maintenance temozolomide (64.6% vs 36.9%) versus placebo (n = 450). The incidences of relevant AEs (bevacizumab vs placebo, respectively) were: arterial thromboembolic events (5.9% vs 1.6%); cerebral hemorrhage (3.3% vs 2.0%); wound-healing complications (6.9% vs 4.7%); thrombocytopenia (34.1% vs 27.3%); radiotherapy-associated skin injury (8.2% vs 9.3%); alopecia (39.0% vs 36.0%); gastrointestinal perforation (including gastrointestinal abscesses and fistulae, 1.7% vs 0.4%); and radiotherapy-associated injury (0.4% vs 0.0%). Overall, 15.8% and 23.8% of bevacizumab- and placebo-treated patients had surgery (including biopsy) after progression. Within 30 days of postprogression surgery, AE incidence was 10.9% (bevacizumab) and 23.4% (placebo).
The safety profile was consistent with that expected from radiotherapy/temozolomide plus bevacizumab. The increased AE incidence with bevacizumab did not impact patients' ability to receive standard-of-care treatment or to undergo further surgery.
对于新诊断的胶质母细胞瘤，提议将贝伐单抗与放疗/替莫唑胺联合使用引发了潜在的安全性担忧。在其他肿瘤类型中，贝伐单抗与中风、出血事件及伤口愈合并发症有关；对于胶质母细胞瘤（通常需手术切除的高血管性肿瘤）而言，这些事件尤其值得关注。关于贝伐单抗与放疗/替莫唑胺相互作用的已发表数据也很有限。我们报告了一项III期随机试验（胶质母细胞瘤中的阿瓦斯汀）的安全性数据，重点关注这些问题。
符合条件的患者接受：放疗和替莫唑胺加贝伐单抗/安慰剂，6个周期；为期4周的治疗间歇期；替莫唑胺加贝伐单抗/安慰剂，6个周期；以及贝伐单抗/安慰剂直至病情进展。全程收集不良事件（AE）数据。
与接受安慰剂治疗的患者（n = 450）相比，接受贝伐单抗治疗的患者（n = 461）的中位安全随访时间更长（12.3个月对8.5个月），且完成6个周期维持性替莫唑胺治疗的比例更高（64.6%对36.9%）。相关不良事件的发生率（贝伐单抗组对安慰剂组）分别为：动脉血栓栓塞事件（5.9%对1.6%）；脑出血（3.3%对2.0%）；伤口愈合并发症（6.9%对4.7%）；血小板减少症（34.1%对27.3%）；放疗相关皮肤损伤（8.2%对9.3%）；脱发（39.0%对36.0%）；胃肠道穿孔（包括胃肠道脓肿和瘘管，1.7%对0.4%）；以及放疗相关损伤（0.4%对0.0%）。总体而言，病情进展后，接受贝伐单抗和安慰剂治疗的患者分别有15.8%和23.8%接受了手术（包括活检）。在病情进展后手术的30天内，不良事件发生率分别为10.9%（贝伐单抗组）和23.4%（安慰剂组）。
安全性概况与放疗/替莫唑胺加贝伐单抗预期的情况一致。贝伐单抗导致的不良事件发生率增加并未影响患者接受标准治疗或接受进一步手术的能力。
