Navid Fariba, Santana Victor M, Neel Michael, McCarville M Beth, Shulkin Barry L, Wu Jianrong, Billups Catherine A, Mao Shenghua, Daryani Vinay M, Stewart Clinton F, Kunkel Michelle, Smith Wendene, Ward Deborah, Pappo Alberto S, Bahrami Armita, Loeb David M, Reikes Willert Jennifer, Rao Bhaskar N, Daw Najat C
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN.
Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN.
Int J Cancer. 2017 Oct 1;141(7):1469-1477. doi: 10.1002/ijc.30841. Epub 2017 Jul 3.
Increased vascular endothelial growth factor (VEGF) expression in osteosarcoma correlates with a poor outcome. We conducted a phase II trial to evaluate the feasibility and efficacy of combining bevacizumab, a monoclonal antibody against VEGF, with methotrexate, doxorubicin and cisplatin (MAP) in patients with localized osteosarcoma. Eligible patients received two courses of MAP chemotherapy before definitive surgery at week 10. Bevacizumab (15 mg/kg) was administered 3 days before starting chemotherapy then on day 1 of weeks 3 and 5 of chemotherapy. After surgery, patients received MAP for a total of 29 weeks; bevacizumab was added every 2 or 3 weeks on day 1 of chemotherapy at least 5 weeks after surgery. Group sequential monitoring rules were used to monitor for unacceptable bevacizumab-related targeted toxicity (grade 4 hypertension, proteinuria or bleeding, grade 3 or 4 thrombosis/embolism, and grade 2-4 major wound complications). Thirty-one patients (median age 12.8 years) with localized osteosarcoma were enrolled. No unacceptable targeted toxicities were observed except for wound complications (9 minor and 6 major), which occurred in 15 patients; none required removal of prosthetic hardware or amputation. The estimated 4-year event-free survival (EFS) rate and overall survival rate were 57.5 ± 10.0% and 83.4 ± 7.8%, respectively. Eight (28%) of 29 evaluable patients had good histologic response (<5% viable tumor) to preoperative chemotherapy. The addition of bevacizumab to MAP for localized osteosarcoma is feasible but frequent wound complications are encountered. The observed histologic response and EFS do not support further evaluation of bevacizumab in osteosarcoma.
骨肉瘤中血管内皮生长因子（VEGF）表达增加与预后不良相关。我们进行了一项II期试验，以评估将抗VEGF单克隆抗体贝伐单抗与甲氨蝶呤、阿霉素和顺铂（MAP）联合用于局限性骨肉瘤患者的可行性和疗效。符合条件的患者在第10周进行确定性手术前接受两个疗程的MAP化疗。贝伐单抗（15mg/kg）在化疗开始前3天给药，然后在化疗第3周和第5周的第1天给药。术后，患者共接受29周的MAP治疗；术后至少5周，在化疗第1天每2或3周加用一次贝伐单抗。采用组序贯监测规则监测不可接受的贝伐单抗相关靶向毒性（4级高血压、蛋白尿或出血，3或4级血栓形成/栓塞，以及2-4级主要伤口并发症）。31例局限性骨肉瘤患者（中位年龄12.8岁）入组。除15例患者出现伤口并发症（9例轻微和6例严重）外，未观察到不可接受的靶向毒性；均无需取出假体或截肢。估计4年无事件生存率（EFS）和总生存率分别为57.5±10.0%和83.4±7.8%。29例可评估患者中有8例（28%）对术前化疗有良好的组织学反应（存活肿瘤<5%）。在局限性骨肉瘤的MAP方案中添加贝伐单抗是可行的，但会遇到频繁的伤口并发症。观察到的组织学反应和EFS不支持在骨肉瘤中进一步评估贝伐单抗。
