Efficacy, Safety, and Biomarkers of Neoadjuvant Bevacizumab, Radiation Therapy, and Fluorouracil in Rectal Cancer: A Multidisciplinary Phase II Study
Efficacy, Safety, and Biomarkers of Neoadjuvant Bevacizumab, Radiation Therapy, and Fluorouracil in Rectal Cancer: A Multidisciplinary Phase II Study
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DOI：
10.1200/jco.2008.21.1771
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发表时间：
2009-06-20
影响因子：
45.3
通讯作者：
Jain, Rakesh K.
中科院分区：
文献类型：
--
作者：
Willett, Christopher G.;Duda, Dan G.;Jain, Rakesh K.
目的评价贝伐单抗联合标准放化疗治疗局部晚期直肠癌的安全性和有效性，并探索疗效的生物标志物。在I/II期研究中，32例患者接受了4个周期的治疗，包括：贝伐单抗5或10 mg/kg，每周期第1天；氟尿嘧啶225 mg/m(2)/24小时，第2~4周期；外照射(50.4Gy28次，5.5周)；以及手术治疗。在治疗前、贝伐单抗治疗期间以及联合治疗期间和治疗后，我们检测了分子、细胞和生理生物标志物。结果32例患者肿瘤从平均大小5 cm(3~12 cm)的肿块退化为平均2.4 cm(0.7~6.0 cm)的溃疡/疤痕。组织学检查显示原发部位无癌或有不同数量的癌细胞散布在纤维化的床上。这种治疗导致了精算的5年局部控制和总存活率为100%。精算的5年无瘤存活率为75%，5名患者术后发生转移。贝伐单抗联合放化疗显示可接受的毒性。贝伐单抗可降低肿瘤间质液体压和血流量。治疗期间血浆可溶性血管内皮生长因子受体1(SVEGFR1)、血浆血管内皮生长因子(VEGF)、胎盘源性生长因子(PlGF)、白介素6(IL-6)及治疗后循环内皮细胞(CECs)水平与治疗结果呈正相关。结论贝伐单抗联合放化疗治疗局部晚期直肠癌安全有效，预后良好。应进一步评估血浆VEGF、PlGF、sVEGFR1、IL-6和CEC作为该方案反应的候选生物标志物。J Clin Oncol27：3020-3026。(C)2009年美国临床肿瘤学会
PurposeTo assess the safety and efficacy of neoadjuvant bevacizumab with standard chemoradiotherapy in locally advanced rectal cancer and explore biomarkers for response.Patients and MethodsIn a phase I/II study, 32 patients received four cycles of therapy consisting of: bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; fluorouracil infusion (225 mg/m(2)/24 hours) during cycles 2 to 4; external-beam irradiation (50.4 Gy in 28 fractions over 5.5 weeks); and surgery 7 to 10 weeks after completion of all therapies. We measured molecular, cellular, and physiologic biomarkers before treatment, during bevacizumab monotherapy, and during and after combination therapy.ResultsTumors regressed from a mass with mean size of 5 cm (range, 3 to 12 cm) to an ulcer/scar with mean size of 2.4 cm (range, 0.7 to 6.0 cm) in all 32 patients. Histologic examination revealed either no cancer or varying numbers of scattered cancer cells in a bed of fibrosis at the primary site. This treatment resulted in an actuarial 5-year local control and overall survival of 100%. Actuarial 5-year disease-free survival was 75% and five patients developed metastases postsurgery. Bevacizumab with chemoradiotherapy showed acceptable toxicity. Bevacizumab decreased tumor interstitial fluid pressure and blood flow. Baseline plasma soluble vascular endothelial growth factor receptor 1 (sVEGFR1), plasma vascular endothelial growth factor (VEGF), placental-derived growth factor (PlGF), and interleukin 6 (IL-6) during treatment, and circulating endothelial cells (CECs) after treatment showed significant correlations with outcome.ConclusionBevacizumab with chemoradiotherapy appears safe and active and yields promising survival results in locally advanced rectal cancer. Plasma VEGF, PlGF, sVEGFR1, and IL-6 and CECs should be further evaluated as candidate biomarkers of response for this regimen. J Clin Oncol 27: 3020-3026. (C) 2009 by American Society of Clinical Oncology