A phase I-II study of weekly oxaliplatin, 5-fiuorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer
A phase I-II study of weekly oxaliplatin, 5-fiuorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer
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DOI：
10.1093/annonc/mdi212
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发表时间：
2005-07-01
影响因子：
50.5
通讯作者：
Monfardini, S
中科院分区：
文献类型：
--
作者：
Aschele, C;Friso, ML;Monfardini, S
背景资料：奥沙利铂（OXA）显著增强了5-氟尿嘧啶（FUra）在晚期结直肠癌患者中的抗肿瘤活性，并在临床前研究中显示出放射增敏特性。因此，本研究旨在验证每周一次OXA和输注FUra联合术前盆腔放疗的可行性，确定推荐剂量（RDs），并初步探讨其临床活性。46例复发性或局部晚期患者用递增剂量的OXA治疗中低位直肠（cT 3 -4和/或N+）腺癌（25、35、45、60 mg/m2，每周一次，持续6周）和FUra（200-225 mg/m2/天，6周输注），同时进行术前盆腔放疗（50.4戈伊/28次）。该研究的第二阶段部分的RD立即低于导致剂量限制性毒性的水平，在超过三分之一的患者，或对应于最后计划的剂量level.Results：在递增阶段，剂量限制性毒性仅发生在一个患者在第四级和一个六名患者治疗的最后计划的剂量水平（III级腹泻）。因此，OXA 60 mg/m2和FUra 225 mg/m2/天是该方案的RD。在全球接受这些剂量治疗的25例患者中（II期部分），III级腹泻的发生率为16%，无IV级毒性。神经毒性不超过II级（12%）。所有患者均完成放疗并按计划进行手术。25例患者中有21例在放化疗后肿瘤分期下降，7例（28%）病理学完全缓解，1 - 2例（48%）残留肿瘤限于ypT 1 - 2N 0。结论：每周一次的OXA，在潜在的全身活性剂量下，可以与全剂量输注的FUra和放疗联合使用。鉴于低毒性和有希望的活性，该方案正在随机研究中与标准的基于FUra的盆腔放化疗进行比较。
Background: Oxaliplatin (OXA) significantly enhanced the antitumour activity of 5-fluorouracil (FUra) in patients with advanced colorectal cancer and displayed radiosensitising properties in preclinical studies. This study was thus performed to test the feasibility, identify the recommended doses (RDs) and explore preliminarily the clinical activity of weekly OXA and infused FUra combined with preoperative pelvic radiotherapy.Patients and methods: Forty-six patients with recurrent or locally advanced (cT3-4 and/or N+) adenocarcinomas of the mid-low rectum were treated with escalating doses of OXA (25, 35, 45, 60 mg/m(2), weekly for 6 weeks) and FUra (200-225 mg/m(2)/day, 6-week infusion) concurrent to preoperative pelvic radiotherapy (50.4 Gy/28 fractions). The RDs for the phase II part of the study were immediately below the level resulting in dose-limiting toxicities in more than one third of the patients, or corresponded to the last planned dose level.Results: In the escalation phase, dose-limiting toxicities only occurred in one patient at the fourth level and one of six patients treated at the last planned dose level (grade III diarrhoea). OXA 60 mg/m2 and FUra 225 mg/m(2)/day are therefore the RDs for the regimen. Among 25 patients globally treated at these doses (phase II part), the incidence of grade III diarrhoea was 16% with no grade IV toxicity. Neurotoxicity did not exceed grade II (12%). All patients completed radiotherapy and were operated on as scheduled. Twenty-one of 25 patients had the tumour down-staged after chemoradiation with seven (28%) pathological complete responses and 12 (48%) residual tumours limited to ypT1-2N0.Conclusions: Weekly OXA, at doses potentially active systemically, can be combined with full-dose, infused FUra and radiotherapy. Given the low toxicity and promising activity, this regimen is being compared to standard FUra-based pelvic chemoradiation in a randomised study.