Bensadoun R J, Etienne M C, Dassonville O, Chauvel P, Pivot X, Marcy P Y, Prevost B, Coche-Dequeant B, Bourdin S, Vallicioni J, Poissonnet G, Courdi A, Teissier E, Lagrange J L, Thyss A, Santini J, Demard F, Schneider M, Milano G
Department of Radiation Oncology, Centre Antoine-Lacassagne, Nice, France.
Int J Radiat Oncol Biol Phys. 1998 Sep 1;42(2):237-45. doi: 10.1016/s0360-3016(98)00235-1.
The aim of this phase II study conducted on unresectable squamous cell carcinoma (USCC) of the oro- and hypopharynx was to associate twice-a-day (b.i.d.) continuous nonaccelerated radiotherapy with concomitant cisplatin (CP)-5-fluorouracil (5-FU) chemotherapy, both given at full dose. Feasibility, efficacy, survival, and pharmacokinetic-pharmacodynamic relationships were analyzed.
Fifty-four consecutive patients with strictly USCC of oro- and/or hypopharynx received continuous b.i.d. radiotherapy (RT) (2 daily fractions of 1.2 Gy, 5 days a week, with a 6-h minimal interval between fractions). Total RT dose was 80.4 Gy on the oropharynx and 75.6 Gy on the hypopharynx. Three chemotherapy (CT) courses of CP-5-FU were given during RT at 21-day intervals (third not delivered after the end of RT). CP dose was 100 mg/m2 (day 1) and 5-FU was given as 5-day continuous infusion (day 2-day 6: 750 mg/m2/day cycle 1, 750 mg total dose/day cycle 2 and 3). Pharmacokinetics was performed for 5-FU (105 h follow-up) and CP (single sample at 16 h). Special attention was paid to supportive care.
Good feasibility of RT was observed (85.2% of patients with total dose > 75 Gy). Five patients received 1 CT cycle, 34: 2 cycles, and 15: 3 cycles. The most frequent and severe acute toxicities were mucositis with grade 3-4 occurring in 28% at cycle 1 and 86% at cycle 2, as well as neutropenia (43% at cycle 2). Locoregional control at 6 months was observed in 66.7% of patients. No late toxicity above grade 2 RTOG was noticed. CP dose and 5-FU AUC(0-105h) were significantly linked to grade 3-4 neutropenia (cycle 2). Cumulative total platinum (Pt) concentration and Karnofsky index were the only independent predictors of locoregional control at 6 months. Finally, total RT dose and total Pt concentration were the only independent predictors of specific survival.
This protocol showed good locoregional response with an acceptable toxicity profile. Pharmacokinetic survey is probably an effective approach to further reduce toxicity and improve efficacy. A multicentric randomized phase III study, now underway, should confirm these encouraging results.
本II期研究针对口咽和下咽不可切除的鳞状细胞癌（USCC），旨在将每日两次（bid）的连续非加速放疗与顺铂（CP）-5-氟尿嘧啶（5-FU）同步化疗联合应用，两者均采用全剂量给药。分析了可行性、疗效、生存率以及药代动力学-药效学关系。
54例连续的口咽和/或下咽严格意义上的USCC患者接受了每日两次的连续放疗（RT）（每日2次，每次1.2 Gy，每周5天，两次分割之间至少间隔6小时）。口咽的总放疗剂量为80.4 Gy，下咽为75.6 Gy。在放疗期间，每21天给予3个周期的CP-5-FU化疗（放疗结束后未给予第3个周期）。CP剂量为100 mg/m²（第1天），5-FU采用5天持续静脉输注（第2天至第6天：第1周期750 mg/m²/天，第2和第3周期总剂量750 mg/天）。对5-FU进行了药代动力学研究（随访105小时），对CP进行了单次取样（16小时）。特别关注了支持性护理。
观察到放疗具有良好的可行性（总剂量>75 Gy的患者占85.2%）。5例患者接受了1个化疗周期，34例接受了2个周期，15例接受了3个周期。最常见和严重的急性毒性反应是黏膜炎，3-4级在第1周期发生率为28%，第2周期为86%，还有中性粒细胞减少（第2周期为43%）。6个月时局部区域控制率在66.7%的患者中观察到。未发现高于2级RTOG的晚期毒性反应。CP剂量和5-FU的AUC(0-105h)与3-4级中性粒细胞减少（第2周期）显著相关。累积总铂（Pt）浓度和卡诺夫斯基指数是6个月时局部区域控制的唯一独立预测因素。最后，总放疗剂量和总Pt浓度是特定生存率的唯一独立预测因素。
该方案显示出良好的局部区域反应，毒性特征可接受。药代动力学研究可能是进一步降低毒性和提高疗效的有效方法。一项正在进行的多中心随机III期研究应能证实这些令人鼓舞的结果。
