Lee D J, Cosmatos D, Marcial V A, Fu K K, Rotman M, Cooper J S, Ortiz H G, Beitler J J, Abrams R A, Curran W J
Division of Radiation Oncology, Johns Hopkins Hospital, Baltimore, MD 21287-8922, USA.
Int J Radiat Oncol Biol Phys. 1995 Jun 15;32(3):567-76. doi: 10.1016/0360-3016(95)00150-W.
The objectives of this study were to determine the efficacy and toxicity of Etanidazole (ETA), a hypoxic cell sensitizer, when combined with conventional radiotherapy (RT) in the management of advanced head and neck carcinomas.
From March 1988 to September 1991, 521 patients who had Stage III or IV head and neck carcinomas were randomized to receive conventional RT alone (66 Gy in 33 fractions to 74 Gy in 37 fractions, 5 fractions per week) or RT+ETA (2.0 g/m2 thrice weekly for 17 doses), of whom 504 were eligible and analyzable. Treatment assignments were stratified before randomization according to the primary site (oral cavity + hypopharynx vs. supraglottic larynx + oropharynx + nasopharynx), T-stage (T1-3 vs. T4), and N-stage (N0-2 vs. N3). Pretreatment characteristics were balanced. In the RT-alone arm, 39% of patients had T3 and 34% had T4 disease, whereas in the RT+ETA arm, 42% of patients had T3 and 33% had T4 disease. Thirty-eight percent of the RT-alone patients and 37% of the RT+ETA patients had N3 disease. The median follow-up of surviving patients was 3.38 years, with a range between 0.96 and 5.63 years.
One hundred and ninety-four of the 252 (77%) RT+ETA patients received at least 14 doses of the drug. Overall RT protocol compliance rate was 82% in the RT-alone arm and 86% in the RT+ETA arm. No Grade 3 or 4 central nervous system or peripheral neuropathy was observed in the RT+ETA arm. Eighteen percent of the patients developed Grade 1 and 5% developed Grade 2 peripheral neuropathy. Other drug related toxicities included nausea/vomiting (27%), low blood counts (15%), and allergy (9%). Most of these toxicities were Grade 1 and 2. The incidence of severe acute and late radiation effects were similar between the two arms. The 2-year actuarial local-regional control rate (LCR) was 40% for the RT-alone arm and 40% for the RT+ETA arm. Two-year actuarial survival was 41% for the RT-alone arm and 43% for the RT+ETA arm (p = 0.65). Multivariate analyses were performed to investigate the influence of covariates on treatment effects. A strong treatment interaction with N-stage was revealed: LCR (50% vs. 40% at 2 years), RT+ETA improved for patients with N0-2 disease but not for N3 patients (22% for RT+ETA and 40% for RT). Further analyses showed that RT+ETA was more advantageous in N0-1 patients, with a 2-year LCR of 55% for RT+ETA vs. 37% for RT only (p = 0.03). A similar phenomenon was observed when using survival as the end point.
The results showed that adding Etanidazole to conventional RT produced no global benefit for patients who had advanced head and neck carcinomas. There was a suggested benefit for patients who had N0-1 disease, and that needs to be confirmed by another study.
本研究的目的是确定乏氧细胞增敏剂依托硝唑（ETA）与传统放疗（RT）联合用于晚期头颈癌治疗时的疗效和毒性。
1988年3月至1991年9月，521例Ⅲ期或Ⅳ期头颈癌患者被随机分为单纯接受传统放疗组（66 Gy分33次至74 Gy分37次，每周5次）或放疗+ETA组（2.0 g/m²，每周3次，共17剂），其中504例符合条件并可进行分析。随机分组前，根据原发部位（口腔+下咽与声门上喉+口咽+鼻咽）、T分期（T1-3与T4）和N分期（N0-2与N3）进行分层。治疗前特征均衡。单纯放疗组中，39%的患者为T3期，34%为T4期疾病；而放疗+ETA组中，42%的患者为T3期，33%为T4期疾病。单纯放疗组38%的患者和放疗+ETA组37%的患者为N3期疾病。存活患者的中位随访时间为3.38年，范围在0.96至5.63年之间。
252例放疗+ETA患者中有194例（77%）接受了至少14剂药物。单纯放疗组的总体放疗方案依从率为82%，放疗+ETA组为86%。放疗+ETA组未观察到3级或4级中枢神经系统或周围神经病变。18%的患者出现1级周围神经病变，5%出现2级周围神经病变。其他与药物相关的毒性包括恶心/呕吐（27%）、血细胞计数低（15%）和过敏（9%）。这些毒性大多为1级和2级。两组严重急性和晚期放射反应的发生率相似。单纯放疗组2年精算局部区域控制率（LCR）为40%，放疗+ETA组为40%。单纯放疗组2年精算生存率为41%，放疗+ETA组为43%（p = 0.65）。进行多因素分析以研究协变量对治疗效果的影响。结果显示与N分期存在强烈的治疗交互作用：LCR（2年时分别为50%和40%），放疗+ETA对N0-2期患者有改善，但对N3期患者无改善（放疗+ETA组为22%，单纯放疗组为40%）。进一步分析表明，放疗+ETA在N0-1期患者中更具优势，放疗+ETA组2年LCR为55%，单纯放疗组为37%（p = 0.03）。以生存作为终点时也观察到类似现象。
结果表明，在传统放疗基础上加用依托硝唑对晚期头颈癌患者未产生整体益处。对N0-1期患者有潜在益处，这需要另一项研究来证实。
