Thymidylate Synthase Genotype-Directed Neoadjuvant Chemoradiation for Patients With Rectal Adenocarcinoma
Thymidylate Synthase Genotype-Directed Neoadjuvant Chemoradiation for Patients With Rectal Adenocarcinoma
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DOI：
10.1200/jco.2010.32.3212
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发表时间：
2011-03-01
影响因子：
45.3
通讯作者：
McLeod, Howard L.
中科院分区：
文献类型：
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作者：
Tan, Benjamin R.;Thomas, Fabienne;McLeod, Howard L.
目的直肠癌新辅助氟尿嘧啶（FU）为主的放化疗（CRT）使约45%的直肠癌患者实现了分期下调（DS）。胸苷酸合成酶基因（TYMS）的多态性以前定义了两个与不同肿瘤DS率相关的风险组（60%对22%）。我们进行了一项前瞻性的单机构II期研究，使用TYMS基因分型，以指导新辅助CRT直肠癌patients with rectal cancer.Patients和方法T3/T4，N 0 -2，M0-1直肠腺癌患者进行评估生殖系TYMS基因分型。TYMS *2/*2、*2/*3或 *2/*4（良好风险）患者接受标准化放疗，使用FU 225 mg/m2/d输注。TYMS *3/*3或 *3/*4（低风险）患者接受FU/RT联合每周静脉伊立替康50 mg/m2治疗（2）。主要终点为病理性DS。次要终点包括完全肿瘤反应（ypT 0），毒性，复发率，和总survival.Results总体而言，135例患者参加，其中27.4%（37 135）被认为是不良风险。预先设定的统计学目标是实现的，DS和ypT 0率达到64.4%和20%的良好的风险和64.5%和42%的低风险patients.Conclusion据我们所知，这是第一项研究，前瞻性地使用TYMS基因分型，以指导新辅助CRT直肠癌患者。当基于TYMS基因型进行个性化治疗时，两个风险组的DS和ypT 0发生率均较高。这些结果是令人鼓舞的，并进一步评估这种基于基因型的策略，使用随机研究设计的局部晚期直肠癌是必要的。J Clin Oncol 29：875-883. (C)2011年美国临床肿瘤学会
Purpose Downstaging (DS) of rectal cancers is achieved in approximately 45% of patients with neoadjuvant fluorouracil (FU) -based chemoradiotherapy (CRT). Polymorphisms in the thymidylate synthase gene (TYMS) had previously defined two risk groups associated with disparate tumor DS rates (60% v 22%). We conducted a prospective single-institution phase II study using TYMS genotyping to direct neoadjuvant CRT for patients with rectal cancer.Patients and Methods Patients with T3/T4, N0-2, M0-1 rectal adenocarcinoma were evaluated for germline TYMS genotyping. Patients with TYMS *2/*2, *2/*3, or *2/*4 (good risk) were treated with standard chemoradiotherapy using infusional FU at 225 mg/m(2)/d. Patients with TYMS *3/*3 or *3/*4 (poor risk) were treated with FU/RT plus weekly intravenous irinotecan at 50 mg/m(2). The primary end point was pathologic DS. Secondary end points included complete tumor response (ypT0), toxicity, recurrence rates, and overall survival.Results Overall, 135 patients were enrolled, of whom 27.4% (37 of 135) were considered poor risk. The prespecified statistical goals were achieved, with DS and ypT0 rates reaching 64.4% and 20% for good-risk and 64.5% and 42% for poor-risk patients, respectively.Conclusion To our knowledge, this is the first study to prospectively use TYMS genotyping to direct neoadjuvant CRT in patients with rectal cancer. High rates of DS and ypT0 were achieved among both risk groups when personalized treatment was based on TYMS genotype. These results are encouraging, and further evaluation of this genotype-based strategy using a randomized study design for locally advanced rectal cancer is warranted. J Clin Oncol 29: 875-883. (C) 2011 by American Society of Clinical Oncology