Sauer R, Fietkau R, Wittekind C, Rödel C, Martus P, Hohenberger W, Tschmelitsch J, Sabitzer H, Karstens J-H, Becker H, Hess C, Raab R
Klinik und Poliklinik für Strahlentherapie, Universität Erlangen-Nürnberg, Universitätsstrasse 27, D-91054 Erlangen, Germany.
Colorectal Dis. 2003 Sep;5(5):406-15. doi: 10.1046/j.1463-1318.2003.00509.x.
The standard treatment for patients with clinically resectable rectal cancer is surgery. Postoperative radiochemotherapy (RCT) is recommended for advanced disease (pT3/4 or pN+). In recent years, encouraging results of pre-operative radiotherapy have been reported. This prospective randomized phase-III-trial (CAO/ARO/AIO-94) compares the efficacy of neoadjuvant RCT to standard postoperative RCT. We report on the design of the study and first results with regard to toxicity of RCT and postoperative morbidity.
Patients with locally advanced operable rectal cancer (uT3/4 or uN+, Mason CS III/IV) were randomly assigned to pre or postoperative RCT: A total dose of 50.4 Gy (single dose 1.8 Gy) was applied to the tumour and the pelvic lymph nodes. 5-FU (1000 mg/m2/d) was administered concomitantly in the 1th and 5th week of radiation as 120 h-continuous infusion. Four additional cycles of 5-FU-chemotherapy (500 mg/m2/d, i.v.-bolus) were applied. RCT was identical in both arms except for a small-volume boost of 5.4 Gy postoperatively. The time interval between RCT and surgery was 4-6 weeks in both arms. Techniques of surgery were standardized and included total mesorectal excision. Primary endpoints of the study are 5-year survival and local and distant control. Secondary endpoints include the rate of curative (R0) resection and sphincter saving procedures, toxicity of RCT, surgical complications and quality of life.
As of July 2002, 805 patients were randomized from 26 participating institutions. Acute toxicity (WHO) of RCT was low, with less than 15% of patients experiencing grade 3 or higher toxicity: The principal toxicity was diarrhea, with 12% in the postoperative RCT-arm and 11% in the pre-operative RCT-arm having grade 3-, and 1% in either arm having grade 4-diarrhea. Erythema, nausea and leukopenia were the next common toxicities, with less than 3% of patients in either arm suffering grade 3 or greater leukopenia or nausea. Postoperative complication rates were similar in both arms, with 12% (postop. RCT) and 12% (pre-op. RCT) of patients, respectively, suffering from anastomotic leakage, 3% (postop. RCT) and 3% (pre-op. RCT) from postoperative bleeding, and 6% (postop. RCT) and 4% (pre-op. RCT) from delayed wound healing.
The patient accrual to the trial is satisfactory. Neoadjuvant RCT is well tolerated and bears no higher risk for postoperative morbidity.
临床可切除直肠癌患者的标准治疗方法是手术。对于进展期疾病（pT3/4或pN+），建议术后进行放化疗（RCT）。近年来，术前放疗取得了令人鼓舞的结果。这项前瞻性随机III期试验（CAO/ARO/AIO-94）比较了新辅助RCT与标准术后RCT的疗效。我们报告该研究的设计以及关于RCT毒性和术后发病率的初步结果。
局部进展期可手术直肠癌患者（uT3/4或uN+，梅森CS III/IV）被随机分配接受术前或术后RCT：肿瘤和盆腔淋巴结接受总量50.4 Gy（单次剂量1.8 Gy）的照射。在放疗的第1周和第5周，5-氟尿嘧啶（5-FU，1000 mg/m²/天）以120小时持续静脉输注的方式同时给药。另外进行4个周期的5-FU化疗（500 mg/m²/天，静脉推注）。除术后有5.4 Gy的小剂量增敏照射外，两组的RCT相同。两组中RCT与手术之间的时间间隔均为4 - 6周。手术技术标准化，包括直肠系膜全切除术。该研究的主要终点是5年生存率、局部和远处控制情况。次要终点包括根治性（R0）切除率和保肛手术率、RCT的毒性、手术并发症及生活质量。
截至2002年7月，来自26个参与机构的805例患者被随机分组。RCT的急性毒性（WHO分级）较低，不到15%的患者出现3级或更高等级的毒性反应：主要毒性反应是腹泻，术后RCT组中有12%、术前RCT组中有11%的患者出现3级腹泻，两组各有1%的患者出现4级腹泻。红斑、恶心和白细胞减少是其次常见的毒性反应，两组中均不到3%的患者出现3级或更严重的白细胞减少或恶心。两组的术后并发症发生率相似，术后RCT组和术前RCT组分别有12%的患者发生吻合口漏，3%的患者发生术后出血，6%（术后RCT组）和4%（术前RCT组）的患者出现伤口愈合延迟。
该试验的患者入组情况令人满意。新辅助RCT耐受性良好，术后发病风险并不更高。
