近日，一项来自德国直肠癌研究小组的最新研究指出，在改良了的基于氟尿嘧啶（5-Fu）的综合疗法中加入奥沙利铂（OX）是可行的，并且，与标准治疗方法相比，这种方法可使更多患者达到完全病理缓解。然而，还需更长时间的随访以便评估患者的无病生存率。该论文近日发表在《柳叶刀·肿瘤》（The Lancet Oncology）杂志上。
术前放化疗、全直肠系膜切除术和应用氟尿嘧啶行辅助化疗是标准的直肠癌综合疗法。为了提高无病生存率（DFS），该项Ⅲ期临床试验研究(CAO/ARO/AIO-04)将奥沙利铂整合到了标准治疗中。
该研究为一项多中心、开放式、随机的Ⅲ期临床试验，研究对象为组织学上证实了的直肠癌患者，这些患者的原发肿瘤分期为T3—T4期或淋巴结病理阳性。从2006年7月25日到2010年2月26日，将患者随机分配到两组：对照组接受标准的基于氟尿嘧啶的综合疗法，包括术前放疗（剂量为50.4 Gy）加氟尿嘧啶输注（1000 mg/m2 第1—5天和第29—33天），接下来行手术和四个周期的氟尿嘧啶推注（500 mg/m2 第1—5天和第29天; 氟尿嘧啶组）；实验组接受术前放疗（剂量为50.4 Gy）加氟尿嘧啶输注（250 mg/m2 第1—14 和第22—35天）和奥沙利铂（50 mg/m2 第1, 8, 22,和29天），紧接着手术和8周期的辅助化疗，方案为奥沙利铂（100 mg/m2 第1 和15天），甲酰四氢叶酸（400 mg/m2 第1 和15天）和氟尿嘧啶输注（2400 mg/m2 第1—2天和第15—16天; 氟尿嘧啶+奥沙利铂组）。
应用电脑生成的块随机码进行随机化，这些随机码是在不设盲情况下通过中心、临床T分期（cT1—4对cT4）和临床N分期（cN0 对cN1—2）进行分层。无病生存率为主要终点。次要终点包括毒性、顺应性和病理缓解，本文也进行了报道。安全性与顺应性分析纳入了治疗后的患者，根据意向-治疗原则分析其有效性终点。本研究在ClinicalTrials.gov上注册，注册号码为NCT00349076。
研究发现，在最初纳入的1265名患者中，1236名可用于评估（氟尿嘧啶+奥沙利铂组613名，氟尿嘧啶组623名）。在术前放化疗期间，606名实际接受了氟尿嘧啶+奥沙利铂化疗的患者中有140名（23%）在术前发生了3-4级中毒反应，而实际接受单纯氟尿嘧啶放化疗的624名患者中有127名（20%）发生3-4级中毒反应。在放化疗期间，与接受单纯氟尿嘧啶放化疗组相比，接受氟尿嘧啶+奥沙利铂组发生3-4级腹泻更常见（73 人〈12%〉对52人〈8%〉），3-4级恶心或呕吐的发生情况也一样（23 人〈4%〉对9人〈1%〉）。606名接受基于氟尿嘧啶+奥沙利铂放化疗的患者中，有516人（85%）进行了足量化疗，571人（94%）接受了足量放疗；624名接受基于氟尿嘧啶的放化疗患者中，行足量化疗和足量放疗的患者数分别为495（79%）和601（96%）。氟尿嘧啶+奥沙利铂化疗组中有591名患者进行了手术，其中有103人（17%）达到了病理完全缓解，单纯氟尿嘧啶化疗组（比值比为1.40，P=0.038）中606人进行了手术，其中有81人（13%）达到了病理完全缓解。在氟尿嘧啶+奥沙利铂组，435名开始辅助化疗的患者中有352人（81%）完成了所有化疗周期（足量或减量），而单纯氟尿嘧啶组，则是463人中的386人（83%）完成了所有化疗周期。（生物谷Bioon.com）
doi:10.1016/S1470-2045(12)70187-0
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Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial
Prof Claus R?del, MDa, Torsten Liersch, MDb, ?, Prof Heinz Becker, MDb, Prof Rainer Fietkau, MDd, Prof Werner Hohenberger, MDe, Prof Torsten Hothorn, PhDg, h, Ullrich Graeven, MDi, Prof Dirk Arnold, MDj, Marga Lang-Welzenbach, MScd, Prof Hans-Rudolf Raab, MDk, Heiko Sülberg, MScl, Prof Christian Wittekind, MDm, Sergej Potapov, MScf, Prof Ludger Staib, MDn, Prof Clemens Hess, MDc, Karin Weigang-K?hler, MDo, Prof Gerhard G Grabenbauer, MDp, Hans Hoffmanns, MDi, Fritz Lindemann, MDq, Anke Schlenska-Lange, MDr, Gunnar Folprecht, MDs, Prof Rolf Sauer, MDd, on behalf of the German Rectal Cancer Study Group
Background
Preoperative chemoradiotherapy, total mesorectal excision surgery, and adjuvant chemotherapy with fluorouracil is the standard combined modality treatment for rectal cancer. With the aim of improving disease-free survival (DFS), this phase 3 study (CAO/ARO/AIO-04) integrated oxaliplatin into standard treatment.
Methods
This was a multicentre, open-label, randomised, phase 3 study in patients with histologically proven carcinoma of the rectum with clinically staged T3–4 or any node-positive disease. Between July 25, 2006, and Feb 26, 2010, patients were randomly assigned to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (1000 mg/m2 days 1–5 and 29–33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m2 days 1–5 and 29; fluorouracil group); and an experimental group receiving preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (250 mg/m2 days 1–14 and 22–35) and oxaliplatin (50 mg/m2 days 1, 8, 22, and 29), followed by surgery and eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m2 days 1 and 15), leucovorin (400 mg/m2 days 1 and 15), and infusional fluorouracil (2400 mg/m2 days 1–2 and 15–16; fluorouracil plus oxaliplatin group). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1–4 vs cT4), and clinical N category (cN0 vs cN1–2) without masking. DFS is the primary endpoint. Secondary endpoints, including toxicity, compliance, and histopathological response are reported here. Safety and compliance analyses included patients as treated, efficacy endpoints were analysed according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT00349076.
Findings
Of the 1265 patients initially enrolled, 1236 were evaluable (613 in the fluorouracil plus oxaliplatin group and 623 in the fluorouracil group). Preoperative grade 3–4 toxic effects occurred in 140 (23%) of 606 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 127 (20%) of 624 patients who actually received fluorouracil chemoradiotherapy. Grade 3–4 diarrhoea was more common in those who received fluorouracil and oxaliplatin during chemoradiotherapy than in those who received fluorouracil during chemoradiotherapy (73 patients [12%] vs 52 patients [8%]), as was grade 3–4 nausea or vomiting (23 [4%] vs nine [1%]). 516 (85%) of the 606 patients who received fluorouracil and oxaliplatin-based chemoradiotherapy had the full dose of chemotherapy, and 571 (94%) had the full dose of radiotherapy; as did 495 (79%) and 601 (96%) of 624 patients who received fluorouracil-based chemoradiotherapy, respectively. A pathological complete response was achieved in 103 (17%) of 591 patients who underwent surgery in the fluorouracil and oxaliplatin group and in 81 (13%) of 606 patients who underwent surgery in the fluorouracil group (odds ratio 1·40, 95% CI 1·02–1·92; p=0·038). In the fluorouracil and oxaliplatin group, 352 (81%) of 435 patients who began adjuvant chemotherapy completed all cycles (with or without dose reduction), as did 386 (83%) of 463 patients in the fluorouracil group.
Interpretation
Inclusion of oxaliplatin into modified fluorouracil-based combined modality treatment was feasible and led to more patients achieving a pathological complete response than did standard treatment. Longer follow-up is needed to assess DFS.
Funding
German Cancer Aid (Deutsche Krebshilfe).
