近日,，一項(xiàng)來(lái)自德國(guó)直腸癌研究小組的最新研究指出,，在改良了的基于氟尿嘧啶（5-Fu）的綜合療法中加入奧沙利鉑（OX）是可行的，并且,，與標(biāo)準(zhǔn)治療方法相比,，這種方法可使更多患者達(dá)到完全病理緩解。然而,，還需更長(zhǎng)時(shí)間的隨訪(fǎng)以便評(píng)估患者的無(wú)病生存率,。該論文近日發(fā)表在《柳葉刀·腫瘤》（The Lancet Oncology）雜志上。
術(shù)前放化療,、全直腸系膜切除術(shù)和應(yīng)用氟尿嘧啶行輔助化療是標(biāo)準(zhǔn)的直腸癌綜合療法,。為了提高無(wú)病生存率（DFS）,，該項(xiàng)Ⅲ期臨床試驗(yàn)研究(CAO/ARO/AIO-04)將奧沙利鉑整合到了標(biāo)準(zhǔn)治療中。
該研究為一項(xiàng)多中心,、開(kāi)放式,、隨機(jī)的Ⅲ期臨床試驗(yàn)，研究對(duì)象為組織學(xué)上證實(shí)了的直腸癌患者,，這些患者的原發(fā)腫瘤分期為T(mén)3—T4期或淋巴結(jié)病理陽(yáng)性,。從2006年7月25日到2010年2月26日，將患者隨機(jī)分配到兩組：對(duì)照組接受標(biāo)準(zhǔn)的基于氟尿嘧啶的綜合療法,，包括術(shù)前放療（劑量為50.4 Gy）加氟尿嘧啶輸注（1000 mg/m2 第1—5天和第29—33天）,，接下來(lái)行手術(shù)和四個(gè)周期的氟尿嘧啶推注（500 mg/m2 第1—5天和第29天; 氟尿嘧啶組）；實(shí)驗(yàn)組接受術(shù)前放療（劑量為50.4 Gy）加氟尿嘧啶輸注（250 mg/m2 第1—14 和第22—35天）和奧沙利鉑（50 mg/m2 第1, 8, 22,和29天）,，緊接著手術(shù)和8周期的輔助化療，方案為奧沙利鉑（100 mg/m2 第1 和15天）,，甲酰四氫葉酸（400 mg/m2 第1 和15天）和氟尿嘧啶輸注（2400 mg/m2 第1—2天和第15—16天; 氟尿嘧啶+奧沙利鉑組）,。
應(yīng)用電腦生成的塊隨機(jī)碼進(jìn)行隨機(jī)化，這些隨機(jī)碼是在不設(shè)盲情況下通過(guò)中心,、臨床T分期（cT1—4對(duì)cT4）和臨床N分期（cN0 對(duì)cN1—2）進(jìn)行分層,。無(wú)病生存率為主要終點(diǎn)。次要終點(diǎn)包括毒性,、順應(yīng)性和病理緩解,，本文也進(jìn)行了報(bào)道。安全性與順應(yīng)性分析納入了治療后的患者,，根據(jù)意向-治療原則分析其有效性終點(diǎn),。本研究在ClinicalTrials.gov上注冊(cè)，注冊(cè)號(hào)碼為NCT00349076,。
研究發(fā)現(xiàn),，在最初納入的1265名患者中，1236名可用于評(píng)估（氟尿嘧啶+奧沙利鉑組613名,，氟尿嘧啶組623名）,。在術(shù)前放化療期間，606名實(shí)際接受了氟尿嘧啶+奧沙利鉑化療的患者中有140名（23%）在術(shù)前發(fā)生了3-4級(jí)中毒反應(yīng),，而實(shí)際接受單純氟尿嘧啶放化療的624名患者中有127名（20%）發(fā)生3-4級(jí)中毒反應(yīng),。在放化療期間，與接受單純氟尿嘧啶放化療組相比,，接受氟尿嘧啶+奧沙利鉑組發(fā)生3-4級(jí)腹瀉更常見(jiàn)（73 人〈12%〉對(duì)52人〈8%〉）,，3-4級(jí)惡心或嘔吐的發(fā)生情況也一樣（23 人〈4%〉對(duì)9人〈1%〉）。606名接受基于氟尿嘧啶+奧沙利鉑放化療的患者中,，有516人（85%）進(jìn)行了足量化療,，571人（94%）接受了足量放療,；624名接受基于氟尿嘧啶的放化療患者中，行足量化療和足量放療的患者數(shù)分別為495（79%）和601（96%）,。氟尿嘧啶+奧沙利鉑化療組中有591名患者進(jìn)行了手術(shù),，其中有103人（17%）達(dá)到了病理完全緩解，單純氟尿嘧啶化療組（比值比為1.40,，P=0.038）中606人進(jìn)行了手術(shù),，其中有81人（13%）達(dá)到了病理完全緩解。在氟尿嘧啶+奧沙利鉑組,，435名開(kāi)始輔助化療的患者中有352人（81%）完成了所有化療周期（足量或減量）,，而單純氟尿嘧啶組，則是463人中的386人（83%）完成了所有化療周期,。（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).
