Garcia-Aguilar Julio, Chow Oliver S, Smith David D, Marcet Jorge E, Cataldo Peter A, Varma Madhulika G, Kumar Anjali S, Oommen Samuel, Coutsoftides Theodore, Hunt Steven R, Stamos Michael J, Ternent Charles A, Herzig Daniel O, Fichera Alessandro, Polite Blase N, Dietz David W, Patil Sujata, Avila Karin
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Lancet Oncol. 2015 Aug;16(8):957-66. doi: 10.1016/S1470-2045(15)00004-2. Epub 2015 Jul 14.
Patients with locally advanced rectal cancer who achieve a pathological complete response to neoadjuvant chemoradiation have an improved prognosis. The need for surgery in these patients has been questioned, but the proportion of patients achieving a pathological complete response is small. We aimed to assess whether adding cycles of mFOLFOX6 between chemoradiation and surgery increased the proportion of patients achieving a pathological complete response.
We did a phase 2, non-randomised trial consisting of four sequential study groups of patients with stage II-III locally advanced rectal cancer at 17 institutions in the USA and Canada. All patients received chemoradiation (fluorouracil 225 mg/m(2) per day by continuous infusion throughout radiotherapy, and 45·0 Gy in 25 fractions, 5 days per week for 5 weeks, followed by a minimum boost of 5·4 Gy). Patients in group 1 had total mesorectal excision 6-8 weeks after chemoradiation. Patients in groups 2-4 received two, four, or six cycles of mFOLFOX6, respectively, between chemoradiation and total mesorectal excision. Each cycle of mFOLFOX6 consisted of racemic leucovorin 200 mg/m(2) or 400 mg/m(2), according to the discretion of the treating investigator, oxaliplatin 85 mg/m(2) in a 2-h infusion, bolus fluorouracil 400 mg/m(2) on day 1, and a 46-h infusion of fluorouracil 2400 mg/m(2). The primary endpoint was the proportion of patients who achieved a pathological complete response, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00335816.
Between March 24, 2004, and Nov 16, 2012, 292 patients were registered, 259 of whom (60 in group 1, 67 in group 2, 67 in group 3, and 65 in group 4) met criteria for analysis. 11 (18%, 95% CI 10-30) of 60 patients in group 1, 17 (25%, 16-37) of 67 in group 2, 20 (30%, 19-42) of 67 in group 3, and 25 (38%, 27-51) of 65 in group 4 achieved a pathological complete response (p=0·0036). Study group was independently associated with pathological complete response (group 4 compared with group 1 odds ratio 3·49, 95% CI 1·39-8·75; p=0·011). In group 2, two (3%) of 67 patients had grade 3 adverse events associated with the neoadjuvant administration of mFOLFOX6 and one (1%) had a grade 4 adverse event; in group 3, 12 (18%) of 67 patients had grade 3 adverse events; in group 4, 18 (28%) of 65 patients had grade 3 adverse events and five (8%) had grade 4 adverse events. The most common grade 3 or higher adverse events associated with the neoadjuvant administration of mFOLFOX6 across groups 2-4 were neutropenia (five in group 3 and six in group 4) and lymphopenia (three in group 3 and four in group 4). Across all study groups, 25 grade 3 or worse surgery-related complications occurred (ten in group 1, five in group 2, three in group 3, and seven in group 4); the most common were pelvic abscesses (seven patients) and anastomotic leaks (seven patients).
Delivery of mFOLFOX6 after chemoradiation and before total mesorectal excision has the potential to increase the proportion of patients eligible for less invasive treatment strategies; this strategy is being tested in phase 3 clinical trials.
National Institutes of Health National Cancer Institute.
对新辅助放化疗达到病理完全缓解的局部晚期直肠癌患者，其预后有所改善。这些患者是否需要手术一直存在疑问，但达到病理完全缓解的患者比例较小。我们旨在评估在放化疗与手术之间增加mFOLFOX6周期是否会提高达到病理完全缓解的患者比例。
我们进行了一项2期非随机试验，在美国和加拿大的17家机构对四组连续的II - III期局部晚期直肠癌患者进行研究。所有患者均接受放化疗（在整个放疗期间每天持续输注氟尿嘧啶225 mg/m²，共45.0 Gy，分25次，每周5天，共5周，随后至少追加5.4 Gy）。第1组患者在放化疗后6 - 8周进行全直肠系膜切除术。第2 - 4组患者在放化疗与全直肠系膜切除术之间分别接受2个、4个或6个周期的mFOLFOX6治疗。mFOLFOX6的每个周期由消旋亚叶酸200 mg/m²或400 mg/m²（由治疗研究者酌情决定）、奥沙利铂85 mg/m²静脉输注2小时、第1天推注氟尿嘧啶400 mg/m²以及46小时持续输注氟尿嘧啶2400 mg/m²组成。主要终点是达到病理完全缓解的患者比例，采用意向性分析。本试验已在ClinicalTrials.gov注册，编号为NCT00335816。
在2004年3月24日至2012年11月16日期间，共登记了292例患者，其中259例（第1组60例、第2组67例、第3组67例、第4组65例）符合分析标准。第1组60例患者中有11例（18%，95%CI 10 - 30）、第2组67例中有17例（25%，16 - 37）、第3组67例中有20例（30%，19 - 42）、第4组65例中有25例（38%，27 - 51）达到病理完全缓解（p = 0.0036）。研究组与病理完全缓解独立相关（第4组与第1组相比，比值比为3.49，95%CI 1.39 - 8.75；p = 0.011）。在第2组中，67例患者中有2例（3%）发生与新辅助使用mFOLFOX6相关的3级不良事件，1例（1%）发生4级不良事件；在第3组中，67例患者中有12例（18%）发生3级不良事件；在第4组中，65例患者中有18例（28%）发生3级不良事件，5例（8%）发生4级不良事件。在第2 - 4组中，与新辅助使用mFOLFOX6相关的最常见3级或更高等级不良事件是中性粒细胞减少（第3组5例，第4组6例）和淋巴细胞减少（第3组3例，第4组4例）。在所有研究组中，发生了25例3级或更严重的手术相关并发症（第1组10例、第2组5例、第3组3例、第4组7例）；最常见的是盆腔脓肿（7例患者）和吻合口漏（7例患者）。
在放化疗后及全直肠系膜切除术之前给予mFOLFOX6有可能增加适合采用侵入性较小治疗策略的患者比例；该策略正在3期临床试验中进行测试。
美国国立卫生研究院国立癌症研究所。
