Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial.
Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial.
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DOI：
10.1016/s1470-2045(17)30318-2
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发表时间：
2017-08
期刊：
影响因子：
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通讯作者：
CONVERT Study Team
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作者：
Faivre-Finn C;Snee M;Ashcroft L;Appel W;Barlesi F;Bhatnagar A;Bezjak A;Cardenal F;Fournel P;Harden S;Le Pechoux C;McMenemin R;Mohammed N;O'Brien M;Pantarotto J;Surmont V;Van Meerbeeck JP;Woll PJ;Lorigan P;Blackhall F;CONVERT Study Team
同步放化疗是局限期小细胞肺癌的标准治疗，但最佳放疗方案和剂量仍存在争议。本研究的目的是建立一个标准化放疗方案治疗局限期小细胞肺癌。CONVERT试验是一项开放标签、III期、随机化优效性试验。我们入组了经细胞学或组织学证实的局限期小细胞肺癌、东部肿瘤协作组体能状态为0-2、肺功能良好的成人患者（年龄≥18岁）。从8个国家的73个中心招募患者。患者被随机分配接受45戈伊放射治疗，每日两次，每次1·5戈伊，共30次，持续19天，或66戈伊，每日一次，每次2戈伊，共33次，持续45天，从顺铂-依托泊苷化疗开始后第22天开始（两组均每3周给予4至6个周期）。使用的分配方法是随机元素最小化，按机构、计划化疗周期数和体能状态分层。治疗组分配未设盲。主要终点是总生存期，定义为从随机化到任何原因死亡的时间，通过改良的意向治疗分析，每日一次组2年总生存期比每日两次组高12%，被认为具有临床意义，显示每日一次方案的优越性。该研究已在ClinicalTrials.gov（NCT 00433563）注册，目前正在随访中。在2008年4月7日至2013年11月29日期间，547例患者入组并随机分配接受每日两次同步放化疗（274例患者）或每日一次同步放化疗（273例患者）。4例患者（每日两次组1例，每日一次组3例）未返回病例报告表，失访;这些患者未纳入我们的分析。在中位随访45个月（IQR 35-58）时，每日两次组的中位总生存期为30个月（95% CI 24-34），每日一次组为25个月（21-31）（每日一次组死亡风险比为1.18 [95% CI 0.95 - 1.45]; p= 0.14）。2-每日两次组的1年总生存率为56%（95% CI 50-62），每日一次组为51%（45-57）（治疗组间的绝对差异为5.3%[95% CI-3.2%至13.7%]）。评价化疗毒性的患者中最常见的3-4级不良事件是中性粒细胞减少（每日两次组266例患者中197例[74%] vs每日一次组263例患者中170例[65%]）。两组的大多数毒性反应相似，除了每日两次放疗组的4级中性粒细胞减少症明显更多（129例[49%] vs 101例[38%]; p= 0.05）。在评估放疗毒性的患者中，两组之间的3-4级食管炎（每日两次组254例患者中的47例[19%] vs每日一次组246例患者中的47例[19%]; p= 0.85）和3-4级放射性肺炎（254例患者中的4例[3%] vs 246例患者中的4例[2%]; p= 0.70）没有差异。11例患者死于治疗相关原因（每日两次组3例，每日一次组8例）。在有限期小细胞肺癌患者中，每日两次和每日一次同步放化疗的生存结局没有差异，两种方案的毒性相似且低于预期。由于该试验的设计目的是显示每日一次放疗的优越性，但没有能力显示等效性，这意味着每日两次放疗应继续被视为这种情况下的标准治疗。英国癌症研究（临床试验奖和咨询委员会）、法国卫生部、加拿大癌症协会研究所、欧洲癌症研究和治疗组织（癌症研究基金、肺癌和放射肿瘤学小组）。
Concurrent chemoradiotherapy is the standard of care in limited-stage small-cell lung cancer, but the optimal radiotherapy schedule and dose remains controversial. The aim of this study was to establish a standard chemoradiotherapy treatment regimen in limited-stage small-cell lung cancer. The CONVERT trial was an open-label, phase 3, randomised superiority trial. We enrolled adult patients (aged ≥18 years) who had cytologically or histologically confirmed limited-stage small-cell lung cancer, Eastern Cooperative Oncology Group performance status of 0–2, and adequate pulmonary function. Patients were recruited from 73 centres in eight countries. Patients were randomly assigned to receive either 45 Gy radiotherapy in 30 twice-daily fractions of 1·5 Gy over 19 days, or 66 Gy in 33 once-daily fractions of 2 Gy over 45 days, starting on day 22 after commencing cisplatin–etoposide chemotherapy (given as four to six cycles every 3 weeks in both groups). The allocation method used was minimisation with a random element, stratified by institution, planned number of chemotherapy cycles, and performance status. Treatment group assignments were not masked. The primary endpoint was overall survival, defined as time from randomisation until death from any cause, analysed by modified intention-to-treat. A 12% higher overall survival at 2 years in the once-daily group versus the twice-daily group was considered to be clinically significant to show superiority of the once-daily regimen. The study is registered with ClinicalTrials.gov (NCT00433563) and is currently in follow-up. Between April 7, 2008, and Nov 29, 2013, 547 patients were enrolled and randomly assigned to receive twice-daily concurrent chemoradiotherapy (274 patients) or once-daily concurrent chemoradiotherapy (273 patients). Four patients (one in the twice-daily group and three in the once-daily group) did not return their case report forms and were lost to follow-up; these patients were not included in our analyses. At a median follow-up of 45 months (IQR 35–58), median overall survival was 30 months (95% CI 24–34) in the twice-daily group versus 25 months (21–31) in the once-daily group (hazard ratio for death in the once daily group 1·18 [95% CI 0·95–1·45]; p=0·14). 2-year overall survival was 56% (95% CI 50–62) in the twice-daily group and 51% (45–57) in the once-daily group (absolute difference between the treatment groups 5·3% [95% CI −3·2% to 13·7%]). The most common grade 3–4 adverse event in patients evaluated for chemotherapy toxicity was neutropenia (197 [74%] of 266 patients in the twice-daily group vs 170 [65%] of 263 in the once-daily group). Most toxicities were similar between the groups, except there was significantly more grade 4 neutropenia with twice-daily radiotherapy (129 [49%] vs 101 [38%]; p=0·05). In patients assessed for radiotherapy toxicity, was no difference in grade 3–4 oesophagitis between the groups (47 [19%] of 254 patients in the twice-daily group vs 47 [19%] of 246 in the once-daily group; p=0·85) and grade 3–4 radiation pneumonitis (4 [3%] of 254 vs 4 [2%] of 246; p=0·70). 11 patients died from treatment-related causes (three in the twice-daily group and eight in the once-daily group). Survival outcomes did not differ between twice-daily and once-daily concurrent chemoradiotherapy in patients with limited-stage small-cell lung cancer, and toxicity was similar and lower than expected with both regimens. Since the trial was designed to show superiority of once-daily radiotherapy and was not powered to show equivalence, the implication is that twice-daily radiotherapy should continue to be considered the standard of care in this setting. Cancer Research UK (Clinical Trials Awards and Advisory Committee), French Ministry of Health, Canadian Cancer Society Research Institute, European Organisation for Research and Treatment of Cancer (Cancer Research Fund, Lung Cancer, and Radiation Oncology Groups).