Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial.
Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial.
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DOI：
10.1016/s1470-2045(18)30079-2
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发表时间：
2018-03
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通讯作者：
PORTEC study group
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作者：
de Boer SM;Powell ME;Mileshkin L;Katsaros D;Bessette P;Haie-Meder C;Ottevanger PB;Ledermann JA;Khaw P;Colombo A;Fyles A;Baron MH;Jürgenliemk-Schulz IM;Kitchener HC;Nijman HW;Wilson G;Brooks S;Carinelli S;Provencher D;Hanzen C;Lutgens LCHW;Smit VTHBM;Singh N;Do V;D'Amico R;Nout RA;Feeney A;Verhoeven-Adema KW;Putter H;Creutzberg CL;PORTEC study group
虽然患有子宫内膜癌的女性通常预后良好，但具有高危疾病特征的女性复发风险增加。PORTEC-3试验旨在研究放疗期间和放疗后辅助化疗（放化疗）与单纯盆腔放疗对高危子宫内膜癌患者的益处。PORTEC-3是一项开放标签、国际、随机、3期试验，涉及妇科癌症国际组合作的6项临床试验中的103个中心。符合条件的女性患有高危子宫内膜癌，FIGO 2009 I期，类腺瘤型3级伴深肌层浸润或淋巴管间隙浸润（或两者），类腺瘤型II或III期，或I至III期伴浆液性或透明细胞组织学。使用偏倚硬币最小化程序，将女性随机分配（1：1）接受单独放疗（48·6戈伊，分1·8戈伊，每周5天给药）或放疗和化疗（包括在放疗期间给予2个周期的顺铂50 mg/m2，随后是4个周期的卡铂AUC 5和紫杉醇175 mg/m2），并对参与中心、淋巴结切除术、癌症分期和组织学类型进行分层。共同主要终点是总生存期和无失败生存期。我们使用Kaplan-Meier方法、对数秩检验和考克斯回归分析进行最终分析，按意向治疗并调整分层因素。在实现完全招募后，研究于2013年12月20日关闭;随访正在进行中。PORTEC-3在ISRCTN注册，编号ISRCTN 14387080，在ClinicalTrials.gov注册，编号NCT 00411138。2006年11月23日至2013年12月20日期间，共有686名女性入组。660例符合条件的患者被纳入最终分析，其中330例被分配接受放化疗，330例被分配接受放疗。中位随访时间为60·2个月（IQR 48·1-73·1）。5-年总生存率为81.8%（95% CI 77.5 - 86.2），放化疗组与76.7%（72·1-81·6）放射治疗（校正风险比[HR] 0.76，95%CI 0.54 - 1.06; p= 0.11）; 5年无失败生存率为75.5%（95% CI 70·3-79·9）与68·6%（63·1-73·4; HR 0·71，95% CI 0·53-0·95; p=0·022）。330例接受放化疗的患者中有198例（60%）在治疗期间发生了3级或更严重的不良事件，而330例接受放疗的患者中有41例（12%）发生了3级或更严重的不良事件（p<0.0001）。神经病变（2级或更严重）在放化疗后比放疗后更常持续存在（3年时20例[8%]女性vs 1例[1%]; p<0.0001）。大多数死亡是由于子宫内膜癌;在四名患者（每组两名）中，死亡原因不确定。放疗组1例死亡是由于疾病进展或晚期治疗并发症; 3例死亡（放化疗组2例，放疗组1例）是由于并发疾病或晚期治疗相关毒性。在高危子宫内膜癌放疗期间和放疗后给予辅助化疗并不能提高5年总生存率，尽管它确实提高了无失败生存率。患有高危子宫内膜癌的妇女应单独咨询这种联合治疗。需要继续随访以评估长期生存率。荷兰癌症协会、英国癌症研究、国家健康和医学研究理事会项目资助和澳大利亚癌症协会、意大利L 'Arzia Italiana del Farmaco和加拿大癌症协会研究所。
Although women with endometrial cancer generally have a favourable prognosis, those with high-risk disease features are at increased risk of recurrence. The PORTEC-3 trial was initiated to investigate the benefit of adjuvant chemotherapy during and after radiotherapy (chemoradiotherapy) versus pelvic radiotherapy alone for women with high-risk endometrial cancer. PORTEC-3 was an open-label, international, randomised, phase 3 trial involving 103 centres in six clinical trials collaborating in the Gynaecological Cancer Intergroup. Eligible women had high-risk endometrial cancer with FIGO 2009 stage I, endometrioid-type grade 3 with deep myometrial invasion or lymph-vascular space invasion (or both), endometrioid-type stage II or III, or stage I to III with serous or clear cell histology. Women were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or radiotherapy and chemotherapy (consisting of two cycles of cisplatin 50 mg/m2 given during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2) using a biased-coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage of cancer, and histological type. The co-primary endpoints were overall survival and failure-free survival. We used the Kaplan-Meier method, log-rank test, and Cox regression analysis for final analysis by intention to treat and adjusted for stratification factors. The study was closed on Dec 20, 2013, after achieving complete accrual; follow-up is ongoing. PORTEC-3 is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138. 686 women were enrolled between Nov 23, 2006, and Dec 20, 2013. 660 eligible patients were included in the final analysis, of whom 330 were assigned to chemoradiotherapy and 330 were assigned to radiotherapy. Median follow-up was 60·2 months (IQR 48·1–73·1). 5-year overall survival was 81·8% (95% CI 77·5–86·2) with chemoradiotherapy versus 76·7% (72·1–81·6) with radiotherapy (adjusted hazard ratio [HR] 0·76, 95% CI 0·54–1·06; p=0·11); 5-year failure-free survival was 75·5% (95% CI 70·3–79·9) versus 68·6% (63·1–73·4; HR 0·71, 95% CI 0·53–0·95; p=0·022). Grade 3 or worse adverse events during treatment occurred in 198 (60%) of 330 who received chemoradiotherapy versus 41 (12%) of 330 patients who received radiotherapy (p<0·0001). Neuropathy (grade 2 or worse) persisted significantly more often after chemoradiotherapy than after radiotherapy (20 [8%] women vs one [1%] at 3 years; p<0·0001). Most deaths were due to endometrial cancer; in four patients (two in each group), the cause of death was uncertain. One death in the radiotherapy group was due to either disease progression or late treatment complications; three deaths (two in the chemoradiotherapy group and one in the radiotherapy group) were due to either intercurrent disease or late treatment-related toxicity. Adjuvant chemotherapy given during and after radiotherapy for high-risk endometrial cancer did not improve 5-year overall survival, although it did increase failure-free survival. Women with high-risk endometrial cancer should be individually counselled about this combined treatment. Continued follow-up is needed to evaluate long-term survival. Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council Project Grant and Cancer Australia, L'Agenzia Italiana del Farmaco, and Canadian Cancer Society Research Institute.