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可手术膀胱癌的围手术期度伐利尤单抗治疗联合新辅助化疗
Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer
背景
新辅助化疗联合后续根治性膀胱切除术是符合顺铂治疗条件的肌层浸润性膀胱癌患者的标准治疗方法。加用围手术期免疫疗法有可能改善疗效。
Neoadjuvant chemotherapy followed by radical cystectomy is the standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer. Adding perioperative immunotherapy may improve outcomes.
方法
在此项3期、开放标签、随机试验中，我们以1:1比例将符合顺铂治疗条件的肌层浸润性膀胱癌患者分成两组，一组接受度伐利尤单抗联合吉西他滨-顺铂新辅助治疗（每3周一个周期，共4个周期），之后接受根治性膀胱切除术和度伐利尤单抗辅助治疗（每4周一个周期，共8个周期）（度伐利尤单抗组），另一组接受吉西他滨-顺铂新辅助治疗，之后只接受根治性膀胱切除术（对照组）。无事件生存期是双重主要终点之一。总生存期是关键次要终点。
In this phase 3, open-label, randomized trial, we assigned, in a 1:1 ratio, cisplatin-eligible patients with muscle-invasive bladder cancer to receive neoadjuvant durvalumab plus gemcitabine–cisplatin every 3 weeks for four cycles, followed by radical cystectomy and adjuvant durvalumab every 4 weeks for eight cycles (durvalumab group), or to receive neoadjuvant gemcitabine–cisplatin followed by radical cystectomy alone (comparison group). Event-free survival was one of two primary end points. Overall survival was the key secondary end point.
结果
共计533例患者被分配到度伐利尤单抗组，530例患者被分配到对照组。度伐利尤单抗组的24个月估计无事件生存率为67.8%（95%置信区间[CI]，63.6~71.7），对照组为59.8%（95% CI，55.4~64.0）（进展、复发、未接受根治性膀胱切除术或全因死亡的风险比，0.68；95% CI，0.56~0.82；分层时序检验P<0.001）。度伐利尤单抗组的24个月估计总生存率为82.2%（95% CI，78.7~85.2），对照组为75.2%（95% CI，71.3~78.8）（死亡风险比，0.75；95% CI，0.59~0.93；分层时序检验P=0.01）。度伐利尤单抗组40.6%的患者和对照组40.9%的患者发生了严重程度为3级或4级的治疗相关不良事件；两组中均有0.6%的患者发生了导致死亡的治疗相关不良事件。度伐利尤单抗组88.0%的患者和对照组83.2%的患者接受了根治性膀胱切除术。
Result
In total, 533 patients were assigned to the durvalumab group and 530 to the comparison group. The estimated event-free survival at 24 months was 67.8% (95% confidence interval [CI], 63.6 to 71.7) in the durvalumab group and 59.8% (95% CI, 55.4 to 64.0) in the comparison group (hazard ratio for progression, recurrence, not undergoing radical cystectomy, or death from any cause, 0.68; 95% CI, 0.56 to 0.82; P<0.001 by stratified log-rank test). The estimated overall survival at 24 months was 82.2% (95% CI, 78.7 to 85.2) in the durvalumab group and 75.2% (95% CI, 71.3 to 78.8) in the comparison group (hazard ratio for death, 0.75; 95% CI, 0.59 to 0.93; P=0.01 by stratified log-rank test). Treatment-related adverse events of grade 3 or 4 in severity occurred in 40.6% of the patients in the durvalumab group and in 40.9% of those in the comparison group; treatment-related adverse events leading to death occurred in 0.6% in each group. Radical cystectomy was performed in 88.0% of the patients in the durvalumab group and in 83.2% of those in the comparison group.
结论
与单纯新辅助化疗相比，围手术期度伐利尤单抗治疗联合新辅助化疗显著提高了无事件生存率和总生存率。（由阿斯利康资助；NIAGARA在ClinicalTrials.gov注册号为NCT03732677；在EudraCT编号为2018-001811-59）。
Conclusions
Perioperative durvalumab plus neoadjuvant chemotherapy led to significant improvements in event-free survival and overall survival as compared with neoadjuvant chemotherapy alone. (Funded by AstraZeneca; NIAGARA ClinicalTrials.gov number, NCT03732677; EudraCT number, 2018-001811-59.)
经导管修复术与二尖瓣外科手术治疗继发性二尖瓣反流的比较
Transcatheter Repair versus Mitral-Valve Surgery for Secondary Mitral Regurgitation
背景
目前针对心力衰竭合并继发性二尖瓣反流患者的治疗建议包括经导管边对边修复术与二尖瓣外科手术。在这一患者人群中，尚缺乏比较两种治疗方案的随机试验数据。
在德国进行的此项非劣效性试验中，接受指南指导的药物治疗后仍有症状的心力衰竭合并继发性二尖瓣反流患者被随机分组（1:1比例），分别接受经导管边对边修复术（介入治疗组）或者二尖瓣外科修复术或置换术（外科手术组）。主要疗效终点是由术后1年内死亡、因心力衰竭住院、二尖瓣再介入治疗、植入辅助装置或卒中构成的复合终点。主要安全性终点是由术后30天内的主要不良事件构成的复合终点。
Methods
In this noninferiority trial conducted in Germany, patients with heart failure and secondary mitral regurgitation who continued to have symptoms despite guideline-directed medical therapy were randomly assigned, in a 1:1 ratio, to undergo either transcatheter edge-to-edge repair (intervention group) or surgical mitral-valve repair or replacement (surgery group). The primary efficacy end point was a composite of death, hospitalization for heart failure, mitral-valve reintervention, implantation of an assist device, or stroke within 1 year after the procedure. The primary safety end point was a composite of major adverse events within 30 days after the procedure.
共计210例患者接受随机分组。患者平均（±SD）年龄为70.5±7.9岁，39.9%为女性，平均左心室射血分数为43.0±11.7%。1年内，介入治疗组有数据的96例患者中的16例（16.7%）和外科手术组有数据的89例患者中的20例（22.5%）发生了主要疗效终点的至少一个构成部分（估计平均差异，－6个百分点；95%置信区间[CI]，－17~6；非劣效性P<0.001）。介入治疗组有数据的101例患者中的15例（14.9%）和外科手术组有数据的93例患者中的51例（54.8%）发生了主要安全性终点事件（估计平均差异，－40个百分点；95% CI，－51~－27；P<0.001）。
Result
A total of 210 patients underwent randomization. The mean (±SD) age of the patients was 70.5±7.9 years, 39.9% were women, and the mean left ventricular ejection fraction was 43.0±11.7%. Within 1 year, at least one of the components of the primary efficacy end point occurred in 16 of the 96 patients with available data (16.7%) in the intervention group and in 20 of the 89 with available data (22.5%) in the surgery group (estimated mean difference, −6 percentage points; 95% confidence interval [CI], −17 to 6; P<0.001 for noninferiority). A primary safety end-point event occurred in 15 of the 101 patients with available data (14.9%) in the intervention group and in 51 of the 93 patients with available data (54.8%) in the surgery group (estimated mean difference, −40 percentage points; 95% CI, −51 to −27; P<0.001).
结论
对于心力衰竭合并继发性二尖瓣反流患者，在由1年内死亡、因心力衰竭再次住院、卒中、再介入治疗或植入左心室辅助装置构成的复合终点方面，导管边对边修复术不劣于二尖瓣外科手术。（由Abbott Vascular资助；MATTERHORN在ClinicalTrials.gov注册号为NCT02371512）。
经导管瓣膜修复术治疗心力衰竭合并中度至重度二尖瓣反流
Transcatheter Valve Repair in Heart Failure with Moderate to Severe Mitral Regurgitation
背景
经导管二尖瓣修复术可否改善心力衰竭合并功能性二尖瓣反流患者的结局，目前尚不确定。
我们开展了一项随机对照试验，该试验在9个国家30个研究中心纳入心力衰竭合并中度至重度功能性二尖瓣反流患者。以1:1比例分配患者接受经导管二尖瓣修复术联合指南推荐的药物治疗（器械组）或单纯药物治疗（对照组）。三项主要终点分别是24个月期间由因心力衰竭首次或反复住院或心血管原因死亡构成的复合终点发生率；24个月期间因心力衰竭首次或反复住院的发生率；堪萨斯城心肌病问卷总分（KCCQ-OS，Kansas City Cardiomyopathy Questionnaire–Overall Summary；评分范围为0~100分，评分较高表示健康状况较好）从基线到12个月的变化。
Methods
We conducted a randomized, controlled trial involving patients with heart failure and moderate to severe functional mitral regurgitation from 30 sites in nine countries. The patients were assigned in a 1:1 ratio to either transcatheter mitral-valve repair and guideline-recommended medical therapy (device group) or medical therapy alone (control group). The three primary end points were the rate of the composite of first or recurrent hospitalization for heart failure or cardiovascular death during 24 months; the rate of first or recurrent hospitalization for heart failure during 24 months; and the change from baseline to 12 months in the score on the Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS; scores range from 0 to 100, with higher scores indicating better health status).
共计505例患者接受了随机分组：250人被分配到器械组，255人被分配到对照组。24个月时，器械组因心力衰竭首次或反复住院或者心血管原因死亡的发生率为37.0起事件/100患者-年，对照组为58.9起事件/100患者-年（率比，0.64；95%置信区间[CI]，0.48~0.85；P=0.002）。器械组因心力衰竭首次或反复住院的发生率为26.9起事件/100患者-年，对照组为46.6起事件/100患者-年（率比，0.59；95% CI，0.42~0.82；P=0.002）。器械组的KCCQ-OS评分平均（±SD）提高了21.6±26.9分，对照组提高了8.0±24.5分（平均差异，10.9分；95% CI，6.8~15.0；P<0.001）。4例患者（1.6%）发生了器械特异性安全性事件。
Result
A total of 505 patients underwent randomization: 250 were assigned to the device group and 255 to the control group. At 24 months, the rate of first or recurrent hospitalization for heart failure or cardiovascular death was 37.0 events per 100 patient-years in the device group and 58.9 events per 100 patient-years in the control group (rate ratio, 0.64; 95% confidence interval [CI], 0.48 to 0.85; P=0.002). The rate of first or recurrent hospitalization for heart failure was 26.9 events per 100 patient-years in the device group and 46.6 events per 100 patient-years in the control group (rate ratio, 0.59; 95% CI, 0.42 to 0.82; P=0.002). The KCCQ-OS score increased by a mean (±SD) of 21.6±26.9 points in the device group and 8.0±24.5 points in the control group (mean difference, 10.9 points; 95% CI, 6.8 to 15.0; P<0.001). Device-specific safety events occurred in 4 patients (1.6%).
结论
在接受药物治疗的心力衰竭合并中度至重度功能性二尖瓣反流患者中，与单纯药物治疗相比，药物治疗联合导管二尖瓣修复术可降低24个月期间因心力衰竭首次或反复住院或者心血管原因死亡的发生率，降低因心力衰竭首次或反复住院的发生率，并且改善12个月时的健康状况。（由Abbott Laboratories资助；RESHAPE-HF2在ClinicalTrials.gov注册号为NCT02444338）。
可切除胃癌的术前放化疗
Preoperative Chemoradiotherapy for Resectable Gastric Cancer
背景
在西方国家，目前可切除胃癌的标准治疗方案是围手术期化疗。术前放化疗也曾被考虑过，比较该方案与单纯围手术期化疗的数据有限。
我们开展了一项国际性3期试验，该试验随机分配可切除胃腺癌或胃食管结合部腺癌患者接受术前放化疗联合围手术期化疗或单纯围手术期化疗（对照组）。两组患者均在手术之前和之后接受表柔比星、顺铂联合氟尿嘧啶治疗或氟尿嘧啶、亚叶酸钙、奥沙利铂联合多西他赛治疗；术前放化疗组还接受放化疗（放疗45 Gy/25次联合氟尿嘧啶输注）。主要终点是总生存期，次要终点包括无进展生存期、病理学完全缓解、毒性效应和生活质量。
Methods
We conducted an international, phase 3 trial in which patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to receive preoperative chemoradiotherapy plus perioperative chemotherapy or perioperative chemotherapy alone (control). In both groups, patients received either epirubicin, cisplatin, and fluorouracil or fluorouracil, leucovorin, oxaliplatin, and docetaxel both before and after surgery; the preoperative-chemoradiotherapy group also received chemoradiotherapy (45 Gy in 25 fractions of radiation, plus fluorouracil infusion). The primary end point was overall survival, and secondary end points included progression-free survival, pathological complete response, toxic effects, and quality of life.
共计574例患者在澳大拉西亚、加拿大和欧洲70研究中心接受了随机分组：286例患者被分配到术前放化疗组，288例患者被分配到围手术期化疗组。术前放化疗组达到病理学完全缓解的患者比例高于围手术期化疗组（17% vs. 8%），前者切除术后的肿瘤降期幅度大于后者。中位67个月随访时，总生存期和无进展生存期无显著组间差异。术前放化疗组的中位总生存期为46个月，围手术期化疗组为49个月（死亡风险比，1.05；95%置信区间，0.83~1.31），中位无进展生存期分别为31个月和32个月。两组患者的治疗相关毒性效应相似。
Result
A total of 574 patients underwent randomization at 70 sites in Australasia, Canada, and Europe: 286 to the preoperative-chemoradiotherapy group and 288 to the perioperative-chemotherapy group. A higher percentage of patients in the preoperative-chemoradiotherapy group than in the perioperative-chemotherapy group had a pathological complete response (17% vs. 8%) and greater tumor downstaging after resection. At a median follow-up of 67 months, no significant between-group differences in overall survival or progression-free survival were noted. The median overall survival was 46 months with preoperative chemoradiotherapy and 49 months with perioperative chemotherapy (hazard ratio for death, 1.05; 95% confidence interval, 0.83 to 1.31), and the median progression-free survival was 31 months and 32 months, respectively. Treatment-related toxic effects were similar in the two groups.
结论
对于可切除胃腺癌和胃食管结合部腺癌患者，与单纯围手术期化疗相比，围手术期化疗联合术前放化疗并未延长总生存期。（由澳大利亚国家健康与医学研究委员会[National Health and Medical Research Council of Australia]等资助；TOPGEAR在ClinicalTrials.gov注册号为NCT01924819）。
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