背景:在肾上腺皮质癌切除后,通常使用米托坦辅助治疗;然而,治疗仍然存在争议,特别是如果复发风险不高。我们旨在评估肾上腺皮质癌患者在完全切除肿瘤后与单独监测相比的辅助米托坦的疗效和安全性,这些患者被认为是低至中度复发风险。
方法:ADIUVO是多中心,开放标签,平行,随机化,在7个国家的23个中心进行的3期试验.18岁或以上患有肾上腺皮质癌和低至中度复发风险的患者(R0,I-III期,和Ki67≤10%)被随机分配至每天2或3次的辅助口服米托坦(剂量由当地研究者调整,目标是达到并维持血浆米托坦浓度为14-20mg/L)2年或单独进行监测。14个研究中心的所有连续患者符合ADIUVO试验的资格标准,他们拒绝随机分组并同意通过欧洲肾上腺肿瘤肾上腺皮质癌研究网络进行数据收集,这些患者被前瞻性纳入ADIUVO观察性研究。主要终点是无复发生存率,定义为从随机分组到任何原因复发或死亡的第一个放射学证据(以先发生者为准)的时间,通过意向治疗对所有随机分配的患者进行评估。总生存率,定义为从随机化日期到任何原因死亡日期的时间,是根据所有随机分配的患者的意向治疗分析的次要终点。对所有坚持指定治疗方案的患者进行安全性评估。定义为在米托坦组中服用至少一片米托坦,在监测组中根本不服用米托坦。ADIUVO试验已在ClinicalTrials.gov注册,NCT00777244,现已完成。
结果:在2008年10月23日至2018年12月27日之间,45例患者被随机分配至米托坦,46例患者被随机分配至单独监测。因为这项研究过早中断,报告5年无复发和总生存期,而不是方案中定义的无复发和总生存期。米托坦组5年无复发生存率为79%(95%CI67-94),监测组为75%(63-90)(风险比0·74[95%CI0·30-1·85])。米托坦组有两人死亡,监测组有五人死亡,5年总生存率无显著差异(米托坦组95%[95%CI89-100]和监测组86%[74-100]).所有42例接受米托坦的患者均有不良事件,8人(19%)停止治疗。没有发生4级不良事件或治疗相关死亡。
结论:辅助米托坦可能不适用于低级别患者,考虑到这些患者的相对良好的预后,局部肾上腺皮质癌,米托坦组的无复发生存率和治疗相关毒性没有显著改善。然而,由于招募缓慢,该研究提前终止,不能排除治疗的有效性.
背景:AIFA,ENSAT癌症健康F2-2010-259735计划,德意志论坛,英国癌症研究中心,和法国卫生部。
Adjuvant treatment with mitotane is commonly used after resection of adrenocortical carcinoma; however, treatment remains controversial, particularly if risk of recurrence is not high. We aimed to assess the efficacy and safety of adjuvant mitotane compared with surveillance alone following complete tumour resection in patients with adrenocortical carcinoma considered to be at low to intermediate risk of recurrence.
ADIUVO was a multicentre, open-label, parallel, randomised, phase 3
trial done in 23 centres across seven countries. Patients aged 18 years or older with adrenocortical carcinoma and low to intermediate risk of recurrence (R0, stage I-III, and Ki67 ≤10%) were randomly assigned to adjuvant oral mitotane two or three times daily (the dose was adjusted by the local investigator with the target of reaching and maintaining plasma mitotane concentrations of 14-20 mg/L) for 2 years or surveillance alone. All consecutive patients at 14
study centres fulfilling the eligibility criteria of the ADIUVO
trial who refused randomisation and agreed on data collection via the European Network for the
Study of Adrenal Tumors adrenocortical carcinoma registry were included prospectively in the ADIUVO Observational
study. The primary endpoint was recurrence-free survival, defined as the time from randomisation to the first radiological evidence of recurrence or death from any cause (whichever occurred first), assessed in all randomly assigned patients by intention to treat. Overall survival, defined as time from the date of randomisation to the date of death from any cause, was a secondary endpoint analysed by intention to treat in all randomly assigned patients. Safety was assessed in all patients who adhered to the assigned regimen, which was defined by taking at least one tablet of mitotane in the mitotane group and no mitotane at all in the surveillance group. The ADIUVO
trial is registered with ClinicalTrials.gov, NCT00777244, and is now complete.
Between Oct 23, 2008, and Dec 27, 2018, 45 patients were randomly assigned to mitotane and 46 to surveillance alone. Because the study was discontinued prematurely, 5-year recurrence-free and overall survival are reported instead of recurrence-free and overall survival as defined in the protocol. 5-year recurrence-free survival was 79% (95% CI 67-94) in the mitotane group and 75% (63-90) in the surveillance group (hazard ratio 0·74 [95% CI 0·30-1·85]). Two people in the mitotane group and five people in the surveillance group died, and 5-year overall survival was not significantly different (95% [95% CI 89-100] in the mitotane group and 86% [74-100] in the surveillance group). All 42 patients who received mitotane had adverse events, and eight (19%) discontinued treatment. There were no grade 4 adverse events or treatment-related deaths.
Adjuvant mitotane might not be indicated in patients with low-grade, localised adrenocortical carcinoma considering the relatively good prognosis of these patients, and no significant improvement in recurrence-free survival and treatment-associated toxicity in the mitotane group. However, the study was discontinued prematurely due to slow recruitment and cannot rule out an efficacy of treatment.
AIFA, ENSAT Cancer Health F2-2010-259735 programme, Deutsche Forschungsgemeinschaft, Cancer Research UK, and the French Ministry of Health.