Effect of adjuvant carboplatin intensified chemotherapy versus standard chemotherapy on survival in women with high risk, early stage, triple negative breast cancer (CITRINE): randomised, open label phase 3 trial.

Methods

Randomised, open label, phase 3 trial.

随机、开放标签、III期试验。

Fudan University Shanghai Cancer Center in China between March 2020 and March 2022.

2020年3月至2022年3月期间，中国复旦大学上海癌症中心。

Female patients with operable high risk triple negative breast cancer (defined as either regional node positive or node negative with a Ki-67 labelling index of ≥50%) after definitive surgery.

在确定性手术后，定义为区域淋巴结阳性或淋巴结阴性且Ki-67标记指数≥50%的可手术高风险三阴性乳腺癌女性患者。

Patients were randomised in a 1:1 ratio into either the carboplatin arm (four cycles of two weekly epirubicin and cyclophosphamide followed by four cycles of weekly paclitaxel combined with carboplatin) or the control arm (four cycles of three weekly or two weekly epirubicin and cyclophosphamide followed by four cycles of weekly paclitaxel).

患者以1:1的比例随机分配到卡铂组（每两周一次的表柔比星和环磷酰胺四个周期，随后是每周一次的紫杉醇联合卡铂四个周期）或对照组（每三周一次或每两周一次的表柔比星和环磷酰胺四个周期，随后是每周一次的紫杉醇四个周期）。

The primary endpoint was disease-free survival in the intention-to-treatpopulation.

主要终点是在意向治疗人群中无病生存期。

Secondary endpoints included recurrence-free survival, distant disease-free survival, overall survival, and safety.

次要终点包括无复发生存期、无远处疾病生存期、总生存期和安全性。

Results

Of the 808 enrolled patients, 807 received study treatment.

在纳入的808名患者中，有807名接受了研究治疗。

At a median follow-up of 44.7 months, estimated percentages of patients who would be disease-free at three years were 92.3% in the carboplatin arm and 85.8% in the control arm (hazard ratio0.64, 95% confidence interval(CI) 0.43 to 0.95; P=0.03).

在中位随访44.7个月时，预计3年内无病生存的患者比例在卡铂组为92.3%，对照组为85.8%（风险比0.64，95%置信区间（CI）0.43至0.95；P=0.03）。

However, the assessment of the proportional hazards assumption showed that it was violated (P=0.02).

然而，对比例风险假设的评估显示该假设被违反（P=0.02）。

A piecewise hazard model showed that the hazard ratiochanged over time: the hazard ratiowas 0.31 (95% CI 0.13 to 0.73) for 0-12 months, 0.65 (0.39 to 1.09) for 12-36 months, and 1.98 (0.69 to 5.69) for >36 months.

分段风险模型显示，风险比随时间变化：0-12个月的风险比为0.31（95%置信区间0.13至0.73），12-36个月的风险比为0.65（0.39至1.09），超过36个月的风险比为1.98（0.69至5.69）。

For secondary endpoints, the carboplatin arm was associated with improved outcomes in three year recurrence-free survival (93.8% v 88.3%; hazard ratio0.59, 95% CI 0.37 to 0.93; P=0.02), three year distant disease-free survival (94.8% v 89.8%; hazard ratio0.61, 0.37 to 0.98; P=0.04), and three year overall survival(98.0% v 94.0%; hazard ratio0.41, 0.20 to 0.83; P=0.01).

次要终点方面，卡铂组在三年无复发生存率（93.8%对比88.3%；风险比0.59，95%置信区间0.37至0.93；P=0.02）、三年无远处转移生存率（94.8%对比89.8%；风险比0.61，0.37至0.98；P=0.04）以及三年总生存率（98.0%对比94.0%；风险比0.41，0.20至0.83；P=0.01）方面显示出改善的结果。

The incidenceof grade 3-4 treatment related adverse events was 66.7% (269 of 403 patients) in the carboplatin arm and 55.0% (222 of 404 patients) in the control arm.

在卡铂组中，3-4级治疗相关不良事件的发生率为66.7%（403名患者中有269名），而在对照组中为55.0%（404名患者中有222名）。

No treatment related deaths occurred.

未发生与治疗相关的死亡事件。

Conclusions

The addition of carboplatin to adjuvant anthracycline/taxane based chemotherapy significantly improved survival outcomes in patients with high risk, early stage, triple negative breast cancer, driven by reduction of early recurrence risk without new safety concerns.

在辅助性葱环类/紫杉烷类化疗中加入卡铂显著提高了高风险早期三阴性乳腺癌患者的生存结果，主要得益于早期复发风险的降低，并且没有引发新的安全问题。

trial_registration

ClinicalTrials.gov NCT04296175.

ClinicalTrials.gov NCT04296175。