Molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer (PORTEC-4a): results of a randomised, open-label, phase 3, multicentre, non-inferiority trial.

Methods

PORTEC-4a was a randomised, open-label, phase 3, multicentre, non-inferiority trial, conducted across eight European countries.

PORTEC-4a是一项随机、开放标签、第三阶段、多中心、非劣效试验，研究在八个欧洲国家进行。

Women (aged ≥18 years and with a WHO performance score of 0-2) with early stage high-intermediate risk endometrial cancer were eligible.

符合条件的女性年龄≥18岁，WHO表现评分为0-2，患有早期高-中危子宫内膜癌。

Patients were randomly assigned post-surgery in a 2:1 ratio to either adjuvant treatment according to their molecular integrated risk profile or to standard vaginal brachytherapy.

患者在手术后按2:1的比例随机分配，接受基于其分子整合风险特征的辅助治疗或标准阴道近距离放射治疗。

Allocation used a biased-coin minimisation with stratification for participating centre, grade, and lymphadenectomy.

分配使用了带有参与中心、等级和淋巴结清扫分层的偏币最小化方法。

Adjuvant treatment in the molecular-profile group in case of favourable profile (POLE-mutated or no specific molecular profile [NSMP]-CTNNB1 wildtype) was observation, for intermediate profile (mismatch repair deficient or NSMP-CTNNB1 mutated) was brachytherapy (21 Gy in three fractions of 7 Gy given at 5 to 7 day intervals), and for unfavourable profile (p53 abnormal or substantial lymphovascular space invasion or L1 cell adhesion molecule overexpression) was pelvic radiotherapy (45·0-48·6 Gy in 1·8-2·0 Gy fractions, 5 days per week).

分子特征组中，若分子特征良好（POLE突变或无特定分子特征[NSMP]-CTNNB1野生型），则进行观察；若分子特征中等（错配修复缺陷或NSMP-CTNNB1突变），则进行近距离放疗（21 Gy，分3次，每次7 Gy，间隔5至7天）；若分子特征不利（p53异常或显著的淋巴血管间隙侵犯或L1细胞粘附分子过度表达），则进行盆腔放疗（45·0-48·6 Gy，每次1·8-2·0 Gy，每周5天）。

The primary endpoint was overall 5-year cumulative incidenceof vaginal recurrence as first event.

主要终点是作为首次事件的5年累积阴道复发发生率。

Kaplan-Meier, Cox model, and cumulative incidencewith competing risks were used for final analysis in the intention-to-treatpopulation.

在意向治疗人群中，使用Kaplan-Meier、Cox模型和考虑竞争风险的累积发生率进行最终分析。

Patient advocates were involved during grant application and trial conduct.

患者倡导者在资助申请和试验过程中被涉及。

The trial is registered with the Netherlands Trial Registry (NTR5841), the ISRCTN registry (ISRCTN11659025), and ClinicalTrials.gov (NCT03469674), and follow-up is ongoing.

该试验已在荷兰试验注册处(NTR5841)、ISRCTN注册处(ISRCTN11659025)和ClinicalTrials.gov(NCT03469674)注册，并且随访正在进行中。

Results

Between June 1, 2016, and Dec 24, 2021, 569 patients were enrolled in PORTEC-4a.

2016年6月1日至2021年12月24日，共有569名患者参与了PORTEC-4a研究。

After the addition of 23 favourable patients out of PORTEC-4, the final combined PORTEC-4a cohort consisted of 564 eligible and evaluable patients (367 in the molecular profile group and 197 in the standard group).

在将PORTEC-4研究中23名预后良好的患者纳入后，最终的PORTEC-4a联合队列由564名符合条件且可评估的患者组成（分子特征组367名，标准组197名）。

All patients were female, the median age was 69·0 years (IQR 63·0-73·5), and data on race and ethnicity were not collected.

所有患者均为女性，中位年龄为69.0岁（四分位数间距63.0-73.5），未收集种族和民族数据。

Median follow-up was 58·1 months (IQR 40·7-63·6).

中位随访时间为58.1个月（四分位数间距40.7-63.6）。

In the molecular profile group 168 (46%) patients had a favourable profile, 148 (40%) had an intermediate profile, and 51 (14%) had an unfavourable profile.

在分子特征组中，168名（46%）患者具有良好的特征，148名（40%）患者具有中等特征，51名（14%）患者具有不良特征。

The 5-year cumulative incidenceof vaginal recurrence was 4·5% (95% CI 2·23-6·76) in the molecular profile group and 1·6% (0·00-3·32) in the standard group (HR 2·71 [95% CI 0·79-9·34]).

分子特征组中，5年累积阴道复发发生率为4.5%（95% 置信区间 2.23-6.76），标准组为1.6%（0.00-3.32）（风险比 2.71 [95% 置信区间 0.79-9.34]）。

The upper-bound of the one-sided confidence intervalof the difference (5·3%) was below the predefined-equivalence margin of 7·0% (pnon-inferiority=0·005).

单侧置信区间的上限（5.3%）低于预设的等效边界7.0%（p非劣效性=0.005）。

The second primary analysis in patients with a favourable molecular profile showed 5-year vaginal recurrence of 4·1% (95% CI 0·81-7·37) in the molecular profile group versus 0·9% (0·00-2·78) in the standard group (HR 3·97 [95% CI 0·48-32·95]).

在具有有利分子特征的患者中进行的次要主要分析显示，分子特征组的5年阴道复发率为4.1%（95%置信区间0.81-7.37），而标准组为0.9%（0.00-2.78）（HR 3.97 [95%置信区间0.48-32.95]）。

Adverse events were mainly grades 1-2, with grade 3 or above related genitourinary toxicities in four (1%) of 367 versus four (2%) of 197, without substantial differences between groups.

不良事件主要为1-2级，与3级或更高级别的泌尿生殖系统毒性相关的有四例（1%）在367例中，与四例（2%）在197例中，两组之间没有显著差异。

Five serious adverse events occurred, of which one was possibly related to treatment (vaginal scar dehiscence).

发生了五例严重不良事件，其中一例可能与治疗有关（阴道疤痕裂开）。

No treatment-related deaths occurred.

未发生与治疗相关的死亡事件。

interpretation

Individualised adjuvant treatment by molecular integrated risk profile is safe and effective for patients with high-intermediate risk endometrial cancer; it spared 46% of patients with a favourable profile from adjuvant treatment, and reduces both overtreatment and undertreatment.

通过分子整合风险评估进行的个体化辅助治疗对高-中等风险子宫内膜癌患者是安全且有效的；该方法使46%具有良好预后特征的患者免于接受辅助治疗，同时减少了过度治疗和治疗不足的情况。

funding

KWF Dutch Cancer Society.

荷兰癌症协会