背景:经验性化疗仍然是未知原发癌(CUP)患者的标准治疗方法。已经开发了基因表达谱分析方法来鉴定CUP患者的起源组织;然而,其临床获益尚未得到证实.我们旨在评估90基因表达测定指导的位点特异性治疗与经验性化疗在CUP患者中的疗效和安全性。
方法:这项随机对照试验在复旦大学上海癌症中心(上海,中国)。我们招募了年龄在18-75岁的患者,先前未经治疗的CUP(组织学证实的转移性腺癌,鳞状细胞癌,低分化癌,或低分化肿瘤)和东部肿瘤协作组(ECOG)的表现状态为0-2,不适合进行局部根治性治疗。通过Pocock和Simon最小化方法将患者随机分配(1:1)以接受特定部位治疗或经验性化疗(紫杉烷[第1天静脉输注175mg/m2]加铂[顺铂75mg/m2或卡铂在第1天静脉输注曲线5下的面积],或吉西他滨[在第1天和第8天通过静脉输注1000mg/m2]加铂[与上述相同])。最小化因素是ECOG表现状态和疾病程度。临床医生和患者没有被掩盖干预措施。通过90基因表达测定预测位点特异性治疗组中的肿瘤起源,并相应地施用治疗。主要终点是意向治疗人群的无进展生存期。试验已经完成,分析是最后的。本研究已在ClinicalTrials.gov(NCT03278600)注册。
结果:2017年9月18日至2021年3月18日,182例患者(男性105例[58%],77[42%]女性)被随机分配接受特定部位治疗(n=91)或经验性化疗(n=91)。在特定部位治疗组中,五种最常见的预测起源组织是胃食管(14[15%]),肺(12[13%]),卵巢(11[12%]),子宫颈(11[12%]),和乳房(九[10%])。在数据截止日期(2023年4月30日),中位随访时间为33·3个月(IQR30·4~51·0),经验性化疗组为30·9个月(27·6~35·5).定点治疗的中位无进展生存期明显长于经验性化疗(9·6个月[95%CI8·4-11·9]vs6·6个月[5·5-7·9];未调整的风险比0·68[95%CI0·49-0·93];p=0·017)。在167名开始计划治疗的患者中,部位特异性治疗组82例患者中的46例(56%)和经验性化疗组85例患者中的52例(61%)出现3级或更严重的治疗相关不良事件;部位特异性治疗和经验性化疗组最常见的是中性粒细胞计数降低(36[44%]vs42[49%]),白细胞计数减少(17[21%]对26[31%]),贫血(十[12%]对九[11%])。在特定部位治疗组中有5例(6%)患者和经验性化疗组中有2例(2%)患者报告了与治疗相关的严重不良事件。没有观察到治疗相关的死亡。
结论:这项单中心随机试验表明,与经验性化疗相比,90基因表达测定指导的位点特异性治疗可以改善既往未治疗过的CUP患者的无进展生存期。通过90基因表达测定进行的位点特异性预测可能会提供更多的疾病信息,并扩展这些患者的治疗性医疗设备。
背景:上海医院发展中心临床研究计划,上海市优秀学术带头人计划,和上海抗癌协会SOAR项目。
■有关摘要的中文翻译,请参见补充材料部分。
BACKGROUND: Empirical chemotherapy remains the standard of care in patients with unfavourable cancer of unknown primary (CUP). Gene-expression profiling assays have been developed to identify the tissue of origin in patients with CUP; however, their clinical benefit has not yet been demonstrated. We aimed to evaluate the efficacy and safety of site-specific therapy directed by a 90-gene expression assay compared with empirical chemotherapy in patients with CUP.
METHODS: This randomised controlled trial was conducted at Fudan University Shanghai Cancer Center (Shanghai, China). We enrolled patients aged 18-75 years, with previously untreated CUP (histologically confirmed metastatic adenocarcinoma, squamous cell carcinoma, poorly differentiated carcinoma, or poorly differentiated neoplasms) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, who were not amenable to local radical treatment. Patients were randomly assigned (1:1) by the Pocock and Simon minimisation method to receive either site-specific therapy or empirical chemotherapy (taxane [175 mg/m2 by intravenous infusion on day 1] plus platinum [cisplatin 75 mg/m2 or
carboplatin area under the curve 5 by intravenous infusion on day 1], or gemcitabine [1000 mg/m2 by intravenous infusion on days 1 and 8] plus platinum [same as above]). The minimisation factors were ECOG performance status and the extent of the disease. Clinicians and patients were not masked to interventions. The tumour origin in the site-specific therapy group was predicted by the 90-gene expression assay and treatments were administered accordingly. The primary endpoint was progression-free survival in the intention-to-treat population. The trial has been completed and the analysis is final. This study is registered with ClinicalTrials.gov (NCT03278600).
RESULTS: Between Sept 18, 2017, and March 18, 2021, 182 patients (105 [58%] male, 77 [42%] female) were randomly assigned to receive site-specific therapy (n=91) or empirical chemotherapy (n=91). The five most commonly predicted tissues of origin in the site-specific therapy group were gastro-oesophagus (14 [15%]), lung (12 [13%]), ovary (11 [12%]), cervix (11 [12%]), and breast (nine [10%]). At the data cutoff date (April 30, 2023), median follow-up was 33·3 months (IQR 30·4-51·0) for the site-specific therapy group and 30·9 months (27·6-35·5) for the empirical chemotherapy group. Median progression-free survival was significantly longer with site-specific therapy than with empirical chemotherapy (9·6 months [95% CI 8·4-11·9] vs 6·6 months [5·5-7·9]; unadjusted hazard ratio 0·68 [95% CI 0·49-0·93]; p=0·017). Among the 167 patients who started planned treatment, 46 (56%) of 82 patients in the site-specific therapy group and 52 (61%) of 85 patients in the empirical chemotherapy group had grade 3 or worse treatment-related adverse events; the most frequent of these in the site-specific therapy and empirical chemotherapy groups were decreased neutrophil count (36 [44%] vs 42 [49%]), decreased white blood cell count (17 [21%] vs 26 [31%]), and anaemia (ten [12%] vs nine [11%]). Treatment-related serious adverse events were reported in five (6%) patients in the site-specific therapy group and two (2%) in the empirical chemotherapy group. No treatment-related deaths were observed.
CONCLUSIONS: This single-centre randomised trial showed that site-specific therapy guided by the 90-gene expression assay could improve progression-free survival compared with empirical chemotherapy among patients with previously untreated CUP. Site-specific prediction by the 90-gene expression assay might provide more disease information and expand the therapeutic armamentarium in these patients.
BACKGROUND: Clinical Research Plan of Shanghai Hospital Development Center, Program for Shanghai Outstanding Academic Leader, and Shanghai Anticancer Association SOAR PROJECT.
UNASSIGNED: For the Chinese translation of the abstract see Supplementary Materials section.