Abstract
Surgery for platinum-sensitive, relapsed ovarian cancer (PSROC) is widely practiced but had contradictory survival outcomes in previous studies. In this multicenter, open-label, phase 3 trial, women with PSROC, and having had one previous therapy and no platinum-based chemotherapy (platinum-free interval) of 6 months or more, were randomly assigned to either the surgery group (182 patients) or the no-surgery group (control) (175 patients). Patients with resectable diseases were eligible according to the international model (iMODEL), combined with a positron emission tomography-computed tomography imaging. Overall survival (OS) and progression-free survival were coprimary endpoints in hierarchical testing, and a significantly longer progression-free survival with surgery was previously reported. Final analysis of OS was planned at data maturity of 59%. Between 19 July 2012 and 3 June 2019, 357 patients were enrolled. Median follow-up was 82.5 months. Median OS was 58.1 months with surgery and 52.1 months for control (hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.61–1.05, P = 0.11). The predefined threshold for statistical significance was not met, but prespecified sensitivity analysis was performed. Overall, 61 of 175 (35%) patients in control had crossed over to surgery following subsequent relapse, and adjusted HR for death in the surgery group compared with control was 0.76, 95% CI 0.58–0.99. In subgroup analysis of relapse sites by imaging, median survival was not estimable in the surgery group and was 69.5 months in control in patients with <20 sites (HR 0.69, 95% CI 0.46–1.03). Patients with a complete resection had the most favorable outcome, with a median OS of 73.0 months. Twenty-four of 182 (13.2%) patients remained relapse free and alive >60 months in the surgery group as compared with five of 175 (2.9%) patients in the control group. In patients with PSROC, surgery did not increase OS in the intention-to-treat population but resulted in a prolongation of survival following adjustment of crossover.
ClinicalTrials.gov registration: NCT01611766.
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Data availability
The study protocol and statistical analysis plan are available in Supplementary Information. Individual participant-level data that underlie the reported results are not publicly available because this is the first phase 3 study to include detailed postprogression data. Patient-level meta-analyses of the SOC-1, GOG-0213 and DEKTOP III trials were discussed and planned within the Gynecological Cancer InterGroup meta-analysis committee. Other requests for access to patient-level data from this study can be submitted via email to [email protected] with a detailed proposal for approval. In response to any inquiry, please be informed that the timeframe for responding is approximately 2 months.
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Acknowledgements
We thank Zhongshan Talent Fund (no. 016, to R.Z.), the National Natural Science Foundation of China (nos. 81972429 and 82273388, to R.Z.) and Shanghai Municipal Science and Technology Major Project (no. 22Y21900300, to R.Z.) for funding this trial. We thank especially members of the Independent Data Monitoring Committee: H. Cui (Chair), X. Chen, X. Wang, Y. Zhu and W. Zhang. We thank J. Zhu (Department of Radiation Oncology, Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou, China); Z. Chen and T. Zhu (Department of Gynecologic Oncology, Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou, China); X. Lu (Department of Gynecologic Oncology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China); Z. Wu (Department of Biostatistics, School of Public Health, Fudan University, Shanghai, China); Y. Zhang (Department of Gynecologic Oncology, Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou, China); Y. Cai (Department of Obstetrics and Gynecology, Zhongda Hospital, Jiangsu, China); G. Cai (Department of Gynecologic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Centre, Guangzhou, China); and S. Yin (Department of Obstetrics and Gynecology, Fudan University Zhongshan Hospital, Shanghai, China) for participation; and F. Liang (Statistical Center, Fudan University Zhongshan Hospital, Shanghai, China) for statistical assistance.
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R.Z. conceived and designed the study. R.J., Y.F., Y.C., R.Z., T.S., J.Z., P.Z., J.L., X.C., H.Y., X.H., S.J. and W.G. collected and assembled data. R.Z., Y.C., R.J. and Y.G. conducted data analysis. R.Z. and Y.C. wrote the first draft of the manuscript. H.J., Y.G. and D.T. performed statistical analysis. R.Z., Y.C., R.J. and H.J. accessed and verified data. Y.C., S.J. and R.J. accessed raw data. All authors were involved in data interpretation and writing and revision and critical review of the manuscript. All authors approved the submitted version and vouch for the accuracy of the data reported and adherence to the protocol.
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Extended data
Extended Data Fig. 1 Kaplan-Meier estimates of updated progression-free survival in the intention-to-treat population.
A two-sided log-rank test was used to compare the time-to-event end points between groups at a 0.05 significance level with no adjustment of multiplicity. HRs and the corresponding 95% two-sided CIs were estimated using an unstratified Cox proportional hazards model. P < 0.0001.
Extended Data Fig. 2 Prespecified descriptive analysis of updated accumulated treatment-free survival.
a, accumulated treatment-free survival (TFSa) for the surgery arm. b, TFSa for the control arm. c, RMST estimates of TFSa. One patient (No. 45) in the surgery group had negative pathology during the assigned secondary cytoreduction. TFSa is defined as the duration of OS minus each treatment period after randomization including the period of surgery (from the date of randomization or next surgery to the date of the first cycle of chemotherapy), chemotherapy, and radiotherapy, without subtracting the time on targeted maintenance therapy. TFS1 = Treatment-free interval before first subsequent therapy initiation or duration of relapse-free survival. TFSa after third-line therapy = TFSa after first subsequent therapy initiation for those with secondary relapse. RMST = Restricted mean survival time.
Extended Data Fig. 3 Kaplan-Meier estimates of updated TFST and TSST.
a, time to first subsequent therapy (TFST). b, time to second subsequent therapy (TSST) in the intention-to-treat population. Hazard ratio and the corresponding 95%CI were estimated using an unstratified Cox proportional hazards model.
Extended Data Fig. 4 Kaplan-Meier estimates of overall survival by number of relapses.
a, OS by lesions in the overall cohort without separating surgery or control arm. b, OS by lesions in surgery and control arms. Hazard ratio and the corresponding 95%CI were estimated using an unstratified Cox proportional hazards model. In the GOG-0213 trial, 55% of the women had 1-2 sites of relapse. NE = not estimable.
Extended Data Fig. 5 Kaplan-Meier estimates of overall survival depending on treatment arms and surgical outcomes in the surgical arm.
Hazard ratio and the corresponding 95%CI were estimated using an unstratified Cox proportional hazards model. NGR = no gross residual disease/complete resection; gross residual = incomplete resection. NE = not estimable. OS = overall survival.
Extended Data Fig. 6 Crossover-adjusted analysis of overall survival by IPCW model.
a, IPCW curves. P values were two-sided with no adjustment of multiplicity, P = 0.019. HRs and the corresponding 95% two-sided CIs were estimated using a Cox proportional hazards model. b, Covariates selection for inverse-probability-of-censoring weights model. Numbers of patients at risk are not included for the IPCW curve due to the lack of a clear clinical interpretation of the number of patients at risk associated with the weighted methodology. * Selected by a model or by clinical consideration; iMODEL score was not selected due to the collinearity with CA125 at 1st relapse and platinum-free interval before 1st relapse. BMI = Body Mass Index. IPCW = inverse probability censoring weighting. CA125 = Cancer antigen 125. ECOG = Eastern Cooperative Oncology Group. FIGO = International Federation of Gynecology and Obstetrics. iMODEL = the international model.
Supplementary information
Supplementary Information
CONSORT Checklist, SOC-1 trial investigators; Supplementary Figs. 1 and 2, Tables 1–5, Protocol and Statistical analysis plan.
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Jiang, R., Feng, Y., Chen, Y. et al. Surgery versus no surgery in platinum-sensitive relapsed ovarian cancer: final overall survival analysis of the SOC-1 randomized phase 3 trial. Nat Med 30, 2181–2188 (2024). https://doi.org/10.1038/s41591-024-02981-0
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DOI: https://doi.org/10.1038/s41591-024-02981-0
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