Pathological Chemotherapy Response Score Predicts Survival in Patients with Advanced Ovarian Cancer Receiving Neoadjuvant Chemotherapy: Systematic Review and Meta-Analysis of Individual Patient Data

Background: The chemotherapy response score (CRS) has been recommended for reporting histological tumour response to neoadjuvant chemotherapy (NACT) in tubo-ovarian high-grade serous carcinoma (HGSC). The CRS reproducibly stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response. Studies have shown an association between CRS and progression-free survival (PFS) but not overall survival (OS). Methods: We undertook a systematic review and meta-analysis and established an international collaboration to pool individual patient data (IPD) from 16 sites in 11 countries. All patients had stage IIIC/IV HGSC, received 3-4 NACT cycles and a minimum 6-month follow-up. Random effects models were used to derive combined odds ratios in the pooled population to investigate associations between CRS and PFS and OS. Findings: 5 studies were identified that included 490 patients: 4 were at low-risk of bias. Unpublished IPD for 875 patients were obtained. 907 patients were included. Median PFS was 15 months (IQR 6-66) and median OS was 28 months (IQR 7-90). The pooled hazard ratio (HR) for PFS (CRS3 compared to CRS1/CRS2) was 0·52 (95%CI, 0·43 - 0·63; P <0·001). No heterogeneity was identified (Q=5·02, p<0·832, I2=0·0%). The pooled HR for OS (CRS3 compared to CRS1/CRS2) was 0·67 (95%CI 0·52 - 0·86, P= 0·001; Figure 2b). No heterogeneity was identified (Q=8·48, p<0·487, I2=0·0%). Interpretation: CRS3 was significantly associated with improved PFS and OS compared to CRS1/2. This robust, reproducible biomarker can be incorporated into therapeutic decision-making and clinical trial design. Funding: There was no funding source for this study. Declaration of Interest: All authors declare no conflict of interest relevant to the submitted work. Ethical Approval: Ethical approval was obtained (St John of God Healthcare Human Research Ethics Committee Reference 1291) for transfer of de-identified individual patient data from participating sites for statistical analysis at the Institute for Health Research, University of Notre Dame, Fremantle, Western Australia. Principal investigators at individual study sites obtained country-specific and local approvals.