From 2006 to 2014, electronic medical records of patients with tubo-ovarian or peritoneal HGSC who underwent NAC and subsequent IDS in the Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine were retrospectively analyzed. The same inclusion and exclusion criteria as those reported by Böhm et al. [5] were applied. In brief, the inclusion criteria were 1) histopathologically confirmed International Federation of Gynecology and Obstetrics (FIGO) stage IIIC–IV HGSC patients; 2) ovarian, tubal, or primary peritoneal HGSC; and 3) IDS. This study was reviewed and approved by the Institutional Review Board at Severance Hospital, Yonsei University Health System, Seoul, Korea (IRB No. 4-2015-1158).

Regarding primary treatment strategy, the selection criteria for NAC were not described in the study of Böhm et al. [5]. In this study, we applied 2 gate models for primary treatment strategies in advanced HGSCs. All patients had preoperative computed tomography (CT) and positron emission tomography (PET)/CT. NAC was performed for those who 1) developed pulmonary and/or hepatic parenchymal metastasis in imaging analyses; 2) were medically inoperable; and 3) were judged unsuitable for optimal debulking surgery due to high tumor burden based on the Fagotti's score (scored over 8) [6]. All surgical procedures were performed by a gynecologic oncology team comprising 5 experienced gynecologic surgeons. IDS was performed via long midline laparotomy, hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and pelvic and paraaortic lymphadenectomy, with or without various radical surgeries (e.g., bowel resection, diaphragmatic resection, and peritonectomy). After surgery, patients received 3–6 cycles of postoperative adjuvant chemotherapy (POAC). Both NAC and POAC were routinely given as a combination of carboplatin and taxane. All therapeutic procedures were provided according to the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology [7].

The resected specimens were formalin-fixed and paraffin-embedded according to standard procedures and stained with hematoxylin and eosin (H&E) in the Department of Pathology, Severance Hospital, Yonsei University College of Medicine. All available H&E-stained slides obtained from IDS specimens were reviewed by an experienced gynecologic pathologist (H.S.K.). The slide with the most viable tumor and/or the least chemotherapy response was selected from each of 3 sites: omentum, right adnexa, and left adnexa. Three pathologists (H.S.K., H.M.K., and C.K.P.) independently scored each slide according to the 3-tiered CRS system proposed by Böhm et al. [5]. In brief, CRS 1 indicates no or minimal tumor response; mainly viable tumor with no or minimal regression-associated fibroinflammatory changes, limited to a few foci; and cases in which it is difficult to decide between regression and tumor-associated desmoplasia or inflammatory cell infiltration (Fig. 1A). CRS 2 indicates appreciable tumor response amid viable tumor that is readily identifiable; multifocal or diffuse regression-associated fibroinflammatory changes with viable tumor in sheets, streaks, or nodules; and extensive regression-associated fibroinflammatory changes with multifocal residual tumor, which is easily identifiable (Fig. 1B). CRS 3 indicates complete or near-complete response with no residual tumor; minimal irregularly scattered tumor foci seen as individual cells, cell groups, or nodules up to 2 mm maximum size; mainly regression-associated fibroinflammatory changes; and no or very little residual tumor in the complete absence of any inflammatory response (Fig. 1C).

Each pathologist was blinded to the results of other pathologists. Following submission of independent scores for reproducibility analysis, all cases in which the score was not unanimous were reviewed jointly using a multi-headed microscope. The agreed upon consensus score was used for outcome analysis.

Fleiss' kappa statistics and Kendall's coefficient of concordance were used to assess levels of agreement among the pathologists. Survival outcomes according to the CRS were analyzed. The PFS and OS curves were drawn using the Kaplan-Meier method, and the curves were compared using a log-rank test. Adjusted hazard ratios (HRs) for PFS and OS were estimated with a Cox proportional hazards model. In addition, the performance of CRS was evaluated using the concordance index (c-index). A bootstrap method (1,000 repetitions) was used to obtain more unbiased estimates of the c-index. Statistical significance was defined as a p<0.050. All statistical analyses were performed using STATA ver. 12.0 (StataCorp LP, College Station, TX, USA).

We found 115 stage IIIC–IV ovarian cancer patients who underwent NAC followed by IDS in our institutional databases. One hundred and ten (95.7%) patients met the inclusion criteria. Three (2.6%) patients with ovarian clear cell carcinoma and 2 (1.7%) with carcinosarcoma were excluded. The baseline characteristics of the patients are summarized in Table 1. The median age of the patients was 57 years (range, 27–80 years). All patients had histopathologically confirmed HGSC and underwent platinum/taxane-based chemotherapy.

The interobserver reproducibility of the 3-tiered CRS system was assessed. The omental CRS showed high reproducibility among the 3 independent pathologists (Fleiss' kappa value=0.656; Kendall's coefficient of concordance=0.669; absolute agreement=71.7%). In addition, we observed comparable reproducibility of the adnexal CRS with that of the omental CRS (Table 2). These findings were not consistent with those from previous data showing that the adnexal CRS showed inferior reproducibility to the omental CRS [5].

The distribution of CRS in our cohort (CRS 1, 5.5%; CRS 2, 51.8%; CRS 3, 42.7%) was significantly different from that of Böhm et al. [5]'s validation cohort (CRS 1, 0%; CRS 2, 70.0%; CRS 3, 30.0%; p<0.050). In our cohort, the omental CRS displayed a significant prognostic value for PFS between CRS 1–2 and CRS 3; the median PFS of patients with CRS 1–2 and CRS 3 tumors was 14.5 and 18.6 months, respectively (p=0.016; Fig. 2A). There were significant differences in PFS between patients with CRS 1 and CRS 2 tumors (p<0.001) and between those with CRS 2 and CRS 3 tumors (p=0.046), respectively (Fig. 2B). Unlike Böhm et al. [5]'s validation cohort, which exhibited no significant difference in survival between CRS 1 and CRS 2 diseases, we did observe a significant difference between those groups. When adjusted for age, stage, and debulking status, the CRS was an independent prognostic factor for PFS (CRS 1–2 vs. CRS 3; adjusted HR=1.74; 95% confidence interval [CI]=1.05–2.87). A log-rank test revealed no significant difference in OS between CRS 1–2 and CRS 3 (p=0.902; Fig. 2C). With interval validation using the bootstrap method (1,000 runs), the c-index for the Cox model was 0.725 (95% CI=0.650–0.793) for recurrence.

No gross residual disease after IDS was achieved in 23.8% of patients with CRS 1–2, whereas 48.9% of patients with CRS 3 (odd ratio [OR]=3.07; 95% CI=1.36–6.92) had no gross residual disease after IDS. However, there was no significant difference in the rate of optimal cytoreduction (residual tumor <1 cm) between patients with CRS 1–2 and CRS 3 tumors (p=0.785), optimal cytoreduction was achieved in 81.0% of and 83.0% of patients with CRS 1–2 and CRS 3 disease, respectively.

Less than 6 months after last POAC, 83.3%, 26.3%, and 23.4% of patients with CRS 1, 2, and 3 had platinum-resistant diseases, respectively. There was a trend towards an inverse association between CRS and the frequency of platinum resistance (CRS 1–2, 31.8%; CRS 3, 23.4%), although the difference was not statistically significant (p=0.336).