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RESULTS
All 85 patients with advanced OCCC between January 2012 and December 2017 were included in this analysis. Subgroup analyses of the relative risk of disease recurrence for patients receiving more than six versus less than six cycles of CT based on clinicopathological prognostic factors are shown in Table 1. The median age at diagnosis was 50 years. In 57 patients (67.1%), the level of CA125 was high before treatment, and 31 patients (36.5%) had ascites. There were 17 patients (20%) with stage II, 58 patients (68.2%) with stage III, and 10 patients (11.8%) with stage IV disease. All patients were treated with varying degrees of tumor cell destruction, with lymph node resection in 53 (62.4%) patients. Metastasis was observed in 19 (35.9%) patients. Forty (40) patients (47.1%) achieved complete tumor reduction, 26 patients (30.6%) achieved ideal tumor reduction, and 19 patients (22.4%) achieved non-ideal tumor reduction. The tumor histopathological type was pure in 76 cases (89.4%). All patients were treated with postoperative adjuvant platinum-based CT; of these, 38 patients (44.7%) underwent more than six cycles of CT. According to the number of CT cycles, we divided the cases into two groups: >6 cycle group and ≤6 cycle group. The two groups were compared for age, preoperative CA125 levels, FIGO stage, lymph node resection, metastasis, residual tumor, histopathological type, ascites, and other clinical features. The differences were not statistically significant (P > 0.05).
The median follow-up time for the cases was 19 months (range, 3–75 months). Among the 85 patients, 49 had disease recurrence, and 35 died. Recurrence occurred in 31 of 35 patients who died, and in 18 of 50 patients who survived. According to the Kaplan-Meier survival curve, the 2-year PFS of the ≤6 cycle group and the >6 cycle group were estimated to be 51.5% and 42.2% (P>0.05), and OS was 59.7% and 64.5% (P>0.05), respectively. The effect of the number of CT cycles on PFS and OS was not statistically significant (Figures 2 and 3). The hazard ratio (HR) of disease recurrence in patients who underwent ≤6 versus >6 cycles of CT was 0.86 (95% CI: 0.49–1.52; p=0.605). The HRs of recurrence based on clinicopathological prognostic factors are shown in Table 1. Univariate analysis showed that there was no significant difference in recurrence risk between the two groups.
Multivariate analysis showed that residual tumor diameter was an independent risk factor for prognosis. In the three groups divided according to their residual tumor diameter (R0, R1 and R2), thorough tumor reduction (R0) significantly improved the prognosis, and the 2-year PFS and OS were significantly higher than those in the other two groups (Table 2). The prognosis of the group with residual tumor ≤1cm (R1) showed no significant difference compared with the >1cm group (R2).
According to the subgroup analysis of residual tumor diameter, there were 40 cases in the R0 group, 26 cases in the R1 group, and 19 cases in the R2 group. Forty-seven (47) patients underwent ≤6 cycles of CT, and 38 patients underwent >6 cycles of CT. For the R0 group, the 2-year PFS of the ≤6 and >6 were 77.7% and 76.0%, respectively, and OS was 81.6% and 87.5%, respectively, with no significant difference in prognosis (P > 0.05). For the R1 group, the 2-year PFS of the ≤6 and >6 cycles groups were 26.3% and 13.9%, respectively, and OS was 41.0% and 55.6%, respectively, with no significant difference in prognosis (P > 0.05). For the R2 group, the 2-year PFS and OS were 33.3% and 0%, respectively, with no significant difference in prognosis (P > 0.05). In conclusion, more than 6 courses of CT did not improve the prognosis, regardless of residual tumor diameter. The results were presented in forest maps (Figures 4 and 5) using the R language.
DISCUSSION
The GOG18 (157) compared the prognosis between 3-cycle CT and 6-cycle CT in early high-risk ovarian cancer and concluded that 6-cycle chemotherapy could not significantly reduce the risk of recurrence, but increased toxic reactions (such as neurotoxicity, granulocytopenia, and anemia). Prendergast et al20 also proposed that the recurrence rate and survival rate of 3-cycle CT corresponded to 6-cycle CT. We speculated that early OCCC patients could benefit from up to 6 CT cycles, and the indications of CT should be closely monitored to reduce toxic reactions. Therefore, the subjects included in this study were mainly stage II–IV patients with advanced OCCC.
Current FIGO and NCCN guidelines recommend adjuvant chemotherapy for all stages of ovarian cancer. For advanced OCCC, the number of chemotherapy cycles is still controversial. In clinical practice, doctors perform over 6 cycles of CT for some patients according to their personal experience as well as the patients’ condition (ie elevated CA125 levels, persistent disease, etc). Bertelsen et al21 conducted three randomized trials comparing the survival benefits of 5–6, 8, 10, and 12 cycles of CT, respectively, showing that the optimal duration of first-line chemotherapy for advanced ovarian cancer was no more than 6 cycles. Therefore, it is generally believed that stage II–IV patients with ovarian cancer can get an objective remission after surgery with 6 cycles of CT. However, it is not clear whether it is suitable for OCCC patients with high platinum resistance. Pectasides et al22 showed that women with clear cell tumors have significantly lower response rates to platinum-based first-line CT compared to those with serous ovarian cancers. Similarly, Sugiyama et al14 compared patients with OCCC versus serous ovarian cancers, reporting that OCCC patients had a significantly lower response rate to CT (11.1%), versus serous ovarian cancer patients (72.5%).
The results of this study showed that, compared with the >6 cycle group, the 2-year overall survival rate of patients in the ≤6 cycle group, as well as the risk of recurrence, was not significantly different. Multivariate analyses also showed that the duration of chemotherapy was not an independent prognostic factor.
Many studies have shown that ideal reductive surgery can prolong the survival time of ovarian cancer patients,23,24 and compared with patients who have achieved the ideal reduction, the risk of death increased by 1.89 times for women who have not.25 However, this study showed that complete tumor reduction could significantly improve OS and PFS in patients with advanced OCCC. On the other hand, an ideal reduction did not improve OS and PFS compared with non-ideal reduction (Table 2). The reason for the significantly poor prognosis of patients without complete reduction surgery may be that patients in this group will relapse within a short period, combined with the cytotoxicity of chemotherapy drugs and the high resistance to platinum. Eventually, patients without complete reduction surgery develop progressive or refractory ovarian cancer, leading to a worse prognosis.
Patients with advanced OCCC often have a complex condition, and the primary staging operation cannot achieve complete tumor cell reduction for all patients. Therefore, it is not clear whether postoperative chemotherapy with different cycles can further improve the prognosis. Suidan et al23 evaluated the prognosis of epithelial ovarian cancer patients receiving CT 6 cycles after ideal tumor cell reduction in stage III/IV, finding no significant statistical difference between OS and PFS at 5 years after 1–2, 3–4, and 5–6 cycles of CT. The literature reported that the overall response rate of patients with OCCC to chemotherapeutic drugs was less than 50% and decreased with increasing stages.26,27 In this study, patients were divided into three groups based on the diameter of their postoperative residual tumor, and the effect of the chemotherapy cycle on prognosis was compared. The results showed no significant difference in PFS and OS between the ≤6-cycle and >6-cycle groups. Moreover, prognosis in patients with advanced OCCC did not improve after >6 cycles of chemotherapy, regardless of whether they underwent complete tumor reduction.
The present study is retrospective in nature. Due to many limitations, inherent selection bias and recall bias may affect the accuracy of the results. Large-scale clinical studies are needed in the future to further clarify the clinicopathological characteristics of patients with advanced OCCC to guide clinical treatment and to predict the survival outcome in such patients. However, due to the low incidence of OCCC, the implementation of large-scale prospective clinical trials is very challenging.
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