Bevacizumab’s role in advanced ovarian clear cell carcinoma warrants more detailed analyses

Dear editors,

Ovarian clear cell carcinoma (OCCC) is a distinct subtype of epithelial ovarian cancer (EOC). Compared to most EOC cases, OCCC typically shows lower responsiveness to chemotherapy and poorer outcomes in advanced stages. Although new treatment modalities have emerged in recent years, most have been studied in high-grade serous histology and Western populations, limiting their applicability to Asian patients with OCCC. Furthermore, the evidence supporting their effectiveness in OCCC remains limited to retrospective and relatively small studies. Previously, we reported potential benefits of bevacizumab in early-stage OCCC [1]. More recently, a Japanese multicenter study by Tate et al. [2] suggested that bevacizumab might also have therapeutic value in advanced-stage OCCC. While the findings are promising, several methodological and interpretative issues in the study may have biased the assessment of bevacizumab’s true effect.

Based on the multivariate Cox proportional models in Table 3, we can generally observe that undergoing interval debulking surgery (i.e., receiving neoadjuvant chemotherapy [NACT]; hazard ratio [HR]=1.96 for both progression-free survival [PFS] and overall survival [OS]), and larger residual tumor (HR=2.65 and 3.19) were the strongest predictors of poor survival outcomes. A recent JAMA publication reported that NACT was associated with a trend toward worse outcomes in patients with OCCC [3]. In prior studies evaluating bevacizumab in EOC, most of which involved patients with high-grade serous histology, the drug might improve PFS but not OS [4,5]. Data on bevacizumab’s role in recurrent EOC remain limited [6,7]. Whether bevacizumab exerts a different effect in the relatively chemo-resistant OCCC subtype is uncertain—despite its reported benefit in this study, with a magnitude of effect comparable to surgical treatment (HRs of 2.78 and 2.70, inferred by inverting the HRs for bevacizumab in Table 3). Additionally, given the well-established importance of achieving no residual tumor during primary debulking, the inclusion of complete resection status in secondary debulking surgery should be considered as a potential confounder in the OS analysis [8].

Given the 10-year duration of this study, several changes may partially explain the observed positive effect of bevacizumab. First, advancements in surgical techniques may have led to a reduction in residual tumors. This is reflected in Table 1, where the proportion of patients with no residual tumor was marginally higher in the post-marketing group compared to the pre-marketing group (64.6% vs. 50.0%, p=0.07). When comparing the groups with and without bevacizumab, the extent of residual tumor did not differ significantly (p=0.12), suggesting that residual disease distribution was generally balanced between these treatment groups. A Cox regression model including both factors may provide insight into the trend over treatment evolution. Second, changes in the criteria for defining recurrence—from biochemical recurrence identified by elevated CA-125 levels to radiologic recurrence based on measurable lesions—may have delayed the documentation of disease progression in the post-marketing setting. This distinction between biochemical and radiologic recurrence should be recognized, particularly in patients without measurable disease [9,10]. Third, not all patients in the post-marketing group received bevacizumab. This may reflect initial physician hesitation due to concerns over side effects, particularly in combination with dose-dense chemotherapy. Such selective prescribing may have introduced bias, favoring patients with relatively better functional status. However, as noted, the true impact is difficult to assess due to the substantial proportion of patients with unknown performance status. Lastly, a higher proportion of patients in the bevacizumab group received dose-dense or weekly chemotherapy regimens. As the Japan Society of Gynecologic Oncology 3016 study have demonstrated improved survival with these regimens, the authors should consider including this variable in the multivariate survival analysis to better isolate the independent effect of bevacizumab [11].

In conclusion, while the current study presents an evidence-based therapeutic option for OCCC patients, its findings should be interpreted with caution. By incorporating pre- and post-marketing periods, the addition of bevacizumab, the influence of dose-dense or weekly chemotherapy regimens, and the uptake of secondary cytoreductive surgery into the Cox regression analysis would provide a more balanced and robust assessment of bevacizumab’s true effect on survival outcomes.