Penetrating complications of bevacizumab-containing chemotherapy in previously-irradiated recurrent cervical cancer: a Korean multicenter retrospective study of the Gynecologic Oncology Research Investigators coLLaborAtion (GORILLA) group (GORILLA1001) (036)

Objectives: Gynecologic Oncology Group 240 study showed that incorporating bevacizumab in the treatment of recurrent, persistent, or metastatic cervical cancer conferred overall survival (OS) benefit. However, fistula occurred significantly higher in the bevacizumab (+) group than the chemotherapy alone group. Moreover, all fistulas in the bevacizumab (+) group were developed in patients who were previously irradiated. This study aimed to evaluate the incidence and to identify risk factors for penetrating complications, including gastrointestinal (GI) and genitourinary (GU) fistula/perforation, of bevacizumab plus chemotherapy in recurrent cervical cancer patients who underwent pelvic radiation therapy (RT). Methods: Medical records of the patients with recurrent cervical cancer who previously underwent pelvic radiation at five university hospitals in Korea from 2007 to 2020 were retrospectively reviewed. Women who received chemotherapy immediately after RT were excluded. Clinical-pathologic factors were compared between groups of the following two settings: 1) fistula/perforation (+) and (-); 2) bevacizumab plus chemotherapy and chemotherapy alone. Univariate and multivariate regression analyses were performed to identify risk factors for penetrating complications. OS was also compared between groups of the two comparisons. Results: Of 219 women with recurrent cervical cancer who previously underwent pelvic RT, 144 (65.8%) received bevacizumab-containing chemotherapy, and 75 (34.2%) received chemotherapy alone. Fistula/perforation of any grade occurred in 36 (16.4%): fistulas alone in 27 (11 GI, 8 GU, and 8 both) and perforations in nine patients. Women receiving bevacizumab experienced fistula/perforation more frequently than those who used chemotherapy alone (20.8% [30/144] vs 8.0% [6/75]; p=0.015) (Table 1). Multivariate regression analysis showed that bevacizumab administration was the only independent risk factor for the occurrence of fistula/perforation. Age, diabetes, hypertension, tumor histology (squamous vs non-squamous), cumulative dose of RT, primary treatment (operation vs. RT vs both), use of intensity-modulated RT, and the time interval between RT and bevacizumab failed to show association with fistula/perforation. During median follow-up of 33.7 months (1.2-185.6 months), significant OS difference was shown neither between bevacizumab (+) versus bevacizumab (-) (HR: 1.03; median 119.8 months [95% CI: 97.3-142.3months] vs 115.7 months [96.0-135.4 months]; p=0.928) nor between fistula/perforation (+) versus fistula/perforation (-) (HR: 1.78; median 84.2 months [59.3-109.0 months] vs 129.5 months [114.1-144.9 months]; p=0.065). Conclusions: The study results suggest that incorporating bevacizumab in the chemotherapy regimen to treat recurrent cervical cancer with a previous history of pelvic RT incurs a considerable risk of GI and/or GU penetrating complications, which might damage the survival outcome as well as the quality of life. The risk and benefit of incorporating bevacizumab in the treatment of previously irradiated recurrent cervical cancer patients are needed to be carefully weighed, considering that effective prevention of the penetrating complications is difficult because of the lack of knowledge regarding other risk factors.