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Use of bevacizumab before or after radiotherapy increases the risk of fistula formation in patients with cervical cancer
  1. Nalee Kim1,
  2. Seo Hee Choi1,
  3. Jee Suk Chang1,
  4. Young-Tae Kim2,
  5. Sang Wun Kim2,
  6. Gun Min Kim3 and
  7. Yong Bae Kim1
  1. 1 Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
  2. 2 Obstetrics and Gynecology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
  3. 3 Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea (the Republic of)
  1. Correspondence to Dr Yong Bae Kim, Radiation Oncology, Yonsei University College of Medicine, Seoul 03722, Korea (the Republic of); ybkim3{at}


Objective Several reports have documented the risk of fistula formation after bevacizumab in patients previously treated with radiation therapy. The aim of this study was to investigate the risk of fistula formation with bevacizumab and radiotherapy compared with radiotherapy alone.

Methods We retrospectively analyzed patients with stage I–IV cervical cancer between January 2013 and December 2018. Patients who had a history of pelvic radiotherapy, who were treated with intracavitary brachytherapy alone, received radiotherapy at another hospital, received concurrent bevacizumab and radiotherapy, or had missing follow-up data or a short follow-up period (<6 months) were excluded. The fistula rates were compared between the groups using the Cox proportional hazards model and propensity score analyses.

Results A total of 302 patients were included in the study: 249 patients were treated with definitive or adjuvant radiotherapy, and 53 patients were treated with radiotherapy before or after bevacizumab. With a median follow-up of 35.9 (IQR 22.8–53.5) months, the 3 year cumulative fistula incidence rate was significantly higher in the radiotherapy + bevacizumab group than in the radiotherapy group (27.0% vs 3.0%, p<0.001). Bevacizumab administration was significantly associated with fistula formation in the multivariable adjusted model (HR 4.76, 95% CI 1.71 to 13.23) and three propensity score adjusted model (all p<0.05). Biologically equivalent dose in 2 Gy fractions for 2 cc of the rectum more than 76 Gy was also associated with fistula formation (HR 4.30, 95% CI 1.52 to 12.18). Additionally, a 10 month interval between radiotherapy and bevacizumab reduced the incidence of fistula formation in the radiotherapy + bevacizumab group (p=0.032).

Conclusions In patients with cervical cancer treated with pelvic radiotherapy, the addition of bevacizumab substantially increased the risk of fistula formation. Physicians should perform pelvic radiotherapy in combination with bevacizumab with caution; moreover, close monitoring for fistula formation is warranted in these patients.

  • vaginal fistula
  • radiotherapy
  • cervical cancer
  • rectovaginal fistula

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  • Editor's note Author Nalee Kim's current affiliation is the Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of).

  • Contributors The study was planned by NK and YBK and conducted by NK, SHC, and YBK. Data were analyzed by NK and SHC. NK was the main author of the draft. All authors contributed to the interpretation of the results, the elaboration of the manuscript, and approval of the final version.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request from Nalee Kim (

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.