Efficacy and safety of bevacizumab in the treatment of advanced or recurrent cervical cancer: a systematic review and a meta-analysis

Background: This meta-analysis aims to evaluate the safety and effectiveness of the combination of chemotherapy and bevacizumab versus chemotherapy alone in treating advanced or refractory cervical cancer (a/r CC), providing guidance for clinical practice. Methods: A computer search of studies on the combination of bevacizumab and chemotherapy was conducted up to 20 March 2024. Literature was screened and assessed based on inclusion and exclusion criteria and relevant data were extracted for analysis. Results: Ten studies were included. The meta-analysis showed that the overall survival (OS) of the platinum-paclitaxel plus bevacizumab group was significantly better than that of the traditional chemotherapy group (hazard ratio (HR) = 0.76, 95% confidence interval (CI): 0.68–0.85, p < 0.001; I2 = 17.2%). Progression-free survival (PFS) was also significantly improved in the combined group (HR = 0.59, 95% CI: 0.49–0.71, p < 0.001; I2 = 0.0%). The combined therapy group had higher rates of complete response (CR)(relative risk (RR) = 1.22, 95% CI: 1.00–1.47, p = 0.046) and partial response (PR) (RR = 1.38, 95% CI: 1.15–1.66, p = 0.001), while the incidence of progression disease (PD) was lower (RR = 0.43, 95% CI: 0.31–0.61, p < 0.001). No significant difference was found in stabilization disease (SD) between the groups (p = 0.998). However, the bevacizumab group exhibited a significantly higher incidence in terms of adverse events, including hypertension (p = 0.029), thrombosis (p < 0.01), and neutropenia (p = 0.011), while other side effects between the two groups, such as pain, gastrointestinal and genitourinary fistulas, and bleeding, showed no significant differences. Conclusion: The combination of bevacizumab and chemotherapy improves the survival and efficacy of patients with a/r CC compared to chemotherapy alone, though it is associated with a higher incidence of certain adverse events. The PROSPERO Registration: CRD42023451617.

Angiogenesis inhibitors; Bevacizumab; Meta-analysis; Advanced or refractory cervical cancer; Targeted drug

[1] Arbyn M, Weiderpass E, Bruni L, de Sanjosé S, Saraiya M, Ferlay J, et al. Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. The Lancet Global Health. 2020; 8: e191–e203.

[2] Öztürk R, Bakir S, Kazankaya F, Paker S, Ertem G. Awareness about gynecologic cancers and related factors among healthy women: a cross-sectional study. Social Work in Public Health. 2021; 36: 847–856.

[3] Gennigens C, Jerusalem G, Lapaille L, De Cuypere M, Streel S, Kridelka F, et al. Recurrent or primary metastatic cervical cancer: current and future treatments. ESMO Open. 2022; 7: 100579.

[4] Hernowo BS, Suryanti S, Wibisono F. Correlation between EGFR expression and radiosensitivity in cervical adenocarcinoma cases. Asian Pacific Journal of Cancer Prevention. 2016; 17: 2535–2537.

[5] Dang A, Jagan Mohan Venkateswara Rao P, Kishore R, Vallish BN. Real world safety of bevacizumab in cancer patients: a systematic literature review of case reports. The International Journal of Risk & Safety in Medicine. 2021; 32: 163–173.

[6] Yagi K, Mitstui M, Zamami Y, Niimura T, Izawa-Ishizawa Y, Goda M, et al. Investigation of drugs affecting hypertension in bevacizumab-treated patients and examination of the impact on the therapeutic effect. Cancer Medicine. 2021; 10: 164–172.

[7] Monk BJ, Sill MW, McMeekin DS, Cohn DE, Ramondetta LM, Boardman CH, et al. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. Journal of Clinical Oncology. 2009; 27: 4649–4655.

[8] Ettinger DS, Wood DE, Aggarwal C, Aisner DL, Akerley W, Bauman JR, et al. NCCN Guidelines Insights: non-small cell lung cancer, version 1.2020. Journal of the National Comprehensive Cancer Network. 2019; 17: 1464–1472.

[9] Chu G, Liu X, Yu W, Chen M, Dong L. Cisplatin plus paclitaxel chemotherapy with or without bevacizumab in postmenopausal women with previously untreated advanced cervical cancer: a retrospective study. BMC Cancer. 2021; 21: 133.

[10] Gopu P, Antony F, Cyriac S, Karakasis K, Oza AM. Updates on systemic therapy for cervical cancer. The Indian Journal of Medical Research. 2021; 154: 293–302.

[11] Colombo N, Dubot C, Lorusso D, Caceres MV, Hasegawa K, Shapira-Frommer R, et al.; KEYNOTE-826 investigators. pembrolizumab for persistent, recurrent, or metastatic cervical cancer. The New England Journal of Medicine. 2021; 385: 1856–1867.

[12] Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. The BMJ. 2021; 372: n71.

[13] Kpoghomou MA, Geneau M, Menard J, Stiti M, Almont T, Ghose B, et al. Assessment of an onco-sexology support and follow-up program in cervical or vaginal cancer patients undergoing brachytherapy. Supportive Care in Cancer. 2021; 29: 4311–4318.

[14] Yang H, Zhang Y, Liu C, Feng B, Zhang J, Zhou Y, et al. The integration of bevacizumab improves tumor response and survival in patients with refractory cervical cancer treated with radical chemoradiotherapy. Annals of Translational Medicine. 2021; 9: 1184.

[15] Liu CH, Kung YH, Chien-Fu Lin J, Chuang CM, Wu HH, Jiang LY, et al. Synergistic therapeutic effect of low-dose bevacizumab with cisplatin-based chemotherapy for advanced or recurrent cervical cancer. Journal of the Chinese Medical Association. 2021; 84: 1139–1144.

[16] Čerina D, Matković V, Katić K, Belac Lovasić I, Šeparović R, Canjko I, et al. Real-world efficacy and safety of bevacizumab in the first-line treatment of metastatic cervical cancer: a cohort study in the total population of Croatian patients. Journal of Oncology. 2021; 2021: 2815623.

[17] Yasunaga M, Yahata H, Okugawa K, Shimokawa M, Maeda Y, Hori E, et al. Prognostic impact of adding bevacizumab to carboplatin and paclitaxel for recurrent, persistent, or metastatic cervical cancer. Taiwanese Journal of Obstetrics & Gynecology. 2022; 61: 818–822.

[18] Tao W, Yang J, Jiang Y, Chen W, Wang Y. Paclitaxel, carboplatin, and bevacizumab in advanced cervical cancer: a treatment response and safety analysis. Dose-Response. 2020; 18: 1559325820941351.

[19] Hwang WY, Chang SJ, Kim HS, Kim NK, Kim TH, Kim Y, et al. Gastrointestinal/genitourinary perforation and fistula formation with or without bevacizumab in patients with previously irradiated recurrent cervical cancer: a Korean multicenter retrospective study of the Gynecologic Oncology Research Investigators Collaboration (GORILLA) group (GORILLA-1001). BMC Cancer. 2022; 22: 603.

[20] Youn SH, Kim YJ, Seo SS, Kang S, Lim MC, Chang HK, et al. Effect of addition of bevacizumab to chemoradiotherapy in newly diagnosed stage IVB cervical cancer: a single institution experience in Korea. International Journal of Gynecological Cancer. 2020; 30: 764–771.

[21] Tewari KS, Sill MW, Penson RT, Huang H, Ramondetta LM, Landrum LM, et al. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). The Lancet. 2017; 390: 1654–1663.

[22] He X, Liu J, Xiao L, Zhao M, Su T, Liu T, et al. Cisplatin-based chemotherapy with or without bevacizumab for Chinese postmenopausal women with advanced cervical cancer: a retrospective observational study. BMC Cancer. 2020; 20: 381.

[23] Lopes-Coelho F, Martins F, Pereira SA, Serpa J. Anti-angiogenic therapy: current challenges and future perspectives. International Journal of Molecular Sciences. 2021; 22: 3765.

[24] Cao Y, Langer R, Ferrara N. Targeting angiogenesis in oncology, ophthalmology and beyond. Nature Reviews. Drug Discovery. 2023; 22: 476–495.

[25] Giudice E, Mirza MR, Lorusso D. Advances in the management of recurrent cervical cancer: state of the art and future perspectives. Current Oncology Reports. 2023; 25: 1307–1326.

[26] Rosen VM, Guerra I, McCormack M, Nogueira-Rodrigues A, Sasse A, Munk VC, et al. Systematic review and network meta-analysis of bevacizumab plus first-line topotecan-paclitaxel or cisplatin-paclitaxel versus non-bevacizumab-containing therapies in persistent, recurrent, or metastatic cervical cancer. International Journal of Gynecological Cancer. 2017; 27: 1237–1246.

[27] Gao F, Yang C. Anti-VEGF/VEGFR2 monoclonal antibodies and their combinations with PD-1/PD-L1 inhibitors in clinic. Current Cancer Drug Targets. 2020; 20: 3–18.

[28] Oaknin A, Gladieff L, Martínez-García J, Villacampa G, Takekuma M, De Giorgi U, et al.; ENGOT-Cx10–GEICO 68-C–JGOG1084–GOG-3030 Investigators. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. The Lancet. 2024; 403: 31–43.

[29] Coleman RL, Lorusso D, Gennigens C, González-Martín A, Randall L, Cibula D, et al.; innovaTV 204/GOG-3023/ENGOT-cx6 Collaborators. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. The Lancet Oncology. 2021; 22: 609–619.

[30] Gao X, Xu N, Li Z, Shen L, Ji K, Zheng Z, et al. Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): a multicentre, open-label, phase 1b/2 trial. The Lancet Oncology. 2023; 24: 1134–1146.