The effect of bevacizumab maintenance therapy on survival in recurrent epithelial ovarian cancer

Objective: We aimed to present our own retrospective data about the effectiveness of Bevacizumab (BV) maintenance therapy on survival to achieve optimal treatment in recurrent ovarian cancer. Methods: The data of patients with recurrent ovarian, tubal, and primary peritoneal cancer presenting to our hospital between October 2008 and December 2019 were retrospectively gathered from the hospital’s electronic archive system. The patients were grouped according to the platinum-free interval state. The patients were divided into two groups of BV maintenance and no BV maintenance and their progression-free and overall survival were calculated. Results: A total of 65 patients with recurrent epithelial ovarian cancer were included in the study. Among these, 35 had received bevacizumab therapy alone and 30 received bevacizumab maintenance therapy. According to the platinum-free interval, 37 of the patients had platinum-sensitive recurrent epithelial ovarian cancer and the remaining 28 had platinum-resistant recurrent epithelial ovarian cancer. The median follow-up was 42 (min: 13–max: 135) months. The average age was 56.5 ± 9.1 in the no bevacizumab maintenance group and 57.5 ± 9.6 in the bevacizumab maintenance group (p: 0.812). Among the platinum-sensitive recurrent epithelial ovarian cancer patients, the median progression-free survival progression-free survival (PFS) was 8 months (95% Confidence Interval (CI); 5.7–10.2) in the no bevacizumab maintenance group and 22 months (95% CI; 18.9–24.1) (p: 0.001) in the bevacizumab maintenance group and for the bevacizumab maintenance patients Hazard Ratio (HR): 0.10 (95% CI; 0.03–0.27) (p: 0.001). While the median overall survival (OS) of platinum-sensitive recurrent epithelial ovarian cancer patients in the no bevacizumab maintenance group was 64 months (95% CI; 21.6–102.3), it was 86 months (95% CI; NA) (p: 0.155) in the group that received bevacizumab maintenance, and for patients who received bevacizumab maintenance therapy, HR: 0.55 (95% CI; 0.18–1.33) (p: 0.166). The median PFS for platinum-resistant recurrent epithelial ovarian cancer patients who received no bevacizumab maintenance was determined as 7 (95% CI; 4.8–9.1) and as 19 months (95% CI; 9.2–26.7) (p: 0.009) for patients who received bevacizumab maintenance therapy, and for patients who received BV maintenance therapy, HR: 0.17 (95% CI; 0.03–0.71) (p: 0.022). In terms of OS, the median OS of platinum-resistant recurrent epithelial ovarian cancer patients who received no bevacizumab maintenance was 34 (95% CI; 31.5–36) months, while it was 45 (95% CI; 42.5–47.4) months in patients who received bevacizumab maintenance (p: 0.231); the HR for death in patients receiving bevacizumab maintenance therapy: 0.50 (95% CI; 0.15–1.61) (p: 0.247). Discussion: While it was shown that bevacizumab maintenance therapy had a significant effect on progression-free survival in both platinum-sensitive and platinum-resistant ovarian cancer, this effect could not be demonstrated for overall survival. Despite this, bevacizumab maintenance therapy can be delivered in recurrent ovarian cancer in addition to standard therapy. Further studies about its effect on overall survival are required.

Recurrent epithelial ovarian cancer; Platinum-sensitive; Platinum-resistant; Bevacizumab maintenance; Survival

[1] Copeland LJ, Brady MF, Burger RA, Rodgers WH, Huang H, Cella D, et al. A phase III trial of maintenance therapy in women with advanced ovarian/fallopian tube/peritoneal cancer after a complete clinical response to first-line therapy: an NRG oncology study. Gynecologic Oncology. 2017; 145: 219.

[2] Bookman MA, Brady MF, McGuire WP, Harper PG, Alberts DS, Friedlander M, et al. Evaluation of New Platinum-Based Treat- ment Regimens in Advanced-Stage Ovarian Cancer: a Phase III Trial of the Gynecologic Cancer InterGroup. Journal of Clinical Oncology. 2009; 27: 1419–1425.

[3] du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J. Role of surgical outcome as prognostic factor in ad- vanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d’Investigateurs Nationaux pour les Etudes des cancers de l’Ovaire (GINECO). Cancer. 2009; 115: 1234–1244.

[4] Markman M, Liu PY, Moon J, Monk BJ, Copeland L, Wilczynski S, et al. Impact on survival of 12 versus 3 monthly cycles of paclitaxel (175 mg/m2) administered to patients with advanced ovarian cancer who attained a complete response to primary platinum- paclitaxel: Follow-up of a Southwest Oncology Group and Gy- necologic Oncology Group phase 3 trial. Gynecologic Oncology. 2009; 114: 195–198.

[5] Gonzalez-Martin A, Gladieff L, Tholander B, Stroyakovsky D, Gore M, Scambia G, et al. Efficacy and safety results from OC-TAVIA, a single-arm phase II study evaluating front-line bevacizumab, carboplatin and weekly paclitaxel for ovarian cancer. Eu- ropean Journal of Cancer. 2013; 49: 3831–3838.

[6] Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. The New England Journal of Medicine. 2011; 365: 2473–2483.

[7] Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, et al. A phase 3 trial of bevacizumab in ovarian cancer. The New England Journal of Medicine. 2012; 366: 2484– 2496.

[8] Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, et al. OCEANS: a Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Chemotherapy with or without Beva- cizumab in Patients with Platinum-Sensitive Recurrent Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer. Journal of Clinical Oncology. 2012; 30: 2039–2045.

[9] Coleman RL, Brady MF, Herzog TJ, Sabbatini P, Armstrong DK, Walker JL, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. The Lancet Oncology. 2017; 18: 779–791.

[10] Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kris- tensen G, et al. Bevacizumab Combined with Chemotherapy for Platinum-Resistant Recurrent Ovarian Cancer: the AURELIA Open-Label Randomized Phase III Trial. Journal of Clinical On- cology. 2014; 32: 1302–1308.

[11] Moore K, Colombo N, Scambia G, Kim B, Oaknin A, Friedlander M, et al. Maintenance Olaparib in Patients with Newly Di- agnosed Advanced Ovarian Cancer. The New England Journal of Medicine. 2018; 379: 2495–2505.

[12] Ray-Coquard I, Pautier P, Pignata S, Pérol D, González-Martín A, Berger R, et al. Olaparib plus Bevacizumab as first-Line Maintenance in Ovarian Cancer. New England Journal of Medicine. 2019; 381: 2416–2428.

[13] Swisher EM, Lin KK, Oza AM, Scott CL, Giordano H, Sun J, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open- label, phase 2 trial. The Lancet Oncology. 2017; 18: 75–87.

[14] Brown MR, Blanchette JO, Kohn EC. Angiogenesis in ovarian cancer. Bailliere’S Best Practice &Amp; Research. Clinical Obstet- rics & Gynaecology. 2000; 14: 901–918.

[15] Ramakrishnan S, Subramanian IV, Yokoyama Y, Geller M. An- giogenesis in normal and neoplastic ovaries. Angiogenesis. 2005; 8: 169–182.

[16] Burger RA. Overview of anti-angiogenic agents in development for ovarian cancer. Gynecologic Oncology. 2011; 121: 230–238.

[17] Yoneda J, Kuniyasu H, Crispens MA, Price JE, Bucana CD, Fidler IJ. Expression of angiogenesis-related genes and progression of human ovarian carcinomas in nude mice. Journal of the National Cancer Institute. 1998; 90: 447–454.

[18] Huang S, Robinson JB, Deguzman A, Bucana CD, Fidler IJ. Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing ex- pression of vascular endothelial growth factor and interleukin 8. Cancer Research. 2000; 60: 5334–5339.

[19] European Medicines Agency. Science Medicines Health. 2015. Available at: http://www.ema.europa.eu/ema/index.jsp?cu rl=pages/medicines/human/medicines/000582/human_me d_000663.jsp&mid=WC0b01ac058001d124 (Accessed: 20 November 2015).

[20] Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2013; 24: vi24–vi32.

[21] Colombo N, Sessa C, Bois AD, Ledermann J, McCluggage W, Mc- Neish I, et al. ESMO–ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease. International Journal of Gynecologic Cancer. 2019; 29: 728–760.

[22] Tewari KS, Burger RA, Enserro D, Norquist BM, Swisher EM, Brady MF, et al. Final overall survival of a randomized trial of bevacizumab for primary treatment of ovarian cancer. Journal of Clinical Oncology. 2019; 37: 2317–2328.

[23] Oza AM, Cook AD, Pfisterer J, Embleton A, Ledermann JA, Pujade-Lauraine E, et al. Standard chemotherapy with or with- out bevacizumab for women with newly diagnosed ovarian can- cer (ICON7): overall survival results of a phase 3 randomised trial. The Lancet Oncology. 2015; 16: 928–936.

[24] U.S. National Library of Medicine. Evaluation of Optimal Treat- ment Duration of Bevacizumab Combination With Standard Chemotherapy in Patients With Ovarian Cancer, AGO-OVAR17 (BOOST). 2011. Available at: https://clinicaltrials.gov/ct2/show/NCT01462890 (Accessed: 1 November 2011).

[25] Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. Journal of the National Cancer Institute. 2000; 92: 205–216.

[26] Rustin GJ, Marples M, Nelstrop AE, Mahmoudi M, Meyer T. Use of CA-125 to define progression of ovarian cancer in patients with persistently elevated levels. Journal of Clinical Oncology. 2001; 19: 4054–4057.

[27] Monk BJ, Choi DC, Pugmire G, Burger RA. Activity of beva- cizumab (rhuMAB VEGF) in advanced refractory epithelial ovar- ian cancer. Gynecologic Oncology. 2005; 96: 902–905.

[28] Hanker LC, Loibl S, Burchardi N, Pfisterer J, Meier W, Pujade-Lauraine E, et al. The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy. Annals of Oncology. 2012; 23: 2605–2612.

[29] Aghajanian C, Goff B, Nycum LR, Wang YV, Husain A, Blank SV. Final overall survival and safety analysis of OCEANS, a phase 3 trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent ovarian cancer. Gynecologic Oncology. 2015; 139: 10–16.