Subscribe to RSS
![](/products/assets/desktop/img/oa-logo.png)
DOI: 10.1055/s-0042-1742321
Therapy for Recurrent High-Grade Epithelial Ovarian Cancer—The Current Status and Future Trends
![](https://www.thieme-connect.de/media/10.1055-s-00050348/202402/lookinside/thumbnails/10-1055-s-0042-1742321_212600368-1.jpg)
Abstract
Ovarian malignancy is the seventh most frequently diagnosed cancer among women. The most common type is epithelial ovarian cancer. Several subtypes with distinct biological and molecular properties exist, and there is inconsistency in availability of and access to different modalities of treatment. The standard first-line management is combining surgery and platinum-based chemotherapy. Most of them are diagnosed at an advanced stage due to which they have poor outcomes. The existing screening tests have a low predictive value. Even with the best available upfront treatment, high rates of recurrences are observed. As a result, there have been major advances in the treatment of recurrences with the development of anti-angiogenic agents and PARP inhibitors. It has led to the improvement in survival and quality of life among the relapsed epithelial ovarian cancers. This review is focused on the management of recurrent epithelial ovarian cancers and future directions based on current evidence. The application of a personalized and structured approach will meaningfully bring changes in the paradigm of care in these groups of patients.
Publication History
Article published online:
29 September 2022
© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
-
References
- 1 Dockery LE, Rubenstein AR, Ding K. et al. Extending the platinum-free interval: the impact of omitting 2nd line platinum chemotherapy in intermediate platinum-sensitive ovarian cancer. Gynecol Oncol 2019; 155 (02) 201-206
- 2 Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E. et al. Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. J Clin Oncol 2010; 28 (20) 3323-3329
- 3 Pignata S, Scambia G, Bologna A. et al. Randomized controlled trial testing the efficacy of platinum-free interval prolongation in advanced ovarian cancer: the MITO-8, MaNGO, BGOG-Ov1, AGO-Ovar2.16, ENGOT-Ov1, GCIG Study. J Clin Oncol 2017; 35 (29) 3347-3353
- 4 Friedlander M, Trimble E, Tinker A. et al; Gynecologic Cancer InterGroup. Clinical trials in recurrent ovarian cancer. Int J Gynecol Cancer 2011; 21 (04) 771-775
- 5 Rabik CA, Dolan ME. Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev 2007; 33 (01) 9-23
- 6 Damia G, Broggini M. Platinum resistance in ovarian cancer: role of DNA repair. Cancers (Basel) 2019; 11 (01) 119
- 7 Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D'Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov 2015; 5 (11) 1137-1154
- 8 Wilkes DC, Sailer V, Xue H. et al. A germline FANCA alteration that is associated with increased sensitivity to DNA damaging agents. Cold Spring Harb Mol Case Stud 2017; 3 (05) a001487
- 9 Carrassa L, Damia G. DNA damage response inhibitors: mechanisms and potential applications in cancer therapy. Cancer Treat Rev 2017; 60: 139-151
- 10 Chilà R, Guffanti F, Damia G. Role and therapeutic potential of CDK12 in human cancers. Cancer Treat Rev 2016; 50: 83-88
- 11 Hill SJ, Decker B, Roberts EA. et al. Prediction of DNA repair inhibitor response in short-term patient-derived ovarian cancer organoids. Cancer Discov 2018; 8 (11) 1404-1421
- 12 Davis A, Tinker AV, Friedlander M. “Platinum resistant” ovarian cancer: what is it, who to treat and how to measure benefit?. Gynecol Oncol 2014; 133 (03) 624-631
- 13 Pujade-Lauraine E, Combe P. Recurrent ovarian cancer. Ann Oncol 2016; 27 (Suppl. 01) i63-i65
- 14 Ferrandina G, Ludovisi M, Lorusso D. et al. Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol 2008; 26 (06) 890-896
- 15 Mutch DG, Orlando M, Goss T. et al. Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol 2007; 25 (19) 2811-2818
- 16 Berg T, Nøttrup TJ, Roed H. Gemcitabine for recurrent ovarian cancer - a systematic review and meta-analysis. Gynecol Oncol 2019; 155 (03) 530-537
- 17 Lihua P, Chen XY, Wu TX, Wu X. Topotecan for ovarian cancer. Cochrane Database Syst Rev 2008; (02) CD005589
- 18 Sharma A, Malik PS, Khurana S. et al. Oral metronomic chemotherapy for recurrent & refractory epithelial ovarian cancer: a retrospective analysis. Indian J Med Res 2019; 150 (06) 575-583
- 19 Friedlander M, Hancock KC, Rischin D. et al. A Phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer. Gynecol Oncol 2010; 119 (01) 32-37
- 20 Ferrandina G, Corrado G, Mascilini F. et al. Metronomic oral cyclophosphamide (MOC) in the salvage therapy of heavily treated recurrent ovarian cancer patients: a retrospective, multicenter study. BMC Cancer 2014; 14: 947
- 21 Musella A, Vertechy L, Romito A. et al. Bevacizumab in ovarian cancer: state of the art and unanswered questions. Chemotherapy 2017; 62 (02) 111-120
- 22 Pujade-Lauraine E, Hilpert F, Weber B. et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol 2014; 32 (13) 1302-1308
- 23 Husain A, Wang YV, Frederiksen R. et al. Independent radiologic review of AURELIA, a phase 3 trial of bevacizumab (BV) plus chemotherapy (CT) for platinum-resistant recurrent ovarian cancer (OC). Paper presented at: ASCO Annual Meet; 2014
- 24 Mullen MM, Kuroki LM, Thaker PH. Novel treatment options in platinum-sensitive recurrent ovarian cancer: a review. Gynecol Oncol 2019; 152 (02) 416-425
- 25 Parmar MK, Ledermann JA, Colombo N. et al; ICON and AGO Collaborators. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 2003; 361 (9375): 2099-2106
- 26 Pfisterer J, Plante M, Vergote I. et al; AGO-OVAR, NCIC CTG, EORTC GCG. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol 2006; 24 (29) 4699-4707
- 27 Garzon S, Laganà AS, Casarin J. et al. Secondary and tertiary ovarian cancer recurrence: what is the best management?. Gland Surg 2020; 9 (04) 1118-1129
- 28 Aghajanian C, Blank SV, Goff BA. et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 2012; 30 (17) 2039-2045
- 29 Aghajanian C, Nycum LR, Goff B. et al. Updated overall survival analysis in OCEANS, a randomized phase 3 trial of gemcitabine (G), carboplatin (C) and bevacizumab (BV) or placebo (PL) followed by BV or PL in platinum sensitive recurrent epithelial ovarian (ROC),primary peritoneal (PPC) or fallopian tube cancer. Ann Oncol 2012; 23 (Suppl. 09) 9319
- 30 Coleman RL, Brady MF, Herzog TJ. 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. Lancet Oncol 2017; 18 (06) 779-791
- 31 Geenen JJJ, Linn SC, Beijnen JH, Schellens JHM. PARP inhibitors in the treatment of triple-negative breast cancer. Clin Pharmacokinet 2018; 57 (04) 427-437
- 32 Pignata S, Lorusso D, Joly F. et al; MITO16b/MANGO–OV2/ENGOT–ov17 Investigators. Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-based doublet alone in patients with platinum-sensitive ovarian cancer: a randomised, phase 3 trial. Lancet Oncol 2021; 22 (02) 267-276
- 33 Ray-Coquard I, Mirza MR, Pignata S, Walther A, Romero I, du Bois A. Therapeutic options following second-line platinum-based chemotherapy in patients with recurrent ovarian cancer: comparison of active surveillance and maintenance treatment. Cancer Treat Rev 2020; 90: 102107
- 34 DiSilvestro P, Alvarez Secord A. Maintenance treatment of recurrent ovarian cancer: is it ready for prime time?. Cancer Treat Rev 2018; 69: 53-65
- 35 Advani SH, Doval DC, Koppikar SB. et al. Use of bevacizumab in advanced ovarian cancer: consensus from an expert panel oncologists. Indian J Gynecol Oncology 2021; 19: article no. 25
- 36 Hanzlikova H, Gittens W, Krejcikova K, Zeng Z, Caldecott KW. Overlapping roles for PARP1 and PARP2 in the recruitment of endogenous XRCC1 and PNKP into oxidized chromatin. Nucleic Acids Res 2017; 45 (05) 2546-2557
- 37 Rose M, Burgess JT, O'Byrne K, Richard DJ, Bolderson E. PARP inhibitors: clinical relevance, mechanisms of action and tumor resistance. Front Cell Dev Biol 2020; 8: 564601
- 38 Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011; 474 (7353): 609-615
- 39 Alsop K, Fereday S, Meldrum C. et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol 2012; 30 (21) 2654-2663
- 40 Dann RB, DeLoia JA, Timms KM. et al. BRCA1/2 mutations and expression: response to platinum chemotherapy in patients with advanced stage epithelial ovarian cancer. Gynecol Oncol 2012; 125 (03) 677-682
- 41 Pujade-Lauraine E, Ledermann JA, Selle F. et al; SOLO2/ENGOT-Ov21 investigators. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2017; 18 (09) 1274-1284
- 42 Mirza MR, Monk BJ, Herrstedt J. et al; ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016; 375 (22) 2154-2164
- 43 Coleman RL, Oza AM, Lorusso D. et al; ARIEL3 investigators. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 390 (10106): 1949-1961
- 44 Sieh W, Köbel M, Longacre TA. et al. Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study. Lancet Oncol 2013; 14 (09) 853-862
- 45 Langdon SP, Gourley C, Gabra H, Stanley B. Endocrine therapy in epithelial ovarian cancer. Expert Rev Anticancer Ther 2017; 17 (02) 109-117
- 46 Paleari L, Gandini S, Provinciali N, Puntoni M, Colombo N, DeCensi A. Clinical benefit and risk of death with endocrine therapy in ovarian cancer: a comprehensive review and meta-analysis. Gynecol Oncol 2017; 146 (03) 504-513
- 47 Stanley B, Hollis RL, Nunes H. et al. Endocrine treatment of high grade serous ovarian carcinoma; quantification of efficacy and identification of response predictors. Gynecol Oncol 2019; 152 (02) 278-285
- 48 Coleman RL, Spirtos NM, Enserro D. et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med 2019; 381 (20) 1929-1939
- 49 Du Bois A, Sehouli J, Vergote I. et al. Randomized phase III study to evaluate the impact of secondary cytoreductive surgery in recurrent ovarian cancer: final analysis of AGO DESKTOP III/ENGOT-ov20. J Clin Oncol 2020; 38: 6000
- 50 Shi T, Zhu J, Feng Y. et al. Secondary cytoreduction followed by chemotherapy versus chemotherapy alone in platinum-sensitive relapsed ovarian cancer (SOC-1): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2021; 22 (04) 439-449
- 51 Petrillo M, De Iaco P, Cianci S. et al. Long-term survival for platinum-sensitive recurrent ovarian cancer patients treated with secondary cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC). Ann Surg Oncol 2016; 23 (05) 1660-1665
- 52 Le Brun JF, Campion L, Berton-Rigaud D. et al. Survival benefit of hyperthermic intraperitoneal chemotherapy for recurrent ovarian cancer: a multi-institutional case control study. Ann Surg Oncol 2014; 21 (11) 3621-3627
- 53 Kurman RJ. Origin and molecular pathogenesis of ovarian high-grade serous carcinoma. Ann Oncol 2013; 24 (Suppl. 10) x16-x21
- 54 Kurman RJ, Shih IeM. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer–shifting the paradigm. Hum Pathol 2011; 42 (07) 918-931
- 55 Kurman RJ, Shih IeM. The dualistic model of ovarian carcinogenesis: revisited, revised, and expanded. Am J Pathol 2016; 186 (04) 733-747
- 56 Kurnit KC, Fleming GF, Lengyel E. Updates and new options in advanced epithelial ovarian cancer treatment. Obstet Gynecol 2021; 137 (01) 108-121
- 57 Singh T, Neal AS, Moatamed NA, Memarzadeh S. Exploring the potential of drug response assays for precision medicine in ovarian cancer. Int J Mol Sci 2020; 22 (01) 305
- 58 Mirza MR, Åvall Lundqvist E, Birrer MJ. et al; AVANOVA investigators. Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial. Lancet Oncol 2019; 20 (10) 1409-1419
- 59 Raza Mirza M, Nyvang G-B, Lund B. et al. Final survival analysis of NSGO-AVANOVA2/ENGOT-OV24: combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer—a randomized controlled chemotherapy-free study. J Clin Oncol 2020; 38 (Suppl. 15) 6012
- 60 Penson RT, Valencia RV, Cibula D. et al. Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): a randomized phase III trial. J Clin Oncol 2020; 38 (11) 1164-1174
- 61 Moore KN, Oza AM, Colombo N. et al. Phase III, randomized trial of mirvetuximab soravtansine versus chemotherapy in patients with platinum-resistant ovarian cancer: primary analysis of FORWARD I. Ann Oncol 2021; 32 (06) 757-765
- 62 O'Malley DM, Matulonis UA, Birrer MJ. et al. Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol 2020; 157 (02) 379-385
- 63 Lheureux S, Cristea MC, Bruce JP. et al. Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 2021; 397 (10271): 281-292
- 64 Konstantinopoulos PA, Cheng SC, Wahner Hendrickson AE. et al. Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol 2020; 21 (07) 957-968
- 65 Zamarin D, Burger RA, Sill MW. et al. Randomized phase II trial of nivolumab versus nivolumab and ipilimumab for recurrent or persistent ovarian cancer: an NRG Oncology Study. J Clin Oncol 2020; 38 (16) 1814-1823
- 66 Zsiros E, Lynam S, Attwood KM. et al. Efficacy and safety of pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide in the treatment of recurrent ovarian cancer: a phase 2 nonrandomized clinical trial. JAMA Oncol 2021; 7 (01) 78-85
- 67 Harter P, Pautier P, Van Nieuwenhuysen E. et al. Atezolizumab in combination with bevacizumab and chemotherapy versus bevacizumab and chemotherapy in recurrent ovarian cancer - a randomized phase III trial (AGO-OVAR 2.29/ENGOT-ov34). Int J Gynecol Cancer 2020; 30 (12) 1997-2001
- 68 Perrone MG, Luisi O, De Grassi A, Ferorelli S, Cormio G, Scilimati A. Translational theragnosis of ovarian cancer: where do we stand?. Curr Med Chem 2020; 27 (34) 5675-5715
- 69 da Cunha Colombo Bonadio RR, Fogace RN, Miranda VC, Diz MDPE. Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management. Clinics (São Paulo) 2018; 73 (Suppl. 01) e450s
- 70 Lee YC, Jivraj N, O'Brien C. et al. Malignant bowel obstruction in advanced gynecologic cancers: an updated review from a multidisciplinary perspective. Obstet Gynecol Int 2018; 1867238
- 71 Kipps E, Tan DS, Kaye SB. Meeting the challenge of ascites in ovarian cancer: new avenues for therapy and research. Nat Rev Cancer 2013; 13 (04) 273-282
- 72 Perroud HA, Scharovsky OG, Rozados VR, Alasino CM. Clinical response in patients with ovarian cancer treated with metronomic chemotherapy. Ecancermedicalscience 2017; 11: 723
- 73 André N, Carré M, Pasquier E. Metronomics: towards personalized chemotherapy?. Nat Rev Clin Oncol 2014; 11 (07) 413-431
- 74 Garcia AA, Hirte H, Fleming G. et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol 2008; 26 (01) 76-82
- 75 Gulia S, Ghosh J, Bajpai J. et al. Pazopanib and oral cyclophosphamide in women with platinum-resistant or -refractory epithelial ovarian cancer. JCO Glob Oncol 2020; 6: 542-547
- 76 Ledermann JA, Raja FA, Fotopoulou C, Gonzalez-Martin A, Colombo N, Sessa C. ESMO Guidelines Working Group. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24 (Suppl. 06) vi24-vi32
- 77 Dunton CJ. New options for the treatment of advanced ovarian cancer. Semin Oncol 1997; 24 (1, suppl 5): S5-S2, S5–S11
- 78 Wiltshaw E, Kroner T. Phase II study of cis-dichlorodiammineplatinum(II) (NSC-119875) in advanced adenocarcinoma of the ovary. Cancer Treat Rep 1976; 60 (01) 55-60
- 79 Lambert HE, Berry RJ. High dose cisplatin compared with high dose cyclophosphamide in the management of advanced epithelial ovarian cancer (FIGO stages III and IV): report from the North Thames Cooperative Group. Br Med J (Clin Res Ed) 1985; 290 (6472): 889-893
- 80 A'Hern RP, Gore ME. Impact of doxorubicin on survival in advanced ovarian cancer. J Clin Oncol 1995; 13 (03) 726-732
- 81 McGuire WP, Hoskins WJ, Brady MF. et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996; 334 (01) 1-6
- 82 Piccart MJ, Bertelsen K, James K. et al. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 2000; 92 (09) 699-708
- 83 Siddik ZH. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 2003; 22 (47) 7265-7279
- 84 Damia G, Imperatori L, Stefanini M, D'Incalci M. Sensitivity of CHO mutant cell lines with specific defects in nucleotide excision repair to different anti-cancer agents. Int J Cancer 1996; 66 (06) 779-783