Advertisement

Is there a “low-risk” patient population in advanced epithelial ovarian cancer?: a critical analysis

      Ovarian cancer is the leading cause of gynecologic cancer–related death in the United States. Historically, studies have demonstrated that ovarian cancer is a heterogeneous disease with several patient and oncologic characteristics, including BRCA status and residual disease at surgery, known to be predictive of clinical outcomes. However, during the last decade, the discovery and approval of bevacizumab and poly(adenosine diphosphate-ribose) polymerase inhibitors have moved the frontline treatment paradigm beyond platinum-doublet therapy for women with advanced ovarian cancer. Subsequently, investigators have sought to assess the therapeutic efficacy of these agents in women who are considered “high” risk and “low” risk to determine which patients may benefit the most from aggressive therapy and in whom additional treatment may be avoided.
      We reviewed historic and contemporary definitions of “high-risk” and “low-risk” ovarian cancer and how this has been incorporated into the subset analyses of randomized, clinical trials of therapeutic agents, including bevacizumab and poly(adenosine diphosphate-ribose) polymerase inhibitors. Next, we provided an in-depth discussion of landmark trials for frontline maintenance therapy with bevacizumab and/or poly(adenosine diphosphate-ribose) polymerase inhibitors, focusing on the impact of treatment efficacy according to a “high-risk” and “low-risk” paradigm. Furthermore, we highlighted that recent data have challenged this dichotomous classification, notably from the Gynecologic Oncology Group-0218, ICON7, SOLO-1, and PAOLA-1 trials. Although some studies have suggested that certain populations of women with advanced ovarian cancer may have a more favorable prognosis and be considered “low risk,” the risk of progression and death remains unacceptably high in all women. Furthermore, in many cases, those considered the lowest risk have the most treatment benefit from maintenance therapy with poly(adenosine diphosphate-ribose) polymerase inhibitors and/or bevacizumab. From these data, we have advocated that virtually all women with advanced ovarian cancer are high risk and that the use of our most effective therapies in the frontline setting holds promise for potentially curing more patients. Lastly, we critically discuss the practice of using subanalyses in clinical trials, with emphasis that although this practice is important for hypothesis generation, caution must be taken before accepting findings from subanalyses as actual treatment effects.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Siegel R.L.
        • Miller K.D.
        • Jemal A.
        Cancer statistics, 2020.
        CA Cancer J Clin. 2020; 70: 7-30
        • Heintz A.P.
        • Odicino F.
        • Maisonneuve P.
        • et al.
        Carcinoma of the ovary. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer.
        Int J Gynaecol Obstet. 2006; 95: S161-S192
        • Rose P.G.
        • Java J.J.
        • Salani R.
        • et al.
        Nomogram for predicting individual survival after recurrence of advanced-stage, high-grade ovarian carcinoma.
        Obstet Gynecol. 2019; 133: 245-254
        • Moore K.
        • Colombo N.
        • Scambia G.
        • et al.
        Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer.
        N Engl J Med. 2018; 379: 2495-2505
        • Ray-Coquard I.
        • Pautier P.
        • Pignata S.
        • et al.
        Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.
        N Engl J Med. 2019; 381: 2416-2428
        • Coleman R.L.
        • Fleming G.F.
        • Brady M.F.
        • et al.
        Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer.
        N Engl J Med. 2019; 381: 2403-2415
        • Burger R.A.
        • Brady M.F.
        • Bookman M.A.
        • et al.
        Incorporation of bevacizumab in the primary treatment of ovarian cancer.
        N Engl J Med. 2011; 365: 2473-2483
        • Tewari K.S.
        • Burger R.A.
        • Enserro D.
        • et al.
        Final overall survival of a randomized trial of bevacizumab for primary treatment of ovarian cancer.
        J Clin Oncol. 2019; 37: 2317-2328
        • Ferriss J.S.
        • Java J.J.
        • Bookman M.A.
        • et al.
        Ascites predicts treatment benefit of bevacizumab in front-line therapy of advanced epithelial ovarian, fallopian tube and peritoneal cancers: an NRG Oncology/GOG study.
        Gynecol Oncol. 2015; 139: 17-22
        • Perren T.J.
        • Swart A.M.
        • Pfisterer J.
        • et al.
        A phase 3 trial of bevacizumab in ovarian cancer.
        N Engl J Med. 2011; 365: 2484-2496
        • Oza A.M.
        • Cook A.D.
        • Pfisterer J.
        • et al.
        Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial.
        Lancet Oncol. 2015; 16: 928-936
        • Winter 3rd, W.E.
        • Maxwell G.L.
        • Tian C.
        • et al.
        Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group study.
        J Clin Oncol. 2007; 25: 3621-3627
        • Hoskins W.J.
        • Bundy B.N.
        • Thigpen J.T.
        • Omura G.A.
        The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study.
        Gynecol Oncol. 1992; 47: 159-166
        • Coleman R.L.
        • Burger R.A.
        • Brady M.F.
        • et al.
        Analysis of survivorship in high-risk patients treated on GOG-218.
        Gynecol Oncol. 2013; 130: e112-e113
        • Poveda A.
        • Floquet A.
        • Ledermann J.A.
        • et al.
        Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial.
        Lancet Oncol. 2021; 22: 620-631
        • Pujade-Lauraine E.
        • Ledermann J.A.
        • Selle F.
        • et al.
        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: 1274-1284
        • Ledermann J.
        • Harter P.
        • Gourley C.
        • et al.
        Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.
        N Engl J Med. 2012; 366: 1382-1392
        • Coleman R.L.
        • Oza A.M.
        • Lorusso D.
        • et al.
        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: 1949-1961
        • González-Martín A.
        • Pothuri B.
        • Vergote I.
        • et al.
        Niraparib in patients with newly diagnosed advanced ovarian cancer.
        N Engl J Med. 2019; 381: 2391-2402
        • Bradley W.
        • Moore K.
        • Colombo N.
        • et al.
        Maintenance olaparib for patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation: 5-year follow-up from SOLO1.
        Gynecol Oncol. 2021; 162: S25-S26
        • Banerjee S.
        • Moore K.N.
        • Colombo N.
        • et al.
        811MO Maintenance olaparib for patients (pts) with newly diagnosed, advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): 5-year (y) follow-up (f/u) from SOLO1.
        Ann Oncol. 2020; 31: S613
        • Armstrong D.K.
        • Alvarez R.D.
        • Bakkum-Gamez J.N.
        • et al.
        Ovarian cancer, version 2.2020, NCCN Clinical Practice Guidelines in Oncology.
        J Natl Compr Canc Netw. 2021; 19: 191-226
        • DiSilvestro P.
        • Colombo N.
        • Scambia G.
        • et al.
        Efficacy of maintenance olaparib for patients with newly diagnosed advanced ovarian cancer with a BRCA mutation: subgroup analysis findings from the SOLO1 trial.
        J Clin Oncol. 2020; 38: 3528-3537
        • Colombo N.
        • Bradley W.
        • Moore K.
        • et al.
        Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: subgroup analysis by risk in the phase III SOLO1 study.
        Int J Gynecol Cancer. 2020; 30 (A76–7): 392
        • Alvarez Secord A.
        • O’Malley D.M.
        • Sood A.K.
        • Westin S.N.
        • Liu J.F.
        Rationale for combination PARP inhibitor and antiangiogenic treatment in advanced epithelial ovarian cancer: a review.
        Gynecol Oncol. 2021; 162: 482-495
        • Liu J.F.
        • Barry W.T.
        • Birrer M.
        • et al.
        Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer.
        Ann Oncol. 2019; 30: 551-557
        • Liu J.F.
        • Brady M.F.
        • Matulonis U.A.
        • et al.
        A phase III study comparing single-agent olaparib or the combination of cediranib and olaparib to standard platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancer.
        J Clin Oncol. 2020; 38: 6003
        • Pautier P.
        • Harter P.
        • Pisano C.
        • et al.
        Progression-free survival (PFS) and second PFS (PFS2) by disease stage in patients (pts) with homologous recombination deficiency (HRD)-positive newly diagnosed advanced ovarian cancer receiving bevacizumab (bev) with olaparib/placebo maintenance in the phase III PAOLA-1/ENGOT-ov25 trial.
        J Clin Oncol. 2021; 39: 5514
        • Ray-Coquard I.
        • Cibula D.
        • Mirza M.R.
        • et al.
        Final results from GCIG/ENGOT/AGO-OVAR 12, a randomised placebo-controlled phase III trial of nintedanib combined with chemotherapy for newly diagnosed advanced ovarian cancer.
        Int J Cancer. 2020; 146: 439-448