Abstract
Ovarian cancer, which ranks fifth in cancer deaths among women, is the most lethal gynecologic malignancy. Epithelial ovarian cancer (EOC) is the most common histologic type, with the 5-year survival for all stages estimated at 45.6%. This rate increases to more than 70% in the minority of patients who are diagnosed at an early stage, but declines to 35% in the vast majority of patients diagnosed at advanced stage. Recurrent EOC is incurable. Platinum sensitivity (or lack thereof) is a major determinant of prognosis. The current standard treatment is primary surgery followed by platinum-based chemotherapy. In recurrent platinum-resistant/platinum-refractory EOC, sequential single-agent salvage chemotherapy is superior to multiagent chemotherapy. Multiagent regimens increase toxicity without clear benefit; however, no preferred sequence of single agents is recommended. The impact of targeted therapies and immunotherapies on progression-free survival and overall survival, which remains dismal, is under active investigation. Currently, clinical trials offer the best hope for the development of a new treatment paradigm in this recalcitrant disease.
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Introduction
Epithelial ovarian cancer (EOC), of which serous is the predominant histology [1], is primarily a disease of postmenopausal women and is the most lethal of all gynecologic malignancies. Annually, EOC is diagnosed in greater than 22,000 women in the USA with more than 14,000 deaths being attributable to this disease [2, 3]. Based on International Federation of Gynecologists and Obstetricians (FIGO) criteria, EOC is surgically staged (Fig. 1).
Following surgical cytoreduction or staging, the treatment of choice for some stage I and all stage II–IV cancers is carboplatin–paclitaxel combination chemotherapy [4]. This can be administered as adjuvant and/or neoadjuvant chemotherapy depending on the patients’ ability to undergo successful cytoreductive surgery [5].
The origins of ovarian cancer are unclear. Continuous or “incessant” ovulation, uninterrupted by pregnancy or oral contraceptive use, was once thought to be the main etiologic factor [6]. However, more recent studies suggest a fallopian tube origin of serous ovarian cancers [6, 7]. Genetic factors such as family history, mismatch repair gene abnormality (Lynch syndrome) and BRCA status also contribute to an individual woman’s risk.
The chief reason for the high mortality rate from OC is late presentation with 75% of cases presenting with advanced stage disease [8]. OC has insidious onset as well as non-specific signs and symptoms. These include pelvic or abdominal pain, early satiety, urinary frequency, constipation and abdominal distension [9]. Delayed detection is also a function of a lack of an accepted general screening test. For these reasons, OC is referred to as “the whispering disease” and the “silent killer” [10, 11]. The main cause of death is metastatic growth that impinges on visceral organ function. After what may have been initially exquisite sensitivity to standard platinum chemotherapies, EOC recurs in the majority of patients and progressive resistance to treatment develops leading to exhaustion of available treatment options [12]. Therefore, the emphasis of treatment in the recurrent setting is palliative, with focus on symptom control, prolongation of survival and quality of life improvement.
Since 1990, the speed of tumor recurrence during a chemotherapy-free interval (CFI) after carboplatin–paclitaxel, empirically divided into 6-month blocks of time, forms the basis for classification of the disease, prediction of clinical course and subsequent management. Per Gynecologic Oncology Group (GOG), classification is as follows (Fig. 2):
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Refractory Relapse during or within 4 weeks following platinum-based chemotherapy
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Resistant Relapse under 6 months from last platinum therapy as platinum resistant
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Partially platinum sensitive Relapse between 6 and 12 months
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Platinum sensitive Relapse after more than 12 months
Platinum-resistant and platinum-refractory disease, which is uniformly fatal [13], carries the worst prognosis compared with platinum-sensitive disease. Median OS decreases over subsequent lines of therapy [14] so that by the fifth relapse, according to Hanker et al. [15] the OS is 5 months (although platinum sensitivity is not specified).
According to NCI Surveillance, Epidemiology and End Results (SEER) statistics, the lifetime risk of developing ovarian cancer is 1.3% [16], which meets requirements for orphan drug designation. Since one quarter (25%) of these patients are platinum resistant [17] (although all patients with recurrent disease eventually develop platinum resistance), the prevalence for platinum-resistant/platinum-refractory ovarian cancer (PRR-ROC) is approximately 50,000 patients, which fits the definition of a rare disease since fewer than 200,000 patients are affected. Current management and treatment options for platinum-resistant and platinum-refractory recurrent ovarian cancer are limited and discussed herein. Accordingly, this review is limited by a paucity of randomized studies in platinum-resistant and platinum-refractory recurrent ovarian cancer.
Treatment options for recurrent resistant or refractory disease
Chemotherapy
While no standard second-line treatment stands out as superior with regard to safety or efficacy, chemotherapy options are non-platinum monotherapy, including paclitaxel, docetaxel, pegylated liposomal doxorubicin (PLD), topotecan and gemcitabine [18]. Overall response rates range from 10 to 35% in phase II studies with relatively short-lived responses of less than 8 months [19]. Combination chemotherapy has been shown to increase toxicity without a clear survival benefit over sequential monotherapy.
Taxanes
In phase II and III trials, single-agent paclitaxel has shown activity as a salvage therapy in recurrent refractory/resistant disease, resulting in objective responses of 22–30% [20]. Low-dose weekly administration of paclitaxel results in equal (PFS), but reduced overall toxicity compared to every-3-week dose administration [21]. Single-agent docetaxel is more toxic than paclitaxel, as grade 4 neutropenia is reported in 75% of docetaxel-treated patients [22].
Pegylated liposomal doxorubicin (PLD)
Polyethylene glycol (PEG)–liposomal doxorubicin is a formulation of the anthracycline doxorubicin encapsulated in PEG-coated liposomes [23]. Because PLD is infused once every 28 days, hematologic and gastrointestinal (GI) toxicity is decreased; cardiomyopathy is also decreased up to a cumulative dose of 440–840 mgs/m2 [24]. In the trial supporting its approval in ovarian cancer, in which PLD was compared with topotecan in platinum-sensitive and platinum-resistant recurrent disease, PLD was associated with an 18% decreased risk of death and lower rates of neutropenia, anemia and thrombocytopenia [25]. However, higher rates of hand–foot syndrome and stomatitis were observed.
Topotecan
The activity of the topoisomerase I inhibitor, topotecan, in platinum-resistant recurrent ovarian cancer is similar to paclitaxel and PLD; however, myelosuppression, particularly neutropenia, limits its use [26]. In a large, multicenter, phase II study, topotecan demonstrated response rates of 5.9% in patients with recurrent resistant disease and 17.8% in patients with recurrent sensitive disease [27]. A phase III randomized trial of topotecan versus paclitaxel in recurrent disease showed similar response rates (20.5% for topotecan and 13.2% for paclitaxel). Median survival time was 61 weeks for topotecan and 43 weeks for paclitaxel (the difference was non-significant; P = 0.515) [28]. No cross-resistance was observed after crossover for progressive disease with response rates of 13.1% for topotecan and 10.2% for paclitaxel [29].
Gemcitabine
In twelve monotherapy studies with 411 mostly platinum-resistant patients, the overall response rates to the nucleoside antimetabolite, gemcitabine ranged from 14 to 22% with a median duration of response from 4 to 10.6 months. Grade 3 or 4 neutropenia was the most common dose-limiting adverse event, which underscores the relative contraindication to treatment with multiagent chemotherapy in the setting of platinum-resistant recurrence, given the increased rates of toxicity [30].
Others
Oral etoposide at a dose of 50 mgs/m2 has the advantage of improved convenience over I.V. administration but is disadvantaged by predominant myelosuppressive effects and a modest response rate of 25% [31]. Single-agent ifosfamide and cyclophosphamide have limited neoplastic efficacy (response rate of 10–15%) with significant renal, CNS or bladder toxicities [32]. The response rate of vinorelbine at a dose of 25–30 mgs/m2 on a 3 weekly schedule is 15–20% with the caveat that it has not been associated with improved quality of life or performance status [33]. A summary of salvage chemotherapy options is shown in Table 1.
Hormonal therapy
Antiestrogens, aromatase inhibitors and gonadotropin releasing hormone analogs have been evaluated in small randomized trials and while the correlation between hormone receptor positivity and response is inconsistent (even though the presence of estrogen and progesterone receptors would be expected to correlate with response to hormonal therapy) and benefits over chemotherapy unclear, these agents have the advantage of low toxicity and high patient acceptance. In the 1991 GOG study with 105 recurrent ovarian cancer patients including those with platinum-sensitive and platinum-resistant cancer, the complete response rate to second-line oral tamoxifen 20 mg/d was 17% and the disease control rate (DCR) including stable disease (SD) was 55% [34]. Overall response rates are not improved significantly by the addition of tamoxifen to cytotoxic agents [35].
Clinical studies with letrozole have provided conflicting results: one study showed an objective response of 15%; the other showed no objective responses [36].
Because hormonal therapy may have some activity in a subset of endocrine-sensitive patients, and is generally a far less toxic treatment than chemotherapy, it continues to be administered in the resistant/refractory setting, despite inconsistent and unclear efficacy data.
Targeted therapies
Bevacizumab
Bevacizumab, the humanized monoclonal antibody against the vascular endothelial growth factor (VEGF), is the most extensively studied targeted agent in EOC since angiogenesis is an important hallmark of the disease. The ICON-7 and GOG-218 phase III trials established bevacizumab as a first-line treatment in platinum-sensitive ovarian cancer [37, 38]. Bevacizumab-related toxicities included hypertension >grade 2 and bowel perforation. Several phase II trials, which have evaluated bevacizumab specifically in platinum-resistant or refractory patients, demonstrated high rates of disease stabilization, an important endpoint in this population, where prolonged stable disease promotes improved quality of life and management as a chronic illness [39].
The FDA-approved bevacizumab at a dose of 10 mg/kg every 2 weeks or 15 mgs/kg every 3 weeks in combination with topotecan (days 1, 8, 15 every 4 weeks), pegylated liposomal doxorubicin (every 4 weeks) or paclitaxel (days 1, 8, 15, 22 every 4 weeks) on the basis of results from the phase III AURELIA trial, which randomized 361 platinum-resistant and platinum-refractory recurrent patients to bevacizumab combination therapy or these three single chemotherapy agents (i.e., topotecan, PLD and paclitaxel) alone. The combination with bevacizumab resulted in an ORR (RECIST) of 27.3% compared to 11.8% for chemotherapy alone (P = 0.001), and a median PFS of 6.7 months versus 3.4 months (HR 0.48, 95% CI 0.38–0.60, P < 0.001) without a significant OS improvement (combination with bevacizumab median OS of 16.6 months versus 13.3 months for chemotherapy alone, HR 0.85, 95% CI 0.66–1.08) [40]. Based on an exploratory analysis, maximum benefit was seen with paclitaxel.
PARP inhibitors
Through the concept of tumor-specific synthetic lethality, whereby the potency of PARP inhibition increases in the presence of a preexisting BRCA1/2 mutation, PARP inhibitors have demonstrated single-agent activity in BRCA-mutated ovarian cancer; in a multicenter phase II trial, which enrolled 193 patients with platinum-resistant ovarian cancer, the response rate was 31.1% (95% CI, 24.6–38.1%) and the rate of stable disease at 8 weeks or greater was 40% (95% CI, 33.4–47.7%). Median PFS and overall survival (OS) were 7.0 months and 16.6 months, respectively. Partially on this basis, the FDA-approved olaparib (400 mg twice daily) as monotherapy for patients with germline BRCA-mutated advanced ovarian cancer treated with 3 or more prior lines of chemotherapy [41]. In addition, rucaparib (Rubraca) was approved in 2016 for germline or somatic BRAC mutations treated with two or more chemotherapies. Accordingly, the race is on with several other PARP inhibitors, including niraparib, talazoparib and veliparib all currently in late phase clinical trial development [42].
Epigenetic inhibitors
The best characterized epigenetic therapies, which target proteins or pathways that tend to silence gene expression, are the DNMT inhibitors such as the FDA-approved azacitidine and decitabine and the HDAC inhibitors such as the FDA-approved vorinostat [also known as suberoylanilide hydroxamic acid (SAHA)], romidepsin, panobinostat and belinostat. Epigenetic therapies offer intriguing potential in resistant/refractory ovarian cancer through the amelioration of epigenetic repression of the genes that are responsible for chemoresistance, resulting in reversal of the resistant phenotype and sensitization/resensitization to first-line platinum doublets. A phase Ib–IIa study of decitabine and carboplatin in 29 platinum-refractory or platinum-resistant ovarian cancer patients demonstrated a disease control rate of 34% with one complete response, three partial responses, and ten stable diseases. However, these epigenetic therapies may maximally resensitize to platinum doublets when they are administered prior to rather than concomitantly with chemotherapy on the premise that it takes time (weeks or even months) to activate silenced genes and reverse chemoresistance [43]. However, this application will require more favorable safety profiles for both HDACs and DNMT inhibitors, as they are associated with toxicities, likely owing to their relative non-specificity [44].
Others
Several targeted therapies including pertuzumab, cediranib, gefitinib and sunitinib are under clinical investigation; however, the “genomic chaos” (i.e., the large number of chromosomal alterations), which characterizes ovarian tumors [45] and which worsens over time due to therapy selective pressures, raises doubts that targeted agents directed at only a few mutations will significantly alter outcomes, especially in resistant or refractory disease. To date, none of these agents have unequivocally demonstrated efficacy.
Immunotherapies
The rationale for the use of immunotherapy in ovarian cancer is that the presence of T cells in the tumor microenvironment correlates with improved progression-free and overall survival, while the presence of regulatory T cells and T cell inhibitory molecules is associated with poorer outcomes [46]. Vaccines, oncolytic viruses, immune checkpoint blockade and adoptive T cell therapy have been associated with clinical activity in small numbers of patients. While these strategies provide a platform for future progress, only FDA-approved checkpoint inhibitors are briefly covered below since preliminary analysis suggests that responses from them may be higher in patients with fewer prior lines of chemotherapy and platinum-sensitive disease [47].
Despite the success of “antibody-based” therapy in ovarian cancer with bevacizumab, the clinical activity reported with checkpoint inhibitors has been modest at best. In a phase II study of the anti-PD-1 antibody, nivolumab, the overall response rate was 15% (3 of 20 patients) with a median PFS of 3.5 months [48]. In another trial with nivolumab 2/8 patients (25%) with resistant ovarian cancer experienced a complete response [49]. Similar response rates (3 of 20 patients; 15%) were reported in a phase IB study of patients with PD-L1-positive ovarian cancer treated with the anti-PD-1 inhibitor, pembrolizumab [50]. In a phase 1b study of 75 patients with platinum-resistant or chemotherapy-refractory ovarian cancer regardless of PD-L1 expression treated with the PD-L1 antagonist, avelumab, the overall response rate was 10.7%, and the DCR was 54.7%, with no complete responses, 8 partial responses and 33 with stable disease [51].
Conclusion
As an invariably fatal disease, with complex mechanisms of resistance that are incompletely understood [52], the current primary intent of treatment for platinum-resistant/platinum-refractory ovarian cancer is to preserve quality of life and palliate symptoms with sequential single-agent chemotherapy. In contrast to the substantial number of innovative agents approved to treat a variety of solid tumors and hematologic malignancies over the past decade, advances in ovarian cancer, particularly platinum-resistant/platinum-refractory ovarian cancer, have been few and far between with a relative paucity of effective new drugs or strategies in the current pipeline.
Molecularly targeted therapies are an attractive alternative or adjunct to traditional chemotherapy. Bevacizumab and olaparib are currently FDA-approved and rucaparib was granted accelerated approval for advanced BRCA-mutated ovarian cancer treated with ≥2 chemotherapies [53]. In addition, multiple promising trials are underway (or will soon be underway), for other PARP inhibitors alone or in combination, which have the potential to improve treatment outcomes. Other potentially promising strategies include: the use of epigenetic therapies to restore/reverse platinum sensitivity and therefore restart end-stage patients on first-line treatment and immunotherapies to incite antitumor T-cell responses.
However, optimism remains tempered by the formidable therapeutic challenge of this recalcitrant disease subtype with poorly understood pharmacological mechanisms of resistance and a track record of failure with previous clinical candidates. Ultimately, vanquishing recurrent EOC will require a concerted effort to tackle platinum resistance with clinical trials featuring innovative strategies and therapies.
References
Cont NT, Ferrero A, Peccatori FA, et al. Medical treatment of early stage and rare histological variants of epithelial ovarian cancer. ecancermedicalscience. 2015;9:584.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.
National Institutes of Health. National Cancer Institute. Surveillance, epidemiology, and end results program. Cancer Stat Facts: Ovarian cancer https://seer.cancer.gov/statfacts/html/ovary.html. Accessed 19 Jan 2017.
Kaye S. Management of partially platinum-sensitive relapsed ovarian cancer. Eur J Cancer. 2008;6(Suppl):16–21.
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed 19 Jan 2017.
Look KY. Epidemiology, etiology, and screening of ovarian cancer. In: Rubin SC, Sutton GP, editors. Ovarian cancer. Philadelphia: Lippincott, Williams and Wilkins; 2001. p. 168–74.
Erickson BK, Conner MG, Landen CN Jr. The role of the fallopian tube in the origin of ovarian cancer. Am J Obstet Gynecol. 2013;209(5):409–14.
Winter WE III, Maxwell GL, Tian C, Sundborg MJ, Rose GS, Rose PG, Rubin SC, Muggia F, McGuire WP, Gynecologic Oncology Group. Tumor residual after surgical cytoreduction in prediction of clinical outcome in stage IV epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2008;26(1):83.
Jayson GC, et al. Ovarian Cancer. Lancet. 2014;384(9951):1376–88.
Bankhead C, Collins C, Stokes-Lampard H, Rose P, Wilson S, Clements A, Mant D, Kehoe S, Austoker J. Identifying symptoms of ovarian cancer: a qualitative and quantitative study. BJOG. 2008;115:1008–14.
Jasen P. From the “Silent Killer” to the “Whispering Disease”: ovarian cancer and the uses of metaphor. Med Hist. 2009;53(4):489–512.
Au KK, Josahkian JA, Francis JA, Squire JA, Koti M. Current state of biomarkers in ovarian cancer prognosis. Future Oncol. 2015;11(23):3187–95.
Liu CM. Cancer of the ovary. N Engl J Med. 2005;352:1268–9.
Bamias A, Bamia C, Zagouri F, Kostouras E, Kakoyianni K, Rodolakis A, Vlahos G, Haidopoulos D, Thomakos N, Antsaklis A, Dimopoulos MA. Improved survival trends in platinum-resistant patients with advanced ovarian, fallopian or peritoneal cancer treated with first-line paclitaxel/platinum chemotherapy: the impact of novel agents. Oncology. 2013;84(3):158–65.
Hanker LC, Loibl S, Burchardi N, Pfisterer J, Meier W, Pujade-Lauraine E, Ray-Coquard I, Sehouli J, Harter P, du Bois A, AGO and GINECO study group. The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy. Ann Oncol. 2012;23(10):2605–12.
National Institutes of Health. National Cancer Institute. Surveillance, epidemiology, and end results program. Statistical summaries: cancer stat fact sheets (ovary) and cancer statistics review (CSR), 1975–2013. http://www.seer.cancer.gov/statistics/summaries.html. Accessed 19 Jan 2017.
Ushijima K. Treatment for recurrent ovarian cancer—at first relapse. J Oncol. 2010;2010:7 (Article ID 497429).
Morgan RJ Jr, Armstrong DK, Alvarez RD, Bakkum-Gamez JN, Behbakht K, Chen LM, Copeland L, Crispens MA, DeRosa M, Dorigo O, Gershenson DM, Gray HJ, Hakam A, Havrilesky LJ, Johnston C, Lele S, Martin L, Matulonis UA, O’Malley DM, Penson RT, Percac-Lima S, Pineda M, Plaxe SC, Powell MA, Ratner E, Remmenga SW, Rose PG, Sabbatini P, Santoso JT, Werner TL, Burns J, Hughes M. Ovarian Cancer, Version 1.2016, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2016;14(9):1134–63.
Markman M, Bookman MA. Second-line treatment of ovarian cancer. Oncologist. 2000;5(1):26–35.
McGuire WP, Rowinsky EK, Rosenshein NB, et al. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian adenocarcinoma. Ann Intern Med. 1989;111:273–9.
Markman M, Hall J, Spitz D, et al. Phase II trial of weekly single-agent paclitaxel in platinum/paclitaxel-refractory ovarian cancer. J Clin Oncol. 2002;20:2365–9.
Rose PG, Blessing JA, Ball HG, et al. A phase II study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2003;88:130–5.
Green AE, Rose PG. Pegylated liposomal doxorubicin in ovarian cancer. Int J Nanomedicine. 2006;1(3):229–39.
Berri G, Billingham M, Alderman E, et al. The use of cardiac biopsy to demonstrate reduced cardiotoxicity in AIDS Kaposi’s Sarcoma patients with pegylated liposomal doxorubicin. Ann Oncol. 1998;9:711–6.
Gordon AN, Tonda M, Sun S, Rackoff W. Doxil Study 30-49 Investigators. Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian cancer. Gynecol Oncol. 2004;95:1–8.
Abushahin G, Singh DK, Lurain JR, et al. Weekly topotecan for recurrent platinum resistant ovarian cancer. Gynecol Oncol. 2008;108:53–7.
Creemers GJ, Bolis G, Gore M, et al. Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: results of a large European phase II study. J Clin Oncol. 1996;14:3056–61.
ten Bokkel Huinink W, Gore M, Carmichael J, et al. Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol. 1997;15:2183–93.
Gore M, ten Bokkel Huinink W, Carmichael J, et al. Clinical evidence for topotecan-paclitaxel non-cross-resistance in ovarian cancer. J Clin Oncol. 2001;19:1893–900.
Lorusso D, Di Stefano A, Fanfani F, Scambia G. Role of gemcitabine in ovarian cancer treatment. Ann Oncol. 2006;17(Suppl 5):v188–94.
Ganghadaran SGD. Management of platinum resistant—refractory ovarian cancer: a short review. J Cancer Res Treat. 2016;4(2):32–6.
Friedlander M, Trimble E, Tinker A, et al. Clinical trials in recurrent ovarian cancer. Int J Gynecol Cancer. 2011;21:771–5.
Rothenberg ML, Liu PY, Wilczynski S, et al. Phase II trial of vinorelbine for relapsed ovarian cancer: a Southwest Oncology Group study. Gynecol Oncol. 2004;95(3):506–12.
Yokoyama Y, Mizunuma H. Recurrent epithelial ovarian cancer and hormone therapy. World J Clin Cases WJCC. 2013;1(6):187–90.
Schwartz PE, Chambers JT, Kohorn EI, Chambers SK, Weitzman H, Voynick IM, et al. Tamoxifen in combination with cytotoxic chemotherapy in advanced epithelial ovarian cancer. A prospective randomized trial. Cancer. 1989;63(6):1074–8.
Kothari R, Argenta P, Fowler J, Carter J, Shimp W. Antiestrogen therapy in recurrent ovarian cancer resulting in 28 months of stable disease: a case report and review of the literature. Arch oncol Inst Oncol Sremska Kamenica Yugosl. 2010;18(1–2):32–5.
Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365:2473–83.
Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365:2484–96.
McClung EC, Wenham RM. Profile of bevacizumab in the treatment of platinum-resistant ovarian cancer: current perspectives. Int J Women’s Health. 2016;8:59–75.
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):1302–8.
Kim G, et al. FDA approval summary: olaparib Monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin Cancer Res. 2015;21(19):4257–61.
Brown JS, Kaye SB. Yap TA.PARP inhibitors: the race is on. Br J Cancer. 2016;114(7):713–5.
Carter CA, Oronsky BT, Caroen SZ, Scicinski JJ, Degesys A, Kim MM, Oronsky AL, Lybeck H, Cabrales P, Oronsky N, Reid T, Roswarski J, Brzezniak C. RRx-001 in refractory small-cell lung carcinoma: a case report of a partial response after a third reintroduction of platinum doublets. Case Rep Oncol. 2016;9(1):171–6.
Jabbour E, Garcia-Manero G, Cornelison AM, Cortes JE, Ravandi F, Daver N, Kadia T, Teng A, Kantarjian H. The effect of decitabine dose modification and myelosuppression on response and survival in patients with myelodysplastic syndromes. Leuk Lymphoma. 2015;56(2):390–4.
Abdallah BY, Horne SD, Kurkinen M, Stevens JB, Liu G, Ye CJ, Barbat J, Bremer SW, Heng HHQ. Ovarian cancer evolution through stochastic genome alterations: defining the genomic role in ovarian cancer. Syst Biol in Reprod Med. 2014;60(1):2–13.
Coukos G, Tanyi J, Kandalaft LE. Opportunities in immunotherapy of ovarian cancer. Ann Oncol. 2016;27(Suppl 1):i11–5.
Ojalvo LS, Nichols PE, Jelovac D, Emens LA. Emerging immunotherapies in ovarian cancer. Discov Med. 2015;20(109):97–109.
Hamanishi J, Mandai M, Ikeda T, et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2015;33(34):4015–22.
Hamanishi J, Mandai M, Ikeda T, et al. Efficacy and safety of anti-PD-1 antibody (Nivolumab: BMS-936558, ONO-4538) in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2014; 32, abstract 5511, ASCO Annual Meeting.
Varga A, Piha-Paul SA, Ott PA, et al. Antitumor activity and safety of pembrolizumab in patients with PD-L1 positive advanced ovarian cancer: Interim results from a phase Ib study. J Clin Oncol. 2015;33(15 Suppl.):5510.
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.
Itamochi H, Kigawa J, Terakawa N. Mechanisms of chemoresistance and poor prognosis in ovarian clear cell carcinoma. Cancer Sci. 2008;99(4):653–8.
FDA News Release. FDA grants accelerated approval to new treatment for advanced ovarian cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm533873.htm. Accessed 19 Jan 2017.
Acknowledgements
The authors wish to thank and acknowledge Dr. Harry Lybeck, possibly the world’s longest living academic professor and physician, currently 98 years old (and counting), for his contributions to this manuscript. Having earned his M.D. and Ph.D. while serving in WWII, Dr. Lybeck climbed to the top of the academic hill but is far from over it. With 70 years of medical experience, Dr. Lybeck is the epitome of a caring, compassionate physician who prioritizes others over himself.
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Oronsky, B., Ray, C.M., Spira, A.I. et al. A brief review of the management of platinum-resistant–platinum-refractory ovarian cancer. Med Oncol 34, 103 (2017). https://doi.org/10.1007/s12032-017-0960-z
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DOI: https://doi.org/10.1007/s12032-017-0960-z