Advanced ovarian cancer: what should be the standard of care?

Antiangiogenesis, Chemotherapy, Clinical trials, Dose dense chemotherapy, Intraperitoneal chemotherapy, Ovarian cancer, Surgery J Gynecol Oncol Vol. 24, No. 1:83-91 http://dx.doi.org/10.3802/jgo.2013.24.1.83 Barbara A. Goff http://dx.doi.org/10.3802/jgo.2013.24.1.8384 www.ejgo.org tions in TP53 and have genetic instability [1-5]. High grade endometrioid tumors are similar to serous tumors but low grade endometrioid tumors often have mutations in the PI3K- CA/AKT/PTEN and Wnt/CTNNB1/Tcf pathways [2]. Mucinous tumors like colorectal tumors often have KRAS mutations [2]. Low grade serous tumors often have mutations in KRAS or BRAF [2]. Better understanding of molecular differences between the types of cancer should lead to better treatment strategies that more specifically target or exploit the abnor - malities in these pathways. Research has shown that in the setting of advanced disease response rates to chemotherapy and survival is significantly different for the specific histologic types of cancer. In studies by Mackay et al. [7] (8,704 patients from 7 GCIG randomized trials) and Winter et al. [8] (1,895 women enrolled in Gyne - cologic Oncology Group [GOG] randomized trials) in which patients with all histologic types of advanced ovarian cancer were treated with taxane/platinum combinations, the serous and endometrioid cancers had the best survival, and clear cell and mucinous had a 2-4 fold increase in death. As we have come to understand, epithelial ovarian cancer is a very heterogeneous disease. Current clinical trials are incorporating this new information and we are beginning to use treatment protocols that are histologic specific. For example, in muci - nous tumors the GOG is conducting a trial comparing the gastrointestinal (GI) regimen capecitabine and oxaliplatin +/- bevacizumab vs. paclitaxel and carboplatin +/- bevacizumab. In clear cell cancers, the GOG is evaluating the combination of paclitaxel, carboplatin and temsirolimus, an mTOR inhibitor which is Food Drug Administration (FDA) approved to treat renal cell carcinoma. In low grade serous tumors, AZD6244, a drug that blocks a protein MEK which has been shown to play a role in tumors with BRAF mutations, is also being investigated. Another successful targeted therapy has been poly (adenosine diphosphate, ADP)-ribose polymerase (PARP) inhibitors for high grade serous tumors. PARP inhibitors prevent repair of DNA damage. Because ovarian cancer cells with BRCA mutations, either germ line or somatic, also have limited ability to repair DNA damage the combination of PARP inhibition with BRCA mutation results in irreparable and lethal DNA damage. This was demonstrated clinically in a study of 65 women with high grade serous or undifferentiated ovarian cancer treated with the PARP inhibitor olaparib. Response rates of 41% were seen in women with BRCA1 or BRCA2 germline mutations but only 24% for those without germline mutations [9]. Surgery has always been the cornerstone in the treatment of ovarian cancer [10,11]. In most cases it is first required for diag- nosis, then staging for early stage disease and cytoreduction in those with advanced stage disease. Approximately 70-80% of women with ovarian, tubal and peritoneal cancers present with advanced stage disease. Although there have never been any prospective randomized trials for cytoreduction, it has been shown in numerous retrospective studies to be one of the most important prognostic factors for survival [10-18]. Over the past decade the definition of “optimal cytoreduc - tion” has changed from less than 1 cm to no visible residual disease [19-21]. Research by multiple investigators has shown that median OS in women with no residual disease will be 70 months or greater [18-21]. In a recent Cochrane analysis of the impact of residual disease on survival in women with ad- vanced ovarian cancer, the hazard ratio for death was 2.2 (95% confidence interval [CI], 1.9 to 2.54) for women with less than 1 cm as compared to women with no residual disease [22]. Therefore, the goal of every cytoreductive procedure should be to debulk the cancer to no visible disease. In addition, several studies suggest that lymphadenectomy, especially in those who have all disease resected, may improve outcomes [18]. Finally, surgical specialization has been associated with higher rates of optimal cytoreduction, appropriate surgical care and survival [23-26]. Whenever possible, a gynecologic oncologist should be involved in the surgical management of all women with ovarian cancer. In general, with gynecologic oncology involvement approximately 60-70% of patients will be able to be optimally cytoreduced using the new definition of no visible residual disease. [12,17]. Neoadjuvant chemotherapy (NACT) is an alternative to primary cytoreduction. The goal is to use chemotherapy prior to surgery to reduce perioperative morbidity and mortality and increase the likelihood of a complete surgical cytoreduc- tion [27]. A recent European Organisation for Research and Treatment of Cancer (EORTC) trial compared NACT vs. primary cytoreduction. Women with stage IIIC and IV epithelial ovar - ian, tubal and peritoneal cancer were randomized to primary debulking surgery (PDS) followed by six cycles of platin based chemotherapy vs. NACT with three cycles of platin based chemotherapy, surgery for cytoreduction and then three more cycles of chemotherapy. This study found that the NACT group had a significantly lower rate of complications, a higher rate of optimal cytoreduction to <1 cm (81% vs. 42%), but no difference in median overall survival (OS; 30 months NCAT vs. 29 months for PDS). This study has been criticized for several reasons. First, only 78% (PDS) and 88% (NACT) actually received a combination of platin and taxane based chemotherapy. In addition, in the PDS group only about 20% of patients were cytoreduced to no residual disease, which is considerably lower than what would be expected in centers of excellence [28]. Finally, median OS was only 30 months which Managing advanced ovarian cancer J Gynecol Oncol Vol. 24, No. 1:83-91 www.ejgo.org  85 is considerably less than the 60+ months expected with opti- mal cytoreduction followed by chemotherapy [19,27]. Views about NACT vary significantly between Society of Gynecologic Oncology (SGO) members and European Society of Gyneco - logic Oncology (ESGO) members. A survey of SGO members found the 82% felt there was not enough evidence to justify the use of NCAT [29]. In contrast, 70% of ESGO members felt there was sufficient evidence to recommend NCAT [30]. There are two other randomized trials that have completed enrollment and will provide additional information about the role of NACT. The first is the chemotherapy or upfront surgery (CHORUS) trial which has a similar design to the EORTC trial and is being conducted in the UK. The Japanese GOG (JGOG) is also conducting a trial comparing PDS followed by eight cycles of chemotherapy to four cycles of NCAT followed by surgery and four more cycles of chemotherapy. Once patients with advanced stage ovarian, tubal and peri - toneal cancer have undergone surgery the next choice is to decide which chemotherapy regimen to prescribe. In 1996 the GOG published the results of their landmark trial showing that patients who received cisplatin and paclitaxel had superior survival to those treated with cisplatin and cyclophosphamide [31]. This was confirmed in additional studies by EORTC [32], and since then platin and taxane have remained the standard for treating these cancers. Given the toxicity associated with the cisplatin/paclitaxel regimen, follow-up studies from GOG and Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) compared paclitaxel in combination with cisplatin or carboplatin and found that the carboplatin combination was equally effective and was better tolerated than paclitaxel and cisplatin [33,34]. An additional trial (Scottish randomized trial in ovarian cancer, SCOTROC) confirmed that docetaxel and carboplatin was equally effective as carboplatin and paclitaxel. While there was more hematologic toxicity with docetaxel, there was less neurotoxicity [35]. Currently there is no role for adding a third agent to carboplatin and paclitaxel. Phase III trials have demonstrated no improvement in survival when additional drugs (topotecan, gemcitabine, or liposomal- doxorubicin) are added to the platin/taxane backbone [19,36]. In addition, high dose chemotherapy with stem cell transplant has been evaluated and found not to have any survival benefit [37]. Finally, the concept of maintenance chemotherapy has been the study of numerous trials. Other than a single GOG trial which found an improvement in progression-free survival (PFS) but not OS for 12 months of maintenance paclitaxel chemotherapy as compared to 3 months, no other studies have found that maintenance after front-line chemotherapy improves outcomes [11,38,39]. Maintenance with biologic agents such as anti-vascular endothelial growth factor (VEGF) or PARP inhibitors has also shown improvement in PFS but not OS [40-42]. The most significant advances in improving survival with chemotherapy have been from changing the route of daily delivery and switching to a dose dense schedule of paclitaxel. In 2005 the GOG published results of GOG 172 (intravenous [IV] paclitaxel IV cisplatin vs. IV paclitaxel intraperitoneal [IP] cisplatin IP paclitaxel) [27]. In this study women who were optimally cytoreduced to less than 1 cm were randomized to one of the two groups. The OS for the IP group was 65.6 months compared to 49.7 months for the IV group. The IP arm was associated with increased toxicity and only 42% of patients in the IP arm were able to complete all 6 cycles of treatment, but quality of life was similar in both groups at 6 months after completion of treatment. Additional clinical trials have also shown improved overall survival with IP treatment [43-45], and the use of IP chemotherapy was advocated in a National Cancer Institute Clinical Alert in 2006 [46]. The other treatment strategy which has been shown to improve OS is dose dense administration of paclitaxel [47]. The JGOG randomized women with stage II-IV ovarian cancer to receive every three week paclitaxel or weekly paclitaxel, with both regimens including carboplatin administered every three weeks. This study found a significant improvement in both PFS and OS, with 5-year survival of 58.7% and 51.1% for dose dense and standard treatment arms respectively. Improvement in survival was seen for all patient subgroups except for women with clear cell carcinoma. Toxicity was similar in both groups with the exception of more anemia and transfusions in the dose dense arm. In addition, both GOG 262 and International Collaborative Ovarian Neoplasm (ICON) 8 are conducting trials to confirm the JGOG findings and preliminary results should be reported soon. Clinical trials are now underway to directly compare IP chemotherapy and dose dense paclitaxel. GOG 252, which has recently completed accrual, is evaluating this in women after an optimal cytoreduction. This study has three treatment arms: arm 1, IV carboplatin with IV dose dense paclitaxel; arm 2, IP carboplatin with IV dose dense paclitaxel; and arm 3, IV paclitaxel IP cisplatin and day 8 IP paclitaxel (GOG 172). In all 3 arms bevacizumab, 15 mg/m 2 , with cycles 2-6 followed by bevacizumab maintenance for an additional 18 months. In the JGOG iPocc trial, carboplatin IV with dose dense paclitaxel is being compared with carboplatin IP with IV dose dense pacli- taxel. These trials will be very important in determining what the optimal standard of care should be for these optimally cytoreduced patients. Another important advance in the treatment of ovarian cancer is the use of agents to inhibit tumor angiogenesis Barbara A. Goff http://dx.doi.org/10.3802/jgo.2013.24.1.8386 www.ejgo.org [40,41,48]. Bevacizumab, a monoclonal antibody directed to vascular endothelial growth factor VEGF has been shown to have significant single agent activity in women with recurrent epithelial cancer. And two large randomized studies, GOG 218 and ICON 7, have now been conducted using bevacizumab with chemotherapy in newly diagnosed patients. In the GOG trial [40], women with advanced stage ovarian cancer were randomized to arm 1, carboplatin and paclitaxel every three weeks with placebo; arm 2, carboplatin paclitaxel bevacizumab (cycles 2-6); arm 3, carboplatin paclitaxel with bevacizumab (cycles 2-6) followed by 15 additional cycles of bevacizumab maintenance. Bevacizumab was given at 15 mg/ kg every 3 weeks. This study found a significant improvement in PFS of 3.8 months, but only for the group that received bevacizumab with chemotherapy and maintenance. Overall survival between the three groups was not significantly differ- ent. In a similar study, ICON 7 [41], women with ovarian cancer stage I-IV were randomized to receive standard carboplatin/ paclitaxel or carboplatin/paclitaxel with bevacizumab every 3 weeks for 6 cycles and then bevacizumab maintenance for an additional 12 cycles. The bevacizumab in this study was dosed at 7.5 mg/kg (50% less than the GOG study). In this study, PFS was significantly longer in the bevacizumab arm, 24 months vs. 22 months, but there was no difference in OS. Subgroup analysis of women with suboptimal stage IIIC and IV disease revealed a significant improvement in PFS, 18 months vs. 14 months and OS 37 months vs. 29 months. While these latter findings require confirmation, it seems that given these results those patients at highest risk for progression may derive the most benefit from bevacizumab given with chemotherapy followed by bevacizumab maintenance. One interesting difference between the GOG study conducted in the United States and the ICON 7 study conducted in Europe was that bevacizumab was available and covered by many insurance carries in the US but not in Europe. So crossover may have confounded the results in the US trial, thus obscuring the expected benefit with bevacizumab. Current clinical trials are evaluating extended maintenance schedules for bevacizumab as well as other antiangiogenic agents. The Trinova-3 study is comparing carboplatin and paclitaxel on an every 3 week schedule given with placebo or AMG 386 (Trebananib), followed by 18 months of AMG 386 or placebo. AMG 386 inhibits angiogenesis by sequestering angiopoietin 1 and 2, thus preventing their interaction with the Tie 2 receptor on endothelial cells. The LUME-OVAR 1 trial is comparing carboplatin and paclitaxel with BIBF1120 (nintedanib) vs. placebo in women with advanced ovarian cancer. In this trial, the BIBF1120 will be continued until progression, adverse event, or for a maximum of 120 weeks after randomization. BIBF1120 is a tyrosine kinase inhibitor which targets vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). The AGO-OVAR16/ VEG110655 trial is a study enrolling women with ovarian cancer who have completed first line chemotherapy without progression. Patients are randomized to placebo or up to 24 months of Pazopanib. Pazopanib is also a tyrosine kinase inhibitor which targets VEGFR, PDGFR, c-kit, and FGFR. These studies should help us better define the role of antiangiogenic treatments in both upfront and maintenance therapy for women with advanced ovarian cancer. In the setting of recurrent disease there are several impor - tant trials addressing the role of secondary cytoreduction. As a general rule, secondary cytoreduction is only appropriate for women with recurrence more than six months from completing chemotherapy. GOG 213 is randomizing women with platin sensitive recurrence who are surgical candidates to cytoreductive surgery or no surgery. A second randomization is also done to allow comparison of carboplatin and paclitaxel either with or without bevacizumab, plus bevacizumab main- tenance until progression in the group randomized to receive bevacizumab. In the AGO-OVAR desktop III trial women with platinum sensitive recurrent disease are also being random - ized to cytoreductive surgery followed by platinum based therapy. Both of these trials, when completed, will help define the role of secondary cytoreduction in this population of patients. In women with platinum sensitive recurrent disease, ICON 4 [49], AGO-OVAR-2.5 [50], and CALYPSO [51] have all shown the value of platinum doublets. These trials combined carbo- platin with paclitaxel, gemcitabine or liposomal doxorubicin, respectively. Which couplet to use in clinical practice is usually influenced by which schedule is most convenient as well as pre-existing and expected toxicities. Overall response rates will be approximately 70% for any of these three couplets. Recently the use of bevacizumab has been evaluated in this population of patients. The OCEANS trial randomized women with first recurrence after more than six months from frontline chemotherapy to carboplatin, gemcitabine and placebo vs. carboplatin, gemcitabine and bevacizumab with bevacizumab maintenance until progression or adverse event [48,52]. The PFS for those who received the placebo was 8.4 months and 12.4 months for bevacizumab, with a hazard ratio of 0.484 (95% CI, 0.388 to 0.605). No patient on bevacizumab developed a GI perforation. Despite the significant improve - ment in PFS this did not translate into improvement in OS between the groups. But two observations still support the use of bevacizumab in this population. First, was the median Managing advanced ovarian cancer J Gynecol Oncol Vol. 24, No. 1:83-91 www.ejgo.org  87 OS for both groups was 33 months from enrollment, which is the longest OS reported for any clinical trial for this population of patients. Second, this finding probably relates to crossover to bevacizumab in the placebo group plus the fact that 55% of patients received at least three additional lines of chemotherapy after progression on study, hence obscuring the possible benefit from bevacizumab. In the setting of platinum resistant disease (defined as relapse less than 6 months from previous platinum therapy), single agent therapy is generally recommended [53-65]. Table 1 shows the most active agents. In contrast with platin- sensitive recurrences, combination chemotherapy has been shown to increase toxicity without improvement in response rate of PFS/OS. However, there may be a role for combining one chemotherapy drug with bevacizumab. In 2012 results of the AURELIA trial were reported to American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) [66,67]. In this study women with platinum resistant ovarian cancer were randomized to standard chemotherapy with or without bevacizumab. Investigators could choose weekly paclitaxel, weekly topotecan or liposomal doxorubicin. Preliminary results found that addition of bevacizumab to all drugs significantly improved the PFS. Overall, the hazard ratio for the bevacizumab treated women was 0.48. This risk of grade 2 GI perforation, fistula, or abscess was less than 3%. A subset analysis based on choice of chemotherapy found that PFS for the 3 chemotherapies with and without bevacizumab respectively was paclitaxel 10 months vs. 4 months, topotecan 6 months vs. 2 months, and liposomal doxorubicin 5 months vs. 4 months. Each of these findings was statistically signifi - cant. The impact of bevacizumab on OS in this population is not yet reported. Substantial progress is being made in the diagnosis and treatment of ovarian, tubal, and peritoneal cancers. We are beginning to understand the molecular heterogeneity of these tumors and how we can use this information to produce less toxic and more targeted therapies. Historical treatment paradigms in ovarian cancer are being challenged and are evolving. In 2013, surgery does remain the cornerstone of di- agnosis and treatment, but ongoing studies will better define when to use neoadjuvant chemotherapy. We also expect clini- cal trials to guide optimal use of intraperitoneal, dose dense, antiangiogenic therapies and targeted maintenance therapies in both the up front and recurrent disease setting. Finally, there are a large number of clinical trials being conducted by cooperative groups and single institutions that are targeting the underlying molecular biology of ovarian cancer. It is likely in the near future that histology will be less important than knowing the molecular alterations in various pathways, which in turn will predict response to certain types of drugs. The promise of personalized medicine is rapidly becoming a reality for the treatment of ovarian cancer and will need to be a factor in future clinical trials. CONFLICT OF INTEREST No potential conflict of interest relevant to this article was reported.

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