In the United States, recommendations for post-treatment monitoring following completion of first-line therapy typically include physical examination and CA-125 monitoring every 2 to 4 months for the first 2 years, with increasing intervals between follow-up visits if there is no evidence of disease recurrence. However, data presented from the MRC OV05/EORTC 55955 study assessing the outcomes of early treatment at the time of biochemical recurrence versus delaying treatment until clinically indicated have suggested that early treatment does not alter overall survival. In this study, 1,442 women with ovarian cancer in complete remission following first-line platinum-based therapy were followed every 3 months by CA-125, but both patients and physicians were blinded to the results. At the time a subject's CA-125 rose to twice the upper limit of normal, she was randomized to either initiation of treatment or continued blinded monitoring until treatment was indicated by other clinical parameters. Of note, choice of treatment was not dictated by the study design and was at the physician's discretion; the availability of clinical trials was also not specified. Although it remains unclear how these results will affect clinical practice, these findings do suggest that treatment of asymptomatic rises in CA-125 in the absence of recurrent cancer either on physical exam and/or radiographic study may not be warranted, and that these patients should be either closely observed or enrolled in clinical trials, if available.
The majority of patients who have advanced-stage ovarian cancer at the time of initial diagnosis will experience recurrence despite the excellent response rate observed with first-line adjuvant chemotherapy. The choice of therapy for recurrent disease is often informed by the treatment-free interval (TFI) prior to disease recurrence, and recurrence is divided into platinum-sensitive (recurring greater than 6 months following treatment with a platinum-based regimen) or platinum-resistant (recurring within 6 months following prior platinum-based therapy). The TFI can predict response to additional therapy, and studies have demonstrated that patients with a longer platinum-free interval are more likely to respond to second-line platinum therapy. Given these findings, the NCCN recommends consideration of a combination platinum-based chemotherapy in patients who have disease relapse greater than 6 months following their last platinum-based therapy.
Combination Chemotherapies for Recurrent Disease
Development of therapeutic treatments for recurrent platinum-sensitive disease has focused on combination regimens, based upon the findings from four randomized phase III trials and one phase II trial, which demonstrated a benefit to combination platinum-based chemotherapy compared to single-agent therapy (see Table 3).[28-31] Earlier trials investigated the combination of carboplatin(Drug information on carboplatin) and paclitaxel(Drug information on paclitaxel)[28,29]; more recently, Pfisterer et al. demonstrated that carboplatin and gemcitabine(Drug information on gemcitabine) also had increased activity compared to carboplatin alone in this setting. The results of this trial led to the approval of the combination of carboplatin and gemcitabine for treatment of recurrent platinum-sensitive ovarian cancer in the United States.
Additional new doublets have been under exploration in platinum-sensitive disease. Preliminary results from the CALYPSO trial were presented at the American Society of Clinical Oncology (ASCO) meeting in June 2009. In this phase III study, 976 patients with recurrent platinum-sensitive disease were randomized to receive either carboplatin and pegylated liposomal doxorubicin(Drug information on doxorubicin) (PLD) or carboplatin and paclitaxel. PFS was significantly prolonged in the carboplatin/PLD arm (11.3 months vs 9.4 months). Of additional interest, the carboplatin/PLD arm experienced only a 5% hypersensitivity rate, compared to 18% in the carboplatin/pacltiaxel arm. The final results for this trial are not yet available, but these preliminary findings suggest a possible role for carboplatin/PLD in the treatment of recurrent platinum-sensitive ovarian cancer.
Non-platinum therapies also remain under investigation. Data were presented from a randomized phase III trial comparing the novel alkaloid trabectedin in combination with PLD to PLD alone. A total of 672 patients were enrolled, and response rates for all patients were 28% in the combination arm compared to 19% in the PLD alone arm. There was no observed difference in overall survival; however, based upon the results of this trial, trabectedin has been approved in Europe for use in ovarian cancer, although the US FDA did not support approval of trabectedin in the United States.
Targeted biologic therapies are also a major area of interest in ovarian cancer research. Activity with the anti-angiogenic agent bevacizumab(Drug information on bevacizumab) has been observed in phase II trials, with response rates of up to 16% in previously treated platinum-resistant recurrent ovarian cancer.[34,35] However, complications have also been observed with bevacizumab therapy in heavily pretreated populations, with one study reporting a gastrointestinal perforation rate of 11%. Patients at higher risk included those who had received three or more prior chemotherapy regimens (including the initial chemotherapy regimen used at diagnosis); the risks of bevacizumab should be carefully considered for these patients as well as those who have extensive bowel involvement or symptoms of a partial or full small bowel obstruction. The activity of cediranib, an oral VEGF kinase inhibitor, has also been demonstrated in phase II trials in recurrent ovarian cancer. A large randomized trial (ICON6) is investigating the utility of combining cediranib with carboplatin and paclitaxel therapy in women with platinum-sensitive relapsed ovarian cancer, and 450 patients are anticipated to be accrued to this study. Three arms are being studied in this trial: 1) standard carboplatin and paclitaxel with placebo therapy followed by maintenance placebo for 18 months, 2) carboplatin and paclitaxel with cediranib, followed by maintenance placebo for 18 months, and 3) carboplatin and paclitaxel with cediranib, followed by maintenance cediranib for 18 months.
One of the most exciting recent advances in targeted therapy in ovarian cancer has been the discovery and use of PARP-inhibitors. These agents work synergistically with the deficiencies of DNA-repair seen in cancers occurring in BRCA1- or BRCA2-carrier patients to damage DNA in tumor cells and cause tumor cell death. In a phase I trial of an oral PARP-inhibitor, olaparib, 12 of 19 patients who were BRCA carriers with ovarian, breast, or prostate cancer demonstrated evidence of clinical benefit from olaparib treatment. In a phase II trial of olaparib in BRCA-deficient advanced ovarian cancer, an overall response rate of 33% and a clinical benefit rate of 57.6% were observed at a dose of olaparib of 400 mg BID. Additional PARP-inhibitors are now under development from a number of pharmaceutical companies, and their roles as single-agent therapy and in combination with chemotherapy are being investigated in both BRCA-deficient and spontaneous ovarian cancer.
Other targeted agents in ovarian cancer are also under active investigation, including additional anti-angiogenic agents and agents targeted against pathways such as Notch. Additionally, there has been increasing interest in drugs that target the PI3-kinase (PI3K) / AKT pathway. Data from phase I clinical trials with PI3K/AKT-directed therapies presented at ASCO in 2009 suggest evidence of activity of these agents in ovarian cancer, and phase II trials are currently under development.
Significant advances in the understanding of the pathogenesis and management of both newly diagnosed and recurrent ovarian cancer have occurred over the past few years, making the possibility of better outcomes for women with advanced ovarian cancer a reality. Recent studies have raised the question of the ideal timing of cytoreductive surgery for newly diagnosed disease and demonstrated benefit with alternative weekly paclitaxel dosing, while ongoing studies continue to clarify the roles of IP chemotherapy and biological agents in this setting. In the setting of recurrence, new chemotherapy combinations are being explored, and investigation of the activity of various targeted agents, including anti-angiogenic agents, PARP-inhibitors, and PI3K/AKT pathway inhibitors, remains an area of active interest.