The search for more effective treatments for advanced ovarian cancer continues as results achieved with current strategies leave considerable room for improvement.
"Progression-free survival, even in optimally debulked patients, is less than 2 years," British oncologist Stanley Kaye, M.D., said during an educational symposium at the European Cancer Conference in Copenhagen in September. "We need to do better. The majority of patients will still have died by 5 years."
Ongoing investigations focus in large part on the development of more effective chemotherapy regimens for primary treatment and relapsed disease. Early clinical evaluations of chemotherapy for ovarian cancer suggested three principles that remain inherent to treatment strategies today: immediate platinum-based therapy is superior to non-platinum therapy, a platinum-based combination is superior to single-agent platinum therapy, and cisplatin and carboplatin yield equivalent outcomes.
Regimens that include anthracyclines showed some promise as first-line therapy for ovarian cancer until results of the second International Collaborative Ovarian Neoplasm (ICON2) trial failed to demonstrate superiority of CAP (cyclophosphamidedoxorubicincisplatin) over carboplatin monotherapy, said Nicoletta Colombo, M.D., a gynecologic oncologist at the European Institute of Oncology in Milan, Italy. The surprising finding that a combination was no better than monotherapy was attributed by some observers to inadequate dosing of cisplatin in the CAP regimen. Despite the findings of ICON2 and other studies, the combination of cyclophosphamide and platinum-based drugs evolved as standard first-line therapy in many parts of the world.
Similar to combination therapy, the evolution of the taxanes as first-line treatment has a somewhat controversial history. The Gynecologic Oncology Group (GOG) 111 trial and the European-Canadian Intergroup trial (OV10) demonstrated an advantage in favor of a paclitaxelcisplatin combination over cisplatincyclophosphamide. Subsequently, the GOG 132 and ICON3 trials failed to show an advantage in overall or disease-free survival for the paclitaxelcarboplatin combination versus platinum alone (cisplatin or carboplatin).
The disparate results of the four evaluations of paclitaxelplatinum combination therapy may be explained by differences in taxane crossover rates, variations in dosage and administration of therapy in experimental arms of the trials, and variations among the control arms. Eventually, a pooled analysis of data from the four trials demonstrated a statistically significant benefit of paclitaxelplatinum combination therapy, which was still smaller than observed in the individual positive trials. Colombo concluded that the best available evidence suggests that either carboplatinpaclitaxel or adequate dosing of single-agent carboplatin can be considered the standard of care for first-line treatment of advanced ovarian cancer.
Second-Line Therapy
The data are less clear about standard treatment for second-line care. For second-line chemotherapy, response is clearly related to the treatment-free interval, Colombo noted. In platinum-sensitive patients, current clinical consensus favors the use of a platinum agent again. Results of the recent ICON4 trial demonstrated improvement in overall and progression-free survival with the combination of paclitaxel and a platinum salt versus platinum alone, suggesting that the combination should be preferred for relapsed ovarian cancer. Although the cumulative clinical trial data are not consistent, the results of ICON4 make a strong case for use of the carboplatinpaclitaxel combination in platinum-sensitive patients.
Because results with existing therapy have been inconsistent and because patients with advanced ovarian cancer continue to have a poor prognosis, there is strong impetus to evaluate new chemotherapy regimens. Increasingly, investigation will focus on second-line therapy.
"If you look at the data from the time a patient is optimally debulked and relapses, there is a longer time from relapse to death than there is between initial surgery and first relapse," said Kaye, a gynecologic oncologist at the Royal Marsden Hospital in London. "There are lots of opportunities for further therapy trials in that area."
Reviewing the current status of clinical investigation, Kaye said that ongoing and planned trials of first-line chemotherapy reflect several strategies. Several trials are evaluating the addition of a third agent to paclitaxelcarboplatin. Candidates under investigation include topotecan, gemcitabine, and liposomal doxorubicin. Sequencing trials, both upcoming and under way, will help determine whether giving carboplatin, a taxane, and (in some cases) a third drug in a certain order improves outcomes. Other strategies under discussion include maintenance therapy and high-dose intraperitoneal therapy.
Investigations of second-line therapy include the evaluation of novel agents (such as signal transduction inhibitors) in platinum-refractory disease and additional studies to determine whether combination therapy is superior to single-agent treatment in platinum-sensitive patients. Other approaches receiving consideration include immunotherapy, resistance modulators, and molecularly targeted agents.
Role of Surgery
In contrast to chemotherapy, surgerys role in the management of ovarian cancer is somewhat clearer, according to Ignace Vergote, M.D., a gynecologic oncologist at University Hospitals in Leuven, Belgium. Primary surgical debulking, or removing tumors or reducing them as much as possible, remains the standard of care for advanced ovarian cancer. Multiple studies have demonstrated that the complete absence of residual tumor is associated with better prognosis and therefore should define optimal debulking. Second-look surgery after completion of first-line therapy has done nothing to improve survival and should not be used outside of clinical research protocols, said Vergote.
In general, secondary debulking should be limited to patients who initially had complete responses to chemotherapy, a long treatment-free interval (ideally, more than 12 months), and resectable disease that is not diffuse.
Laparoscopy has a limited role in the management of ovarian cancer, including no role in the early-stage disease, said Vergote. Open laparoscopy is useful for making a histologic diagnosis, evaluating feasibility of surgery, and deciding whether a patient should be referred to a tertiary care center.
In contrast to a field such as breast cancer, ovarian cancer has thus far reaped few benefits from translational research, said Ate van der Zee, M.D., a gynecologic oncologist at University Hospital in Groningen, The Netherlands. Considerable effort has focused on identifying markers of resistance to chemotherapy. Classic prognostic factors poorly predict response to therapy in ovarian cancer.
Numerous studies have evaluated the potential of testing for abnormal expression of the p53 gene for predicting drug resistance. Results have been inconsistent, and the potential contributions of p53 to ovarian cancer prognosis remains controversial, said van der Zee.
One area of emphasis is microarray analysis, which has been studied for prediction of outcome in breast cancer. However, studies to develop genetic signatures associated with ovarian cancer remain in early stages of planning and execution.
"The biggest problem [with translational research] in ovarian cancer is the lack of really large series of well-defined clinical samples," said van der Zee. "For profiling approaches, frozen tissue samples are needed, along with clinical data. As compared to breast cancer, we do not yet have the necessary materials in ovarian cancer."
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