Pursuit of optimum outcomes in ovarian cancer: methodological approaches to therapy.

The treatment of ovarian cancer is an evolving area and important clinical questions remain unanswered at all stages from early disease to relapse. This review outlines current practice at each disease stage, some of the current unanswered questions and issues surrounding the design of clinical trials to answer these questions. The gold standard test for new treatments must remain the randomised controlled trial with survival as the major endpoint because other outcome measures such as radiological response do not bear a strong relationship to survival. Patient factors greatly influence the likelihood of response to treatment and subsequent survival, hence failure to control for these in trial design may lead to spurious results. Quality of life is an important endpoint but quality-of-life measures in clinical trials should be interpreted carefully. The introduction of novel, target directed anticancer therapies will require new study designs as the phase I/II/III paradigm may not be relevant. It is current practice to offer adjuvant chemotherapy to women with early stage disease who are considered at high risk of relapse despite conflicting evidence from clinical trials. Current questions include the optimal choice of regimen and the duration of treatment. However, the relative rarity of early stage disease and the likely small difference between treatments makes evaluations difficult. Advanced disease is currently treated using a combination of surgical cytoreduction and platinum-paclitaxel chemotherapy. Women with poor risk disease are unlikely to be cured of their disease and the investigation of strategies to minimise treatment may be appropriate. Conversely, women with good risk disease may be better candidates for experimental treatment to increase cure rate. Strategies that have been tried include dose-intensification, high-dose therapy and intraperitoneal therapy. Whereas there is some evidence to support the latter, there is no current evidence for dose-intensification or high-dose therapy, and these must remain areas of investigation. Most current trials investigate the addition of agents to platinum-paclitaxel. Relapsed disease is an important area. Despite this, only 9 randomised controlled trials have been undertaken. Uncertainties exist in the role of surgery, both surgical cytoreduction and palliative surgery. The mainstay of treatment at disease relapse is chemotherapy and the choice of agent revolves around the concept of platinum sensitivity. Many agents are active in platinum-resistant disease, but uncertainties remain about the relative efficacies of each and the place of combination therapy.