Introduction
Article Outline
Background
Ovarian cancer is the most deadly of the gynecologic malignancies; it is the sixth most common female cancer worldwide and the fifth-leading cause of death for women in the United States and Western and Northern Europe.1 Because of the lack of reliable or specific early symptoms, almost 90% of patients are diagnosed with metastatic disease, which has a cure rate of only 15% to 20% and a 5-year survival rate of approximately 45%.1 In contrast, the small proportion of patients diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage I disease, in which the tumor is confined to the ovaries, have a 5-year survival rate in excess of 90%.
The current standard of care for patients with limited (FIGO stage I–II) ovarian cancer involves the use of prognostic factors to classify patients according to the risk of tumor recurrence. Low-risk patients receive surgical resection only, whereas those at high risk for recurrence receive adjuvant treatment. The current standard of care for newly diagnosed advanced (FIGO stage III–IV) ovarian cancer is surgical bulk reduction followed by six cycles of paclitaxel plus carboplatin. Although this approach has resulted in improved progression-free survival and more long-term survivors, the overall frequency of relapse, and hence need for second-line therapy, is 62%.2
The management of relapsed ovarian cancer is complex. The major goals of treatment are symptom palliation, prolonging progression-free survival, and improving quality of life. Given the wide range of drugs that are active in ovarian cancer, selection of the most appropriate treatment should involve careful consideration of the extent and severity of the disease, the potential side effects of the agent, and patient preference. Several agents (platinum, paclitaxel, topotecan, liposomal doxorubicin, docetaxel, gemcitabine, and etoposide) have shown notable activity in recurrent ovarian cancer, but very few trials have clearly shown a survival advantage for a particular drug or regimen. Patients with recurrent disease can be classified as having either “platinum-resistant” or “platinum-sensitive” disease. Currently, there is no widely accepted standard treatment for relapsed platinum-resistant disease, and, in the absence of any demonstrable superiority of combination therapy over single-agent therapy, sequential single-agent therapy is administered, taking side-effect profiles and quality-of-life issues into consideration. In contrast, platinum-sensitive disease until recently was usually treated with single-agent platinum; based on its favorable therapeutic profile, carboplatin became the platinum agent of choice.
Although significant progress has been made in refining current chemotherapy regimens used in treating relapsed ovarian cancer, the median survival time for patients after recurrence is approximately 2 years and the majority of patients will die of their disease. These disappointing results continue to encourage research into the overall management of patients with ovarian cancer, not only for the development of novel therapies but also for the improvement of current therapies and the optimization of treatment strategies. New treatment approaches under investigation for patients with advanced ovarian cancer include consolidation and maintenance therapy, intraperitoneal administration of cytotoxic agents, new combination chemotherapy regimens, and the development of new cytotoxic agents (eg, epothilones, TLK 286, and yondelis). In addition, novel biologic agents that target cancer key biochemical pathways involved in tumorigenesis include cytokines, monoclonal antibodies, vaccines, protease inhibitors, and gene replacement systems. Ongoing trials are evaluating these new agents, as single agents or in combination, in patients with ovarian cancer. Further development and investigation of these agents might eventually lead to a combination of treatments that ultimately results in improved survival.
The management of patients with ovarian cancer is now viewed as an ongoing, long-term challenge. Thus, the management of patients with ovarian cancer should take into consideration the need to define trigger points for initiating or changing treatment (eg, sequential increases in serum cancer antigen 125 levels, appearance of symptoms, or cumulative toxicities), the anticipation of impending treatment decision points, the recognition that the over-treatment of patients early in the disease process might adversely affect future treatment opportunities, and a renewed emphasis on patient education and participation in decision-making.
Scope of the Supplement
This supplement issue of Seminars in Oncology reviews current and evolving therapies for the treatment of ovarian cancer.
The first article, by Robert F. Ozols, reviews the use of systemic therapies for treating ovarian cancer and provides an update of new treatments. Although carboplatin plus paclitaxel is currently the standard treatment of ovarian cancer, the rate of patient survival is still very low. Maintenance paclitaxel has been shown to improve progression-free survival, a result that has encouraged further research with maintenance approaches. Intraperitoneal drug delivery has also recently been shown to improve survival in selected patients, although toxicity may limit widespread application. Ongoing clinical trials are evaluating biologic agents (interferon-α and metalloproteinase inhibitors) in maintenance therapy, the use of inhibitors of epidermal growth factor receptor and angiogenesis, new combinations of established agents, and combinations of cytotoxic therapies with targeted therapies for improving survival outcomes.
In the second article, Pfisterer and Ledermann discuss the management of recurrent ovarian cancer, specifically in platinum-sensitive patients, and present details of studies evaluating the use of combination chemotherapy for treating relapsed patients. Platinum plus paclitaxel has been shown to improve progression-free survival and overall survival in patients with relapsed ovarian cancer, but concerns about the levels of associated neurotoxicity still exist. Carboplatin plus gemcitabine has also shown benefit for relapsed patients, but without the toxicity experienced with the platinum plus paclitaxel regimen. Results of recent trials will likely establish the efficacy of combination chemotherapy for platinum-sensitive patients.
Pecorelli et al provide an overview of gemcitabine in ovarian cancer, highlighting its use in advanced-stage disease and its potential for the treatment of early stage disease. Gemcitabine has shown significant activity in recurrent/progressive patients, having shown synergism with cisplatin and a mild toxicity profile both in platinum-sensitive and platinum-resistant (and also taxane-pretreated) recurrent/progressive patients. In addition, first-line combination chemotherapy including gemcitabine has shown promising response rates in phase I and II studies. Pecorelli et al suggest that, while several studies of novel therapies are ongoing, a more realistic treatment approach is to consider the optimization of available drugs such as gemcitabine.
Tate Thigpen’s article provides an overview of the integration of other cytotoxic agents into the paclitaxel plus carboplatin standard, and focuses, in particular, on gemcitabine. The author presents results of studies that have evaluated the use of gemcitabine doublets, gemcitabine triplets, or sequential regimens for the treatment of ovarian cancer. Prospective randomized trials have been comparing these approaches to paclitaxel plus carboplatin and the results of these studies will be available in the next year.
In the final article, Maurie Markman highlights several unresolved issues in the chemotherapeutic management of gynecologic malignancies. Issues include administration of chemotherapy (patient and regimen selection, and choice of number of treatment courses to be given), efficacy of treatment regimen, and whether maintenance therapy should be given. One of the biggest issues concerns the treatment of recurrent, potentially platinum-sensitive ovarian cancer, and involves the choice of second-line treatment, role of intraperitoneal therapy, and definition of the optimal treatment of metastatic or recurrent ovarian cancer. These issues will need to be addressed in the future to provide a firm definition as to which patients are suitable candidates for treatment with specific management approaches.
Overall, this supplement provides an overview of new and emerging therapies for the treatment of ovarian cancer, and presents interesting perspectives on issues related to current and future therapies, as well as the optimal management of patients. It is important that novel approaches to treatment continue to be developed to enhance the effectiveness of current therapy and find new ways of improving the survival and quality of life of patients with gynecologic malignancies.
Eli Lilly and Company is gratefully acknowledged for providing an educational grant to support the production and publication of this supplement. We also wish to thank the authors for their valuable contributions.
References
- Cancer Facts and Figures 2006. Atlanta, GA, American Cancer Society. Available at: http://www.cancer.org/docroot/stt/stt_0.asp (accessed March 10, 2006)
- . First-line therapy for ovarian carcinoma (What’s next?) . Cancer Invest . 2004;22(suppl 2):21–28
PII: S0093-7754(06)00117-5
doi:10.1053/j.seminoncol.2006.03.010
© 2006 Elsevier Inc. All rights reserved.
