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Johns Hopkins University Baltimore, Maryland
Ovarian cancer continues to be a leading cause of cancer-related deaths in women in the U.S. and is the leading cause of deaths attributed to gynecologic malignancies. The American Cancer Society estimates that approximately 23,300 new cases of ovarian cancer will be reported in the year 2002, which will contribute to an estimated 13,900 deaths [1]. Likewise, other gynecologic cancers, such as uterine and cervical cancer, will contribute an estimated additional 58,100 new cases and 12,300 deaths in the year 2002. Although the number of new cases has been relatively stable over time, advances in the early detection and treatment of ovarian cancer have led to gains in 5-year survival among women diagnosed with this disease, with 52% of women diagnosed between 1992-1997 surviving 5 years or longer, compared with 41% diagnosed between 1983-1985 [1].
Because ovarian cancer is usually asymptomatic in its early stages, the disease often has spread outside of the pelvic region at the time of diagnosis and requires debulking surgery followed by systemic chemotherapy. First-line chemotherapy involves platinum-based treatments, including the widely adopted regimens of cisplatin/paclitaxel, carboplatin/paclitaxel, and single-agent carboplatin. Although these regimens yield relatively satisfactory tumor response rates, the majority of patients experience disease recurrence and receive additional treatments. For such patients, a number of antitumor agents with novel mechanisms of action (topotecan, gemcitabine, liposomal doxorubicin, docetaxel, etoposide) have been applied, in addition to retreatment with platinum, with the goal of re-establishing remission or disease control, minimizing disease-related symptoms, improving quality of life, and extending patient survival. Of these agents, topotecan (Hycamtin®; GlaxoSmithKline; Philadelphia, PA) is the best-characterized agent in the recurrent setting.
Topotecan is an S-phase 1-dependent cytotoxic agent that targets the topoisomerase I enzyme and exhibits broad activity in solid tumors, including ovarian cancer. Response rates in patients with recurrent ovarian cancer range from 13%-33%, with a median survival of 44-81+ weeks [2–6]. Topotecan continues to be a clinically valuable tool as single-agent therapy and in novel combinations in the second-line and salvage settings and, more recently, in the first-line treatment of ovarian cancer.
This special issue of The Oncologist is devoted to reviewing and updating the clinical data related to the use of topotecan and other novel chemotherapeutic agents in the treatment of gynecologic malignancies. In addition to providing an update on the role of topotecan, a number of other important topics will be reviewed, including current standards in the treatment of gynecologic malignancies, common toxicities and their management, the chronic nature of ovarian cancer, and implications for patient long-term treatment planning and quality of life.
The supplement begins with an overview of the data addressing the chronic nature of ovarian cancer. In this review, I will build a compelling case that the proportion of ovarian cancer patients diagnosed today who survive 5 years or more (i.e., 52%) is approaching or comparable with that observed for other chronic diseases, including other types of malignancies (colorectal and hematologic [leukemia]) and congestive heart failure. As a consequence, the long-term planning of patient care has become increasingly important in terms of disease control, toxicity management, and quality of life. This review will conclude with a case study illustrating two differing approaches brought to bear on patient management in the context of the long-term survivability potential of this disease.
The long-term management of chemotherapy-induced toxicity represents an increasingly important consideration in patient care. Charles Dunton provides a state-of-the-art review of the hematologic and nonhematologic toxicities associated with commonly used therapies and provides strategies to prevent or manage severe toxicity (see pp 11-19 [7]). In addition, the review builds on the previously introduced concept of sequence planning, with an emphasis on the management of cumulative toxicity.
The focus subsequently shifts to the important role of topotecan in the second-line and salvage settings; an update of topotecan in these settings is provided and a plan to take the novel agent into the first-line setting as a component of platinum-based therapy is presented. Thomas Herzog begins with a summary of the role of topotecan in recurrent ovarian cancer, followed by a brief review of the antitumor activity of other agents used in the recurrent setting (see pp 3-10 [8]). Herzog concludes with a synopsis of several exciting studies with topotecan-based regimens that are planned or under way under the auspices of the Gynecologic Oncology Group.
Because the major toxicity associated with standard topotecan administered once daily for 5 consecutive days of a 21-day course is myelosuppression, alternate doses and schedules have been vigorously pursued with the goal of improving tolerability while maintaining or improving antitumor activity. Robert Morris reviews the rationale and clinical efficacy and safety of topotecan delivered in a variety of doses and novel schedules, including weekly, continuous intravenous 24-hour, continuous intravenous 21-day, 3-day, and lower-dose topotecan (see pp 29-35 [9]). Of these approaches, Morris provides compelling evidence that weekly and lower-dose topotecan have the greatest promise. In particular, these regimens offer improved tolerability and antitumor activity that is comparable to standard 5-day topotecan. The convenience of weekly administration may offer opportunities for combining topotecan with other active agents.
The supplement focus subsequently narrows to provide a preliminary summary of the antitumor activity of topotecan in first-line ovarian cancer treatment. Robert Coleman begins with a review of current standards in first-line therapy and the rationale for incorporating topotecan into standard therapy (see pp 46-55 [10]). The article continues with an overview of the four approaches under investigation for first-line topotecan (replacement regimen, triplet regimen, consolidation regimen, and sequential doublet regimen) and concludes with a synopsis of clinical findings using each of these approaches.
Finally, James Fiorica explores the potential role of topotecan in the treatment of other gynecologic malignancies, including cervical and uterine cancers (see pp 36-45 [11]). In particular, there is a large unmet medical need for active treatments for cervical and uterine cancers. Fiorica continues with a discussion of the clinical rationale for topotecan in other gynecologic malignancies and summarizes the exciting results of topotecan treatment in patients with cervical and uterine cancer. The review concludes with a presentation of future trials of topotecan in these undertreated disease states.
In summary, there is a high degree of optimism and enthusiasm among oncologists that the gains made thus far in the long-term survival and quality of life of patients with ovarian cancer will continue well into the future, as the delivery of existing therapies is refined and as new approaches are introduced. In this context, it is my hope that you will find this special issue of The Oncologist to be an important educational resource that provides a state-of-the-art synopsis regarding the current and potential uses of topotecan and other novel agents in the treatment of gynecologic cancers. The information reviewed in this supplement provides the rationale for continued investigation and clinical development of topotecan in single-agent studies and in new combinations with conventional chemotherapy and with novel biologic agents, angiogenesis inhibitors, and potent inhibitors of signal transduction pathways.
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