The American Cancer Society has estimated that in 2002 ovarian cancer will strike 23,300 women, and 13,900 women will die from the disease. Five-year survival is about 80% for women with stage I disease, 50% for women with stage II disease, 25% for women with stage III disease, and 15% for women with stage IV disease. Among women with advanced-stage disease, optimal debulking surgery, as well as platinum/taxane-based adjuvant therapy prolongs disease-free and median survival.[2,3] Population-based data suggests that guidelines for therapy are not uniformly followed in community practice. In addition, older patients appear to receive less aggressive treatment than younger patients.
Part 1 of this two-part series will discuss prevention, screening, adjuvant treatment, neoadjuvant chemotherapy, and adjuvant chemotherapy trials for ovarian cancer. Part 2, to be published in next month’s issue of ONCOLOGY, will detail diagnosis and treatment trials for recurrent disease.
About 5% of ovarian cancer appears linked to an inherited predisposition. The most common genetic syndromes are mutations at the BRCA1 and BRCA2 loci. The risk of ovarian cancer is higher with BRCA1 mutations than BRCA2 mutations. Other known risk factors for ovarian cancer include northern European descent, nulliparity, and advancing age. Protective factors include pregnancy, lactation, and use of hormonal contraceptives. In the United States, ovarian cancer is more common in the northern states than the southern states. It has been hypothesized that higher levels of sun exposure in southern latitudes, resulting in increased vitamin D levels, may also be protective against the development of ovarian cancer.
There is no consensus yet as to the existence or the nature of premalignant ovarian neoplasia. Reliable intermediate biomarkers for use in prevention studies have not been identified. Several prevention studies are underway evaluating retinoids/progestins, which appear to have activity in primate models.[9-11] Phase II studies are being conduced in women at high genetic risk for ovarian cancer, who have decided to undergo prophylactic oophorectomy (Gynecologic Oncology Group [GOG]-0190). The intervention is given during a defined window of opportunity between the decision to undergo surgical removal of the ovaries and the actual procedure.
To date, an effective screening algorithm for ovarian cancer has not been identified. The best imaging modality for the adnexa, transvaginal ultrasound, lacks both adequate sensitivity and specificity for diagnosing early ovarian cancer. The serum marker CA-125, which is used to monitor response to therapy among women with advanced ovarian cancer, similarly lacks both sensitivity and specificity; up to 50% of women with early ovarian cancer have CA-125 levels in the normal range. Aggressive efforts are under way through the NCI’s Early Detection Research Network, Ovarian Cancer Specialized Programs of Research Excellence, Cancer Diagnosis Program (Diagnostic Research Branch, Program for the Assessment of Clinical Cancer Tests), and Center for Cancer Research, to identify more effective markers, marker combinations, and screening algorithms. Proteomics appear particularly promising in this regard.
The NCI has recruited 74,000 women to the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), which is evaluating screening for prostate, lung, colon, and ovarian cancer. In this trial, women are randomized to yearly monitoring of their CA-125 level and transvaginal ultrasound, or normal clinical care. They are to undergo such evaluation for 6 years, then are followed for an additional 7 years. The United Kingdom, under the leadership of Drs. Ian Jacobs and Usha Menon, has recently started an even larger screening trial (in 100,000 women), evaluating both transvaginal ultrasound and serial, individualized CA-125 levels.
The NCI’s Cancer Genetics Network has recently undertaken a screening trial for women at high risk for familial ovarian cancer (Massachusetts General Hospital [MGH]-000084). The trial, led by Dr. Steven Skates, has already accrued 1,000 patients. Dr. Mark Greene, of the NCI’s Division of Cancer Epidemiology and Genetics and the GOG, has developed a complementary study to quantitate the benefit of prophylactic oophorectomy in women at high familial risk (GOG-0199).
Primary Treatment Trials
Recent studies have documented the importance of surgery in the treatment of ovarian cancer. Comprehensive surgical exploration, accompanied by systematic biopsies of intra-abdominal tissues and retroperitoneal lymph nodes, must be performed to accurately stage ovarian cancer. In addition, removal of gross disease via surgical debulking significantly improves outcome for women with advanced (stage III and IV) ovarian cancers.
Patients found to have stage IA/IB, grade 1 or 2 epithelial ovarian cancer may not require adjuvant therapy. In general, women with stage I, grade 3, stage IC, and stage II ovarian cancer are recommended to undergo adjuvant chemotherapy. However, recent European data suggested that this treatment improves recurrence-free survival, but not overall survival in women with accurate surgical staging. Adjuvant therapy is generally based empirically on regimens with documented activity in women with recurrent or advanced ovarian cancer. Most regimens are based on platinum or the combination of a platinum and taxane, generally for three to six courses. The GOG has completed a trial in which women with early-stage ovarian cancer were randomized to three vs six cycles of carboplatin (Paraplatin)/paclitaxel (GOG-0157). The current GOG trial randomizes the same population of women to three courses of carboplatin/paclitaxel with or without weekly low-dose paclitaxel (40 mg/m2) for 24 weeks, which is thought to have an antiangiogenic effect (GOG-0175).
For women with advanced (ie, stage III/IV) ovarian cancer, adjuvant chemotherapy generally consists of six to eight courses of intravenous platinum/taxane therapy. Although several trials suggest that concomitant intravenous and intraperitoneal therapy of the same agents may improve survival, intraperitoneal therapy has gone out of vogue in the community setting and is rarely employed.[19-21] Similarly, despite promising data associated with the use of whole abdominal radiation, radiation therapy is rarely, if ever, used in primary adjuvant therapy for epithelial ovarian cancer.
Several trials are under way to evaluate the addition of another agent to the platinum/taxane combination. Despite advances in our understanding of the molecular biology of ovarian cancer, we have yet to define a comprehensive set of molecular targets or determine how best to optimize individual therapy based on the molecular characteristics of a patient’s cancer. The agents currently under evaluation in phase III trials are primarily cytotoxic agents that have demonstrated activity in women with recurrent, platinum-resistant ovarian cancer. Agents currently under evaluation include the topoisomerase I inhibitor topotecan (Hycamtin), gemcitabine (Gemzar), and two anthracyclines, epirubicin (Ellence) and liposomal doxurubicin.
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