Dr. Markman carefully reviews many of the important advances in the management of ovarian cancer that have taken place since the 1980s. Although there is no question that there has been an improvement in both survival and quality of life, ovarian cancer remains the fifth leading cause of cancer death in women.
A subset of patients with ovarian cancer not reviewed by Dr. Markman are young women with germ cell tumors of the ovary, for whom there truly have been dramatic improvements in survival and quality of life. Prior to the development of platinum-based chemotherapy, young women with germ cell tumors frequently died of their disease despite aggressive surgery and extended chemotherapy. Now, not only is death in this setting infrequent, but most young women with germ cell tumors of the ovary are treated with conservative surgery, maintaining their ability to subsequently have a normal pregnancy.
In contrast, women with advanced ovarian cancer who undergo aggressive cytoreductive surgery but have residual tumor nodules greater than 1 cm (suboptimally debulked) have less than a 10% long-term survival, and only 20% to 25% of those women who undergo optimal cytoreductive surgery will be alive at 10 years. While germ cell tumors of the ovary and the more common epithelial ovarian cancer (which occurs in elderly women) are clearly different biologic and clinical entities, the goals of therapy remain the same: to improve survival and to maintain quality of life. What then are the challenges that need to be met before we can achieve the same results that we have been able to accomplish in younger women with germ cell tumors of the ovary?
A major problem of ovarian cancer continues to be that the majority of women (75%) are diagnosed with advanced-stage disease. Although in the last 20 years it appears that we have been making progress in diagnosing some epithelial tumors at earlier stages, there are still no effective screening techniques for ovarian cancer, and most patients are diagnosed with intraperitoneal carcinomatosis. Screening with either serum CA-125 levels or transvaginal sonography lacks the requisite sensitivity and specificity. Whether the identification of novel tumor markers and proteomic assays will lead to earlier diagnosis remains uncertain. Part of the problem is the relatively low incidence of ovarian cancer, which mandates a very high screening specificity in order to avoid unnecessary laparotomies for false-positive tests.
A major accomplishment in the past 2 decades has been the identification of the role of BRCA1/2 mutations in characterizing women at high risk for breast and ovarian cancers. Even in this group of women, screening is not relied upon and women undergo prophylactic oophorectomies after childbearing. Future studies may identify the mechanisms by which mutations in these genes increase the risk for ovarian cancer. This, in turn, may facilitate the development of chemopreventive strategies to obviate the need for prophylactic surgery.
Surgery in Ovarian Cancer
Few would argue with the accepted dogma that cytoreductive surgery benefits patients with ovarian cancer. As Dr. Markman points out, however, the optimal manner in which chemotherapy and surgery are utilized in the management of patients with advanced ovarian cancer remains unknown. Ovarian cancer is a highly chemosensitive disease, and neoadjuvant chemotherapy has the potential for chemically debulking patients, making subsequent surgery perhaps less morbid and even more effective by increasing the number of patients who are left with minimal or no disease after surgery. Unfortunately—in contrast to other solid tumors in which neoadjuvant chemotherapy has been explored in prospective randomized trials—only one ongoing trial in Europe is addressing this clinically important issue in ovarian cancer.
In the past 25 years, a series of clinical trials have been performed in patients with early- and advanced-stage ovarian cancer, both to identify which patients may benefit from treatment and to develop more effective systemic treatments. It is now clear that women with FIGO stage IA and IB and well-differentiated tumors do not require adjuvant chemotherapy, as their relapse rate is less than 5%. Randomized trials have demonstrated that women with early-stage high-risk disease (stage IC as well as select stage IA and IB patients with poorly differentiated tumors) have improved survival from immediate chemotherapy, compared to observation followed by treatment at relapse.
Dr. Ozols is a consultant for Bristol-Myers Squibb, Eli Lilly, Genentech, Telik, and Unither.
1. Markman M: Management of ovarian cancer: An impressive history of improvement in survival and quality of life. Oncology (Williston Park) 20:347-354, 2006.
2. Trimbos JB, Parmar M, Vergote I, et al: International Collaborative Ovarian Neoplasm trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: Two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst 95:105-112, 2003.
3. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 12:2654-2666, 1994.
4. du Bois A, Quinn M, Thigpen T, et al: 2004 consensus statements on the management of ovarian cancer: Final document of the 3rd International Gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference (GCIG OCCC 2004). Ann Oncol 16:viii7-viii12, 2005.
5. Ozols RF, Bundy BN, Greer BE, et al: Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 17:3194-3200, 2003.
6. Armstrong DK, Bundy B, Wenzel L, et al: Phase III randomized trial of intravenous cisplatin and paclitaxel versus an intensive regimen of intravenous paclitaxel, intraperitoneal cisplatin and intraperitoneal paclitaxel in stage III ovarian cancer: A Gynecologic Oncology Group study. N Engl J Med 354:34-43, 2006.
7. Clinical advisory: NCI issues clinical announcement for preferred method of treatment for advanced ovarian cancer. Available at www.nlm.nih.gov/databases/alerts/ovarian_ip_chemo.html. Accessed March 9, 2006.
8. Ozols RF, Bookman MA, Young RC: Intraperitoneal therapy: An alternative perspective. Gynecol Oncol. In press.
9. Markman M, Rothman R, Hakes T, et al: Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 9:389-393, 1991.
10. Burger RA, Sill M, Monk J, et al: Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC): A Gynecologic Oncology Group (GOG) study (abstract 5009). J Clin Oncol 23(16S):457s, 2005.