With regard to early-stage ovarian cancer, Bagley et al reported in 1972 that the mean 5-year survival rate in patients with stage IA disease (limited to one ovary) was only 63%. Conversely, they found that approximately 40% of these patients would be dead from the disease in less than 5 yearsthis from the earliest-stage ovarian cancer. Therapy for early-stage ovarian cancer at that time consisted of total abdominal hysterectomy and bilateral salpingo-oophorectomy with or without pelvic or abdominal radiation.
In a 1978 collective review, we learned that most of the women thought previously to have early-stage disease, actually had stage III (abdominal) disease with unrecognized microscopic disease in the undersurface of the diaphragm, omentum, and pelvic and para-aortic lymph nodes to explain this high mortality. This retrospective analysis was confirmed in 1982 by the first prospective study of surgical staging in clinically localized ovarian cancer reported by the Ovarian Cancer Study Group.
Among researchers using cisplatin when it was a new agent, Vogl et al in 1979 reported results that had previously not even been envisioned in advanced ovarian cancera 90.4% clinical response rate with a 47.6% complete response rate.
The 1980s and 1990s
Thirteen years after the report of the effectiveness of cisplatin as second-line therapy, McGuire et al in 1989 added another nuance to the treatment of ovarian cancer in their report, "Taxol: A Unique Anti-neoplastic Agent With Significant Activity in Advanced Ovarian Epithelial Neoplasms." But it was the 1996 report on a randomized phase III trial of cisplatin plus paclitaxel compared to cisplatin and cyclophosphamide that resulted in near unanimity that paclitaxel and a platinum compound was the best available therapy for advanced ovarian cancer. Of concern, however, was the fact that women who received paclitaxel/cisplatin had a median progression-free survival that was only 4.5 months longer than those receiving cisplatin and cyclophosphamide. None of the women in this trial had what would be considered optimal surgery prior to starting chemotherapythat is, they all had residual implants greater than 1 cm.
The 21st Century
In the latest refinement, researchers demonstrated that carboplatin plus paclitaxel was as effective as cisplatin plus paclitaxel and less toxic in women with stage III optimally resected (less than 1 cm residual) ovarian cancer. However, they rightly pointed out that "more than 70% of the patients have experienced disease recurrence with a median time to progression of less than two years" and that "the results also emphasize the need for more effective therapy." I could not agree more.
Ovarian cancer remains the number 1 killer from gynecologic malignancies. Given that every woman with ovarian cancer deserves and should have excellent surgery, I consider the landmark dates in lowering mortality in this setting to be 1956 (melphalan), 1976 (cisplatin), and 1996 (cisplatin/paclitaxel). We cannot wait another 20 years (ie, 2016) for another small incremental step in lowering that mortality.
Is the treatment of ovarian cancer at a crossroads? In the 2006 American Society of Clinical Oncology (ASCO) proceedings, there were 95 abstracts on gynecologic malignancies, 60% of which were on ovarian cancer. As I wrote in the April 2006 issue of ONCOLOGY, I do not believe "that more (three drugs vs two drugs) is better." This is supported by two important studies (abstracts 5002 and 5003 from ASCO 2006), in which the addition of a third drug to standard therapy did not improve progression-free survival. I also wrote that "what we need are novel agents to act against molecular targets." Regrettably, three important ASCO abstracts (5006, 5018, 5019) on one of the most promising new agents, bevacizumab (Avastin), revealed a high rate of life-threatening intestinal perforations that preclude the drug's use at this time.
Ovarian cancer therapy is indeed at a crossroads. It is time for a sea change in our approach to treating this disease.
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