Advanced Ovarian Carcinoma Stages Iii And Iv Evolution of Platinum and Taxane Agents

Epithelial ovarian cancer is a chemosensitive disease, and cytotoxic chemotherapy plays a pivotal role in its management. Chemotherapy following optimal surgical cytoreduction (all tumor residual nodules less than 1 cm) achieves a complete remission for most patients with advanced epithelial ovarian cancer, which we will define as stages III and IV. In spite of this, most patients experience a relapse and ultimately develop progressive disease with their tumors becoming increasingly chemoresistant. Overall, only about 15% of women with advanced disease survive beyond 5 years. Survival rates are less than 10% for women with stage IV disease, but they may approach 35% for women with optimally debulked stage III disease.43

Chemotherapy for epithelial ovarian cancer has evolved dramatically over the last 25 years. In the early 1980s, the standard regimen for advanced epithelial ovarian cancer was cyclophosphamide and doxorubicin, a combination derived through studies conducted by the GOG.44 During the 1980s and 1990s, two new classes of agents were discovered: platinums and taxanes. These agents have had a dramatic impact on outcomes for patients with advanced epithelial ovarian cancer. Platinum agents work by damaging DNA.45 Cisplatin and carboplatin undergo hydrolysis after administration and then produce intrastrand and interstrand adducts in DNA that limit cell division, ultimately inducing apoptosis.46 Taxanes bind to tubulin polymers (microtubules), disrupting normal microtubule activity and halting mitosis that leads to apoptosis.

Many clinical trials have shown the value of platinum in epithelial ovarian cancer. An early GOG study randomized women with large-volume advanced epithelial ovarian cancer to cyclophosphamide plus doxorubicin with or without cisplatin.47 The addition of cisplatin resulted in significant improvements in complete response rate (51% versus 26%) and progression-free survival (13 versus 8 months). Other studies noted similar findings in which the addition of platinum to an alkylating agent improved progression-free survival in advanced epithelial ovarian cancer.48 This clinical evidence led to the regimen of cyclophosphamide, doxorubicin, and cisplatin becoming the treatment of choice for advanced epithelial ovarian cancer during the 1980s. Doxorubicin was later removed from this standard regimen because randomized trials failed to demonstrate a survival advantage by including it in platinum-based combinations.49 A meta-analysis demonstrated a slight survival benefit with the three-drug regimen; however, the authors concluded that the small survival advantage did not justify the added toxicity from doxorubicin.50

Although the addition of cisplatin to alkylating agents did appear to improve response rate and progression-free intervals in advanced disease, demonstration of a distinct survival advantage in randomized clinical trials has been elusive. In 2000, a Cochrane Database meta-analysis of over 8700 women treated on 49 different trials reported that the survival hazard ratio was 0.88 (95% CI 0.79-0.98) in favor of platinum combination chemotherapy.51

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