New cytotoxics and non-cytotoxics in epithelial ovarian cancer

Several new cytotoxic agents with activity in relapsed ovarian cancer are being combined with paclitaxel plus platinum as the first step to assess their impact in randomized trials against the standard treatment. These include topotecan, gemcitabine, epirubicin, and liposomal doxorubicin. Because of overlapping toxicities, there have been challenges in combining some of these agents in full dose with combination paclitaxel plus platinum. These have been overcome by use of sequenced administration. In addition to these new agents, novel non-cytotoxic drugs targeting specific signaling molecules or the tumor microenvironment provide additional avenues for clinical investigation. Many of these agents are rational to assess in ovarian cancer where laboratory research has pinpointed a number of alterations in molecules involved in cell signaling and cell cycle control. Examples include the antibody to HER 2/neu, agents targeting protein kinase C alpha, the p53 gene, and matrix metalloproteinase inhibitors. The challenges facing their assessment include how to determine adequate dosing when toxic effects are minimal and how to assess evidence of antitumor activity, short of conducting randomized studies. Finally, how best to use such agents together with conventional chemotherapy, in combination or in sequence, is unknown. Large clinical studies with some of these agents will provide some answers to their impact and how best to use them in the first-line management of advanced epithelial ovarian cancer.