Treatment Modality in Patients with Platinum-resistant Relapse

Currently, there is no widely accepted standard therapy for relapsed resistant disease. In the absence of demonstrated superiority of combination over single-agent treatment, therapy for advanced resistant disease is sequential single-agent treatment.

Several agents have been studied, including paclitaxel, pegylated liposomal doxorubicin, topotecan, oral etoposide, gemcitabine, hexamethymelamine, oxaliplatin or vinorelbine. Table 2 summarizes some of the agents used in recurrent resistant ovarian cancer along with their respective response rates.

The response rate for the different single agents demonstrating activity for the treatment of recurrent resistant ovarian cancer are within the narrow range of 15–25%. In the few randomized comparative studies that have been performed, no agent demonstrated superior efficacy in this setting.^29–31 Therefore, the choice of treatment in the platinumresistant patient population is based on side effect profile and other quality-of-life issues.

Because each of the active agents in recurrent ovarian cancer has a unique mechanism of action, the toxicity profiles are often non-overlapping. It is therefore easier to identify more favourable or less favourable toxicities based on patient preference and/or available supportive therapies. For example, in trials with both pegylated liposomal doxorubicin and topotecan, paclitaxel was associated with a greater incidence of alopecia, which can confer negative psychological effects on patients and which cannot be reversed until after therapy has been discontinued.^29,32 Similarly, topotecan was associated with a greater incidence of myelosuppression when compared with pegylated liposomal doxorubicin, resulting in greater use of haematopoietic growth factors and dosing modifications.³¹ By contrast, the most common adverse event associated with pegylated liposomal doxorubicin is Hand-Foot Syndrome, (HFS) and mucositis.³¹

Patient compliance and preference has also emerged as an important consideration in selecting a therapeutic option. Because the three proven active monotherapy agents are all administered via IV infusion, the duration of infusion and the frequency of administration can serve as points of differentiation. For example, although the duration of topotecan infusion is only 30 minutes, the fivetimes- weekly regimen might prove difficult for some patients. Overall, particularly when the primary goal of therapy is palliation, taking into account patient preference and compliance is of paramount importance.

Currently, there are a number of on-going randomised trials exploring the efficacy of monotherapy compared to dual therapy.

Future Therapies

Despite the progress made in refining the chemotherapy regimens used in the treatment of relapsing ovarian cancer, the majority of patients with this disease will eventually die of their disease. Although a number of newer chemotherapeutic agents are being developed, much of the focus of research efforts has shifted towards novel agents, including targeted agents towards specific molecular pathways.

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib are currently being studied in ovarian cancer. These agents are attractive because they are administered orally and are associated with minimal adverse effects. Preclinical data suggest that gefitinib may act synergistically with chemotherapy in ovarian tumours that have high expression of the EGFR^.33 Erlotinib has already been evaluated in a phase II study, the preliminary results of which have already been released.³⁴ Three patients out of 34 had partial responses, and 14 patients (42%) had stable disease. Erlotinib is currently in a phase III randomised trial to evaluate its efficacy as maintenance treatment after first-line, platinum-based chemotherapy.

Vascular endothelial growth factor (VEGF) overexpression in ovarian cancer cells is thought to be an important factor in tumour angiogenesis and biologic aggressiveness. A number of agents are being developed to target VEGF in the treatment of various solid tumours. Bevacizumab is a recombinant monoclonal antibody to VEGF that has been studied in a number of solid tumours, including renal cell, colorectal and lung cancer.The activity and tolerability of bevacizumab in the treatment of persistent or recurrent ovarian cancer is currently being assessed. Bevacizumab has shown efficacy in patients with resistant ovarian cancer; however, the safety–benefit ratio of bevacizumab is under debate in this patient group, due to reports of gastrointestinal perforations in the bevacizumab treatment group^.35 Despite these concerns, bevacizumab is currently being assessed as first-line combination therapy in both Europe and the US.

Other novel agents being evaluated in the treatment of ovarian cancer include the proteasome inhibitor PS-341 (bortezomib), the matrix metalloproteinase inhibitor BAY 12-9566 and the small molecule SU6668, which inhibits the Flk- 1/KDR, platelet-derived growth factor, and fibroblast growth factor receptors.