Controversies in chemotherapy — what is standard treatment?

Abstract

This paper discusses some current controversies regarding optimal first-line treatment for patients with advanced ovarian cancer. Despite improvements seen in median and overall survival using platinum-based chemotherapy, longterm survival rates for patients with advanced epithelial ovarian carcinoma remain disappointing and several efforts have been made recently to develop more effective primary therapy. In the early 1990s, paclitaxel was first tested in ovarian cancer. In GOG111, the cisplatin+paclitaxel regimen was judged to be superior compared with the platinum-cyclophosphamide control arm, with an improvement of overall response rate, median progression-free interval and overall median survival. These favourable data were confirmed by the OV 10 trial. In contrast, in a further GOG trial (GOG132), there was no difference in survival between cisplatin alone and the combination of paclitaxel and cisplatin. ICON3, the first and only trial comparing paclitaxel plus carboplatin against carboplatin alone or a (non-taxane) cisplatin-based control arm, again failed to demonstrate any advantage for the platinum-taxane arm, either in progression-free survival or in overall survival. The results of ICON3, in accordance with the GOG132 study, appear to contradict the earlier positive results seen for paclitaxel and cisplatin in the GOG111 and OV10. Several hypotheses have been raised to explain this discrepancy including differences in the extent and timing of crossover to taxanes in the control group, differences in the type of patients included, differences in the efficacy of research regimens or in the efficacy of the control regimens. A meta-analysis with individual patient data demonstrated a substantial heterogeneity between groups using different control arms, possibly indicating that the cyclophosphamide/cisplatin regimen used in the two “positive” trials may be less effective than the control regimen used in the other trials. It will be almost impossible to achieve an agreement on these proposed explanations. However, this meta-analysis provides evidence that the introduction of taxanes can lead to a survival advantage vastly inferior to that expected after the results of the GOG111 and OV10 trials. Ongoing research is focusing on the addition of a third drug to platinum/taxane in regimens consisting of triplets or sequential doublets. Determining the characteristics to define the patient population with relapse is important to evaluate the therapeutic options with the greatest likelihood of success. Appropriate salvage therapy is based on the timing and nature of the recurrence and the extent of prior chemotherapy. The main objectives of salvage chemotherapy include (1) improvement in quality of life and symptoms, (2) tumour load reduction and survival advantage, and (3) evaluation of potentially active new drugs to be included in first-line treatment. Since the goal is palliation in most cases, monotherapy is generally indicated. Unfortunately, durable responses to salvage chemotherapy are rare and cure almost impossible. The sequential use of the agents currently available for salvage treatment in monotherapy may transform ovarian cancer into a chronic disease and increase the length of survival. Perhaps the most interesting role of second-line chemotherapy is to identify, new potentially active drugs, which can then be used upfront. For patients with platinum-sensitive disease, it was unclear, until recently, whether the platinum-based combination was superior to single-agent platinum at the time of relapse. The recent results of ICON4 seem to indicate an advantage in both survival and progression-free survival for patients with relapsing platinum-sensitive ovarian cancer treated with the combination platinum/taxane compared with conventional platinum-based chemotherapy.