Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial

Authors: The ICON and AGO Collaborators
Source:Lancet, Vol 361, 2099-2106, 2003

Background

• Ovarian cancer is the fourth most common cancer in women and among the most aggressive.
• Most women diagnosed with ovarian cancer will develop recurrent disease and die within 5 years. Hence, effective salvage therapy is an extremely critical part of treatment.
• First line treatment consists of platinum-based chemotherapy (cisplatin or more increasingly, carboplatin) with or without a taxane.
• Upon relapse, patients are often treated according to their recurrence-free interval: Patients relapsing more than 6 months after treatment (the majority of patients) are often retreated with platinum-based chemotherapy, while those who relapse within 6 months are often treated with paclitaxel.
• Small, nonrandomized studies have demonstrated a response rate to platinum plus paclitaxel chemotherapy of up to 90% in patients with relapsed but still platinum sensitive disease, though no randomized trial has been done to directly compare paclitaxel plus platinum to conventional platinum-based chemotherapy
• This study was run to assess the efficacy of paclitaxel in combination with platinum-based chemotherapy versus platinum-based chemotherapy alone.

Materials and Methods

• This study actually reports on three very similar protocols, all randomizing between paclitaxel + platinum versus platinum alone.
• Eligible patients included those with relapsed epithelial ovarian cancer who had previously received platinum-based chemotherapy (one protocol specified the necessity to have been treated with platinum and paclitaxel chemotherapy) and who were disease-free for at least 6 months (at least 12 months in one of the protocols).
• Patients were randomized to receive either conventional platinum-based chemotherapy (carboplatin AUC 5, cisplatin 75 mg/m2) or platinum + paclitaxel (175 mg/ m2 or 185 mg/ m2) in 3 week cycles.
• Patients were specified to receive 6 cycles (or 3 cycles +3 additional according to response) of chemotherapy.
• Patients were stratified so that subgroup analyses could be done according to time since last completion of chemotherapy, number of previous lines of chemotherapy, previous treatment with taxanes or not, type of platinum agent, age, and performance status.
• Quality of life analyses were also done, with attention to fatigue, nausea and vomiting, pain, and global health status.
• Median follow up was 46 months

Results

• 802 patients enrolled in the study (410 to conventional platinum-based chemotherapy, 392 to paclitaxel + platinum chemotherapy).
• Pre-treatment characteristics between the two groups were similar with the majority previously receiving carboplatin or carboplatin + paclitaxel chemotherapy, >90% only receiving one previous course of chemotherapy and >75% with a greater than 12 mo interval since last chemotherapy.
• 95% of patients randomized to platinum + paclitaxel chemotherapy received it as per protocol (80% received carboplatin + paclitaxel).
• Those patients randomized to platinum-based regimens received various types of chemotherapy, the most common of which were carboplatin alone (71%) and CAP (17%).
• 2 year overall survival was better in the paclitaxel + platinum group (57% vs. 50%, p=.02)
• Median survival was also higher in the paclitaxel + platinum group (29 mo vs. 24 mo)
• 1 year progression free survival favored the paclitaxel + platinum group (50% vs. 40%)
• Hazard ratios favored paclitaxel + platinum for all subgroups (including the ~40% who had previously received paclitaxel), though none reached statistical significance
• Toxicity profiles differed in a few distinct areas: 20% had grade 2-4 neurological toxicity in the paclitaxel + platinum group versus 1% in the conventional arm; 86% experienced alopecia in the paclitaxel + platinum arm compared with 25% in the conventional arm; 46% had hematological toxicity in the conventional arm versus 29% in the paclitaxel + platinum arm
• In the quality of life assessment, most patients had no or little functional difficulties prior to treatment, with return to baseline after treatment. The only score that differed among the groups was a transient difference in nausea and vomiting, which was worse in the conventional platinum chemotherapy arm

Author's Conclusions

• This study suggests a beneficial effect for paclitaxel in combination with platinum chemotherapy for both progression free survival and overall survival in patients with platinum-sensitive relapsed ovarian cancer
• All women who relapse more than 6 months after the completion of previous platinum-based chemotherapy should be considered for treatment with platinum + paclitaxel
• Paclitaxel was most commonly combined with carboplatin in this study, reflecting community practice

Scientific Implications

This study demonstrates an increase in efficacy with paclitaxel + platinum chemotherapy over conventional platinum based chemotherapy. As most patients with relapsed ovarian cancer will ultimately die of their disease and treatment of the relapse can almost be considered palliative, it is important to also look into toxicity and quality of life in these patients. From this data, it seems as though paclitaxel can be added without any large amount of increased toxicity, though patients should be aware of the risk of neuropathy from paclitaxel and the high risk of alopecia seen when using paclitaxel. It should be mentioned that this group of patients had a good performance status and a longer time to relapse (the majority of over 12 months). This has a couple of implications. First, their disease is likely less aggressive than those patients who relapse sooner. Also, these patients still have relatively platinum-sensitive disease. These characteristics could explain why this study was so positive with respect to the benefit seen with paclitaxel and platinum. However, these patients comprise a majority of patients with relapsed ovarian cancer, and it seems that major consideration should be given to adding paclitaxel to conventional platinum based chemotherapy regimens in the salvage setting.