Platinum-Paclitaxel As Second-Line Chemotherapy for Relapsed Ovarian Cancer
Platinum-Paclitaxel As Second-Line Chemotherapy for Relapsed Ovarian Cancer
Abstract & Commentary
Synopsis: There has been some controversy on the role of taxanes in combination with platinum for the treatment of ovarian cancer. In the current report, patients who relapsed after a disease-free interval of 6 months or more were randomized in 2 large, multicenter trials conducted in Europe to receive either platinum (or typical platinum-based regimens) or paclitaxel plus platinum. Analysis of the data after a median follow-up of 42 months demonstrated progression-free and overall survival advantage for those receiving platinum with paclitaxel. Although complexities in the study design make conclusions far from absolute, the data presented make a strong case for paclitaxel in this setting.
Source: The ICON and AGO Collaborators. Lancet. 2003;361:2099-2106.
Despite improvements in first-line chemotherapy for ovarian cancer, most patients recur within 3 years of diagnosis.1 The choice of second-line chemotherapy remains controversial, and it is apparent that the success of second-line therapy depends, to a large extent, on the disease-free interval (DFI) after initial chemotherapy. The standard of care recently has been to tailor chemotherapy based upon whether the DFI was greater than 6 months. Platinum-based chemotherapy is most frequently given when the DFI is 6 months or greater, but alternative agents are often chosen if the interval had been less than 6 months. The current report represented a joint effort from the International Collaborative Ovarian Neoplasm 4 (ICON 4) and Arbeitsgemeinschaft Gynaekologische Onkologie (AGO), both of which conducted multicenter, randomized trials for patients who had recurrent ovarian cancer and were considered platinum-sensitive on the basis of a greater than 6 month DFI after initial chemotherapy. All patients received platinum chemotherapy initially, and some had also received paclitaxel as part of the first-time treatment. The ICON 4 and AGO trials were run parallel to each other. Enrolled in this study were 802 patients from 119 different hospitals throughout Europe. Eligible patients had relapsed epithelial ovarian cancer requiring chemotherapy; previously received platinum-based chemotherapy; and were treatment free for greater than 6 months (AGO) or 12 months (ICON 4).
The patients were randomly assigned to either conventional platinum-based therapy or platinum and paclitaxel. Chemotherapy was administered every 3 weeks. The dose of carboplatin was determined by the area under the curve (AUC) method of Calvert and was a minimum of 5. Patients who enrolled through ICON 4 received either carboplatin or cisplatin. The carboplatin was set at a dose of AUC 5, whereas the cisplatin was given at a minimum dose of 75 mg/m2 (if given as a single agent) or 50 mg/m2 (if given in combination with other drugs). Patients in ICON 4 assigned paclitaxel plus platinum chemotherapy were to receive 175 mg/m2 of paclitaxel given in a 3-hour infusion, followed by either the carboplatin or cisplatin at the dose mentioned above. Patients in the AGO protocol assigned paclitaxel plus carboplatin received 185 mg/m2 of paclitaxel given in a 3-hour infusion, followed by carboplatin as noted above. Analysis was by intention to treat.
After a median follow-up of 42 months, 530 patients had died. The survival curves revealed a difference in favor of paclitaxel plus platinum (hazard ratio, 0.82; 95% CI, 0.69-0.97; P = .02). This corresponded to an absolute difference in 2-year survival of 7% between the group receiving paclitaxel and that receiving platinum without paclitaxel (57 vs 50%; 95% CI for a difference, 1%-12%), and median survival of 5 months (29 vs 24 months; CI for a difference, 1 month-11 months). Of the 820 patients randomized, 717 developed progressive disease or died. The progression-free survival curves showed a difference in favor of paclitaxel plus platinum (hazard ratio, 0.76; [0.66-0.89], P = .0004), corresponding to an absolute difference in 1-year progression-free survival of 10% (50 vs 40% [4-15]) and in median progression survival of 3 months (13 vs 10 months [1-5]). Thus, the paclitaxel plus platinum chemotherapy was noted to improve survival and progression-free survival among patients with relapsed, platinum-sensitive ovarian cancer.
Comment by William B. Ershler, MD
The findings from this analysis were presented at the ASCO meeting this year and generated a lively discussion, particularly in light of prior data published from ICON indicating no advantage to using paclitaxel with carboplatin as initial therapy for ovarian cancer.2 The prior ICON study, which had demonstrated no added benefit of paclitaxel, runs counter to the common impression of the superiority of taxane-platinum combinations in the initial therapy for ovarian cancer, and some interpreted the current finding as an endorsement of the importance of paclitaxel in the treatment of this disease. The presenters at ASCO, in defense of the prior ICON findings, speculated that patients with recurrent disease were less capable of receiving full-dose platinum, and thus benefited from the added taxane. They pointed out that in the current trial only 40% of patients received 90% or more of the planned dose of carboplatin.
Another finding from this study that was quite important and perhaps unexpected was that the combination of paclitaxel plus platinum resulted in no added impairment in quality of life, including measures of global health status, fatigue, nausea, vomiting, and pain. Thus, the study had demonstrated added benefit from paclitaxel in combination with platinum chemotherapy in terms of both survival and progression-free survival in those with relapsed ovarian cancer and a DFI of 6 months or more.
As pointed out in the accompanying editorial,3 a number of questions remain. In that editorial, Kaye points out that the extent of benefit in certain subgroups was only modest, and before a global recommendation can be fully endorsed (and established as standard of care), additional, confirmatory studies would be indicated. For example, women who relapsed between 6 and 12 months after initial therapy had only modest demonstrable benefit compared to those with a DFI of greater than 12 months. Similarly, those who had received paclitaxel as initial therapy had less convincing demonstrable benefit with paclitaxel as salvage therapy.
Although the data give some guidance with regard to optimal management, the use of a chemotherapy strategy that was not curative initially defines the scope of expectations in terms of quality of life and added months of survival. However, the need to develop new, more effective agents and combinations should remain the primary goal for the overall advancement of care for ovarian cancer. Short of the appearance of effective new agents and approaches, the reapplication of drugs that produced a DFI of a year or so can, at best, be expected to do the same again, and this falls far short of the ultimate goal of cure.
References
1. Parkin DM, et al. Eur J Cancer. 2001;37:S4-S66.
2. ICON Collaborators. Lancet. 2002;360:505-515.
3. Kaye SB. Lancet. 2003;361:2094-2095.
Dr. Ershler is UNOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, D.C.
There has been some controversy on the role of taxanes in combination with platinum for the treatment of ovarian cancer. In the current report, patients who relapsed after a disease-free interval of 6 months or more were randomized in 2 large, multicenter trials conducted in Europe to receive either platinum (or typical platinum-based regimens) or paclitaxel plus platinum.Subscribe Now for Access
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