Paclitaxel and Platinum versus Platinum-based Chemotherapy in Relapsed Ovarian Cancer: ICON 4

Neha Vapiwala, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 13, 2003

Presenter: Jonathan A. Ledermann, MD
Affiliation: University College, London, UK/ MRC

The optimal second-line chemotherapy for platinum-sensitive patients with relapsed ovarian cancer is an issue of ongoing research. Despite advances in therapy over the years, there remain unacceptably high relapse rates in patients following initial chemotherapy. About half of relapsed patients are "platinum-sensitive", defined as relapsing after at least 9 months of platinum-based treatment. In contrast, those who relapse within 6-9 months of diagnosis are described as either primarily refractory or platinum-resistant. This study represents an international collaboration comparing paclitaxel in combination with platinum-based chemotherapy versus platinum-based chemotherapy alone in relapsed platinum-sensitive patients.

Methods:

Total of 802 patients randomized
2/3 from MRC UK
1/4 from IRFMN, Italian group
remainder from AGO, German group

Randomized to receive one of two treatments:

(n= 410) conventional : carboplatin AUC 5/6 OR cisplatin 50 mg/m2 (single agent) or 75 mg/m2 (combo agent)
(n= 392) experimental : carboplatin AUC 5/6 AND paclitaxel 175 mg/m2

Both arms well-balanced for various factors.
Performance status 0-1 = 93% overall
Previous carbo-taxane treatment = 1/3 overall
Previous carbo alone treatment = 1/3 overall
Previous taxane exposure = 43% overall
Only 1 previous line of chemo = 92%

Overall, 74% of patients received >/= 6 cycles (more of these patients came from experimental arm).

Protocol compliance:
arm 1 = 71%
arm 2 = 81%

Results:

Median follow-up = 42 mos
Overall number of deaths = 530 (66%)
Overall survival significantly better arm 2 vs. arm 1 with hazard ratio = 0.82 (p<0.023); absolute difference = 7% at 2 years (from 50 to 57%)
Progression-free survival significantly better in arm 2 vs. arm 1 with hazard ratio = 0.76 (p<0.001); absolute difference = 10% at 1 year (from 40 to 50%).
AGO data only
CR/PR rates arm 1 = 54% vs. arm 2 = 66%
MRC data only
No significant difference in quality-of-life
No differences seen on various subgroup analyses.

Author's Conclusions:
Increase in overall and progression-free survival is seen with the use of paclitaxel in combination with platinum-based chemotherapy in platinum-sensitive patients with relapsed ovarian cancer.

No evidence suggesting differences between the two arms based on the following subgroup analyses: randomization group (MRC vs. Italy vs. AGO), time since completion of last chemotherapy, previous taxane exposure, age, performance status, and number of previous lines of chemo.

Scientific Implications:
The data presented here will likely have a significant impact on treatment decisions in this specific group of patients. It is noteworthy that the benefit in survival seen here with combination taxane-platinum conflicts with findings from an older trial (ICON 3), which showed no difference with taxanes as first-line therapy. There are several explanations for this. First, the two trials feature different patient poulations, as this study had a higher number of platinum-sensitive patients. Secondly, the relative proportion of tumor cells with p53 mutations is known to increase following first-line treatment, further making the current patient group different from that in ICON 3. Finally, as many as 75% of patients received >90% of the planned cisplatin dose, whereas only 40% did so in this study. Of note, an improvement in PFS (and possibly OS as the data matures) has been reported in the similarly-designed Spanish GEICO trial, reinforcing the importance of this treatment approach. The next stage might involve incorporation of biologic agents to the above combination regimen.