ICON3 Challenges Paclitaxel/Carbo Superiority in Ovarian Cancer

ASCO—In contrast to many recent studies, the ICON3 trial finds that paclitaxel (Taxol) plus carboplatin (Paraplatin) is no more effective than other chemotherapy regimens as first-line therapy of ovarian cancer. ICON3—the Third International Collaborative Ovarian Neoplasm study—is an international multicenter trial involving 2,074 women with newly diagnosed ovarian cancer requiring chemotherapy.

Nicoletta Colombo, MD, vice director, Division of Gynecology, European Institute of Oncology, Milan, Italy, presented preliminary results at the 36th Annual Meeting of the American Society of Clinical Oncology (ASCO), New Orleans.

The trial tested paclitaxel plus car-boplatin against either carboplatin by itself or cyclophosphamide plus doxorubicin plus cisplatin (Platinol) (CAP). Dr. Colombo said that because the ICON2 study had found no difference between carboplatin and CAP in effectiveness, in ICON3 investigators were allowed to choose which control regimen to use.

However, in a commentary, Robert Young, MD, of Fox Chase Cancer Center, called this decision “a serious flaw in the design of the trial. One of the basic tenets of randomized clinical trials is that they not only control for those things you think are important in outcome, they also control effectively for those things you don’t realize are important.”

In ICON3, paclitaxel was given as a 3-hour infusion at 175 mg/kg². The dose of carboplatin was determined by Calvert’s area-under-the-curve method. In the CAP control group, cyclophosphamide was given at 500 mg/m², doxorubicin at 50 mg/m², and cisplatin at 50 mg/m². For all groups, treatment was administered every 3 weeks for six cycles.

The researchers found no differences between the paclitaxel/carboplatin group and the control groups. At 1 year, the progression-free survival rate was 61% in the paclitaxel/carboplatin group vs 60% in the control subjects.

Median progression-free survival was 16.8 months (treatment group) vs 16.2 months (control group). Similarly, overall survival at 2 years was 64% (treatment) vs 62% (control), with median overall survival of 38.7 months (treatment) vs 36 months (control).

Absence of Significance

“I would like to highlight the absence of statistical significance and the size of the effect we are seeing,” Dr. Colombo said. “In other words, even though in the future, given the large number of patients included in ICON3, we may be able to pick up a statistically significant difference, this will be probably in the range of 2% more patients surviving in the research arm compared to the controls.”

Both Drs. Colombo and Young pointed out that these results are at odds with some other studies of paclitaxel plus a platinum-based agent. In those studies, women in the control arm had shorter progression-free survival and overall survival than in ICON3.

Dr. Young said that all of the relevant studies, including ICON3, were well designed and had good total patient numbers. “So it’s unclear why ICON3’s control subjects did better,” he said.

He concluded that, despite the ICON3 results, “for previously untreated advanced ovarian cancer with substantial residual disease, the treatment of choice should be Taxol/carboplatin. . . . For patients with limited or no residual disease, again I would select Taxol/carboplatin.” He said that the optimal dose remains to be determined.