Doxorubicin/Cisplatin/Paclitaxel Regimen Improves Survival in Endometrial Cancer

CHICAGO—Adding paclitaxel (Taxol) and G-CSF support to the standard regimen of doxorubicin and cisplatin (Platinol) improved response rates and increased survival by about 3 months for patients with advanced or recurrent endometrial cancer in a randomized controlled phase III trial conducted by the Gynecologic Oncology Group (GOG) (ASCO abstract 807).

Gini F. Fleming, MD, of the University of Chicago reported that the three-drug regimen called TAP (taxane/anthracycline/platinum) increased 12-month survival from 50% to 59%, complete response from 7% to 22% ,and partial response from 27% to 36%. It also advanced median progression-free survival from 5.3 months to 8.3 months and median overall survival from 12.1 months to 15.3 months (see Table 1).

TAP was well tolerated hematologically, but produced more neuropathy and gastrointestinal toxicity than the two-drug regimen identified as AP (anthracycline/platinum), according to Dr. Fleming.

About half the women in both arms of the study (54% on TAP and 47% on AP) did not complete all seven cycles of chemotherapy. Five treatment-related deaths and five nonfatal cases of grade 3 congestive heart failure were recorded among the 134 patients in the TAP arm; neither occurred among the 131 patients who received the standard protocol.

The trial, GOG177, enrolled 273 patients from December 1998 to August 2000. Eight patients were later excluded and three patients on the TAP arm never received therapy, but were included in the final analysis. None had had prior chemotherapy.

HER2/neu Overexpression

The investigators were also interested in the extent of HER2/neu overexpression in patients with advanced or recurrent endometrial cancer and whether overexpression affected the outcome of doxorubicin-based therapy. They were able to obtain tissues samples, mostly from primary tumors, for about 88% of patients in the trial.

About 20% (16% AP and 19% TAP) of the samples demonstrated 3+ HER2/neu overexpression on the DAKO HercepTest. Dr. Fleming said, however, that HER2/neu status did not predict response or survival.

50% Stopped Therapy

The study protocol called for both regimens to be repeated every 21 days for seven cycles. The AP cohort was to receive 60 mg/m² of doxorubicin plus 50 mg/m² of cisplatin in one day. About two-thirds of all the patients received a starting dose of 45 mg/m² of doxorubicin, however, as Dr. Fleming reported that patients who were over 65 or who had prior pelvic radiotherapy were given a lower dose when they started the AP protocol.

The TAP regimen was delivered over 2 days, with patients receiving 45 mg/m² of doxorubicin plus 50 mg/m² of cisplatin on day 1, followed by 160 mg/m² for 3 hours of paclitaxel on day 2 with G-CSF support on days 3 to 12. "This was a theoretical attempt to minimize any cardiac and neural toxicity from the combination of these three agents," Dr. Fleming said.

Only about half of the patients on either arm completed all seven cycles, according to Dr. Fleming. More patients on the AP arm came off therapy because of progression—34% vs 14% on TAP. More patients on TAP had to stop treatment because of toxicity—24% vs 10% on AP. Sixteen patients on TAP but only one on AP developed grade 3 sensory neuropathy.

‘Convincingly Superior’

Franco M Muggia, MD, of New York University School of Medicine described GOG 177 as a very important trial and pronounced TAP to be "convincingly superior"—with one caveat. More women in the AP arm had recurrent disease (71% vs 58% on TAP), whereas more women on the TAP arm had stage III disease (15% vs 7% on AP) and stage IV disease (27% vs 22% on AP).

"I think GOG 177 boosts the role of chemotherapy in advanced and recurrent endometrial cancer," he said. "I think we need to pay attention that there is a great deal of activity from the three drug classes when they are combined, and they are leading to a prolongation of survival."

Future Directions

Dr. Muggia suggested that future studies consider substituting carboplatin for cisplatin and pegylated liposomal doxorubicin for conventional doxorubicin. He also recommended exploring different strategies such as sequential doublets and developing more user-friendly three-drug regimens.

Dr. Fleming said she has proposed trials to reduce the toxicity of the three-drug regimen, possibly with a neuroprotective agent. She also said that she would like to see a large randomized trial, comparing TAP to treatment with paclitaxel and carboplatin (Paraplatin) in endometrial cancer.

Questioning whether AP is the standard treatment for endometrial cancer, Dr. Fleming replied: "My perception is that carboplatin/paclitaxel is what a lot of people in the United States use because they’re used to it in ovarian cancer. I don’t know if there is a standard. That’s part of the problem,’’ she told ONI, adding that whether or not AP was the standard, "The regimen shouldn’t be standard anymore."