Carboplatin/Paclitaxel Appears To Be as Effective as Cisplatin/Paclitaxel in Ovarian Cancer

LOS ANGELES--Interim analysis of a major German-Austrian trial comparing cisplatin (Platinol)/paclitaxel (Taxol) with carboplatin (Paraplatin)/paclitaxel as first-line treatment in ovarian cancer found significantly less toxicity with carboplatin/paclitaxel, with no apparent loss of efficacy.

Andreas du Bois, MD, reporting on behalf of the Austrian-German Oncology (AGO) Study Group, said that the carboplatin/paclitaxel combination has been recommended as the new "standard therapy" combination for all future phase III studies by this group.

A total of 798 patients were randomized to first-line treatment with either cisplatin/paclitaxel or carboplatin/paclitaxel. Paclitaxel (185 mg/m²) was given as a 3-hour infusion. Cisplatin was given at 75 mg/m², and carboplatin was given to an area under the curve (AUC) of 6. Cycles were repeated every 3 weeks for a maximum of 6 courses.

Inclusion criteria were epithelial ovarian cancer of FIGO stage IIC-IV and no prior radio- or chemotherapy. "No secondary debulking was allowed, so if patients were scheduled to receive a second cytoreductive surgery after 3 cycles, they could not be entered into the study," Dr. du Bois said.

Maintenance therapy (ie, unauthorized second-line treatment) after completion of primary treatment was not allowed.

Dr. du Bois reported data from 702 evaluable patients. "The median observation period for these patients is 70 weeks," he said. At study entry, 209 patients had measurable disease, and three-fourths of them are evaluable for response. Toxicity data are based on more than 3,500 courses in 690 patients.

Treatment delays of more than 1 week were uncommon in either group (6% with carboplatin, 5% with cisplatin). Fewer than 5% of courses were delivered with reduced doses. Most patients received at least 5 or 6 courses of chemotherapy, although 10% to 15% of patients stopped before that, mostly due to progressive disease.

Eight patients switched over from the cisplatin arm to the carboplatin arm due to toxicity. No patients switched from carboplatin to cisplatin.

Toxicity Results

Toxicity problems were more common and more significant overall on the cisplatin/paclitaxel arm (see Table). "Hematologic toxicity (thrombocytopenia and neutropenia) was more common in the carboplatin arm, but most of the myelosuppression did not result in clinically relevant toxicity," Dr. du Bois said.

Nonhematologic toxicity was significantly more frequent in the cisplatin-treated patients. "When we consider all grade 3-4 toxicities, 56% of patients in the cisplatin group experienced at least one course with grade 3-4 toxicity, compared to 37% of carboplatin-treated patients," he said.

The most striking differences were seen in GI toxicity, especially emesis and nausea. "Grade 3-4 toxicity, which means severe nausea and vomiting, was threefold increased in the cisplatin group, compared to carboplatin," he said.

Neuropathy occurred much more frequently in the cisplatin arm. Overall, significantly fewer of the carboplatin-treated patients had neurotoxicity, and it occurred a little later, he said.

"Our latest analysis showed that one-third of cisplatin-treated patients still show neurotoxicity after 1 year of follow-up vs about 10% of carboplatin-treated patients," Dr. du Bois said. "This is important because a substantial proportion of patients came back for second-line treatment and those still suffering from neurotoxicity were not able to receive potentially neurotoxicity-causing agents again."

Differences in nonhematologic toxicity translated into differences in quality of life. "The cisplatin-treated patients had a decreased quality of life, whereas carboplatin treatment led to maintenance of quality of life after course 3. This is highly significant," he said.

The investigators wondered why quality of life would improve while patients were still on chemotherapy. "This may be because the baseline estimation of quality of life was done about 2 weeks after radical surgery, 1 or 2 days after communication of the diagnosis to the patient, and surely reflects depression," Dr. du Bois said. "Quality of life apparently increases when the patient has time to accept the diagnosis and recover from surgery; then the differences become obviously related to therapy."

The efficacy data, although not fully mature, show no significant differences in response rate, complete remission rate, or progression-free survival.

Response rates were slightly but not significantly higher with cis-platin (80% vs 68% for carboplatin), "but this did not translate into improved progression-free survival," he said. Median progression-free survival was 75 weeks for carboplatin and 73 weeks for cisplatin. Overall 1-year survival is about 91% in both groups.

"Our conclusions are that carboplatin/paclitaxel compared to cisplatin/paclitaxel is less toxic and allows better quality of life during chemotherapy," Dr. du Bois said.

He noted that although the data are not yet mature enough to state that the two regimens are equivalent regarding overall survival, the researchers believe this will prove to be the case.

"Therefore," he said, "the AGO recommends that carboplatin/paclitaxel be used as standard therapy in its future phase III trials. It is also an acceptable alternative to cisplatin/paclitaxel for patients not eligible for ongoing trials."

The discussant for the study, Tate Thigpen, MD, of the University of Mississippi, said that longer follow-up is necessary before conclusions regarding efficacy can be made. "We must ensure that substituting carboplatin for cisplatin is a safe thing to do for our patients in terms of efficacy," he said.

A new study similar to the AGO trial, GOG-158, has completed accrual of 817 stage III ovarian cancer patients. This study is powered to have a 90% probability of detecting a 30% difference in survival between cisplatin/paclitaxel and carboplatin/paclitaxel.

To date, he said, there have been 253 events in GOG-158, an insufficient number to allow reporting of survival data. "Our goal is 382 events," he said. In contrast, AGO with 702 evaluable patients reported on survival with only 222 events.

Based on the AGO data, Dr. Thigpen said, "it is fair to say that paclitaxel/carboplatin has better patient tolerance than paclitaxel/cisplatin, but conclusions regarding efficacy are premature at present and require further follow-up."

Dr. du Bois did not disagree with that statement, but said that "our response data and progression-free survival data, especially in the suboptimal disease group, are very close to mature. We needed data to help in the design of new studies, so for that purpose, I think it is justified to look at these data at this time."