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American Society of Clinical Oncology 35th Annual
Meeting
Day 2 - May 16,
1999
Maurie Markman, MD
Click
Here to listen to an audio interview with Dr. Markman. Duration: 4 min. 57
sec.
In 1996, the Gynecologic Oncology Group (GOG) published the results of a randomized Phase III trial that compared the then "standard chemotherapy" regimen of cisplatin (75 mg/m2) plus cyclophosphamide (75 mg/m2) to an experimental regimen of cisplatin (75 mg/m2) plus paclitaxel (135 mg/m2 delivered over 24 hours). This landmark study demonstrated that the paclitaxel-containing regimen resulted in a major improvement in both progression-free and overall survival in suboptimal residual advanced ovarian cancer. These results significantly changed the management of this difficult malignancy.
A consortium of investigators from Canada and Europe subsequently confirmed the results of the GOG trial, demonstrating that a regimen of cisplatin plus 3-hour infusional paclitaxel improved both progression-free and overall survival in advanced ovarian cancer. Unfortunately, this study also demonstrated that the combination of cisplatin and 3-hour infusional paclitaxel resulted in a significantly greater risk of clinically relevant peripheral neuropathy, compared with the control arm in that study, cisplatin plus cyclophosphamide.
Dr. R. Ozols[1] reported the preliminary results of a GOG trial (GOG 158) conducted in optimal residual stage III ovarian cancer (ie, largest residual tumor nodule within the peritoneal cavity </=1cm in maximum diameter) comparing carboplatin (AUC 7.5) plus paclitaxel (175 mg/m2 administered over 3 hours) to a control regimen of cisplatin (75 mg/m2) plus paclitaxel (135 mg/m2 over 24 hours). Both regimens were administered on a 21-day schedule for 6 courses. Approximately one third of the 840 patients entered into this trial had no gross residual tumor at the initiation of chemotherapy.
With a median follow-up of 19 months, there is no difference in either progression-free or overall survival between the 2 treatment arms. As might have been anticipated, nausea and vomiting and metabolic abnormalities were more frequent in the cisplatin-containing arm, and thrombocytopenia more frequent in the carboplatin-containing arm. Grade 4 neutropenia was also more common in the cisplatin program. There was no significant difference between the programs with regard to the incidence of grade 2-3 neurotoxicity, perhaps reflecting the relatively high dose of carboplatin (AUC 7.5) in combination with 3-hour paclitaxel employed in the trial.
There was also no difference in overall survival between the treatment arms, although the total number of events does not permit a definitive statement regarding survival at this point in time. However, as of this date, overall survival is actually slightly (but not significantly) in favor of the carboplatin-containing regimen. Therefore, it is extremely unlikely that there will be any difference between the regimens in favor of cisplatin.
The GOG investigators concluded that the combination of carboplatin and paclitaxel is the preferred treatment program due to its more favorable toxicity profile and ease of administration. They recommend that this regimen be considered standard of care in the treatment of advanced ovarian cancer.
In the second study, Dr. A. du Bois,[2] reporting for the AUG Study Group, described the follow-up of 798 patients with advanced ovarian cancer treated on a trial comparing cisplatin (75 mg/m2) plus paclitaxel (185 mg/m2 over 3 hours) to carboplatin (AUC 6) plus paclitaxel (185 mg/m2 over 3 hours). Treatment was repeated on a 21-day schedule. With a median follow-up of 100 weeks, there has been no difference in either progression-free or overall survival.
The toxicity of the carboplatin-based regimen (specifically emesis and neurotoxicity) was shown to be significantly less than that observed with cisplatin. Grade 3-4 emesis was 7% in the carboplatin regimen compared with 19% in the cisplatin regimen. Grade 3-4 neurotoxicity was 8% and 19% in patients treated with carboplatin and cisplatin, respectively. Formal quality-of-life analysis results were also in favor of the carboplatin-based regimen. The authors concluded that carboplatin-paclitaxel is the preferred regimen for the treatment of advanced ovarian cancer, based on a more favorable toxicity profile.
Carboplatin was given at an AUC of 5 with paclitaxel administered at a dose of 175 mg/m2 over 3 hours. In the CAP regimen, the doses were cisplatin 50 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2. Of the patients in this trial, 20% had stage 1 or 2 disease, 65% had stage 3 disease, and 15% had stage 4 disease. Patients were able to receive approximately 85% of the planned cycles of therapy, regardless of the randomized regimen.
With a median follow-up of only 18 months, the investigators were unable to observe any difference between the study arms with regard to progression-free or overall survival for the entire group. However, subset analysis revealed a trend for improved survival in those patients with larger bulk disease treated with the carboplatin regimen.
Dr. W. McGuire[4] cited the latter subset analysis results as good reason not to conclude that this was a "negative" trial in terms of the clinical utility of a combination carboplatin/paclitaxel regimen. He also suggested that population differences between countries could help explain the differences between the results of ICON-3 and the previously noted GOG and Canadian-European studies, which found a major advantage of cisplatin/paclitaxel over cisplatin/cyclophosphamide in advanced ovarian cancer.
There was an important influence of stage on 5-year survival (stage I, 77%; stage II, 65%), which was not influenced by treatment. Toxicity overall was reasonable in both arms of the study, but there were more bowel problems associated with intraperitoneal P-32, and some patients experienced difficulty with isotope distribution. As a result of the somewhat more favorable toxicity profile and modest impact on progression-free survival, the investigators concluded that cisplatin-based chemotherapy should be considered the standard treatment option in patients with high-risk ovarian cancer receiving chemotherapy.
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