"Dose-Dense" Chemotherapy Regimen May Improve Outcomes in Advanced Ovarian Cancer
By Laurie Barclay, MD
Medscape Medical News
September 23, 2009 — A "dose-dense" chemotherapy regimen may improve outcomes in advanced ovarian cancer, according to the results of a multicenter, phase 3, open-label, randomized controlled trial reported online September 20 in The Lancet.
"Paclitaxel and carboplatin given every 3 weeks is standard treatment for advanced ovarian carcinoma," write Noriyuki Katsumata, from the National Cancer Center Hospital in Tokyo, Japan, and colleagues. "Attempts to improve patient survival by including other drugs have yielded disappointing results. We compared a conventional regimen of paclitaxel and carboplatin with a dose-dense weekly regimen in women with advanced ovarian cancer."
At 85 centers in Japan, 637 patients with stage II to IV epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer were enrolled and assigned by computer-generated randomization sequence to receive 6 cycles of either a conventional (n = 320) or dose-dense (n = 317) chemotherapy regimen.
The conventional regimen consisted of paclitaxel (180 mg/m2; 3-hour intravenous infusion) plus carboplatin (area under the curve, 6 mg/mL/minute), given on day 1 of a 21-day cycle. The dose-dense regimen was paclitaxel (80 mg/m2; 1-hour intravenous infusion) given on days 1, 8, and 15 plus carboplatin given on day 1 of a 21-day cycle. Analysis was by intention to treat, with a main study outcome of progression-free survival.
Of the 637 enrolled patients, 631 were eligible for treatment and were included in the intention-to-treat population (312 assigned to the dose-dense regimen and 319 to the conventional regimen). Compared with the conventional treatment group, the dose-dense treatment group had longer median progression-free survival (28.0 months [95% confidence interval (CI), 22.3 – 35.4] vs 17.2 months [95% CI, 15.7 – 21.1]; hazard ratio [HR], 0.71; 95% CI, 0.58 – 0.88; P = .0015). At 3 years, overall survival was 72.1% in the dose-dense regimen group compared with 65.1% in the conventional treatment group (HR, 0.75; 95% CI, 0.57 – 0.98; P = .03).
Early discontinuation of treatment occurred in 165 patients in the dose-dense regimen group and in 117 patients in the conventional regimen group. Withdrawal because of toxicity was higher in the dose-dense regimen group (113 vs 69), but reasons for dropout were otherwise balanced between the groups. Neutropenia was the most frequently observed adverse event (dose-dense regimen, 286 [92%] of 312 patients; conventional regimen, 276 [88%] of 314 patients). Compared with the conventional treatment group, the dose-dense treatment group had a higher frequency of grade 3 and 4 anemia (214 [69%] vs 137 [44%]; P < .0001). Other toxic effects occurred with similar frequencies in both groups.
"Dose-dense weekly paclitaxel plus carboplatin improved survival compared with the conventional regimen and represents a new treatment option in women with advanced epithelial ovarian cancer," the study authors write.
Limitations of this study include completion of treatment according to the study protocol by less than half the patients assigned to the dose-dense regimen. In addition, this study was not designed to evaluate the association between the duration of treatment and clinical outcomes.
In an accompanying comment, Michael A. Bookman, from the Arizona Cancer Center, Tucson, calls this an important phase 3 trial that will affect future trial design and evolving standards of care.
"The mature data for progression-free survival are highly significant and are generally predictive of overall survival in ovarian cancer," Dr. Bookman writes. "Confirmatory trials are planned within member groups of [the Gynecologic Cancer Intergroup] to assess once-per-week intravenous dosing, with and without bevacizumab. The use of such dose-dense therapy should be decided on an individual basis together with other options for women with advanced-stage ovarian cancer, including intraperitoneal therapy, neoadjuvant treatment, or substitution of docetaxel."
Bristol-Myers Squibb supported this study and has various financial relationships with 3 of the study authors. Dr. Bookman has served on ad hoc advisory boards for Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, sanofi-aventis, Novartis, Pfizer, Abbott Pharmaceuticals, and Boehringer Ingelheim.
