Modified Chemotherapy Regimen Effective in Advanced Ovarian CancerWomen with advanced ovarian cancer lived longer overall and longer without their tumors growing after receiving a modified regimen of a standard chemotherapy drug combination, Japanese researchers have reported. In a large phase III clinical trial, the researchers randomly assigned women to receive six cycles of carboplatin and paclitaxel (Taxol) every 3 weeks (standard regimen) or six cycles of carboplatin every 3 weeks and a lower dose of paclitaxel once a week (dose-dense regimen). Initial results of the trial were published September 18, 2009, in The Lancet. (See the journal abstract.)
Although the dose-dense regimen had more toxic effects than the standard regimen, survival benefits of this magnitude "have been rare in women with advanced ovarian cancer," wrote Noriyuki Katsumata, MD, and his colleagues from the Japanese Gynecologic Oncology Group (JGOG).
The results, explained Ted Trimble, MD, MPH, from NCI's Division of Cancer Treatment and Diagnosis, are consistent with what has been seen in breast cancer using a dose-dense chemotherapy regimen. The idea, he continued, is "to balance efficacy and toxicity by using a weekly schedule rather than every 3 weeks."
Although the findings are important, "they won't change practice overnight," Dr. Trimble said. There are still several significant unknowns, including whether a lower dose of paclitaxel might be as effective but less toxic; the optimal timing of surgery; and where intraperitoneal chemotherapy fits into the treatment mix. The JGOG trial results, however, will influence the design of a number of phase III clinical trials, all of which include dose-dense chemotherapy, he added.
More than 630 women at 85 hospitals across Japan were enrolled in the trial. After 3 years of follow-up, women who received the dose-dense treatment had a median progression-free survival of 28.0 months, compared with 17.2 months for those who received the standard treatment. Overall survival at 3 years was higher in the dose-dense regimen group (72.1 percent) than in the conventional treatment group (65.1 percent).
On August 13, 2013, the researchers published long-term survival results in Lancet Oncology. (See the journal abstract .) After a median of 6.4 years of follow-up, median overall survival was significantly longer for women in the dose-dense group (8.4 years) compared with those in the standard treatment group (5.2 years). Median progression-free survival in the updated analysis was nearly identical to that reported in the initial analysis: 28.2 months for women in the dose-dense group versus 17.5 months for those in the standard treatment group.
The dose-dense chemotherapy regimen used in the trial was also dose-intense, meaning that the total dose of paclitaxel patients received was actually higher than in those who received standard treatment. This increase was associated with toxic side effects that caused treatment delays and modifications and also led to patients receiving less carboplatin than intended. In fact, more than half of the women in the dose-dense group discontinued treatment early, and most of them did so because of the toxicity.
Although it is possible that the dose intensity was responsible for the survival improvements, the more frequent, lower-dose treatment schedule is the most "plausible explanation," wrote Michael A. Bookman, MD, chief of the Hematology/Oncology Section at the Arizona Cancer Center, in a 2009 editorial in The Lancet. As a result, "similar results might be achieved" with a lower dose, he concluded, "with improved tolerability."
As for why the dose-dense approach is more effective than the standard approach, the Japanese researchers suggested that it hampers the formation of blood vessels that feed tumors. In animal model studies, dose-dense chemotherapy, like a similar treatment also under active investigation called metronomic chemotherapy, has been shown to have such an antiangiogenic effect. And in the JGOG trial, the researchers noted, tumor shrinkage following treatment did not differ between those receiving dose-dense chemotherapy and standard chemotherapy. This suggests that the dose-dense treatment "might promote tumor dormancy by maintaining tumor size and preventing outgrowth," they wrote.
The U.S.-based Gynecologic Oncology Group is conducting a phase III clinical trial in advanced ovarian cancer of dose-dense chemotherapy in combination with the targeted antiangiogenic drug bevacizumab (Avastin), said Ronald Alvarez, MD, director of the Division of Gynecologic Oncology at the University of Alabama at Birmingham. This should help to confirm the Japanese trial's results.
In the meantime, "Given the potential toxicity, clinicians should discuss with their patients the risks versus the benefits of this approach in comparison with other treatment strategies," Dr. Alvarez said, particularly with patients who have advanced disease and whose tumors could not be mostly eradicated by surgery.
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