Testing Dose-Dense Paclitaxel for Ovarian and Related Cancers
Name of the Trial
Phase III Randomized Study of Two Different Dose Schedules of Paclitaxel in Combination with Carboplatin with versus without Concurrent and Consolidation Bevacizumab in Patients With Stage III-IV Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube Cancer (GOG-0262). See the protocol summary.
Dr. John Chan, Gynecologic Oncology Group
Why This Trial Is Important
Women with ovarian epithelial, fallopian tube, or primary peritoneal cancer usually undergo surgery to determine the extent of their disease (primary staging) and to remove as much cancerous tissue as possible (cytoreduction). Advanced cancer (stage III or IV) is typically treated with combination chemotherapy using a taxane drug, such as paclitaxel, and a platinum-based drug, carboplatin. Emerging evidence suggests the addition of drugs that target angiogenesis may improve outcomes for these patients.
Although standard combination chemotherapy is frequently successful in bringing about a remission, the disease in many women eventually develops resistance to this therapy and subsequently recurs. Doctors are eager to identify new approaches to overcome drug resistance and prolong disease remission and patient survival.
Paclitaxel kills cancer cells by blocking cell division (mitosis), which induces cell death, or apoptosis. Animal studies have shown, however, that the apoptosis induced by paclitaxel begins to subside about 4 days after the drug is administered, suggesting that more frequent and lower-dose administration may improve efficacy. Consequently, doctors have developed a new “dose-dense” administration schedule, with lower doses of paclitaxel given every week instead of a single higher dose given every 3 weeks.
Clinical trials in patients with breast cancer have shown that a dose-dense regimen of paclitaxel produces better responses and stabilization of disease than the standard every 3-weeks dosing schedule. In early clinical trials in patients with advanced ovarian cancer, objective response were obtained in women whose disease was resistant to standard therapy. To explore this finding further, the U.S. Gynecologic Oncology Group (GOG) conducted a phase II study of weekly paclitaxel in women with advanced platinum- and paclitaxel-resistant ovarian cancer and showed a benefit even in this treatment-resistant group of women.
Further bolstering evidence of dose-dense paclitaxel’s promise in ovarian cancer, the Japanese GOG conducted a phase III randomized clinical trial and showed that women receiving dose-dense therapy experienced statistically significantly longer progression-free survival and were more likely to be alive after 2 years.
In GOG-0262, women with stage III or IV ovarian epithelial, fallopian tube, or primary peritoneal cancer will be randomly assigned to receive either standard or dose-dense paclitaxel in addition to standard carboplatin (given once every 3 weeks). Prior to randomization, women enrolled in the study may elect whether to receive the antiangiogenesis drug bevacizumab during and after chemotherapy. Doctors will monitor women in the trial for progression-free and overall survival, side effects, and quality of life.
“We know that some drugs given at different schedules can produce additional benefits. With dose-dense paclitaxel, not only is there a direct cytotoxic effect, but we can potentially see antiangiogenic benefits above and beyond the effects of paclitaxel given at the standard schedule,” explained Dr. Chan.
“Data from phase II studies show that dose-dense paclitaxel has activity in highly resistant ovarian cancer,” said Dr. Chan. “And the Japanese study has produced promising data, but there are differences in the prevailing ovarian cancer cell types, and possibly the genomic and toxicity profiles, of ovarian cancer in Asians compared to Western women. As such, these results need to be confirmed in other ethnicities before the dose-dense regimen can be considered the new standard of care.”