Tag Archives: Japanese Gynecological Oncology Group

Modified Chemo Regime Increases Survival In Advanced Ovarian Cancer Patients But Adds Toxicity

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Women with advanced ovarian cancer lived longer and without their tumors growing after receiving a modified regimen of a standard chemotherapy drug combination, Japanese researchers reported last week. In a large phase III clinical trial, women who received carboplatin every 3 weeks and a reduced dose of paclitaxel (Taxol®) once a week for 3 weeks instead of carboplatin and a higher single dose of paclitaxel every 3 weeks had a 29 percent improvement in progression-free survival and a 25 percent improvement in overall survival after 3 years of follow-up.

Women with advanced ovarian cancer lived longer and without their tumors growing after receiving a modified regimen of a standard chemotherapy drug combination, Japanese researchers reported last week. In a large phase III clinical trial, women who received carboplatin every 3 weeks and a reduced dose of paclitaxel (Taxol®) once a week for 3 weeks instead of carboplatin and a higher single dose of paclitaxel every 3 weeks had a 29 percent improvement in progression-free survival and a 25 percent improvement in overall survival after 3 years of follow-up. The results were published online September 18 in The Lancet.

Although the toxicities of this dose-dense regimen were greater than they were in women who received the standard combination, survival benefits of this magnitude “have been rare in women with advanced ovarian cancer,” wrote Dr. Noriyuki Katsumata and colleagues from the Japanese Gynecologic Oncology Group (JGOG).

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Edward L. Trimble, MD, MPH; Head - Gynecologic Cancer Therapeutics and Quality of Cancer Care Therapeutics, Clinical Investigation Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis.

The results, explained Dr. Ted Trimble, 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 enrolled in the trial. Patients were randomly assigned to either of the two treatment groups. After 3 years of follow-up, women who received the dose-dense treatment had a median progression-free survival of 28 months, compared with 17 months for those who received the standard treatment.

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Michael A. Bookman, M.D., Chief, Hematology/Oncology Section, Arizona Cancer Center

Not enough time has passed to determine with statistical confidence whether the overall survival advantage will be maintained. However, in ovarian cancer, improvements in progression-free survival tend to predict overall survival, said Dr. Michael A. Bookman, chief of the Hematology/Oncology Section at the Arizona Cancer Center, in an accompanying editorial in The Lancet.

The dose-dense chemotherapy regimen used in the trial was also dose-intense, meaning the total dose of paclitaxel patients received was actually higher than in those who received standard treatment. This was associated with some toxic side effects that caused treatment delays and modifications and also led to patients receiving less caboplatin 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’s possible that the dose intensity was responsible for the survival improvements, Dr. Bookman wrote, the more frequent, lower-dose treatment schedule is the most “plausible explanation.” 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.

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Ronald Alvarez, M.D., Director, Division of Gynecologic Oncology, University of Alabama at Birmingham

The U.S.-based Gynecologic Oncology Group is planning to launch a phase III clinical trial in advanced ovarian cancer combining the dose-dense approach with the targeted antiangiogenic drug bevacizumab (Avastin), said Dr. Ronald Alvarez, 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 those patients who have advanced disease and whose tumors could not be mostly eradicated by surgery.

Source: Modified Chemo Regimen Effective in Advanced Ovarian Cancer, by Carmen Phillips, NCI Cancer Bulletin Volume 6 / Number 18, National Cancer Institute, September 22, 2009.

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“Dose Dense” Administration of Paclitaxel and Carboplatin Increases Progression Free and Overall Survival in Ovarian Cancer Patients – Is There a New Standard of Care?

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“A recent Phase III clinical trial reported that dose dense administration of paclitaxel and carboplatin increased progression free survival (PFS) and overall survival (OS) of ovarian cancer patients when compared to the conventional dose administration of those same drugs. The clinical trial results were reported by the Japanese Gynecologic Oncology Group (JGOG) at the 2008 American Society of Clinical Oncology Annual Meeting held in Chicago, Illinois on May 30th through June 3, 2008. ”

A recent Phase III clinical trial reported that dose dense administration of paclitaxel and carboplatin increased progression free survival (PFS) and overall survival (OS) of ovarian cancer patients when compared to the conventional dose administration of those same drugs. The clinical trial results were reported by the Japanese Gynecologic Oncology Group (JGOG) at the 2008 American Society of Clinical Oncology Annual Meeting held in Chicago, Illinois on May 30th through June 3, 2008.

The administration of paclitaxel (Taxol™) and carboplatin (Paraplatin™) (referred to as “c-TC”) every three weeks is considered the standard of care for the treatment of ovarian cancer. The clinical trial compared the c-TC with dose dense weekly administration with TC (referred to as “dd-TC”) as first-line chemotherapy for stage II-IV epithelial ovarian, fallopian tube or primary peritoneal cancer. The patients in the trial were randomly assigned to receive carboplatin with either (i) paclitaxel at 180 mg/m² on day 1 (conventional) or (ii) paclitaxel at 80 mg/m² on days 1, 8, and 15 (dose dense). The treatments were repeated every 3 weeks for six cycles; in responding patients, three additional cycles were administered. The primary goal of the trial was to determine patient PFS.

Of 637 patients who underwent randomization, 631 were eligible to participate in the trial. After median follow-up of 29 months, the median duration of PFS in the c-TC group and dd-TC group was 17.1 and 27.9 months, respectively, and overall survival at 2 years was 77.7% and 83.6%, respectively. Among 282 patients with measurable disease, the objective response rates were 53.3% and 55.8% in the c-TC and dd- TC groups respectively. Grade 3 and 4 anemia was reported more frequently in the dd-TC group, and other toxicities were similar in both groups. Based on these findings, the trial investigators concluded that the dd-TC improves PFS as compared with c-TC in patients with advanced epithelial ovarian cancer.

[Source: Randomized phase III trial of conventional paclitaxel and carboplatin (c-TC) versus dose dense weekly paclitaxel and carboplatin (dd-TC) in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: Japanese Gynecologic Oncology; S. Isonishi et. al., J. Clin. Oncol. 26: 2008 (May 20 suppl; abstr 5506).]

Comment: It is likely that “dose dense” administration of paclitaxel and carboplatin will become the new standard of care. The institution of a new stardard of care may not be officially established until a second clinical trial repeats the results of the JGOG clinical trial. This result is not entirely surprising because “dose dense” administration of chemotherapy is already the standard of care in the treatment of metastatic breast cancer (click here).