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

Posted by Paul Cacciatore on September 24, 2009

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).

trimble

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.

bookman

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.

alvarez

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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One Response to “Modified Chemo Regime Increases Survival In Advanced Ovarian Cancer Patients But Adds Toxicity”

  1. Gregory D. Pawelski said

    I’ve always felt the way my wife was treated for her cancer back in 1972 was the reason she survived so long (twenty-four years before a recurrence). In my paper “Cancer Medicine’s Dark Corners,” written years ago, I’ve pointed out that “by giving chemotherapy more often, at lower doses, it can prevent the regrowth of blood vessels that feed tumors.”

    Her postoperative chemotherapy regimen was among the slowest acting and least toxic of the alkylating agents (pill-dose). Depression of the immune system was slow and reversible, allowing it to regenerate and contribute to recovery. A malfunctioning immune system can fail to stop the growth of cancer cells.

    The lower-dose regimen may have attacked the blood vessels that fed the tumor (although not known at the time). Her type of treatment sounded very similar to the Angiogenesis and Low Dose Chemotherapy treatment that is finding increasing acceptance in some cancer centers today.

    She also may have had some of her own anti-angiogenesis predisposition. In fact, it has been shown that low-dose chemotherapy induces an anti-angiogenic effect (sometimes referred to as ‘metronomic’ chemotherapy), the protocol mechanism that Judah Folkman discovered.

    Unlike standard chemotherapy, which is given in high doses to kill as many cancer cells as possible, the lower-dose regimen is meant to attack the blood vessels that feed the tumor. Tumors create their own supply lines by secreting substances that stimulate the formation of new blood vessels and researchers suspect that frequent low doses of certain drugs may disrupt the growth of those new vessels, starving the tumor.

    This approach to treatment is based on something that can frequently occur in people, when a tumor becomes resistant to chemotherapy and high doses stop working. It is believed that angiogenesis plays a role. Angiogenesis is essential to the survival of many tumors. Many chemotherapy drugs, in addition to killing tumor cells, also fight angiogenesis.

    But, if these medicines stop angiogenesis, chemotherapy should work better than it does. Blood vessel cells are less likely than tumor cells to become resistant to chemotherapy, so if cancer cells become drug resistant, these medicines should still be able to shrink tumors by destroying their blood supply.

    The reason chemotherapy was not stopping angiogenesis was that chemotherapy is usually given in big doses, with breaks of several weeks between doses to let the body recover. During the breaks, the tumor’s blood vessels could grow back. By giving chemotherapy more often, at lower doses, it might prevent the regrowth of blood vessels and kill the tumor or at least slow its growth.

    This study seems to confirm it. I’m glad more researchers are finding out more about the way it happens and what players are involved so more cancer patients can benefit from these kind of treatment protocols.

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