First Evidence That Chemotherapy Extends Life in Advanced Prostate Cancer

June 7, 2004. Chemotherapy regimens that include the drug docetaxel (trade name Taxotere®) extend median survival by two to three months in patients with advanced prostate cancer that is no longer responsive to hormone therapy, two large phase III studies have shown. These are the first clinical trials to show that chemotherapy can improve survival in advanced prostate cancer.

Background

Therapies that lower the body’s level of the male sex hormone testosterone, which encourages prostate cancer growth, are the mainstay of treatment for prostate cancer that has spread to other organs. However, many patients stop responding to hormonal therapies after two to three years of treatment. No effective therapy currently exists for advanced prostate cancer that stops responding to hormonal therapy.

Chemotherapy with the drugs prednisone and mitoxantrone has been shown to reduce pain in men with advanced prostate cancer that has spread to the bones, but this regimen does not help patients to live any longer. Several previous studies of different chemotherapy regimens had failed to identify a drug or combination of drugs that extended patients’ survival.

Study 1 (Southwest Oncology Group and others)

This study involved 770 men with advanced prostate cancer no longer responding to hormonal therapy. The men were randomly assigned to treatment with the drugs docetaxel and estramustine or with prednisone and mitoxantrone. The latter treatment is the only currently approved treatment for prostate cancer patients at this point in their disease.

The trial was conducted by a number of cooperative groups sponsored by the National Cancer Institute, led by the Southwest Oncology Group (SWOG). (See the protocol summary.)

Study 1 Results

After a median follow-up period of 32 months, men who received docetaxel and estramustine lived for a median of 18 months. By contrast, men treated with prednisone and mitoxantrone lived for a median of 16 months, said one of the lead researchers, Daniel Petrylak, M.D., of Columbia University in New York. Progression of disease was delayed for twice as long (six months compared with three months) in patients treated with docetaxel and estramustine.

Severe side effects – particularly stomach and heart problems – occurred more frequently in the docetaxel/estramustine group. However, the number of patient deaths due to adverse reactions to chemotherapy was about the same in both groups.

Levels of prostate-specific antigen (PSA) - an enzyme that can be elevated in men with prostate cancer - declined more in patients treated with docetaxel/estramustine than in those on standard therapy, Petrylak added. (See the journal abstract.)

Study 2 (Aventis Pharmaceuticals, Inc.)

This study involved 1,006 men in the United States, Canada, Europe, and Latin America. As with the SWOG study, all participants had advanced prostate cancer that had stopped responding to hormonal therapy. The men were randomly assigned to one of three treatment groups:

• One group got weekly doses of the drugs prednisone and docetaxel.
• A second group got a higher dose of docetaxel, plus prednisone, every three weeks.
• A third group got the standard treatment of prednisone and mitoxantrone every three weeks.

This study was supported by Aventis Pharmaceuticals, Inc., which manufactures docetaxel.

Study 2 Results

Patients were followed for a median of 20.7 months. Those who received docetaxel and prednisone at three-week intervals survived a median of 18.9 months. By contrast, median survival for patients treated with weekly docetaxel and prednisone was 17.4 months. Patients treated with prednisone and mitoxantrone lived for a median of 16.5 months.

More patients on the three-week docetaxel/prednisone regimen suffered low white blood cell counts; nevertheless, their levels of infection and fatigue were similar to the other groups.

As in Study 1, more patients in the groups treated with docetaxel experienced a drop in their PSA levels compared to the prednisone and mitoxantrone group, said principal investigator Mario Eisenberger, M.D., of Johns Hopkins University in Baltimore. (See the journal abstract.)

On the basis of this study’s findings, the U.S. Food and Drug Administration recently approved docetaxel, in combination with prednisone, to treat advanced prostate cancer that is no longer responding to hormonal therapy. The SWOG trial (Study 1) provided additional data to support the approval.

Limitations

During the discussion at the ASCO presentation, Bruce J. Roth, M.D., of Vanderbilt-Ingram Cancer Center cautioned that the results “don’t support the routine use of chemotherapy in less advanced prostate cancer.”

Comment

Whether earlier use of chemotherapy can prolong survival in patients at a less-advanced stage of their disease is something that is being investigated in several phase III clinical trials currently enrolling participants.

As a result of these findings, however, “docetaxel is definitely a new standard of care” for patients with advanced prostate cancer that is resistant to hormone therapy, said Petrylak.

“These results are a reason for celebration as well as for optimism for the future,” added Eisenberger. They put to rest concerns that advanced prostate cancer would not respond to chemotherapy, he said. In an extremely severe disease such as advanced prostate cancer, he added, a treatment must be very effective to achieve a two- to three-month increase in median survival.