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A bold proposal to streamline clinical trials

A bold proposal to streamline clinical trials

SAN ANTONIO—If therapeutic agents are documented to be more effective than standard therapies in the advanced breast cancer setting, they will also be effective in the adjuvant setting. This renders randomized phase III adjuvant trials unnecessary in many cases, and means that undue delays in moving new agents up-front are costing lives, Joseph Ragaz, MD, professor of medicine and oncology, McGill University, Montreal, said at the 2007 San Antonio Breast Can-cer Symposium (abstract 14).

Dr. Ragaz projected, for example, that the 5-year delay between the observation of tamoxifen's efficacy and its inclusion in adjuvant guidelines could have saved up to 100,000 lives. Along with his co-author, John J. Spinelli, PhD, senior biostatistician, British Columbia Cancer Agency, Vancouver, he took issue with the clinical trials process and proposed some changes.

In their study, all pivotal trials of hormonal, chemotherapy, and biological agents that have been tested in the same design, first in stage IV and then in the adjuvant setting, were reviewed. The data have confirmed that all those commonly used systemic agents that were efficacious, though not curative, in stage IV disease were more efficacious, and in many cases curative, in the adjuvant setting.

For instance, for tamoxifen, CMF, anthracyclines, taxanes, and aromatase inhibitors, as compared to the standards of care in pivotal trials, high response rates were achieved, but there were no cures. In the adjuvant setting, however, not only was risk of relapse reduced by about 20% to 40%, but mortality was also reduced by 15% to 40%. Population studies have also shown that the incorporation of systemic therapies results in mortality reductions, he said.

"If introduction of systemic therapies does cure disease, does withholding of systemic therapy due to delays [in the clinical trial process] prevent the materialization of survival gains?" Dr. Ragaz asked.

The answer, he said, is yes. "It is estimated that 400,000 women are alive today as a result of tamoxifen therapy," Dr. Ragaz said. "In the adjuvant setting, tamoxifen saves about 20,000 breast cancer deaths worldwide each year. The projections show that if tamoxifen had been activated in 1980 instead of 1985, it could have saved 100,000 more lives."

Similarly, for adjuvant trastuzumab (Herceptin), the median number of recurrences avoided per 1,000 new patients is 15 in low-risk patients, 38 in intermediate-risk patients, and 53 in high-risk patients. If adjuvant trastuzumab had been included in the guidelines in 2001 rather than 2006, close to 50,000 breast cancer recurrences could have been avoided over those 5 years, he estimated.

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