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Widespread Use of Docetaxel Preceded Phase III Evidence of Usefulness in Patients With Metastatic Prostate Cancer

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Key Points

  • Docetaxel was being widely used by patients with metastatic prostate cancer before phase III evidence showed superiority over standard of care and approval by the U.S. Food and Drug Administration.
  • The diffusion of docetaxel across different cancers around the same time (and in most cases before FDA approval) suggests that a drug used for one type of cancer is more likely to be prescribed in other cancers.
  • By enabling the widespread diffusion of a new therapy before phase III evidence, the off-label mechanism may undermine the clinical trial process.

Docetaxel was being widely used by patients with metastatic prostate cancer before phase III evidence that it was more effective than standard-of-care for patients with castration-resistant prostate cancer, according to an analysis of Medicare claims from before and after the trial results and approval of docetaxel by the U.S. Food and Drug Administration. The uptake of new treatments, or diffusion, “prior to definitive evidence indicates the prevalence of off-label chemotherapy use,” wrote Unger et al in the Journal of the National Cancer Institute.

Using the Surveillance, Epidemiology, and End Results Program (SEER)–Medicare database, researchers identified 6,561 metastatic prostate cancer patients diagnosed from 1995 to 2007, and analyzed Medicare claims through 2008. Among the 1,350 men who subsequently received chemotherapy, 5-year “cumulative incidence of docetaxel use after diagnosis of metastatic prostate cancer increased from 2% for patients diagnosed in 1996 or 1997 to 33% for patients diagnosed in 2004 or 2005,” the authors reported.

“Eighty percent of docetaxel diffusion occurred prior to the May 2004 release of phase III results showing superiority of docetaxel over standard-of-care,” the researchers, reported. By 2008, the observed proportion of men with metastatic prostate cancer whose first chemotherapy was docetaxel was 95%.

Rapid Uptake Is Cause for Concern

“The rapid uptake of docetaxel in [castration-resistant prostate cancer] prior to definitive evidence from a phase III trial is a concern,” the researchers wrote. “Considerations that may have led to early adoption of docetaxel include prior FDA indications in other solid tumors and the fact that conventional treatment, mitoxantrone, provided only palliative relief, whereas early pilot trials for docetaxel showed the additional promise of a survival benefit.”

Comparing patterns of the uptake of treatment or diffusion for metastatic prostate cancer to those in metastatic breast, non–small cell lung cancer (NSCLC), ovarian, and gastric cancers, investigators found that “uptake of docetaxel began and achieved maximums at similar times for all cancers, regardless of whether FDA approval was received early in the period (breast and NSCLC), late in the period (prostate and gastric), or never (ovarian cancer). Maximum diffusion was notably higher among prostate cancer patients, likely because of fewer effective chemotherapy options.”

Potential Risks of Off-label Use

The diffusion of docetaxel across different cancers around the same time and in most cases before FDA approval “suggests that once oncologists begin to use a drug for a given cancer, they may be more likely to do so for other cancers; the mechanism that allows this is off-label drug use,” the researchers wrote. They remarked that Medicare contractors are required to pay for cancer drug prescriptions if selected standard medical compendia support their use and that taxane-based therapy, including docetaxel, was included in standard medical compendia for treatment of castration-resistant prostate cancer before publication of phase III evidence.

“Currently the FDA is reviewing whether to loosen constraints on the marketing or drugs prescribed off label,” the investigators noted. “In contrast, our findings point to the potential risks of off-label use. By enabling the widespread diffusion of a new therapy prior to definitive phase III evidence, the off-label mechanism undermines the assumption that phase III comparative clinical trials necessarily determine which treatments become standard care. In this setting, inappropriate use is inevitable, with potential costs in increased morbidity and mortality if a different drug may have been more appropriate. Inappropriate use also places an unnecessary financial burden on healthcare payers. As declared by ASCO, medical compendia, which facilitate off-label reimbursement, require greater oversight, especially if they serve as the arbiters of reimbursement for Medicare, a federal program. Ultimately, greater levels of investment in clinical research are required to produce the highest levels of evidence—especially phase III trial evidence—for a given indication, in order to reduce the tendency for off-label use,” the authors concluded.

Opportunities for Improvement in Subpopulations

Rapid and widespread use of docetaxel was not observed among all study participants receiving chemotherapy for metastatic prostate cancer. Statistically significant docetaxel uptake (P < .01) was seen in patients older than 65 years of age, blacks, patients in lower income areas, and those who experienced poverty. This observation “presents opportunities to improve the uptake of proven new therapies in subpopulations,” the authors wrote, adding that direct-to-consumer advertising “could be a useful tool.”

Another potential method cited for encouraging more rapid adoption of new treatments was “enhancing communication channels among physicians, especially between key opinion leaders and their colleagues,” the authors noted. “One factor that has been repeatedly identified to increase adoption rates is attendance at scientific symposia, which serve as forums for disseminating information about new treatments.”

Joseph M. Unger, PhD, MS, of Fred Hutchinson Cancer Research Center, is the corresponding author for the Journal of the National Cancer Institute article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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