International Journal of Radiation Oncology*Biology*Physics
Clinical investigation: prostateProstate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial☆
Introduction
Since the use of prostate-specific antigen (PSA) has been introduced as a surrogate end point after radiotherapy (RT) for the treatment of prostate cancer, it has become apparent that the standard doses of 65–70 Gy result in far fewer cures than once believed. These data have provided the stimulus for dose escalation using conventional conformal and intensity-modulated RT techniques. In nearly every retrospective and prospective PSA era trial that has evaluated prostate cancer radiation dose response, an improvement in outcome has been substantiated for intermediate- and high-risk patients 1, 2, 3, 4, 5, 6, 7. To our knowledge, the M. D. Anderson Cancer Center (MDACC) randomized dose escalation trial initiated in 1993 is the most mature Phase III PSA era evidence published to date that supports dose escalation for prostate cancer. The preliminary MDACC report, based on an analysis with a median follow-up of 40 months, indicated that intermediate- and high-risk patients with a pretreatment PSA level >10 ng/mL significantly benefited from an increase in isocenter dose to 78 Gy from 70 Gy (7). No significant increase in bladder or rectal toxicity was observed 8, 9. The current report represents a scheduled analysis with extension of the median follow-up to 60 months.
Section snippets
Protocol eligibility and goals
All patients entered into the trial signed an MDACC Institutional Review Board-approved consent form. Patients with Stage T1–3, Nx/N0, M0 were entered between 1993 and 1998. All patients had a pretreatment PSA measurement, were free of evidence of metastasis, and had no prior history of pelvic RT, radical prostatectomy, or androgen ablation, as described previously (7). The intent was to deliver RT without neoadjuvant or adjuvant androgen ablation. Stratification at protocol entry was based on
Results
The crude numbers of patients with biochemical, local, regional, and distant failure are shown in Table 1. Also displayed are the number of deaths. The only statistically significant effect of dose on failure was for biochemical failure, which was 32% for the 70 Gy group and 21% for the 78 Gy group. These findings are reflected in the Kaplan-Meier survival analyses of FFF. It should be noted that only 1 patient was considered to have treatment failure without a rising PSA. Therefore, the FFF
Prostate cancer radiation dose response
Reports of a radiation dose response for prostate cancer date to articles by Hanks et al. 19, 20 and Perez et al. 21, 22 in the 1980s. These early descriptions provided incentive for treating the prostate to ≥70 Gy, but the concern of untoward toxicity restrained additional efforts. With the development of new methods for limiting doses to the rectum and bladder, and the disclosure of higher failure rates than expected using PSA as an end point, there has been a resurgence in the exploration of
Conclusions
Although the weight of the available dose escalation data sanctions the adoption of treatment to higher doses for patients at intermediate-to-high risk, there is no conclusive proof that survival will be affected. A possible explanation for the findings described is that the number of tumor clonogens has been reduced substantially without complete tumor eradication and/or tumor growth has been slowed, thereby delaying detection of failure using a rising PSA as an end point. In either case, one
Acknowledgements
The authors thank Alecia Arciniega for assistance with database management.
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This study was supported in part by Grants CA 06294 and CA 16672 awarded by the National Cancer Institute, U.S. Department of Health and Human Services, DOD Grant DAMD 17-98-1-8483, and the Prostate Cancer Research Program at M. D. Anderson Cancer Center.