Dose escalation in localized prostate cancer: make no assumptions

This issue of the IJROBP contains the latest report from the MDACC randomized trial of radiation dose in localized prostate cancer (1). Although the current report looked specifically at rebiopsy issues in a subset of patients, its publication provides an opportunity to take stock of what we truly know about dose issues in prostate cancer in 2002. We do know that local recurrence is a common event after conventional doses of external beam radiotherapy (RT). Crook et al. (2) reported on a cohort of men with T1-T3 disease who had their prostates sequentially rebiopsied 4 years after radical treatment with 66 Gy. Thirtyeight percent demonstrated residual cancer (2). Several other groups have shown a strong connection between positive rebiopsy findings and subsequent metastasis. The temporal relationship between the two suggests that locally persistent tumor may act as the source of metastases in these patients. If true, any improvement in local control should have an effect on metastasis-free, and thus overall, survival. We also know that the instinctive response of radiation oncologists when faced with a local control problem is to increase the delivered radiation dose in an attempt to climb the dose–response curve. The curve is sigmoid, and, therefore, the greatest gains will come if the curve is steep and the current control rates are in the middle range. The early retrospective data of Hanks suggested that these assumptions were correct, and, with ever improving planning and delivery systems, the race was on between academic institutions eager to plant their flag at ever higher points on the curve. The dose can be divided conveniently into three categories: conventional (66–72 Gy); high (72–78 Gy), requiring three-dimensional conformal techniques; and ultrahigh ( 78 Gy), requiring more sophisticated techniques such as intensity-modulated RT or proton beam. One must not forget the “no dose” category of elderly men with early disease whose lives are not threatened by their prostate cancer. These men may not need RT at all and thus certainly do not need the risks of any kind of high-dose therapy. It is instructive to look at the experience with high and ultrahigh dose external beam RT (EBRT) during the past decade. The reporting of these data has been complicated by the many statistical pitfalls inherent in retrospective studies. The U.S. Preventative Services Task Force has clearly stated what should be obvious, that the strength of a medical recommendation can only be based on the strength of the supporting evidence. They have classified the quality of data into several categories. Class One evidence is the randomized controlled trial. Class Two is subcategorized by diminishing quality into prospective but nonrandomized, retrospective case controlled, and retrospective comparative. Class Three evidence is that from single-institution reviews and anecdotal experience. Few published EBRT dose series rise above the second subgroup of the second class and most are well below that. The M. D. Anderson, Fox Chase, and Memorial Sloan-Kettering Cancer Centers have all published their single-institution experience with dose escalation and concluded across the board advantages for all categories of localized prostate cancer. Despite passionate advocacy, these studies should be regarded with substantial caution. A particular problem inherent in all of them is their comparison of contemporary high-dose patients with historical conventional dose controls. This matters in small part because of stage migration over the years even within risk categories. Today’s T1c cancer may not be the same as yesterday’s. It matters in large part because of the use of the ASTRO definition of failure, which is peculiarly time sensitive. Vicini et al. (3) have clearly demonstrated the importance of having comparable follow-up in the groups being compared. They analyzed 389 men treated by EBRT and followed for 5 years. The analysis of the biochemical disease-free outcome was performed repeatedly on this same group but censoring men with shorter and shorter follow-up. They showed that for these men, freedom from failure looked better and better with diminishing follow-up. Those with Gleason scores of 6 and initial PSA values of 10 ng/mL had a 3-year biochemical disease-free rate of 89% or 76% depending on whether the median follow-up was 3 or 6 years. Those with Gleason scores of 7 and PSA values 10 ng/mL had an even greater dis-