Resolving the Optimal Timing of Radiotherapy After Radical Prostatectomy: The Need for Further Research

TO THE EDITOR: Van der Kwast and colleagues recently provided an excellent summary of the published randomized controlled trials of postoperative radiotherapy after radical prostatectomy. They highlight remaining areas of uncertainty and, in particular, the ongoing doubt concerning the optimum timing of postoperative treatment. The possibility of a second wave of metastases arising from residual local disease, before elevation of serum prostate-specific antigen (PSA) levels is detected, is a strong argument for immediate (adjuvant) radiotherapy. In contrast, the financial cost and the morbidity of radiotherapy, together with the pattern of failure analysis of the Southwest Oncology Group 8794 trial, argue for a policy of deferred (salvage) radiotherapy at the time of PSA failure. Given the large number of men treated with radical prostatectomy and the trend towards surgical treatment of men with high-risk and locally advanced disease, the optimum timing of postoperative radiotherapy is an important and unresolved issue. The completed randomized trials described by Van der Kwast et al, although valuable, do little to resolve this issue because they compared immediate radiotherapy with a policy of deferring radiotherapy until clinical (and not biochemical) progression. A large-scale randomized controlled trial is required to study the timing of postoperative radiotherapy with respect to long-term clinical outcomes. The recently opened Radiotherapy and Androgen Deprivation in Combination After Local Surgery (RADICALS) trial is an Intergroup phase III trial, run by the Medical Research Council Clinical Trials Unit in the United Kingdom, and by the National Cancer Institute Clinical Trials Group in Canada, that aims to recruit over 4,000 patients (ISRCTN40814031). The trial has a pragmatic design: men who have had a radical prostatectomy, and for whom there is uncertainty regarding the optimum timing of postoperative radiotherapy, may be randomly assigned to either adjuvant radiotherapy or early salvage radiotherapy at PSA failure. This is the Radiotherapy Timing Randomisation and will recruit around 2,700 patients. In addition, all men receiving postoperative radiotherapy, whether in the adjuvant or salvage setting, may also be randomized between radiotherapy alone, radiotherapy plus 6 months of hormone therapy, or radiotherapy plus 24 months of hormone therapy (Hormone Duration Randomisation). The RADICALS recruitment target is ambitious but achievable. We are grateful to Van der Kwast and his colleagues for highlighting the uncertainty regarding the optimum timing of postoperative radiotherapy following radical prostatectomy. This uncertainty can only be resolved by appropriately designed phase III trials. Centers or trial groups that would be interested in taking part in the RADICALS trial are invited to contact the Medical Research Council’s Clinical Trials Unit by visiting their Web site.

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