PCa Commentary
 

Early Androgen Deprivation Benefits Men In High Risk disease category Who Have PSA Relapse After Radical Prostatectomy (May 2004)

What were the features of the high risk group for which the study found benefit? They designated as "high-risk" men with a Gleason score >7, a PSA doubling time (PSADT) of <12 months, and men in whom the prostate capsule was positive and the pathological Gleason sum was >6; or positive surgical margins, lymph nodes, or seminal vesicles. The low risk group, which gained no benefit from early AD, had organ confined disease, or "extracapsular extension only and negative surgical margins with Gleason sum <6." This low risk group was considered "curable" by the Johns Hopkins' definition. The authors chose the PSA threshold for PSA relapse at 2 ng/ml so as to match the same value chosen by Pound in his 1999 study of time to metastatic disease after a post RP PSA relapse when no AD was given (his finding: a median of 8 years to metastatic disease). However, it was conceded that perhaps a better choice would have been the .4 ng/ml threshold suggested by Amling (Mayo Clinic), since "this cut point was associated with an approximate 75% chance of further biochemical and/or clinical progression during the next 3 years." The calculation of the PSA-DT was based on a minimum of 2 PSA values that exceeded 0.2 ng/ml separated by 3 months; the median number of PSA tests was 5. The median follow-up after PSAR was 4.7 months and treatment included LH-RH agents alone or combined with an antiandrogen, or orchidectomy. The results in the early AD group were further categorized as to the PSA level at the initiation of AD treatment. The analytic end point of the study was the development of clinical metastases. Results: It was ONLY in the high-risk group that early AD conferred benefit. The hazard ratio for benefit was 2.1, p = <0.01. My non-statistical observation of their graph showing the "event tics" concludes that at eight years after PSA relapse, if AD was commenced at PSA level <5 ng/ml., approximately 80% of men in the high risk early AD group were free of clinical metastases versus 60% for the high-risk no-treatment group. This graph will, of course, change with further follow-up. It is interesting that the freedom from clinical metastases at this eight year point degrades only to 75% for the high-risk treated group if the start of AD was at PSA < 10 ng/ml. There was no benefit to early AD in the low risk group.  The authors clearly point up that the ultimate clinical value of early AD in the high-risk category is unknown, since AD will surely be administered upon clinical relapse to the men in the "no-treatment" group. But many clinicians will conclude there is value to the postponement of clinical metastases by the early administration of AD as long as the associated adverse treatment consequences are acceptable to the men involved.

This study was not designed to encompass the additional associated and relevant issue of how this data can be applied to a cohort of men who have undergone salvage radiotherapy? (See first article in this commentary.) It would seem that the study's information is not explicitly transferable since the distribution of PSA producing disease, i.e. From local relapse versus distant disease, will of necessity be different between these two situations. But the Moul study very likely may offer useful guidance in the decision about AD intervention when PSA failure follows the use of salvage radiotherapy, and a rapid PSA-DT might serve as a possible linking bridge to the Moul data.

Bottom Line: The Moul article concludes: "We now demonstrate that in the risk stratified setting of high-risk disease [pathologic Gleason sum >7 or PSA-DT 12 months or less] early use of AD was a significant and independent predictor of delayed clinical metastases." This information can be useful in patient counseling.

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