Ed Weber, M.D., Editor
November – December, 2014

There are no established guidelines for starting hormone therapy in response to a rising PSA after primary therapy. Customarily clinicians commence treatment for PSA-only relapses based on their own personal preference and in response the anxiety of their patient. 

Abstract 5003, presented at the 2014 Annual Meeting of ASCO: 
    

Whether a benefit results from immediate hormone suppression as compared to deferred therapy was addressed by Drs. Garcia-Albeniz, Matthew Cooperberg, Peter Carroll and others based on an extensive review of patient outcomes.

Their conclusion: there is “little or no benefit” for immediate hormone suppression vs. deferred intervention in asymptomatic patients with PSA-only relapse when the deferred androgen deprivation therapy (ADT) was withheld for at least two years after PSA rise. In the deferred group, ADT was initiated only upon demonstration of metastatic disease, the development of symptoms, or a short PSA doubling time of <3 months.The study followed 2022 men, median age 69 years, staged <cT3aN0M0, with PSA relapse set at >0.2 ng/ml for surgical patients and upon three monthly rising PSA values for men treated with radiotherapy (31.8% of the total). A minority of men (33.8%) had a Gleason score of >7. “Immediate treatment” was defined as ADT started within 3 months after primary therapy.

Eligibility required a normal CT and bone scan. For the entire group the time from primary therapy to PSA relapse was a median of 27 months (range 14-51), and follow-up thereafter was a median of 53.2 months. 

Results: There was no significant difference in “all cause mortality” between the immediate vs. deferred group. At five years a prostate-cancer survival benefit of 5.6% accrued to the immediate ADT group.

How can these important findings be applied in clinical practice? What further details could be helpful in selecting those men who would be best served by early ADT and identifying those in whom ADT can be safely delayed, sparing men from an unnecessary period of testosterone deficiency and the attendant adverse effects? Repeated studies have shown that hormone suppression does not prolong survival, but there is strong consensus that ADT can forestall the onset of metastatic disease. 

Guidance for starting ADT sufficiently early enough to avert symptoms, but not unnecessarily early, would be desirable. The three metrics highlighted in this Commentary may be useful in achieving that balance.
  
When the Albeniz study is fully presented in print it is likely there will be reference to the important earlier work on this issue. Consensus arising from many studies points to the importance of three metrics guiding the decision of when to institute ADT: 

  1. the duration between primary therapy and PSA rise,
  2. PSA doubling time following initial treatment,
  3. and the pretreatment Gleason score.

The classic study was presented in JAMA, 1999, by Drs. Walsh, Partin, and Pound et al., “Natural History of Progression After PSA Elevation Following Radical Prostatectomy.” The study reviewed the course of 1997 men after surgery who received no treatment until distant metastases were diagnosed.

The time intervals measured were:

  • time from surgery to a biochemical recurrence (BCR) of PSA of >0.2 ng/mL;
  • time from PSA rise to metastases, and time from metastases to death. 

Of the total group, 304 men exhibited a PSA rise. This group was heavily weighted with men with extra capsular extension and high-risk features. From their data comes the oft-repeated generalization: median time from PSA relapse to metastases — 8 years, and median time to death — 5 years. 

Nuance, however, was found in subgroup analysis:

For men with Gleason scores 5-7 the actuarial median time from PSA rise to metastases was about 12 years; for those with score 8-10 metastases developed in about 5 years. For those whose PSA recurred in <2 years after surgery the median time to metastases was 5 years.Men with PSADT >10 months developed metastases at >10 years; for those with PSADT <10 the median time to metastases was about 5 years.In a follow-up study Drs. Freedland, Walsh, Partin, Eisenberger et al. built upon and expanded the earlier data base in, “Risk of Prostate Cancer-Specific Mortality Following Biochemical Recurrence After Radical Prostatectomy” (JAMA  2005). Their goal was “to identify men who are at high risk for prostate cancer death who may benefit from aggressive salvage treatment and to identify men who are at low risk of prostate cancer death and can be safely observed.” The median follow-up was extended to 10 years.

In a change from the 1999 study, this study found optimal risk stratification using

  1. time from surgery, 3 or less years vs >3; 
  2. Gleason score 7 (3+4 or 4+3) vs 8-10;  and
  3. PSADT, <3 months vs three other longer time intervals.

The authors acknowledged that other studies support different PSADTs for predicting prostate cancer mortality, i.e. 6, 10 and 12 months. Dr. Eric Kline, Cleveland Clinic, in a recent MadPage video stated his preference for starting ADT in men with PSADT of <6 months.     Ten-year cancer-specific survival (CSS) data from the Freedland study based on the three parameters:     CSS is predicted to be 90% at 10 years for those men whose BCR occurs > 3 years after surgery. For BCR    
     less than 3 years after surgery the 10-year CCS prediction is 75%;  
     
     For men with GS  < 7 the 10-year CSS is predicted to be 90%; and for men with GS 8-10, 65%;            Ten-year CSS prediction for 4 values for PSADT:  < 3 months,  25%;  3 - 9 mo, 65%;  9.0 - 14.9 mo, 85%;  > 15mo, 95%.

   BOTTOM LINE:

There still are no “guidelines”, but there is agreement on three factors that can inform the decision as to when to start ADT for PSA-only relapse. Drs. D’Amico, Catallona et al. in their study, “Predictors of Mortality After Androgen-Deprivation Therapy in Patient with Rapidly Rising Prostate-Specific Antigen Levels After Local therapy for Prostate Cancer,” (CANCER  2006) stressed the importance in decision making of considering these three metrics highlighted above. “These factors have been used as the basis of initiating salvage androgen-deprivation therapy (ADT) before the appearance of metastatic disease and for estimating the subsequent risk of PCSM” [prostate cancer-specific mortality]. 
    
Consideration of these metrics can offer a sense of which clinical situations merit early ADT and those where ADT can be delayed, avoiding testosterone deficiency until warranted.

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