Response to androgen blockade
After the initiation of androgen deprivation therapy (ADT), most patients with prostate cancer will show some evidence of clinical response; the magnitude and rapidity of that response remain the best predictors of its durability. Assuming that ADT effectively targets the androgen-sensitive population of prostate cancer cells, an incomplete or sluggish response is evidence of a significant androgen-refractory population. Early in the clinical use of prostate specific antigen (PSA) as a biomarker of prostate cancer, it was recognized that decline of PSA level could predict response. For example, patients who had more than an 80% drop of PSA level within 1 month of initiation of androgen deprivation therapy had significantly longer disease-free progression rate. Likewise, the nadir PSA predicted the progression-free interval, as did pretreatment testosterone levels. A rise in prostate specific antigen level, evidence of the emergence of androgen-refractory disease, preceded bone metastatic progression by several months, with a mean lead time of 7.3 months.
More recent studies of PSA response to ADT have confirmed and amplified those observations. The odds ratio for progression to androgen-refractory disease within 24 months of starting androgen deprivation therapy was almost 15 times higher for patients who did not achieve undetectable PSA. For each unit increase in Gleason score, the cumulative hazard of androgen-refractory progression was nearly 70%. In one cohort of Asian men, nadir prostate specific antigen was the most accurate predictor of disease progression and was independently prognostic of survival; achieving a PSA level of 1.1 ng/mL or less at 6 months after initiation of ADT was the most sensitive and specific predictor of progression at 2 years. Considering the kinetics of PSA rise before ADT compared with the rate of prostate specific antigen decline after ADT also predicted outcome, specifically prostate cancer–specific mortality. If the pre-ADT rise in PSA level was rapid and the decline after ADT was slow, the cancerspecific mortality was significantly worse than for those with slow rises of PSA level before ADT and rapid declines after androgen deprivation therapy.
Almost without exception, those no longer responding to ADT (androgen refractory) remain on ADT. Therefore, factors influencing survival in that disease state should be considered in this discussion. In most cases, available data are based on pretreatment or post-treatment responses to other systemic treatments. Consistently predictive variables (by both univariate and multivariate analysis) of survival in this state include performance status, serum lactate dehydrogenase concentration, serum alkaline phosphatase concentration, hemoglobin level, and prostate specific antigen response to secondary therapy. The survival of men treated on seven sequential chemotherapy protocols at one institution provided an early experience in developing predictive measures. A 50% decline in PSA level in response to chemotherapy was one of the most significant variables predicting survival. A nomogram based on a larger group of patients found the presence of visceral disease, Gleason score, performance status, baseline PSA level, serum lactate dehydrogenase and alkaline phosphatase concentrations, and hemoglobin level useful in modeling prognosis.
Response to androgen blockade
The magnitude and rapidity of the initial response to ADT are strong predictors of the durability of that response.