THE IMPORTANCE OF FRAILTY WHEN CONSIDERING ANDROGEN-DEPRIVATION THERAPY FOR LOW-RISK BIOCHEMICAL RECURRENCE OF PROSTATE CANCER: A DECISION ANALYSIS

Purpose: Androgen deprivation therapy (ADT) is standard of care for biochemically recurrent prostate cancer (BCR), but ADT has well-established negative effects on health (eg. increased cardiovascular disease (CVD), diabetes, and fracture risk). ADT also puts men at risk for phenotypic clinical frailty, an increasingly recognized condition with increased morality in community-dwelling older adults. The optimal timing of ADT should be based on risks of BCR, and benefits and harms of ADT. We compare ADT given at different start-times with consideration of non-cancer morbidity and mortality.

Method: A Markov decision model was built to compare the effects of ADT on low-risk BCR patients. We compare ADT started immediately at recognition of BCR with the effects of ADT given at the time of visualizable metastasis or clinical symptoms. The model accounts for excess morbidity and mortality due to ADT, including CVD, fractures, and frailty.  Parameters were obtained from published studies and public national data. Frailty risk from ADT was conservatively estimated using onset among men with the lowest quartile of testosterone in a large geriatric multi-site community sample. Utilities were derived either from the literature. Outcomes are incremental life expectancy (LE) and quality-adjusted life expectancy (QALE) over a lifetime horizon, as well as distribution of mortality causes.

Result: The incremental difference in LE between immediate treatment and treatment at time of metastases is only 1 day (13.2 vs 13.3 years), agreeing with studies that have found no survival benefit to immediate ADT for BCR. When evaluating QALE, even if ADT removed metastatic symptoms completely, the difference is similarly small (less than one quality-adjusted day). Of deaths, fractures and clinical frailty together comprise 7.0% (5.1% frailty) of deaths in men on ADT, exceeding the 5.4% of deaths due to prostate cancer. For ADT given at metastasis, cancer causes a larger share of deaths (8.6%) but frailty and fractures remain important at 5.8% (3.8% clinical frailty). In sensitivity analysis, increasing the probability of excess cardiovascular events and mortality lowered frailty mortality, as it is a competing risk. 

Conclusion: With only recently emerging data regarding frailty from ADT, this condition has previously been omitted from treatment analyses for low-risk BCR. However, ADT-related frailty is an important cause of death in this population, and should be considered along with cancer mortality.