A FRAMEWORK FOR TREATMENT DECISION MAKING AT PROSTATE CANCER RECURRENCE: TRADING OFF BENEFIT AND HARM

Purpose: When cancer recurrence can be ascertained by means of a biomarker in the absence of clinical symptoms evidence, the appropriate management is uncertain. In the case of PSAA recurrence (PSA-R) following primary therapy for prostate cancer, the time to clinical metastasis is lengthy in many case; in these cases salvage therapy (ST) may be harmful.  We sought to develop a framework for quantifying benefit-harm tradeoffs of immediate ST in the setting of PSA-R and to estimate harm versus benefit overall and within patient subgroups in an established cohort with PSA-R after RP. 

Methods: Data consisted of 1,045 cases from Johns Hopkins University who were diagnosed with localized prostate cancer between 1980 and 2015 and experienced PSA-R after RP. 52.1% received some form of ST consisting of radiation therapy, hormone therapy or both. We used marginal structural models (MSM) to estimate the benefit of ST administered at PSA-R while accounting for time-dependent selection into ST. The fitted MSM was then used as a basis for a simulation model that projected times to metastasis in the absence and presence of ST and time to other-cause death. Benefit was estimated as the reduction in the fraction of cases metastasizing over 10 years and harm as the fraction of cases overtreated, in the sense that without ST they would not have reached the point of clinical metastasis in their lifetimes.   

Results: The median follow-up time after PSA-R was 5 years and 26% of the cohort experienced metastatic progression. The hazard ratio associated with ST was 0.41 (95% CI (0.31,0.55)) indicating an almost 60% reduction in the risk of metastasis associated with ST. The projected 10-year cumulative risk in the absence and presence of ST was 43% and 23% respectively. The benefit of treating all cases at PSA-R was 20% reduction in the 10-year risk of metastasis with 30% overtreated (harm/benefit=1.5). Men with Gleason score 6 or below had 9% benefit with 61% overtreated (harm/benefit=6.95) and men with Gleason score 6 or below and 5+ years from RP to PSA-R  had 5% benefit with 74% overtreated (harm/benefit 14.9). 

Conclusion: Management of PSA-R should take into account the benefits of and harms of ST. Benefit-harm tradeoffs are highly variable across some of patient risk. Selective ST approaches may improve harm-benefit tradeoffs relative to treating all patients at PSA-R.