Primary Androgen-Deprivation Therapy (ADT) for Localized Prostate Cancer: Potential for Harm May Outweigh Benefit in Low-Risk Disease
The use of ADT as primary therapy in low-risk prostate cancer seems increasingly ill advised.
Long-term follow-up of men treated with primary androgen-deprivation therapy (ADT) for localized prostate cancer (PC) revealed no benefit in terms of increased survival.
The study, led by Grace Lu-Yao, MD, of Rutgers Cancer Institute of New Jersey in New Brunswick, New Jersey, was published online in JAMA Internal Medicine and detailed researchers' findings after 15 years of follow-up. The results of this study add to the growing body of evidence that primary ADT adds little benefit in the management of low-risk PC.
Of the estimated 233,000 cases diagnosed annually in the United States, about 90% are in men diagnosed with stage 1 PC localized to the prostate.1,2 Most cases are diagnosed in men older than age 50 years, including 60% in men aged 65 years and older. These men are also those most likely to have one or several comorbidities, principally cardiovascular disease (CVD) or type 2 diabetes.
Established side effects of ADT include greater risk for bone fracture and osteoporosis, increase in type 2 diabetes and CVD incidence, obesity, insulin resistance, deleterious lipid changes, and vasomotor instability.3,4 Loss of skeletal muscle and increases in body fat have been seen as early as 3 to 6 months after ADT initiation.5 ADT also contributes to poorer quality of life. As many as 90% of men treated with ADT develop anemia, 91% report sexual dysfunction, 43% report fatigue, and 80% report hot flashes.
The risks imparted by ADT are not negligible for older men. In data from the Surveillance, Epidemiology, and End Results (SEER) database, men diagnosed with PC that were alive 5 years later who received ADT had a 19.4% fracture risk compared with 12.6% fracture risk among men who did not receive ADT (P<0.001).5 One cohort study of 19,271 men found that use of ADT for localized PC was associated with an increased risk for all-cause and PC-specific mortality compared with active surveillance (also called watchful waiting).6
SEER data suggest a 16% increase in risk of coronary heart disease or sudden cardiac death that was apparent within 4 months of treatment initiation.5 Given the age of most men diagnosed with early stage PC, CVD is a more likely cause of death than cancer, making cardiovascular and metabolic changes associated with ADT in asymptomatic men an important consideration.5
The current study builds on earlier research by Dr. Lu-Yao and colleagues, in which they reported that primary ADT conferred no survival benefit for men with localized, moderately differentiated PC, and in fact was associated with worse disease-specific survival rates, but very slightly improved survival among men with poorly differentiated disease.7
The current study analyzed data from 25,125 men diagnosed with localized (stage T1-T2) PC between 1992 and 2009 who received primary ADT and no definitive therapy (eg, surgery) within 6 months of initial diagnosis.
Primary ADT consisted of surgical or chemical androgen deprivation. Results were compared with a matched cohort of men who received conservative therapy, defined as no ADT, surgery, or radiotherapy within 6 months of diagnosis (41,592 patients).
Study endpoints were disease-specific survival and overall survival.2 In a Cox analysis, patients in the primary ADT group had shorter disease-specific survival and overall survival rates, reflecting the fact that patients in that group were more likely to have worse measurable disease factors (ie, comorbidities, cancer grade, or PSA levels) at diagnosis.
Using a stratified instrumental variables approach, designed to account for both measured and unmeasured variables (eg, weight or diet), men who did or did not receive primary ADT had remarkably similar survival times. The risk of PC-specific mortality at 15 years was 1.7 with ADT and 1.6 with conservative management; overall mortality risk was 10.1 with ADT and 9.8 without. Each of the various subset analyses yielded similar results, adding up to the conclusion that primary ADT versus conservative management yielded no long-term survival benefit whatsoever.2
Another study published this year in the Journal of Clinical Oncology yielded a similar finding. Using a retrospective cohort analysis of 15,170 men diagnosed between 1995 and 2008 who were followed through the end of 2010, researchers found no effect of primary ADT on PC-specific or overall mortality among men with low-risk PC. Use of primary ADT in this study was associated with a 12% reduction in overall mortality among men at high risk for PC progression.8