The role, timing, and clinical use of androgen deprivation therapy (ADT) in prostate cancer remain a controversial topic for clinicians. Drs. Fang, Merrick, and Wallner provide a compelling review of the clinical benefits and side effects of ADT in high-risk prostate cancer. The number of patients presenting with advanced disease remains significant despite the stage migration of prostate cancer during the PSA (prostate-specific antigen) era.
The authors describe recent evidence of survival benefit with the use of ADT in some clinical settings. As they note, neoadjuvant/concomitant/adjuvant ADT has been shown in randomized controlled trials to increase disease-free survival and overall survival in men with high-risk disease treated with radiotherapy (RT). However, the optimal duration of neoadjuvant/concomitant/adjuvant ADT remains uncertain.[1] Shorter courses of neoadjuvant/concomitant/adjuvant ADT for high-risk disease may decrease the morbidity of ADT, as a result of more rapid recovery of normal serum androgen levels. Unfortunately, the data in support of neoadjuvant/concomitant/adjuvant ADT in intermediate- and high-risk patients have been extrapolated to patients with low-risk, clinically localized prostate cancer and patients with biochemical recurrence of prostate cancer—two situations in which clinical benefit is uncertain.
A paucity of literature supports the use of ADT in high-risk patients receiving other treatment modalities for clinically localized prostate cancer. ADT for primary treatment of clinical stage T1–2 prostate cancer has been associated with increased cancer-specific mortality and no change in overall survival.[2] No Level 1 evidence provides proof of survival benefit for neoadjuvant, concomitant, or adjuvant ADT in men treated with radical prostatectomy who do not have lymph node involvement. Our institution is accruing to the Radiation Therapy Oncology Group trial RTOG 0534, which seeks to establish the role of adjuvant RT with or without ADT and with or without extended pelvic fields for men at high risk of treatment failure after radical prostatectomy.
The authors describe the potential use of RT dose escalation in lieu of ADT for high-risk prostate cancer, but supporting evidence is awaited. The Massachusetts General Hospital trial of RT dose escalation (without ADT) showed improvement in biochemical recurrence for men at low and intermediate risk but no difference in high-risk patients. The UK Medical Research Council trial MRC RT01 incorporated ADT in all patients, therefore it is not possible to distinguish the effect of ADT in this study. RTOG 0815 will compare outcomes of escalating RT with and without ADT.
ADT impairs quality of life, and the authors outline well its many serious adverse effects, which include development of insulin resistance; progressive bone demineralization; and unfavorable changes in body composition, lipid profiles, and arterial walls. These changes may be responsible for an increased incidence of cardiovascular events and large bone fractures, both of which directly affect overall survival. Substantial data suggest that the hypogonadal state resulting from ADT creates a state similar to the metabolic syndrome, which is potentially dangerous because it is associated with diabetes and cardiovascular disease. Many ADT-induced changes are complex and not clearly adverse, however; as the authors point out, ADT changes high-density lipoprotein (HDL) levels favorably and produces changes in inflammatory mediators that are inconsistent with the metabolic syndrome.[3]
It is difficult to ascertain whether the physiologic effects of ADT translate into a reduced overall survival. The authors highlight population-based cohort analyses that demonstrated significant increases in cardiac morbidity and mortality in patients treated with ADT. The patient populations, however, are diverse in terms of stage at presentation, comorbid history, treatment received, and indication for and method of administration of ADT; these data are difficult to extrapolate to men with clinically localized, high-risk disease. Additionally, many of the post hoc analyses of clinical trials failed to demonstrate significant differences in cardiovascular morbidity. However, the cardiac complications of ADT are seen more consistently in studies evaluating subsets of elderly patients and those with a history of cardiac disease.
The 2009 National Comprehensive Cancer Network (NCCN) prostate cancer treatment guidelines recognized the adverse effects of ADT and recommended advising patients and medical providers of these risks. Providers should undertake screening and intervention when appropriate for osteoporosis, diabetes, and cardiovascular disease in men receiving ADT. These recommendations were strengthened by the joint science advisory released February 2010 by the American Heart Association, American Cancer Society, and the American Urologic Association. The advisory recommended that patients beginning ADT be referred to their primary care physician for monitoring, which should include periodic assessment of blood pressure, lipid profile, and glucose level beginning within 3 to 6 months after initiation of ADT. The advisory did not recommend referral prior to initiation of ADT nor any specific interventions upon initiation of ADT.
The data regarding fragility fractures in patients on ADT also are largely retrospective and population-based, but are likewise compelling. Metastatic fractures were excluded from analysis, which is appropriate for consideration of adverse events, but comparison rather than exclusion might be more revealing, as a benefit of ADT may be the reduction of pathologic fractures.
Lastly, the use of ADT is influenced by the clinician and the patient. As the authors note, certain physician characteristics have been shown to influence the use of ADT; these include academic affiliation, years since medical school graduation, and board certification. Moreover, a recent study found that the level of patient anxiety was an independent risk factor for initiation of ADT upon biochemical recurrence after treatment of clinically localized prostate cancer.[4] Clinicians must educate patients fully about the risks and benefits of ADT, so as not to allow them to receive treatments that are not guideline-compliant without full disclosure.
ADT should be administered to carefully selected patients. The high quality of data defines clearly the benefits and risks of using neoadjuvant/concomitant/adjuvant ADT with radiation for high-risk patients. However, one must resist the temptation to extrapolate those data to other patient populations in which ADT has not been studied rigorously. Potential benefits of ADT must be weighed against the known adverse effects, with particular attention paid to the age and medical history of the patient. Monitoring for and managing ADT side effects is crucial, especially when ADT is considered for longer periods of time. Two or 3 years of neoadjuvant/concomitant/adjuvant ADT should be used when possible in high-risk patients undergoing potentially curative RT, and a shorter ADT course of 6 months should be considered for intermediate- or high-risk patients who are physiologically older. ADT should be used with radical prostatectomy in lymph node–negative patients only in the setting of a clinical trial.
Financial Disclosure: The authors have no significant financial interest of other relationship with the manufacturers of any products or providers of any service mentioned in this article.
