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Toward the Optimal Use of Androgen Suppression Therapy in the Radiotherapeutic Management of Prostate Cancer

Brigham and Women's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

Several randomized trials^1-3 have documented a prolongation in the time to prostate-specific antigen (PSA) recurrence, prostate cancer–specific mortality or all-cause mortality (ACM) when 6 months to 3 years of androgen suppression therapy (AST) and radiation therapy (RT) were used to treat men with high-risk prostate cancer on the basis of the PSA level (> 10 ng/mL), Gleason score (7 to 10) or the 2002 American Joint Commission of Cancer (AJCC)⁴ clinical T (tumor) category (T2b to T4) as compared with RT alone. Therefore, for men with localized high grade or locally advanced prostate cancer, the combination of RT and AST has become a standard of care, although the optimal duration of AST remains uncertain.

On the basis of this evidence,^1-3 the use of AST in conjunction with RT has increased markedly.⁵ Specifically, an increasing number of men in the United States—especially those older than 80 years—are receiving AST alone or as part of their management for newly diagnosed or recurrent prostate cancer.⁶ Yet AST also can cause anemia, an increase in body mass index, insulin resistance, increased arterial stiffness, and less favorable lipid profiles.^7-10 These changes may explain the adverse impact on health-related quality of life (HRQOL) and the use of neoadjuvant AST before prostate brachytherapy as compared with prostate brachytherapy alone.¹¹ These changes also can persist after discontinuing AST, especially in men of advanced age.¹² Some of these symptoms satisfy the criteria for metabolic syndrome,¹³ a condition associated with an increased risk of death resulting from myocardial infarction, despite the absence of cardiovascular disease or diabetes.¹⁴ A meta-analysis of randomized trials^2-3 shows that 6 months of AST administration shortens the time to a fatal myocardial infarction in men of advanced age.¹⁵ In addition, a review of the Surveillance, Epidemiology, and End Results (SEER) and Medicare databases shows an association between new diagnoses of diabetes and cardiac disease and AST use.¹⁶ Therefore, evidence is needed to determine the minimum duration of AST that provides the maximal prolongation in overall survival while minimizing the impact on HRQOL in an individual man planning to undergo RT for high-risk localized or locally advanced prostate cancer.

A first attempt toward achieving this goal will be provided by the European Organisation for Research and treatment of Cancer (EORTC), which has completed a randomized phase III clinical trial (EORTC 22961)¹⁷ comparing the use of an additional 2.5 years of luteinizing hormone–releasing hormone agonist monotherapy with no further AST in men with locally advanced prostate cancer who initially receive RT and 6 months of combined AST. The results of this trial will determine whether AST beyond 6 months is needed in men undergoing RT plus AST for high-risk localized or locally advanced prostate cancer. A second attempt to address the question of the optimal duration of AST is provided by Heymann et al in this issue of the Journal of Clinical Oncology.¹⁸

Specifically, Heymann et al prospectively evaluated in a phase II study 123 men with clinical T1a-4 adenocarcinoma of the prostate who were treated with 75.6 Gy of RT after maximal PSA response to neoadjuvant AST and who then went on to complete a total course of 9 months of AST. The primary end point of their study was time to PSA failure, defined as the occurrence of two consecutive rises above a PSA level of 1.5 ng/mL. The clinical team responsible for the management of the patient assessed toxicity and the median follow-up was 45 months (range, 0 to 81). The authors concluded that disease control was excellent and that erectile dysfunction was limited. They also noted that men whose testosterone achieved a normal level (270 ng/dL or higher) after discontinuing the AST had significantly longer estimates of overall survival compared with men whose testosterone level did not normalize. Several aspects of the studies findings and conclusions require further consideration.

First, the association of the normalization of the serum testosterone level and a prolongation in time to ACM may be explained by data¹⁹ showing that younger men are more likely to normalize serum testosterone levels and do so more quickly after discontinuing AST as compared with older men. Younger men are also expected to live longer than older men. As a result, the observation of normalization of testosterone level and prolonged survival may be explained on the basis of age. An age-adjusted Kaplan-Meier plot²⁰ of overall survival could address this issue directly. The authors state that age did not predict for overall mortality, but this may be due to the small number of deaths; that is, the study was underpowered to evaluate any associations with time to death from all causes and, therefore, any cause. The association between advancing age and a shorter time to death is an accepted and humbling truth.

Second, I do agree with the authors' conclusion in the final sentence of the discussion section, which stated that only a randomized phase III trial comparing the approach performed in the current phase II study¹⁸ to current standards of 6 months^2-3 or 2 to 3 years^1,21 of AST is needed before this approach could be considered as a treatment option for men with intermediate- or high-risk prostate cancer. Phase II studies can document the feasibility of an approach and may generate hypotheses, but cannot make definitive comments about efficacy compared with standard approaches because of the lack of comparable follow-up, identical end points, and assurance that both known and unknown confounding factors are balanced between the two treatment arms. Therefore, the current study shows that the approach of initiating RT after maximal response to AST is feasible, but how PSA control and cancer-specific and all-cause survival compare with current standards remains unanswered.

Finally, with regard to HRQOL, the authors conclude that erectile dysfunction was reduced in most patients using their treatment approach. This comment needs to be considered with caution, because toxicities were scored by the medical team and not on the basis of patient-reported data gathered in an anonymous setting using a validated instrument. Prior evidence²² supports the conclusion that an underestimate of toxicity can occur when the assessment source is the medical team as compared with a validated patient-completed, disease-targeted and anonymous HRQOL instrument.²³

In summary, the current phase II study by Heymann et al provides clinical trialists with an opportunity to assess in a phase III randomized trial the PSA response–based approach to neoadjuvant AST administration with the current standards of care for men with intermediate- and high-risk prostate cancer. Given the growing list of toxicities^7-11,15,16 of AST, some of which can shorten life, especially in advanced-age men,¹⁵ administering as little AST as possible while still maintaining the approximately 100% reduction (hazard ratio, approximately 0.5) in ACM^1,3 is our current challenge. During the next few years, data that will shed light on whether more than 6 months of AST is needed to prolong survival in men treated with RT for localized high risk or locally advanced prostate cancer will be provided by the completed EORTC randomized study 22961.¹⁷

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author indicated no potential conflicts of interest.

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