AB03. Intermittent androgen suppression: current status

Abstract: Hormone therapy has been a major treatment for advanced prostate cancer. This therapy aims at inhibiting growth of prostate tumor cells by deprivation of male hormones which stimulate prostate cells to grow. However, in spite of its temporally high effectiveness for tumor regression, most patients suffer from a relapse within a few years after initiation of treatment. The main cause of relapse is that cancer cells become resistant to hormone suppression. The toxicities of androgen deprivation have been well described, with a number of potential adverse effects on quality of life, including sexual dysfunction, hot flashes, fatigue, anemia, decreased bone density and muscle mass, altered blood lipid profile, depression, cognitive dysfunction, and worsening of the metabolic syndrome with effects on glucose metabolism and cardiovascular morbidity. The introduction of PSA testing into clinical practice in the early 1990’s provided an objective evaluation of the efficacy of definitive treatment and biochemical failure became an accepted end point. This ability to determine early treatment failure created a clinical dilemma for the practitioner. The justification for lifelong androgen deprivation is more apparent in the face of obvious clinical disease than in an asymptomatic individual with a slowly rising PSA, either with or without primary therapy aimed at the prostate.

A possible clinical strategy to prevent or delay hormone-refractoriness of prostate tumor is intermittent hormone therapy. This treatment is also effective in reduction of side effects during off-treatment periods and thereby quality of life of patients can be improved. Bruchovsky and Goldenberg used the androgen-dependent Shionogi carcinoma to demonstrate that castration followed by re-exposure to androgens prior to tumor progression caused surviving stem cells to remain androgen-dependent, and thus amenable to further treatment by repeated androgen withdrawal. Successive castration and re-exposure to androgens in the mouse model produced multiple apoptotic regressions, resulting in a 3-fold delay in development of androgen independence. Cycles of androgen deprivation followed by re-exposure to testosterone form the basis of intermittent androgen deprivation (IAD).

Multiple phase 2 clinical studies and 3 definitive phase-III trials of IAS have been published and will be reviewed. All phase 2 studies, including a meta-analysis strongly suggested that IAS is not inferior to continuous therapy and offers the potentials of QOL improvement and financial savings. The optimal protocol of IAS therapy, that is, how to determine the appropriate lower and upper thresholds of the serum PSA level for switching on- and off-treatment periods is quite varied but the most common approach is to treat for 6 to 8 months and resume at a predetermined PSA level. In clinical practice, a tailor-made patient-specific regimen is usually adopted because the best protocol of hormone therapy must depend upon individual patients. The multicentre randomized, prospective studies (NCIC PR8, SWOG 9346 and SEUG 9901) have been somewhat controversial. The large PR7 trial of IAS for men suffering PSA relapse after radiation strongly suggests non-inferiority. However, the PR8 study of men with metastatic cancer was not definitive in its conclusions and actually reported as “not non-inferior”. Many, but not all intermittent patients showed significant improvements in global QOL.

A recently published metaanalysis of 5,508 patients in 9 RCT’s confirmed a cost savings of 48% with a pooled hazard ration for overall survival of 1.02 in favour of IAS (95% CI, 0.94 to 1.11). The HR for cancer specific survival was 1.08 for IAS vs. CAS (95% CI, 0.85 to 1.38). The authors pointed out some limitations of their metaanalysis but concluded that there was no notable compromise in health outcomes in eligible men treated with IAS as all showed either superiority or equivalence. They do caution the use of IAS in men with asymptomatic non-metastatic disease which reflects the question of appropriate timing of therapy along this disease’s continuum. Future work in this field includes the question of exogenous testosterone replacement for men in whom endogenous levels do not recover, the role of mathematical modeling in predicting an individual’s likely response to cycled therapy, choline PET scanning and the layering on of novel agents with low toxicity during the off-treatment interval.

Keywords: Prostate cancer; hormone therapy; androgen suppression