A B S T R A C T PurposeTo investigate changes in bone mineral density (BMD) and fracture risk in men who received intermittent androgen deprivation (IAD) for nonmetastatic, hormone-sensitive prostate cancer. Patients and MethodsMen with prostate cancer who lacked radiographically detectable metastases were treated in a prospective trial of IAD. After 9 months of treatment with leuprolide and flutamide, androgen deprivation therapy (ADT) was stopped until prostate-specific antigen reached a threshold (1 ng/mL for radical prostatectomy; 4 ng/mL for radiation or primary ADT) for a new cycle. Dual-energy x-ray absorptiometry (DXA) scans were performed before starting ADT and subsequently with each change in therapy. At least two consecutive DXA scans were required for this analysis. Computed tomography, bone scintigraphy, and lumbar spine x-rays were performed at the beginning and end of each treatment period. ResultsFifty-six of 100 patients met criteria for this analysis. The median age at study entry was 64.5 years (range, 49.8 to 80.9 years). The average percentage change in BMD during the first on-treatment period was Ϫ3.4% (P Ͻ .001) for the spine and Ϫ1.2% (P ϭ .001) for the left hip. During the first off-treatment period (median, 37.4 weeks; range, 13.4 weeks to 8.7ϩ years), BMD recovery at the spine was significant, with an average percentage change of ϩ1.4% (P ϭ .002). Subsequent periods had heterogeneous changes of BMD without significant average changes. After a median of 5.5 years (range, 1.1 to 13.8ϩ) years on trial, one patient (1.8%) had a compression fracture associated with trauma. ConclusionPatients experienced the greatest average change in BMD during early treatment periods of IAD with a smaller average change thereafter. Fractures were rare.
Microabstract The kinetics and relationships between testosterone (T) and prostate-specific antigen (PSA) during the first off-treatment interval in men with non-metastatic prostate cancer treated prospectively on a clinical trial of intermittent androgen deprivation were analyzed. Time to PSA rise and time to PSA rise after first T>50 ng/dL were prognostic for progression to castration-resistance. Background Intermittent androgen deprivation (IAD) represents an alternative to continuous AD with quality-of-life benefit and no evidence of inferior overall survival for non-metastatic prostate cancer. Early markers of prognosis for men treated with IAD have not been described. Methods Men with non-metastatic prostate cancer were treated with 9 months of leuprolide and flutamide followed by a variable “off-treatment” interval; AD was resumed when prostate specific antigen (PSA) reached a pre-specified value (1 ng/mL - radical prostatectomy; 4 ng/mL - intact prostate). Cycles were repeated until castration-resistance (CRPC), defined as two PSA rises with testosterone (T) ≤50 ng/dL. We evaluated kinetics and relationships of PSA and T levels, focusing on times to rise in each level, during the first off-treatment interval. Associations with CRPC and prostate cancer mortality (PCM) were estimated using Cox proportional hazards models controlling for age and Gleason score. Results Each 30-day increase in time to PSA rise was associated with a 21% reduction in the risk of developing CRPC (95% CI, 3–36%; P=0.02). Longer time (≥60 days) to PSA rise after rise to T >50 ng/dL was associated with a 71% reduction in the risk of developing CRPC (95% CI, 92% reduction to 2% inflation; P=0.05). Time to first T >50 ng/dL and PSA doubling time were not prognostic for progression to CRPC. No time interval was prognostic for PCM. Conclusion During the first off-treatment interval of IAD, longer times to PSA rise overall and after T >50 ng/dL were associated with reduced risk of developing CRPC.
209 Background: Exisulind is an apoptotic drug shown in vitro to inhibit expression and function of the androgen receptor. At lower doses as a single agent and in combination with chemotherapy it has demonstrated limited efficacy. In this pilot study, the potential for high dose exisulind to prolong the duration of the off treatment interval of IAD was studied. Methods: Eligible patients (pts) underwent prior definitive local therapy, had BCR, and received at least one full prior cycle of IAD, defined as a 9-month on- and variable off-treatment period (terminated by reaching PSA threshold 1 ng/mL for radical prostatectomy and 4 ng/mL for radiation). Exisulind (250 mg po bid) was started 3 months before completing the 2nd on-treatment period and continued through the 2nd off treatment interval and other IAD cycles until castration resistance (CRPC). We used a Cox proportional hazards model to estimate the association between receiving exisulind and time to resuming AD for pts who initiated exisulind during their 2nd on-treatment period. The model controlled for 1st off-treatment duration. Results: Nineteen pts were enrolled and treated with exisulind. Median age was 62 (range 50-75) years. Median PSA at diagnosis was 11 (3.9-99) ng/mL and 5 (1-19.2) ng/mL at initiation of IAD. Median Gleason score was 8 (6-9). Median duration of exisulind treatment was 1.5 (0.5-7.7) yrs and median follow-up was 9.3 (1.1-10.1) yrs. In 9 evaluable pts, taking exisulind was associated with a non-significant prolongation of the off treatment interval (15% decreased risk of progressing to PSA threshold and the next AD cycle, HR 0.85, 95% CI 0.41, 1.75, p=0.654). Six pts (32%) required at least one dose hold, 9 (47%) underwent a dose reduction for toxicity, and 7 (37%) came off trial for drug toxicity. Most common adverse events were elevated liver function tests (53%) and fatigue (42%). Median time to CRPC was 5.5 (0.3-not reached) yrs. Conclusions: High-dose exisulind was poorly tolerated and did not clearly extend the duration of 2nd off-treatment intervals compared to the 1st. More potent contemporary agents may be more beneficial in this setting. Clinical trial information: NCT00283803.
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