Cessation Of Androgen Deprivation Therapy Research Articles

086 Testosterone recovery profiles after cessation of androgen deprivation therapy (ADT)

086 Testosterone recovery profiles after cessation of androgen deprivation therapy (ADT)

PD31-06 TESTOSTERONE RECOVERY IN PATIENTS TREATED WITH INTENSITY-MODULATED RADIATION THERAPY COMBINED WITH ANDROGEN DEPRIVATION THERAPY

You have accessJournal of UrologySexual Function/Dysfunction: Medical, Hormonal & Non-surgical Therapy I1 Apr 2018PD31-06 TESTOSTERONE RECOVERY IN PATIENTS TREATED WITH INTENSITY-MODULATED RADIATION THERAPY COMBINED WITH ANDROGEN DEPRIVATION THERAPY Kazuo Nishimura, Sohei Kuribayashi, Hirotaka Tsuji, Satoru Yumiba, Koji Hatano, Yasutomo Nakai, Masashi Nakayama, Ken-ichi Kakimoto, Koji Konishi, and Teruki Teshima Kazuo NishimuraKazuo Nishimura More articles by this author , Sohei KuribayashiSohei Kuribayashi More articles by this author , Hirotaka TsujiHirotaka Tsuji More articles by this author , Satoru YumibaSatoru Yumiba More articles by this author , Koji HatanoKoji Hatano More articles by this author , Yasutomo NakaiYasutomo Nakai More articles by this author , Masashi NakayamaMasashi Nakayama More articles by this author , Ken-ichi KakimotoKen-ichi Kakimoto More articles by this author , Koji KonishiKoji Konishi More articles by this author , and Teruki TeshimaTeruki Teshima More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1537AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES External-beam radiation therapy (EBRT) plus androgen deprivation therapy (ADT) improves overall survival in men with localized and locally advanced prostate cancer (PCa). However, little is known about testosterone recovery after cessation of ADT combined with intensity-modulated radiation therapy (IMRT). METHODS We reviewed our database of patients receiving IMRT combined with ADT for PCa at our institution between December 2006 and June 2014 with a minimum follow-up of 3 years. Testosterone (T) serum concentration was analyzed according to prostate-specific antigen (PSA) progression after cessation of ADT. T recovery was defined as T value > 200 ng/dl. The Kaplan-Meier method was used to estimate the cumulative incidence of T recovery. A log-rank test was performed to compare these estimates. Different factors (age, baseline PSA, clinical stage, Gleason score, body mass index [BMI], ADT duration, and type of ADT) were assessed for time to T recovery (TTR) using multivariate Cox regression analysis. RESULTS The study comprised 132 men with a median age of 70 (49-79) years. Clinical stages were: T1c-T2cN0M0 in 71 patients, T3a-3bN0M0 in 59 patients, and T1c-T3bN1M0 in 2 patients. Of these, 73 patients received a luteinizing hormone-releasing hormone (LH-RH) agonist alone and 59 received an LH-RH agonist with an antiandrogen as primary ADT. Median duration of ADT was 28 (2-69) months. At last follow up, 90 (68%) of patients achieved T recovery with a median duration of 17 (4-41) months after cessation of ADT. ADT duration (<1 year, 1-2.5 years, >2.5 years) and age (<65 vs. >65 years) were significantly associated with TTR (p<0.001 and p = 0.011) (Figure 1 and 2). Baseline PSA, clinical stage, Gleason score, BMI, and type of ADT were not associated with TTR. CONCLUSIONS Approximately one-third of patients did not achieve T recovery after cessation of ADT combined with IMRT. ADT duration and age were significantly associated with T recovery. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e641-e642 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Kazuo Nishimura More articles by this author Sohei Kuribayashi More articles by this author Hirotaka Tsuji More articles by this author Satoru Yumiba More articles by this author Koji Hatano More articles by this author Yasutomo Nakai More articles by this author Masashi Nakayama More articles by this author Ken-ichi Kakimoto More articles by this author Koji Konishi More articles by this author Teruki Teshima More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

036 Testosterone Recovery Profiles after Cessation of Androgen Deprivation Therapy (ADT)

It has been demonstrated that the combination use of ADT improves overall and cancer-specific survival in men with unfavorable prostate cancer (PCa). After cessation of ADT, testosterone (T) levels are expected to recover from castrate to normal levels. However, very little is known about T recovery profiles in this population, and many patients remain on castrate levels indefinitely. The aim of this study was to evaluate T recovery after cessation of ADT in PCa patients. We reviewed our prospectively maintained database for PCa patients who received ADT therapy at our institution. Serum early morning total T (TT) levels were measured at baseline and periodically after ADT cessation. Multivariable time-to-event analysis (Cox proportional hazards) was performed to determine predictors of TT recovery after ADT cessation and included the following variables: patient age, baseline T level, and duration of ADT. 1641 men with a mean age of 66 (43-94) years were included. Primary treatment for PCa was RP in 36%, while the remainder had either RT or primary ADT. The majority received a GnRH agonist as mainstay for ADT. Mean duration of ADT was 28.8±39 months [0.5 to 324]. Distribution of ADT exposure was: <6 months (m) 33%, 6-12m 19%, 12-24m 16%, >24m 33%. Median follow-up was 47.5±45 months. Mean TT values were: baseline 358 ng/dl, 6-12m post ADT cessation 96 ng/dl, 12-18 174 ng/dl, 18-24m 228 ng/dl, >24m 273 ng/dl. At last follow-up: 77% men had TT level above castrate level, 45% had TT >300ng/dl and 39% returned to pre-treatment TT level. On multivariable analysis age over 65 years (HR 2.01, 95%CI 1.48-2.71, P<0.0001), ADT duration of 6 months or greater (HR 1.42, 95%CI 1.07-1.90, P=0.02), and baseline T of 400 ng/dl or more (HR 1.80, 95%CI 1.36-2.40, P<0.0001) were all significantly associated with a slower recovery time.

Time on androgen deprivation therapy and adaptations to exercise: secondary analysis from a 12-month randomized controlled trial in men with prostate cancer.

To explore if duration of previous exposure to androgen deprivation therapy (ADT) in men with prostate cancer (PCa) undertaking a year-long exercise programme moderates the exercise response with regard to body composition and muscle performance, and also to explore the moderator effects of baseline testosterone, time since ADT, and baseline value of the outcome. In a multicentre randomized controlled trial, 100 men who had previously undergone either 6 months (short-term) or 18 months (long-term) of ADT in combination with radiotherapy, as part of the TROG 03.04 RADAR trial, were randomized to 6 months supervised exercise, followed by a 6-month home-based maintenance programme, or to printed physical activity educational material for 12 months across 13 university-affiliated exercise clinics in Australia and New Zealand. The participants were long-term survivors of PCa with a mean age of 71.7 ± 6.4 years, and were assessed for lower extremity performance (repeated chair rise), with a subset of men (n = 57) undergoing additional measures for upper and lower body muscle strength and body composition (lean mass, fat mass, appendicular skeletal muscle [ASM]) by dual X-ray absorptiometry. Data were analysed using generalized estimating equations. Time on ADT significantly moderated the exercise effects on chair rise (βinteraction = -1.3 s, 95% confidence interval [CI] -2.6 to 0.0), whole-body lean mass (βinteraction = 1194 g, 95% CI 234 to 2153) and ASM mass (βinteraction = 562 g, 95% CI 49 to 1075), and approached significance for fat mass (βinteraction = -1107 g, 95% CI -2346 to 132), with greater benefits for men previously on long-term ADT. At 6 months, the intervention effects on chair rise time -1.5 s (95% CI -2.5 to -0.5), whole-body lean mass 824 g (95% CI 8 to 1640), ASM mass 709 g (95% CI 260 to 1158), and fat mass -1377 g (95% CI -2156 to -598) were significant for men previously on long-term ADT, but not for men on short-term ADT. At 12 months, the intervention effects for men on long-term ADT remained significant for the chair rise, with improved performance (-2.0 s, 95% CI -3.0 to -1.0) and increased ASM (537 g, 95% CI 153 to 921). Time on ADT did not moderate the exercise effects on muscle strength, nor did time since ADT cessation moderate any intervention effects. Similarly, testosterone and baseline values of the outcome had negligible moderator effects. Men with PCa previously treated long-term with ADT respond more favourably to exercise in terms of lower body muscle performance and body composition (lean and fat mass, and ASM) than those with short-term ADT exposure. As a result, men who were formerly on long-term androgen suppression regimens should be especially prescribed exercise medicine interventions to alleviate residual treatment-related adverse effects.

The Relationship between Hot Flashes and Testosterone Recovery after 12 Months of Androgen Suppression for Men with Localised Prostate Cancer in the ASCENDE-RT Trial

AimsThis study describes the proportion of men who experienced hot flashes (flashes), and the testosterone level at onset, peak frequency and cessation of flashes after 12 months of androgen deprivation therapy (ADT) in men undergoing curative-intent external beam radiation therapy (± brachytherapy boost). We also aimed to characterise testosterone recovery in this population. Materials and methodsThis was a pre-specified secondary analysis of the ASCENDE-RT clinical trial. Three hundred and ninety-eight men were randomised. All received 12 months of ADT. The presence and frequency of flashes were patient reported. Cessation of flashes was defined as the first date a patient reported resolution of this symptom. Testosterone recovery was defined as any single serum testosterone above the threshold of 5, 7.5 or 10 nmol/l. ResultsThe median age and follow-up were 68 years and 6.1 years. Flashes were reported in 93% of men. Flashes began and reached peak frequency at a median time of 4.0 months from the first luteinizing hormone-releasing hormone injection when testosterone levels had fallen to castrate. The median time to cessation of flashes was 7.6 months after the cessation of ADT (last injection + 3 months), when the median testosterone had risen to 5.7 nmol/l. A resolution of flashes was reported in 99% of patients. Baseline testosterone was available in 338 patients (85%). The median baseline testosterone was 13.2 nmol/l. The median (95% confidence interval) time of testosterone recovery to thresholds of 5 nmol/l, 7.5 nmol/l and 10 nmol/l were 9 (9–10) months, 13 (10–15) months and 18 (17–19) months from the cessation of ADT. At the time of censor, 96, 94 and 91% of patients had recovered testosterone to thresholds of 5, 7.5 and 10 nmol/l. ConclusionFlashes occur at castrate levels of testosterone, with cessation of hot flashes antedating full recovery of testosterone in most patients. Rates of testosterone recovery after 12 months of ADT exceed 90%, although it can be delayed.

Cessation of long-term adjuvant androgen deprivation therapy after radical prostatectomy: is it feasible?

Adjuvant androgen deprivation therapy is a common treatment option for prostate cancer after radical prostatectomy, especially in Asia. However, no study has investigated the oncological outcome after cessation of long-term adjuvant androgen deprivation therapy with favorable prostate-specific antigen control. Among 855 patients undergoing radical prostatectomy at our institution between 2000 and 2012, we identified 56 men with pT2-4N0-1M0 prostate cancer who had received long-term (>2 years) adjuvant androgen deprivation therapy after radical prostatectomy and subsequently stopped it under a condition of continued prostate-specific antigen values <0.1 ng/mL. The oncological outcome was evaluated using biochemical recurrence, defined as two consecutive prostate-specific antigen values ≥0.2 ng/mL, as the primary endpoint. Cox proportional hazards model was used for multivariate analysis. Age at androgen deprivation therapy cessation was dichotomized as <68 years and ≥68 years, based on the most discriminatory cutoff. Median duration of adjuvant androgen deprivation therapy was 70 months. Overall, 13 of 56 (23%) patients developed biochemical recurrence with a median follow-up period of 41 months after androgen deprivation therapy cessation. Multivariate analysis identified age at androgen deprivation therapy cessation <68 years and pN1 as independent predictors of biochemical recurrence. Predisposition of younger age to poorer survival may be related to more frequent testosterone recovery in younger men (73 vs 33%, P = 0.0299). One patient had evidence of clinical metastasis and no one died of prostate cancer. Androgen deprivation therapy cessation would be feasible in most men who received long-term adjuvant androgen deprivation therapy after radical prostatectomy with favorable prostate-specific antigen control. Risk factors of biochemical recurrence after androgen deprivation therapy cessation included younger age at androgen deprivation therapy cessation and pN1.

Hormonal response recovery after long-term androgen deprivation therapy in patients with prostate cancer

Objective: The aim of this study was to evaluate hormonal recovery after cessation of androgen deprivation therapy (ADT) in a group of elderly prostate cancer patients.Materials and methods: Forty patients with locally advanced or metastatic prostate cancer, with a mean age of 71.5 years [95% confidence interval (CI) 69.1–73.9], were treated with ADT for a mean duration of 74.6 months (95% CI 59.7–89.5 months). Mean follow-up time after ADT cessation was 36.5 months (95% CI 30.6–42.3 months). Serum testosterone and luteinizing hormone (LH) were determined at 6 month intervals after ADT cessation.Results: After 18 months of follow-up, all patients had recovered normal LH levels, while 38% of patients still presented castration levels of testosterone (< 50 ng/dl). A multivariate analysis was performed to find factors related to testosterone recovery (testosterone >50 ng/dl). Neither age at start of ADT nor clinical stage reached statistical significance. Only time under ADT was correlated with testosterone recovery (p = .031). Kaplan–Meier curves were obtained. Mean time for testosterone recovery was 14.5 months (95% CI 6.5–22.6 months) in patients treated with ADT for less than 60 months compared to 29.3 months (95% CI 19.6–39.1 months) in patients treated with ADT for more than 60 months (log-rank p = .029).Conclusions: Age did not correlate with testosterone recovery in a group of elderly prostate cancer patients in whom ADT was stopped. Testosterone recovery after ADT cessation was significantly correlated with time under ADT treatment. Significant implications related to economic aspects of the dosage schedule may be considered.

Cessation of Primary Androgen Deprivation Therapy for Men With Localized Prostate Cancer

IntroductionSubstantial numbers of men with localized prostate cancer undergo long-term primary androgen deprivation therapy (ADT). Whether long-term ADT is required for patients with localized prostate cancer, especially elderly men, remains unknown. In the present study, we explored the possibility of ADT cessation after a favorable response to primary ADT in patients with localized prostate cancer. Patients and MethodsWe retrospectively reviewed men with localized prostate cancer who had achieved a good initial response to primary ADT and stopped it thereafter. Prostate-specific antigen (PSA) recurrence was defined as 2 consecutive increases > 4 ng/mL. A total of 34 patients (age, 62-89 years) were followed up for > 24 months after ADT cessation. ResultsThe ADT duration and follow-up period after ADT cessation was 10 to 162 months (median, 33.5 months) and 24 to 95 months (median, 37 months), respectively. PSA recurrence was observed in 10 of 34 patients (29.4%), and the 5-year PSA progression-free rate was 66.2%. PSA recurrence was observed in 100% (6 of 6) and 14.3% (4 of 28) of men who had received ADT for < 16 months and > 16 months, respectively. ADT was reinstated in 5 patients after PSA recurrence; and their PSA levels declined rapidly, and no clinical progression was observed. The 5-year overall and disease-specific survival rate was 65.1% and 100%, respectively. ConclusionADT can be stopped for men with localized prostate cancer, especially elderly men, after a favorable response to primary ADT.

Recovery of serum testosterone following neoadjuvant and adjuvant androgen deprivation therapy in men treated with prostate brachytherapy.

To investigate the time course of testosterone (T) recovery after cessation of androgen deprivation therapy (ADT) in patients treated with brachytherapy. One-hundred and seventy-four patients treated between June 1999 and February 2009 were studied. Patients were divided into a short-term usage group (≤ 12 mo, n = 91) and a long-term usage group (≥ 36 mo, n = 83) according to the duration of gonadotropin-releasing hormone agonist therapy. Median follow-up was 29 mo in the short-term group and was 60 mo in the long-term group. Cumulative incidence rates of T recovery to normal and supracastrate levels at 24 mo after cessation were 28.8% and 74.6%, respectively, in the long-term usage group, whereas these values were 96.4% and 98.8% in the short-term usage group. T recovery to normal and supracastrate levels occurred significantly more rapidly in the short-term than in the long-term usage group (P < 0.001 and P < 0.001, respectively). Five years after cessation, 22.6% of patients maintained a castrate T level in the long-term usage group. On multivariate analysis, lower T levels (< 10 ng/dL) at cessation of ADT was significantly associated with prolonged T recovery to supracastrate levels in the long-term usage group (P = 0.002). Lower T levels at cessation of ADT were associated with prolonged T recovery in the long-term usage group. Five years after cessation of long-term ADT, approximately one-fifth of patients still had castrate T levels. When determining the therapeutic effect, especially biochemical control, we should consider this delay in T recovery.

Kinetics of testosterone recovery in clinically localized prostate cancer patients treated with radical prostatectomy and subsequent short-term adjuvant androgen deprivation therapy

Androgen deprivation therapy (ADT) is a standard treatment for metastatic, recurrent and locally advanced prostate cancer (PCa). The aim of this study is to investigate the timing and extent of testosterone recovery in clinically localized PCa patients treated with radical prostatectomy (RP) and subsequent short-term adjuvant ADT. A total of 95 localized PCa patients underwent RP and 9-month adjuvant ADT were included in this prospective study. Serum testosterone level was measured before adjuvant ADT, at ADT cessation, and at 1, 3, 6, 9 and 12 months after cessation of ADT. A Cox proportional hazards model was used to assess variables associated with the time of testosterone normalization. The results showed that median patient age was 67 years and median testosterone level before adjuvant ADT was 361 (230-905) ng dl(-1). All patients finished 9-month adjuvant ADT and achieved castrate testosterone level. At 3 months after ADT cessation, testosterone recovered to supracastrate level in 97.9% patients and to normal level in 36.9% patients. The percentage of patients who recovered to normal testosterone level increased to 66.3%, 86.3% and 92.6% at 6, 9 and 12 months, respectively. Cox regression model found that higher baseline testosterone level (≥ 300 ng dl(-1)) was the only variable associated with a shorter time to testosterone normalization (hazard ratio: 1.98; P = 0.012). In conclusion, in most patients, testosterone recovered to supracastrate level at 3 months and to normal level at 12 months after 9-month adjuvant ADT cessation. Patients with higher baseline testosterone level need shorter time of testosterone normalization.

Cognitive and mood changes in men undergoing intermittent combined androgen blockade for non-metastatic prostate cancer.

Men with prostate-specific antigen (PSA)-only relapse of prostate cancer after primary therapy are generally fully functional and asymptomatic with a life expectancy of up to 10 or more years. Androgen deprivation therapy (ADT) is a common treatment option. This study examined mood and cognitive changes in otherwise healthy men with prostate cancer prior to, during and after ADT. Twenty hormone naïve, eugonadal prostate cancer patients without evidence of metastases and with a rising PSA were treated with intermittent ADT consisting of 9 months of complete androgen blockade (CAB) achieved with combined leuprolide and flutamide followed by an 'off treatment' period. Cognitive function tests and mood measures were administered at baseline, after 3 and 9 months of ADT and after 3 months of no treatment. Twenty healthy control patients without prostate cancer range matched for age and education were tested at the same time intervals. ADT patients evidenced a significant decline in spatial reasoning, spatial abilities and working memory during treatment compared with baseline. No changes were noted for measures of verbal or spatial memory, selective attention or language. Significant changes in self-rated mood such as increased depression, tension, anxiety, fatigue and irritability were evident during treatment compared with baseline for ADT patients. No significant changes in either cognitive tests or mood measures were noted for the healthy control group. These findings, suggest that 9 months of combined androgen blockade may result in some adverse changes in cognition and mood. However, many but not all of these changes can return to baseline after cessation of ADT.

Serum Testosterone Recovery After Cessation of Long-Term Luteinizing Hormone-Releasing Hormone Agonist in Patients with Prostate Cancer

The time to testosterone recovery after the cessation of androgen deprivation therapy appears to be dependent on the therapy duration. Most men will recover normal testosterone levels within 18 months according to the findings from studies that frequently involved fewer than 3 years of androgen deprivation therapy. Our goal was to assess the proportion of patients who remain castrated after cessation of longer duration luteinizing hormone-releasing hormone (LHRH) agonist therapy for prostate cancer. We reviewed 15 patients who had received at least 48 months of continuous goserelin injection therapy for prostate cancer and had not been receiving the therapy for at least 18 months. The serum testosterone and prostate-specific antigen data were obtained. The mean duration of LHRH agonist therapy was 73 months (range 48 to 110). At the cessation of therapy after a mean follow-up of 31 months, 53% had testosterone levels that remained castrated. Only 1 patient achieved normal testosterone levels. Of the patients with greater than castrate testosterone levels, 71% experienced a prostate-specific antigen rise. All the men with an intact prostate who had testosterone recovery to greater than castrate levels had a prostate-specific antigen increase, which might represent a return toward the pretreatment baseline. Of the patients who started therapy after age 70 years, 78% remained castrated versus 17% of those who started before 70 years. Of the men who had received 4 or more years of LHRH agonist therapy for prostate cancer, 53% remained castrated up to 2.5 years after therapy cessation. Patients who started LHRH agonist therapy after age 70 were more likely to remain castrate after stopping long-term therapy.

Time course of serum testosterone and luteinizing hormone levels after cessation of long‐term luteinizing hormone‐releasing hormone agonist treatment in patients with prostate cancer

In order to elucidate the influence of hormone-releasing hormone (LH-RH) agonist therapy cessation on pituitary/testicular function and its clinical implications, we investigated prospectively hormonal (luteinizing hormone: LH; testosterone: T) responses in patients with prostate cancer who received long-term LH-RH 10 agonist therapy. A consecutive 32 patients who had received LH-RH agonist therapy over 24 months were enrolled. As a baseline, T and LH were measured at the time of LH-RH agonist therapy cessation, monthly for 3 months, and subsequently, every 3 months. The median duration of LH-RH agonist therapy was 30 months (24-87 months) with median follow-up duration of 24 months following cessation. All patients had castrated T levels and suppressed LH levels at baseline. Median duration of castrated T levels following cessation was 6 months. Median time to normalization of T levels was 24 months. LH levels returned to normal within 3 months in all cases. Patients who received androgen deprivation therapy for 30 months or longer required a longer time for recovery of T levels. Patients over 65 years of age showed a statistically significant longer time for recovery of T levels (P=0.0167). Long-term LH-RH agonist therapy has remarkable effects on serum T level that last for a significant time after cessation, a fact that should be applied to the interpretation of both PSA and serum T levels after cessation of androgen deprivation therapy.

A prospective analysis of correlates of time to testosterone recovery after cessation of androgen deprivation therapy (ADT)

Hormonal therapy has an increasing role in the treatment of localized prostate cancer. The duration and schedule of ADT varies widely in prostate cancer patients treated curatively with radiation. Testosterone levels may decrease temporarily or permanently after ADT has been discontinued. Delays in testosterone recovery confound interpretation of biochemical outcomes and negatively impact quality of life. The time course of testosterone recovery in patients maintained on ADT longer than one year has not previously been reported.

A prospective analysis of correlates of time to testosterone recovery after cessation of androgen deprivation therapy (ADT)

Hormonal therapy has an increasing role in the treatment of localized prostate cancer. The duration and schedule of ADT varies widely in prostate cancer patients treated curatively with radiation. Testosterone levels may decrease temporarily or permanently after ADT has been discontinued. Delays in testosterone recovery confound interpretation of biochemical outcomes and negatively impact quality of life. The time course of testosterone recovery in patients maintained on ADT longer than one year has not previously been reported.