Short-term Androgen Deprivation Therapy Research Articles

Does Second Review of Prostate Needle Biopsy Pathology Impact Radiation Therapy Management? A Tertiary Cancer Center Study

Prostate cancer (PC) therapy options are determined by patient risk stratification, based on Gleason score (GS), PSA and clinical staging. Studies have reported GS interobserver variability between pathologists. It is unclear how these differences impact radiation oncology-related recommendations. We aim to determine the frequency of diagnostic discordance between outside pathologists (OP) and specialized urologic pathologists (UP), and impact on active surveillance (AS) or radiation (RT) recommendations. 208 second opinion needle prostate biopsy pathology reviews were performed by UP at our institution in 2016. Our cohort consisted of 154 cases after excluding those with inadequate specimens, lack of initial pathology report, metastatic disease, and history of local therapy. Number of cores involved and highest GS reported at our institution by UP were compared to those reported by OP. NCCN risk groups were determined for patients with available PSA and cT classification (n=130). Risk groups included low (LR), favorable intermediate (FIR), unfavorable intermediate (UIR) and high risk (HR). FIR >75 yo and all LR were considered candidates for AS. LR and FIR were eligible for EBRT or brachytherapy alone (BA). FIR and UIR were eligible for RT with short term androgen deprivation therapy (EBRT + ST-ADT) +/- brachytherapy boost (BB) for only UIR. HR was eligible for EBRT with long term ADT (LT-ADT) +/- BB. Prostate size and IPSS were available to determine BA/BB eligibility in 112 patients. The agreement of treatment options between institutions was tested by McNemar’s exact tests. Discrepancy in highest GS was noted in 25% of cases. 6/12 cases initially reported as negative for cancer were identified to have PC. 29% of cases with PC had changes in % positive cores. NCCN risk group changed based on UP review in 25% (n=32) of cases, upgrading 34% and downgrading 66% of these patients. After UP review, the following patients were not found suitable for initial eligible treatment: 7% initially eligible for AS, 9% for BA, 7% for EBRT, 18% for EBRT + ST-ADT, 24% for EBRT + ST-ADT +BB, 31% for RT + LT-ADT and 29% for EBRT + LT-ADT +BB. Based on UP review, 10 new patients out of the total cohort (8%) were eligible for AS, 5 (4%) for BA, 14 (11%) for EBRT, 12 (9%) for EBRT + ST-ADT, 7 (5%) for EBRT + ST-ADT+ BB and 2 (2%) for EBRT + LT-ADT. 8 (6%) became eligible for brachytherapy (6 for BA and 2 for EBRT + ST-ADT+BB), but found to be poor candidates based on IPSS or prostate size. There was a change in treatment eligibility for 25% of the entire cohort. McNemar’s exact test showed UP review significantly differed impacting eligibility for EBRT + LT ADT (p=0.02) and EBRT alone (p=0.03) but not eligibility for AS (p=0.09), BA (p=0.12), EBRT + ST-ADT (p=0.66) or EBRT + ST-ADT + BB (p=1.0). UP review of prostate biopsies impacts risk groups, modifying RT recommendations. Second pathology review by a UP should be strongly considered prior to final treatment decisions for PC patients.

The Response of Male Erectile Tissues to Androgen Deprivation Therapy and Radiation

Androgen deprivation therapy (ADT) plays an important role in the treatment of men undergoing radiation therapy (RT) for high-risk prostate cancer. Erectile dysfunction (ED) is a common side effect after combined RT and ADT. Both RT and ADT may have cardiovascular effects, thus we hypothesized that penile vascular tissue contracts in response to ADT and RT, and that this change correlates with worsening ED. Penile bulb (PB) volume and corpus cavernosum (CC) width were measured retrospectively on computed tomography (CT) scans obtained pre and post-neoadjuvant ADT (but prior to RT) in a cohort of prostate cancer patients treated with prostate RT+ADT. The same measurements were also obtained from a cohort of male cancer patients treated with RT alone using two CT image sets obtained with similar chronologic spacing. PB volume was measured based on RTOG contouring guidelines. CC width was measured at the position of the anterior border of the inferior pubic ramus. To confirm these findings with a separate image modality and to allow analysis of post-RT changes, we evaluated penile tissue changes with pre-treatment, post-neoadjuvant ADT, and post-RT Magnetic Resonance Imaging (MRI) in prostate cancer patients treated with RT+ADT. Sexual Health Inventory for Men (SHIM) scores were obtained pre-treatment and at least 18 months (range 18-30 months) after discontinuing ADT. Worsening ED was defined as an escalation in SHIM severity classification or initiation of medication for ED. Two-tailed paired t-tests were used to compare differences between cohorts and time points. In the prostate cancer RT+ADT cohort (n=41), both the PB (-3.28 cm3, 95%CI: -4.097 to -2.469; p<0.0001) and the CC (-0.12 cm, 95%CI: -0.1554 to -0.0909; p<0.0001) underwent significant reductions in size in response to neoadjuvant ADT. In the cohort not exposed to ADT (n=20), there was no significant change in PB (+1.38 cm3, 95%CI: -0.9424 to 3.709; p=0.2283) and CC (+0.04 cm, 95%CI: -0.0669 to 0.1510; p=0.4298). Findings from the MRI cohort (n=25) with imaging at three time points confirmed a significant PB reduction after neoadjuvant ADT (-104.4 mm2, 95% CI -137.6 to-71.22, p<0.0001), but not after subsequent treatment with RT (-18.34 mm2. 95% CI -49.81 to 13.13, p=0.2407). In the subset of RT+ADT patients with available SHIM data at late follow up (n=17), there was a nonsignificant trend toward worsening of ED with greater reductions in the percent volume of the PB (p=0.4346) and the percent width of the CC (p=0.112) with neoadjuvant ADT. This retrospective series demonstrates a significant reduction in the volume of erectile tissue with short-term neoadjuvant ADT, and no significant change with the addition of RT. Additional work is needed to determine if these changes persist at later time points or correlate to late ED in larger cohorts.

Recovery of Serum Testosterone Levels and Sexual Function in Patients Treated With Short-term Luteinizing Hormone-releasing Hormone Antagonist as a Neoadjuvant Therapy Before External Radiotherapy for Intermediate-risk Prostate Cancer: Preliminary Prospective Study.

External beam radiation therapy (EBRT) with short-term androgen deprivation therapy is the standard of care for intermediate-risk prostate cancer patients. However, no study to date has evaluated the hormonal kinetics or sexual and hormonal function recovery after cessation of short-term luteinizing hormone (LH)-releasing hormone (LHRH) antagonist treatment. Ten intermediate-risk prostate cancer patients (mean age, 69.9 years) were included. All patients received 4 months of LHRH antagonist (degarelix) treatment followed by EBRT. The testosterone, luteinizing hormone (LH), follicle-stimulating hormone, and prostate-specific antigen levels were measured and Expanded Prostate Cancer Index Composite questionnaires were completed before LHRH antagonist therapy at baseline; 1, 2, 3, and 4 months after the first injection of LHRH antagonist treatment; and every 2 months thereafter until 18 months. The testosterone levels were at the castration level at 1 month after the first LHRH antagonist injection. The median interval to recover a normal testosterone level (> 7.2 nmol/L) was 7 months after the last LHRH antagonist administration. The LH and follicle-stimulating hormone levels decreased but had increased more than twice above baseline at 15 months after the last LHRH antagonist injection. The sexual function and hormonal bother subdomain scores and sexual and hormonal domain scores decreased once after LHRH antagonist treatment but had significantly recovered thereafter (P< .05). In most patients, the testosterone level had normalized within 9 months after the last LHRH administration. Sexual and hormonal function recovered after short-term LHRH antagonist administration for neoadjuvant therapy before EBRT.

Longer-Term Androgen Deprivation Therapy Improves Cancer-Specific Survival in Patients With Gleason Score 9-10 Prostate Adenocarcinoma: An Individual Patient-Level Meta-analysis of RTOG 8531, 8610, and 9202

It has been suggested that Gleason grade 5 prostate carcinoma (PCa) is less responsive to androgen deprivation therapy (ADT) than lower grade PCa. Three randomized trials—RTOG 8531, 8610, and 9202—have examined the effect of ADT utilization and duration when used in concert with definitive radiotherapy (RT). The purpose of this study was to evaluate the effect of ADT on clinical outcomes of patients with Gleason score (GS) 9-10 PCa, who by definition had Gleason grade 5-containing PCa. Patients enrolled in RTOG 8531 were randomized to lifelong ADT vs. RT alone, those in RTOG 8610 to short-term ADT (STADT, 4 mos) vs. RT alone, and those in RTOG 9202 to long-term ADT (LTADT, 28 mos) vs. STADT. Data was obtained from the NRG via a data sharing agreement to allow for analysis of a total of 351 patients enrolled on these protocols who had GS 9-10 PCa. For overall survival (OS) and distant metastasis-free survival (DMFS), patient-level data were used to obtain hazard ratio (HR) and standard error estimates of pair-wise treatment effects after fitting multivariate Cox proportional hazards models adjusting for age, GS (9 or 10) and T-stage. For cancer-specific survival (CSS), HRs were obtained by fitting cause-specific competing risk models to the data. A Network Meta-Analysis (NMA) approach was adopted for pair-wise meta-analysis of all pairs of treatments. Along with analyzing within-trial comparisons between two treatments, the NMA framework enables incorporation of indirect comparisons constructed from two trials that have one treatment in common. The median follow-up was 6.01 years. Overall, lifelong ADT was associated with significantly improved DMFS, CSS, and OS when compared with RT alone and STADT; only DMFS was improved with lifelong ADT versus LTADT (Table 1). LTADT offered significantly higher DMFS than STADT ADT, but not RT alone. Though not statistically significant, the HRs for STADT vs. RT alone were in the direction of an inferior effect on all three outcomes.Abstract 287; Table 1Results of Network Meta-AnalysisDMFSCSSOSRT Alone As ReferenceSTADT1.27 (.71, 2.26)1.22 (0.64, 2.35)1.52 (0.7, 2.66)LTADT0.88 (0.45, 1.72)0.68 (0.28, 1.64)1.18 (0.61, 2.28)Lifelong ADT0.37 (0.24, 0.57)**0.34 (0.18, 0.61)**0.56 (0.37, 0.85) **STADT as ReferenceLTADT0.69 (0.49, 0.98)**0.56 (0.31, 1.00)0.77 (0.54, 1.110)Lifelong ADT0.29 (0.14, 0.60)**0.27 (0.11, 0.67)**0.37 (0.18, 0.74)**LTADT as ReferenceLifelong ADT2.38 (1.07, 5.30)**2.03 (0.70, 5.88)2.10 (0.96, 4.58)**P<0.05. Open table in a new tab **P<0.05. GS 9-10 PCa appear to show a temporal dose-response to ADT, contrary to the hypothesis that grade 5 cancers are relatively hormone-insensitive. The inferior outcomes with STADT are likely the result of a small sample size. The extension of these findings in the modern era of dose-escalated radiotherapy constitutes an area of future study.

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.

A pilot study of the effects of androgen deprivation therapy on physical function and comprehensive geriatric health in older men with prostate cancer.

e16510 Background: Alteration of the androgen axis through androgen deprivation therapy (ADT) is the mainstay of prostate cancer (PCa) treatment. Unfortunately, the resultant hypogonadal state has detrimental effects on muscle and bone and may impair physical function (PF). Older patients may be more vulnerable to PF changes while on ADT. We conducted a pilot study to evaluate the changes in PF and geriatric health in older men initiating ADT using tests easily employed in routine clinical practice. Methods: Men with PCa initiating ADT were enrolled and were assessed every 3 months (mos) for up to 12 mos. PF was measured using the short physical performance battery (SPPB) and geriatric health was screened using the Vulnerable Elders Survey (VES13) which predicts potential death or decline over 2 years. The primary endpoint was change in SPPB and VES13 at 3 mos. Results: We enrolled 17 patients with a median age of 75 years (range 67-85) beginning ADT therapy. Fourteen patients had metastasis, 2 had locally advanced disease, and 1 had biochemical recurrence. The majority had Gleason score (GS) 7 cancer (9/17), 7/17 GS 8-10, and 1/17 with GS 6. Eight patients had normal SPPB baseline scores and 9 had moderate impairment (moderate frailty risk) (Mean 10, SD 1.71). Seven had a clinically significant decline in the SPPB at 3 mos, with 1 patient testing as severely impaired. The VES13 screening tool identified 6/17 patients as vulnerable at baseline (Mean 3, SD 3.92). At 3 months, 3/17 patients had a decline in VES13 and 6/17 with an improvement. Of the 10 patients who were followed for at least 6 months, 5 had worsening of the VES13 and 2 had a worsening in SPPB. Conclusions: Older patients initiating ADT have baseline vulnerabilities in geriatric health with little immediate detriment after treatment initiation, perhaps due to overall health improvement with treatment initiation. Changes in PF, however, are seen within the first 3 months of ADT in nearly half of our patients, warranting further investigation into early rehabilitation of men even on short-term ADT. The SPPB is easily employed in clinic and important as reliance on VES13 alone is likely to miss patients with PF impairments.

MP57-12 SHORT-TERM ANDROGEN DEPRIVATION THERAPY INCREASES BRAIN-TYPE NATRIURETIC PEPTIDE LEVELS IN PATIENTS WITH PROSTATE CANCER: POSSIBLE ADVERSE IMPACT ON CARDIAC FUNCTION

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) IV1 Apr 2017MP57-12 SHORT-TERM ANDROGEN DEPRIVATION THERAPY INCREASES BRAIN-TYPE NATRIURETIC PEPTIDE LEVELS IN PATIENTS WITH PROSTATE CANCER: POSSIBLE ADVERSE IMPACT ON CARDIAC FUNCTION Masaya Ito, Masaharu Inoue, Hajime Tanaka, Toshiki Kijima, Soichiro Yoshida, Minato Yokoyama, Junichiro Ishioka, Noboru Numao, Yoh Matsuoka, Kazutaka Saito, Kazunori Kihara, and Yasuhisa Fujii Masaya ItoMasaya Ito More articles by this author , Masaharu InoueMasaharu Inoue More articles by this author , Hajime TanakaHajime Tanaka More articles by this author , Toshiki KijimaToshiki Kijima More articles by this author , Soichiro YoshidaSoichiro Yoshida More articles by this author , Minato YokoyamaMinato Yokoyama More articles by this author , Junichiro IshiokaJunichiro Ishioka More articles by this author , Noboru NumaoNoboru Numao More articles by this author , Yoh MatsuokaYoh Matsuoka More articles by this author , Kazutaka SaitoKazutaka Saito More articles by this author , Kazunori KiharaKazunori Kihara More articles by this author , and Yasuhisa FujiiYasuhisa Fujii More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1786AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Androgen deprivation therapy (ADT) plays an important role in managing prostate cancer, both as a primary treatment for metastatic disease and as a useful adjunct to radiotherapy or surgery with curative intent. However, some reports showed that ADT significantly increased cardiovascular risk. It has also been proposed that gonadotrophin-releasing hormone (GnRH) agonist may have negative effects on cardiac function at the receptor level. At present, little is known as to whether or not short-term ADT affects cardiac function. Brain-type natriuretic peptide (BNP) is in widespread use as a cardiac marker that can identify the risk of cardiovascular events. In order to assess the adverse impact of short-term ADT on cardiac function, we evaluated the change in BNP levels in patients undergoing radical prostatectomy (RP) with or without preoperative ADT. METHODS Between 2014 and 2016, 112 Japanese patients underwent RP in our hospital. Of them, 64 patients whose BNP levels were available and who had no prior cardiovascular disease were included in this retrospective study. BNP levels were evaluated before prostate biopsy and before RP. In this cohort, 31 patients received ADT preoperatively by combined androgen blockade using GnRH agonist and bicalutamide (ADT group), and the other 33 patients underwent RP without ADT (control group). The change in BNP levels was assessed in each group. RESULTS The median age and initial PSA level were 68 years and 8.8 ng/ml, respectively. No patients newly developed cardiovascular events during the study period. There were no significant differences between the two groups in age, body mass index, serum testosterone level, and comorbidities such as hypertension, diabetes, and dyslipidemia. The median BNP level before prostate biopsy was 13.9 pg/ml in the ADT group and 12.1 pg/ml in the control group (p = 0.73). The median interval between evaluations of the BNP level was 12 (range 9-26) months in the ADT group and 6 (range 1-9) months in the control group. The median duration of ADT in the ADT group was 12 (range 8-25) months. In the ADT group, the median BNP level after ADT was 23.1 pg/ml, which was significantly higher than that before ADT (p < 0.01). In the control group, the median BNP level before RP was 12.8 pg/ml, showing no significant change from that before prostate biopsy (p = 0.54). CONCLUSIONS The current study demonstrated a significant increase in BNP levels after short-term ADT in patients with prostate cancer, which might reflect the adverse impact of ADT on cardiac function. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e768 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Masaya Ito More articles by this author Masaharu Inoue More articles by this author Hajime Tanaka More articles by this author Toshiki Kijima More articles by this author Soichiro Yoshida More articles by this author Minato Yokoyama More articles by this author Junichiro Ishioka More articles by this author Noboru Numao More articles by this author Yoh Matsuoka More articles by this author Kazutaka Saito More articles by this author Kazunori Kihara More articles by this author Yasuhisa Fujii More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Androgen deprivation therapy in the treatment of locally advanced, nonmetastatic prostate cancer: practical experience and a review of the clinical trial evidence.

Following new scientific insights, initial management for patients with high-risk nonmetastatic prostate cancer has changed considerably and rapidly over the last few years. Several clinical and pathologic variables should be taken into account when deciding the best treatment choice for those patients. These variables are summarized and discussed in detail. High radiation doses to the prostate are essential to achieve good local control in patients with high-risk nonmetastatic disease. Addition of androgen deprivation therapy (ADT) to radiation therapy has significantly improved overall survival and cancer-specific survival compared with radiation therapy alone without significantly increasing toxicity. Long-term neo(adjuvant) ADT (2-3 years) to radiation therapy significantly improved cancer-specific survival compared with short-term ADT (4-6 months). Radical prostatectomy with extended pelvic lymph node dissection is considered a reasonable option in experienced hands. ADT alone is an inappropriate treatment option for patients with high-risk nonmetastatic disease. Management decisions for these patients should be discussed by a multidisciplinary team.

Is there a relationship between testosterone levels at the end of short-term androgen deprivation therapy and outcomes in intermediate risk prostate cancer? Prospective data from a phase III trial.

78 Background: The purpose of this analysis was to assess whether the testosterone level measured at the end of short term androgen deprivation therapy (STADT) and prostate radiotherapy (RT) has an impact on treatment outcomes in patients with intermediate risk prostate cancer (IRPC) treated on a randomized trial (PCS III ClinicalTrials.gov #NCT00223145). Methods: From December 2000 to September 2010, 400 patients with IRPC received 6 months of STADT (bicalutamide 50mg die and goserelin 10.8mg x 2) and RT. Castrate level of testosterone was defined as &lt;1.7 nmol/L: lower level &lt;0.7 and upper level 0.7-1.7. In 347/400 patients, testosterone levels were available at the end of STADT and were divided into 3 groups based on measured testosterone levels: &lt;0.7, 0.7 to 1.7 and &gt;1.7 nmol/L. Patient’s characteristics were compared with ANOVA and Fisher’s exact test. Biochemical failure, prostate cancer recurrence and death were compared with Cox regression. Results: Patient’s characteristics were well balanced between the 3 groups with no statistical difference for age, performance status, PSA at start, Gleason score and stage. At the end of STADT 55.3% (192/347) presented testosterone levels &lt;0.7 and 38.9% (135/347) levels between 0.7 and 1.7 for a total of 94.2% (327/ 347) reaching castrate levels ≤1.7 nmol/L. In 5.8% of patients (20/347) a castrate testosterone level was not achieved. With a median follow-up of 8.1 years, outcomes are shown in the table. Conclusions: In IRPC patients treated with STADT and RT, the majority of patients (94.2%) achieve a castrate level of testosterone (&lt;1.7 nmol/L). Although we could not show a difference in outcomes between castrate and non-castrate patients, these data have to be viewed with caution given the small number of non-castrate patients studied. Source of Funding: AstraZeneca Pharmaceuticals Grant. Clinical trial information: NCT00223145. [Table: see text]

A nomogram for testosterone recovery following combined androgen deprivation therapy and radiation therapy for prostate cancer.

67 Background: Combined androgen deprivation therapy (ADT) and radiation therapy (RT) is a frequently used localized prostate cancer (PC) treatment. Testosterone recovery (TR) after combined ADT-RT is not well-characterized. We studied TR in men who received RT and either short-term (ST) ADT or long-term (LT) ADT with LHRH agonists. Methods: We identified consecutive localized PC patients treated with ADT-RT at the Durham VA Medical Center (DVAMC) from 1/2011-10/2016. All patients had a documented baseline testosterone (T) level. Individual patient records were reviewed. TR was defined as time from last ADT injection to T normalization ( &gt; 240 ng/dL). The Kaplan-Meier method was used to estimate time to TR. Cox proportional hazards models were generated to identify TR predictors with a nomogram built based on a parsimonious multivariate model. Results: 252 patients were identified. Median follow-up was 26.7 months. Median age was 65. Prior to treatment, 69% had a normal baseline T. 67% were treated with STADT, median duration 6 months. 33% were treated with LTADT, median duration 18 months. Median time for TR was 22.6 months for all patients (19.5 months for STADT and 25.6 months for LTADT). At 1 and 2 years post ADT, estimated TR was 13% and 53% (17% and 57% for STADT and 3% and 42% for LTADT). 2-year biochemical control was 99.2% and 97.6% for STADT and LTADT, respectively; 98.9% and 98.6% for those with and without TR, respectively. On multivariate analysis, higher pre-treatment T (HR = 1.004 95% CI 1.003-1.006, p &lt; 0.001), use of STADT (HR = 2.48 95% CI 1.45-4.25, p = 0.001), and lower BMI (HR = 0.95 95% CI 0.91-0.98, p = 0.001) were associated with shorter time to TR. White race was a negative TR predictor (HR = 0.65 95% CI 0.43-0.9992, p = 0.049). Age, smoking, and Charlson Comorbidity Index were not significant independent TR predictors. A nomogram was generated to predict probability of TR at 1, 2, and 3 years. Conclusions: In this VA population of localized PC patients treated from 2011-2016, TR following the use of ADT-RT was variable. Using pre-treatment T levels, ADT duration, BMI, and race, a predictive nomogram can estimate the likelihood of TR.

Duration of Androgen Deprivation in Locally Advanced Prostate Cancer: Long-Term Update of NRG Oncology RTOG 9202

Trial RTOG 9202 was a phase 3 randomized trial designed to determine the optimal duration of androgen deprivation therapy (ADT) when combined with definitive radiation therapy (RT) in the treatment of locally advanced nonmetastatic adenocarcinoma of the prostate. Long-term follow-up results of this study now available are relevant to the management of this disease. Men (N=1554) with adenocarcinoma of the prostate (cT2c-T4, N0-Nx) with a prostate-specific antigen (PSA) <150ng/mL and no evidence of distant metastasis were randomized (June 1992 to April 1995) to short-term ADT (STAD: 4months of flutamide 250mg 3 times per day and goserelin 3.6mg per month) and definitive RT versus long-term ADT (LTAD: STAD with definitive RT plus an additional 24months of monthly goserelin). Among 1520 protocol-eligible and evaluable patients, the median follow-up time for this analysis was 19.6years. In analysis adjusted for prognostic covariates, LTAD improved disease-free survival (29% relative reduction in failure rate, P<.0001), local progression (46% relative reduction, P=.02), distant metastases (36% relative reduction, P<.0001), disease-specific survival (30% relative reduction, P=.003), and overall survival (12% relative reduction, P=.03). Other-cause mortality (non-prostate cancer) did not differ (5% relative reduction, P=.48). LTAD and RT is superior to STAD and RT for the treatment of locally advanced nonmetastatic adenocarcinoma of the prostate and should be considered the standard of care.

High biologically effective dose radiation therapy using brachytherapy in combination with external beam radiotherapy for high-risk prostate cancer.

PurposeTo evaluate the outcomes of high-risk prostate cancer patients treated with biologically effective dose (BED) ≥ 220 Gy of high-dose radiotherapy, using low-dose-rate (LDR) brachytherapy in combination with external beam radiotherapy (EBRT) and short-term androgen deprivation therapy (ADT).Material and methodsFrom 2005 to 2013, a total of 143 patients with high-risk prostate cancer were treated by radiotherapy of BED ≥ 220 Gy with a combination of LDR brachytherapy, EBRT, and androgen deprivation therapy (ADT). The high-risk patients in the present study included both high-risk and very high-risk prostate cancer. The number of high-risk features were: 60 patients with 1 high-risk factor (42%), 61 patients with 2 high-risk factors (43%), and 22 patients with 3 high-risk factors (15%) including five N1 disease. External beam radiotherapy fields included prostate and seminal vesicles only or whole pelvis depending on the extension of the disease. Biochemical failure was defined by the Phoenix definition.ResultsSix patients developed biochemical failure, thus providing a 5-year actual biochemical failure-free survival (BFFS) rate of 95.2%. Biochemical failure was observed exclusively in cases with distant metastasis in the present study. All six patients with biochemical relapse had clinical failure due to bone metastasis, thus yielding a 5-year freedom from clinical failure (FFCF) rate of 93.0%. None of the cases with N1 disease experienced biochemical failure. We observed four deaths, including one death from prostate cancer, therefore yielding a cause-specific survival (CSS) rate of 97.2%, and an overall survival (OS) rate of 95.5%.ConclusionsHigh-dose (BED ≥ 220 Gy) radiotherapy by LDR in combination with EBRT has shown an excellent outcome on BFFS in high-risk and very high-risk cancer, although causal relationship between BED and BFFS remain to be explained further.

Impact of treatment on progression to castration-resistance, metastases, and death in men with localized high-grade prostate cancer.

Men with high‐grade prostate cancer (HGPC) are at greatest risk of disease progression. Clinical risk factors associated with castration‐resistant prostate cancer (CRPC), metastases, and prostate cancer‐specific mortality (PCSM) were identified in a contemporary HGPC cohort. Clinical data was collected from men diagnosed with Gleason sum (GS) ≥8 at the Greater Los Angeles Veterans Affairs (GLA‐VA) Healthcare System between 2000 and 2013. Multivariable competing risks regression analyses assessed progression to CRPC, metastases, and PCSM within three treatment strata. The cumulative incidence of disease progression was calculated at 2, 5, and 10‐year time points. Review of 2149 prostate cancer cases yielded 322 with HGPC. Median survival times for cancer‐specific and overall mortality were significantly shorter in men treated with primary androgen deprivation therapy (ADT) (P = 0.0002 and P < 0.0001). Multivariable analyses revealed that clinical stage N1, GS 10, and treatment with primary ADT were significantly associated with increased risk of CRPC, metastases, and PCSM. Significant differences in these outcomes were not observed in men treated with radical prostatectomy (RP) when compared to those treated with radiation therapy combined with short‐term ADT (XRT‐ADT). Ten‐year event rates of progression to CRPC, metastases, and PCSM, for men treated with primary ADT, were 45.5%, 25.4%, and 25.1%, respectively. In conclusion, GS 10 and lymph node involvement, as well as primary ADT treatment in men with HGPC was associated with increased risk of CRPC, metastases, and PCSM. Curative‐intent treatment with RP or XRT‐ADT is associated with reduced progression rates and death in men with HGPC.

Recommandations en onco-urologie 2016-2018 du CCAFU : Cancer de la prostate

ObjectivesThe purpose of the guidelines national committee CCAFU was to propose updated french guidelines for localized and metastatic prostate cancer (PCa). MethodsA Medline search was achieved between 2013 and 2016, as regards diagnosis, options of treatment and follow-up of PCa, to evaluate different references with levels of evidence. ResultsEpidemiology, classification, staging systems, diagnostic evaluation are reported. Disease management options are detailed. Recommandations are reported according to the different clinical situations. Active surveillance is a major option in low risk PCa. Radical prostatectomy remains a standard of care of localized PCa. The three-dimensional conformal radiotherapy is the technical standard. A dose of > 74Gy is recommended. Moderate hypofractionation provides short-term biochemical control comparable to conventional fractionation. In case of intermediate risk PCa, radiotherapy can be combined with short-term androgen deprivation therapy (ADT). In case of high risk disease, long-term ADT remains the standard of care. ADT is the backbone therapy of metastatic disease. In men with metastases at first presentation, upfront chemotherapy combined with ADT should be considered as a new standard. In case of metastatic castration-resistant PCa (mCRPC), new hormonal treatments and chemotherapy provide a better control of tumor progression and increase survival. ConclusionsThese updated french guidelines will contribute to increase the level of urological care for the diagnosis and treatment for prostate cancer.© 2016 Elsevier Masson SAS. All rights reserved.

Sexual Function After Hypofractionated Versus Conventionally Fractionated Radiotherapy for Prostate Cancer: Results From the Randomized Phase III HYPRO Trial

IntroductionHypofractionated radiotherapy could increase the radiobiological tumor dose for localized prostate cancer. The effects of hypofractionation on sexual function are not well known. AimTo compare sexual function in patients with prostate cancer treated with 78 Gy in 39 fractions of 2 Gy or 64.6 Gy in 19 fractions of 3.4 Gy. MethodsIn total, 820 men with intermediate- to high-risk T1b-T4NX-0MX-0 prostate cancer were enrolled in the phase III HYPRO trial (2007–2010) and randomized to conventional fractionation (39 × 2 Gy) or hypofractionation (19 × 3.4 Gy). Sexual function was assessed at baseline and at 6, 12, 24, and 36 months after treatment using the International Index of Erectile Function (IIEF). For this analysis, patients (n = 322) with a baseline assessment, at least one follow-up assessment, and no or short-term (6-month) androgen-deprivation therapy were included. Main Outcome MeasuresMean IIEF domain scores were compared between treatments in the total population and the hormone-naïve population (n = 197) using the independent t-test. Incidences of severe erectile dysfunction (domain score < 11) at last follow-up were calculated in patients with partial or full baseline function. Binary logistic regression analyses were applied to calculate the odds ratio of hypofractionation vs conventional fractionation and to adjust for clinical factors. ResultsMedian age was 71 years (interquartile range = 67–71) and median follow-up was 37 months (interquartile range = 25–38). Androgen-deprivation therapy was prescribed in 125 (39%). IIEF domain scores decreased after treatment but were comparable between treatment arms at baseline and during follow-up. Orgasmic function scores in hormone-naïve patients were significantly higher at 3 years after hypofractionation (4.08 vs 2.65, P = .031). In patients (n = 120) with partial or full baseline erectile function, the incidence of erectile dysfunction at last follow-up was 34.4% for hypofractionated treatment vs 39.3% for conventional treatment (adjusted odds ratio = 0.84, 95% CI = 0.37–1.90, P = .67). ConclusionNo significant differences in erectile functioning between conventional and hypofractionated radiotherapy were found. Hormone-naïve patients reported significantly higher orgasmic function scores at 3 years after hypofractionation.

Editorial Comment Regarding “Multivariate Analyses of the Factors Associated With Sexual İntercourse, Marriage, and Paternity of Hypospadias Patients”

Hypofractionated radiotherapy could increase the radiobiological tumor dose for localized prostate cancer. The effects of hypofractionation on sexual function are not well known.To compare sexual function in patients with prostate cancer treated with 78 Gy in 39 fractions of 2 Gy or 64.6 Gy in 19 fractions of 3.4 Gy.In total, 820 men with intermediate- to high-risk T1b-T4NX-0MX-0 prostate cancer were enrolled in the phase III HYPRO trial (2007–2010) and randomized to conventional fractionation (39 × 2 Gy) or hypofractionation (19 × 3.4 Gy). Sexual function was assessed at baseline and at 6, 12, 24, and 36 months after treatment using the International Index of Erectile Function (IIEF). For this analysis, patients (n = 322) with a baseline assessment, at least one follow-up assessment, and no or short-term (6-month) androgen-deprivation therapy were included.Mean IIEF domain scores were compared between treatments in the total population and the hormone-naïve population (n = 197) using the independent t-test. Incidences of severe erectile dysfunction (domain score < 11) at last follow-up were calculated in patients with partial or full baseline function. Binary logistic regression analyses were applied to calculate the odds ratio of hypofractionation vs conventional fractionation and to adjust for clinical factors.Median age was 71 years (interquartile range = 67–71) and median follow-up was 37 months (interquartile range = 25–38). Androgen-deprivation therapy was prescribed in 125 (39%). IIEF domain scores decreased after treatment but were comparable between treatment arms at baseline and during follow-up. Orgasmic function scores in hormone-naïve patients were significantly higher at 3 years after hypofractionation (4.08 vs 2.65, P = .031). In patients (n = 120) with partial or full baseline erectile function, the incidence of erectile dysfunction at last follow-up was 34.4% for hypofractionated treatment vs 39.3% for conventional treatment (adjusted odds ratio = 0.84, 95% CI = 0.37–1.90, P = .67).No significant differences in erectile functioning between conventional and hypofractionated radiotherapy were found. Hormone-naïve patients reported significantly higher orgasmic function scores at 3 years after hypofractionation.

Prognostic value of biochemical response to neoadjuvant androgen deprivation before external beam radiotherapy for prostate cancer: A systematic review of the literature.

External beam radiation therapy (EBRT) in combination with androgen deprivation therapy (ADT) is considered a standard treatment option for patients with aggressive localized and locally-advanced prostate cancer. Randomized phase III trials have provided evidence for combining EBRT to short-term ADT for intermediate-risk disease and to long-term ADT for patients harboring high-risk tumors. Even if several improvements and developments have been made in the last years in terms of radiotherapy delivery techniques, image-guided radiotherapy, and better sparing of the organs at risk the current use of ADT remains still linked to a therapeutic algorithm based on the prostate cancer risk classification as proposed by clinical trials. Emerging literature has recently shown that the biochemical response to a course of neoadjuvant ADT before EBRT, called the "prostate-specific antigen (PSA) nadir" (lowest value after treatment), may influence the long-term biochemical tumor-control outcomes of prostate cancer patients. An individualized approach adapting the duration of hormonal treatment according to the PSA response during the neoadjuvant phase, as well using new generation hormonal agents, may represent a new therapeutic strategy and a future way to improve the therapeutic ratio for prostate cancer patients. In this systematic review of the literature we explored the prognostic value of the PSA response to the neoadjuvant ADT phase and the rationale to adjust the use of ADT and EBRT in patients with intermediate- and high-risk prostate cancer based on the biochemical response to the neoadjuvant androgen ablation phase.

Radiation Therapy With or Without Short-Term Androgen Deprivation Therapy in Intermediate-Risk Prostate Cancer: Results of a Phase 3 Trial

Radiation Therapy With or Without Short-Term Androgen Deprivation Therapy in Intermediate-Risk Prostate Cancer: Results of a Phase 3 Trial

Duration of Androgen Deprivation Therapy for High-Risk Prostate Cancer: Application of Randomized Trial Data in a Tertiary Referral Cancer Center

IntroductionWe evaluated the incidence and predictors of the use of long-term (2-3 years) versus shorter term androgen deprivation therapy (ADT) in radiation-managed men with high-risk prostate cancer. Patients and MethodsWe identified 302 patients from the Dana-Farber Cancer Institute patient registry who had been diagnosed with high-risk prostate cancer (T3a or prostate-specific antigen [PSA] > 20 ng/mL or Gleason score 8-10) from 1993 to 2015. We assessed the intended duration of ADT and used multivariable Cox regression to evaluate the predictors of receiving a shorter course of ADT than recommended by the guidelines (< 2 years). ResultsThe course of ADT intended by physicians increased after the 2008/2009 publication of trials showing the superiority of long-term versus short-term ADT, with 43.5% intending ≥ 2 years before versus 61.4% after (P = .014). Starting in 2010, 49.4% of patients actually received < 2 years of ADT. The most common reasons for receipt of shorter course ADT were intolerance of ADT side effects, patient comorbidity/age, the presence of T3a on magnetic resonance imaging only as the sole high-risk feature, or participation in a clinical trial. Moderate to severe comorbidity assessed using the Adult Comorbidity Evaluation-27 (adjusted hazard ratio [AHR] = 2.94), Gleason score < 8 (AHR = 5.66), and PSA < 20 ng/mL (AHR = 4.19) all predicted for receipt of shorter course ADT (P < .05 for all). ConclusionIn a tertiary-care setting, the rates of long-course ADT for high-risk disease have increased since the 2008/2009 trials supporting its use. However, approximately one half of patients continued to receive shorter course ADT, often because of intolerance of side effects, underlying comorbidity, or physician judgment about the aggressiveness of the disease.

The Need for Androgen Deprivation Therapy in Patients With Intermediate-Risk Prostate Cancer Treated With Dose-Escalated External Beam Radiation Therapy

INTRODUCTION To evaluate if androgen deprivation therapy (ADT) improves outcomes for patients with localized, intermediate-risk prostate cancer treated with definitive external beam radiation therapy (EBRT) in the dose-escalated era. MATERIALS AND METHODS This is a retrospective study using a single institutional database. We included patients with localized, intermediate-risk prostate cancer treated with dose-escalated radiation therapy (RT) with 3D conformal radiotherapy or intensity-modulated radiotherapy (74-80 Gy in daily fraction of 1.8 Gy-2.0 Gy, or 70.2 Gy in daily fraction of 2.7 Gy) from 1992 to 2013. To further risk stratify the patients, PSA 10 ng/mL-20 ng/mL, Gleason 3+4, and T2b-T2c were assigned risk score (RS) of 1, while Gleason 4+3 was assigned RS of 2. Patients with prior treatment for prostate cancer, those on long term ADT (>= 23 months), or those with follow up = 2, there were still no significant differences in FFBF, FFDM, or OS when patients treated with ADT were compared to those treated with radiation alone. In multivariable analyses adjusting for RS and age, the adjusted hazard ratio for ADT use was sHR = 0.89 (95% CI = 0.64-1.66, p = 0.64) for BCF; sHR = 1.13 (95% CI = 0.48-2.65, p = 0.77) for DM. For overall mortality, adjusted HR = 1.23 (95% CI = 0.76-2.01, p = 0.40) where comorbidities (including diabetes, cardiac disease, and hypertension) were also included as covariates. CONCLUSION Our study suggested that treatment of intermediate-risk prostate cancer with definitive dose-escalated EBRT alone resulted in acceptable outcomes, and it failed to show improved outcomes in patients who received short term ADT.