Changes in physical functioning and muscle strength in men receiving androgen deprivation therapy for prostate cancer: a controlled comparison.

PURPOSE: The purpose of the study is to examine changes in muscle strength and self-reported physical functioning in men receiving androgen deprivation therapy (ADT) for prostate cancer compared to matched controls. METHODS: Prostate cancer patients scheduled to begin ADT (n = 62) were assessed within 20 days of starting ADT and 6 and 12 months later. Age and geographically matched prostate cancer controls treated with prostatectomy only (n = 86) were assessed at similar time intervals. Grip strength measured upper body strength, the Chair Rise Test measured lower body strength, and the SF-12 Physical Functioning scale measured self-reported physical functioning. RESULTS: As expected, self-reported physical functioning and upper body muscle strength declined in ADT recipients but remained stable in prostate cancer controls. Contrary to expectations, lower body muscle strength remained stable in ADT recipients but improved in prostate cancer controls. Higher Gleason scores, more medical comorbidities, and less exercise at baseline predicted greater declines in physical functioning in ADT recipients. CONCLUSIONS: ADT is associated with declines in self-reported physical functioning and upper body muscle strength as well as worse lower body muscle strength relative to prostate cancer controls. These findings should be included in patient education regarding the risks and benefits of ADT. Findings also underscore the importance of conducting research on ways to prevent or reverse declines in physical functioning in this patient population.

Depressive symptomatology in men receiving androgen deprivation therapy for prostate cancer: a controlled comparison.

OBJECTIVE: Prostate cancer patients who receive androgen deprivation therapy (ADT) often experience many physical and psychological side effects. ADT may be associated with increased risk for depression, but the relationship between ADT and depression is not fully understood. This study used a longitudinal design to assess depressive symptomatology in patients receiving ADT compared with two groups of matched controls. METHODS: Participants were men initiating ADT treatment (ADT+ group; n = 61) and their matched controls: prostate cancer patients treated with radical prostatectomy (ADT- group; n = 61), and no-cancer controls (CA- group; n = 61). Depressive symptomatology was assessed using the Center for Epidemiological Studies Depression Scale at ADT initiation and again 6 months later. Differences in depressive symptomatology and rates of clinically significant depressive symptomatology were analyzed between groups at each time point and within groups over time. RESULTS: Between baseline and follow-up, ADT+ participants demonstrated increased depressive symptomatology and increased rates of clinically significant depressive symptomatology (ps < 0.05). ADT+ participants also reported greater depressive symptomatology than both control groups at follow-up (ps < 0.001). Rates of clinically significant depressive symptomatology were higher in the ADT+ group than the ADT- and CA- groups at both time points (baseline: 28%, 5%, 12%; follow-up: 39%, 9%, 11%). CONCLUSIONS: Findings support the hypothesis that ADT administration yields increases in depression and suggest that the mechanism behind ADT's association with depression should be explored and that prostate cancer patients treated with ADT should receive particular focus in depression screening and intervention.

Clinical implications of a prostate-specific antigen bounce after radiation therapy for prostate cancer.

BACKGROUND: The objectives are to determine predictors of a prostate-specific antigen (PSA) bounce, whether a PSA bounce after radiotherapy for prostate cancer is associated with biochemical disease-free survival (bDFS), and the time course to a PSA bounce versus a biochemical failure post-irradiation. METHODS: Between July 2000 and December 2012, 691 prostate cancer patients without regional or distant metastases were treated with external beam radiation therapy and/or brachytherapy, and had at least 12 months of follow-up. A PSA bounce was defined as a temporary PSA increase of ≥ 0.4 ng/mL. bDFS was defined according to the nadir + 2 definition. RESULTS: The median follow-up was 42 months. The median time to first PSA bounce was 17 months (95% confidence interval 15-18 months). In contrast, the median time to biochemical failure was 41 months (95% confidence interval 28-53 months). Two hundred and twenty-six of 691 (33%) patients had at least one PSA bounce with a median magnitude of 1.0 ng/mL (range 0.4-17.0). A Gleason score of 6 (p < 0.0001) predicted a PSA bounce on multivariate analysis. Patients with a PSA bounce experienced improved bDFS on multivariate analysis (p = 0.002). CONCLUSIONS: Patients with a Gleason score of 6 were more likely to experience a PSA bounce which was associated with improved bDFS. A PSA bounce occurred sooner after radiotherapy than a biochemical failure. The authors recommend against performing prostate biopsies within 24-30 months of radiotherapy since an elevated PSA may simply represent a benign PSA bounce.

External beam radiation therapy and a low-dose-rate brachytherapy boost without or with androgen deprivation therapy for prostate cancer.

PURPOSE: To assess outcomes with external beam radiation therapy (EBRT) and a low-dose-rate (LDR) brachytherapy boost without or with androgen deprivation therapy (ADT) for prostate cancer. MATERIALS AND METHODS: From January 2001 through August 2011, 120 intermediate-risk or high-risk prostate cancer patients were treated with EBRT to a total dose of 4,500 cGy in 25 daily fractions and a palladium-103 LDR brachytherapy boost of 10,000 cGy (n = 90) or an iodine-125 LDR brachytherapy boost of 11,000 cGy (n = 30). ADT, consisting of a gonadotropin-releasing hormone agonist ± an anti-androgen, was administered to 29/92 (32%) intermediate-risk patients for a median duration of 4 months and 26/28 (93%) high-risk patients for a median duration of 28 months. RESULTS: Median follow-up was 5.2 years (range, 1.1-12.8 years). There was no statistically-significant difference in biochemical disease-free survival (bDFS), distant metastasis-free survival (DMFS), or overall survival (OS) without or with ADT. Also, therewas no statistically-significant difference in bDFS, DMFS, or OS with a palladium-103 vs. an iodine-125 LDR brachytherapy boost. CONCLUSIONS: There was no statistically-significant difference in outcomes with the addition of ADT, though the power of the current study was limited. The Radiation Therapy Oncology Group 0815 and 0924 phase III trials, which have accrual targets of more than 1,500 men, will help to clarify the role ADT in locally-advanced prostate cancer patients treated with EBRT and a brachytherapy boost. Palladium-103 and iodine- 125 provide similar bDFS, DMFS, and OS.

Deletion polymorphism of UDP-glucuronosyltransferase 2B17 and risk of prostate cancer in African American and Caucasian men.

PURPOSE: UDP-glucuronosyltransferases (UGT) are a family of enzymes that glucuronidate many endogenous chemicals, including androgens. This makes them more hydrophilic, alters biological activity, and facilitates their excretion. A deletion polymorphism in the UGT2B17 gene was recently described that was associated with a reduced rate of glucuronidation in vivo. The purpose of this study was to determine if the deletion polymorphism is associated with susceptibility to prostate cancer. MATERIALS AND METHODS: UGT2B17 expression was determined by reverse transcription-PCR of pathologically normal prostate tissues (n = 5). In a case-control study with 420 patients with incident primary prostate cancer (127 African Americans and 293 Caucasians) and 487 controls (120 African Americans and 367 Caucasians), the frequency of UGT2B17 deletion polymorphism in genomic DNA was compared between cases and controls with PCR analysis. RESULTS: UGT2B17 mRNA was detected only in individuals with at least one UGT2B17 allele. The frequency of the null genotype was present in 0.11 and 0.12 of Caucasian and African American controls, respectively. When all subjects were considered, a significant association was found between the UGT2B17 deletion polymorphism and prostate cancer risk [odds ratio (OR), 1.7; 95% confidence interval (95% CI), 1.2-2.6]. There was an increase in prostate cancer risk among individuals with UGT2B17 deletion polymorphism in Caucasians (OR, 1.9; 95% CI, 1.2-3.0) but not in African Americans (OR, 1.3; 95% CI, 0.6-2.7). CONCLUSIONS: These results suggest that the UGT2B17 enzyme may play a role in the metabolism of androgens in prostate tissue and that the UGT2B17 deletion polymorphism is associated with prostate cancer risk.

Treatment of intermediate-risk prostate cancer with brachytherapy without supplemental pelvic radiotherapy: a review of the H. Lee Moffitt Cancer Center experience.

PURPOSE: To determine the biochemical outcomes of patients with intermediate-risk prostate cancer treated at the H. Lee Moffitt Cancer Center with an I-125 permanent seed implant without supplemental pelvic radiotherapy. METHODS AND MATERIALS: Under an institutional review board approved protocol, the charts of 88 patients with intermediate-risk prostate cancer and a minimum follow-up of 36 months treated with brachytherapy without supplemental pelvic radiotherapy were reviewed. Median follow-up for the whole cohort was 57 months (range 37-121). Biochemical failure was defined using the American Society for Therapeutic Radiology and Oncology definition. RESULTS: The 5-year biochemical failure-free survival for the cohort was 83%. Patients with perineural invasion had a worse biochemical outcome, which was statistically significant (perineural invasion vs. no perineural invasion, 5-year biochemical failure-free survival 64% vs. 89%, P = 0.004). None of the following factors were found significant in this subset of patients: Gleason scores 6 versus 7, primary Gleason grades 3 versus 4, percentage of core positive <20% versus >20%, number of cores positive <2 versus 2 versus >2, hormonal therapy versus no hormonal therapy, T1 versus T2, prostate-specific antigen <10 versus >10, or > or =2 intermediate risk factors versus 1 intermediate risk factor. CONCLUSIONS: Our data suggest that patients with intermediate-risk prostate cancer may be treated effectively with brachytherapy without supplemental pelvic radiotherapy. However, because of the limited nature of our study, we cannot exclude that patients with intermediate-risk prostate cancer may benefit from supplemental external beam radiotherapy.

A dosimetric analysis of unstranded seeds versus customized stranded seeds in transperineal interstitial permanent prostate seed brachytherapy.

PURPOSE: This study aimed to retrospectively analyze the dosimetric and toxicity results from 272 patients with localized prostate cancer treated consecutively using loose or stranded radioactive seeds by transrectal ultrasound-guided transperineal permanent prostate seed brachytherapy. METHODS AND MATERIALS: Two hundred seventy-two patients with localized prostate cancer treated between February 2002 and June 2004 were analyzed. All patients were treated with radioactive iodine-125 or palladium-103 using unstranded or loose seeds (USS) (159 patients) or customized stranded seeds (CSS) at variable spacing (5-50 mm) (113 patients) (Vari-Strand; BrachySciences, Oxford, CT). A single experienced brachytherapist performed all implants. RESULTS: There was a slight improvement in the dosimetric parameter D90 between the CSS (101.9%) and USS (99.3%) groups (p = 0.041). However, overall implant quality based on Radiation Therapy Oncology Group (RTOG) guidelines was similar between both groups. CONCLUSIONS: We conclude that the D90 value calculated for CSS is statistically improved when compared to the USS cohort, but without a clinically significant difference. There was no difference in the toxicity scores in either group. Overall quality between groups is comparable in our institution.

Perceptions of Prostate Cancer Screening Controversy and Informed Decision Making: Implications for Development of a Targeted Decision Aid for Unaffected Male First-Degree Relatives.

PURPOSE: First-degree relatives (FDRs) of prostate cancer (PC) patients should consider multiple concurrent personal risk factors when engaging in informed decision making (IDM) about PC screening. This study assessed perceptions of IDM recommendations and risk-appropriate strategies for IDM among FDRs of varied race/ethnicity. DESIGN: A cross-sectional, qualitative study design was used. SETTING: Study setting was a cancer center in southwest Florida. PARTICIPANTS: The study comprised 44 participants (24 PC patients and 20 unaffected FDRs). METHOD: Focus groups and individual interviews were conducted and analyzed using content analysis and constant comparison methods. RESULTS: Patients and FDRs found the PC screening debate and IDM recommendations to be complex and counterintuitive. They overwhelmingly believed screening saves lives and does not have associated harms. There was a strongly expressed need to improve communication between patients and FDRs. A single decision aid that addresses the needs of all FDRs, rather than one separating by race/ethnicity, was recommended as sufficient by study participants. These perspectives guided the development of an innovative decision aid that deconstructs the screening controversy and IDM processes into simpler concepts and provides step-by-step strategies for FDRs to engage in IDM. CONCLUSION: Implementing IDM among FDRs is challenging because the IDM paradigm departs from historical messages promoting routine screening. These contradictions should be recognized and addressed for men to participate effectively in IDM. A randomized pilot study evaluating outcomes of the resulting decision aid is underway.

Health-related quality-of-life changes due to high-dose-rate brachytherapy, low-dose-rate brachytherapy, or intensity-modulated radiation therapy for prostate cancer.

PURPOSE: To compare urinary, bowel, and sexual health-related quality-of-life (HRQOL) changes due to high-dose-rate (HDR) brachytherapy, low-dose-rate (LDR) brachytherapy, or intensity-modulated radiation therapy (IMRT) monotherapy for prostate cancer. METHODS AND MATERIALS: Between January 2002 and September 2013, 413 low-risk or favorable intermediate-risk prostate cancer patients were treated with HDR brachytherapy monotherapy to 2700-2800 cGy in two fractions (n = 85), iodine-125 LDR brachytherapy monotherapy to 14,500 cGy in one fraction (n = 249), or IMRT monotherapy to 7400-8100 cGy in 37-45 fractions (n = 79) without pelvic lymph node irradiation. No androgen deprivation therapy was given. Patients used an international prostate symptoms score questionnaire, an expanded prostate cancer index composite-26 bowel questionnaire, and a sexual health inventory for men questionnaire to assess their urinary, bowel, and sexual HRQOL, respectively, pretreatment and at 1, 3, 6, 9, 12, and 18 months posttreatment. RESULTS: Median follow-up was 32 months. HDR brachytherapy and IMRT patients had significantly less deterioration in their urinary HRQOL than LDR brachytherapy patients at 1 and 3 months after irradiation. The only significant decrease in bowel HRQOL between the groups was seen 18 months after treatment, at which point IMRT patients had a slight, but significant, deterioration in their bowel HRQOL compared with HDR and LDR brachytherapy patients. HDR brachytherapy patients had worse sexual HRQOL than both LDR brachytherapy and IMRT patients after treatment. CONCLUSIONS: IMRT and HDR brachytherapy cause less severe acute worsening of urinary HRQOL than LDR brachytherapy. However, IMRT causes a slight, but significant, worsening of bowel HRQOL compared with HDR and LDR brachytherapy.

Informed decision making among first-degree relatives of prostate cancer survivors: a pilot randomized trial.

BACKGROUND: First degree relatives (FDRs) of men diagnosed with prostate cancer (PCa) are at increased risk for developing the disease, due in part to multiple concurrent risk factors. There is a lack of innovative targeted decision aids to help FDRs make an informed decision about whether or not to undergo PCa screening. PURPOSE: This randomized pilot trial evaluated the efficacy of a targeted PCa screening decision aid in unaffected FDRs of PCa survivors. METHODS: Seventy-eight Black and White FDRs were randomized to one of two decision aid groups; 39 to a FDR-targeted decision aid and 39 to a general decision aid. The targeted decision aid group received a general PCa decision aid booklet plus a newly developed decision aid DVD targeted specifically for FDRs. PCa screening decision outcomes included knowledge, decisional conflict, distress, and satisfaction with screening decision. Outcomes were assessed at baseline and 4 weeks after baseline. RESULTS: There were no differences by intervention group for knowledge, decisional conflict, distress, or satisfaction with screening decision (p>0.05). However, men in both groups had significant increases in knowledge and decreases in decisional conflict (p<0.001). These changes were most pronounced (p<0.05) for younger men compared to older men. CONCLUSION: Results suggest that general and targeted information can play an important role in increasing knowledge and decreasing decisional conflict among FDRs. Additional research is needed to identify subgroups of men who benefit the most and better understand the outcomes of a screening decision aid among diverse samples of FDRs.

Combination of external beam radiotherapy (EBRT) with intratumoral injection of dendritic cells as neo-adjuvant treatment of high-risk soft tissue sarcoma patients.

PURPOSE: The goal of this study was to determine the effect of combination of intratumoral administration of dendritic cells (DC) and fractionated external beam radiation (EBRT) on tumor-specific immune responses in patients with soft-tissue sarcoma (STS). METHODS AND MATERIAL: Seventeen patients with large (>5 cm) high-grade STS were enrolled in the study. They were treated in the neoadjuvant setting with 5,040 cGy of EBRT, split into 28 fractions and delivered 5 days per week, combined with intratumoral injection of 10(7) DCs followed by complete resection. DCs were injected on the second, third, and fourth Friday of the treatment cycle. Clinical evaluation and immunological assessments were performed. RESULTS: The treatment was well tolerated. No patient had tumor-specific immune responses before combined EBRT/DC therapy; 9 patients (52.9%) developed tumor-specific immune responses, which lasted from 11 to 42 weeks. Twelve of 17 patients (70.6%) were progression free after 1 year. Treatment caused a dramatic accumulation of T cells in the tumor. The presence of CD4(+) T cells in the tumor positively correlated with tumor-specific immune responses that developed following combined therapy. Accumulation of myeloid-derived suppressor cells but not regulatory T cells negatively correlated with the development of tumor-specific immune responses. Experiments with (111)In labeled DCs demonstrated that these antigen presenting cells need at least 48 h to start migrating from tumor site. CONCLUSIONS: Combination of intratumoral DC administration with EBRT was safe and resulted in induction of antitumor immune responses. This suggests that this therapy is promising and needs further testing in clinical trials design to assess clinical efficacy.

Serial assessment of lymphocytes and apoptosis in the prostate during coordinated intraprostatic dendritic cell injection and radiotherapy.

Local radiotherapy plus intratumoral syngeneic dendritic cell injection can mediate apoptosis/cell death and immunological tumor eradication in murine models. A novel method of coordinated intraprostatic, autologous dendritic cell injection together with radiation therapy was prospectively evaluated in five HLA-A2(+) subjects with high-risk, localized prostate cancer, using androgen suppression, 45 Gy external beam radiation therapy in 25 fractions over 5 weeks, dendritic cell injections after fractions 5, 15 and 25 and then interstitial radioactive seed placement. Serial prostate biopsies before and during treatment showed increased apoptotic cells and parenchymal distribution of CD8(+) cells. CD8(+) T-cell responses to test peptides were assessed using an enzyme-linked immunosorbent spot IFN-γ production assay, demonstrating some prostate cancer-specific protein-derived peptides associated with increased titer. In conclusion, the technique was feasible and well-tolerated and specific immune responses were observable. Future trials could further test the utility of this approach and improve on temporal coordination of intratumoral dendritic cell introduction with particular timelines of therapy-induced apoptosis.

External beam radiation therapy and a low-dose-rate brachytherapy boost without or with androgen deprivation therapy for prostate cancer

Purpose To assess outcomes with external beam radiation therapy (EBRT) and a low-dose-rate (LDR) brachytherapy boost without or with androgen deprivation therapy (ADT) for prostate cancer. Materials and Methods From January 2001 through August 2011, 120 intermediate-risk or high-risk prostate cancer patients were treated with EBRT to a total dose of 4,500 cGy in 25 daily fractions and a palladium-103 LDR brachytherapy boost of 10,000 cGy (n = 90) or an iodine-125 LDR brachytherapy boost of 11,000 cGy (n = 30). ADT, consisting of a gonadotropin-releasing hormone agonist ± an anti-androgen, was administered to 29/92 (32%) intermediate-risk patients for a median duration of 4 months and 26/28 (93%) high-risk patients for a median duration of 28 months. Results Median follow-up was 5.2 years (range, 1.1-12.8 years). There was no statistically-significant difference in biochemical disease-free survival (bDFS), distant metastasis-free survival (DMFS), or overall survival (OS) without or with ADT. Also, there was no statistically-significant difference in bDFS, DMFS, or OS with a palladium-103 vs. an iodine-125 LDR brachytherapy boost. Conclusions There was no statistically-significant difference in outcomes with the addition of ADT, though the power of the current study was limited. The Radiation Therapy Oncology Group 0815 and 0924 phase III trials, which have accrual targets of more than 1,500 men, will help to clarify the role ADT in locally-advanced prostate cancer patients treated with EBRT and a brachytherapy boost. Palladium-103 and iodine-125 provide similar bDFS, DMFS, and OS. .

Modern brachytherapy for treatment of prostate cancer.

BACKGROUND: Prostate cancer is the most common cancer diagnosed in men. An increasing number of these patients are seeking minimally invasive procedures such as transperineal interstitial permanent radioactive seed prostate brachytherapy. METHODS: This paper reviews the historical perspective and the current advances in transperineal interstitial permanent radioactive seed prostate brachytherapy. The 10- to 15-year results data now published for brachytherapy alone or in combination with external-beam irradiation are also reviewed. RESULTS: Modern brachytherapy using transperineal interstitial permanent radioactive seed prostate brachytherapy offers patients an excellent quality of life with convenient outpatient treatment with long-term (10- to 15-year) biochemical relapse-free survival rates ranging from 67% to 87%, depending on risk stratification. CONCLUSIONS: Modern-day brachytherapy utilizing either radioactive iodine-125 or palladium-103 alone or in combination with supplemental external-beam treatment offers patients a successful treatment outcome with acceptable toxicity.

Association between polymorphisms in HSD3B1 and UGT2B17 and prostate cancer risk.

OBJECTIVES: Androgens, especially dihydrotestosterone, have been postulated to modify the risk of prostate cancer. 3-Beta-hydroxysteroid dehydrogenase1 (HSD3B1) and uridine diphosphate-glucuronosyltransferase 2B17 (UGT2B17) are enzymes that inactivate dihydrotestosterone in the prostate and may affect dihydrotestosterone concentration in prostatic tissue. The purpose of this study was to determine whether polymorphisms in HSD3B1 and UGT2B17 increase the risk of prostate cancer. METHODS: In a case-control study of 356 patients with incident primary prostate cancer and 363 age-matched controls, the frequencies of HSD3B1 N367T and UGT2B17 null polymorphisms in genomic DNA were compared between the patients and controls. RESULTS: No evidence was found for a main effect of the HSD3B1 codon 367 polymorphism on prostate cancer risk. However, among white men with family history of prostate cancer, the HSD3B1 367Thr allele was positively associated with prostate cancer (odds ratio 3.0, 95% confidence interval 1.0 to 9.2). A significant association was observed between the UGT2B17 null polymorphism and prostate cancer risk (odds ratio 1.7, 95% confidence interval 1.03 to 2.9). An association with the UGT2B17 null polymorphism was further elevated (odds ratio 2.7, 95% confidence interval 1.1 to 6.5) among individuals with HSD3B1 Asn/Asn genotype. CONCLUSIONS: These results suggest that the HSD3B1 N367T and UGT2B17 null polymorphisms may modify the risk of prostate cancer, particularly among men with a family history of the disease.

Treatment decision-making strategies and influences in patients with localized prostate carcinoma.

BACKGROUND: Patients diagnosed with localized prostate carcinoma need to interpret complicated medical information to make an informed treatment selection from among treatments that have comparable efficacy but differing side effects. The authors reported initial results for treatment decision-making strategies among men receiving definitive treatment for localized prostate carcinoma. METHODS: One hundred nineteen men treated with radical prostatectomy (44%) or brachytherapy (56%) consented to participate. Guided by a cognitive-affective theoretic framework, the authors assessed differences in decision-making strategies, and treatment and disease-relevant beliefs and affects, in addition to demographic and clinical variables. RESULTS: Approximately half of patients reported difficulty (49%) and distress (45%) while making treatment decisions, but no regrets (74%) regarding the treatment choice they made. Patients who underwent prostatectomy were younger, were more likely to be employed, had worse tumor grade, and had a shorter time since diagnosis (P < 0.01) compared with patients who did not undergo prostatectomy. In multivariate analyses, compared with patients who received radical prostatectomy, patients who received brachytherapy were more likely to say that they chose this treatment because it was "the least invasive" and they "wanted to avoid surgery" (P < 0.0001). CONCLUSIONS: In general, patients who received brachytherapy chose this treatment because of quality of life considerations, whereas "cure" and complete removal of the tumor were the main motivations for patients selecting radical prostatectomy. Long-term data are needed to evaluate distress and decisional regret as patients experience treatment-related chronic side effects and efficacy outcomes. Decision-making aids or other interventions to reduce decisional difficulty and emotional distress during decision making were indicated.