Shawn Malone

Resistance Exercise in Men Receiving Androgen Deprivation Therapy for Prostate Cancer

PURPOSE Androgen deprivation therapy is a common treatment in men with prostate cancer that may cause fatigue, functional decline, increased body fatness, and loss of lean body tissue. These physical changes can negatively affect health-related quality of life. Resistance exercise may help to counter some of these side effects by reducing fatigue, elevating mood, building muscle mass, and reducing body fat. METHODS In a two-site study, 155 men with prostate cancer who were scheduled to receive androgen deprivation therapy for at least 3 months after recruitment were randomly assigned to an intervention group that participated in a resistance exercise program three times per week for 12 weeks (82 men) or to a waiting list control group (73 men). The primary outcomes were fatigue and disease-specific quality of life as assessed by self-reported questionnaires after 12 weeks. Secondary outcomes were muscular fitness and body composition. RESULTS Men assigned to resistance exercise had less interference from fatigue on activities of daily living (P =.002) and higher quality of life (P =.001) than men in the control group. Men in the intervention group demonstrated higher levels of upper body (P =.009) and lower body (P <.001) muscular fitness than men in the control group. The 12-week resistance exercise intervention did not improve body composition as measured by changes in body weight, body mass index, waist circumference, or subcutaneous skinfolds. CONCLUSION Resistance exercise reduces fatigue and improves quality of life and muscular fitness in men with prostate cancer receiving androgen deprivation therapy. This form of exercise can be an important component of supportive care for these patients.

Influence of Androgen Suppression Therapy for Prostate Cancer on the Frequency and Timing of Fatal Myocardial Infarctions

PURPOSE We evaluated whether the timing of fatal myocardial infarction (MI) was influenced by the administration of androgen suppression therapy (AST). PATIENTS AND METHODS The study cohort comprised 1,372 men who were enrolled onto three randomized trials between February 1995 and June 2001. In the three trials, the men were randomly assigned to receive radiation therapy with 0 versus 3 versus 6, 3 versus 8, or 0 versus 6 months of AST. Fine and Grays regression was used to determine the clinical factors associated with the time to fatal MI, and estimates of time to fatal MI were calculated using a cumulative incidence method. When comparing the cumulative incidence estimates using Grays k-sample P values, increased weight was ascribed to the earlier data because recovery of testosterone is expected for most men within 2 years after short-course AST. RESULTS Men age 65 years or older who received 6 months of AST experienced shorter times to fatal MIs compared with men in this age group who did not receive AST (P = .017) and men younger than 65 years (P = .016). No significant difference (P = .97) was observed in the time to fatal MIs in men age 65 years or older who received 6 to 8 months of AST compared with 3 months of AST. CONCLUSION The use of AST is associated with earlier onset of fatal MIs in men age 65 years or older who are treated for 6 months compared with men who are not treated with AST.

Randomized Controlled Trial of Resistance or Aerobic Exercise in Men Receiving Radiation Therapy for Prostate Cancer

PURPOSE Radiotherapy for prostate cancer (PCa) may cause unfavorable changes in fatigue, quality of life (QOL), and physical fitness. We report results from the Prostate Cancer Radiotherapy and Exercise Versus Normal Treatment study examining the effects of 24 weeks of resistance or aerobic training versus usual care on fatigue, QOL, physical fitness, body composition, prostate-specific antigen, testosterone, hemoglobin, and lipid levels in men with PCa receiving radiotherapy. PATIENTS AND METHODS Between 2003 and 2006, we conducted a randomized controlled trial in Ottawa, Canada, where 121 PCa patients initiating radiotherapy with or without androgen deprivation therapy were randomly assigned to usual care (n = 41), resistance (n = 40), or aerobic exercise (n = 40) for 24 weeks. Our primary end point was fatigue assessed by the Functional Assessment of Cancer Therapy-Fatigue scale. RESULTS The follow-up assessment rate for our primary end point of fatigue was 92.6%. Median adherence to prescribed exercise was 85.5%. Mixed-model repeated measures analyses indicated both resistance (P =.010) and aerobic exercise (P = .004) mitigated fatigue over the short term. Resistance exercise also produced longer-term improvements (P = .002). Compared with usual care, resistance training improved QOL (P = .015), aerobic fitness (P = .041), upper- (P < .001) and lower-body (P < .001) strength, and triglycerides (P = .036), while preventing an increase in body fat (P = .049). Aerobic training also improved fitness (P = .052). One serious adverse event occurred in the group that performed aerobic exercise. CONCLUSION In the short term, both resistance and aerobic exercise mitigated fatigue in men with PCa receiving radiotherapy. Resistance exercise generated longer-term improvements and additional benefits for QOL, strength, triglycerides, and body fat.

Intermittent Androgen Suppression for Rising PSA Level after Radiotherapy

BACKGROUND Intermittent androgen deprivation for prostate-specific antigen (PSA) elevation after radiotherapy may improve quality of life and delay hormone resistance. We assessed overall survival with intermittent versus continuous androgen deprivation in a noninferiority randomized trial. METHODS We enrolled patients with a PSA level greater than 3 ng per milliliter more than 1 year after primary or salvage radiotherapy for localized prostate cancer. Intermittent treatment was provided in 8-month cycles, with nontreatment periods determined according to the PSA level. The primary end point was overall survival. Secondary end points included quality of life, time to castration-resistant disease, and duration of nontreatment intervals. RESULTS Of 1386 enrolled patients, 690 were randomly assigned to intermittent therapy and 696 to continuous therapy. Median follow-up was 6.9 years. There were no significant between-group differences in adverse events. In the intermittent-therapy group, full testosterone recovery occurred in 35% of patients, and testosterone recovery to the trial-entry threshold occurred in 79%. Intermittent therapy provided potential benefits with respect to physical function, fatigue, urinary problems, hot flashes, libido, and erectile function. There were 268 deaths in the intermittent-therapy group and 256 in the continuous-therapy group. Median overall survival was 8.8 years in the intermittent-therapy group versus 9.1 years in the continuous-therapy group (hazard ratio for death, 1.02; 95% confidence interval, 0.86 to 1.21). The estimated 7-year cumulative rates of disease-related death were 18% and 15% in the two groups, respectively (P=0.24). CONCLUSIONS Intermittent androgen deprivation was noninferior to continuous therapy with respect to overall survival. Some quality-of-life factors improved with intermittent therapy. (Funded by the Canadian Cancer Society Research Institute and others; ClinicalTrials.gov number, NCT00003653.).

POSTRADIOTHERAPY PROSTATE BIOPSIES: WHAT DO THEY REALLY MEAN? RESULTS FOR 498 PATIENTS

PURPOSE Postradiotherapy (RT) prostate biopsies are prone to problems in interpretation. False negatives due to sampling error, false positives due to delayed tumor regression, and indeterminate biopsies showing radiation effect in residual tumor of uncertain viability are common occurrences. METHODS AND MATERIALS A cohort of 498 men treated with conventional RT from 06/87-10/96 were followed prospectively with systematic transrectal ultrasound (TRUS)-guided post-RT prostate biopsies, starting 12-18 months after RT. If there was residual tumor but further decline in serum prostate-specific antigen (PSA), biopsies were repeated every 6-12 months. Patients with negative biopsies were rebiopsied at 36 months. Residual tumor was evaluated for RT effect and proliferation markers. The 498 men had 978 biopsies. Median time of the first biopsy (n = 498) was 13 months, biopsy #2 (n = 342) 28 months, biopsy #3 (n = 110) 36 months, biopsy #4 (n = 28) 44 months, and biopsy #5 (n = 4) 55 months. Median follow-up is 54 months (range 13-131). One hundred seventy-five patients (34%) had prior hormonal therapy for a median of 5 months (range 1-60). RESULTS Clinical stage distribution was T1b: 46; T1c: 50; T2a: 115; T2b/c: 170; T3: 108; T4: 11; Tx: 1. Distribution by Gleason score was: 28% Gleason score 2-4; 42%: 5-6; 18%: 7; and 12%: 8-10. Seventy-one men have died, 26 of prostate cancer and 45 of other causes. Actuarial failure-free survival by T stage at 5 years is T1b: 78%; T1c: 76%; T2a: 60%; T2b/c: 55%; T3: 30%; and T4: 0%. Actuarial freedom from local failure at 5 years is T1b: 83%; T1c: 88%; T2a: 72%; T2b/c: 66%; T3: 58%; and T4: 0%. The proportion of indeterminate biopsies decreases with time, being 33% for biopsy 1, 24% for biopsy 2, 18% for biopsy 3, and 7% for biopsy 4. Thirty percent of indeterminate biopsies resolved to NED status, regardless of the degree of RT effect, 18% progressed to local failure, and 34% remained as biopsy failures with indeterminate status within the time frame of this report. Positive staining for proliferation markers was associated with both subsequent local failure and also any type of failure. In multivariate analysis, only PSA nadir (p = 0.0002) and biopsy status at 24-36 months (p = 0. 0005) were independent predictors of outcome. CONCLUSIONS Post-RT prostate biopsies are not a gold standard of treatment efficacy, but are an independent predictor of outcome. Positive immunohistochemical staining for markers of cellular proliferation is associated with subsequent local failure. Indeterminate biopsies, even when showing marked RT effect, cannot be considered negative.

Respiratory-induced prostate motion: quantification and characterization

PURPOSE The precise localization of the prostate is critical for dose-escalated conformal radiotherapy. This study identifies and characterizes a potential cause of inaccurate prostatic localization-respiratory-induced movement. METHODS AND MATERIALS Prostate movement during respiration was measured fluoroscopically using implanted gold fiducial markers. Twenty sequential patients with CT(1)-T(3) N(0) M(0) prostate carcinoma were evaluated prone, immobilized in customized thermoplastic shells. A second 20 patients were evaluated both prone (with and without their thermoplastic shells) and supine (without their shells). RESULTS When the patients were immobilized prone in thermoplastic shells, the prostate moved synchronously with respiration. In the study the prostate was displaced a mean distance of 3.3 +/- 1.8 (SD) mm (range, 1-10.2 mm), with 23% (9/40) of the displacements being 4 mm or greater. The respiratory-associated prostate movement decreased significantly when the thermoplastic shells were removed. CONCLUSION Significant prostate movement can be induced by respiration when patients are immobilized in thermoplastic shells. This movement presumably is related to transmitted intraabdominal pressure within the confined space of the shells. Careful attention to the details of immobilization and to the possibility of respiratory-induced prostate movements is important when employing small field margins in prostatic radiotherapy.

Intermittent androgen suppression in the management of prostate cancer.

OBJECTIVES Intermittent androgen suppression (IAS) has been suggested as a means of attenuating the androgen deprivation syndrome in men with incurable prostate cancer. Laboratory data suggest that intermittent therapy may prolong the duration of androgen dependence. METHODS Since October 1993, 54 patients have entered a Phase II protocol consisting of 8 months of total androgen blockade (TAB) using leuprolide (Lupron) depot and nilutamide (Anandron) followed by an off-treatment interval of variable length. Eleven patients had biopsy-proven local failure after radiotherapy, 4 had biochemical failure, 24 had distant metastases (fewer than six axial sites on bone scan), 11 had combined local and distant failure, and 4 were treated as primary management for nodal disease. Mean prostate-specific antigen (PSA) at entry was 37 ng/mL (range 3.8 to 196). After 8 months of TAB, hormonal therapy was discontinued for those patients whose PSA was less than 4.0 ng/mL and stable or decreasing and was resumed (cycle 2) when PSA increased to greater than 10 ng/mL. RESULTS As of April 1 998, mean follow-up was 33 months (range 14 to 53). Patients have completed at least one, and up to five treatment cycles. The mean time to nadir PSA in cycle 1 was 20 weeks, and the mean time off was 35 weeks (31 weeks for those with metastatic disease versus 39 for local or biochemical failure). In cycle 2, the mean time to PSA nadir was 17 weeks, and the mean time off was 30 weeks (28 weeks for metastatic disease and 38 weeks for local or biochemical failure). In cycle 3, the time to PSA nadir was 19 weeks. Full testosterone data are available for 40 patients in cycle 1. Normal levels were achieved during the off-treatment interval in 73% by a mean of 18 weeks (median 9). Testosterone normalization in cycle 2 was achieved in 71% at a mean time of 17 weeks (median 14). CONCLUSIONS TAB can be used intermittently, and appears to be more appropriate for patients with local or biochemical failure. Testosterone recovery is not universal in the off-treatment intervals. IAS needs to be investigated in a randomized trial to determine the effect on overall survival and quality of life.

Final report of multicenter Canadian Phase III randomized trial of 3 versus 8 months of neoadjuvant androgen deprivation therapy before conventional-dose radiotherapy for clinically localized prostate cancer.

PURPOSE To evaluate the effect of 3 vs. 8 months of neoadjuvant hormonal therapy before conventional-dose radiotherapy (RT) on disease-free survival for localized prostate cancer. METHODS AND MATERIALS Between February 1995 and June 2001, 378 men were randomized to either 3 or 8 months of flutamide and goserelin before 66 Gy RT at four participating centers. The median baseline prostate-specific antigen level was 9.7 ng/mL (range, 1.3-189). Of the 378 men, 26% had low-, 43% intermediate-, and 31% high-risk disease. The two arms were balanced in terms of age, Gleason score, clinical T category, risk group, and presenting prostate-specific antigen level. The median follow-up for living patients was 6.6 years (range, 1.6-10.1). Of the 378 patients, 361 were evaluable, and 290 were still living. RESULTS The 5-year actuarial freedom from failure rate for the 3- vs. 8-month arms was 72% vs. 75%, respectively (p = 0.18). No difference was found in the failure types between the two arms. The median prostate-specific antigen level at the last follow-up visit for patients without treatment failure was 0.6 ng/mL in the 3-month arm vs. 0.50 ng/mL in the 8-month arm. The disease-free survival rate at 5 years was improved for the high-risk patients in the 8-month arm (71% vs. 42%, p = 0.01). CONCLUSION A longer period of NHT before standard-dose RT did not alter the patterns of failure when combined with 66-Gy RT. High-risk patients in the 8-month arm had significant improvement in the 5-year disease-free survival rate.

Final results of the Canadian prospective phase II trial of intermittent androgen suppression for men in biochemical recurrence after radiotherapy for locally advanced prostate cancer: clinical parameters.

This prospective Phase II study was undertaken to evaluate intermittent androgen suppression as a form of therapy in men with localized prostate cancer who failed after they received external beam irradiation.

A prospective comparison of three systems of patient immobilization for prostate radiotherapy

PURPOSE The study compared the setup reliability of 3 patient immobilization systems, a rubber leg cushion, the alpha cradle, and the thermoplastic Hipfix device, in 77 patients with cT1-T3, N0, M0 prostate cancer receiving conformal radiotherapy. METHODS AND MATERIALS Port films were analyzed and compared to simulation films to estimate the setup errors in the three coordinate axes (anterior-posterior, cranial-caudal, medial-lateral). A total vector error was calculated from these shifts. RESULTS The Hipfix was found significantly superior to the other two devices in reducing mean setup errors in all axes (p < 0.005). The average field-positioning error with the Hipfix ranged from 1.9 mm to 2.6 mm for all axes, whereas the deviation for the other two systems ranged from 2.7 to 3. 4 mm. Errors greater than 10 mm were virtually eliminated with the Hipfix system. There was a reduction in the mean total vector error in the alpha cradle and Hipfix patient cohorts over time, reflecting improved efficacy as a result of experience. CONCLUSION There was a significant difference in the performance of each immobilization device. The Hipfix was consistently more reliable in reducing setup errors than the other devices.