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.     

Efficacy of walking exercise in promoting cognitive-psychosocial functions in men with prostate cancer receiving androgen deprivation therapy

ABSTRACT: BACKGROUND: Prostate cancer is the most commonly diagnosed non-melanoma cancer among men. Androgen deprivation therapy (ADT) has been the core therapy for men with advanced prostate cancer. It is only in recent years that clinicians began to recognize the cognitive-psychosocial side effects from ADT, which significantly compromise the quality of life of prostate cancer survivors. The objectives of the study are to determine the efficacy of a simple and accessible home-based, walking exercise program in promoting cognitive and psychosocial functions of men with prostate cancer receiving ADT. METHOD: S A 6-month prospective, single-blinded, randomized controlled trial will be conducted to compare the Exercise Group with the Control Group. Twenty men with prostate cancer starting ADT will be recruited and randomly assigned to one of the two groups: the Exercise Group will receive instructions in setting up an individualized 6-month home-based, walking exercise program, while the Control Group will receive standard medical advice from the attending physician. The primary outcomes will be psychosocial and cognitive functions. Cognitive functions including memory, attention, working memory, and executive function will be assessed using a battery of neurocognitive tests at baseline and 6 months. Psychosocial functions including depression, anxiety and self-esteem will be assessed at baseline, 3 and 6 months using the Center for Epidemiological Studies Depression Scale, Spielberger State-Trait Anxiety Inventory, and Rosenberg Self-Esteem Scale. DISCUSSION The significance of the cognitive-psychosocial side effects of ADT in men with prostate cancer has only been recently recognized, and the management remains unclear. This study addresses this issue by designing a simple and accessible home-based, exercise program that may potentially have significant impact on reducing the cognitive and psychosocial side effects of ADT, and ultimately improving the health-related quality of life in men with prostate cancer receiving ADT.     

A comprehensive bone-health management approach for men with prostate cancer receiving androgen deprivation therapy

For advanced and metastatic prostate cancer, androgen deprivation therapy (adt) is the mainstay of treatment. Awareness of the potential bone-health complications consequent to adt use is increasing. Many studies have shown that prolonged adt leads to significant bone loss and increased fracture risk that negatively affect quality of life. Clinical practice guidelines for preserving bone health in men with prostate cancer on adt vary across Canada. This paper reviews recent studies on bone health in men with prostate cancer receiving adt and the current evidence regarding bone-health monitoring and management in reference to Canadian provincial guidelines. Based on this narrative review, we provide general bone-health management recommendations for men with prostate cancer receiving adt.     

A phase II trial for the optimisation of treatment position in the radiation therapy of prostate cancer

BACKGROUND: Patient immobilisation and position are important contributors to the reproducibility and accuracy of radiation therapy. In addition the choice of position can alter the external contour of the treated area and has the potential to alter the spatial relationship between internal organs. The published literature demonstrates variation in the use of the prone and supine position for prostate cancer radiation therapy. Previous investigators using different protocols for patient preparation, imaging and target volume definition have demonstrated changes in the calculated therapeutic ratio comparing the two positions. We did not use rigid immobilisation, laxatives, rectal catheters or bladder voiding and assessed if in the prone position would cause a reduction of the dose to the rectum. We performed a prospective comparison of the two positions in 26 patients to determine if the differences in the spatial relation between the rectum and the planning target volume (PTV) would impact on dose-volume histograms to organs at risk (OAR). We also determined if any such improvement might permit dose escalation. MATERIALS AND METHODS: Twenty-six patients with clinically localized prostate cancer consented to participate in this study. All patients underwent a planning CT scan in both the prone and supine treatment positions. The PTV and OAR were drawn on each set of scans by one of the investigators. The PTV included the prostate and seminal vesicles with a 1cm margin except posteriorly where this margin was reduced to 5mm. The outer circumference of the bladder, rectal wall, small bowel (when present) was drawn along with femoral heads. 3D conformal treatment plans were computed using Helax TMS version 6.1B. A 3-field treatment technique was employed with energy of 10/15 MV. The prescribed dose was 70 Gy and the PTV was encompassed by the 95% isodose and the maximum dose was always less than 107%. Cumulative dose-volume histograms were calculated for the PTV, rectum, bladder, femoral heads and small bowel (when present). These non-uniform histograms for both the prone and supine treatment positions were transformed into uniform ones using the effective volume method [Kutcher J, Burman C. Calculation of probability factors for non-uniform normal tissue irradiation: the effective volume method. Med Phys 1987;14:487]. RESULTS: Twenty-one of the 26 (80%) patients had a lower effective volume of rectum irradiated if the prone instead of the supine treatment position was used. The median value of the effective volume in the supine treatment position was 31.74 Gy while the median value in the prone position was 22.48 Gy. The dose escalation was applied to the patients in the prone treatment position until the effective volume for the rectum was the same as that in the supine position. The range of dose escalation possible for these patients was 0.1-7.9 Gy. These patients could potentially have the dose escalated from the prescribed dose of 70 Gy for the supine position without any increase in side effects. For the five patients where no potential benefit was found when changing treatment position, only two patients displayed a significant (>1 Gy) advantage for the supine treatment position. Twenty-one of the 26 patients also showed an advantage for the prone treatment position in relation to bladder dose. CONCLUSION: The use of the prone position reduced the dose to the unprepared rectum and unvoided bladder in the majority of cases. It should be considered particularly in cases where large posterior seminal vesicles cause significant overlap between the planning target volume and the rectum.     

A phase II clinical trial of sorafenib in androgen-independent prostate cancer.

PURPOSE: To determine if sorafenib is associated with a 4-month probability of progression-free survival, which is consistent with 50%, as determined by clinical, radiographic, and prostate-specific antigen (PSA) criteria in patients with metastatic androgen-independent prostate cancer (AIPC). EXPERIMENTAL DESIGN: Patients with progressive metastatic AIPC were enrolled in an open-label, single-arm phase II study. Sorafenib was given continuously at a dose of 400 mg orally twice daily in 28-day cycles. Clinical assessment and PSA measurement were done every cycle whereas radiographic measurements were carried out every two cycles. RESULTS: Twenty-two patients were enrolled in the study to date, completing a planned first stage of the trial. Baseline patient characteristics included a median age of 63.9 years (range, 50-77 years), Gleason score of 9 (range, 4-9.5), and PSA concentration of 53.3 ng/mL (range, 2-1,905 ng/mL). Fifty-nine percent of patients had received one prior chemotherapy regimen. Of the 21 patients with progressive disease, 13 progressed only by PSA criteria in the absence of evidence of clinical and radiographic progression. Two patients were found to have dramatic reduction of bone metastatic lesions as shown by bone scan, although they met PSA progression criteria at the time when scans were obtained. Toxicities likely related to treatment included one grade 3 hypertension; one grade 3 hand-foot syndrome; and grade 1/2 toxicities: fatigue, anorexia, hypertension, skin rash, nausea, and diarrhea. Results from in vitro studies suggested that PSA is not a good marker of sorafenib activity. The geometric mean exposure (AUC(0-12)) and maximum concentration (C(max)) were 9.76 h mg/L and 1.28 mg/L, respectively. The time to maximum concentration (t(max)) and accumulation ratio (after second dose) ranged from 2 to 12 h and 0.68 to 6.43, respectively. CONCLUSIONS: Sorafenib is relatively well tolerated in AIPC with two patients showing evidence of improved bony metastatic lesions. Interpretation of this study is complicated by discordant radiographic and PSA responses. PSA may not be an adequate biomarker for monitoring sorafenib activity. Based on these observations, further investigation using only clinical and radiographic end points as progression criteria is warranted. Accrual to the second stage of trial is ongoing.     

Rhodamine-123: therapy for hormone refractory prostate cancer, a phase I clinical trial

Rhodamine-123, a lipophilic, cationic, rhodocyanine dye, has been reported to have carcinoma selective toxicity in vitro and in vivo. This phase I clinical trial established the safety and pharmacokinetics of Rhodamine-123 administered to men with hormone refractory prostate cancer. A single dose toxicity study of Rhodamine-123 determined the maximum tolerated dose. A multiple dose toxicity study assessed the safety of Rhodamine-123 at the maximum tolerated dose level. Transient and variable toxicities noted following Rhodamine-123 infusion resolved within 6 hours following infusion. Pharmacokinetic analyses of sera showed no accumulation of drug with repeated monthly administrations. Drug retention was confirmed in prostatic tissue following Rhodamine-123 administration. PSA doubling times lengthened variably suggesting drug efficacy but the data were not statistically significant. The maximum tolerated dose of Rhodamine-123 is 96 mg/m2. The drug can be safely administered at monthly intervals without detectable drug accumulation in serum. Rhodamine-123 is retained by prostatic tumor tissue.     

Depression in men receiving androgen deprivation therapy for prostate cancer: a pilot study

PURPOSE: Prostate cancer is the most common malignancy in men and one of the leading causes of cancer death in men internationally. Treatment for prostate cancer frequently includes androgen deprivation therapy (ADT). Reports of depressive symptoms arising during ADT are emerging. This study examines the prevalence rates and risk factors associated with major depression in this population. METHOD: 45 men with prostate cancer receiving ADT at the MGH Cancer Center were surveyed for depression with the SCID for Axis I disorders for DSM-IV and the Beck Depression Inventory. RESULTS: Major depressive disorder was prevalent in 12.8% of the men with prostate cancer receiving ADT, eight times the national rate of depression in men, 32 times the rate in men over 65 years old. Major depression was not associated with worsening disease, medical response to ADT, receiving chemotherapy, or the type of ADT. Past history of depression was associated with current depression in this population (p<0.000). No first onset cases of depression occurred on ADT in this sample. CONCLUSION: This data suggests a significant rate of major depression in men with prostate cancer receiving ADT and that men with past histories of depression may be at particular risk for recurrence of their depression while undergoing this treatment.     

New clinical imaging modalities in prostate cancer

In all prostate cancer disease states, exciting novel imaging technology is being tested that may affect the future care of our patients. New US, MRI, and nuclear medicine techniques are improving both the ability to stage patients and to follow treatment-related changes. See Table 3 for a summary of these novel imaging techniques. Important issues still need to be resolved, including standardizing patient populations within trials, demonstrating the reproducibility of these techniques between different centers, and understanding how information gained from these techniques should influence patient care. We eagerly await answers to these questions.     

Lessons from phase III clinical trials on anti-VEGF therapy for cancer

In randomized phase III trials two anti-vascular endothelial growth factor (VEGF) approaches have yielded survival benefit in patients with metastatic cancer. In one approach, the addition of bevacizumab, a VEGF-specific antibody, to standard chemotherapy improved overall survival in colorectal and lung cancer patients and progression-free survival in breast cancer patients. In the second approach, multitargeted tyrosine kinase inhibitors that block VEGF receptor and other kinases in both endothelial and cancer cells, demonstrated survival benefit in gastrointestinal stromal tumor and renal-cell-carcinoma patients. By contrast, adding bevacizumab to chemotherapy failed to increase survival in patients with previously treated and refractory metastatic breast cancer. Furthermore, addition of vatalanib, a kinase inhibitor developed as a VEGF receptor-selective agent, to chemotherapy did not show a similar benefit in metastatic colorectal cancer patients. These contrasting responses raise critical questions about how these agents work and how to combine them optimally. We summarize three of the many potential mechanisms of action of anti-VEGF agents, and also discuss progress relating to the identification of potential biomarkers for anti-VEGF-agent efficacy in humans.     

A randomized, controlled trial of aerobic exercise for treatment-related fatigue in men receiving radical external beam radiotherapy for localized prostate carcinoma

BACKGROUND: Advice to rest and take things easy if patients become fatigued during radiotherapy may be detrimental. Aerobic walking improves physical functioning and has been an intervention for chemotherapy-related fatigue. A prospective, randomized, controlled trial was performed to determine whether aerobic exercise would reduce the incidence of fatigue and prevent deterioration in physical functioning during radiotherapy for localized prostate carcinoma. METHODS: Sixty-six men were randomized before they received radical radiotherapy for localized prostate carcinoma, with 33 men randomized to an exercise group and 33 men randomized to a control group. Outcome measures were fatigue and distance walked in a modified shuttle test before and after radiotherapy. RESULTS: There were no significant between group differences noted with regard to fatigue scores at baseline (P = 0.55) or after 4 weeks of radiotherapy (P = 0.18). Men in the control group had significant increases in fatigue scores from baseline to the end of radiotherapy (P = 0.013), with no significant increases observed in the exercise group (P = 0.203). A nonsignificant reduction (2.4%) in shuttle test distance at the end of radiotherapy was observed in the control group; however, in the exercise group, there was a significant increase (13.2%) in distance walked (P = 0.0003). CONCLUSIONS: Men who followed advice to rest and take things easy if they became fatigued demonstrated a slight deterioration in physical functioning and a significant increase in fatigue at the end of radiotherapy. Home-based, moderate-intensity walking produced a significant improvement in physical functioning with no significant increase in fatigue. Improved physical functioning may be necessary to combat radiation fatigue.     

Relationship between hot flashes and distress in men receiving androgen deprivation therapy for prostate cancer

Objective: Side effects of cancer treatment have been found to have a significant impact on patients' psychological well‐being. Each of the primary treatment options for prostate cancer is associated with significant side effects that can have a dramatic impact on quality of life. Hot flashes are a notable side effect of androgen deprivation therapy (ADT) and a potential source of distress due to their episodic nature and low frequency in a normal aging male population. The current study sought to examine the relationship between hot flashes and cancer‐related distress during the first three months of ADT. Methods: Participants were 68 men with various stages of prostate cancer scheduled to begin ADT for the first time. Study measures were completed at the beginning of treatment and 3 months later. Results: Repeated measures ANOVA indicated that men who did not experience hot flashes had a significant decrease in total cancer‐related distress and avoidance over the 3‐month period, while men with hot flashes exhibited no change in distress. Among men with hot flashes, results of hierarchical regression analyses indicated that a worse experience with hot flashes was a significant predictor of greater increases in intrusion and total cancer‐related distress over the 3‐month period. Conclusions: These results suggest that hot flashes serve to maintain levels of distress during the treatment period. Further research should extend these findings by lengthening the follow‐up period and using ecological momentary assessment to refine measurement of these constructs and provide evidence for the direction of causality between hot flashes and distress. Copyright © 2008 John Wiley & Sons, Ltd.     

Complete androgen blockade as treatment for advanced prostate cancer: clinical response and side-effects

Treatment of advanced prostatic cancer is currently based on hormonal manipulation. In 1982 Labrié supported a new concept of hormonal treatment based on complete androgen blockade. The objective of this study was to evaluate the effects of total androgen suppression, achieved by the combination of a LHRH agonist (buserelin) plus a pure anti-androgen (flutamide) in the long-term treatment of advanced prostate cancer. Forty-seven untreated consenting patients with advanced prostatic cancer entered in the study, and 41 of these proved evaluable for response and toxicity. Buserelin and Flutamide were administered three times daily, intranasally and orally respectively, at a dose of 1.2 mg and 750 mg for twelve months. Circulating testosterone levels, regularly measured during the study, were reduced by the treatment to castrated levels. Clinical results are encouraging for the high rate of objective and clinical responses PR + SD = 37 (90%), for its duration (12 months), for the significant improvement of urological symptoms and for the decrease of cancer-related pain, even in cases with detectable bone metastases. Compliance was excellent in all the subjects and no patient was forced to interrupt treatment because of cardiovascular toxicity or severe side-effects, which were limited to occasional loss of libido and potency, hot-flashes, mild diarrhea and nausea.     

A phase III, double-blind, placebo-controlled prospective randomized clinical trial of d-threo-methylphenidate HCl in brain tumor patients receiving radiation therapy

PURPOSE: The quality of life (QOL) and neurocognitive function of patients with brain tumors are negatively affected by the symptoms of their disease and brain radiation therapy (RT). We assessed the effect of prophylactic d-threo-methylphenidate HCl (d-MPH), a central nervous system (CNS) stimulant on QOL and cognitive function in patients undergoing RT. METHODS AND MATERIALS: Sixty-eight patients with primary or metastatic brain tumors were randomly assigned to receive d-MPH or placebo. The starting dose of d-MPH was 5 mg twice daily (b.i.d.) and was escalated by 5 mg b.i.d. to a maximum of 15 mg b.i.d. The placebo was administered as one pill b.i.d. escalating three pills b.i.d. The primary outcome was fatigue. Patients were assessed at baseline, the end of radiation therapy, and 4, 8, and 12 weeks after brain RT using the Functional Assessment of Cancer Therapy with brain and fatigue (FACIT-F) subscales, as well as the Center for Epidemiologic Studies Scale and Mini-Mental Status Exam. RESULTS: The Mean Fatigue Subscale Score at baseline was 34.7 for the d-MPH arm and 33.3 for the placebo arm (p = 0.61). At 8 weeks after the completion of brain RT, there was no difference in fatigue between patient groups. The adjusted least squares estimate of the Mean Fatigue Subscale Score was 33.7 for the d-MPH and 35.6 for the placebo arm (p = 0.64). Secondary outcomes were not different between the two treatment arms. CONCLUSIONS: Prophylactic use of d-MPH in brain tumor patients undergoing RT did not result in an improvement in QOL.     

Improvements in clinical benefit with vinorelbine in the treatment of hormone-refractory prostate cancer: A phase II trial

Background: Clinical activity is difficult to assess by traditional response endpoints in patients with advanced prostate cancer. We used clinical benefit response to assess the activity of vinorelbine (Navelbine®) in patients with hormone-refractory prostate cancer.Patients and methods: Forty-nine men with hormone-refractory prostate cancer received vinorelbine weekly for eight weeks followed by every-other-week dosing. Clinical benefit response was defined by improvement in 1 of the following categories for at least 12 weeks and stable response or better in the other 2: pain index (analgesic consumption and pain intensity), Karnofsky performance status, and tumor status.Results: Of 37 evaluable patients, 14 (39%) achieved clinical benefit for a median duration of 6 months (range 3–24 months). Toxicities consisted primarily of brief neutropenia and mild nausea.Conclusion: These findings indicate that vinorelbine is well tolerated in men with hormone-refractory prostate cancer and produces durable clinical benefit as defined by improvement in pain index and performance status.     

Predictors of clinical metastasis in prostate cancer patients receiving androgen deprivation therapy

BACKGROUND:

Virtually all patients with prostate cancer who receive androgen deprivation therapy (ADT) will ultimately develop evidence of resistance to treatment. The prognosis for patients who develop metastatic castrate‐resistant disease is reported to be poor, with overall survival historically estimated to be 24 to 36 months. The goal of the current study was to identify predictors of clinical disease progression in patients with prostate cancer who were receiving ADT.

METHODS:

Of the 13,740 men with biopsy–proven prostate cancer who were enrolled in the Cancer of the Prostate Strategic Urological Research Endeavor (CaPSURE) database from 1995 to 2007, 4003 men treated with ADT after diagnosis without evidence of metastases at treatment initiation were identified. The primary endpoint was the development of bone metastasis. Clinical and pathologic characteristics were compared between patients who developed metastasis and those who did not using chi‐square tests in a Cox proportional hazards regression model.

RESULTS:

The mean age of the men in the cohort was 70 years (range, 39‐94 years). One hundred ninety‐one men (4.8%) progressed to metastatic disease at a median of 18 months from the initiation of ADT (range, 1‐139 months). On multivariate analyses, risk category (hazards ratio [HR], 2.58; P < .0001), percent of biopsies positive >33% (HR, 3.36; P = .003), age ≤65 years at diagnosis (HR, 2.11; P = .001, and prostate–specific antigen velocity on ADT (HR, 1.04; P < .001) were found to be significantly associated with the development of metastatic disease after ADT.

CONCLUSIONS:

Younger men with high–risk disease appear to have worse prognosis than older men with similar disease. This, along with the other prognostic variables established in the current study, may help identify candidates for clinical trials evaluating secondary treatments for patients with castrate‐resistant disease. Cancer 2009. © 2009 American Cancer Society.