An Updated Analysis of the Survival Endpoints of ASCENDE-RT.

PURPOSE: Using the primary endpoint of time to biochemical progression (TTP), Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (ASCENDE-RT) randomized National Comprehensive Cancer Network patients with intermediate and high-risk prostate cancer to low-dose-rate brachytherapy boost (LDR-PB) or dose-escalated external beam boost (DE-EBRT). Randomization to the LDR-PB arm resulted in a 2-fold reduction in biochemical progression compared with the DE-EBRT group at a median follow-up of 6.5 years (P < .001). Herein, the primary endpoint and secondary survival endpoints of the ASCENDE-RT trial are updated at a 10-year median follow-up. METHODS: Patients were randomly assigned to either the LDR-PB or the DE-EBRT arm (1:1). All patients received 1 year of androgen deprivation therapy and 46 Gy in 23 fractions of pelvic RT. Patients in the DE-EBRT arm received an additional 32 Gy in 16 fractions, and those in the LDR-PB arm received an 125I implant prescribed to a minimum peripheral dose of 115 Gy. Two hundred patients were randomized to the DE-EBRT arm and 198 to the LDR-PB arm. RESULTS: The 10-year Kaplan-Meier TTP estimate was 85% ± 5% for LDR-PB compared with 67% ± 7% for DE-EBRT (log rank P < .001). Ten-year time to distant metastasis (DM) was 88% ± 5% for the LDR-PB arm and 86% ± 6% for the DE-EBRT arm (P = .56). There were 117 (29%) deaths. Ten-year overall survival (OS) estimates were 80% ± 6% for the LDR-PB arm and 75% ± 7% for the DE-EBRT arm (P = .51). There were 30 (8%) patients who died of prostate cancer: 12 (6%) in the LDR-PB arm, including 2 treatment-related deaths, and 18 (9%) in the DE-EBRT arm. CONCLUSIONS: Men randomized to the LDR-PB boost arm of the ASCENDE-RT trial continue to experience a large advantage in TTP compared with those randomized to the DE-EBRT arm. ASCENDE-RT was not powered to detect differences in its secondary survival endpoints (OS, DM, and time to prostate cancer-specific death) and none are apparent.

Prospective analysis of patient reported symptoms and quality of life in patients with incurable lung cancer treated in a rapid access clinic.

INTRODUCTION: The Vancouver Rapid Access (VARA) clinic was designed to provide palliative radiotherapy and holistic care to patients with incurable lung cancer. Analysis of the pilot phase demonstrated improved radiotherapy wait-times and access to supportive services compared to standard practice. This study aims to prospectively assess the impact of the clinic on patient reported symptoms and quality of life. MATERIALS AND METHODS: Patient assessments are completed at baseline and by a telephone follow up four-weeks later using Likert scales adapted from the Edmonton Symptom Assessment System (scale 0-10) and European Organization for Research and Treatment of Cancer questionnaires (scale 1-4). Patient reported outcomes at follow-up are compared to baseline using wilcoxon signed-rank test for categorical variables and paired sample t-test for continuous variables. RESULTS: Baseline data was collected on 125 patients, 109 received palliative radiotherapy (87%). At the 4 week follow up, 22 patients had died. Seventy-one of the remaining 103 patients completed the follow-up questionnaire, resulting in a 69% response rate among survivors. The mean patient reported overall health score, improved from 4.8 to 6.1 (p<0.01). All respiratory symptoms except chest pain (p=0.06) were associated with a statistically significant improvement after the clinic, whereas all respiratory symptoms improved post radiotherapy. Mean bone pain scores decreased from 5.5 to 2.7 (p<0.01). Assessment of symptoms secondary to brain metastases is limited by small patient numbers. CONCLUSION: The VARA clinic provides timely access to palliative radiotherapy and supportive services resulting in improved patient reported outcomes. Despite a high symptom and disease burden, patients report improved overall health and palliation of respiratory symptoms and bony pain. The studies completed on the VARA clinic to date, continue to support its value in our center.

Volumetric Radiosurgery for 1 to 10 Brain Metastases: A Multicenter, Single-Arm, Phase 2 Study.

PURPOSE: Interest is growing in treating multiple brain metastases with radiosurgery. We report on the effectiveness and tolerability of volumetric radiosurgery (VRS). METHODS AND MATERIALS: We enrolled patients with a ≥6-month estimated life expectancy and 1 to 10 brain metastases with a diameter of ≤3 cm at 5 cancer centers. Volumetric radiosurgery was delivered in 5 fractions with 98% target coverage, prescribed as 95% of 50 Gy (47.5 Gy in 5 fractions) to the metastases with no margin and 95% of 40 Gy (38 Gy in 5 fractions) to their 2-mm planning target volumes, concurrent with 20 Gy to the whole brain planning target volume. The treatment was delivered with daily image guidance using conventional linear accelerators and volumetric modulated arc therapy. A magnetic resonance imaging scan was obtained every 3 months. The primary endpoint was the 3-month objective response in the brain according to the Response Evaluation Criteria in Solid Tumors, version 1.1. The principal secondary endpoint was 1-year actuarial control of treated metastases. Toxicities were graded using the Common Terminology Criteria for Adverse Events, version 4.0. The present study is registered with ClinicalTrials.gov (clinicaltrials.gov identifier NCT01046123). RESULTS: From July 2010 to May 2013, 60 patients underwent VRS with 47.5 Gy in 5 fractions for 12 metastases in the thalamus and basal ganglia (deep metastases) and 207 non-deep metastases. The median follow-up period was 30.5 months, and the median survival was 10.1 months. For the 43 patients assessable at 3 months, the objective response in the brain was 56%. The treated metastases were controlled in 88% of patients at 1 year and 84% at 3 years. Overall survival did not differ for patients with 4 to 10 versus 1 to 3 metastases (hazard ratio 1.18, P=.6). The crude incidence of severe radionecrosis (grade 3-5) was 25% (3 of 12) per deep metastasis, 1.9% (4 of 219) per non-deep metastasis, and 10% (6 of 60) per patient. CONCLUSIONS: For non-deep brain metastases, 47.5 Gy in 5 fractions was tolerable. Volumetric radiosurgery was effective for long-term control of treated brain metastases.

The Vancouver rapid access clinic for palliative lung radiation, providing more than just rapid access.

PURPOSE: The Vancouver Rapid Access (VARA) clinic aimed to deliver urgent palliative radiotherapy (RT) and holistic care to patients with newly diagnosed incurable lung cancer. The purpose of this paper is to describe the 9-month pilot phase of the clinic and to compare its efficacy to standard practice. METHODS: A multidisciplinary team performed the initial consult, and if appropriate, the patient received RT the same day and was connected with supportive services as required. Patient and treatment details were prospectively collected. A retrospective chart review of similar patients in standard practice 1 year prior to VARA was performed. Variables compared between VARA and standard practice included RT wait times and supportive service referrals. RESULTS: During the pilot phase, 58 patients were assessed. Forty percent were inpatients, and 62% had an ECOG 2 or higher. Fifty-four patients received RT; the majority (72%) received RT on the same day as their consultation, compared to 41% in standard practice (p < 0.001). The most common sites treated were the bone (42%), lung (34%), and brain (14%). More than half of VARA patients (54%) were referred to an additional health service such as home care nursing compared to 31% of standard practice patients (p = 0.01). The VARA clinic decreased the proportion of patients double-booked into an oncologists schedule from 23 to 13% (p < 0.001). CONCLUSIONS: The VARA clinic has improved wait times for palliative RT, increased patient access to supportive services, and improved the workload for lung radiation oncologists. This clinic could serve as a model for other patients with incurable cancer.

Late urinary side effects 10 years after low-dose-rate prostate brachytherapy: population-based results from a multiphysician practice treating with a standardized protocol and uniform dosimetric goals.

PURPOSE: To determine late urinary toxicity (>12 months) in a large cohort of uniformly treated low-dose-rate prostate brachytherapy patients. METHODS AND MATERIALS: From 1998 to 2009, 2709 patients with National Comprehensive Cancer Network-defined low-risk and low-tier intermediate-risk prostate cancer were treated with Iodine 125 ((125)I) low-dose-rate prostate brachytherapy; 2011 patients with a minimum of 25 months of follow-up were included in the study. Baseline patients, treatment, implant factors, and late urinary toxicity (Radiation Therapy Oncology Group [RTOG] grading system and International Prostate Symptom Score [IPSS]) were recorded prospectively. Time to IPSS resolution, late RTOG genitourinary toxicity was examined with Kaplan-Meier and log-rank tests. Cox proportional hazards regression was done for individual covariates and multivariable models. RESULTS: Median follow-up was 54.5 months (range, 2-13 years). Actuarial toxicity rates reached 27% and 10% (RTOG ≥2 and ≥3, respectively) at 9-13 years. Symptoms resolved quickly in the majority of patients (88% in 6-12 months). The prevalence of RTOG 0, 1, 2, 3, and 4 toxicity with a minimum of 7 years' follow-up was 70%, 21%, 6.4%, 2.3%, and 0.08%, respectively. Patients with a larger prostate volume, higher baseline IPSS, higher D90, acute toxicity, and age >70 years had more late RTOG ≥2 toxicity (all P≤.02). The IPSS resolved slower in patients with lower baseline IPSS and larger ultrasound prostate volume, those not receiving androgen deprivation therapy, and those with higher D90. The crude rate of RTOG 3 toxicity was 6%. Overall the rate of transurethral resection of the prostate was 1.9%; strictures, 2%; incontinence, 1.3%; severe symptoms, 1.8%; late catheterization, 1.3%; and hematuria, 0.8%. The majority (80%) resolved their symptoms in 6-12 months. CONCLUSION: Long-term urinary toxicity after brachytherapy is low. Although actuarial rates increase with longer follow-up (27% RTOG 2 and 10% RTOG 3 at 13 years), symptoms resolve relatively quickly; between 5 and 13 years' follow-up, >90% of patients have minimal urinary toxicity. Refining patient selection criteria, planning, and treatment delivery may further reduce toxicity.

Whole prostate D90 and V100: a dose-response analysis of 2000 consecutive (125)I monotherapy patients.

PURPOSE: To examine the relationship between whole prostate dose metrics and disease-free survival (DFS) after (125)I low-dose-rate prostate brachytherapy (LDR-PB). METHODS AND MATERIALS: Data for the first 2000 LDR-PB monotherapy implants were extracted from a database containing patient, tumor, dosimetric, and outcomes information. By National Comprehensive Cancer Network criteria, half (n = 1006) had low-risk disease and half (n = 990) had intermediate-risk disease (four had high-risk disease). Most patients (58.4%) and 75.3% of intermediate-risk patients received 3 months neoadjuvant and 3 months concomitant androgen deprivation therapy (ADT). Univariate and multivariate analyses were conducted using recognized prognostic factors and the whole prostate dose metrics D90 (the minimum dose received by 90% of the postimplant CT-based prostate volume) and V100 (the percent of the postimplant CT-based prostate volume that received at least 100% of the prescription dose). RESULTS: The median followup is 5 years (maximum, 12.5 years); the 5-, 7-, and 10-year actuarial DFS estimates are 96.0%, 94.4%, and 93.0%, respectively. Of the recognized prognostic factors, only pretreatment prostate-specific antigen (p = 0.012) and Gleason sum (p = 0.010) were predictive of DFS. When analyzed as continuous variables, dose metrics were not predictive of DFS. However, most nonsignificant trends favored higher doses, and D90 values <130 Gy were predictive of an increased risk of recurrence in the non-ADT subset (N = 833; log rank, p = 0.018). CONCLUSIONS: Although D90 values of <130 Gy were predictive of an increased risk of recurrence in the non-ADT subset, neither D90 nor V100, when used as continuous variables, was predictive of DFS when applied to the entire cohort or in the subset analysis. This observation informs us that dose metrics are not equivalent to oncologic end points and must be calibrated against DFS for each physician and each institution offering LDR-PB.

Population-based 10-year oncologic outcomes after low-dose-rate brachytherapy for low-risk and intermediate-risk prostate cancer.

BACKGROUND: The objective of this study was to report the rates of disease-free survival (DFS), cause-specific survival (CSS), and overall survival after low-dose-rate (LDR) prostate brachytherapy (PB). METHODS: Data from 1006 consecutive patients with prostate cancer who received LDR-PB and underwent implantation on or before October 23, 2003 were extracted from a prospective database on November 11, 2011. The selected patients had low-risk (58%) or intermediate-risk (42%) disease according to National Comprehensive Cancer Network criteria. The Phoenix threshold was used to define biochemical relapse. Sixty-five percent of patients received 3 months of neoadjuvant androgen-deprivation therapy (ADT) and 3 months of concomitant ADT. Univariate and multivariate analyses are reported in relation to patient, tumor, and treatment variables. RESULTS: The median follow-up was 7.5 years. By using Fine and Gray competing risks analysis, the 5-year and 10-year actuarial DFS rates were 96.7% (95% confidence interval, 95.2%-97.7%) and 94.1% (95% confidence interval, 92%-95.6%), respectively. When applied to the whole cohort, none of the usual prognostic variables, including dose metrics, were correlated with DFS. However, in both univariate and multivariate models, increasing dose was the only covariate that correlated with improved DFS for the subset of men (N = 348) who did not receive ADT (P = .043). The actuarial 10-year CSS rate was 99.1% (95% confidence interval, 97.3%-99.7%). The overall survival rate was 93.8% at 5 years (95% confidence interval, 92%-95.1%) and 83.5% at 10 years (95% confidence interval, 79.8%-86.6%). Only age at implantation (P = .0001) was correlated with overall survival in multivariate analysis. CONCLUSIONS: In a consecutive cohort of 1006 men with National Comprehensive Cancer Network low-risk and intermediate-risk prostate cancer, the actuarial rate of recurrent disease after LDR-PB was approximately 3% at 5 years and 6% at 10 years.

Outcomes following iodine-125 brachytherapy in patients with Gleason 7, intermediate risk prostate cancer: a population-based cohort study.

BACKGROUND AND PURPOSE: To evaluate outcome in patients with Gleason 7 prostate cancer treated with iodine-125 brachytherapy at the British Columbia Cancer Agency. MATERIALS AND METHODS: Between 20th July 1998 and 7th February 2006, 1500 patients underwent I-125 prostate brachytherapy without supplemental external beam radiation therapy. Of these, 439 had Gleason 7 disease; 362 had Gleason 3+4 and 77 had 4+3 disease. Generally, patients received 6 months of androgen suppression. We compared biochemical no evidence of disease (bNED) between patients with Gleason ≤ 6 and Gleason 7 and between Gleason 3+4 and 4+3 using the Phoenix definition of biochemical recurrence. RESULTS: Median follow-up was 60 months. Estimated 5 year bNED was 97% for patients with Gleason score ≤ 6 and 94% for patients with Gleason 7 disease (p=0.037). Estimated bNED was 95% and 94% for 3+4 and 4+3, respectively (p=0.791). There was no difference in bNED between implants achieving D90 ≥ versus

Gender comparisons of exercise-induced oxidative stress: influence of antioxidant supplementation.

The purpose of this study was to determine the influence of gender and antioxidant supplementation on exercise-induced oxidative stress. Twenty-five men and 23 women ran for 30 min at 80% VO2 max, once before and once after 2 weeks of supplementation, and again after a 1-week wash-out period. Subjects were randomly assigned to either placebo (P), antioxidant (A: 400 IU vitamin E+1 g vitamin C), or a fruit and vegetable powder (FV) treatment. Blood was obtained at rest and immediately after exercise. Before supplementation, women had higher resting reduced glutathione, total glutathione, and plasma vitamin E compared with men. With both A and FV supplementations, plasma vitamin E gender differences disappeared. Protein carbonyls, oxidized glutathione, and malondialdehyde all increased similarly for both genders in response to exercise. Both A and FV attenuated the reduced glutathione decrease and the oxidized glutathione and protein carbonyls increase compared with P, with no gender differences. 8-hydroxydeoxyguanosine was lower with treatment A compared with FV and P only for men. Plasma vitamin C increased 39% (A) and 21% (FV) compared with P. These data indicate that women have higher resting antioxidant levels than men. Markers of oxidative stress increased similarly in both genders in response to exercise of similar intensity and duration. Two weeks of antioxidant supplementation can attenuate exercise-induced oxidative stress equally in both genders.

Oxidative stress response to aerobic exercise: comparison of antioxidant supplements.

PURPOSE: To compare the effects of two antioxidant formulas on biomarkers of oxidative stress before and after aerobic exercise. METHODS: Aerobically trained men (N=25) and women (N=23) were assigned to one of three treatments: 400 IU of vitamin E+1 g of vitamin C (V; N=15), a fruit and vegetable juice powder concentrate (FV; N=16), or a placebo (P; N=17). Subjects ran for 30 min at 80% VO(2 max) before, after 2 wk of supplementation, and after a 1-wk washout period. Blood samples were taken before and immediately after exercise and analyzed for protein carbonyls (PC), malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), and vitamins C and E. RESULTS: The V treatment increased plasma vitamin C and E after 2 wk (P

Urinary incontinence in prostate cancer patients treated with external beam radiotherapy.

BACKGROUND AND PURPOSE: To describe the incidence of urinary incontinence among prostate cancer patients treated with external beam radiotherapy (RT) and to investigate associated risk factors. PATIENTS AND METHODS: One thousand and hundred ninety-two patients with >or=24 months follow-up were the subjects of this series. All patients received between 50 and 72 Gy in 20-37 fractions (median 66 Gy/33#). Post-RT urinary incontinence was scored by direct patient interviewing according to the modified RTOG/SOMA scale: Grade 1--occasional use of incontinence pads, Grade 2--intermittent use of incontinence pads, Grade 3--persistent use of incontinence pads, and Grade 4--permanent catheter. Risk-factors investigated were: age, diabetes, TURP prior to RT, elapsed time from TURP to RT, clinical stage, RT dose and presence of Grade >or=2 acute GU and GI toxicity. Non-parametric, actuarial univariated (Kaplan-Meier) and multivariated tests (MVA, Cox regression) were performed. RESULTS: Median follow-up for the group is 52 months (24-109). Thirty-four patients (2.9%) had incontinence prior to RT, which was more common in TURP patients (7.8% vs 1.6% P<0.001). These are excluded from further analysis. Fifty-seven patients (4.9%) developed Grade 1 incontinence, 7 (0.6%) Grade 2, and 7 (0.6%) Grade 3. There was no Grade 4 incontinence. Actuarial rates for Grade >or=1 and >or=2 incontinence at 5 years are 7 and 1.7%, respectively. Risk factors on MVA associated with the development of Grade 1 or worse incontinence are pre-RT TURP (5-year rates 10% vs 6%, P=0.026), presence of Grade >or=2 acute GU toxicity (5-year rates 11% vs 5%, P=0.002). Age, diabetes, clinical stage, elapsed time from TURP to RT, RT dose or fraction size, acute GI toxicity were not significant. Patients who underwent post-RT TURP or dilatation for obstructive symptoms (4.3%), were more likely to develop Grade 2-3 incontinence (5-year rate 8 vs 1.5%, P=0.0015). CONCLUSIONS: Grade 2 or greater urinary incontinence is rare among patients who have been treated with external beam radiotherapy. Associated risk factors are pre-RT TURP and the presence of increased acute GU toxicity. Post-radiaton TURP increases the risk of incontinence five-fold.

Combined antioxidant treatment effects on blood oxidative stress after eccentric exercise.

PURPOSE: This study was designed to ascertain the effects of a combination antioxidant therapy on plasma protein carbonyls (PC), malondialdehyde (MDA), and whole blood total (TGSH), oxidized (GSSG), and reduced (GSH) glutathione in non-resistance trained females after eccentric resistance exercise. METHODS: Eighteen women (aged 19-31 yr) were randomized in a double-blind manner to either an antioxidant supplement (N = 9; 400 IU vitamin E, 1 g vitamin C, and 90 mug selenium per day) or a lactose placebo (N = 9) for 14 d before and for 2 d after eccentric elbow flexor exercise. Blood samples taken before and immediately, 2, 6, 24, and 48 h postexercise were analyzed for PC, MDA, TGSH, and GSSG. RESULTS: No treatment by time interaction was noted for any variable, with all blood markers experiencing a change after the exercise in both conditions. Time main effects were observed for PC, MDA, and GSSG, with values elevated above preexercise after the eccentric exercise, whereas GSH concentration decreased after the eccentric exercise. Antioxidant supplementation resulted in a condition main effect for PC and MDA, with lower values compared with placebo. The antioxidant treatment attenuated the rise in both PC (75%) and MDA (100%). CONCLUSION: These data suggest that eccentric resistance exercise can increase blood biomarkers of oxidative stress in non-resistance trained females, and this vitamin E, C, and selenium supplementation can attenuate the rise in PC and MDA.

Oxidative stress response in normal and antioxidant supplemented rats to a downhill run: changes in blood and skeletal muscles.

The purpose of this study was to determine if changes in oxidative stress biomarkers in blood and skeletal muscles are similar in normal and antioxidant supplemented rats after a downhill run. Sixty-six male Sprague-Dawley rats were pretreated with a normal rat diet or diet + antioxidants (2,000 mg vitamin C + 1,000 IU vitamin E/kg diet) for 2 weeks. Exercised rats ran 90 min on a rodent treadmill at a speed of 16 m/min at -16 degrees grade. Rats were sacrificed either at rest, immediately, 2 hrs, or 48 hrs postexercise. Malondialdehyde (MDA) and protein carbonyl (PC) concentrations and glutathione status in blood, vastus lateralis (white fast-twitch), vastus intermedius (red fast-twitch), and soleus (slow-twitch) muscles were determined. A significant increase from rest in PC occurred in plasma, vastus intermedius and soleus muscle 2 hrs after the downhill run (p < 0.05), with no changes observed at any other times postexercise. Antioxidant supplementation significantly decreased PC concentrations in both vastus intermedius and soleus muscles at all times combined (p < 0.05). MDA and glutathione status in blood and muscles were unaffected by either the downhill run or antioxidant treatment. For PC and MDA, the concentrations were lower in blood as compared to skeletal muscle, with the opposite finding for oxidized glutathione; however, the pattern of response postexercise was similar. These data indicate that (a) PC, but not MDA or oxidized glutathione, is elevated transiently following downhill running in male rats; (b) the elevation in PC postexercise occurs in plasma, vastus intermedius, and soleus muscles; (c) antioxidant therapy can attenuate PC in vastus intermedius, and soleus muscles; and (d) while the concentrations of oxidative stress biomarkers differ between blood and the various skeletal muscles, the pattern of response postexercise is similar.

Effects of antioxidant therapy in women exposed to eccentric exercise.

The purpose of this study was to determine the effects of antioxidant therapy on indirect markers of muscle damage following eccentric exercise (EE). Eighteen women were randomized to an antioxidant supplement or a placebo before a bout of EE. Plasma creatine kinase (CK) activity, muscle soreness (MS), maximal isometric force (MIF), and range of motion (ROM) were assessed before and through 14 d postexercise. Eccentric exercise resulted in an increase in CK activity and MS, and a drop in MIF and ROM during the days following EE, which returned to baseline values 14 d after EE in both groups. Antioxidants attenuated the CK activity and MS response to the EE, while little difference was noted between groups in MIF or ROM. These findings suggest that antioxidant supplementation was helpful in reducing the elevations in plasma CK activity and MS, with little impact on MIF and ROM loss.