Is Ultrahypofractionated Whole Pelvis Radiation Therapy (WPRT) as Well Tolerated as Conventionally Fractionated WPRT in Patients With Prostate Cancer? Early Results From the HOPE Trial.

OBJECTIVE: The aim of this work was to evaluate the acute toxicity and quality-of-life (QOL) impact of ultrahypofractionated whole pelvis radiation therapy (WPRT) compared with conventional WPRT fractionation after high-dose-rate prostate brachytherapy (HDR-BT). METHODS AND MATERIALS: The HOPE trial is a phase 2, multi-institutional randomized controlled trial of men with prostate-confined disease and National Comprehensive Cancer Network unfavorable intermediate-, high-, or very-high-risk prostate cancer. Patients were randomly assigned to receive conventionally fractionated WPRT (standard arm) or ultrahypofractionated WPRT (experimental arm) in a 1:1 ratio. All patients underwent radiation therapy with 15 Gy HDR-BT boost in a single fraction followed by WPRT delivered with conventional fractionation (45 Gy in 25 daily fractions or 46 Gy in 23 fractions) or ultrahypofractionation (25 Gy in 5 fractions delivered on alternate days). Acute toxicities measured during radiation therapy and at 6 weeks posttreatment were assessed using the clinician-reported Common Terminology Criteria for Adverse Events version 5.0, and QOL was measured using the Expanded Prostate Cancer Index Composite (EPIC-50) and International Prostate Symptom Score (IPSS). RESULTS: A total of 80 patients were enrolled and treated across 3 Canadian institutions, of whom 39 and 41 patients received external radiation therapy with conventionally fractionated and ultrahypofractionated WPRT, respectively. All patients received androgen deprivation therapy except for 2 patients treated in the ultrahypofractionated arm. The baseline clinical characteristics of the 2 arms were similar, with 51 (63.8%) patients having high or very-high-risk prostate cancer disease. Treatment was well tolerated with no significant differences in the rate of acute adverse events between arms. No grade 4 adverse events or treatment-related deaths were reported. Ultrahypofractionated WPRT had a less detrimental impact on the EPIC-50 bowel total, function, and bother domain scores compared with conventional WPRT in the acute setting. By contrast, more patients treated with ultrahypofractionated WPRT reached the minimum clinical important difference on the EPIC-50 urinary domains. No significant QOL differences between arms were noted in the sexual and hormonal domains. CONCLUSIONS: Ultrahypofractionated WPRT after HDR-BT is a well-tolerated treatment strategy in the acute setting that has less detrimental impact on bowel QOL domains compared with conventional WPRT.

Low dose rate brachytherapy for primary treatment of localized prostate cancer: A systemic review and executive summary of an evidence-based consensus statement.

PURPOSE: The purpose of this guideline is to present evidence-based consensus recommendations for low dose rate (LDR) permanent seed brachytherapy for the primary treatment of prostate cancer. METHODS AND MATERIALS: The American Brachytherapy Society convened a task force for addressing key questions concerning ultrasound-based LDR prostate brachytherapy for the primary treatment of prostate cancer. A comprehensive literature search was conducted to identify prospective and multi-institutional retrospective studies involving LDR brachytherapy as monotherapy or boost in combination with external beam radiation therapy with or without adjuvant androgen deprivation therapy. Outcomes included disease control, toxicity, and quality of life. RESULTS: LDR prostate brachytherapy monotherapy is an appropriate treatment option for low risk and favorable intermediate risk disease. LDR brachytherapy boost in combination with external beam radiation therapy is appropriate for unfavorable intermediate risk and high-risk disease. Androgen deprivation therapy is recommended in unfavorable intermediate risk and high-risk disease. Acceptable radionuclides for LDR brachytherapy include iodine-125, palladium-103, and cesium-131. Although brachytherapy monotherapy is associated with increased urinary obstructive and irritative symptoms that peak within the first 3 months after treatment, the median time toward symptom resolution is approximately 1 year for iodine-125 and 6 months for palladium-103. Such symptoms can be mitigated with short-term use of alpha blockers. Combination therapy is associated with worse urinary, bowel, and sexual symptoms than monotherapy. A prostate specific antigen <= 0.2 ng/mL at 4 years after LDR brachytherapy may be considered a biochemical definition of cure. CONCLUSIONS: LDR brachytherapy is a convenient, effective, and well-tolerated treatment for prostate cancer.

Dose to the dominant intraprostatic lesion using HDR vs. LDR monotherapy: A Phase II randomized trial.

PURPOSE: To present the dosimetric results of a Phase II randomized trial comparing dose escalation to the MRI-defined dominant intraprostatic lesion (DIL) using either low-dose-rate (LDR) or high-dose-rate (HDR) prostate brachytherapy. MATERIAL AND METHODS: Patients receiving prostate brachytherapy as monotherapy were randomized to LDR or HDR brachytherapy. Prostate and DILs were contoured on preoperative multiparametric MRI. These images were registered with transrectal ultrasound for treatment planning. LDR brachytherapy was preplanned using I-125 seeds. HDR brachytherapy used intraoperative transrectal ultrasound-based planning to deliver 27 Gy/2 fractions in separate implants. DIL location was classified as peripheral, central, or anterior. A student t-test compared DIL D90 between modalities and DIL locations. RESULTS: Of 60 patients, 31 underwent LDR and 29 HDR brachytherapy. Up to three DILs were identified per patient (100 total) with 74 peripheral, six central, and 20 anterior DILs. Mean DIL volume was 1.9 cc (SD: 1.7 cc) for LDR and 1.6 cc (SD 1.3 cc) for HDR (p = 0.279). Mean DIL D90 was 151% (SD 30%) for LDR and 132% (SD 13%) for HDR. For LDR, mean peripheral DIL D90 was 159% (SD 27%) and central or anterior 127% (SD 13%). HDR peripheral DILs received 137% (SD 12%) and central or anterior 119% (SD 7%). DIL D90 for peripheral lesions was higher than anterior and central (p < 0.001). CONCLUSIONS: DIL location affects dose escalation, particularly because of urethral proximity, such as for anterior and central DILs. HDR brachytherapy may dose escalate better when target DIL is close to critical organs.

External validation of the ProCaRS nomograms and comparison of existing risk-stratification tools for localized prostate cancer.

INTRODUCTION: The purpose of this study was to perform a direct comparison of several existing risk-stratification tools for localized prostate cancer in terms of their ability to predict for biochemical failure-free survival (BFFS). Two large databases were used and an external validation of two recently developed nomograms on an independent cohort was also performed in this analysis. METHODS: Patients who were treated with external beam radiotherapy (EBRT) and/or brachytherapy for localized prostate cancer were selected from the multi-institutional Genitourinary Radiation Oncologists of Canada (GUROC) Prostate Cancer Risk Stratification (ProCaRS) database (n=7974) and the Centre Hospitalier de l'Université de Montréal (CHUM) validation database (n=2266). The primary outcome was BFFS using the Phoenix definition. Concordance index (C-index) reported from Cox proportional hazards regression using 10-fold cross validation and decision curve analysis (DCA) were used to predict BFFS. RESULTS: C-index identified Cancer of the Prostate Risk Assessment (CAPRA) score and ProCaRS as superior to the historical GUROC and National Comprehensive Cancer Network (NCCN) risk-stratification systems. CAPRA modeled as five and three categories were superior to GUROC and NCCN only for the CHUM database. C-indices for CAPRA score, ProCaRS, GUROC, and NCCN were 0.72, 0.72, 0.71, and 0.72, respectively, for the ProCaRS database, and 0.66, 0.63, 0.57, and 0.60, respectively, for the CHUM database. However, many of these comparisons did not demonstrate a clinically meaningful difference. DCA identified minimal differences across the different risk-stratification systems, with no system emerging with optimal net benefit. External validation of the ProCaRS nomograms yielded favourable calibrations of R2=0.778 (low-dose rate [LDR]-brachytherapy) and R2=0.868 (EBRT). CONCLUSIONS: This study externally validated two ProCaRS nomograms for BFFS that may help clinicians in treatment selection and outcome prediction. A direct comparison between existing risk-stratification tools demonstrated minimal clinically significant differences in discriminative ability between the systems, favouring the CAPRA and ProCaRS systems. The incorporation of novel prognostic variables, such as genomic markers, is needed.

Long-term results of an RTOG Phase II trial (00-19) of external-beam radiation therapy combined with permanent source brachytherapy for intermediate-risk clinically localized adenocarcinoma of the prostate.

PURPOSE: External-beam radiation therapy combined with low-doserate permanent brachytherapy are commonly used to treat men with localized prostate cancer. This Phase II trial was performed to document late gastrointestinal or genitourinary toxicity as well as biochemical control for this treatment in a multi-institutional cooperative group setting. This report defines the long-term results of this trial. METHODS AND MATERIALS: All eligible patients received external-beam radiation (45 Gy in 25 fractions) followed 2-6 weeks later by a permanent iodine 125 implant of 108 Gy. Late toxicity was defined by the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late radiation morbidity scoring scheme. Biochemical control was defined by the American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus definition and the ASTRO Phoenix definition. RESULTS: One hundred thirty-eight patients were enrolled from 20 institutions, and 131 were eligible. Median follow-up (living patients) was 8.2 years (range, 2.7-9.3 years). The 8-year estimate of late grade >3 genitourinary and/or gastrointestinal toxicity was 15%. The most common grade >3 toxicities were urinary frequency, dysuria, and proctitis. There were two grade 4 toxicities, both bladder necrosis, and no grade 5 toxicities. In addition, 42% of patients complained of grade 3 impotence (no erections) at 8 years. The 8-year estimate of biochemical failure was 18% and 21% by the Phoenix and ASTRO consensus definitions, respectively. CONCLUSION: Biochemical control for this treatment seems durable with 8 years of follow-up and is similar to high-dose external beam radiation alone or brachytherapy alone. Late toxicity in this multi-institutional trial is higher than reports from similar cohorts of patients treated with high-dose external-beam radiation alone or permanent low-doserate brachytherapy alone, perhaps suggesting further attention to strategies that limit doses to normal structures or to unimodal radiotherapy techniques.

The efficacy of hyperbaric oxygen therapy in the treatment of medically refractory soft tissue necrosis after penile brachytherapy.

PURPOSE: Soft tissue necrosis is reported in up to 26% of patients undergoing radiotherapy for penile cancer. Management options include local irrigation, wound debridement, antibiotics, anti-inflammatory medication, and analgesics. Refractory lesions may be treated with partial penectomy. Hyperbaric oxygen therapy (HBO) has a well-defined role in the treatment of late radiation toxicities. We present experience with HBO for medically refractory soft tissue necrosis after penile brachytherapy. METHODS AND MATERIALS: From November 2001 to January 2009, 7 men of 43 treated with penile brachytherapy for squamous carcinoma developed refractory soft tissue necrosis and were treated with HBO. All had received a prescribed dose of 60 Gy through interstitial brachytherapy using Paris system guidelines. All had failed conservative medical therapies for soft tissue necrosis. RESULTS: Median age was 55 years (range, 35-72 years). Comorbidities potentially effecting wound healing included hypertension (2), current smokers (5), former smoker (1) but no diabetes mellitus, or peripheral vascular disease. Median time between completion of brachytherapy and appearance of soft tissue necrosis was 13 months (range, 9-24 months) and the median interval before starting HBO was 7.5 months (range, 3-13 months). The median number of "dives" per HBO course was 40 (30-53). All 7 experienced an excellent response with healing of the necrosis and resolution of symptoms, although 3 required an additional course, 2 for consolidation of healing, and 1 for a relapse 4 months later. No patient was submitted to penectomy. CONCLUSIONS: HBO should be considered as a treatment option in patients with refractory soft tissue necrosis of the penis after brachytherapy.

Median 5 year follow-up of 125iodine brachytherapy as monotherapy in men aged

OBJECTIVES: To report the genitourinary (GU) and gastrointestinal (GI) toxicity rates, erectile function preservation, and biochemical outcome (bNED) in men aged

Sequential comparison of seed loss and prostate dosimetry of stranded seeds with loose seeds in 125I permanent implant for low-risk prostate cancer.

PURPOSE: To compare stranded seeds (SSs) with loose seeds (LSs) in terms of prostate edema, dosimetry, and seed loss after (125)I brachytherapy. METHODS AND MATERIALS: Two prospective cohorts of 20 men participated in an institutional review board-approved protocols to study postimplant prostate edema and its effect on dosimetry. The LS cohort underwent brachytherapy between September 2002 and July 2003 and the SS cohort between April 2006 and January 2007. Both cohorts were evaluated sequentially using computed tomography-magnetic resonance imaging fusion-based dosimetry on Days 0, 7, and 30. No hormonal therapy or supplemental beam radiotherapy was used. RESULTS: Prostate edema was less in the SS cohort at all points (p = NS). On Day 0, all the prostate dosimetric factors were greater in the LS group than in the SS group (p = 0.003). However, by Days 7 and 30, the dosimetry was similar between the two cohorts. No seeds migrated to the lung in the SS cohort compared with a total of five seeds in 4 patients in the LS cohort. However, the overall seed loss was greater in the SS cohort (24 seeds in 6 patients; 1.1% of total vs. 0.6% for LSs), with most seeds lost through urine (22 seeds in 5 patients). CONCLUSION: Despite elimination of venous seed migration, greater seed loss was observed with SSs compared with LSs, with the primary site of loss being the urinary tract. Modification of the technique might be necessary to minimize this. Prostate dosimetry on Days 7 and 30 was similar between the SS and LS cohorts.

Long-term urinary sequelae following 125iodine prostate brachytherapy.

PURPOSE: We describe long-term urinary function in men treated with 125iodine brachytherapy without supplemental beam irradiation. MATERIALS AND METHODS: A total of 484 men with favorable risk prostate cancer received 125I prostate brachytherapy with a followup ranging from 12 to 93 months (median 41). Prior hormonal therapy (2 to 6 months) was used in 14% of patients to reduce prostate size. Urinary function was assessed before implant by the International Prostate Symptom Score and a voiding study, and in followup by International Prostate Symptom Score. Urinary retention and catheterization, urgency and urge incontinence, persistently increased International Prostate Symptom Score, stricture, and the need for surgical intervention are reported. RESULTS: Beyond 1 year 73.3% of men had no significant urinary sequelae. A flare in the International Prostate Symptom Score to greater than 15 and at least 5 points above baseline occurred in 23%, lasting a median of 3 months. Symptoms of retention requiring catheterization or surgical intervention were seen in 3.4% (1.7% stricture, 0.4% transurethral resection of the prostate, 2.7% catheter). Of the 13 men requiring catheterization at any time after 1 year, 5 (1% of total) remain dependent on clean intermittent catheterization. Median duration of catheter use for those with resolution is 4.5 months. Moderate to severe urinary urgency occurred in 6.4% of patients but it was unresponsive to anticholinergics in only 0.8%. CONCLUSIONS: In this group 27% of men experienced late urinary morbidity following 125I prostate brachytherapy. Rates may vary according to technique and selection factors. The majority responded well to medical or surgical intervention, with 0.8% persistent urgency, and 1% catheter dependence.

PSA kinetics and PSA bounce following permanent seed prostate brachytherapy.

PURPOSE: To report the incidence, timing, and magnitude of the benign prostate-specific antigen (PSA) bounce after 125I prostate brachytherapy and correlate the bounce with clinical and/or dosimetric factors. METHODS AND MATERIALS: From March 1999 to August 2003, a total of 292 men received 125I prostate brachytherapy without androgen deprivation or supplemental beam radiotherapy and have PSA follow-up >30 months. Implants were preplanned using transrectal ultrasound (TRUS) and performed under transrectal ultrasound/fluoroscopy guidance using preloaded needles. A PSA bounce is defined as an increase >or=0.2 ng/ml with spontaneous return to prebounce level or lower. RESULTS: Resolved PSA bounces were seen in 40% of men with follow-up >30 months. Median onset was 15 months, and median magnitude was 0.76 ng/ml. Magnitude >2 ng/ml was seen in 15%. The only clinical or dosimetric factor predictive of bounce in multivariate analysis was younger age. Median time to increasing PSA level indicative of failure was 30 months. CONCLUSIONS: Benign PSA bounces are common after 125I prostate brachytherapy, especially in younger men. An increase >2 ng/ml above the nadir was seen in 15%. Magnitude of increase does not distinguish bounce from failure. Time to the start of the PSA increase can be helpful, but is not absolute. The PSA bounce does not predict subsequent failure. Caution is advised in interpreting an early increasing PSA level in the first 30 months after 125I brachytherapy in favorable-risk patients.