Hyaluronic Acid Spacer for Hypofractionated Prostate Radiation Therapy: A Randomized Clinical Trial.

Importance: Hypofractionated radiation therapy (RT) for prostate cancer has been associated with greater acute grade 2 gastrointestinal (GI) toxic effects compared with conventionally fractionated RT. Objective: To evaluate whether a hyaluronic acid rectal spacer could (1) improve rectal dosimetry and (2) affect acute grade 2 or higher GI toxic effects for hypofractionated RT. Design, Setting, and Participants: This randomized clinical trial was conducted from March 2020 to June 2021 among 12 centers within the US, Australia, and Spain, with a 6-month follow-up. Adult patients with biopsy-proven, T1 to T2 prostate cancer with a Gleason score 7 or less and prostate-specific antigen level of 20 ng/mL or less (to convert to µg/L, multiply by 1) were blinded to the treatment arms. Of the 260 consented patients, 201 patients (77.3%) were randomized (2:1) to the presence or absence of the spacer. Patients were stratified by intended 4-month androgen deprivation therapy use and erectile quality. Main Outcomes and Measures: For the primary outcome, we hypothesized that more than 70% of patients in the spacer group would achieve a 25% or greater reduction in the rectal volume receiving 54 Gy (V54). For the secondary outcome, we hypothesized that the spacer group would have noninferior acute (within 3 months) grade 2 or higher GI toxic effects compared with the control group, with a margin of 10%. Results: Of the 201 randomized patients, 8 (4.0%) were Asian, 26 (12.9%) Black, 42 (20.9%) Hispanic or Latino, and 153 (76.1%) White; the mean (SD) age for the spacer group was 68.6 (7.2) years and 68.4 (7.3) years for the control group. For the primary outcome, 131 of 133 (98.5%; 95% CI, 94.7%-99.8%) patients in the spacer group experienced a 25% or greater reduction in rectum V54, which was greater than the minimally acceptable 70% (P < .001). The mean (SD) reduction was 85.0% (20.9%). For the secondary outcome, 4 of 136 patients (2.9%) in the spacer group and 9 of 65 patients (13.8%) in the control group experienced acute grade 2 or higher GI toxic effects (difference, -10.9%; 95% 1-sided upper confidence limit, -3.5; P = .01). Conclusions and Relevance: The trial results suggest that rectal spacing with hyaluronic acid improved rectal dosimetry and reduced acute grade 2 or higher GI toxic effects. Rectal spacing should potentially be considered for minimizing the risk of acute grade 2 or higher toxic effects for hypofractionated RT. Trial Registration: ClinicalTrials.gov Identifier: NCT04189913.

177Lu-Prostate-Specific Membrane Antigen Ligand After 223Ra Treatment in Men with Bone-Metastatic Castration-Resistant Prostate Cancer: Real-World Clinical Experience.

We analyzed real-world clinical outcomes of sequential α-/ß-emitter therapy for metastatic castration-resistant prostate cancer (mCRPC). Methods: We assessed safety and overall survival in 26 patients who received 177Lu-prostate-specific membrane antigen ligand (177Lu-PSMA) after 223Ra in the ongoing noninterventional REASSURE study (223Ra α-Emitter Agent in Nonintervention Safety Study in mCRPC Population for Long-Term Evaluation; NCT02141438). Results: Patients received 223Ra for a median of 6 injections and subsequent 177Lu-PSMA for a median of 3.5 mo (≥ the fourth therapy in 69%). The median time between 223Ra and 177Lu-PSMA treatment was 8 mo (range, 1-31 mo). Grade 3 hematologic events occurred in 9 of 26 patients (during or after 177Lu-PSMA treatment in 5/9 patients; 8/9 patients had also received docetaxel). Median overall survival was 28.0 mo from the 223Ra start and 13.2 mo from the 177Lu-PSMA start. Conclusion: Although the small sample size precludes definitive conclusions, these preliminary data, especially the 177Lu-PSMA treatment duration, suggest that the use of 177Lu-PSMA after 223Ra is feasible in this real-world setting.

The Oral Gonadotropin-releasing Hormone Receptor Antagonist Relugolix as Neoadjuvant/Adjuvant Androgen Deprivation Therapy to External Beam Radiotherapy in Patients with Localised Intermediate-risk Prostate Cancer: A Randomised, Open-label, Parallel-group Phase 2 Trial.

BACKGROUND: External beam radiotherapy (EBRT) with neoadjuvant/adjuvant androgen deprivation therapy (ADT) is an established treatment option to prolong survival for patients with intermediate- and high-risk prostate cancer (PCa). Relugolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, was evaluated in this clinical setting in comparison with degarelix, an injectable GnRH antagonist. OBJECTIVE: To evaluate the safety and efficacy of relugolix to achieve and maintain castration. DESIGN, SETTING, AND PARTICIPANTS: A phase 2 open-label study was conducted in 103 intermediate-risk PCa patients undergoing primary EBRT and neoadjuvant/adjuvant ADT between June 2014 and December 2015. INTERVENTION: Patients randomly assigned (3:2) to 24-wk treatment with either daily oral relugolix or 4-wk subcutaneous depot degarelix (reference control). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the rate of effective castration (testosterone <1.73nmol/l) in relugolix patients between 4 and 24 wk of treatment. Secondary endpoints included rate of profound castration (testosterone <0.7nmol/l), prostate-specific antigen (PSA) levels, prostate volume, quality of life (QoL) assessed using the Aging Males' Symptoms scale, and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (30-item EORTC core questionnaire [EORTC QLQ-C30] and 25-item EORTC prostate cancer module [EORTC QLQ-PR25]) questionnaires, and safety. No formal statistical comparisons with degarelix were planned. RESULTS AND LIMITATIONS: Castration rates during treatment were 95% and 82% with relugolix and 89% and 68% with degarelix for 1.73 and 0.7nmol/l thresholds, respectively. Median time to castration in the relugolix arm was 4 d. During treatment, PSA levels and prostate volumes were reduced in both groups. Three months after discontinuing treatment, 52% of men on relugolix and 16% on degarelix experienced testosterone recovery (statistical significance of differences not tested). Mean and median QoL scores improved following treatment discontinuation. The most common adverse event was hot flush (relugolix 57%; degarelix 61%). Lack of blinding was a potential limitation. CONCLUSIONS: Relugolix achieved testosterone suppression to castrate levels within days and maintained it over 24 wk with a safety profile consistent with its mechanism of action. PATIENT SUMMARY: Oral once-daily relugolix may be a novel oral alternative to injectable androgen deprivation therapies.

Who Benefits From a Prostate Rectal Spacer? Secondary Analysis of a Phase III Trial.

PURPOSE: Previously a phase III trial of a hydrogel rectal spacer during prostate radiation therapy found decreased toxicity and a clinically significant improvement in bowel quality of life (QOL) at 3 years by the Expanded Prostate Cancer Index. We performed a secondary analysis to identify men less likely to benefit. METHODS AND MATERIALS: Clinical and dosimetric data for the 222 patients enrolled on the SpaceOAR phase III trial were analyzed. The volume of rectum treated to 70 Gy (V70) and the quantitative analysis of normal tissue effects in the clinic (QUANTEC) rectal dose goals were used as surrogates for clinical benefit and plan quality. Mean bowel QOL was assessed at 15 and 36 months posttreatment and the likelihood of 1× (5 points) or 2× (10 points) minimally important difference changes were assessed. RESULTS: Rectal V70 was correlated with physician scored toxicity (P = .033) and was used as a surrogate for plan quality. There was no correlation between prostate volume and rectal V70 (r = 0.077). Rectal V70 pre- and post-hydrogel was 13% and 3% for the smallest prostates (<40 mL) and 12% and 2% for the largest (>80 mL). The relative reduction in rectal V70 of 78% did not vary by prespacer V70, but the absolute reduction was greater for a higher V70. All spacer plans met the 5 QUANTEC rectal dose constraints, although 92% of control plans met all constraints. At 3 years, those not meeting all QUANTEC goals had a 15.0-point (standard deviation 15.1) decline, control patients meeting QUANTEC goals had a 4.0-point (9.5) decline, and spacer had >0.5 (7.6; P < .01). Previous surgery was not correlated with QOL (P = .8). Across prognostic groups, including age, body mass index, previous surgery, target volume, or quality of radiation plans, there was no statistically significant heterogeneity in the relative benefit of spacer in decreasing the risk of 1× or 2× the minimally important difference declines. CONCLUSIONS: There was little heterogeneity in the likelihood of spacer reducing the risk of declines in bowel QOL across clinical and dosimetric variables. Even for the >95% of plans meeting QUANTEC rectal criteria, hydrogel spacer provided potentially meaningful benefits.

Sexual quality of life following prostate intensity modulated radiation therapy (IMRT) with a rectal/prostate spacer: Secondary analysis of a phase 3 trial.

BACKGROUND: We previously reported the results of a phase 3 trial evaluating a prostate/rectal hydrogel spacer during prostate intensity modulated radiation therapy, which resulted in decreased rectal dose and toxicity and less decline in bowel quality of life (QOL). A secondary analysis was performed to correlate penile bulb dose and sexual QOL. METHODS AND MATERIALS: Sexual QOL was measured with the Expanded Prostate Cancer Index Composite (EPIC) by mean scores, the proportion of patients with a minimal clinically important difference (MID), and analyses of the different items composing the sexual domain. RESULTS: A total of 222 men enrolled with median follow-up of 37 months. Hydrogel reduced penile bulb mean dose, maximum dose, and percentage of penile bulb receiving 10 to 30 Gy (all P < .05) with mean dose indirectly correlated with erections sufficient for intercourse at 15 months (P = .03). Baseline EPIC was low (53 [standard deviation ± 24]) with no difference between arms (P > .1). A total of 41% (88/222) of men had adequate baseline sexual QOL (EPIC >60 (mean, 77 [± 8.3]). This subgroup at 3 years had better sexual function (P = .03) with a spacer with a smaller difference in sexual bother (P = .1), which resulted in a higher EPIC summary on the spacer arm (58 [±24.1] vs control 45 [± 24.4]) meeting threshold for MID without statistical significance (P = .07). There were statistically nonsignificant differences favoring spacer for the proportion of men with MID and 2× MID declines in sexual QOL with 53% vs 75% having an 11-point decline (P = .064) and 41% vs 60% with a 22-point decline (P = .11). At 3 years, more men potent at baseline and treated with spacer had "erections sufficient for intercourse" (control 37.5% vs spacer 66.7%, P = .046) as well as statistically higher scores on 7 of 13 items in the sexual domain (all P < .05). CONCLUSIONS: The use of a hydrogel spacer decreased dose to the penile bulb, which was associated with improved erectile function compared with the control group based on patient-reported sexual QOL.

Continued Benefit to Rectal Separation for Prostate Radiation Therapy: Final Results of a Phase III Trial.

PURPOSE: SpaceOAR, a Food and Drug Administration-approved hydrogel intended to create a rectal-prostate space, was evaluated in a single-blind phase III trial of image guided intensity modulated radiation therapy. A total of 222 men were randomized 2:1 to the spacer or control group and received 79.2 Gy in 1.8-Gy fractions to the prostate with or without the seminal vesicles. The present study reports the final results with a median follow-up period of 3 years. METHODS AND MATERIALS: Cumulative (Common Terminology Criteria for Adverse Events, version 4.0) toxicity was evaluated using the log-rank test. Quality of life (QOL) was examined using the Expanded Prostate Cancer Index Composite (EPIC), and the mean changes from baseline in the EPIC domains were tested using repeated measures models. The proportions of men with minimally important differences (MIDs) in each domain were tested using repeated measures logistic models with prespecified thresholds. RESULTS: The 3-year incidence of grade ≥1 (9.2% vs 2.0%; P=.028) and grade ≥2 (5.7% vs 0%; P=.012) rectal toxicity favored the spacer arm. Grade ≥1 urinary incontinence was also lower in the spacer arm (15% vs 4%; P=.046), with no difference in grade ≥2 urinary toxicity (7% vs 7%; P=0.7). From 6 months onward, bowel QOL consistently favored the spacer group (P=.002), with the difference at 3 years (5.8 points; P<.05) meeting the threshold for a MID. The control group had a 3.9-point greater decline in urinary QOL compared with the spacer group at 3 years (P<.05), but the difference did not meet the MID threshold. At 3 years, more men in the control group than in the spacer group had experienced a MID decline in bowel QOL (41% vs 14%; P=.002) and urinary QOL (30% vs 17%; P=.04). Furthermore, the control group were also more likely to have experienced large declines (twice the MID) in bowel QOL (21% vs 5%; P=.02) and urinary QOL (23% vs 8%; P=.02). CONCLUSIONS: The benefit of a hydrogel spacer in reducing the rectal dose, toxicity, and QOL declines after image guided intensity modulated radiation therapy for prostate cancer was maintained or increased with a longer follow-up period, providing stronger evidence for the benefit of hydrogel spacer use in prostate radiation therapy.

Hydrogel Spacer Application Technique, Patient Tolerance and Impact on Prostate Intensity Modulated Radiation Therapy: Results from a Prospective, Multicenter, Pivotal Randomized Controlled Trial.

INTRODUCTION: We evaluate the safety, tolerability and impact on therapy of an absorbable hydrogel perirectal spacer (SpaceOAR® system) designed to reduce the rectal radiation dose during prostate cancer radiotherapy. METHODS: A multicenter, pivotal, randomized controlled trial was conducted in 222 men with stage T1 or T2 prostate cancer treated to 79.2 Gy with image guided intensity modulated radiation therapy in 44 fractions. Patients were randomized 2:1 to receive fiducial markers and perirectal spacer injection (spacer group) or fiducial markers alone (control group). Spacer placement, tolerability, perirectal space creation, impact on rectal dose and impact on quality of life were assessed. RESULTS: Most spacer procedures were conducted with the patient under general or local anesthesia. Procedures were rated easy or very easy in 98.7% of cases with a 99.3% success rate. Mild transient rectal events were noted in 10% of patients in the spacer group (eg pain, discomfort). Mean perirectal space was 12.6 mm after implant and 10.9 mm at 12.4 weeks with absorption at 12 months. A 25% or greater reduction in rectal V70 dose was produced in 97.3% of patients in the spacer group. The spacer group experienced a significant reduction in late rectal toxicity severity (p=0.044) as well as lower rates of decrease in bowel quality of life at 6, 12 and 15 months compared to the control group. There were no unanticipated adverse spacer effects or spacer related adverse events. CONCLUSIONS: Hydrogel spacer application was straightforward and repeatable, resulting in consistent perirectal space creation and rectal dose reduction. Spacer application has the potential to improve prostate radiotherapy outcomes and enable advanced radiotherapy protocols.

Hydrogel Spacer Prospective Multicenter Randomized Controlled Pivotal Trial: Dosimetric and Clinical Effects of Perirectal Spacer Application in Men Undergoing Prostate Image Guided Intensity Modulated Radiation Therapy.

PURPOSE: Perirectal spacing, whereby biomaterials are placed between the prostate and rectum, shows promise in reducing rectal dose during prostate cancer radiation therapy. A prospective multicenter randomized controlled pivotal trial was performed to assess outcomes following absorbable spacer (SpaceOAR system) implantation. METHODS AND MATERIALS: Overall, 222 patients with clinical stage T1 or T2 prostate cancer underwent computed tomography (CT) and magnetic resonance imaging (MRI) scans for treatment planning, followed with fiducial marker placement, and were randomized to receive spacer injection or no injection (control). Patients received postprocedure CT and MRI planning scans and underwent image guided intensity modulated radiation therapy (79.2 Gy in 1.8-Gy fractions). Spacer safety and impact on rectal irradiation, toxicity, and quality of life were assessed throughout 15 months. RESULTS: Spacer application was rated as "easy" or "very easy" 98.7% of the time, with a 99% hydrogel placement success rate. Perirectal spaces were 12.6 ± 3.9 mm and 1.6 ± 2.0 mm in the spacer and control groups, respectively. There were no device-related adverse events, rectal perforations, serious bleeding, or infections within either group. Pre-to postspacer plans had a significant reduction in mean rectal V70 (12.4% to 3.3%, P<.0001). Overall acute rectal adverse event rates were similar between groups, with fewer spacer patients experiencing rectal pain (P=.02). A significant reduction in late (3-15 months) rectal toxicity severity in the spacer group was observed (P=.04), with a 2.0% and 7.0% late rectal toxicity incidence in the spacer and control groups, respectively. There was no late rectal toxicity greater than grade 1 in the spacer group. At 15 months 11.6% and 21.4% of spacer and control patients, respectively, experienced 10-point declines in bowel quality of life. MRI scans at 12 months verified spacer absorption. CONCLUSIONS: Spacer application was well tolerated. Increased perirectal space reduced rectal irradiation, reduced rectal toxicity severity, and decreased rates of patients experiencing declines in bowel quality of life. The spacer appears to be an effective tool, potentially enabling advanced prostate RT protocols.

First report on the use of a thinner (125)I radioactive seed within 20-gauge needles for permanent radioactive seed prostate brachytherapy: evaluation of postimplant dosimetry and acute toxicity.

PURPOSE: To compare postoperative dosimetry and acute toxicity of new 0.5-mm (125)I seeds in 20-gauge (20G) diameter prostate brachytherapy (PB) needles with standard 0.8-mm seeds in 18G needles. METHODS AND MATERIALS: Postoperative dosimetry was performed on 100 consecutive PB patients treated with ThinSeeds in 20G needles and compared with 100 consecutively treated PB patients using standard-sized seeds and needles (18G). Dosimetry was performed on postoperative Day 1 CT scans. Acute urinary retention was also compared between these two groups. Acute toxicity was evaluated in 22 consecutively treated patients with thinner seeds/needles and compared with 22 consecutive concurrent patients treated with standard seeds and needles. All patients were evaluated by pre- and post-PB self-administered surveys, physical examinations on post-PB Day 1, and telephone surveys on Day 7. Endpoints included dysuria, acute urinary retention, hematuria, perineal pain/bruising, and International Prostate Symptom Score. RESULTS: Post-PB dosimetric comparison demonstrated that the V100 (95% vs. 91%), D90 (161Gy vs.149Gy), V150 (55% vs. 45%), and RV100 (0.43cc vs. 0.30cc) were significantly (p<0.0004) higher in the 20G group. Urinary retention rates were 8% and 7% and median catheter-dependent durations were 7 and 14 days for the 20G and 18G groups, respectively. No significant differences were found for dysuria, hematuria, or International Prostate Symptom Score. Post-PB Day 1 perineal bruising and pain scores on Days 1 and 7 were significantly less (p<0.04) in 20G cohort. CONCLUSIONS: Smaller diameter needles and seeds resulted in improved post-PB Day 1 V100 and D90 dosimetry, and significantly less acute perineal pain and bruising.

Outcomes after prostate brachytherapy are even better than predicted.

BACKGROUND: During the first 3 years after prostate cancer treatment with radiation therapy, benign prostate-specific antigen (PSA) bounces are difficult for clinicians to distinguish from a biochemical recurrence, which can result in unnecessary interventions and erroneous predictions of outcomes. The objective of this study was to evaluate a commonly used PSA failure definition in a multinational, multi-institutional study after monotherapy with prostate brachytherapy. METHODS: Participants were selected from 2919 men who underwent permanent prostate brachytherapy at the University Medical Center Utrecht, Princess Margaret Hospital, or Seattle Prostate Institute between 1998 and 2006. Inclusion required not having received androgen-deprivation therapy and having at least 30 months of follow-up. Failure was defined as any post-treatment use of hormone therapy, clinical relapse, or prostogram-defined biochemical (PSA) failure. Cases in which the nomogram predicted biochemical failure were evaluated at each institution to verify biochemical status over time and the actual clinical outcome at 5 years. RESULTS: The median follow-up for the 1816 patients was 5.2 years. Concordance between the prostogram-predicted and actual outcomes, as measured by the Harrell c statistic, was 0.655 (95% confidence interval [CI], 0.536-0.774; P = .010) for the Princess Margaret group, 0.493 (95% CI, 0.259-0.648; P = .955) for the Seattle group, and 0.696 (95% CI, 0.648-0.744, P < .001) for the Utrecht group. The overall mean difference in biochemical recurrence-free survival at 5 years between actual outcomes and prostogram-defined outcomes was 9.2% (95% CI, 7.7%-10.6%). The total numbers of prostogram-defined and actual biochemical failures were 312 and 157, respectively (P = .001). CONCLUSIONS: The widely used prostogram could not adequately distinguish a benign PSA bounce from a biochemical recurrence after prostate brachytherapy and could not be used to counsel patients about their predicted outcomes after treatment. The authors conclude that, to avoid unnecessary active interventions after treatment, clinicians should monitor PSA levels for at least 3 years and provide reassurance to patients that a PSA rise during this time is common and may not indicate a treatment failure.

The effect of pro-qura case volume on post-implant prostate dosimetry.

PURPOSE: To evaluate the effect of prostate brachytherapy case volume on postimplant dosimetric quality in Pro-Qura proctored programs. METHODS AND MATERIALS: From August 1999 to December 2008, the computed tomography datasets for 6,600 prostate implants performed by 129 brachytherapists were submitted to Pro-Qura for dosimetric analysis. Brachytherapists were divided into three roughly equal-sized terciles based on total case volume. Postimplant computed tomography scans were obtained at a median of 30 days. Excellent target coverage was defined by a V100≥90% and D90≥100% minimum prescribed peripheral dose. To determine if the number of excellent implants improved with increasing case numbers, each brachytherapist's series of implants was bisected into early and late experience by a moveable critical point. RESULTS: For the entire cohort, the mean V100 and D90 were 89.2% and 102.8%, respectively, with 47.7% of the implants scored as excellent. Brachytherapists in the highest-case tercile had a significantly greater fraction of excellent target coverage (57.9%) than did those in the two lower terciles (39.5% and 45.7%, p=0.015). Twenty-one (25.6%) of the 82 brachytherapists with sufficient case volume for dosimetric improvement analyses demonstrated quality improvement over time. Although there was no significant difference between prostate volume and seed strength, the number of seeds used was significantly greater in adequate implants. CONCLUSIONS: The highest-volume brachytherapists were most likely to obtain excellent target coverage. We are encouraged that in general practice, nearly 48% of all implants were scored excellent. It is conceivable that with greater expert third-party involvement, an even greater percentage of cases with excellent target coverage will become reality.

Postimplant rectal dosimetry is not dependent on 103Pd or 125I seed activity.

PURPOSE: In this study, the effect of prostate brachytherapy seed activity on postimplant rectal dosimetry was evaluated in Pro-Qura (Prostate Brachytherapy Quality Assurance; Seattle, WA) proctored, community-based programs. METHODS AND MATERIALS: Twenty-three hundred patients (1563 iodine-125 [(125)I] and 737 palladium-103 [(103)Pd]) from 78 brachytherapists with postimplant rectal dosimetry were identified. Seed activity was stratified into three tertiles for each isotope (≤0.300, 0.301-0.326, and >0.326 mCi/seed for (125)I and ≤1.330, 1.331-1.547, and >1.547 mCi/seed for (103)Pd). Postimplant dosimetry was performed in a standardized fashion. The rectum was contoured by outlining the outer rectal wall. The volume of the rectum receiving 100% of the prescription dose (R(100)) was calculated in cubic centimeters. The prostate V(100) and D(90) volumes were also calculated. RESULTS: The mean prostate volume was 35.8 and 32.3 cm(3) for (125)I and (103)Pd. The median time to postimplant CT was 30 days. For (125)I, the V(100) increased from 91.0% to 93.7% (p=0.012) and the D(90) increased from 105.9% to 108.7% (p<0.001) for the lowest to the highest (125)I seed activities. In contrast, no significant changes in V(100) (p=0.751) or D(90) (p=0.200) were discerned when stratified by seed activity. For both isotopes, there was no correlation between seed activity and R(100), and R(100) was highest for the intermediate seed activities. Overall, the R(100) was lower for (103)Pd vs. (125)I (0.63 vs. 0.82 cm(3), p<0.001). CONCLUSIONS: Within the confines of seed activities used in this study, higher activity seeds did not result in a deleterious effect on rectal dose. Higher activity seeds were associated with improved prostate dosimetry for (125)I, whereas (103)Pd dosimetry was not dependent on seed activity.

Fifteen-year biochemical relapse-free survival, cause-specific survival, and overall survival following I(125) prostate brachytherapy in clinically localized prostate cancer: Seattle experience.

PURPOSE: To report 15-year biochemical relapse-free survival (BRFS), cause-specific survival (CSS), and overall survival (OS) outcomes of patients treated with I(125) brachytherapy monotherapy for clinically localized prostate cancer early in the Seattle experience. METHODS AND MATERIALS: Two hundred fifteen patients with clinically localized prostate cancer were consecutively treated from 1988 to 1992 with I(125) monotherapy. They were prospectively followed as a tight cohort. They were evaluated for BRFS, CSS, and OS. Multivariate analysis was used to evaluate outcomes by pretreatment clinical prognostic factors. BRFS was analyzed by the Phoenix (nadir + 2 ng/mL) definition. CSS and OS were evaluated by chart review, death certificates, and referring physician follow-up notes. Gleason scoring was performed by general pathologists at a community hospital in Seattle. Time to biochemical failure (BF) was calculated and compared by Kaplan-Meier plots. RESULTS: Fifteen-year BRFS for the entire cohort was 80.4%. BRFS by D'Amico risk group classification cohort analysis was 85.9%, 79.9%, and 62.2% for low, intermediate, and high-risk patients, respectively. Follow-up ranged from 3.6 to 18.4 years; median follow-up was 15.4 years for biochemically free of disease patients. Overall median follow-up was 11.7 years. The median time to BF in those who failed was 5.1 years. CSS was 84%. OS was 37.1%. Average age at time of treatment was 70 years. There was no significant difference in BRFS between low and intermediate risk groups. CONCLUSION: I(125) monotherapy results in excellent 15-year BRFS and CSS, especially when taking into account the era of treatment effect.

Optimal equations for describing the relationship between prostate volume, number of sources, and total activity in permanent prostate brachytherapy.

OBJECTIVES: To determine whether there is an optimal type of mathematical equation for predicting seed and activity requirements for permanent prostate brachytherapy. METHODS: Four institutions with extensive brachytherapy experience each submitted details of more than 40 implants. The data was used to generate power and linear equations to reflect the relationship between preimplant volume and the number of seeds implanted, and preimplant volume and the total implant activity. We compared the R and standard error of the generated equations to determine which type of equation better fit the data. RESULTS: For the limited range of prostate volumes commonly implanted (20-60 mL), power and linear equations predict seed and activity requirements comparably well. CONCLUSIONS: Linear and power equations are equally suitable for generating institution-specific nomograms.

Permanent prostate brachytherapy preplanned technique: The modern Seattle method step-by-step and dosimetric outcomes.

PURPOSE: To describe, step-by-step, the current Seattle preplan technique, and report the dosimetric outcomes on 1,131 consecutively such treated prostate brachytherapy patients. METHODS AND MATERIALS: One thousand one hundred thirty one patients with prostate cancer were treated with iodine-125 ((125)I), palladium-103 ((103)Pd), or cesium-131 ((131)Cs) using a preplanned template-guided transrectal ultrasound-guided approach between January 2005 and August 2007. Day one computed tomography (CT) scans were taken for postimplantation dose-volume histogram evaluations. Postoperative prostate contours were drawn by one author (DN) on CT images taken on postoperative day one. RESULTS: The volume of prostate receiving 100% of prescription dose (V(100)) and percent dose to 90% of the prostate (%D(90)) were 95% and 106% for 558 monotherapy (125)I implants, 91% and 102% for 327 (103)Pd implants, and 97% and 111.5% for 13 (131)Cs implants, respectively. The median V(100) and percent D(90) were 91% and 101% for five boost (125)I implants, 92% and 104% for 228 boost (103)Pd implants. The median rectal volume receiving 100% of prescription dose (RV(100)) for (125)I, (103)Pd, and (131)Cs monotherapy implants were 0.3, 0.13, and 0.38cc, and for (125)I and (103)Pd boost implants were 0.16 and 0.13cc, respectively. No patient received an RV(100) of >0.92cc. CONCLUSIONS: Modern preplanned template and ultrasound-guided prostate brachytherapy can consistently result in excellent prostate dosimetry and rectal sparing.

Prostate tumor alignment and continuous, real-time adaptive radiation therapy using electromagnetic fiducials: clinical and cost-utility analyses.

OBJECTIVE: To evaluate the accuracy, utility, and cost effectiveness of a new electromagnetic patient positioning and continuous, real-time monitoring system, which uses permanently implanted resonant transponders in the target (Calypso 4D Localization System and Beacon transponders, Seattle, WA) to continuously monitor tumor location and movement during external beam radiation therapy of the prostate. MATERIALS AND METHODS: This clinical trial studied 43 patients at 5 sites. All patients were implanted with 3 transponders each. In 41 patients, the system was used for initial alignment at each therapy session. Thirty-five patients had continuous monitoring during their radiation treatment. Over 1,000 alignment comparisons were made to a commercially available kV X-ray positioning system (BrainLAB ExacTrac, Munich, Germany). Using decision analysis and Markov processes, the outcomes of patients were simulated over a 5-year period and measured in terms of costs from a payer's perspective and quality-adjusted life years (QALYs). RESULTS: All patients had satisfactory transponder implantations for monitoring purposes. In over 75% of the treatment sessions, the correction to conventional positioning (laser and tattoos) directed by an electromagnetic patient positioning and monitoring system was greater than 5 mm. Ninety-seven percent (34/35) of the patients who underwent continuous monitoring had target motion that exceeded preset limits at some point during the course of their radiation therapy. Exceeding preset thresholds resulted in user intervention at least once during the therapy in 80% of the patients (28/35). Compared with localization using ultrasound, electronic portal imaging devices (EPID), or computed tomography (CT), localization with the electromagnetic patient positioning and monitoring system yielded superior gains in QALYs at comparable costs. CONCLUSIONS: Most patients positioned with conventional tattoos and lasers for prostate radiation therapy were found by use of the electromagnetic patient positioning and monitoring system to have alignment errors exceeding 5 mm. Almost all patients undergoing external beam radiation of the prostate have been shown to have target organ movement exceeding 3 mm during radiation therapy delivery. The ability of the electromagnetic technology to monitor tumor target location during the same time as radiation therapy is being delivered allows clinicians to provide real time adaptive radiation therapy for prostate cancer. This permits clinicians to intervene when the prostate moves outside the radiation isocenter, which should decrease adverse events and improve patient outcomes. Additionally, a cost-utility analysis has demonstrated that the electromagnetic patient positioning and monitoring system offers patient outcome benefits at a cost that falls well within the payer's customary willingness to pay (WTP) threshold of $50,000 per QALY.

Analysis of the Pro-Qura Database: rectal dose, implant quality, and brachytherapist's experience.

PURPOSE: This study analyzed rectal dosimetry outcomes of Pro-Qura proctored implants to assess the achievability of proposed rectal dose constraints in the setting of standardized pre- and postimplant dosimetry in community-based brachytherapy programs. METHODS AND MATERIALS: From August 2005 to July 2007, 713 postimplant CT scans were evaluated from 26 brachytherapists actively participating in Pro-Qura. Postimplant dosimetry was performed in a standardized fashion. The entirety of the rectal wall was contoured and evaluated for dose. Rectal dose was defined in terms of the volume of the rectum receiving 100% of the prescription dose (R(100)). Criteria for implant adequacy for both (103)Pd and (125)I included a prostate the percentage of the prostate volume covered by the prescription dose (V(100))>80%, a prostate the maximum dose covering 90% of the prostate volume (D(90)) of 90-140%, and an R(100)<1.0cm(3) for early (Day 0-7) dosimetry and <1.3cm(3) for late (Day 20-45) dosimetry. RESULTS: Mean prostatic volume was 35.1cm(3). The mean time from implant to CT scan was 29.9 days (range, 0-45 days). The respective mean overall prostate V(100) and D(90) were 89% and 101%, respectively, and remained consistent for sequence groups 1 through 6. Overall, the mean R(100) was 0.97+/-1.04cm(3). The R(100) was 1.15cm(3) for sequence Group 1 and with each subsequent sequence group decreased with a nadir of 0.83cm(3) in sequence Group 6 (p=0.22). Rectal dosimetry was deemed inadequate in 39% of Group 1 implants but only 22% in Group 6 (p=0.016). The reduced rectal doses did not impact prostate gland coverage. CONCLUSIONS: Using standardized dosimetry, R(100) improved with increasing brachytherapist's experience, reaching a plateau after approximately 20 patients.

Effects of the time interval between prostate brachytherapy and postimplant dosimetric evaluation in community practice: analysis of the Pro-Qura database.

OBJECTIVE: To evaluate the influence of postimplant dosimetric timing on prostate brachytherapy quality in community practice. MATERIALS AND METHODS: The Pro-Qura database was stratified by multiple time intervals between the implant and postimplant dosimetric analysis. Postimplant dosimetry was performed in a standardized fashion. Criteria for implant adequacy included V(100) >80%, D(90) >90%, and V(150) <60% for I-125 and <75% for Pd-103. Implants with V(100) <80% and D(90) <90% were deemed "too cool." Implants were considered "too hot" if D(90) >140% of prescription dose and/or V(150) >150% for I-125 and >75% for Pd-103. RESULTS: For I-125, the average V(100) and D(90) increased from 88.6% to 89.8%, and 102.8% to 103.1% for day 0 and day 30 dosimetry. For Pd-103 implants the change was more pronounced, with V(100) and D(90) increasing from 81.6% to 87.8% (P < 0.001) and 88.7% to 100.0% (P < 0.001) for day 0, and day 30, respectively. The percentage of implants considered too cool based on a V(100) and D(90) criteria decreased from 18.8% and 26.9% on day 0 to 11.0% and 19.7% on day 30, respectively. Implants determined to be too hot based on a V(150) >60% (I-125)/>75% (Pd-103) or D(90) >140% were 16.4% and 2.2% on day 0 and 16.0% and 0.7% on day 30, respectively. CONCLUSION: In community-based brachytherapy programs, postimplant dosimetry performed at day 30 resulted in a statistically and clinically significant improvement in postimplant dosimetry compared with day 0. The influence of timing is substantially greater for Pd-103 than I-125.

Inter-institutional variation of implant activity for permanent prostate brachytherapy.

PURPOSE: Despite the existence of guidelines for permanent prostate brachytherapy, it is unclear whether there is interinstitutional consensus concerning the parameters of an ideal implant. METHODS AND MATERIAL: Three institutions with extensive prostate brachytherapy expertise submitted information regarding their implant philosophy and dosimetric constraints, as well as data on up to 50 radioiodine implants. Regression analyses were performed to reflect each institution's utilization of seeds and implanted activity. RESULTS: Despite almost identical implant philosophy, target volume, and dosimetric constraints, there were statistically significant interinstitutional differences in the number of seeds and total implant activity across the range of prostate volumes. For larger volumes, the variation in implanted activity was 25%; for smaller glands, it exceeded 40%. CONCLUSIONS: There remain wide variations in implanted activity between institutions espousing seemingly identical implant strategies, prescription, and dosimetry constraints. Brachytherapists should therefore be wary of using nomograms generated at other institutions.