The addition of androgen deprivation therapy and pelvic lymph node treatment to prostate bed salvage radiotherapy (NRG Oncology/RTOG 0534 SPPORT): an international, multicentre, randomised phase 3 trial.

BACKGROUND: In men with a detectable prostate-specific antigen (PSA) level after prostatectomy for prostate cancer, salvage prostate bed radiotherapy (PBRT) results in about 70% of patients being free of progression at 5 years. A three-group randomised trial was designed to determine whether incremental gains in patient outcomes can be achieved by adding either 4-6 months of short-term androgen deprivation therapy (ADT) to PBRT, or both short-term ADT and pelvic lymph node radiotherapy (PLNRT) to PBRT. METHODS: The international, multicentre, randomised, controlled SPPORT trial was done at 283 radiation oncology cancer treatment centres in the USA, Canada, and Israel. Eligible patients (aged ≥18 years) were those who after prostatectomy for adenocarcinoma of the prostate had a persistently detectable or an initially undetectable and rising PSA of between 0·1 and 2·0 ng/mL. Patients with and without lymphadenectomy (N0/Nx) were eligible if there was no clinical or pathological evidence of lymph node involvement. Other eligibility criteria included pT2 or pT3 disease, prostatectomy Gleason score of 9 or less, and a Zubrod performance status of 0-1. Eligible patients were randomly assigned to receive PBRT alone at a dose of 64·8-70·2 Gy at 1·8 Gy per fraction daily (group 1), PBRT plus short-term ADT (group 2), or PLNRT (45 Gy at 1·8 Gy per fraction, and then a volume reduction made to the planning target volume for the remaining 19·8-25 ·2 Gy) plus PBRT plus short-term ADT (group 3). The primary endpoint was freedom from progression, in which progression was defined as biochemical failure according to the Phoenix definition (PSA ≥2 ng/mL over the nadir PSA), clinical failure (local, regional, or distant), or death from any cause. A planned interim analysis of 1191 patents with minimum potential follow-up time of 5 years applied a Haybittle-Peto boundary of p<0·001 (one sided) for comparison of 5-year freedom from progression rates between the treatment groups. This trial is registered with ClinicalTrials.gov, NCT00567580. The primary objectives of the trial have been completed, although long-term follow-up is continuing. FINDINGS: Between March 31, 2008, and March 30, 2015, 1792 eligible patients were enrolled and randomly assigned to the three treatment groups (592 to group 1 [PBRT alone], 602 to group 2 [PBRT plus short-term ADT], and 598 to group 3 [PLNRT plus PBRT plus short-term ADT]). 76 patients subsequently found to be ineligible were excluded from the analyses; thus, the evaluable patient population comprised 1716 patients. At the interim analysis (n=1191 patients; data cutoff May 23, 2018), the Haybittle-Peto boundary for 5-year freedom from progression was exceeded when group 1 was compared with group 3 (difference 17·9%, SE 2·9%; p<0·0001). The difference between groups 2 and 3 did not exceed the boundary (p=0·0063). With additional follow-up beyond the interim analysis (the final planned analysis; data cutoff May 26, 2021), at a median follow-up among survivors of 8·2 years (IQR 6·6-9·4), the 5-year freedom from progression rates in all 1716 eligible patients were 70·9% (95% CI 67·0-74·9) in group 1, 81·3% (78·0-84·6) in group 2, and 87·4% (84·7-90·2) in group 3. Per protocol criteria, freedom from progression in group 3 was superior to groups 1 and 2. Acute (≤3 months after radiotherapy) grade 2 or worse adverse events were significantly more common in group 3 (246 [44%] of 563 patients) than in group 2 (201 [36%] of 563; p=0·0034), which, in turn, were more common than in group 1 (98 [18%] of 547; p<0·0001). Similar findings were observed for grade 3 or worse adverse events. However, late toxicity (>3 months after radiotherapy) did not differ significantly between the groups, apart from more late grade 2 or worse blood or bone marrow events in group 3 versus group 2 (one-sided p=0·0060) attributable to the addition of PLNRT in this group. INTERPRETATION: The results of this randomised trial establish the benefit of adding short-term ADT to PBRT to prevent progression in prostate cancer. To our knowledge, these are the first such findings to show that extending salvage radiotherapy to treat the pelvic lymph nodes when combined with short-term ADT results in meaningful reductions in progression after prostatectomy in patients with prostate cancer. FUNDING: National Cancer Institute.

Intermittent androgen suppression for rising PSA level after radiotherapy.

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

Analysis of outcomes after non-contour-based dose painting of dominant intra-epithelial lesion in intra-operative low-dose rate brachytherapy.

PURPOSE: To compare the outcomes of patients with intermediate risk prostate cancer (IR-PCa) treated with low-dose rate I-125 seed brachytherapy (LDR-BT) and targeted dose painting of a histologic dominant intra-epithelial lesion (DIL) to those without a DIL. METHODS: 455 patients with IR-PCa were treated at a single center with intra-operatively planned LDR-BT, each following the same in-house dose constraints. Patients with a DIL on pathology had hot spots localized to that region but no specific contouring during the procedure. RESULTS: 396 (87%) patients had a DIL. Baseline tumor characteristics and overall prostate dosimetry were similar between patients with and without DIL except the median number of biopsy cores taken: 10 (10-12) vs 12 (10-12) (p = 0.002).19 (5%) and 18 (5%) of patients with and 1 (2%) and 0 (0%) of those without DIL experienced CTCAE grade 2 and 3 toxicity respectively. Overall, toxicity grade did not significantly correlate with presence of DIL (p = 0.10).Estimated 7-year freedom from biochemical failure (FFBF) was 84% (95% confidence interval: 79-89) and 70% (54-89) in patients with and without a DIL (log-rank p = 0.315). In DIL patients, cox regression revealed location of DIL ("Base" vs "Apex" HR: 1.03; 1.00-1.06; p = 0.03) and older age (70 vs 60 HR: 1.62; 1.06-2.49; p = 0.03) was associated with poor FFBF. CONCLUSIONS: Targeting DIL through dose painting during intraoperatively planned LDR-BT provided no statistically significant change in FFBF. Patients with DILs in the prostate base had slightly lower FFBF despite DIL boost.

Enhanced efficiency and ergonomics of an intraoperative automated prostate brachytherapy delivery technique.

INTRODUCTION: In 2003, the Tom Baker Cancer Centre started a prostate brachytherapy program using Iodine-125 seeds, intraoperative treatment planning, and an automated remote afterloader, the seedSelectron. Over a 3-month period in 2004-2005, technologic changes were implemented with the intent of reducing the time spent in the operating room and improving ergonomics for the radiation oncologist/surgeon. New commercial software including inverse planning was installed, concurrent needle insertion and seed train building was implemented, and additional hardware (a slave monitor) was connected to the system. PURPOSE: To demonstrate that, with these enhancements, dosimetry is not compromised, whereas efficiency is significantly improved. METHODS: Interactive inverse planning was used to create the treatment plans in the operating room. Seed-spacer trains were built concurrently with each needle's insertion guided by rotating the ultrasound probe to the correct sagittal plane using the Needle Navigator feature. Needles were built, inserted, and delivered one needle at a time. Needle coordinate and insert positions were verified on the live ultrasound image displayed on both the slave monitor positioned above the patient's pelvis and the operator console. Dosimetry parameters (D(90) and V(100)), numbers of seeds, and OR times were compared for 20 patients before and 11 patients after the implementation of the concurrent insertion and build protocol combined with inverse planning and the slave monitor. RESULTS: Operating room (OR) times (probe in to probe out) were reduced by 33 min and the number of seeds per unit volume by 3% on an average. The majority of the decrease in time is due to the concurrent building and insertion of needles. Before and after the new technique, average postplan D(90) and V(100) values at 4 weeks after the implant were the same to within 4 Gy and 0.1%, respectively. The range (max-min) of D(90) decreased by 20% of the mean dose and the V(100) range decreased by 6% with the new technique. Adding the slave monitor improved quality assurance of the delivery process and ergonomics for physicians. CONCLUSIONS: The concurrent insertion and build protocol, together with inverse planning and the slave monitor, have decreased OR times with greater consistency in the delivered dose distribution.

Parameters predicting for prostate specific antigen response rates at one year post low-dose-rate intraoperative prostate brachytherapy.

PURPOSE: To develop a model for prostate specific antigen (PSA) values at one year among patients treated with intraoperatively planned 125I prostate brachytherapy (IOPB). MATERIAL AND METHODS: Four hundred and deven patients treated with IOPB for prostate adenocarcinoma were divided into four groups: those with PSA values ≥ 3 ng/ml; < 3 and ≥ 2; < 2 and ≥ 1 or PSA < 1 between 10.5 and 14.5 months post implantation (1yPSA). Ordinal regression analysis was then performed between patient, tumor, and treatment characteristics. 1yPSA values were also compared with toxicity outcomes. RESULTS: Median 1yPSA was 0.77 (0.04-17.36). Thirty-two patients (8%) had a PSA ≥ 3; 35 (9%) had PSA < 3, ≥ 2; 87 (21%) had PSA < 2, ≥ 1, and most patients 254 (62%) had PSA < 1. PSA response was independent of gland volume, Gleason score, clinical stage, seed activity, V90, V200, D90, or number of needles and seeds used. Older patients had significantly lower 1yPSA; median ages 65.1 (46.5-81.0), 62.1 (50.4-79.5), 60.5 (47.1-80.3), and 58.1 (45.1-74.2) years for each of the 1yPSA groups respectively (p < 0.001). Also, both implant V150 (p < 0.001) and initial PSA values (p = 0.04) were predictive of 1yPSA values. There was no correlation between 1yPSA values and toxicity encountered. CONCLUSIONS: PSA response at 1 year post IOPB appears to be dependent on patient age, initial PSA, and implant V150. Our results provide reassurance that parameters other than biochemical failure influence 1yPSA values.

Institutional long-term outcomes at the first Canadian center performing intraoperatively planned low-dose-rate brachytherapy alone in low- and intermediate-risk prostate cancer.

PURPOSE: The aim of this study is to report the long-term outcomes and toxicities from a large cohort of patients with localized prostate cancer treated with low-dose-rate intraoperatively planned brachytherapy. METHODS AND MATERIALS: Prostate-specific antigen levels, urinary symptoms, and erectile function were recorded at baseline, and each followup visit was then entered into a prospective database. Urinary toxicity requiring procedural intervention was retrospectively verified using an integrated electronic medical system. A separate cross-sectional survey was performed to measure postimplant sexual function. RESULTS: A total of 822 patients with low and favorable intermediate-risk prostate cancer were treated at our institution between 2003 and 2013. The Kaplan-Meier estimates for biochemical recurrence for our cohort were 95% and 87% at 5 and 10 years, respectively. Cystoscopy, transurethral resection of prostate, or dilatation was required for 7.1% of 720 patients with more than 2 years of followup. At a median followup of 3.7 years, 64.4% of patients retained adequate erectile function for intercourse, with 54% of patients who were no longer sexually active postimplant reporting social factors as the primary reason. CONCLUSIONS: Our institutional experience with intraoperative low-dose-rate prostate brachytherapy yielded excellent long-term results with a low incidence of urinary and sexual toxicity.

Multicenter Evaluation of Biochemical Relapse-Free Survival Outcomes for Intraoperatively Planned Prostate Brachytherapy Using an Automated Delivery System.

PURPOSE: To report biochemical recurrence in prostate cancer treated with intraoperatively planned low-dose-rate prostate brachytherapy using an automated delivery system (IO-LDRB). METHODS AND MATERIALS: Between 2003 and 2013, 2608 patients from 3 centers were treated with IO-LDRB as single-modality treatment for low or low-tier intermediate-risk prostate cancer. Databases from the 3 centers have been analyzed. These independent databases were collected prospectively. Patient, tumor, and treatment characteristics were then compared, Kaplan-Meier survival estimates of biochemical relapse-free survival (bRFS) were generated, and the Cox proportional hazards model was used to determine factors predicting for relapse. RESULTS: A total of 2608 patients with a median follow-up of 4.7 (interquartile range, 3.1-6.9) years were analyzed. Median age was 64 (range, 42-84) years. In these patients, median initial prostate-specific antigen was 5.5 ng/mL, 74% were T1, and 26% were T2; 73% were Gleason 6, and 25% Gleason 7. Median percentage of biopsy cores positive was 33%, and median gland volume was 34.2 cm3. Eleven percent of patients received hormones for a median of 3.0 months before implantation. Median seed activity was 0.437 mCi, D90 (dose covering 90% of the prostate volume) was 186.7 Gy, and V100 was 99.37%. Biochemical relapse was observed in 124 patients (4.8%), and median time to failure was 4.0 years. Predicted bRFS was 93% at 7 years. On Cox regression bRFS was dependent only on D90 at the time of implantation and prostate-specific antigen density. CONCLUSIONS: This study demonstrates that IO-LDRB is an effective treatment option for patients with low and low-tier intermediate-risk prostate cancer. Rates of biochemical relapse remain low several years after treatment. These results compared favorably to published manual preplan technique results.

Implanted brachytherapy seed movement reflecting transrectal ultrasound probe-induced prostate deformation.

PURPOSE: Compression of the prostate during transrectal ultrasound-guided permanent prostate brachytherapy is not accounted for during treatment planning. Dosimetry effects are expected to be small but have not been reported. The study aims to characterize the seed movement and prostate deformation due to probe pressure and to estimate the effects on dosimetry. METHODS AND MATERIALS: C-arm fluoroscopy imaging was performed to reconstruct the implanted seed distributions (compressed and relaxed prostate) for 10 patients immediately after implantation. The compressed prostate was delineated on ultrasound and registered to the fluoroscopy-derived seed distribution via manual seed localization. Thin-plate spline mapping, generated with implanted seeds as control points, was used to characterize the deformation field and to infer the prostate contour in the absence of probe compression. Differences in TG-43 dosimetry for the compressed prostate and that on probe removal were calculated. RESULTS: Systematic seed movement patterns were observed on probe removal. Elastic decompression was characterized by expansion in the anterior-posterior direction and contraction in the superior-inferior and lateral directions up to 4 mm. Bilateral shearing in the anterior direction was up to 6 mm, resulting in contraction of the 145 Gy prescription isodose line by 2 mm with potential consequences for the posterior-lateral margin. The average whole prostate D90 increased by 2% of prescription dose (6% max; p < 0.01). CONCLUSIONS: The current investigation presents a novel study on ultrasound probe-induced deformation. Seed movements were characterized, and the associated dosimetry effects were nonnegligible, contrary to common expectation.

Is tissue harmonic ultrasound imaging (THI) of the prostatic urethra and rectum superior to brightness (B) mode imaging? An observer study.

Quality ultrasound images are an essential part of prostate brachytherapy procedure. The authors have previously reported that tissue harmonic ultrasound images (THI) are superior to brightness (B) mode for the prostate. The objective of the current study was to compare both imaging modes for visualization of the prostatic urethra and rectum. B and THI mode transrectal ultrasound images were acquired for ten patients. The prostatic urethra and rectal wall were contoured by a radiation oncologist (RO) and five observers on randomly presented images. The contours on one patient were repeated four additional times by four observers. All the images were qualitatively scored using a five-level Likert scale. The values of the Pearson product-moment correlation coefficients showed that the observers were in close agreement with the RO. Two sample paired student t-test showed that the rectum volumes with THI were significantly smaller than B-mode, but no significant difference for urethra. Two-factor analysis of variances showed significant observer variability in defining the rectum and urethra in both imaging modes. Observer consistency of the rectum volumes, estimated by standard deviations as percentages of means was significantly improved for THI. The Likert scale based qualitative assessment supported quantitative observations. The significant improvement in image quality of the prostate (reported previously) and rectum with THI may offer better-quality treatment plans for prostate brachytherapy and potential improvement in local control.