306 Background: Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (ASCENDE-RT) trial randomized patients to prostate brachytherapy (PB) or the External beam RT (EBRT) boost (1:1). All patients received 1 year of androgen deprivation therapy and 46 Gy in 23 fractions of pelvic RT. Patients in the EBRT arm received an additional 32 Gy in 16 fractions, and those in the PB arm received a 115 Gy 125I implant. The trial previously demonstrated a large difference in biochemical relapse favoring brachytherapy (PB) boost. At present, the median follow-up from start of treatment of all patients is 15 (IQR 10.7, 17.8) years. Herein we report the 15-year actuarial survival events. Methods: Two hundred patients with a median age of 68 (IQR 62,73) were randomized to EBRT and 198 to PB. Active study follow-up stopped at 10 years. Cause of death was determined on chart review and study report forms during active study follow-up, and was augmented with death registry data, and medical records audits thereafter. Fifteen-year overall survival and cumulative risk of death from prostate cancer were estimated using Cox and Fine and Gray analysis respectively with multivariable analysis (MVA) significant variables on univariate including - randomization, clinical T stage, log of initial PSA, Gleason grade group (1-3 vs 4-5), percent positive cores, and age at treatment. A sensitivity analysis included unknown cause of death as prostate death. Results: 213 patients (54%) have died: 64 (16%) of prostate cancer, 48 (12%) of other cancer, 35 (9%) of cardiovascular disease, 49 (12%) of other known causes, and 17 (4%) of unknown cause of death. The age of patients alive at last censoring was 82 (IQR 77,88). Overall survival at 15 years was 55.0% (95% CI 48.4 – 62.4) and 60.9% (95% CI 54.4 – 68.1) for EBRT and PB arms respectively, (HR 1.02, 95%CI 0.78 – 1.33, p = 0.908 on MVA). The cumulative incidence of prostate death at 15 years was 8.6% (95%CI 5.2 – 13.0) for PB and 16.4% (95%CI 11.6 – 22.0) for EBRT (p=0.007). In a sensitivity analysis where cases of unknown cause of death were counted as prostate deaths, the cumulative incidence of prostate death at 15 years was 14.3% (95%CI 9.8 – 19.5) for PB and 19.4% (95%CI 14.2 – 25.3) for EBRT (p=0.067). Conclusions: At 15 years, there is no definite evidence of an overall survival benefit with PB boost in ASCENDE-RT and the trend to a prostate cancer specific survival advantage with PB is limited by ascertainment of cause of death. Thus, although prostate cancer was the single most common cause of mortality in ASCENDE-RT, our results suggest that even large improvements in b-NED, such as those demonstrated with PB in ASCENDE-RT, are unlikely to improve 15-year overall survival by more than 10% for a population whose median age, performance status, and prognostic variables are similar to ASCENDE-RT participants. Clinical trial information: NCT00175396 .

This article describes a novel system for quantitative and volumetric measurement of tissue elasticity in the prostate using simultaneous multi-frequency tissue excitation. Elasticity is computed by using a local frequency estimator to measure the three-dimensional local wavelengths of steady-state shear waves within the prostate gland. The shear wave is created using a mechanical voice coil shaker which transmits simultaneous multi-frequency vibrations transperineally. Radio frequency data is streamed directly from a BK Medical 8848 transrectal ultrasound transducer to an external computer where tissue displacement due to the excitation is measured using a speckle tracking algorithm. Bandpass sampling is used that eliminates the need for an ultra-fast frame rate to track the tissue motion and allows for accurate reconstruction at a sampling frequency that is below the Nyquist rate. A roll motor with computer control is used to rotate the transducer and obtain 3D data. Two commercially available phantoms were used to validate both the accuracy of the elasticity measurements as well as the functional feasibility of using the system for in vivo prostate imaging. The phantom measurements were compared with 3D Magnetic Resonance Elastography (MRE), where a high correlation of 96% was achieved. In addition, the system has been used in two separate clinical studies as a method for cancer identification. Qualitative and quantitative results of 11 patients from these clinical studies are presented here. Furthermore, an AUC of 0.87±0.12 was achieved for malignant vs. benign classification using a binary support vector machine classifier trained with data from the latest clinical study with leave one patient out cross-validation.

Purpose Optimizing Prostate Cancer Treatment in Men with Advanced Local disease (OPTiMAL) is a single-arm phase II study targeted towards unfavourable risk patients. As a successor to the largest randomized clinical trial (ASCENDE) comparing low-dose-rate prostate brachytherapy (LDR-PB) boost to external beam radiation therapy (EBRT) boost for prostate cancer (PCa) treatment, this study is designed to continue the use of the LDR-PB boost that resulted in high levels of biochemical progression-free survival (b-PFS) in ASCENDE while also aiming to reduce adverse side effects by lowering the overall dose and also limiting high dose regions to identified sites of disease. Materials and Methods The central treatment policy in OPTiMAL is to give 100% of the minimum prescribed brachytherapy dose (mpd) to the whole prostate gland while limiting regions with ≥150% of the mpd−as much as possible−to areas containing PCa as determined from transperineal template-guided mapping biopsy (TTMB). In addition, the mpd has been lowered to 100 Gy relative to the 115 Gy ASCENDE dose, and EBRT is delivered after the implant to enable the implanted seeds to be used for prostate localization on verification images. Treatment also includes androgen deprivation therapy (ADT) between TTMB and implant. An important additional aim of the OPTiMAL study is to use the TTMB results as a “ground truth” for investigating the potential of multi-modal advanced imaging of the prostate to better delineate tumours and target them appropriately during treatment. Imaging modalities included in the study are as follows: (1) multi-parametric magnetic resonance imaging (mpMRI) following a protocol compatible with PI-RADs V2, (2) magnetic resonance elastography (MRE) (in the same mpMRI session), (3) multi-parametric transrectal ultrasound (mpTRUS), including shear wave absolute vibro-elastography imaging (SWAVE), strain elastography, and time-series B-mode, all acquired immediately prior to and with the patient in position for the TTMB. Although OPTiMAL does not specifically use the findings from these multi-modal imaging studies for brachytherapy treatment planning, the potential of these multi-modal images for PCa localization is being studied by comparing the findings with the TTMB results. Biopsy core locations in the prostate are tracked during the procedure using ultrasound imaging and the VariPath module in VariSeed software (Varian Medical Systems, Palo Alto, CA, United States). Once available, pathology findings are allocated to the tracked cores within the VariPath software and then localized in the multi-modal images using intensity and surface-based image registration to the TTMB ultrasound images and labels. Results The OPTiMAL study is ongoing and 11 patients have been enrolled so far with 10 patients fulfilling all requirements for LDR-PB boost treatment. Advanced imaging data have been collected for 5 of the patients. Initial analysis of the elastography data (MRE, SWAVE) indicates a positive correlation with the TTMB ground truth. Fig 1 illustrates the correlation of the TTMB findings with the elastography images for P10. Conclusions Initial analysis suggests that such multi-modal imaging data has the potential to localize tumours reliably which can eventually replace the invasive TTMB procedure altogether. We are currently recruiting more patients and with more imaging and follow-up (relapse rate, side effects endured) data available, a deeper analysis will be conducted. Optimizing Prostate Cancer Treatment in Men with Advanced Local disease (OPTiMAL) is a single-arm phase II study targeted towards unfavourable risk patients. As a successor to the largest randomized clinical trial (ASCENDE) comparing low-dose-rate prostate brachytherapy (LDR-PB) boost to external beam radiation therapy (EBRT) boost for prostate cancer (PCa) treatment, this study is designed to continue the use of the LDR-PB boost that resulted in high levels of biochemical progression-free survival (b-PFS) in ASCENDE while also aiming to reduce adverse side effects by lowering the overall dose and also limiting high dose regions to identified sites of disease. The central treatment policy in OPTiMAL is to give 100% of the minimum prescribed brachytherapy dose (mpd) to the whole prostate gland while limiting regions with ≥150% of the mpd−as much as possible−to areas containing PCa as determined from transperineal template-guided mapping biopsy (TTMB). In addition, the mpd has been lowered to 100 Gy relative to the 115 Gy ASCENDE dose, and EBRT is delivered after the implant to enable the implanted seeds to be used for prostate localization on verification images. Treatment also includes androgen deprivation therapy (ADT) between TTMB and implant. An important additional aim of the OPTiMAL study is to use the TTMB results as a “ground truth” for investigating the potential of multi-modal advanced imaging of the prostate to better delineate tumours and target them appropriately during treatment. Imaging modalities included in the study are as follows: (1) multi-parametric magnetic resonance imaging (mpMRI) following a protocol compatible with PI-RADs V2, (2) magnetic resonance elastography (MRE) (in the same mpMRI session), (3) multi-parametric transrectal ultrasound (mpTRUS), including shear wave absolute vibro-elastography imaging (SWAVE), strain elastography, and time-series B-mode, all acquired immediately prior to and with the patient in position for the TTMB. Although OPTiMAL does not specifically use the findings from these multi-modal imaging studies for brachytherapy treatment planning, the potential of these multi-modal images for PCa localization is being studied by comparing the findings with the TTMB results. Biopsy core locations in the prostate are tracked during the procedure using ultrasound imaging and the VariPath module in VariSeed software (Varian Medical Systems, Palo Alto, CA, United States). Once available, pathology findings are allocated to the tracked cores within the VariPath software and then localized in the multi-modal images using intensity and surface-based image registration to the TTMB ultrasound images and labels. The OPTiMAL study is ongoing and 11 patients have been enrolled so far with 10 patients fulfilling all requirements for LDR-PB boost treatment. Advanced imaging data have been collected for 5 of the patients. Initial analysis of the elastography data (MRE, SWAVE) indicates a positive correlation with the TTMB ground truth. Fig 1 illustrates the correlation of the TTMB findings with the elastography images for P10. Initial analysis suggests that such multi-modal imaging data has the potential to localize tumours reliably which can eventually replace the invasive TTMB procedure altogether. We are currently recruiting more patients and with more imaging and follow-up (relapse rate, side effects endured) data available, a deeper analysis will be conducted.

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 DEEBRT 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. (c) 2022 Elsevier Inc. All rights reserved.

PURPOSE To evaluate the outcomes of unfavorable intermediate-risk (UIR) and high-risk (HR) prostate cancer patients treated with combined external beam radiation therapy (EBRT) and low-dose-rate prostate brachytherapy (LDR-PB). METHODS AND MATERIALS A population-based cohort of 568 prostate cancer patients treated with combined EBRT and LDR-PB from 2010 to 2016 was analyzed. All patients received EBRT followed by LDR-PB boost. Outcomes were compared with the results for the brachytherapy arm of the ASCENDE-RT trial. RESULTS The median followup was 4.5 years. Sixty-nine percent (N = 391) had HR disease. Ninety-four percent of the HR and 57% of UIR were treated with androgen deprivation therapy (ADT) with a median duration of 12 months. The 5-year K-M biochemical progression-free survival (b-PFS), metastasis-free survival (MFS), and overall survival (OS) were 84 ± 2%, 90 ± 2%, and 88 ± 2%, similar to 89 ± 5%, 94 ± 4%, and 92 ± 4% for the ASCENDE-RT LDR-PB arm. The likelihood of achieving a PSA ≤0.2 ng/mL at 4 years was 88%, similar to 86% in the ASCENDE-RT LDR-PB arm. Thirty-three men (5.8%) would have been ineligible for ASCENDE-RT due to high-risk features. The 5-year K-M b-PFS, MFS and OS estimates were 86 ± 2%, 92 ± 1% and 89 ± 2% for the ASCENDE-RT eligible versus 56 ± 10% (p < 0.001), 73 ± 8% (p < 0.001), and 77 ± 9% (p = 0.098) for the ineligible patients. CONCLUSIONS In this population-based cohort, combining LDR-PB with pelvic EBRT (+/- ADT) achieves very favorable b-PFS that compares to the LDR-PB arm of the ASCENDE-RT, supporting the generalizability of those results. Men ineligible for ASCENDE-RT, based on prognostic features, have a much higher risk of biochemical recurrence and metastatic relapse.

Pathology from trans-perineal template mapping biopsy (TTMB) can be used as labels to train prostate cancer classifiers. In this work, we propose a framework to register TTMB cores to advanced volumetric ultrasound data such as multi-parametric transrectal ultrasound (mpTRUS). The framework has mainly two steps. First, needle trajectories are calculated with respect to the needle guiding template—considering deflections in their paths. In standard TTMB, a sparsely sampled ultrasound volume is taken prior to the procedure which contains the template overlaid on top of it. The position of this template is detected automatically, and the cores are mapped following the calculated needle trajectories. Second, the TTMB volume is aligned to the mpTRUS volume by a two-step registration method. Using the same transformations from the registration step, the cores are registered from the TTMB volume to the mpTRUS volume. TTMB and mpTRUS of 10 patients were available for this work. The target registration errors (TRE) of the volumes using landmarks picked by three research assistants (RA) and one radiation oncologist (RO) were on average 1.32 ± 0.7 mm and 1.03 ± 0.6 mm, respectively. Additionally, on average, our framework takes only 97 s to register the cores. Our proposed framework allows a quick way to find the spatial location of the cores with respect to volumetric ultrasound. Furthermore, knowing the correct location of the pathology will facilitate focal treatment and will aid in training imaging-based cancer classifiers.

Consolidative radiation therapy (RT) for advanced-stage diffuse large B-cell lymphoma (DLBCL) remains controversial, with routine practice continuing to include RT in patients with initial bulky disease or residual masses. Positron emission tomography (PET)-computed tomography is a sensitive modality for detecting the presence of residual disease at the end of treatment (EOT). A PET-guided approach to selectively administering RT has been the policy in British Columbia since 2005. Patients with advanced-stage DLBCL diagnosed from 1 January 2005 to 1 March 2017 and treated with at least 6 cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituximab), who underwent EOT PET, were included in this analysis. Those with complete metabolic response (PET-negative [PET-NEG]) were observed; those with PET-positive (PET-POS) scans were offered consolidative RT, when feasible. Of the patient records reviewed, 723 were identified, with median follow-up of 4.3 years: 517 (72%) were PET-NEG; 206 (28%) were PET-POS. Time to progression (TTP) and overall survival (OS) at 3 years were 83% vs 56% and 87% vs 64%, in patients with PET-NEG and PET-POS scans, respectively. PET-POS patients with nonprogressing disease treated with consolidative RT (109 and 206; 53%) had outcomes approaching those of PET-NEG patients, with 3-year estimates of 76% and 80% for TTP and OS. PET-NEG patients who had bulky disease (≥10 cm) at diagnosis had outcomes indistinguishable from those without bulk, despite the omission of RT. These data suggest that patients with advanced-stage DLBCL who are PET-NEG at EOT and receive no RT have excellent outcomes. 18F-fluorodeoxyglucose-PET can reliably guide selective administration of consolidative RT, even in patients with initially bulky disease.

Purpose: To report the primary endpoint of biochemical progression-free survival (bPFS) and secondary survival endpoints from ASCENDE-RT, a randomized trial comparing 2 methods of dose escalation for intermediate-and high-risk prostate cancer.Methods and Materials: ASCENDE-RTenrolled 398men, with amedian age of 68 years; 69% (n = 276) had high-risk disease. After stratification by risk group, the subjects were randomized to a standard arm with 12 months of androgen deprivation therapy, pelvic irradiation to 46 Gy, followed by a dose-escalated external beamradiation therapy (DE-EBRT) boost to 78 Gy, or an experimental arm that substituted a low-dose-rate prostate brachytherapy (LDR-PB) boost. Of the 398 trial subjects, 200 were assigned to DE-EBRT boost and 198 to LDR-PB boost. The median follow-up was 6.5 years.Results: In an intent-to-treat analysis, men randomized to DE-EBRTwere twice as likely to experience biochemical failure (multivariable analysis [MVA] hazard ratio [HR] 2.04; P= .004). The 5-, 7-, and 9-year Kaplan-Meier b-PFS estimates were 89%, 86%, and 83% for the LDR-PB boost versus 84%, 75%, and 62% for the DE-EBRT boost (log-rank P<.001). The LDR-PB boost benefited both intermediate- and high-risk patients. Because the b-PFS curves for the treatment arms diverge sharply after 4 years, the relative advantage of the LDR-PB should increase with longer follow-up. OnMVA, the only variables correlated with reduced overall survival were age (MVA HR 1.06/y; P = .004) and biochemical failure (MVA HR 6.30; P<.001). Although biochemical failure was associated with increased mortality and randomization to DE-EBRT doubled the rate of biochemical failure, no significant overall survival difference was observed between the treatment arms (MVA HR 1.13; P= .62).Conclusions: Compared with 78 Gy EBRT, men randomized to the LDR-PB boost were twice as likely to be free of biochemical failure at amedian follow-up of 6.5 years. (C) 2016 Elsevier Inc. All rights reserved.

PURPOSE: The purpose of the study was to assess the feasibility of performing intraoperative dosimetry for permanent prostate brachytherapy by combining transrectal ultrasound (TRUS) and fluoroscopy/cone beam CT [CBCT] images and accounting for the effect of prostate deformation. METHODS AND MATERIALS: 13 patients underwent TRUS and multiview two-dimensional fluoroscopic imaging partway through the implant, as well as repeat fluoroscopic imaging with the TRUS probe inserted and retracted, and finally three-dimensional CBCT imaging at the end of the implant. The locations of all the implanted seeds were obtained from the fluoroscopy/CBCT images and were registered to prostate contours delineated on the TRUS images based on a common subset of seeds identified on both image sets. Prostate contours were also deformed, using a finite-element model, to take into account the effect of the TRUS probe pressure. Prostate dosimetry parameters were obtained for fluoroscopic and CBCT-dosimetry approaches and compared with the standard-of-care Day-0 postimplant CT dosimetry. RESULTS: High linear correlation (R-2 > 0.8) was observed in the measured values of prostate D-90%, V-100%, and V-150%, between the two intraoperative dosimetry approaches. The prostate D-90% and V-100% obtained from intraoperative dosimetry methods were in agreement with the postimplant CT dosimetry. Only the prostate V(150% )was on average 4.1% (p-value <0.05) higher in the CBCT-dosimetry approach and 6.7% (p-value <0.05) higher in postimplant CT dosimetry compared with the fluoroscopic dosimetry approach. Deformation of the prostate by the ultrasound probe appeared to have a minimal effect on prostate dosimetry. CONCLUSIONS: The results of this study have shown that both of the proposed dosimetric evaluation approaches have potential for real-time intraoperative dosimetry. (C) 2020 American Brachy-therapy Society. Published by Elsevier Inc. All rights reserved.

Background and purpose: To identify a PSA threshold value at an intermediate follow-up time after low dose rate (LDR) prostate brachytherapy associated with cure, defined as long-term (10-15 year) freedom from prostate cancer. Materials and methods: Data from 7 institutions for 14,220 patients with localized prostate cancer treated with LDR brachytherapy, either alone (8552) or with external beam radiotherapy (n = 1175), androgen deprivation (n = 3165), or both (n = 1328), were analyzed. Risk distribution was 42.4% favorable, 49.2% intermediate, and 8.4% high-risk. Patients with clinical failure before 3.5 years were excluded. Kaplan-Meier analysis was used with clinical failure (local, distant, regional or biochemical triggering salvage) as an endpoint for each of four PSA categories: PSA <= 0.2, >0.2 to <= 0.5, >0.5 to <= 1.0, and >1.0 ng/mL. PSA levels at 4 years (+/- 6 months) in 8746 patients without clinical failure were correlated with disease status at 10-15 years. Results: For the 77.1% of patients with 4-year PSA <= 0.2, the freedom-from-recurrence (FFR) rates were 98.7% (95% CI 98.3-99.0) at 10 years and 96.1% (95% CI 94.8-97.2) at 15 years. Three independent validation cohorts confirmed 97-99% 10-year FFR rates with 4-year PSA <= 0.2. Successive PSA categories were associated with diminished disease-free rates at 10 and 15 years. PSA category was strongly associated with treatment success (p < 0.0005). Conclusions: Since 98.7% of patients with PSA <= 0.2 ng/mL at 4 years after LDR prostate brachytherapy were disease-free beyond 10 years, we suggest adopting this biochemical definition of cure for patients with >= 4 years' follow-up after LDR brachytherapy. (C) 2020 Elsevier B.V. All rights reserved.

Purpose: To determine whether the use of 6 months' adjuvant androgen deprivation therapy (ADT) combined with brachytherapy for intermediate-risk (IR) and low-risk (LR) prostate cancer is associated with an increased risk of cardiovascular death. Methods and Materials: This is a retrospective analysis of prospectively collected data from men treated in the British Columbia Cancer Agency brachytherapy program from 1998 to 2012. Men were categorized by risk group and ADT use. Cardiac and other comorbidities were recorded and compared between groups. Biochemical control (Phoenix definition, nadir thorn + 2 ng/mL) was ascertained. Overall, prostate, cardiac, and other-cause mortality were analyzed by the Kaplan-Meier method and Fine and Gray competing-risk analysis. Results: The study included 3155 men (1142 with LR cancer and 2013 with IR cancer) who have been followed up for a median of 7.9 years. ADT was received by 47% of IR patients and 37% of LR patients for a median of 6 months. Men with IR cancer were older and had more cardiac and other comorbidities than LR cases (P<.01). Biochemical control improved from 86% to 89% at 10 years with the use of ADT (P=.006). Overall survival was inferior in patients receiving ADT (84% vs 86% at 10 years, P=.0274), and on competing-risk analysis, cardiovascular mortality in patients receiving ADT was higher in IR cases, 5.2% versus 3.6% at 10 years (P=.0493), but not in LR cases. Multivariate analysis confirmed increased cardiac mortality in IR patients receiving ADT (hazard ratio, 1.95 [95% confidence interval, 1.15-3.34]; P=.014). Conclusions: ADT adds little meaningful benefit in terms of biochemical control for IR men treated with low-dose-rate brachytherapy but likely decreases overall survival because of increased cardiac mortality. IR patients were older and had more cardiac risk factors than LR prostate cases; this may be because of a screening effect, case selection, or common etiologic cause. (C) 2017 Elsevier Inc. All rights reserved.

To analyze the effect of prognostic variables and treatment factors on biochemical progression free survival (b-PFS) using a consecutive cohort of 4150 Iodine-125 low-dose-rate prostate brachytherapy (LDR-PB) monotherapy patients treated in a multi-centre, multi-practitioner setting.

Purpose To compare biochemical failure using a prostate-specific antigen (PSA) threshold of >0.2 ng/mL to that using Phoenix threshold (nadir+2 ng/mL). Methods and Materials Androgen suppression combined with elective nodal and dose-escalated radiation therapy (the ASCENDE-RT trial) is a randomized control trial in which 276 high-risk and 122 intermediate-risk patients were randomized to (1) a standard arm with 12 months of androgen deprivation therapy, pelvic external beam radiation therapy (EBRT) to 46 Gy, and an EBRT boost (dose-escalated EBRT [DE-EBRT]) to 78 Gy, or (2) an experimental arm which substituted a low-dose-rate prostate brachytherapy boost (LDR-PB). The primary endpoint was biochemical progression-free survival (b-PFS) using the Phoenix threshold. In this reanalysis of ASCENDE-RT, the b-PFS using phoenix is compared to the surgical PSA threshold of >0.2 ng/mL. Results Compared to nadir+2 ng/mL, the >0.2 ng/mL PSA threshold doubled the number of relapse events from 69 to 139. However, the increase was confined to the DE-EBRT subjects. The 7-year Kaplan-Meier b-PFS after DE-EBRT declined from 76% using nadir+2 ng/mL to 38% using the >0.2 ng/mL threshold (p < 0.001). Among the LDR-PB subset, there was no significant difference in b-PFS; the 7-year Kaplan-Meier b-PFS was 85% (>0.2 ng/mL) versus 88% (nadir+2 ng/mL) (p = 0.319). Conclusions Replacing Phoenix with a surgical threshold greatly increased biochemical failure after DE-EBRT boost but had no effect after LDR-PB. As a result of this finding, PSA outcomes after surgery or brachytherapy can be directly compared by using the surgical definition of PSA failure. In this context, a brachytherapy boost appears to produce superior b-PFS compared to contemporary surgical series.

Limited-stage Hodgkin lymphoma (HL) is a highly curable malignancy when treated with combination chemotherapy with or without radiotherapy (RT). The majority of patients experience long-term survival but remain at risk for late treatment-related complications, particularly those related to RT, including second malignancies and cardiovascular disease. In an attempt to balance the risks and benefits of the use of RT for patients with limited stage HL, especially potential long-term toxicity, the Lymphoma Tumor Group at BC Cancer introduced a treatment policy change in July 2005 recommending an approach based on 18F-fluorodeoxyglucose (FDG) positron emission tomography after two cycles of chemotherapy (PET2). Patients achieving a complete response (CR) after two cycles of ABVD, defined as a negative PET2, were recommended to receive two additional cycles of ABVD without RT. Patients with a positive PET2 were switched to involved nodal radiotherapy (INRT), with the rationale that using non-cross-resistant RT has the potential to eradicate possible residual disease implied by persistent PET positivity despite ABVD. Patients age >15 years diagnosed with limited stage classical HL between July 2005 and April 2016 were identified in the BC Cancer Lymphoid Cancer Database. Limited stage was defined as Ann Arbor stage IA, IB or IIA, with or without associated contiguous extranodal extension, and with the largest single mass measuring <10 cm. Patients were not otherwise categorized into favorable or unfavorable subgroups because erythrocyte sedimentation rate is not routinely tested at our institution. Diagnostic biopsies were reviewed by an expert BC Cancer hematopathologist and classified according to the World Health Organization Classification. PET2 scans were performed and reported centrally at the BC Cancer – Vancouver Cancer Centre. Before January 2014, PET scans were interpreted based on the International Harmonization Project to categorize PET2 results as negative, indeterminate, or positive to guide therapy. Those with an indeterminate score were recommended to be treated as PET positive and receive INRT. This was replaced by the 5-point Deauville (D) scale in January 2014 where D1 and D2 were considered PET negative (i.e., a CR), D3-5 were considered PET positive, and cases with new uptake not felt to represent lymphoma were assigned a ‘X’ score. Importantly, both systems considered the PET2 as positive if the maximum uptake was greater than the mediastinum and, therefore, requiring RT (i.e., including those with an indeterminate score). A total of 286 prospectively diagnosed patients with stage IA, IB, or IIA HL diagnosed between 2005 – 2016 were identified. Of these, 47 were excluded for the following reasons: 37 nodular lymphocyte predominant HL, 9 illness/frailty at baseline precluding a PET-driven curative approach, and 1 in whom PET2 was not performed. Clinical characteristics of the 239 patients included in the current analysis are listed in Table 1. Patients were intended to receive two cycles of ABVD with curative intent, although 4 patients received a third cycle due to difficulty scheduling PET scans and 5 patients received ABVD-based alternating or hybrid regimens, which were considered to be equivalent to ABVD, by physician choice. Following two cycles of initial chemotherapy, PET2 was negative in 210 (88%) patients, and positive in 29 (12%). The IHP response criteria were applied in 173 (72%) patients while Deauville criteria were applied to the remaining 66 (28%) patients, with no difference in the proportion of patients achieving a PET2 negative scan (88% vs. 86%, respectively, P=0.660). Among the 210 PET2-negative patients planned for treatment with 2 additional cycles of ABVD, the majority (n=206, 98%) received 2 additional cycles of ABVD, although 4 of the 206 were not able to complete all 4 cycles (total 2 cycles [n=1], 3 cycles [n=3]) due to patient refusal (n=2) or chemotherapy toxicity (n=2, both with severe fatigue), and did not receive further therapy. The remaining 4 PET2-negative patients were immediately switched to INRT after the two initial cycles of ABVD by physician/patient preference due to perceived intolerance to chemotherapy. All 29 PET2-positive patients (median SUVmax 2.8 [range 1.5 – 26]) received consolidative INRT. Of these

Purpose: Defining biochemical failure as nadir + 2 may overestimate cure after radiotherapy. We assessed long-term prostate specific antigen stability after low dose rate prostate brachytherapy and predictors of biochemical failure when prostate specific antigen was slowly rising below the nadir + 2 ng/ml threshold. Materials and Methods: A total of 2,339 patients with low or intermediate risk prostate cancer received 125 iodine brachytherapy from 1998 to 2010 with a minimum 3-year followup. In addition, 49.7% of the patients received 6 months of androgen deprivation. Clinical, dosimetric and prostate specific antigen data were retrieved from a prospective database. Biochemical results were classified as stable or rising prostate specific antigen (0.2 ng/ml or greater and increased 0.1 ng/ml or greater during the preceding 2 years), or biochemical failure (defined as nadir + 2). Multivariate analysis was done to identify predictors of failure used to create logistic regression models. Results: At a median followup of 89 months (range 37 to 199) prostate specific antigen was stable (nadir 0.03 ng/ml and at 60 months 0.04 ng/ml) in 2,004 patients (86%) and rising (nadir 0.16 ng/ml and at 60 months 0.29 ng/ml) in 145 (6%) while biochemical failure (nadir 0.51 ng/ml, p <0.001) was noted in 190 (8%). When there was no prior androgen deprivation therapy, the prostate specific antigen nadir and prostate specific antigen at 60 months were the strongest predictors of failure (OR 20.6 and 18.3, respectively, each p <0.0001). The logistic regression model had 85% sensitivity and 98% specificity, and predicted failure in 8 of 82 men (9.8%). A second model was created for the group with androgen deprivation therapy and rising prostate specific antigen using the predictive factors prostate specific antigen at 60 months (OR 53.9, p <0.0001) and T stage (OR 0.25, p = 0.0008). This model predicted biochemical failure in 30 of 56 men (54%) with 85% sensitivity and 93% specificity. The 2 predictive models yield an anticipated 90% cure rate in the entire cohort. Conclusions: Brachytherapy is highly curative with stable prostate specific antigen at a surgical ablation level in 86% of patients. Rising prostate specific antigen is rare at a 6% incidence and often innocuous.

Purpose: To report the patient-reported health-related quality of life (HR-QoL) outcomes for a multicenter randomized trial evaluating the safety and efficacy of 2 different techniques for dose escalation.Methods and Materials: A total of 357 men with intermediate-and high-risk prostate cancer were stratified by risk group and randomized (1:1) to either a dose-escalated external beam (DE-EBRT) boost (n=177) or a low-dose-rate prostate brachytherapy (LDR-PB) boost (n=180) as part of combined modality therapy. The HR-QoL was assessed using the SF36v2 questionnaire, with additional scales for urinary, bowel, and sexual function. Date of starting androgen deprivation therapy was considered time zero, the median follow-up of 6 years. Scales were scored from 0 to 100; a decline in a mean score >= 10 compared with baseline was considered a clinically significant decline. This was an intent-to-treat analysis.Results: Mean domain scores at baseline were well balanced between the 2 treatment arms. A clinically significant decline in mean scores in both the arms compared with baseline was noted for role physical (DE-EBRT [-11.4] and LDR-PB [-15.3]) and sexual function scale (DE-EBRT [-15.1] and LDR-PB [-19.2]). There was a significantly larger drop in mean scores in the LDR-PB group compared with the DE-EBRT group for physical function (-15.3 vs -6.9; P=.03), urinary function (-3.6 vs -0.5; P=.04).Conclusion: At 6 years' follow up, there were no significant differences in mean scores in 9 of 11 scales compared with baseline in both arms. A clinically significant decline in mean scores was noted in both arms for role physical and sexual function scales. There was a statistically significant decline in physical function and urinary function scales in the LDR-PB arm compared with the DE-EBRT arm. Crown Copyright (C) 2017 Published by Elsevier Inc. All rights reserved.

To the Editor: We read with interest a recent report from the Cleveland Clinic ( 1 Ciezki J.P. Weller M.D. Reddy C.A. et al. A comparison between low-dose-rate brachytherapy with or without androgen deprivation , and radical prostatectomy with or without adjuvant or salvage radiation therapy for high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2017; 97: 962-975 Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar ) detailing 5- and 10-year oncologic endpoints for National Comprehensive Cancer Network high-risk prostate cancer (HRCaP) based on a large consecutive cohort treated at that facility. Although the article has much to recommend it, we were disappointed to find a factually incorrect and potentially misleading comment in the Discussion (page 969, paragraph 2); we quote:Comparisons between the ASCENDE-RT trial and this series for bRFS are challenging because only two-thirds of the patients in ASCENDE-RT had HRCaP, whereas the remaining one third had intermediate-risk disease. Yet, the control arm (EBRT + ADT) of ASCENDE-RT fared about 20% worse than the patients in any of the modalities in this series, depending on the bRFS definition used (15). The difference is difficult to explain because one would expect the reverse, given the longer duration of ADT in ASCENDE-RT versus this series (12 months vs 6 months) and underscores the hazards of using bRFS as an endpoint to evaluate treatment efficacy. A Comparison Between Low-Dose-Rate Brachytherapy With or Without Androgen Deprivation, External Beam Radiation Therapy With or Without Androgen Deprivation, and Radical Prostatectomy With or Without Adjuvant or Salvage Radiation Therapy for High-Risk Prostate CancerInternational Journal of Radiation Oncology, Biology, PhysicsVol. 97Issue 5PreviewWe compare the efficacy and toxicity among the 3 major modalities available used to treat high-risk prostate cancer (HRCaP). Full-Text PDF In Reply to Morris and TyldesleyInternational Journal of Radiation Oncology, Biology, PhysicsVol. 99Issue 1PreviewTo the Editor: We thank Drs Morris and Tyldesley for pointing out our error in reporting the results of the ASCENDE-RT trial (1, 2). When reading the abstract (3) we were mistaken in reading the “Results” section. Specifically, the results reporting begins with reference to biochemical failure scored via the Phoenix definition (4) and then proceeds to report specific percentages using a 0.2-ng/mL threshold definition. We made an error in assuming that the entire reporting of biochemical results was according to the definition mentioned in the initial sentences. Full-Text PDF

AIMS:This study describes the proportion of men who experienced hot flashes (flashes), and the testosterone level at onset, peak frequency and cessation of flashes after 12 months of androgen deprivation therapy (ADT) in men undergoing curative-intent external beam radiation therapy (± brachytherapy boost). We also aimed to characterise testosterone recovery in this population. MATERIALS AND METHODS:This was a pre-specified secondary analysis of the ASCENDE-RT clinical trial. Three hundred and ninety-eight men were randomised. All received 12 months of ADT. The presence and frequency of flashes were patient reported. Cessation of flashes was defined as the first date a patient reported resolution of this symptom. Testosterone recovery was defined as any single serum testosterone above the threshold of 5, 7.5 or 10 nmol/l. RESULTS:The median age and follow-up were 68 years and 6.1 years. Flashes were reported in 93% of men. Flashes began and reached peak frequency at a median time of 4.0 months from the first luteinizing hormone-releasing hormone injection when testosterone levels had fallen to castrate. The median time to cessation of flashes was 7.6 months after the cessation of ADT (last injection + 3 months), when the median testosterone had risen to 5.7 nmol/l. A resolution of flashes was reported in 99% of patients. Baseline testosterone was available in 338 patients (85%). The median baseline testosterone was 13.2 nmol/l. The median (95% confidence interval) time of testosterone recovery to thresholds of 5 nmol/l, 7.5 nmol/l and 10 nmol/l were 9 (9-10) months, 13 (10-15) months and 18 (17-19) months from the cessation of ADT. At the time of censor, 96, 94 and 91% of patients had recovered testosterone to thresholds of 5, 7.5 and 10 nmol/l. CONCLUSION:Flashes occur at castrate levels of testosterone, with cessation of hot flashes antedating full recovery of testosterone in most patients. Rates of testosterone recovery after 12 months of ADT exceed 90%, although it can be delayed.