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Introduction: Recent advances in image-guided brachytherapy have allowed for treatment volume reduction in the treatment of prostate cancer, with the aim to optimize disease control and reduce toxicities. This systematic review reports on the efficacy and safety of focal brachytherapy for treatment of patients with localized prostate cancer., Methods: Medline, Embase, Web of Science and Cochrane were searched from inception to July 2023. Studies were included if they reported on focal brachytherapy, and described either dosimetry or clinical outcomes in the monotherapy or salvage setting. Meta-analysis was conducted to estimate biochemical control (BC) at 12-60 months. The review protocol was registered on PROSPERO (CRD42022320921)., Results: 26 studies reporting on 1492 patients were included in this review. 14 studies reported on monotherapy, 10 on salvage and 2 on boost. The majority of studies used MRI and/or biopsy or PET for target identification, and MRI fusion and transrectal ultrasound (TRUS) for image guidance technique. BC for monotherapy was 97% (95%CI: 86-99%) at 24 months, and 82% (95%CI: 65-92%) at 60 months. BC for salvage was 67% (95%CI: 62-72%) at 24 months, and 35% (95%CI: 17-58%) at 60 months. Low rates of toxicity were reported across studies., Conclusion: Focal brachytherapy has promising efficacy and safety profiles. Future studies may compare focal brachytherapy to whole-gland treatments, to investigate relative efficacy and safety., Advances in Knowledge: In well-selected patients, partial or focal brachytherapy represents an evidence-based option with acceptable BC rates and a favourable toxicity profile., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Institute of Radiology.)

Breast-conserving surgery followed by adjuvant radiation to reduce the risk of ipsilateral breast tumor recurrence is the mainstay of treatment for early-stage breast cancer (ESBC). However, improved understanding of the heterogeneity of the clinical and molecular characteristics of ESBC has led to greater efforts to personalize approaches to treatment. Furthermore, advances in the understanding of the radiobiology of breast cancer have led to several practice-changing trials on the effectiveness and tolerability of moderate and ultrahypofractionated radiation. Here, we review the recent evidence and ongoing research in the radiotherapeutic management of ESBC, including the use of boost for high-risk disease and opportunities for accelerated fractionation, partial breast irradiation, and radiation omission for low-risk disease. We also discuss how molecular profiling can inform decision-making and new opportunities for primary radiation therapy and reirradiation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Objectives: To compare the outcomes and treatment burden of primary retroperitoneal lymph node dissection (pRPLND) alone versus pRPLND + adjuvant chemotherapy (AC) in patients with pathological stage II (PSII) non-seminomatous germ cell tumours (NSGCT)., Patients and Methods: Retrospective review of the Princess Margaret Cancer Center eTestes cancer database identified patients with PSII NSGCT after pRPLND between 1995 and 2020. The primary outcome was relapse-free survival (RFS). Secondary outcomes included disease-specific survival (DSS), burden of relapse treatment, and factors associated with relapse., Results: A total of 109 PSII patients were included in the study. There were 96 patients treated with pRPLND alone and 13 treated with pRPLND + AC. The median follow-up was 61 months. The 5-year RFS was 72% for the pRPLND-only group vs 92% for the pRPLND + AC group (hazard ratio [HR] 4.372, 95% confidence interval [CI] 0.59-32.36; P = 0.11). Within the pRPLND-only group the 5-year RFS differed by pN stage (pN1 = 94% vs pN2/N3 = 67%, P = 0.03). Despite a higher relapse rate within the pRPLND-only group, the DSS was similar at 5 years (98% pRPLND only vs 100% pRPLND + AC, P = 0.48). Only 24 (25%) of the patients in the pRPLND-only group required any subsequent chemotherapy. Despite achieving similar survival, the cumulative post-RPLND treatment burden was less for the pRPLND-only group than the pRPLND+AC group overall (average 1.23 vs 2.46 cycles of chemotherapy per patient in group)., Conclusion: The majority of patients with PSII NSGCT treated with pRPLND alone do not experience a recurrence or require chemotherapy. Despite a lower relapse risk when AC is given, no difference in survival was seen but higher chemotherapy burden was entertained. AC may constitute overtreatment for most patients with PSII NSGCT treated with pRPLND., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Purpose: In oligoprogressive (OP) cancer, there are a limited number of metastatic areas progressing on a background of stable or responding to widespread cancer. Although the standard of care for OP is changing systemic therapy (ST), stereotactic body radiation therapy (SBRT) is being explored as an alternative local therapy targeting the sites of progression., Methods and Materials: RADIANT (NCT04122469) was a single-center phase 2 study of patients with metastatic genitourinary (GU), breast, and gastrointestinal (GI) cancers, receiving ST for ≥3 months, with radiographic OP disease in ≤5 sites. Patients received SBRT for all OP disease in 1 to 5 fractions and were maintained on ST. The primary endpoint was the cumulative incidence of change in ST, which was estimated using the Aalen-Johansen method. Secondary endpoints included progression-free survival (PFS) and overall survival estimated using the Kaplan-Meier method, as well as toxicity and health-related quality of life. Comparisons between diagnosis groups were done using the log-rank test. A 2-sided p value <.05 was considered statistically significant., Results: Seventy patients were analyzed, with a median age of 69 years; 32 patients (46%) were women; the median number of lines of prior ST was 3. Primary sites were GU (n = 32; 46%), breast (n = 23; 33%), and GI (n = 15; 21%). The median follow-up was 12.3 months (IQR, 8.2-21.6 months). At 1 year, change in ST occurred in 47% (95% CI, 36%-61%) (GU 45%, breast 41%, and GI 60%; p = .23). PFS at 1 year was 32% (95% CI, 23%-45%), and median PFS was 4.7 months (95% CI, 3.8-8.1) (GU 4.8, breast 6.5, and GI 3.2), which significantly differed by disease type (p = .006). Overall survival was 75% at 1 year (95% CI, 65%-87%), which significantly differed between cancer types (GU 86%, breast 96%, and GI 22%; p < .001). The cumulative incidence of late grade ≥2 toxicity was 1.2%, with 1 patient experiencing late grade 3 toxicity and no grade 4 to 5 acute or late toxicities. Health-related quality of life declined from the mean (SD) of 66.9 (20.2) at baseline to 60.5 (22.2) at 6 months, which did not meet the threshold for a minimal clinically important difference., Conclusions: SBRT for OP metastases delayed change in ST in approximately half of patients, warranting investigation in randomized trials., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Emerging randomized data, mostly from phase II trials, have suggested that patients with oligometastatic cancers may benefit from ablative treatments such as stereotactic ablative radiotherapy (SABR). However, phase III data testing this paradigm are lacking, and many studies have examined SABR in the setting of metachronous oligometastatic disease. The goal of the SABR-SYNC trial is to assess the effect of SABR in patients with oligometastatic cancers and a synchronous primary tumor., Methods: One hundred and eighty patients will be randomized in a 1:2 ratio between standard of care (SOC) palliative-intent treatments vs. SOC + ablative therapy (SABR preferred) to all sites of known disease. Randomization will be stratified based on histology and number of metastases at enrollment. SABR may be delivered in 1-, 3- and 5-fraction regimens, with recommended doses of 20 Gy, 30 Gy, and 35 Gy, respectively. Non-SABR local modalities (e.g. surgery, thermal ablation, conventional radiation) may be used for treatment of the primary or metastases at the discretion of the treating physicians, if those modalities are clinically preferred. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, time to development of new metastatic lesions, time to initiation of next systemic therapy, quality of life, and toxicity. Translational endpoints include assessment of circulating tumor DNA and immunological predictors of outcomes., Discussion: SABR-SYNC will provide phase III data to assess the impact of SABR on overall survival in a population of patients with synchronous oligometastases. The translational component will attempt to identify novel prognostic and predictive biomarkers to aid in clinical decision making., Trial Registration: Clinicaltrials.gov NCT05717166 (registration date: Feb. 8, 2023)., (© 2024. The Author(s).)

Background and Purpose: Data is needed regarding the use of ultrahypofractionated radiotherapy (UHRT) in the context of prostate cancer elective nodal irradiation (ENI), and how this compares to conventionally fractionated radiotherapy (CFRT) ENI with CFRT or moderately hypofractionated radiotherapy (MHRT) to the prostate., Materials and Methods: Between 2011-2019, 3 prospective clinical trials of unfavourable intermediate or high-risk prostate cancer receiving CFRT (78 Gy in 39 fractions to prostate; 46 Gy in 23 fractions to pelvis), MHRT (68 Gy in 25 fractions to prostate; 48 Gy to pelvis), or UHRT (35-40 Gy in 5 fractions to prostate +/- boost to 50 Gy to intraprostatic lesion; 25 Gy to pelvis) were conducted. Primary endpoints included biochemical failure (Phoenix definition), and acute and late toxicities (CTCAE v3.0/4.0)., Results: Two-hundred-forty patients were enrolled: 90 (37.5 %) had CFRT, 90 (37.5 %) MHRT, and 60 (25 %) UHRT. Median follow-up time was 71.6 months (IQR 53.6-94.8). Cumulative incidence of biochemical failure (95 % CI) at 5-years was 11.7 % (3.5-19.8 %) for CFRT, 6.5 % (0.8-12.2 %) MHRT, and 1.8 % (0-5.2 %) UHRT, which was not significantly different between treatments (p = 0.38). Acute grade ≥ 2 genitourinary toxicity was significantly worse for UHRT versus CFRT and MHRT, but not for acute grade ≥ 3 genitourinary, or acute gastrointestinal toxicities. UHRT was not associated with worse late toxicities., Conclusion: ENI with UHRT resulted in similar oncologic outcomes to CFRT ENI with prostate CFRT/MHRT, with worse acute grade ≥ 2 GU toxicity but no differences in late toxicity. Randomized phase 3 trials of ENI using UHRT techniques are much anticipated., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RMG reports honoraria from Bayer, Tolmar, Knight, and TerSera; Research funding from Astellas and TerSera. CLT reports travel accommodations/expenses & honoraria for past educational seminars by Elekta; belongs to the Elekta MR-Linac Consortium; advisor/consultant with Sanofi and AbbVie. AL reports honoraria/travel from AbbVie, Astellas, Bayer, Janssen, Knight, TerSera; Grant/research support from TerSera and Tolmar; Advisory boards/consulting for Astellas, Bayer, Janssen, Sanofi, Tolmar and TerSera; Patents/licenses for endorectal immobilization device (GU-Lok); Employment: spouse is national sales director, Sanofi Canada. PC reports honoraria from TerSera and AstraZeneca. All other authors report no disclosures., (© 2024 The Authors.)

Introduction: Current management of metastatic prostate cancer (mPC) includes androgen receptor axis-targeted therapy (ARATs), which is associated with substantial toxicity in older adults. Geriatric assessment and management and remote symptom monitoring have been shown to reduce toxicity and improve quality of life in patients undergoing chemotherapy, but their efficacy in patients being treated with ARATs has not been explored. The purpose of this study is to examine whether these interventions, alone or in combination, can improve treatment tolerability and quality of life (QOL) for older adults with metastatic prostate cancer on ARATs., Materials and Methods: TOPCOP3 is a multi-centre, factorial pilot clinical trial coupled with an embedded process evaluation. The study includes four treatment arms: geriatric assessment and management (GA + M); remote symptom monitoring (RSM); geriatric assessment and management plus remote symptom monitoring; and usual care and will be followed for six months. The aim is to recruit 168 patients between two cancer centres in Toronto, Canada. Eligible participants will be randomized equally via REDCap. Participants in all arms will complete a comprehensive baseline assessment upon enrollment following the Geriatric Core dataset, as well as follow-up assessments at 1.5, 3, 4.5, and 6 months. The co-primary outcomes will be grade 3-5 toxicity and QOL. Toxicities will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. QOL will be measured by patient self-reporting using the EuroQol 5 dimensions of health questionnaire. Secondary outcomes include fatigue, insomnia, and depression. Finally, four process evaluation outcomes will also be observed, namely feasibility, fidelity, and acceptability, along with implementation barriers and facilitators., Discussion: Data will be collected to observe the effects of GA + M and RSM on QOL and toxicities experienced by older adults receiving ARATs for metastatic prostate cancer. Data will also be collected to help the design and conduct of a definitive multicentre phase III randomized controlled trial. This study will extend supportive care interventions for older adults with cancer into new areas and inform the design of larger trials., Trial Registration: The trial is registered at clinicaltrials.gov (registration number: NCT05582772)., Competing Interests: Declaration of Competing Interest Dr. Krzyzanowska reports grants and personal fees from Eisai, grants and personal fees from Lilly, personal fees from Ipsen, personal fees from Bayer, grants from Exelixis, all outside the submitted work. Dr. Glicksman reports grants from Astellas Pharma, grants and personal fees from TreSera, personal fees from Bayer, personal fees from Tolmar, personal fees from Knight Therapeutics, all outside the submitted work. Dr. Emmenegger reports personal fees from Amgen, personal fees from AstraZeneca, grants and personal fees from Astellas, grants and personal fees from Bayer, grants and personal fees from Janssen, grants and personal fees from Merck, grants and personal fees from Novartis, personal fees from Pfizer, grants from Clovis, grants from Roche-Genentech, all outside the submitted work., (Copyright © 2023. Published by Elsevier Ltd.)

Background: The relapse rate in patients with clinical stage I (CSI) seminomatous germ cell tumor of the testis (SGCTT) who were undergoing surveillance after radical orchidectomy is 4-30%, depending on tumor size and rete testis invasion (RTI). However, the level of evidence supporting the use of both risk factors in clinical decision-making is low., Objective: We aimed to identify the most important prognostic factors for relapse in CSI SGCTT patients., Design, Setting, and Participants: Individual patient data for 1016 CSI SGCTT patients diagnosed between 1994 and 2019 with normal postorchidectomy serum tumor marker levels and undergoing surveillance were collected from nine institutions., Outcome Measurements and Statistical Analysis: Multivariable Cox proportional hazard regression models were fit to identify the most important prognostic factors. The primary endpoint was the time to first relapse by imaging and/or markers. Relapse probabilities were estimated by the Kaplan-Meier method., Results and Limitations: After a median follow-up of 7.7 yr, 149 (14.7%) patients had relapsed. Categorical tumor size (≤2, >2-5, and >5 cm), presence of RTI, and lymphovascular invasion were used to form three risk groups: low (56.4%), intermediate (41.3%), and high (2.3%) risks with 5-yr cumulative relapse probabilities of 8%, 20%, and 44%, respectively. The model outperformed the currently used model with tumor size ≤4 versus >4 cm and presence of RTI (Harrell's C index 0.65 vs 0.61). The low- and intermediate-risk groups were validated successfully in an independent cohort of 285 patients., Conclusions: The risk of relapse after radical orchidectomy in CSI SGCTT patients under surveillance is low. We propose a new risk stratification model that outperformed the current model and identified a small subgroup with a high risk of relapse., Patient Summary: The risk of relapse after radical orchidectomy in patients with clinical stage I seminomatous germ cell tumor of the testis is low. We propose a new risk stratification model that outperformed the current model and identified a small subgroup with a high risk of relapse., (Copyright © 2023. Published by Elsevier B.V.)

Purpose: The aim of this work is to report on the results of a phase 2 randomized trial of moderately hypofractionated (MH) versus conventionally fractionated (CF) radiation therapy to the prostate with elective nodal irradiation., Methods and Materials: This was a single-center, prospective, phase 2 randomized study. Patients with high-risk disease (cT3, prostate-specific antigen level >20 ng/mL, or Gleason score 8-10) were eligible. Patients were randomized to either MH using a simultaneous integrated boost (68 Gy in 25 fractions to prostate; 48 Gy to pelvis) or CF (46 Gy in 23 fractions with a sequential boost to the prostate of 32 Gy in 16 fractions), with long-term androgen deprivation therapy. The primary endpoint was grade ≥2 acute gastrointestinal (GI) and genitourinary (GU) toxicity (Common Terminology Criteria for Adverse Events version 3.0). Secondary endpoints included late GI and GU toxicity, quality of life, and oncologic outcomes., Results: One-hundred eighty patients were enrolled; 90 were randomized to and received MH and 90 to CF. The median follow-up was 67.4 months. Seventy-five patients (41.7%) experienced a grade ≥2 acute GI and/or GU toxicity, including 34 (37.8%) in the MH and 41 (45.6%) in the CF arms, respectively (P = .29). Late grade ≥2 GI (P = .07) and GU (P = .25) toxicity was not significantly different between arms; however, late grade ≥3 GI toxicity was worse in the MH group (P = .01). There were no statistically significant quality-of-life differences between the 2 treatments. There were no statistically significant differences observed in cumulative incidence of biochemical failure (P = .71) or distant metastasis (P = .31) and overall survival (P = .46)., Conclusions: MH to the prostate and pelvis with androgen deprivation therapy for men with high-risk localized prostate cancer was not significantly different than CF with regard to acute toxicity, quality of life, and oncologic efficacy. However, late grade ≥3 GI toxicity was more common in the MH arm., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Stereotactic ablative radiation therapy (SBRT) is an emerging treatment option for primary renal cell carcinoma (RCC), particularly in patients who are unsuitable for surgery. The aim of this review is to assess the effect of increasing the biologically equivalent dose (BED) via various radiation fractionation regimens on clinical outcomes., Methods: A literature search was conducted in PubMed (Medline), EMBASE, and the Cochrane Library for studies published up to October 2023. Studies reporting on patients with localized RCC receiving SBRT were included to determine its effectiveness on local control, progression-free survival, and overall survival. A random effects model was used to meta-regress clinical outcomes relative to the BED for each study and heterogeneity was assessed by I 2 ., Results: A total of 724 patients with RCC from 22 studies were included, with a mean age of 72.7 years (range: 44.0-81.0). Local control was excellent with an estimate of 99 % (95 %CI: 97-100 %, I 2  = 19 %), 98 % (95 %CI: 96-99 %, I 2  = 8 %), and 94 % (95 %CI: 90-97 %, I 2  = 11 %) at one year, two years, and five years respectively. No definitive association between increasing BED and local control, progression-free survival and overall survival was observed. No publication bias was observed., Conclusions: A significant dose response relationship between oncological outcomes and was not identified, and excellent local control outcomes were observed at the full range of doses. Until new evidence points otherwise, we support current recommendations against routine dose escalation beyond 25-26 Gy in one fraction or 42-48 Gy in three fractions, and to consider de-escalation or compromising target coverage if required to achieve safe organ at risk doses., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RG: institutional grant funding- Astellas, TerSera. Honoraria: Bayer, Tolmar, Knight, TerSera. SR: Institutional grant funding – Astra Zeneca, Knight therapeutics. Honoraria – Bayer, Astra Zeneca, Tersera, Sanofi, Verity pharma., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: An integrated magnetic resonance scanner and linear accelerator (MR-linac) was implemented with daily online adaptive radiation therapy (ART). This study evaluated patient-reported experiences with their overall hospital care as well as treatment in the MR-linac environment., Methods: Patients pre-screened for MR eligibility and claustrophobia were referred to simulation on a 1.5 T MR-linac. Patient-reported experience measures were captured using two validated surveys. The 15-item MR-anxiety questionnaire (MR-AQ) was administered immediately after the first treatment to rate MR-related anxiety and relaxation. The 40-item satisfaction with cancer care questionnaire rating doctors, radiation therapists, the services and care organization and their outpatient experience was administered immediately after the last treatment using five-point Likert responses. Results were analyzed using descriptive statistics., Results: 205 patients were included in this analysis. Multiple sites were treated across the pelvis and abdomen with a median treatment time per fraction of 46 and 66 min respectively. Patients rated MR-related anxiety as "not at all" (87%), "somewhat" (11%), "moderately" (1%) and "very much so" (1%). Positive satisfaction responses ranged from 78 to 100% (median 93%) across all items. All radiation therapist-specific items were rated positively as 96-100%. The five lowest rated items (range 78-85%) were related to general provision of information, coordination, and communication. Overall hospital care was rated positively at 99%., Conclusion: In this large, single-institution prospective cohort, all patients had low MR-related anxiety and completed treatment as planned despite lengthy ART treatments with the MR-linac. Patients overall were highly satisfied with their cancer care involving ART using an MR-linac., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Background Prostate-specific membrane antigen (PSMA) PET is useful in the early detection of oligorecurrent prostate cancer (PCa), but whether PSMA PET parameters can be used to identify patients who would benefit from metastasis-directed therapy (MDT) with radiation or surgery remains uncertain. Purpose To assess the association of PSMA PET parameters with outcomes of patients with oligorecurrent PCa after MDT. Materials and Methods In this retrospective analysis of a single-center phase II trial that enrolled patients with biochemical recurrence of PCa after maximal local therapy and with no evidence of disease at conventional imaging, patients underwent PSMA PET (between May 2017 and November 2021), and unveiled recurrences were treated with MDT. Maximum standardized uptake value (SUV max ) and mean standardized uptake value (SUV mean ) and PSMA tumor volume derived using thresholds of 2.5 (SUV mean2.5 ) and 41% (SUV mean41% ), respectively, were recorded for sites of recurrence on PSMA PET scans, and a molecular imaging PSMA score was assigned. These parameters were also corrected for smooth filter and partial volume effects, and the PSMA score was reassigned. Cox proportional hazards models were used to evaluate the relationship between PSMA PET parameters and outcomes. Results A total of 74 men (mean age, 68.3 years ± 6.6 [SD]) with biochemical recurrence of PCa were included. PSMA PET revealed 145 lesions in the entire cohort, of which 125 (86%) were metastatic lymph nodes. Application of the correction factor changed the PSMA score in 88 of 145 lesions (61%). Mean SUV max , SUV mean2.5 , and SUV mean41% were associated with lower risk of biochemical progression (hazard ratio [HR] range, 0.77-0.95; 95% CI: 0.61, 1.00; P = .03 to P = .04). For corrected parameters, mean SUV max , mean SUV mean2.5 , mean SUV mean41% , mean PSMA score, maximum SUV mean2.5 , maximum SUV mean41% , and maximum PSMA score were associated with a lower risk of biochemical progression (HR, 0.61-0.98; 95% CI: 0.39, 1.00; P = .01 to P = .04). Conclusion Measured and corrected PSMA PET parameters were associated with biochemical progression in men with oligorecurrent PCa treated with MDT. Clinical trial registration no. NCT03160794 © RSNA, 2023 See also the editorial by Civelek in this issue.

Purpose: To develop a practice-based training strategy to transition from radiation oncologist to therapist-driven prostate MR-Linac adaptive radiotherapy., Methods and Materials: In phase 1, 7 therapists independently contoured the prostate and organs-at-risk on T2-weighted MR images from 11 previously treated MR-Linac prostate patients. Contours were evaluated quantitatively (i.e. Dice similarity coefficient [DSC] calculated against oncologist generated online contours) and qualitatively (i.e. oncologist using a 5-point Likert scale; a score ≥ 4 was deemed a pass, a 90% pass rate was required to proceed to the next phase). Phase 2 consisted of supervised online workflow with therapists required no intervention from the oncologist on 10 total cases to advance. Phase 3 involved unsupervised therapist-driven workflow, with offline support from oncologists prior to the next fraction., Results: In phase 1, the mean DSC was 0.92 (range 0.85-0.97), and mean Likert score was 3.7 for the prostate. Five therapists did not attain a pass rate (3-5 cases with prostate contour score < 4), underwent follow-up one-on-one review, and performed contours on a further training set (n = 5). Each participant completed a median of 12 (range 10-13) cases in phase 2; of 82 cases, minor direction were required from the oncologist on 5 regarding target contouring. Radiation oncologists reviewed 179 treatment fractions in phase 3, and deemed 5 cases acceptable but with suggestions for next fraction; all other cases were accepted without suggestions., Conclusion: A training stepwise program was developed and successfully implemented to enable a therapist-driven workflow for online prostate MR-Linac adaptive radiotherapy., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

We conducted and previously published a phase 2 trial of metastasis-directed therapy (MDT) in men with recurrence of prostate cancer at a low prostate-specific antigen level following radical prostatectomy and postoperative radiotherapy. All patients had negative conventional imaging and underwent prostate-specific membrane antigen (PSMA) positron emission tomography (PET). Patients without visible disease ( n  = 16) or with metastatic disease not amenable to MDT ( n  = 19) were excluded from the interventional study. The remaining patients with disease visible on PSMA-PET received MDT ( n  = 37). We analyzed all three groups to identify distinct phenotypes in the era of molecular imaging-based characterization of recurrent disease. Median follow up was 37 mo (interquartile range 27.5-43.0). There was no significant difference in time to the development of metastasis on conventional imaging among the groups; however, castrate-resistant prostate cancer-free survival was significantly shorter for patients with PSMA-avid disease not amenable to MDT ( p  = 0.047). Our findings suggest that PSMA-PET findings can help in discriminating diverging clinical phenotypes among men with disease recurrence and negative conventional imaging after local therapies with curative intent. There is a pressing need for better characterization of this rapidly growing population of patients with recurrent disease defined by PSMA-PET to derive robust selection criteria and outcome definitions for ongoing and future studies., Patient Summary: In men with prostate cancer with rising PSA levels following surgery and radiation, a newer type of scan called PSMA-PET (prostate-specific membrane antigen positron emission tomography) can be used to characterize and differentiate the patterns of recurrence, and inform future cancer outcomes., (© 2023 The Author(s).)

Radiotherapy is a mainstay treatment option for localized prostate cancer (PCa), with oncological outcomes similar to those with surgery. Standard-of-care radiotherapy approaches include brachytherapy, hypofractionated external beam radiotherapy (EBRT), and EBRT with brachytherapy boost. Given the long survival associated with PCa and these curative-intent radiotherapy approaches, late toxicity is a paramount consideration. In this narrative mini-review, we summarize late toxicities associated with standard-of-care radiotherapy approaches including stereotactic body radiotherapy, an advanced radiotherapy technique supported by accumulating evidence. We also discuss stereotactic magnetic resonance imaging-guided adaptive radiotherapy (SMART), an emerging paradigm that may further improve the therapeutic index of radiotherapy and reduce late toxicities. PATIENT SUMMARY: This mini-review summarizes late side effects associated with standard and advanced radiotherapy techniques for localized prostate cancer. We also discuss a new radiotherapy approach called SMART that may reduce late side effects and increase treatment effectiveness., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: To compare the long-term oncologic outcomes of intermediate risk (IR) prostate cancer (PCa) patients treated with low dose-rate brachytherapy (LDR-BT) or moderate hypofractionated external beam radiotherapy (HF-EBRT)., Methods and Materials: Patients diagnosed with IR PCa and treated with LDR-BT or HF-EBRT between January 2005 and December 2013 were included. Brachytherapy treatment involved a transperineal implant of iodine-125 to a dose of 145 Gy to the PTV, while HF-EBRT was delivered using intensity modulated radiotherapy with 60 Gy in 20 fractions. The Phoenix ''nadir +2'' threshold was used to define biochemical relapse (BR). The cumulative incidence function (CIF) of BR and metastases was reported for each group and compared using the Gray's test to account for the competing risk of death. The Kaplan-Meier (KM) method was used to estimate overall survival (OS) and prostate cancer specific survival (PCSS). Univariate (UVA) and multivariable (MVA) analysis of the CIF of BR and metastases were performed. A 2-tailed p-value ≤ 0.05 was considered statistically significant., Results: Overall, 122 and 124 patients were treated with LDR-BT and HF-EBRT respectively. Median follow-up was 95 months [interquartile range (IQR): 79-118] in the LDR-BT group and 96 months (IQR: 63-123) in the HF-EBRT group. BR was observed in 5 patients treated with LDR-BT and 34 treated with HF-EBRT. At 60 and 90 months, the CIF of BR was 0.9% and 3.5% in the LDR-BT group vs. 16.6% and 23.7% in the HF-EBRT (p < 0.001). The CIF of metastases at 90 and 108 months, was 0% and 1.6% vs. 3.4% and 9.1% in the LDR-BT and HF-EBRT groups (p = 0.003), respectively. At the last follow-up, 3 patients treated with HF-EBRT died from their cancer [PCSS of 97.5% at 8 years and none died in the LDR-BT group (p = 0.09). On UVA and MVA risk group and treatment modality were independently associated with CIF of BR. On UVA HF-EBRT and ISUP grade group 3 were associated with metastases., Conclusion: LDR-BT was associated with higher biochemical and metastases control in our cohort when compared to moderately HF-EBRT. In the absence of a randomized trial, LDR-BT when feasible should be offered to patients with a life expectancy of >8 years., (Copyright © 2022 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: The role of metastasis-directed therapy (MDT) in molecularly defined oligorecurrent prostate cancer (PCa) remains irresolute. We present extended follow-up and an independent validation cohort of a prospective trial., Methods and Materials: This study consists of 2 sequential single-arm phase-2 trials of patients with biochemical recurrence (prostate specific antigen [PSA] 0.4-3.0 ng/mL) and negative conventional imaging after radical prostatectomy and postoperative radiation therapy. All patients underwent [ 18 F]DCFPyL positron emission tomography/computed tomography. Patients with molecularly defined oligorecurrent prostate cancer underwent MDT with stereotactic body radiation therapy or surgery, without androgen deprivation therapy (ADT). The primary end point was biochemical response (≥50% PSA decline from baseline). Secondary end points included PSA progression-free survival and ADT-free survival. The sample size of 37 MDT patients was determined based on a Simon's 2-stage design with biochemical response rate >20%, and this design was also applied for the subsequent independent validation cohort., Results: Seventy-four patients underwent MDT: 37 each in the initial and validation cohorts. Both cohorts met the prespecified biochemical response rate and completed the planned 2-stages of accrual. For the pooled cohort, the median number of prostate specific membrane antigen positron emission tomography avid lesions was 2 and most (87%) recurrences were nodal. Sixty-four (87%) had stereotactic body radiation therapy and 10 (13%) had surgery. Median follow-up (interquartile range [IQR]) for the initial, validation and combined cohorts were 41 (35-46) months, 14 months (7-21), and 24 months (14-41), respectively. The biochemical response rates for the initial, validation and combined cohorts were 59%, 43%, and 51%, respectively. For the combined cohort, median biochemical progression-free survival was 21 months (95% confidence interval, 13-not reached), and median ADT-free survival was 45 months (95% confidence interval, 31-not reached)., Conclusions: Half of patients treated with MDT for molecularly defined-only oligorecurrent prostate cancer exhibited a biochemical response. This study provides necessary and validated evidence to support randomized trials aiming to determine whether MDT (alone or with systemic therapy) can affect clinically meaningful end points., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Collaborative partnerships, which link two health organizations with shared characteristics to achieve common goals and to improve healthcare quality, are becoming increasingly common in oncology. The purpose of this study is to review the collaboration between King Hussein Cancer Center (KHCC) and Princess Margaret Cancer Centre (PM). The context, input, process, and product (CIPP) model, a quasi-experimental form of program evaluation, has been applied to the KHCC-PM collaboration. This model is well suited to evaluate complex collaborations as it does not assume linear relationships. Data sources include stakeholders' judgements of the collaboration, assessment of achievements, and informal interviews with key participants involved in the program. KHCC and PM are recognized as high-caliber comprehensive cancer centers, with a common goal of delivering high-quality care to patients. Through personal relationships among faculty in the centers and the perceived opportunities for mutual benefit, KHCC and PM signed a memorandum of understanding in 2013 to enter into a formal partnership. This partnership has been an evolving process that started with collaboration on education and grew to include clinical care. Research is an area for potential future collaboration. Enabling factors in the collaboration include dedication of individuals involved, trusting relationships amongst faculty, and the reciprocal nature of the relationship. Challenges have been financial, competing interests, and the absence of a successful collaborative model to follow. The KHCC and PM collaboration has been successful. A strategic plan is being developed and followed to guide areas of expansion., (© 2020. American Association for Cancer Education.)

Background: We have recommended active surveillance as the preferred management option for clinical stage I (CSI) testicular germ cell tumors (GCTs) since 1980. Over time, the recommended intensity of surveillance has decreased; however, the impact on relapse detection has not been investigated., Objective: To examine relapse rate, time to relapse, extent of disease, and burden of treatment at relapse across decreasing surveillance intensity over time., Design Setting and Participants: CSI GCT patients under active surveillance from 1981 to 2021 were included in this study., Outcome Measurements and Statistical Analysis: Through four major iterations in both nonseminomatous (NSGCT) and seminoma surveillance schedules, visit frequency, blood testing, and imaging have been decreased successively. Low-dose, noncontrast computed tomography (CT) scans were adopted in 2011. Categorical variables and time to relapse were compared using chi-square and Fisher's exact or Kruskal-Wallis test, respectively., Results and Limitations: A total of 1583 consecutive patients (942 with seminoma and 641 with NSGCT) were included. In seminoma, chest x-rays were reduced from 13 to one and CT scans were reduced from 20 to ten. Relapse rate, time to relapse, N or M category, and International Germ Cell Cancer Collaborative Group (IGCCCG) classification did not change. In NSGCT, chest x-rays were reduced from 27 to zero and CT scans were reduced from 11 to five. Relapse rate (from 46.2% to 21.2%, p  = 0.002) and the median time to relapse (from 6.54 to 4.47 mo, p  = 0.025) decreased. No difference in relapsed disease burden was identified by N, M, and S category or IGCCCG classification. Treatment burden at relapse and GCT cancer deaths remained similar for seminoma and NSGCT. Limitations include the retrospective design and large time period covered., Conclusions: Despite considerable reductions in surveillance intensity, we did not observe an increase in disease extent, treatment burden, or GCT cancer deaths upon relapse. These results support that our current lower-intensity active surveillance schedules are safe for managing CSI GCT., Patient Summary: Our current reduced-intensity surveillance schedules for clinical stage I germ cell tumors appear to be safe., (© 2022 The Author(s).)

Introduction: Identifying the optimal management of unfavorable-risk (Prostate Cancer Risk Stratification [ProCaRS] high intermediate-, high-, and very high-risk categories) non-metastatic prostate cancer is an important public health concern given the large burden of this disease. We compared the rate of metastatic progression-free survival among men diagnosed with unfavorable-risk non-metastatic prostate cancer who were initially treated with radiation therapy or radical prostatectomy., Methods: Information was obtained from medical records at two academic centers in Canada from 333 men diagnosed with unfavorable-risk non-metastatic prostate cancer between 2007 and 2012. Median followup was 90.4 months. Men were eligible for the study if they received either primary radiation therapy (n=164) or radical prostatectomy (n=169), in addition to various adjuvant and salvage therapies when deemed clinically appropriate. Patients were matched on prognostic covariates using two matching techniques. Multivariable Cox proportional hazards models were used to estimate the hazard ratios (HR) and confidence intervals (CI) for metastatic progression-free survival between groups., Results: After matching, treatment groups were balanced on prognostic variables except for percent core positivity. Hazard ratios from all Cox proportional hazards models (i.e., before and after matching, and with and without multivariable adjustment) showed no difference in the rate of metastatic progression-free survival between groups (adjusted unmatched HR 1.16, 95% CI 0.63, 2.13, p=0.64)., Conclusions: Metastatic progression-free survival did not differ between men diagnosed with unfavorable risk non-metastatic prostate cancer who were treated with either radiation therapy or radical prostatectomy.

Background and Purpose: The Phoenix definition for biochemical failure (BCF) after radiotherapy uses nadir PSA (nPSA) + 2 ng/mL to classify a BCF and was derived from conventionally fractionated radiotherapy, which produces significantly higher nPSAs than stereotactic body radiotherapy (SBRT). We investigated whether an alternative nPSA-based threshold could be used to define post-SBRT BCFs., Materials and Methods: PSA kinetics data on 2038 patients from 9 institutions were retrospectively analyzed for low- and intermediate-risk PCa patients treated with SBRT without ADT. We evaluated the performance of various nPSA-based definitions. We also investigated the relationship of relative PSA decline (rPSA, PSA 18month /PSA 6month ) and timing of reaching nPSA + 2 with BCF., Results: Median follow-up was 71.9 months. BCF occurred in 6.9% of patients. Median nPSA was 0.16 ng/mL. False positivity of nPSA + 2 was 30.2%, compared to 40.9%, 57.8%, and 71.0% for nPSA + 1.5, nPSA + 1.0, and nPSA + 0.5, respectively. Among patients with BCF, the median lead time gained from an earlier nPSA + threshold definition over the Phoenix definition was minimal. Patients with BCF had significantly lower rates of early PSA decline (mean rPSA 1.19 vs. 0.39, p < 0.0001) and were significantly more likely to reach nPSA + 2 ≥ 18 months (83.3% vs. 21.1%, p < 0.0001). The proposed criterion (rPSA ≥ 2.6 or nPSA + 2 ≥ 18 months) had a sensitivity and specificity of 92.4% and 81.5%, respectively, for predicting BCF in patients meeting the Phoenix definition and decreased its false positivity to 6.4%., Conclusion: The Phoenix definition remains an excellent definition for BCF post-SBRT. Its high false positivity can be mitigated by applying additional criteria (rPSA ≥ 2.6 or time to nPSA + 2 ≥ 18 months)., Competing Interests: Declaration of Competing Interest A.U.K. reports funding support from grant P50CA09213 from the Prostate Cancer National Institutes of Health Specialized Programs of Research Excellence, as well as grant RSD1836 from the Radiological Society of North America, the STOP Cancer organization, the Jonsson Comprehensive Cancer Center, and the Prostate Cancer Foundation. N.N. reports research support from Janssen and Lantheus, and consulting for Oncolinea. All other authors have no conflict of interest to declare., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: In 2015, men undergoing radical prostatectomy in Ontario, Canada were recommended to undergo multidisciplinary care by seeing a radiation oncologist or discussion at multidisciplinary rounds before surgery. The a priori target rate was ≥76%. We used population-based data to explore factors associated with not receiving multidisciplinary care prior to radical prostatectomy., Materials and Methods: Men who underwent radical prostatectomy for localized prostate cancer in Ontario between 2007 and 2017 were identified using administrative data. Physician billings identified patients who received multidisciplinary care. Multivariable logistic regression was used to predict receipt of multidisciplinary care., Results: A total of 31,485 men underwent radical prostatectomy between 2007 and 2017. Of these patients 28.7% saw a radiation oncologist, 1.2% underwent multidisciplinary discussion and 1.9% had both before surgery. Multidisciplinary care receipt increased from 17.8% in 2007 to 47.8% in 2017 (p <0.001). The odds ratio between the highest and lowest geographic regions was 7.93 (95% CI 6.17-10.18, p <0.001). Lower odds of multidisciplinary care receipt were observed for men further from the nearest cancer center (OR 0.74 per 50 km, 95% CI 0.71-0.78, p <0.001) and higher odds for the highest versus lowest income quintile (OR 1.41, 95% CI 1.29-1.54, p <0.001). Of 128 urologists who performed ≥10 radical prostatectomies between 2016 and 2017, 29 (22.7%) met the target of having ≥76% of men seen for multidisciplinary care prior to surgery., Conclusions: Despite increasing utilization, many men do not receive multidisciplinary care prior to radical prostatectomy. While geography and the urologist appear to be the greatest factors predicting multidisciplinary care receipt, these factors are closely intertwined.

Patients with localized prostate cancer comprise a large volume of treatments in radiation therapy centers. Occasionally, individual patient anatomy makes the safe delivery of an effective dose of radiation therapy challenging. We describe 2 cases of patients with a small bowel deep in the pelvis within the planning target volume with subsequent suboptimal radiation therapy treatment plans. We explore how we used the GU-Lok, a prostate immobilization device, to move the small bowel away from the prostate, and tighten target volume margins to help facilitate safe and effective treatment., (Copyright © 2021 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: To report on long-term results of elective pelvic nodal irradiation (EPNI) and a simultaneous hypofractionated prostate boost for high-risk prostate cancer., Materials and Methods: This was a prospective single-arm study. Patients with high-risk disease (cT3, PSA >20 ng/mL, or Gleason score 8-10) were eligible. Patients received 45 Gy in 25 fractions to the prostate and pelvic lymph nodes with a simultaneous intensity-modulated radiotherapy boost of 22.5 Gy to the prostate (total dose 67.5 Gy in 25 fractions), with androgen deprivation therapy (ADT) for 2-3 years. The primary endpoint was biochemical failure. Secondary endpoints included distant metastases and overall survival. Multivariable analysis was performed to look for predictive factors. Late toxicity was assessed using CTCAE v3.0., Results: 230 patients enrolled. Median follow-up was 11.2 years (IQR 8.1-12.9). At 10 years, cumulative incidence of biochemical failure was 33.4%, distant metastasis was 16.5%, and overall survival was 76.3%. On multivariable analysis, PSA nadir ≥0.05 ng/mL was associated with biochemical failure (HR 6.8, 95% CI 4-11.8, p < 0.001) and distant metastases (HR 7.5, 95% CI 3.9-14.5, p < 0.0001). PSA nadir ≥0.1 ng/mL (HR 5.2, 95% 2.2-12, p = 0.0001) and ADT use ≤12 months (versus >24 months) (HR 2.3, 95% CI 1.3-3.9, p = 0.004) were associated with worse survival. The 5-year cumulative incidence of any late grade ≥3 gastrointestinal and genitourinary toxicity was 2.3% and 7.5%, respectively., Conclusion: EPNI and a simultaneous hypofractionated prostate boost combined with long-term ADT for high-risk prostate cancer resulted in acceptable 10-year biochemical control and survival with low grade ≥3 toxicity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Purpose: The role of elective nodal irradiation (ENI) in localized prostate cancer (PCa) is controversial. With increasing use of SBRT to the prostate, data is needed regarding the safety and efficacy of ENI using ultra-hypofractionated radiation (UHRT)., Materials and Methods: Between 2013-2020, 4 prospective clinical trials of intermediate or high-risk PCa receiving dose-escalated RT to the prostate (via HDR brachytherapy or SBRT boost) and ENI using UHRT (25 Gy in 5 weekly fractions) were conducted. Primary endpoints included acute genitourinary and gastrointestinal toxicities (CTCAE v3.0/4.0), and secondary endpoints included late genitourinary and gastrointestinal toxicities, patient-reported quality of life (EPIC) and biochemical failure (Phoenix definition)., Results: One-hundred sixty-five patients were enrolled, of whom 98 (59%) had high-risk disease. ADT was used in 141 (85%). Median follow-up was 38 months (IQR 10-63). The worst acute genitourinary and gastrointestinal toxicities respectively were 48% and 7.5% for grade 2, and 2.7% and 0% for grade 3. Cumulative incidence of late grade 2+ genitourinary and gastrointestinal toxicities at 36 months were 58% and 11.3% and for late grade 3+ toxicities were 1% and 0%, respectively. No grade 4+ acute or late toxicities were observed. Bowel and sexual toxicity significantly worsened up to 1-year compared to baseline. Over time, urinary (p < 0.0001), bowel (p = 0.0018) and sexual (p < 0.0001) scores significantly improved. The 3-year biochemical recurrence-free survival was 98%., Conclusion: ENI using UHRT is associated with low incidence of grade 3+ toxicity, while grade 1-2 acute genitourinary and gastrointestinal toxicity is common. Randomized phase 3 trials are needed., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The hypothesis of a curable oligometastatic prostate cancer (PCa) state remains to be clinically-proven. Conventional imaging often fails to localize early recurrences, hampering the potential for radical approaches., Objective: We hypothesize that prostate-specific membrane antigen (PSMA)-targeted PET-MR/CT allows for earlier detection and localization of oligorecurrent-PCa, unveiling a molecularly-defined state amenable to curative-intent metastasis-directed treatment (MDT)., Design/setting/participants: Single-institution single-arm phase-two study. Patients with rising PSA (0.4-3.0 ng/mL) after maximal local therapy (radical prostatectomy and post-operative radiotherapy), negative conventional staging, and no prior salvage hormonal therapy (HT) were eligible., Interventions: All patients underwent [ 18 F]DCFPyL PET-MR/CT. Patients with molecularly-defined oligorecurrent-PCa had MDT (stereotactic ablative body radiotherapy [SABR] or surgery) without HT., Outcome Measurements/statistical Analysis: Primary endpoint was biochemical response (complete, i.e. biochemical 'no evidence of disease' [bNED], or partial response [100% or ≥50% PSA decline from baseline, respectively]) after MDT. Simon's two-stage design was employed (null and alternate hypotheses <5% and >20% response rate, respectively), with α and β of 0.1., Results: Seventy-two patients were enrolled (May/2017-July/2019). Thirty-eight (53%) had PSMA-detected oligorecurrent-PCa amenable for MDT. Thirty-seven (51%) agreed to MDT: 10 and 27 underwent surgery and SABR, respectively. Median follow-up was 15.9 months (IQR 9.8-19.1). Of patients receiving MDT, the overall response rate was 60%, including 22% rendered bNED. One (2.7%) grade 3 toxicity (intra-operative ureteric injury) was observed., Conclusions: PSMA-defined oligorecurrent-PCa can be rendered bNED, a necessary step towards cure, in 1 of 5 patients receiving MDT alone. Randomized trials are justified to determine if MDT +/- systemic agents can expand the curative therapeutic armamentarium for PCa., Patient Summary: We studied men treated for prostate cancer with rising PSA. We found PSMA imaging detected recurrent cancer in three-quarters of patients, and targeted treatment to these areas significantly decreased PSA in half of patients., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: Guidelines on mammographic surveillance after breast cancer treatment have been disseminated internationally and incorporated into Choosing Wisely recommendations to reduce low-value care. However, adherence within different countries before their publication is unknown., Methods and Materials: Low-value mammography, defined as "short-interval" (within 6 months of radiation) or "high-frequency" (>1 within 12 months of radiation), was compared in Medicare fee-for-service in the United States and Ontario, Canada. Women ≥65 years diagnosed with breast cancer who underwent breast-conserving therapy with a minimum of 24 months of follow-up were included (n = 19,715 United States; 6479 Ontario). Secondary outcomes were patient and physician characteristics associated with discordance., Results: Short-interval mammography was higher in the United States than in Ontario (55.9% vs 38.0%, P < .001), as was high-frequency (39.6% vs 7.9%, P < .001). In Ontario, younger age (42% ≥85 vs 58% <74 years, P < .001) and chemotherapy (69% vs 51%, P < .001) were associated with short-interval mammography; in the United States, age, earlier diagnosis year, stage, chemotherapy, rurality, and academic center treatment were associated with greater use. Chemotherapy was associated with high-frequency mammography in both countries (13% vs 7% in Ontario, P < .001; 69% vs 51% in United States, P = .02); younger age, earlier diagnosis year, stage, and nonacademic center treatment were associated in the United States. In both countries, radiation oncologists had the highest proportion of providers ordering low-value mammograms., Conclusions: Despite significant evidence guiding surveillance mammography recommendations, there are high rates of short-interval mammography in both the United States and Ontario, and high rates of high-frequency mammography in the United States. Further international efforts, such as Choosing Wisely, are needed to reduce low-value mammography., (Copyright © 2021 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Objectives: To assess whether free PSA ratio (FPSAR) at biochemical recurrence (BCR) can predict metastasis, castrate-resistant prostate cancer (CRPC), and cancer-specific survival (CSS), following therapy for localised disease., Patients and Methods: A single-centre retrospective cohort study (NCT03927287) including a discovery cohort composed of patients with an FPSAR after radical prostatectomy (RP) or radiotherapy (RT) between 2000 and 2017. For validation, an independent Biobank cohort of patients with BCR after RP was tested. Using a defined FPSAR cut-off, the metastasis-free-survival (MFS), CRPC-free survival, and CSS were compared. Multivariable Cox models determined the association between post-treatment FPSAR, metastases, and CRPC., Results: Overall, 822 patients (305 RP- and 363 RT-treated patients and 154 Biobank patients) were analysed. In the RP cohort, a total of 272/305 (89.1%) and 33/305 (10.9%) had a FPSAR test incidentally and reflexively, respectively. In the RT cohort, 155/363 (42.7%) and 208/263 (57.3%) had a FPSAR test incidentally and reflexively, respectively. However, in the prospective Biobank RP cohort, FPSAR testing was done on all samples of patients diagnosed with BCR. A FPSAR cut-off of 0.10 was determined using receiver operating characteristic analyses in both the RP and RT cohorts. A FPSAR of <0.10 resulted in longer median MFS (14.8 vs 9.3 years and 14.8 vs 13 years, respectively), and longer median CRPC-free survival (median not reached vs 9.9 years and 20.7 vs 13.8 years, respectively). Multivariable analyses showed that a FPSAR of ≥0.10 was associated with increased metastasis in the RP cohort (hazard ratio [HR] 1.915, 95% confidence interval [CI] 1.241-2.955) and RT cohort (HR 1.754, 95% CI 1.112-2.769), and increased CRPC in the RP cohort (HR 2.470, 95% CI 1.493-4.088). Findings were validated in the Biobank cohort., Conclusions: A post-treatment FPSAR of ≥0.10 is associated with more aggressive disease, suggesting a potentially novel role for this biomarker., (© 2020 The Authors BJU International © 2020 BJU International Published by John Wiley & Sons Ltd.)

Stereotactic radiotherapy (SBRT) has been applied to treat cardiac arrhythmias, but our institution had not yet implemented this technique. Here, we explain how we used implementation science and knowledge translation to provide cardiac SBRT to a critically ill patient with malignancy-associated refractory ventricular tachycardia. We reviewed the critical factors that enabled the implementation of this urgent treatment, such as the context of the implementation, the characteristics of the intervention, and the stakeholders. These principles can be used by other radiation programs to implement novel treatments in urgent settings, where the gold standard process of planning and developing policies and protocols is not possible., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2021, Glicksman et al.)

Purpose: To assess the impact of RTOG-9601 and GETUG-AFU-16 on the routine use of combination androgen deprivation therapy (ADT) with postoperative radiotherapy (PORT) for prostate cancer (CaP)., Material and Methods: Patients with localized CaP treated with radical prostatectomy (RP) and PORT with or without ADT at a comprehensive cancer center from January 2006 to June 2007 (Period 1 = P1), July 2011 to December 2012 (Period 2 = P2), and January 2017 to June 2018 (Period 3 = P3) were included. Clinicopathologic features and treatment characteristics were analyzed and compared. Multivariable logistic regression was used to assess prognostic factors and association with ADT use. Statistical tests were two-sided and a P value <0.05 was considered significant. To validate the findings, United States National Cancer Database (NCDB) and Surveillance, Epidemiology, and End Results (SEER) data were collected to assess rates of combined ADT and PORT from 2004 to 2015., Results: Five hundred and two patients were included: 152 (P1), 185 (P2), and 165 (P3). PORT was most commonly delivered as early SRT (delivered >1 year post-RP with undetectable PSA or PSA >0.05 and ≤0.5 ng/ml) in all periods. The use of combination PORT and ADT increased over time: 14.5% (P1), 32% (P2), and 41% (P3) (P < 0.001). The proportion of patients that met eligibility criteria for either GETUG-AFU-16 or RTOG-9601 decreased from 47% (P1) to 35% (P3) (P = 0.04). International Society of Urological Pathology grade ≥4 (P < 0.002) and pre-PORT PSA >0.5 ng/ml (P < 0.001) were associated with use of ADT. Positive surgical margin status had a negative association (RR 0.5, P < 0.002). The NCDB demonstrated similar trends for use of combined ADT with PORT, increasing from 37% to 49% from 2004 to 2015., Conclusion: The use of combined ADT with PORT increased over time. However, only a third of contemporary patients undergoing PORT are represented in the major trials supporting the evidence for combination treatment, highlighting the need to characterize the modern impact of this intensification strategy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction Despite treatment advances, the prognosis of locally advanced pancreatic cancer is poor. Treatment remains varied and includes systemic and radiotherapy (RT). Stereotactic body radiotherapy (SBRT), highly conformal high-dose RT per fraction, is an emerging treatment option. Materials and methods We performed a single-institution retrospective review of patients with pancreatic adenocarcinoma treated with SBRT from 2015-2017. The median dose was 27 Gy (range: 21-36 Gy) in three fractions. Endpoints included local progression (RECIST 1.1; Response Evaluation Criteria in Solid Tumors 1.1), distant metastasis, overall survival, and toxicity. Results Forty-one patients were treated, with a median follow-up of eight months. Patients who received SBRT had unresectable (49%), metastatic (17%), or borderline resectable (7%) disease, declined surgery (17%), medically inoperable (7%), or developed local recurrence following the Whipple procedure (2%). The six-month and one-year rates of local progression-free survival, distant metastasis-free survival, and overall survival were 62% and 55%, 44% and 32%, and 70% and 49%, respectively. Five patients (12%) experienced seven late gastrointestinal (GI) grade 3 events. Conclusion  SBRT may be considered a treatment option to achieve local control of pancreatic cancer and is associated with a modest risk of severe late GI toxicities. Systemic therapies remain important, given the proportion of patients who develop distant metastases., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Glicksman et al.)

Introduction: The oligometastatic (OM) disease hypothesis of an intermediate metastatic state with limited distant disease deposits amenable for curative therapies remains debatable. Over a third of prostate cancer (PCa) patients treated with radical prostatectomy and postoperative radiotherapy experience disease recurrence; these patients are considered incurable by current standards. Often the recurrence cannot be localised by conventional imaging (CT and bone scan). Combined anatomical imaging with CT and/or MR with positron emission tomography (PET) using a novel second-generation prostate-specific membrane antigen (PSMA) probe, [ 18 F]DCFPyL, is a promising imaging modality to unveil disease deposits in these patients. A new and earlier molecularly defined oligorecurrent (OR) state may be amenable to focal-targeted ablative curative-intent therapies, such as stereotactic ablative radiotherapy (SABR) or surgery, thereby significantly delaying or completely avoiding the need for palliative therapies in men with recurrent PCa after maximal local treatments., Methods and Analysis: This ongoing single-institution phase II study will enrol up to 75 patients total, to include up to 37 patients with response-evaluable disease, who have rising prostate-specific antigen (range 0.4-3.0 ng/mL) following maximal local therapies with no evidence of disease on conventional imaging. These patients will undergo [ 18 F]DCFPyL PET-MR/CT imaging to detect disease deposits, which will then be treated with SABR or surgery. The primary endpoints are performance of [ 18 F]DCFPyL PET-MR/CT, and treatment response rates following SABR or surgery. Demographics and disease characteristics will be summarised and analysed descriptively. Response rates will be described with waterfall plots and proportions., Ethics and Dissemination: Ethics approval was obtained from the institutional Research Ethics Board. All patients will provide written informed consent. [ 18 F]DCFPyL has approval from Health Canada. The results of the study will be disseminated by the principal investigator. Patients will not be identifiable as individuals in any publication or presentation of this study., Trial Registration Numbers: NCT03160794., Competing Interests: Competing interests: UM declares a competing interest with Point Biopharm Inc. as a consultant., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Rising cancer incidence combined with improvements in systemic and local therapies extending life expectancy are translating into more patients with spinal metastases. This makes the multidisciplinary management of spinal metastases and development of new therapies increasingly important. Spinal metastases may cause significant pain and reduced quality of life and lead to permanent neurological disability if compression of the spinal cord and/or nerve root occurs. Until recently, treatments for spinal metastases were not optimal and provided temporary local control and pain relief. Spinal stereotactic ablative radiotherapy (SABR) is an effective approach associated with an improved therapeutic ratio, with evolving clinical application., Objective: To review the literature of spinal SABR for spinal metastases, discuss a multidisciplinary approach to appropriate patient selection and technical considerations, and summarize current efforts to combine spinal SABR with systemic therapies., Evidence Review: The MEDLINE database was searched to identify articles reporting on spinal SABR to September 30, 2018. Articles including clinical trials, prospective and retrospective studies, systematic reviews, and consensus recommendations were selected for relevance to multidisciplinary management of spinal metastases., Results: Fifty-nine unique publications with 5655 patients who underwent SABR for spinal metastases were included. Four comprehensive frameworks for patient selection were discussed. Spinal SABR was associated with 1-year local control rates of approximately 80% to 90% in the de novo setting, greater than 80% in the postoperative setting, and greater than 65% in the reirradiation setting. The most commonly discussed adverse effect was development of a vertebral compression fracture with variable rates, most commonly reported as approximately 10% to 15%. High-level data on the combination of SABR with modern therapies are still lacking. At present, 19 clinical trials are ongoing, mainly focusing on combined modality therapies, radiotherapy prescription dose, and oligometastic disease., Conclusions and Relevance: These findings suggest that spinal SABR may be an effective treatment option for well-selected patients with spinal metastases, achieving high rates of local tumor control with moderate rates of adverse effects. Optimal management should include review by a multidisciplinary care team.

The use of combination RT and androgen deprivation therapy in many prostate cancer curative-intent treatment scenarios is supported by level 1 evidence. However, in our current clinical paradigm, we have no ability to determine a priori which patients truly benefit from combination therapy and therefore apply the combination RT and androgen deprivation therapy intensification strategy to all patients, which results in overtreatment or undertreatment of the majority of our patients. Genomics has the ability to more deeply and objectively characterize the disease, in turn refining our prognostication capabilities and enabling the individualization of treatments. We review the commercially available prostate cancer genomic tests, focusing on those able to predict patient outcomes following radiotherapy or guide radiotherapy treatment decisions.

Purpose: Ontario Health (Cancer Care Ontario), formerly known as CCO, is the provincial governmental agency in Ontario, Canada responsible for developing radiation therapy-specific capital investment strategies, updated every 5 years, to ensure equitable access and to gain the highest value from these investments in infrastructure. These plans are informed by the changing landscape of health care delivery, technologic advancements affecting radiation therapy care, patient desire for care closer to home, and expected increases in utilization of radiation therapy services. In this article, we describe the development, model, and final recommendations of CCO's fifth radiation therapy capital investment strategy., Methods and Materials: A panel of multidisciplinary provincial experts, in combination with 2 patient and family advisors, developed planning principles to guide the development of a patient-centered strategy. Adaption of the previously used model for radiation therapy planning was used., Results: The development of the capital investment strategy took place from fall 2017 to fall 2018. The model included 3 main factors: patient demand (including utilization targets), machine throughput, and machine demand and supply. The final recommendation is for an investment of 26 new radiation therapy machines in the province by 2028., Conclusions: The strategy plans for continued province-wide access to quality radiation therapy care and ensures machines are added to the system at the right place and in the right time. Ongoing data collection throughout this period is necessary to ensure the strategy achieves its goals and to allow for planning of future strategies., (© 2020 The Authors.)

Background: The risk of gastrointestinal (GI) toxicity may limit the use of curative-intent radical radiotherapy (RT) for prostate cancer (PCa) in circumstances where morbidity of treatment may exceed an acceptable threshold. Rectal spacers are used to expand the distance between the anterior rectal wall and the prostate, consequently sparing the rectum from the high-dose region., Case Presentations: We report three clinical scenarios of PCa patients treated at our institution, where risk of RT-associated rectal toxicity may be increased: inflammatory bowel disease (IBD), salvage brachytherapy (BT) after previous external beam RT (EBRT), and tailored dose-escalation with focal BT to the gross tumor volume followed by stereotactic body RT. Prior to RT, a polyethylene glycol (PEG) hydrogel spacer was successfully placed in all cases. Treatment comprised magnetic resonance (MR) guided high dose-rate BT ± EBRT. All patients completed treatment uneventfully, without any significant GI toxicity at last follow-up., Conclusions: These cases illustrate the utility of PEG hydrogel spacer, where concerns of radiation induced toxicity may have previously limited the application of radiotherapy. The synergistic use of these novel devices together with MR-guided BT may expand the indications and therapeutic index of curative-intent RT-based treatments, while minimizing the risks of GI toxicity., (© 2019 The Authors.)

Purpose: Neoadjuvant radiation therapy (RT) improves disease control in various cancers and has become an established oncologic treatment strategy. During 2001 to 2004, we conducted a phase 1 pilot study assessing the role of short-course preoperative RT (PreORT) for men with unfavorable intermediate- and high-risk localized prostate cancer. Herein, we present long-term follow-up toxicity and oncologic outcomes., Methods and Materials: Eligible patients had histologically proven prostate cancer, cT1-T2N0M0 disease, prostate-specific antigen >15 to 35 ng/mL regardless of Gleason score, or prostate-specific antigen 10 to 15 ng/mL with Gleason score ≥7. Patients received 25 Gy in 5 consecutive daily fractions (5 Gy per fraction) to the prostate only, followed by radical prostatectomy within 14 days after RT completion. Primary outcomes were intraoperative morbidity and late genitourinary (GU) and gastrointestinal toxicities., Results: In total, 15 patients were enrolled; 14 patients completed PreORT followed by radical prostatectomy, which also included bilateral lymph node dissections in 13 cases. Median follow-up was 12.2 years (range, 6.7-16.3). Late GU toxicity was common, with 2 patients (13.3%) experiencing G2 toxicity and 6 patients (40%) G3 toxicity. There were no patients with G4 to G5 late GU toxicity. Late gastrointestinal toxicity was infrequent, with only 1 patient (6.7%) experiencing transient G2 proctitis. At last follow-up, 8 (53.3%) and 6 (40%) patients experienced biochemical and metastatic disease recurrence, respectively., Conclusions: The use of PreORT in men with high-risk prostate cancer is associated with unexpected high rates of late GU toxicity. Future studies examining the role of RT preradical prostatectomy must cautiously select RT technique and dose schedule. Importantly, long-term follow-up data are essential to fully determine the therapeutic index of PreORT in the management of localized disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: In 2003 and 2004, Cancer Care Ontario (CCO) divested its assets and staff to regional hospitals, leading to decreased contact between radiation therapy departments across Ontario's Regional Cancer Centres (RCCs). The Radiation Treatment Program (RTP) at CCO developed a communities-of-practice (CoPs) program to rebuild the provincial radiation therapy community to facilitate collaboration among centers, with the goals of decreasing variation in practice and improving the quality of patient care. RTP's CoPs are led and driven by volunteer frontline health care practitioners who identify and prioritize key quality issues and select corresponding projects to pursue., Methods and Materials: An evaluation of RTP's CoPs was conducted to assess whether they were successful in knowledge creation, knowledge transfer and exchange, and community building. The framework was developed based on the Centers for Disease Control and Prevention CoP evaluation framework and tools. Data were collected using prospectively administered member surveys (257 surveys), publications, and semistructured interviews (18 participants)., Results: A total of 95% of participants reported that CoP projects were very relevant to their practice, and 50% reported changes in their practice stemming from CoP involvement. In addition, 90% of participants reported growth of their professional network as a result of CoPs. Overall, 93% of participants and 100% of interviewees reported that CoPs are a worthwhile initiative. The largest challenge of CoPs was the time commitment required to participate., Conclusions: This approach of member-driven CoPs should be explored and modeled in other health care settings as a means to develop and share knowledge to reduce variation in care and improve the quality of radiation therapy care., (Copyright © 2018 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: Extraprostatic extension (EPE) is defined as local spread of prostate cancer (PC) beyond prostate boundaries. Although extensively evaluated in radical prostatectomy (RP) specimens, its significance in prostate biopsy (PB) specimens is understudied., Objective: To analyze the clinicopathologic characteristics and treatment outcomes for patients with nonmetastatic PC with EPE on diagnostic PB., Design, Setting, and Participants: We identified all patients at Princess Margaret Cancer Center with EPE on their diagnostic PB between 2005 and 2016. All patients underwent definitive curative-intent treatment with either RP or radiotherapy (RT) with or without androgen deprivation therapy (ADT)., Outcome Measurements and Statistical Analyses: Clinicopathologic variables were compared using a χ 2 or Kruskal-Wallis test; log-rank analyses were applied for outcomes comparison. Primary and secondary endpoints were 5-yr biochemical recurrence (BCR) and the occurrence of metastasis or cancer-specific death, respectively., Results and Limitations: A total of 127 patients with reported EPE in their PB were identified. One-third of patients underwent RP (n=43) and two-thirds received RT (n=84). Baseline prognostic variables (prostate-specific antigen, clinical T stage, biopsy pathologic grade group, and proportion of cores involved with PC) were similar between the treatment groups. More than two-thirds of RT patients received concomitant ADT (median duration 36 mo, interquartile range 24-36), while 39.5% of RP patients received postoperative radiotherapy±ADT. Of the RP patients, 95.3% had ≥pT3a disease and 27.9% had pN1 disease. Median follow-up after RP and RT was similar (43.7 vs 45.8 mo; p=0.516). The 5-yr BCR and metastasis rates in the RP versus RT groups were 25.6% versus 11.9% (p=0.09) and 7% versus 11.9% (p=0.386), respectively. Only one patient died from metastatic PC (RT group). Limitations include the single-center and retrospective design with a moderate sample size and relatively short follow-up., Conclusions: EPE on PB is an infrequent finding that is strongly associated with high-risk clinicopathologic prognostic features that accurately predict EPE in RP specimens. Despite entailing aggressive disease characteristics, EPE on PB should not preclude patients from receiving definitive radical local therapy., Patient Summary: Extraprostatic extension on prostate biopsies is an uncommon finding, but is strongly correlated to additional aggressive disease features. This finding accurately predicts the presence of extraprostatic extension on the final prostate specimen after surgery. Despite the associated high-risk features, finding extraprostatic extension in prostate biopsies should not preclude patients from undergoing curative-intent radical local therapy., (Copyright © 2018. Published by Elsevier B.V.)

Purpose: The NCCN Guidelines® recently endorsed a subclassification of intermediate risk prostate cancer into favorable and unfavorable subgroups. However, this subclassification was developed in a treatment heterogeneous cohort. Thus, to our knowledge the natural history of androgen deprivation treatment naïve favorable and unfavorable intermediate risk prostate cancer cases remains unknown., Materials and Methods: Groups at 3 academic centers pooled data on patients with intermediate risk prostate cancer treated with radical monotherapy (dose escalated external beam radiotherapy, brachytherapy or radical prostatectomy) without combined androgen deprivation treatment. We used the cumulative incidence with competing risk analysis to estimate biochemical recurrence, distant metastasis and prostate cancer specific mortality., Results: A total of 2,550 men at intermediate risk were included in study, of whom 1,063 and 1,487 were at favorable and unfavorable risk, respectively. Of the men 1,149 underwent radical prostatectomy, 1,143 underwent dose escalated external beam radiotherapy and 258 underwent brachytherapy. Median followup after the different treatments ranged from 60.4 to 107.4 months. The 10-year cumulative incidence of distant metastasis in the favorable vs unfavorable risk groups was 0.2% (95% CI 0.2-0.2) vs 11.6% (95% CI 7.7-15.5) for radical prostatectomy (p <0.001), 2.8% (95% CI 0.8-4.8) vs 13.5% (95% CI 9.6-17.4) for dose escalated external beam radiotherapy (p <0.001) and 3.5% (95% CI 0-7.4) vs 10.2% (95% CI 4.3-16.1) for brachytherapy (p = 0.063). The 10-year rate of prostate cancer specific mortality in the favorable vs unfavorable risk groups was 0% (95% CI 0-0) vs 3.7% (95% CI 1.7-5.7) for radical prostatectomy (p = 0.016), 0.5% (95% CI 0.5-0.5) vs 5.6% (95% CI 3.6-7.6) for dose escalated external beam radiotherapy (p = 0.015) and 0% (95% CI 0-0) vs 2.5% (95% CI 0.5-4.5) for brachytherapy (p = 0.028)., Conclusions: This multicenter international effort independently validates the prognostic value of the intermediate risk prostate cancer subclassification in androgen deprivation treatment naïve cases across all radical treatment modalities. It is unlikely that treatment intensification would meaningfully improve oncologic outcomes in men at favorable intermediate risk.

Background and Purpose: Hypoxia, high interstitial fluid pressure (IFP) and immune effects have individually been shown to modulate radiotherapy (RT) response in cervical cancer. The aim of this study was to investigate the interplay between hypoxia or IFP and circulating neutrophil levels, and their combined effect on survival following RT., Material and Methods: A total of 287 FIGO stage IB to IIIB cervical cancer patients treated with RT or RT and cisplatin (RTCT) were included. Tumor hypoxia and IFP were measured at baseline prior to treatment. Absolute neutrophil count (ANC) was measured at baseline and weekly during treatment. Median follow up was 7.1 years., Results: High nadir ANC at the point of maximal myelosuppression was a stronger predictor of inferior survival than high baseline ANC after adjusting for clinical prognostic factors and treatment (RT vs. RTCT). The predictive effect of nadir ANC was most evident in patients with well-oxygenated tumors or tumors with high IFP at diagnosis., Conclusions: This study provides new information about the combined influence of the tumor microenvironment and myeloid cells on the survival of cervical cancer patients treated with RT/RTCT to motivate the development of new treatments based on molecular targeting of immune-based radioresistance pathways.

Treatment of testicular cancer is dependent on the stage of disease at presentation. Stage 1 testicular cancer is treated with radical orchiectomy, followed by active surveillance, radiotherapy, or chemotherapy. Occasionally, unusual and unexpected postoperative changes can be seen on computed tomography (CT), and may raise concern for metastatic disease. Here, we present two cases of testicular cancer patients who developed retroperitoneal hematomas post-radical orchiectomy, one as a classical clinical presentation, and the other as an atypical radiological entity only. The first is a case of a 38-year-old male with a non-seminoma testicular cancer, who developed severe flank pain, hemodynamic instability, and progressive anemia from a retroperitoneal hematoma in the immediate (<24 hours) postoperative period, requiring urgent surgical evacuation. The second is a case of a 33-year-old male with a testicular seminoma who had a large, suspicious retroperitoneal mass on a staging CT scan concerning for metastatic disease, which was later diagnosed as a retroperitoneal hematoma. These cases reveal the clinical variability with which a retroperitoneal hematoma post-radical orchiectomy may present. In addition, the second case demonstrates the importance of recognizing radiological postoperative changes and ensuring that these findings are not mistaken for and treated as metastatic disease.

Background: The role of hormone therapy (HT) with dose-escalated external-beam radiotherapy (DE-EBRT) in the treatment of intermediate-risk prostate cancer (IRPC) remains controversial. The authors report the long-term outcome of a phase 3 study of DE-EBRT with or without HT for patients with localized prostate cancer (LPC)., Methods: From 1999 to 2006, 252 of an intended 338 patients with LPC were randomized to receive DE-EBRT with or without 5 months of neoadjuvant and concurrent bicalutamide 150 mg once daily. The study was closed early because of contemporary concerns surrounding bicalutamide. The primary outcome was biochemical failure (BF) incidence, and the secondary endpoints were overall survival (OS), local control (LC), and quality of life. The BF and OS rates were estimated using the cumulative incidence function and Kaplan-Meier methods and were compared using the Gray test and the log-rank test., Results: Eleven patients were excluded from analysis. Characteristics were well balanced in each treatment arm. Ninety-five percent of patients had IRPC. The prescribed dose increased from 75.6 grays (Gy) in 42 fractions to 78 Gy in 39 fractions over the period. At a median follow-up of 9.1 years, 98 BFs occurred, with no significant effect of HT versus no HT on the BF rate (40% vs 47%; P = .32), the OS rate (82% vs 86%; P = .37), the LC rate (52% vs 48 %; P = .32) or quality of life, in the patients who completed the questionnaires. Dose escalation to 75.6 Gy versus >75.6 Gy reduced the BF rate by 26% (P = .004)., Conclusions: For patients who predominantly have IRPC, the addition of HT to DE-EBRT did not significantly affect BF, OS, or LC. Bicalutamide appeared to be well tolerated. The conclusions from the study are limited by incomplete recruitment. Cancer 2016;122:2595-603. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Purpose: Preclinical studies have shown that angiogenesis inhibition can improve response to radiation therapy (RT). The purpose of this phase 1 study was to examine the angiogenesis inhibitor sorafenib in patients with cervical cancer receiving radical RT and concurrent cisplatin (RTCT)., Methods and Materials: Thirteen patients with stage IB to IIIB cervical cancer participated. Sorafenib was administered daily for 7 days before the start of standard RTCT in patients with early-stage, low-risk disease and also during RTCT in patients with high-risk disease. Biomarkers of tumor vascularity, perfusion, and hypoxia were measured at baseline and again after 7 days of sorafenib alone before the start of RTCT. The median follow-up time was 4.5 years., Results: Initial complete response was seen in 12 patients. One patient died without achieving disease control, and 4 experienced recurrent disease. One patient with an extensive, infiltrative tumor experienced pelvic fistulas during treatment. The 4-year actuarial survival was 85%. Late grade 3 gastrointestinal toxicity developed in 4 patients. Sorafenib alone produced a reduction in tumor perfusion/permeability and an increase in hypoxia, which resulted in early closure of the study., Conclusions: Sorafenib increased tumor hypoxia, raising concern that it might impair rather than improve disease control when added to RTCT., (Copyright © 2016 Elsevier Inc. All rights reserved.)