Primary retroperitoneal lymph node dissection for metastatic non-seminomatous germ cell tumours: outcomes and adjuvant chemotherapy.

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.

A randomized phase III trial of stereotactic ablative radiotherapy for patients with up to 10 oligometastases and a synchronous primary tumor (SABR-SYNC): study protocol.

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).

Association of PSMA PET-derived Parameters and Outcomes of Patients Treated for Oligorecurrent Prostate Cancer.

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 (SUVmax) and mean standardized uptake value (SUVmean) and PSMA tumor volume derived using thresholds of 2.5 (SUVmean2.5) and 41% (SUVmean41%), 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 SUVmax, SUVmean2.5, and SUVmean41% 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 SUVmax, mean SUVmean2.5, mean SUVmean41%, mean PSMA score, maximum SUVmean2.5, maximum SUVmean41%, 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.

Radiation Oncologist Consultations Prior to Radical Prostatectomy: Disparities and Opportunities.

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.

Enhancing International Cancer Organization Collaborations: King Hussein Cancer Center and Princess Margaret Cancer Centre Model for Collaboration.

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.

Can post-treatment free PSA ratio be used to predict adverse outcomes in recurrent prostate cancer?

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.

International Multicenter Validation of an Intermediate Risk Subclassification of Prostate Cancer Managed with Radical Treatment without Hormone Therapy.

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.

PMH 9907: Long-term outcomes of a randomized phase 3 study of short-term bicalutamide hormone therapy and dose-escalated external-beam radiation therapy for localized prostate cancer.

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.

Early-Stage Breast Cancer: A Critical Review of Current and Emerging Practice.

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 have led to greater efforts to personalize approaches to treatment. Further, 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 ultra-hypofractionated 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 radiotherapy and reirradiation.

Dose-response of localized renal cell carcinoma after stereotactic body radiation therapy: A meta-analysis.

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 I2. 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 %, I2 = 19 %), 98 % (95 %CI: 96-99 %, I2 = 8 %), and 94 % (95 %CI: 90-97 %, I2 = 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.

Randomized Trial of Concomitant Hypofractionated Intensity Modulated Radiation Therapy Boost Versus Conventionally Fractionated Intensity Modulated Radiation Therapy Boost for Localized High-Risk Prostate Cancer (pHART2-RCT).

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.

The role of stereotactic body radiotherapy in oligoprogressive malignant disease (RADIANT): oncologic outcomes from a phase 2 non-randomized controlled trial.

BACKGROUND: In oligoprogressive (OP) cancer there are a limited numbers of metastatic areas progressing on a background of stable or responding widespread cancer. While the standard-of-care for OP is changing systemic therapy (ST), stereotactic body radiotherapy (SBRT) is being explored as an alternative local therapy targeting the sites of progression. MATERIALS/METHODS: XXX (NCTXXX) was a single-centre 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 to all OP disease in 1-5 fractions, and were maintained on ST. The primary endpoint was the cumulative incidence of change in ST estimated using Aalen-Johansen method. Secondary endpoints included progression-free survival (PFS) and overall survival (OS) estimated using Kaplan-Meier method, toxicity, and health-related quality-of-life (HRQOL). Comparisons between diagnosis groups were done using log-rank test. A two-sided p-value of <0.05 was considered as statistical significance. RESULTS: Seventy patients were analyzed, with median age 69 years; 32 patients (46%) were female; 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%). Median follow-up was 12.3 months (IQR 8.2-21.6). At 1-year, change in ST occurred in 47% (95% CI 36-61%) (GU 45%, breast 41%, GI 60%, p=0.23). 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, GI 3.2), which significantly differed by disease type (p=0.006). OS was 75% at 1-year (95% CI 65-87%), which significantly differed between cancer type (GU 86%, breast 96%, GI 22%, p<0.001). Cumulative incidence of late grade >2 toxicity was 1.2%, with 1 patient experiencing late grade 3 toxicity, and no grade 4-5 acute or late toxicities. HRQOL declined from mean (standard deviation) 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.

Prospective evaluation of patient-reported anxiety and experiences with adaptive radiation therapy on an MR-linac.

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.

TOward a comPrehensive supportive Care intervention for Older men with metastatic Prostate cancer (TOPCOP3): A pilot randomized controlled trial and process evaluation.

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).

Late Toxicities of Prostate Radiotherapy: Can We Further SMARTen Up the Therapeutic Index?

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.

Oligometastasis in Prostate Cancer: Can We Learn from Those "Excluded" from a Phase 2 Trial?

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.

Long-term oncologic outcomes of low dose-rate brachytherapy compared to hypofractionated external beam radiotherapy for intermediate -risk prostate cancer.

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.

Practice-based training strategy for therapist-driven prostate MR-Linac adaptive radiotherapy.

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.

Prognostic Factor Risk Groups for Clinical Stage I Seminoma: An Individual Patient Data Analysis by the European Association of Urology Testicular Cancer Guidelines Panel and Guidelines Office.

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.

Safety of Minimizing Intensity of Follow-up on Active Surveillance for Clinical Stage I Testicular Germ Cell Tumors.

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.