Is radiotherapy after radical prostatectomy associated with higher other-cause mortality?

PURPOSE: The aim of this study was to reveal the association between the other-cause mortality (OCM) and post-radical prostatectomy (RP) salvage radiotherapy (sRT) in men with prostate cancer (PCa). METHODS: A retrospective study was carried out with patients who had PCa and underwent RP ± sRT in a high-volume cancer center between 2005 and February 2019. Data from 1955 patients were subjected to a 1:1 matching for age, initial PSA, pathological (p)T/N stages, and ISUP score, which yielding 439 RP + RT (group 1) vs 439 RP-only cases (group 2), without any residual difference. Primary and secondary endpoints of the study were OCM and cancer-specific mortality (CSM). Kaplan-Meier, log-rank, and cox regression tests were used for purpose of the study. RESULTS: The median follow-up time after RP was 5.3 years (interquartile range: 4.0-7.3). After matching, of all deaths that occurred during the study period, 16 in group 1 and 35 in group 2 were attributed to other causes (p = 0.006). 5-year OCM rate of patients who received sRT (1.2%) was significantly lower compared to patients that underwent RP-only (4.4%, p < 0.001). 19 versus 16 patients died of PCa, respectively (p = 0.61). There was no CSM risk difference between groups (p = 0.29). Older patients had an increased risk of OCM (hazard ratio [HR]:1.10 [95%CI 1.05-1.17], p < 0.001) and post-RP RT was associated with lower OCM (HR: 0.28 [95%CI 0.15-0.51], p < 0.001) in multivariable model. pT/N stages and ISUP score were strongly associated with CSM, but not with OCM. CONCLUSION: OCM was not higher in patients who had sRT with or without ADT. Excess OCM in favor of RP-only patients may be cautiously explained with higher-performance status/life expectancy of patients who selected for RT after RP in our cohort.

Radical prostatectomy versus external beam radiotherapy with androgen deprivation therapy for high-risk prostate cancer: a systematic review.

BACKGROUND: To summarize recent evidence in terms of health-related quality of life (HRQoL), functional and oncological outcomes following radical prostatectomy (RP) compared to external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) for high-risk prostate cancer (PCa). METHODS: We searched Medline, Embase, Cochrane Database of Systematic Reviews, Cochrane Controlled Trial Register and the International Standard Randomized Controlled Trial Number registry on 29 march 2021. Comparative studies, published since 2016, that reported on treatment with RP versus dose-escalated EBRT and ADT for high-risk non-metastatic PCa were included. The Newcastle-Ottawa Scale was used to appraise quality and risk of bias. A qualitative synthesis was performed. RESULTS: Nineteen studies, all non-randomized, met the inclusion criteria. Risk of bias assessment indicated low (n = 14) to moderate/high (n = 5) risk of bias. Only three studies reported functional outcomes and/or HRQoL using different measurement instruments and methods. A clinically meaningful difference in HRQoL was not observed. All studies reported oncological outcomes and survival was generally good (5-year survival rates > 90%). In the majority of studies, a statistically significant difference between both treatment groups was not observed, or only differences in biochemical recurrence-free survival were reported. CONCLUSIONS: Evidence clearly demonstrating superiority in terms of oncological outcomes of either RP or EBRT combined with ADT is lacking. Studies reporting functional outcomes and HRQoL are very scarce and the magnitude of the effect of RP versus dose-escalated EBRT with ADT on HRQoL and functional outcomes remains largely unknown.

Quality of early prostate cancer follow-up care from the patients' perspective.

PURPOSE: To develop optimal cancer survivorship care programs, this study assessed the quality of prostate cancer follow-up care as experienced by patients shortly after completion of primary treatment. METHODS: We surveyed 402 patients with localized prostate cancer participating in a randomized controlled trial comparing specialist versus primary care-based follow-up. For the current study, we used patient-reported data at the time of the first follow-up visit at the hospital, prior to randomization. We assessed patients' ratings of the quality of follow-up care using the Assessment of Patient Experiences of Cancer Care survey. This survey includes 13 scales about different aspects of care and an overall rating of care. Multivariable linear regression analysis was used to identify factors associated with perceived follow-up quality. RESULTS: Patients reported positive experiences at first follow-up for 9 of 13 scales, with mean (M) scores ranging from 79 to 97 (on a 0-100 response scale). Patients reported most frequently (over 70%) suboptimal care regarding symptom management (84%; M = 44, SD = 37), health promotion (75%; M = 45, SD = 39), and physician's knowledge about patients' life (84%; M = 65, SD = 23). Overall, patients' lower quality of follow-up ratings were associated with younger age, higher education level, having more than one comorbid condition, having undergone primary surgery, and experiencing significant symptoms. CONCLUSION: Patients with prostate cancer are generally positive about their initial, hospital-based follow-up care. However, efforts should be made to improve symptom management, health promotion, and physician's knowledge about patients' life. These findings point to areas where prostate cancer follow-up care can be improved.

Optimal 68Ga-PSMA and 18F-PSMA PET window levelling for gross tumour volume delineation in primary prostate cancer.

PURPOSE: This study proposes optimal tracer-specific threshold-based window levels for PSMA PET-based intraprostatic gross tumour volume (GTV) contouring to reduce interobserver delineation variability. METHODS: Nine 68Ga-PSMA-11 and nine 18F-PSMA-1007 PET scans including GTV delineations of four expert teams (GTVmanual) and a majority-voted GTV (GTVmajority) were assessed with respect to a registered histopathological GTV (GTVhisto) as the gold standard reference. The standard uptake values (SUVs) per voxel were converted to a percentage (SUV%) relative to the SUVmax. The statistically optimised SUV% threshold (SOST) was defined as those that maximises accuracy for threshold-based contouring. A leave-one-out cross-validation receiver operating characteristic (ROC) curve analysis was performed to determine the SOST for each tracer. The SOST analysis was performed twice, first using the GTVhisto contour as training structure (GTVSOST-H) and second using the GTVmajority contour as training structure (GTVSOST-MA) to correct for any limited misregistration. The accuracy of both GTVSOST-H and GTVSOST-MA was calculated relative to GTVhisto in the 'leave-one-out' patient of each fold and compared with the accuracy of GTVmanual. RESULTS: ROC curve analysis for 68Ga-PSMA-11 PET revealed a median threshold of 25 SUV% (range, 22-27 SUV%) and 41 SUV% (40-43 SUV%) for GTVSOST-H and GTVSOST-MA, respectively. For 18F-PSMA-1007 PET, a median threshold of 42 SUV% (39-45 SUV%) for GTVSOST-H and 44 SUV% (42-45 SUV%) for GTVSOST-MA was found. A significant pairwise difference was observed when comparing the accuracy of the GTVSOST-H contours with the median accuracy of the GTVmanual contours (median, - 2.5%; IQR, - 26.5-0.2%; p = 0.020), whereas no significant pairwise difference was found for the GTVSOST-MA contours (median, - 0.3%; IQR, - 4.4-0.6%; p = 0.199). CONCLUSIONS: Threshold-based contouring using GTVmajority-trained SOSTs achieves an accuracy comparable with manual contours in delineating GTVhisto. The median SOSTs of 41 SUV% for 68Ga-PSMA-11 PET and 44 SUV% for 18F-PSMA-1007 PET form a base for tracer-specific window levelling. TRIAL REGISTRATION: Clinicaltrials.gov ; NCT03327675; 31-10-2017.

Histopathological Features of MRI-Invisible Regions of Prostate Cancer Lesions.

BACKGROUND: Previous studies have reported tumor volume underestimation with multiparametric (mp)MRI in prostate cancer diagnosis. PURPOSE: To investigate why some parts of lesions are not visible on mpMRI by comparing their histopathology features to those of visible regions. STUDY TYPE: Retrospective. POPULATION: Thirty-four patients with biopsy-proven prostate cancer scheduled for prostatectomy (median 68.7 years). FIELD STRENGTH/SEQUENCE: T2 -weighted, diffusion-weighted imaging, T2 mapping, and dynamic contrast-enhanced MRI on two 3T systems and one 1.5T system. ASSESSMENT: Two readers delineated suspicious lesions on mpMRI. A pathologist delineated the lesions on histopathology. A patient-customized mold enabled the registration of histopathology and MRI. On histopathology we identified mpMRI visible and invisible lesions. Subsequently, within the visible lesions we identified regions that were visible and regions that were invisible on mpMRI. For each lesion and region the following characteristics were determined: size, location, International Society of Urological Pathology (ISUP) grade, and Gleason subpatterns (density [dense/intermediate], tumor morphology [homogeneous/heterogeneous], cribriform growth [yes/no]). STATISTICAL TESTS: With generalized linear mixed-effect modeling we investigated which features explain why a lesion or a region was invisible on MRI. We compared imaging values (T2 , ADC, and Ktrans ) for these features with one-way analysis of variance (ANOVA). RESULTS: Small, anterior, and ISUP grade 1-2 lesions (n = 34) were missed more frequent than large, posterior, ISUP grade ≥ 3 lesions (n = 35). Invisible regions on mpMRI had lower tumor density, heterogeneous tumor morphology, and were located in the transition zone. Both T2 and ADC values were higher in "intermediate" compared with "dense" regions (P = 0.002 and < 0.001) and in regions with heterogeneous compared with homogeneous morphology (P < 0.001 and 0.03). Ktrans was not significantly different (P = 0.24 and 0.99). DATA CONCLUSION: Regions of prostate cancer lesions that are invisible on mpMRI have different histopathology features than visible regions. This may have implications for monitoring during active surveillance and focal treatment strategies. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:1235-1246.

Management of the penile squamous cell carcinoma patient after node positive radical inguinal lymph node dissection: current evidence and future prospects.

PURPOSE OF REVIEW: The level of evidence for current (adjuvant) treatment strategies after node positive inguinal lymphadenectomy is relatively low because of a paucity of prospective studies and controversy exist between the two major guidelines. The present review aims to provide a review of current literature on the available treatment options of patients after a tumor positive inguinal lymph node dissection. RECENT FINDINGS: Patients without inguinal extranodal extension or less than two tumor positive inguinal nodes are at low risk of ipsilateral pelvic nodal disease. Patients with pN1 disease are unlikely to benefit from adjuvant treatment, whereas patients with pN2 disease might benefit from adjuvant radiotherapy. For patients with high risk of pelvic nodal disease, prophylactic pelvic lymph node dissection (PLND) is advised by current guidelines. The InPACT study investigates whether adjuvant chemoradiotherapy could be used instead of prophylactic PLND. Subgroup analyses of retrospective cohorts suggest that patients with pN3 disease based on tumor positive pelvic nodes may benefit from adjuvant radiotherapy or chemotherapy. Given the weak level of evidence and substantial toxicity associated with current regimens, adjuvant chemotherapy cannot be generally recommended. SUMMARY: Despite current treatment strategies, patients with pN2-pN3 disease still have a poor prognosis. Prospective international multicenter studies are necessary to identify the best treatment options for patients with advanced node positive penile squamous cell carcinoma.

Improved repeatability of dynamic contrast-enhanced MRI using the complex MRI signal to derive arterial input functions: a test-retest study in prostate cancer patients.

PURPOSE: The arterial input function (AIF) is a major source of uncertainty in tracer kinetic (TK) analysis of dynamic contrast-enhanced (DCE)-MRI data. The aim of this study was to investigate the repeatability of AIFs extracted from the complex signal and of the resulting TK parameters in prostate cancer patients. METHODS: Twenty-two patients with biopsy-proven prostate cancer underwent a 3T MRI exam twice. DCE-MRI data were acquired with a 3D spoiled gradient echo sequence. AIFs were extracted from the magnitude of the signal (AIFMAGN ), phase (AIFPHASE ), and complex signal (AIFCOMPLEX ). The Tofts model was applied to extract Ktrans , kep and ve . Repeatability of AIF curve characteristics and TK parameters was assessed with the within-subject coefficient of variation (wCV). RESULTS: The wCV for peak height and full width at half maximum for AIFCOMPLEX (7% and 8%) indicated an improved repeatability compared to AIFMAGN (12% and 12%) and AIFPHASE (12% and 7%). This translated in lower wCV values for Ktrans (11%) with AIFCOMPLEX in comparison to AIFMAGN (24%) and AIFPHASE (15%). For kep , the wCV was 16% with AIFMAGN , 13% with AIFPHASE , and 13% with AIFCOMPLEX . CONCLUSION: Repeatability of AIFPHASE and AIFCOMPLEX is higher than for AIFMAGN , resulting in a better repeatability of TK parameters. Thus, use of either AIFPHASE or AIFCOMPLEX improves the robustness of quantitative analysis of DCE-MRI in prostate cancer.

Concurrent Radiotherapy and Panitumumab after Lymph Node Dissection and Induction Chemotherapy for Invasive Bladder Cancer.

PURPOSE: In this prospective study we evaluated the safety and efficacy of concurrent radiotherapy and panitumumab following neoadjuvant/induction chemotherapy and pelvic lymph node dissection as a bladder preserving therapy for invasive bladder cancer. MATERIALS AND METHODS: Patients with cT1-4N0-2M0 bladder cancer were treated with pelvic lymph node dissection and 4 cycles of platinum based induction chemotherapy followed by a 6½-week schedule of weekly panitumumab (2.5 mg/kg) and concurrent radiotherapy to the bladder (33 × 2 Gy). As the primary objective we compared concurrent radiotherapy and panitumumab toxicity to a historical control toxicity rate of concurrent cisplatin/radiotherapy (less than 35% of patients with Grade 3-5 toxicity). A sample size of 31 patients was estimated. Secondary end points included complete remission at 3-month followup, the bladder preservation rate, EGFR (epidermal growth factor receptor) expression and RAS mutational status. RESULTS: Of the 38 cases initially included in this study 34 were staged cN0. After pelvic lymph node dissection 7 cases (21%) were up staged to pN+. Of the 38 patients 31 started concurrent radiotherapy and panitumumab. During concurrent radiotherapy and panitumumab 5 patients (16%, 95% CI 0-31) experienced systemic or local grade 3-4 toxicity. Four patients did not complete treatment due to adverse events. Complete remission was achieved in 29 of 31 patients (94%, 95% CI 83-100). At a median followup of 34 months 4 patients had local recurrence, for which 3 (10%) underwent salvage cystectomy. Two tumors showed EGFR or RAS mutation while 84% showed positive EGFR expression. CONCLUSIONS: Concurrent radiotherapy and panitumumab following induction chemotherapy and pelvic lymph node dissection has a safety profile that is noninferior to the historical profile of concurrent cisplatin/radiotherapy. The high complete remission and bladder preservation rates are promising and warrant further study.

Quantitative 3T multiparametric MRI of benign and malignant prostatic tissue in patients with and without local recurrent prostate cancer after external-beam radiation therapy.

BACKGROUND: Post-radiotherapy locally recurrent prostate cancer (PCa) patients are candidates for focal salvage treatment. Multiparametric MRI (mp-MRI) is attractive for tumor localization. However, radiotherapy-induced tissue changes complicate image interpretation. To develop focal salvage strategies, accurate tumor localization and distinction from benign tissue is necessary. PURPOSE: To quantitatively characterize radio-recurrent tumor and benign radiation-induced changes using mp-MRI, and investigate which sequences optimize the distinction between tumor and benign surroundings. STUDY TYPE: Prospective case-control. SUBJECTS: Thirty-three patients with biochemical failure after external-beam radiotherapy (cases), 35 patients without post-radiotherapy recurrent disease (controls), and 13 patients with primary PCa (untreated). FIELD STRENGTH/SEQUENCES: 3T; quantitative mp-MRI: T2 -mapping, ADC, and Ktrans and kep maps. ASSESSMENT: Quantitative image-analysis of prostatic regions, within and between cases, controls, and untreated patients. STATISTICAL TESTS: Within-groups: nonparametric Friedman analysis of variance with post-hoc Wilcoxon signed-rank tests; between-groups: Mann-Whitney tests. All with Bonferroni corrections. Generalized linear mixed modeling to ascertain the contribution of each map and location to tumor likelihood. RESULTS: Benign imaging values were comparable between cases and controls (P = 0.15 for ADC in the central gland up to 0.91 for kep in the peripheral zone), both with similarly high peri-urethral Ktrans and kep values (min-1 ) (median [range]: Ktrans = 0.22 [0.14-0.43] and 0.22 [0.14-0.36], P = 0.60, kep = 0.43 [0.24-0.57] and 0.48 [0.32-0.67], P = 0.05). After radiotherapy, benign central gland values were significantly decreased for all maps (P ≤ 0.001) as well as T2 , Ktrans , and kep of benign peripheral zone (all with P ≤ 0.002). All imaging maps distinguished recurrent tumor from benign peripheral zone, but only ADC, Ktrans , and kep were able to distinguish it from benign central gland. Recurrent tumor and peri-urethral Ktrans values were not significantly different (P = 0.81), but kep values were (P < 0.001). Combining all quantitative maps and voxel location resulted in an optimal distinction between tumor and benign voxels. DATA CONCLUSION: Mp-MRI can distinguish recurrent tumor from benign tissue. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;50:269-278.

Quantitative 3-T multi-parametric MRI and step-section pathology of recurrent prostate cancer patients after radiation therapy.

OBJECTIVES: Diagnosis of radio-recurrent prostate cancer using multi-parametric MRI (mp-MRI) can be challenging due to the presence of radiation effects. We aim to characterize imaging of prostate tissue after radiation therapy (RT), using histopathology as ground truth, and to investigate the visibility of tumor lesions on mp-MRI. METHODS: Tumor delineated histopathology slides from salvage radical prostatectomy patients, primarily treated with RT, were registered to MRI. Median T2-weighted, ADC, Ktrans, and kep values in tumor and other regions were calculated. Two radiologists independently performed mp-MRI-based tumor delineations which were compared with the true pathological extent. General linear mixed-effect modeling was used to establish the contribution of each imaging modality and combinations thereof in distinguishing tumor and benign voxels. RESULTS: Nineteen of the 21 included patients had tumor in the available histopathology slides. Recurrence was predominantly multifocal with large tumor foci seen after external beam radiotherapy, whereas these were small and sparse after low-dose-rate brachytherapy. MRI-based delineations missed small foci and slightly underestimated tumor extent. The combination of T2-weighted, ADC, Ktrans, and kep had the best performance in distinguishing tumor and benign voxels. CONCLUSIONS: Using high-resolution histopathology delineations, the real tumor extent and size were found to be underestimated on MRI. mp-MRI obtained the best performance in identifying tumor voxels. Appropriate margins around the visible tumor-suspected region should be included when designing focal salvage strategies. Recurrent tumor delineation guidelines are warranted. KEY POINTS: • Compared to the use of individual sequences, multi-parametric MRI obtained the best performance in distinguishing recurrent tumor from benign voxels. • Delineations based on mp-MRI miss smaller foci and slightly underestimate tumor volume of local recurrent prostate cancer. • Focal salvage strategies should include appropriate margins around the visible tumor.

Performance of a fast and high-resolution multi-echo spin-echo sequence for prostate T2 mapping across multiple systems.

PURPOSE: To evaluate the performance of a multi-echo spin-echo sequence with k-t undersampling scheme (k-t T2 ) in prostate cancer. METHODS: Phantom experiments were performed at five systems to estimate the bias, short-term repeatability, and reproducibility across all systems expressed with the within-subject coefficient of variation (wCV). Monthly measurements were performed on two systems for long-term repeatability estimation. To evaluate clinical repeatability, two T2 maps (voxel size 0.8 × 0.8 × 3 mm3 ; 5 min) were acquired at separate visits on one system for 13 prostate cancer patients. Repeatability was assessed per patient in relation to spatial resolution. T2 values were compared for tumor, peripheral zone, and transition zone. RESULTS: Phantom measurements showed a small bias (median = -0.9 ms) and good short-term repeatability (median wCV = 0.5%). Long-term repeatability was 0.9 and 1.1% and reproducibility between systems was 1.7%. The median bias observed in patients was -1.1 ms. At voxel level, the median wCV was 15%, dropping to 4% for structures of 0.5 cm3 . The median tumor T2 values (79 ms) were significantly lower (P < 0.001) than in the peripheral zone (149 ms), but overlapped with the transition zone (91 ms). CONCLUSIONS: Reproducible T2 mapping of the prostate is feasible with good spatial resolution in a clinically reasonable scan time, allowing reliable measurement of T2 in structures as small as 0.5 cm3 . Magn Reson Med 79:1586-1594, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Impact of contrast agent injection duration on dynamic contrast-enhanced MRI quantification in prostate cancer.

The volume transfer constant Ktrans , which describes the leakage of contrast agent (CA) from vasculature into tissue, is the most commonly reported quantitative parameter for dynamic contrast-enhanced (DCE-) MRI. However, the variation in reported Ktrans values between studies from different institutes is large. One of the primary sources of uncertainty is quantification of the arterial input function (AIF). The aim of this study is to determine the influence of the CA injection duration on the AIF and tracer kinetic analysis (TKA) parameters (i.e. Ktrans , kep and ve ). Thirty-one patients with prostate cancer received two DCE-MRI examinations with an injection duration of 5 s in the first examination and a prolonged injection duration in the second examination, varying between 7.5 s and 30 s. The DCE examination was carried out on a 3.0 T MRI scanner using a transversal T1 -weighted 3D spoiled gradient echo sequence (300 s duration, dynamic scan time of 2.5 s). Data of 29 of the 31 were further analysed. AIFs were determined from the phase signal in the left and right femoral arteries. Ktrans , kep and ve were estimated with the standard Tofts model for regions of healthy peripheral zone and tumour tissue. We observed a significantly smaller peak height and increased width in the AIF for injection durations of 15 s and longer. However, we did not find significant differences in Ktrans , kep or ve for the studied injection durations. The study demonstrates that the TKA parameters Ktrans , kep and ve , measured in the prostate, do not show a significant change as a function of injection duration.

Validation and head-to-head comparison of three nomograms predicting probability of lymph node invasion of prostate cancer in patients undergoing extended and/or sentinel lymph node dissection.

PURPOSE: The updated Winter nomogram is the only nomogram predicting lymph node invasion (LNI) in prostate cancer (PCa) patients based on sentinel node (SN) dissection (sLND). The aim of the study was to externally validate the Winter nomogram and examine its performance in patients undergoing extended pelvic lymph node dissection (ePLND), ePLND combined with SN biopsy (SNB) and sLND only. The results were compared with the Memorial Sloan Kettering Cancer Center (MSKCC) and updated Briganti nomograms. METHODS: This retrospective study included 1183 patients with localized PCa undergoing robot-assisted laparoscopic radical prostatectomy (RARP) combined with pelvic lymphadenectomy and 224 patients treated with sLND and external beam radiotherapy (EBRT), aiming to offer pelvic radiotherapy only in case of histologically positive SNs. In the RARP population, ePLND was applied in 956 (80.8%) patients,while 227 (19.2%) patients were offered ePLND combined with additional SNB. RESULTS: The median numbers of removed nodes were 10 (interquartile range, IQR = 6-14), 15 (IQR = 10-20) and 7 (IQR = 4-10) in the ePLND, ePLND + SNB, and sLND groups, respectively. Corresponding LNI rates were 16.6%, 25.5% and 42%. Based on the AUC, the performance of the Briganti nomogram (0.756) in the ePLND group was superior to both the MSKCC (0.744) and Winter nomogram (0.746). The Winter nomogram, however, was the best predictor of LNI in both the ePLND + SNB (0.735) and sLND (0.709) populations. In the calibration analysis, all nomograms showed better accuracy in the low/intermediate risk patients, while in the high-risk population, an overestimation of the risk for LNI was observed. CONCLUSION: The SN-based updated nomogram showed better prediction in the SN population. The results were also comparable, relative to predictive tools developed with (e)PLND, suggesting a difference in sampling accuracy between SNB and non-SNB. Patients who benefit most from the nomogram would be those with a low/intermediate risk of LN metastasis.

Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): late toxicity results from a randomised, non-inferiority, phase 3 trial.

BACKGROUND: Several studies have reported a low α to ß ratio for prostate cancer, suggesting that hypofractionation could enhance the biological tumour dose without increasing genitourinary and gastrointestinal toxicity. We tested this theory in the phase 3 HYPRO trial for patients with intermediate-risk and high-risk prostate cancer. We have previously reported acute incidence of genitourinary and gastrointestinal toxicity; here we report data for late genitourinary and gastrointestinal toxicity. METHODS: In this randomised non-inferiority phase 3 trial, done in seven radiotherapy centres in the Netherlands, we enrolled intermediate-risk or high-risk patients aged between 44 and 85 years with histologically confirmed stage T1b-T4 NX-0MX-0 prostate cancer, a prostate-specific antigen concentration of 60 ng/mL or lower, and WHO performance status of 0-2. A web-based application was used to randomly assign (1:1) patients to receive either standard fractionation with 39 fractions of 2 Gy in 8 weeks (five fractions per week) or hypofractionation with 19 fractions of 3·4 Gy in 6·5 weeks (three fractions per week). Randomisation was done with the minimisation procedure, stratified by treatment centre and risk group. The primary endpoint was to detect a 10% enhancement in 5-year relapse-free survival with hypofractionation. A key additional endpoint was non-inferiority of hypofractionation in cumulative incidence of grade 2 or worse acute and late genitourinary and gastrointestinal toxicity. We planned to reject inferiority of hypofractionation for late genitourinary toxicity if the estimated hazard ratio (HR) was less than 1·11 and for gastrointestinal toxicity was less than 1·13. We scored toxicity with the Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer (RTOG/EORTC) criteria from both physicians' records (clinical record form) and patients' self-assessment questionnaires. Analyses were done in the intention-to-treat population. Patient recruitment for the HYPRO trial was completed in 2010. The trial was registered with www.controlled-trials.com, number ISRCTN85138529. FINDINGS: Between March 19, 2007, and Dec 3, 2010, 820 patients (410 in both groups) were randomly assigned. Analyses for late toxicity included 387 assessable patients in the standard fractionation group and 395 in the hypofractionation group. The median follow-up was 60 months (IQR 51·2-67·3). The database for all analyses (both groups and both genitourinary and gastrointestinal toxicities) was locked on March 26, 2015. The incidence of grade 2 or worse genitourinary toxicity at 3 years was 39·0% (95% CI 34·2-44·1) in the standard fractionation group and 41·3% (36·6-46·4) in the hypofractionation group. The estimated HR for the cumulative incidence of grade 2 or worse late genitourinary toxicity was 1·16 (90% CI 0·98-1·38), suggesting that non-inferiority could not be shown. The incidence of grade 2 or worse gastrointestinal toxicity at 3 years was 17·7% (14·1-21·9) in standard fractionation and 21·9% (18·1-26·4) hypofractionation. With an estimated HR of 1·19 (90% CI 0·93-1·52) for the cumulative incidence of grade 2 or worse late gastrointestinal toxicity, we could not confirm non-inferiority of hypofractionation for cumulative late gastrointestinal toxicity. Cumulative grade 3 or worse late genitourinary toxicity was significantly higher in the hypofractionation group than in the standard fractionation group (19·0% [95% CI 15·2-23·2] vs 12·9% [9·7-16·7], respectively; p=0·021), but there was no significant difference between cumulative grade 3 or worse late gastrointestinal toxicity (2·6% [95% CI 1·2-4·7]) in the standard fractionation group and 3·3% [1·7-5·6] in the hypofractionation group; p=0·55). INTERPRETATION: Our data could not confirm that hypofractionation was non-inferior for cumulative late genitourinary and gastrointestinal toxicity compared with standard fractionation. Before final conclusions can be made about the utility of hypofractionation, efficacy outcomes need to be reported. FUNDING: The Dutch Cancer Society.

Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial.

BACKGROUND: Studies have reported a low α/ß ratio for prostate cancer, suggesting that hypofractionation could enhance the biological tumour dose without increasing genitourinary and gastrointestinal toxicity. In the multicentre phase 3, HYpofractionated irradiation for PROstate cancer (HYPRO) trial, hypofractionated radiotherapy was compared with conventionally fractionated radiotherapy for treatment of prostate cancer. We have previously reported acute and late incidence of genitourinary and gastrointestinal toxicity; here we report protocol-defined 5-year relapse-free survival outcomes. METHODS: We did an open-label, randomised, phase 3 trial at seven Dutch radiotherapy centres. We enrolled patients with intermediate-risk to high-risk T1b-T4NX-N0MX-M0 localised prostate cancer, a prostate-specific antigen concentration of 60 µg/L or less, and a WHO performance status of 0-2. We used a web-based application to randomly assign (1:1) patients to either hypofractionated radiotherapy of 64·6 Gy (19 fractions of 3·4 Gy, three fractions per week) or conventionally fractionated radiotherapy of 78·0 Gy (39 fractions of 2·0 Gy, five fractions per week). Based on an estimated α/ß ratio for prostate cancer of 1·5 Gy, the equivalent total dose in fractions of 2·0 Gy was 90·4 Gy for hypofractionation compared with 78·0 Gy for conventional fractionation. The primary endpoint was relapse-free survival. All analyses were done on an intention-to-treat basis in all eligible patients. The HYPRO trial completed recruitment in 2010 and follow-up is ongoing. This trial is registered with ISRCTN, number ISRCTN85138529. FINDINGS: Between March 19, 2007, and Dec 3, 2010, 820 patients were enrolled, of whom 804 were eligible and assessable for intention-to-treat analyses. Of these, 407 were assigned hypofractionated radiotherapy and 397 were allocated conventionally fractionated radiotherapy. 537 (67%) of 804 patients received concomitant androgen deprivation therapy for a median duration of 32 months (IQR 10-44). Median follow-up was 60 months (IQR 51-69). Treatment failure was reported in 169 (21%) of 804 patients, 80 (20%) in the hypofractionation group and 89 (22%) in the conventional fractionation group. 5-year relapse-free survival was 80·5% (95% CI 75·7-84·4) for patients assigned hypofractionation and 77·1% (71·9-81·5) for those allocated conventional fractionation (adjusted hazard radio 0·86, 95% CI 0·63-1·16; log-rank p=0·36). There were no treatment-related deaths. INTERPRETATION: Hypofractionated radiotherapy was not superior to conventional radiotherapy with respect to 5-year relapse-free survival. Our hypofractionated radiotherapy regimen cannot be regarded as the new standard of care for patients with intermediate-risk or high-risk prostate cancer. FUNDING: Dutch Cancer Society.

Sexual Function After Hypofractionated Versus Conventionally Fractionated Radiotherapy for Prostate Cancer: Results From the Randomized Phase III HYPRO Trial.

INTRODUCTION: Hypofractionated radiotherapy could increase the radiobiological tumor dose for localized prostate cancer. The effects of hypofractionation on sexual function are not well known. AIM: To compare sexual function in patients with prostate cancer treated with 78 Gy in 39 fractions of 2 Gy or 64.6 Gy in 19 fractions of 3.4 Gy. METHODS: In total, 820 men with intermediate- to high-risk T1b-T4NX-0MX-0 prostate cancer were enrolled in the phase III HYPRO trial (2007-2010) and randomized to conventional fractionation (39 × 2 Gy) or hypofractionation (19 × 3.4 Gy). Sexual function was assessed at baseline and at 6, 12, 24, and 36 months after treatment using the International Index of Erectile Function (IIEF). For this analysis, patients (n = 322) with a baseline assessment, at least one follow-up assessment, and no or short-term (6-month) androgen-deprivation therapy were included. MAIN OUTCOME MEASURES: Mean IIEF domain scores were compared between treatments in the total population and the hormone-naïve population (n = 197) using the independent t-test. Incidences of severe erectile dysfunction (domain score < 11) at last follow-up were calculated in patients with partial or full baseline function. Binary logistic regression analyses were applied to calculate the odds ratio of hypofractionation vs conventional fractionation and to adjust for clinical factors. RESULTS: Median age was 71 years (interquartile range = 67-71) and median follow-up was 37 months (interquartile range = 25-38). Androgen-deprivation therapy was prescribed in 125 (39%). IIEF domain scores decreased after treatment but were comparable between treatment arms at baseline and during follow-up. Orgasmic function scores in hormone-naïve patients were significantly higher at 3 years after hypofractionation (4.08 vs 2.65, P = .031). In patients (n = 120) with partial or full baseline erectile function, the incidence of erectile dysfunction at last follow-up was 34.4% for hypofractionated treatment vs 39.3% for conventional treatment (adjusted odds ratio = 0.84, 95% CI = 0.37-1.90, P = .67). CONCLUSION: No significant differences in erectile functioning between conventional and hypofractionated radiotherapy were found. Hormone-naïve patients reported significantly higher orgasmic function scores at 3 years after hypofractionation.

Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): acute toxicity results from a randomised non-inferiority phase 3 trial.

BACKGROUND: In 2007, we began the randomised phase 3 multicentre HYPRO trial to investigate the effect of hypofractionated radiotherapy compared with conventionally fractionated radiotherapy on relapse-free survival in patients with prostate cancer. Here, we examine whether patients experience differences in acute gastrointestinal and genitourinary adverse effects. METHODS: In this randomised non-inferiority phase 3 trial, done in seven radiotherapy centres in the Netherlands, we enrolled intermediate-risk or high-risk patients aged between 44 and 85 years with histologically confirmed stage T1b-T4 NX-0MX-0 prostate cancer, a PSA concentration of 60 ng/mL or lower, and WHO performance status of 0-2. A web-based application was used to randomly assign (1:1) patients to receive either standard fractionation with 39 fractions of 2 Gy in 8 weeks (five fractions per week) or hypofractionation with 19 fractions of 3·4 Gy in 6·5 weeks (three fractions per week). Randomisation was done with minimisation procedure, stratified by treatment centre and risk group. The primary endpoint is 5-year relapse-free survival. Here we report data for the acute toxicity outcomes: the cumulative incidence of grade 2 or worse acute and late genitourinary and gastrointestinal toxicity. Non-inferiority of hypofractionation was tested separately for genitourinary and gastrointestinal acute toxic effects, with a null hypothesis that cumulative incidences of each type of adverse event were not more than 8% higher in the hypofractionation group than in the standard fractionation group. We scored acute genitourinary and gastrointestinal toxic effects according to RTOG-EORTC criteria from both case report forms and patients' self-assessment questionnaires, at baseline, twice during radiotherapy, and 3 months after completion of radiotherapy. Analyses were done in the intention-to-treat population. Patient recruitment has been completed. This study is registered with www.controlled-trials.com, number ISRCTN85138529. FINDINGS: Between March 19, 2007, and Dec 3, 2010, 820 patients were randomly assigned to treatment with standard fractionation (n=410) or hypofractionation (n=410). 3 months after radiotherapy, 73 (22%) patients in the standard fractionation group and 75 (23%) patients in the hypofractionation group reported grade 2 or worse genitourinary toxicity; grade 2 or worse gastrointestinal toxicity was noted in 43 (13%) patients in the standard fractionation group and in 42 (13%) in the hypofractionation group. Grade 4 acute genitourinary toxicity was reported for two patients, one (<1%) in each group. No grade 4 acute gastrointestinal toxicities were observed. We noted no significant difference in cumulative incidence by 120 days after radiotherapy of grade 2 or worse acute genitourinary toxicity (57·8% [95% CI 52·9-62·7] in the standard fractionation group vs 60·5% (55·8-65·3) in the hypofractionation group; difference 2·7%, 90% CI -2·99 to 8·48; odds ratio [OR] 1·12, 95% CI 0·84-1·49; p=0·43). The cumulative incidence of grade 2 or worse acute gastrointestinal toxicity by 120 days after radiotherapy was higher in patients given hypofractionation (31·2% [95% CI 26·6-35·8] in the standard fractionation group vs 42·0% [37·2-46·9] in the hypofractionation group; difference 10·8%, 90% CI 5·25-16·43; OR 1·6; p=0·0015; non-inferiority not confirmed). INTERPRETATION: Hypofractionated radiotherapy was not non-inferior to standard fractionated radiotherapy in terms of acute genitourinary and gastrointestinal toxicity for men with intermediate-risk and high-risk prostate cancer. In fact, the cumulative incidence of grade 2 or worse acute gastrointestinal toxicity was significantly higher in patients given hypofractionation than in those given standard fractionated radiotherapy. Patients remain in follow-up for efficacy endpoints. FUNDING: The Dutch Cancer Society.

MRI-guided radiotherapy in twenty fractions for localised prostate cancer; results from the MOMENTUM study.

Background and purpose: MRI-guided radiotherapy (MRIgRT) offers multiple potential advantages over CT-guidance. This study examines the potential clinical benefits of MRIgRT for men with localised prostate cancer, in the setting of moderately hypofractionated radiotherapy. We evaluate two-year toxicity outcomes, early biochemical response and patient-reported outcomes (PRO), using data obtained from a multicentre international registry study, for the first group of patients with prostate cancer who underwent treatment on a 1.5 T MR-Linac. Materials and methods: Patients who were enrolled within the MOMENTUM study and received radical treatment with 60 Gy in 20 fractions were identified. PSA levels and CTCAE version 5.0 toxicity data were measured at follow-up visits. Those patients who consented to PRO data collection also completed EQ-5D-5L, EORTC QLQ-C30 and EORTC QLQ-PR25 questionnaires. Results: Between November 2018 and June 2022, 146 patients who had MRIgRT for localised prostate cancer on the 1.5 T MR-Linac were eligible for this study. Grade 2 and worse gastro-intestinal (GI) toxicity was reported in 3 % of patients at three months whilst grade 2 and worse genitourinary (GU) toxicity was 7 % at three months. There was a significant decrease in the median PSA at 12 months. The results from both the EQ-5D-5L data and EORTC global health status scale indicate a decline in the quality of life (QoL) during the first six months. The mean change in score for the EORTC scale showed a decrease of 11.4 points, which is considered clinically important. QoL improved back to baseline by 24 months. Worsening of hormonal symptoms in the first six months was reported with a return to baseline by 24 months and sexual activity in all men worsened in the first three months and returned to baseline at 12 months. Conclusion: This study establishes the feasibility of online-MRIgRT for localised prostate on a 1.5 T MR-Linac with low rates of toxicity, similar to that published in the literature. However, the clinical benefits of MRIgRT over conventional radiotherapy in the setting of moderate hypofractionation is not evident. Further research will focus on the delivery of ultrahypofractionated regimens, where the potential advantages of MRIgRT for prostate cancer may become more discernible.

Development of Prostate Bed Delineation Consensus Guidelines for Magnetic Resonance Image-Guided Radiotherapy and Assessment of Its Effect on Interobserver Variability.

PURPOSE: The use of magnetic resonance imaging (MRI) in radiotherapy planning is becoming more widespread, particularly with the emergence of MRI-guided radiotherapy systems. Existing guidelines for defining the prostate bed clinical target volume (CTV) show considerable heterogeneity. This study aimed to establish baseline interobserver variability (IOV) for prostate bed CTV contouring on MRI, develop international consensus guidelines, and evaluate its effect on IOV. METHODS AND MATERIALS: Participants delineated the CTV on 3 MRI scans, obtained from the Elekta Unity MR-Linac, as per their normal practice. Radiation oncologist contours were visually examined for discrepancies, and interobserver comparisons were evaluated against simultaneous truth and performance level estimation (STAPLE) contours using overlap metrics (Dice similarity coefficient and Cohen's kappa), distance metrics (mean distance to agreement and Hausdorff distance), and volume measurements. A literature review of postradical prostatectomy local recurrence patterns was performed and presented alongside IOV results to the participants. Consensus guidelines were collectively constructed, and IOV assessment was repeated using these guidelines. RESULTS: Sixteen radiation oncologists' contours were included in the final analysis. Visual evaluation demonstrated significant differences in the superior, inferior, and anterior borders. Baseline IOV assessment indicated moderate agreement for the overlap metrics while volume and distance metrics demonstrated greater variability. Consensus for optimal prostate bed CTV boundaries was established during a virtual meeting. After guideline development, a decrease in IOV was observed. The maximum volume ratio decreased from 4.7 to 3.1 and volume coefficient of variation reduced from 40% to 34%. The mean Dice similarity coefficient rose from 0.72 to 0.75 and the mean distance to agreement decreased from 3.63 to 2.95 mm. CONCLUSIONS: Interobserver variability in prostate bed contouring exists among international genitourinary experts, although this is lower than previously reported. Consensus guidelines for MRI-based prostate bed contouring have been developed, and this has resulted in an improvement in contouring concordance. However, IOV persists and strategies such as an education program, development of a contouring atlas, and further refinement of the guidelines may lead to additional improvements.