Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localised prostate cancer after radical prostatectomy (GETUG-AFU 17): a randomised, phase 3 trial.

BACKGROUND: Adjuvant radiotherapy reduces the risk of biochemical progression in prostate cancer patients after radical prostatectomy. We aimed to compare adjuvant versus early salvage radiotherapy after radical prostatectomy, combined with short-term hormonal therapy, in terms of oncological outcomes and tolerance. METHODS: GETUG-AFU 17 was a randomised, open-label, multicentre, phase 3 trial done at 46 French hospitals. Men aged at least 18 years who had an Eastern Cooperative Oncology Group performance status of 1 or less, localised adenocarcinoma of the prostate treated with radical prostatectomy, who had pathologically-staged pT3a, pT3b, or pT4a (with bladder neck invasion), pNx (without pelvic lymph nodes dissection), or pN0 (with negative lymph nodes dissection) disease, and who had positive surgical margins were eligible for inclusion in the study. Eligible patients were randomly assigned (1:1) to either immediate adjuvant radiotherapy or delayed salvage radiotherapy at the time of biochemical relapse. Random assignment, by minimisation, was done using web-based software and stratified by Gleason score, pT stage, and centre. All patients received 6 months of triptorelin (intramuscular injection every 3 months). The primary endpoint was event-free survival. Efficacy and safety analyses were done on the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT00667069. FINDINGS: Between March 7, 2008, and June 23, 2016, 424 patients were enrolled. We planned to enrol 718 patients, with 359 in each study group. However, on May 20, 2016, the independent data monitoring committee recommended early termination of enrolment because of unexpectedly low event rates. At database lock on Dec 19, 2019, the overall median follow-up time from random assignment was 75 months (IQR 50-100), 74 months (47-100) in the adjuvant radiotherapy group and 78 months (52-101) in the salvage radiotherapy group. In the salvage radiotherapy group, 115 (54%) of 212 patients initiated study treatment after biochemical relapse. 205 (97%) of 212 patients started treatment in the adjuvant group. 5-year event-free survival was 92% (95% CI 86-95) in the adjuvant radiotherapy group and 90% (85-94) in the salvage radiotherapy group (HR 0·81, 95% CI 0·48-1·36; log-rank p=0·42). Acute grade 3 or worse toxic effects occurred in six (3%) of 212 patients in the adjuvant radiotherapy group and in four (2%) of 212 patients in the salvage radiotherapy group. Late grade 2 or worse genitourinary toxicities were reported in 125 (59%) of 212 patients in the adjuvant radiotherapy group and 46 (22%) of 212 patients in the salvage radiotherapy group. Late genitourinary adverse events of grade 2 or worse were reported in 58 (27%) of 212 patients in the adjuvant radiotherapy group versus 14 (7%) of 212 patients in the salvage radiotherapy group (p<0·0001). Late erectile dysfunction was grade 2 or worse in 60 (28%) of 212 in the adjuvant radiotherapy group and 17 (8%) of 212 in the salvage radiotherapy group (p<0·0001). INTERPRETATION: Although our analysis lacked statistical power, we found no benefit for event-free survival in patients assigned to adjuvant radiotherapy compared with patients assigned to salvage radiotherapy. Adjuvant radiotherapy increased the risk of genitourinary toxicity and erectile dysfunction. A policy of early salvage radiotherapy could spare men from overtreatment with radiotherapy and the associated adverse events. FUNDING: French Health Ministry and Ipsen.

Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): a 112-month follow-up of a phase 3, randomised trial.

BACKGROUND: Radiotherapy is the standard salvage treatment after radical prostatectomy. To date, the role of androgen deprivation therapy has not been formally shown. In this follow-up study, we aimed to update the results of the GETUG-AFU 16 trial, which assessed the efficacy of radiotherapy plus androgen suppression versus radiotherapy alone. METHODS: GETUG-AFU 16 was an open-label, multicentre, phase 3, randomised, controlled trial that enrolled men (aged ≥18 years) with Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed adenocarcinoma of the prostate (but no previous androgen suppression or pelvic radiotherapy), stage pT2, T3, or T4a (bladder neck involvement only) and pN0 or pNx according to the tumour, node, metastasis (TNM) staging system, whose prostate-specific antigen (PSA) concentration increased from 0·1 ng/mL to between 0·2 ng/mL and 2·0 ng/mL after radical prostatectomy, without evidence of clinical disease. Patients were assigned through central randomisation (1:1) to short-term androgen suppression (subcutaneous injection of 10·8 mg goserelin on the first day of irradiation and 3 months later) plus radiotherapy (3D conformal radiotherapy or intensity modulated radiotherapy of 66 Gy in 33 fractions, 5 days a week for 7 weeks) or radiotherapy alone. Randomisation was stratified using a permuted block method (block sizes of two and four) according to investigational site, radiotherapy modality, and prognosis. The primary endpoint was progression-free survival in the intention-to-treat population. This post-hoc one-shot data collection done 4 years after last data cutoff included patients who were alive at the time of the primary analysis and updated long-term patient status by including dates for first local progression, metastatic disease diagnosis, or death (if any of these had occurred) or the date of the last tumour evaluation or last PSA measurement. Survival at 120 months was reported. Late serious adverse effects were assessed. This trial is registered on ClinicalTrials.gov, NCT00423475. FINDINGS: Between Oct 19, 2006, and March 30, 2010, 743 patients were randomly assigned, 374 to radiotherapy alone and 369 to radiotherapy plus goserelin. At the time of data cutoff (March 12, 2019), the median follow-up was 112 months (IQR 102-123). The 120-month progression-free survival was 64% (95% CI 58-69) for patients treated with radiotherapy plus goserelin and 49% (43-54) for patients treated with radiotherapy alone (hazard ratio 0·54, 0·43-0·68; stratified log-rank test p<0·0001). Two cases of secondary cancer occurred since the primary analysis, but were not considered to be treatment related. No treatment-related deaths occurred. INTERPRETATION: The 120-month progression-free survival confirmed the results from the primary analysis. Salvage radiotherapy combined with short-term androgen suppression significantly reduced risk of biochemical or clinical progression and death compared with salvage radiotherapy alone. The results of the GETUG-AFU 16 trial confirm the efficacy of androgen suppression plus radiotherapy as salvage treatment in patients with increasing PSA concentration after radical prostatectomy for prostate cancer. FUNDING: The French Health ministry, AstraZeneca, la Ligue Contre le Cancer, and La Ligue de Haute-Savoie.

Consolidative Radiotherapy for Metastatic Urothelial Bladder Cancer Patients with No Progression and with No More than Five Residual Metastatic Lesions Following First-Line Systemic Therapy: A Retrospective Analysis.

Local consolidative radiotherapy in the treatment of metastatic malignancies has shown promising results in several types of tumors. The objective of this study was to assess consolidative radiotherapy to the bladder and to residual metastases in metastatic urothelial bladder cancer with no progression following first-line systemic therapy. MATERIALS/METHODS: Patients who received first-line therapy for the treatment of metastatic urothelial bladder cancer (mUBC) and who were progression-free following treatment with no more than five residual metastases were retrospectively identified through the database of four Comprehensive Cancer Centers, between January 2005 and December 2018. Among them, patients who received subsequent definitive radiotherapy (of EQD2Gy > 45Gy) to the bladder and residual metastases were included in the consolidative group (irradiated (IR) group), and the other patients were included in the observation group (NIR group). Progression-free survival (PFS) and overall survival (OS) were determined from the start of the first-line chemotherapy using the Kaplan-Meier method. To prevent immortal time bias, a Cox model with time-dependent covariates and 6-month landmark analyses were performed to examine OS and PFS. RESULTS: A total of 91 patients with at least stable disease following first-line therapy and with no more than five residual metastases were analyzed: 51 in the IR group and 40 in the NIR group. Metachronous metastatic disease was more frequent in the NIR group (19% vs. 5%, p = 0.02); the median number of metastases in the IR group vs. in the NIR group was 2 (1-9) vs. 3 (1-5) (p = 0.04) at metastatic presentation, and 1 (0-5) vs. 2 (0-5) (p = 0.18) after completion of chemotherapy (residual lesions), respectively. Two grade 3 toxicities (3.9%) and no grade 4 toxicity were reported in the IR group related to radiotherapy. With a median follow up of 85.9 months (95% IC (36.7; 101.6)), median OS and PFS were 21.7 months (95% IC (17.1; 29.7)) and 11.1 months (95% IC (9.9; 14.1)) for the whole cohort, respectively. In multivariable analysis, consolidative radiotherapy conferred a benefit in both PFS (HR = 0.49, p = 0.007) and OS (HR = 0.47, p = 0.015) in the whole population; in the landmark analysis at 6 months, radiotherapy was associated with improved OS (HR = 0.48, p = 0.026), with a trend for PFS (HR = 0.57, p = 0.082). CONCLUSION: Consolidative radiotherapy for mUBC patients who have not progressed after first-line therapy and with limited residual disease seems to confer both OS and PFS benefits. The role of consolidative radiotherapy in the context of avelumab maintenance should be addressed prospectively.

Managing Discordant Findings Between Multiparametric Magnetic Resonance Imaging and Transrectal Magnetic Resonance Imaging-directed Prostate Biopsy-The Key Role of Magnetic Resonance Imaging-directed Transperineal Biopsy.

BACKGROUND: Discordant findings between multiparametric magnetic resonance imaging (mpMRI) and transrectal image-guided biopsies of the prostate (TRUS-P) may result in inadequate risk stratification of localized prostate cancer. OBJECTIVE: To assess transperineal image-guided biopsies of the index target (TPER-IT) in terms of disease reclassification and treatment recommendations. DESIGN, SETTING, AND PARTICIPANTS: Cases referred for suspicion or treatment of localized prostate cancer were reviewed in a multidisciplinary setting, and discordance was characterized into three scenarios: type I-negative biopsies or International Society of Urological Pathology (ISUP) grade 1 cancer in Prostate Imaging Reporting and Data System (PI-RADS) ≥4 index target (IT); type II-negative biopsies or ISUP grade 1 cancer in anterior IT; and type III-<3 mm stretch of cancer in PI-RADS ≥3 IT. Discordant findings were characterized in 132/558 (23.7%) patients after TRUS-P. Of these patients, 102 received reassessment TPER-IT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary objective was to report changes in treatment recommendations after TPER-IT. Therefore, cores obtained by primary TRUS-P and TPER-IT were analyzed in terms of cancer detection, ISUP grade, and Cambridge Prognostic Group classification using descriptive statistics. RESULTS AND LIMITATIONS: TPER-IT biopsies that consisted of fewer cores than the initial TRUS-P (seven vs 14, p < 0.0001) resulted in more cancer tissue materials for analysis (56 vs 42.5 mm, p = 0.0003). As a result, 40% of patients initially considered for follow-up (12/30) and 49% for active surveillance (30/61) were reassigned after TPER-IT to surgery or intensity-modulated radiotherapy. CONCLUSIONS: Nonconcordance between pathology and imaging was observed in a significant proportion of patients receiving TRUS-P. TPER-IT better informed the presence and grade of cancer, resulting in a significant impact on treatment recommendations. A multidisciplinary review of mpMRI and TRUS-P findings and reassessment TPER-IT in type I-II discordances is recommended. PATIENT SUMMARY: In this report, patients with suspicious imaging of the prostate, but no or well-differentiated cancer on transrectal image-guided -biopsies, were offered transperineal image-guided biopsies for reassessment. We found that a large share of these had a more aggressive cancer than initially suspected. We conclude that discordant results warrant reassessment transperineal image-guided biopsies as these may impact disease risk classification and treatment recommendations.

Highly hypofractionated schedules for localized prostate cancer: Recommendations of the GETUG radiation oncology group.

Stereotactic body radiotherapy (SBRT) has become treatment option for localized prostate cancer but the evidence base remains incomplete. Several clinical studies, both prospective and retrospective, have been published. However, treatment techniques, target volumes and dose constraints lack consistency between studies. Based on the current available literature, the French Genito-Urinary Group (GETUG) suggests that.

Distinct Outcomes of Oropharyngeal Squamous Cell Carcinoma Patients after Distant Failure According to p16 Status: Implication in Therapeutic Options.

INTRODUCTION: Recent modifications in the epidemiology of oropharyngeal squamous cell carcinoma (OSCC) have led to the increase of Human papillomavirus (HPV) related metastatic head and neck cancer patients with high life expectancy even at advanced stage, low comorbidity and still restricted systemic therapy opportunities. In the recent era of ablative therapies' development, oligometastatic HPV OSCC patients are indubitably good candidates for intensified treatment. However, data related to outcomes after optimised management of metastatic sites are dramatically missing. MATERIALS AND PATIENTS: In our cohort of 186 unselected consecutive OSCC patients treated with curative intent at our institution between 2009 and 2013, we analysed the incidence, treatment and outcomes of distant metastatic (DM) failure according to p16 status. RESULTS: After a median follow-up of 4.2 years (95% CI: 3.8-4.4) from primary diagnosis of OSCC, 21/95 p16- patients (22.1%) vs. 8/91 (8.8%) p16+ patients presented DM failure with a median interval of 11 (range 0-46) and 28 months (range 0-71), respectively (p = 0.10). Overall survival (OS) after DM failure was significantly higher in p16+ patients with a two-year OS rate of 75% and 15% for p16+ and p16-, respectively (p = 0.002). In eight HPV-related metastatic patients, three underwent ablative lung metastasis treatment and are still complete responders four to five years later. CONCLUSION: This study highlights distinct outcomes of metastatic HPV-related OSCC patients emphasised by three long-term complete responders after lung ablative treatment. In patients with high life expectancy and limited tumour burden, the question of ablative treatment such as metastasectomy or stereotactic ablative radiotherapy (SBRT) should be addressed.

Laparoscopic closure of the pouch of Douglas by a peritoneal running suture. A minimally invasive and prosthetic-free technique to prevent excessive dose delivery to the small bowel during pelvic irradiation for prostate cancer.

BACKGROUND AND PURPOSE: Prostate radiotherapy relies on the delivery of high doses that can be obstructed when a small bowel loop descends in the pelvis. We present a laparoscopic minimally invasive prosthetic-free technique closing the Douglas' pouch with a peritoneal running suture to cordon off the bowel from the pelvis and hence allow optimal irradiation. MATERIALS AND METHODS: Prostate cancer patients referred for radiotherapy and whose planning-CT revealed a bowel loop trapped in the pelvis were proposed the procedure, followed by a new planning-CT. This proof-of-concept study reports postoperative follow-up and dosimetric benefits. RESULTS: The procedure was performed in ten patients (2016-2020) as a same-day surgery for nine. Median operative time was 34 min (range 22-50) and no relevant intraoperative complication occurred. The third patient of the series presented a small bowel hernia through the peritoneal suture at the 15th postoperative day requiring a laparotomic desincarceration without major consequences. Regarding the small bowel, median D1cc (dose to 1 cc) was 65.5 Gy and 55.5 Gy (p = 0.005) before and after procedure. Median V60 (volume receiving ≥60 Gy) was 10.2 cc and 0.0 cc (p = 0.005). In the immediate vicinity of the small bowel (5 mm), median D1cc was 68.3 Gy and 57.7 Gy (p = 0.005). Radiotherapy was safely delivered to all patients. CONCLUSION: Laparoscopic closure of the Douglas' pouch by a peritoneal suture is an efficient technique to cordon off inconvenient ectopic small bowel loops. It prevents excessive bowel irradiation and hence facilitates curative prostate radiotherapy. The technique could be applied to other pelvic malignancies.

Recommendations for planning and delivery of radical radiotherapy for localized urothelial carcinoma of the bladder.

PURPOSE: Curative radio-chemotherapy is recognized as a standard treatment option for muscle-invasive bladder cancer (MIBC). Nevertheless, the technical aspects for MIBC radiotherapy are heterogeneous with a lack of practical recommendations. METHODS AND MATERIALS: In 2018, a workshop identified the need for two cooperative groups to develop consistent, evidence-based guidelines for irradiation technique in the delivery of curative radiotherapy. Two radiation oncologists performed a review of the literature addressing several topics relative to radical bladder radiotherapy: planning computed tomography acquisition, target volume delineation, radiation schedules (total dose and fractionation) and dose delivery (including radiotherapy techniques, image-guided radiotherapy (IGRT) and adaptive treatment modalities). Searches for original and review articles in the PubMed and Google Scholar databases were conducted from January 1990 until March 2020. During a meeting conducted in October 2020, results on 32 topics were presented and discussed with a working group involving 15 radiation oncologists, 3 urologists and one medical oncologist. We applied the American Urological Association guideline development's method to define a consensus strategy. RESULTS: A consensus was obtained for all 34 except 4 items. The group did not obtain an agreement on CT enhancement added value for planning, PTV margins definition for empty bladder and full bladder protocols, and for pelvic lymph-nodes irradiation. High quality evidence was shown in 6 items; 8 items were considered as low quality of evidence. CONCLUSION: The current recommendations propose a homogenized modality of treatment both for routine clinical practice and for future clinical trials, following the best evidence to date, analyzed with a robust methodology. The XXX group formulates practical guidelines for the implementation of innovative techniques such as adaptive radiotherapy.

New approach of ultra-focal brachytherapy for low- and intermediate-risk prostate cancer with custom-linked I-125 seeds: A feasibility study of optimal dose coverage.

PURPOSE: To present the feasibility study of optimal dose coverage in ultra-focal brachytherapy (UFB) with multiparametric MRI for low- and intermediate-risk prostate cancer. METHODS AND MATERIALS: UFB provisional dose plans for small target volumes (<7 cc) were calculated on a prostate training phantom to optimize the seeds number and strength. Clinical UFB consisted in a contour-based nonrigid registration (MRI/Ultrasound) to implant a fiducial marker at the location of the tumor focus. Dosimetry was performed with iodine-125 seeds and a prescribed dose of 160 Gy. On CT scans acquired at 1 month, dose coverage of 152 Gy to the ultra-focal gross tumor volume was evaluated. Registrations between magnetic resonance and CT scans were assessed on the first 8 patients with three software solutions: VariSeed, 3D Slicer, and Mirada, and quantitative evaluations of the registrations were performed. Impact of these registrations on the initial dose matrix was performed. RESULTS: Mean differences between simulated dose plans and extrapolated Bard nomogram for UFB volumes were 36.3% (26-56) for the total activity, 18.3% (10-30) for seed strength, and 22.5% (16-38) for number of seeds. Registration method implemented in Mirada performed significantly better than VariSeed and 3D Slicer (p = 0.0117 and p = 0.0357, respectively). For dose plan evaluation between Mirada and VariSeed, D100% (Gy) for ultra-focal gross tumor volume had a mean difference of 28.06 Gy, mean values being still above the objective of 152 Gy. D90% for the prostate had a mean difference of 1.17 Gy. For urethra and rectum, dose limits were far below the recommendations. CONCLUSIONS: This UFB study confirmed the possibility to treat with optimal dose coverage target volumes smaller than 7 cc.