Publications by authors named "Paul Sargos"

52 Publications

Prostate cancer and PARP inhibitors: progress and challenges.

J Hematol Oncol 2021 Mar 29;14(1):51. Epub 2021 Mar 29.

Department of Medical Oncology, Institut Bergonie, Bordeaux, France.

Despite survival improvements achieved over the last two decades, prostate cancer remains lethal at the metastatic castration-resistant stage (mCRPC) and new therapeutic approaches are needed. Germinal and/or somatic alterations of DNA-damage response pathway genes are found in a substantial number of patients with advanced prostate cancers, mainly of poor prognosis. Such alterations induce a dependency for single strand break reparation through the poly(adenosine diphosphate-ribose) polymerase (PARP) system, providing the rationale to develop PARP inhibitors. In solid tumors, the first demonstration of an improvement in overall survival was provided by olaparib in patients with mCRPC harboring homologous recombination repair deficiencies. Although this represents a major milestone, a number of issues relating to PARP inhibitors remain. This timely review synthesizes and discusses the rationale and development of PARP inhibitors, biomarker-based approaches associated and the future challenges related to their prescription as well as patient pathways.
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http://dx.doi.org/10.1186/s13045-021-01061-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008655PMC
March 2021

Deep Neural Networks Outperform the CAPRA Score in Predicting Biochemical Recurrence After Prostatectomy.

Front Oncol 2020 11;10:607923. Epub 2021 Feb 11.

Department of Urology, CHU de Toulouse, Toulouse, France.

Background: Use of predictive models for the prediction of biochemical recurrence (BCR) is gaining attention for prostate cancer (PCa). Specifically, BCR occurs in approximately 20-40% of patients five years after radical prostatectomy (RP) and the ability to predict BCR may help clinicians to make better treatment decisions. We aim to investigate the accuracy of CAPRA score compared to others models in predicting the 3-year BCR of PCa patients.

Material And Methods: A total of 5043 men who underwent RP were analyzed retrospectively. The accuracy of CAPRA score, Cox regression analysis, logistic regression, K-nearest neighbor (KNN), random forest (RF) and a densely connected feed-forward neural network (DNN) classifier were compared in terms of 3-year BCR predictive value. The area under the receiver operating characteristic curve was mainly used to assess the performance of the predictive models in predicting the 3 years BCR of PCa patients. Pre-operative data such as PSA level, Gleason grade, and T stage were included in the multivariate analysis. To measure potential improvements to the model performance due to additional data, each model was trained once more with an additional set of post-operative surgical data from definitive pathology.

Results: Using the CAPRA score variables, DNN predictive model showed the highest AUC value of 0.7 comparing to the CAPRA score, logistic regression, KNN, RF, and cox regression with 0.63, 0.63, 0.55, 0.64, and 0.64, respectively. After including the post-operative variables to the model, the AUC values based on KNN, RF, and cox regression and DNN were improved to 0.77, 0.74, 0.75, and 0.84, respectively.

Conclusions: Our results showed that the DNN has the potential to predict the 3-year BCR and outperformed the CAPRA score and other predictive models.
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http://dx.doi.org/10.3389/fonc.2020.607923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906005PMC
February 2021

Management of Muscle-Invasive Bladder Cancer During a Pandemic: Impact of Treatment Delay on Survival Outcomes for Patients Treated With Definitive Concurrent Chemoradiotherapy.

Clin Genitourin Cancer 2021 02 22;19(1):41-46.e1. Epub 2020 Jun 22.

Department of Radiation Oncology, Washington University School of Medicine in St Louis, St Louis, MO; Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. Electronic address:

Introduction: During the coronavirus disease 2019 (COVID-19) pandemic, providers and patients must engage in shared decision making to ensure that the benefit of early intervention for muscle-invasive bladder cancer exceeds the risk of contracting COVID-19 in the clinical setting. It is unknown whether treatment delays for patients eligible for curative chemoradiation (CRT) compromise long-term outcomes.

Patients And Methods: We used the National Cancer Data Base to investigate whether there is an association between a ≥ 90-day delay from transurethral resection of bladder tumor (TURBT) in initiating CRT and overall survival. We included patients with cT2-4N0M0 muscle-invasive bladder cancer from 2004 to 2015 who underwent TURBT and curative-intent concurrent CRT. Patients were grouped on the basis of timing of CRT: ≤ 89 days after TURBT (earlier) vs. ≥ 90 and < 180 days after TURBT (delayed).

Results: A total of 1387 (87.5%) received earlier CRT (median, 45 days after TURBT; interquartile range, 34-59 days), and 197 (12.5%) received delayed CRT (median, 111 days after TURBT; interquartile range, 98-130 days). Median overall survival was 29.0 months (95% CI, 26.0-32.0) versus 27.0 months (95% CI, 19.75-34.24) for earlier and delayed CRT (P = .94). On multivariable analysis, delayed CRT was not associated with an overall survival difference (hazard ratio, 1.05; 95% CI, 0.87-1.27; P = .60).

Conclusion: Although these results are limited and require validation, short, strategic treatment delays during a pandemic can be considered on the basis of clinician judgment.
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http://dx.doi.org/10.1016/j.clgc.2020.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306737PMC
February 2021

Prostate Bed Delineation Guidelines for Postoperative Radiation Therapy: On Behalf Of The Francophone Group of Urological Radiation Therapy.

Int J Radiat Oncol Biol Phys 2021 Apr 10;109(5):1243-1253. Epub 2020 Nov 10.

Radiation Oncology Department, Center Hospitalier Lyon Sud, Pierre Benite, France. Electronic address:

Purpose: Prostate bed (PB) irradiation is considered the standard postoperative treatment after radical prostatectomy (RP) for tumors with high-risk features or persistent prostate-specific antigen, or for salvage treatment in case of biological relapse. Four consensus guidelines have been published to standardize practices and reduce the interobserver variability in PB delineation but with discordant recommendations. To improve the reproducibility in the PB delineation, the Francophone Group of Urological Radiotherapy (Groupe Francophone de Radiothérapie Urologique [GFRU]) worked to propose a new and more reproducible consensus guideline for PB clinical target volume (CTV) definition.

Methods And Materials: A 4-step procedure was used. First, a group of 10 GFRU prostate experts evaluated the 4 existing delineation guidelines for postoperative radiation therapy (European Organization for Research and Treatment of Cancer; the Faculty of Radiation Oncology Genito-Urinary Group; the Radiation Therapy Oncology Group; and the Princess Margaret Hospital) to identify divergent issues. Second, data sets of 50 magnetic resonance imaging studies (25 after RP and 25 with an intact prostate gland) were analyzed to identify the relevant anatomic boundaries of the PB. Third, a literature review of surgical, anatomic, histologic, and imaging data was performed to identify the relevant PB boundaries. Fourth, a final consensus on PB CTV definition was reached among experts.

Results: Definitive limits of the PB CTV delineation were defined using easily visible landmarks on computed tomography scans (CT). The purpose was to ensure a better reproducibility of PB definition for any radiation oncologist even without experience in postoperative radiation therapy.

Conclusions: New recommendations for PB delineation based on simple anatomic boundaries and available as a CT image atlas are proposed by the GFRU. Improvement in uniformity in PB CTV definition and treatment homogeneity in the context of clinical trials are expected.
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http://dx.doi.org/10.1016/j.ijrobp.2020.11.010DOI Listing
April 2021

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.

Lancet Oncol 2020 10;21(10):1341-1352

Institut Bergonié, Bordeaux, France.

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.
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http://dx.doi.org/10.1016/S1470-2045(20)30454-XDOI Listing
October 2020

Adjuvant or early salvage radiotherapy for the treatment of localised and locally advanced prostate cancer: a prospectively planned systematic review and meta-analysis of aggregate data.

Lancet 2020 Oct 28;396(10260):1422-1431. Epub 2020 Sep 28.

MRC Clinical Trials Unit, University College London, London, UK.

Background: It is unclear whether adjuvant or early salvage radiotherapy following radical prostatectomy is more appropriate for men who present with localised or locally advanced prostate cancer. We aimed to prospectively plan a systematic review of randomised controlled trials (RCTs) comparing these radiotherapy approaches.

Methods: We used a prospective framework for adaptive meta-analysis (FAME), starting the review process while eligible trials were ongoing. RCTs were eligible if they aimed to compare immediate adjuvant radiotherapy versus early salvage radiotherapy, following radical prostatectomy in men (age ≥18 years) with intermediate-risk or high-risk, localised or locally advanced prostate cancer. We searched trial registers and conference proceedings until July 8, 2020, to identify eligible RCTs. By establishing the ARTISTIC collaboration with relevant trialists, we were able to anticipate when eligible trial results would emerge, and we developed and registered a protocol with PROSPERO before knowledge of the trial results (CRD42019132669). We used a harmonised definition of event-free survival, as the time from randomisation until the first evidence of either biochemical progression (prostate-specific antigen [PSA] ≥0·4 ng/mL and rising after completion of any postoperative radiotherapy), clinical or radiological progression, initiation of a non-trial treatment, death from prostate cancer, or a PSA level of at least 2·0 ng/mL at any time after randomisation. We predicted when we would have sufficient power to assess whether adjuvant radiotherapy was superior to early salvage radiotherapy. Investigators supplied results for event-free survival, both overall and within predefined patient subgroups. Hazard ratios (HRs) for the effects of radiotherapy timing on event-free survival and subgroup interactions were combined using fixed-effect meta-analysis.

Findings: We identified three eligible trials and were able to obtain updated results for event-free survival for 2153 patients recruited between November, 2007, and December, 2016. Median follow-up ranged from 60 months to 78 months, with a maximum follow-up of 132 months. 1075 patients were randomly assigned to receive adjuvant radiotherapy and 1078 to a policy of early salvage radiotherapy, of whom 421 (39·1%) had commenced treatment at the time of analysis. Patient characteristics were balanced within trials and overall. Median age was similar between trials at 64 or 65 years (with IQRs ranging from 59 to 68 years) across the three trials and most patients (1671 [77·6%]) had a Gleason score of 7. All trials were assessed as having low risk of bias. Based on 270 events, the meta-analysis showed no evidence that event-free survival was improved with adjuvant radiotherapy compared with early salvage radiotherapy (HR 0·95, 95% CI 0·75-1·21; p=0·70), with only a 1 percentage point (95% CI -2 to 3) change in 5-year event-free survival (89% vs 88%). Results were consistent across trials (heterogeneity p=0·18; I=42%).

Interpretation: This collaborative and prospectively designed systematic review and meta-analysis suggests that adjuvant radiotherapy does not improve event-free survival in men with localised or locally advanced prostate cancer. Until data on long-term outcomes are available, early salvage treatment would seem the preferable treatment policy as it offers the opportunity to spare many men radiotherapy and its associated side-effects.

Funding: UK Medical Research Council.
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http://dx.doi.org/10.1016/S0140-6736(20)31952-8DOI Listing
October 2020

Modeling texture in deep 3D CNN for survival analysis.

IEEE J Biomed Health Inform 2020 Sep 22;PP. Epub 2020 Sep 22.

Radiomics has shown remarkable potential for predicting the survival outcome for various types of cancers such as pancreatic ductal adenocarcinoma (PDAC). However, to date, there has been limited research using convolutional neural networks (CNN) with radiomic methods for this task, due to their requirement for large training sets. To overcome this issue, we propose a new type of radiomic descriptor modeling the distribution of learned features with a Gaussian mixture model (GMM). These parametric features (GMM-CNN) are computed from gross tumor volumes of PDAC patients defined semiautomatically in pre-operative computed tomography (CT) scans. We use the proposed GMM-CNN features as input to a robust classifier based on random forests (RF) to predict the survival outcome of patients with PDAC. Our experiments assess the advantage of GMM-CNN compared to employing the same 3D CNN model directly, standard radiomic (i.e., histogram, texture and shape), conditional entropy (CENT) based on 3DCNN, and clinical features (i.e., serum carbohydrate antigen 19-9 and chemotherapy neoadjuvant). Using the RF model (100 samples for training; 59 samples for validation), GMM-CNN features provided the highest area under the ROC curve (AUC) of 72.0% (p = 6.4105) compared to 64.0% (p = 0.01) for the 3D CNN model output, 66.8% (p = 0.01) for standard radiomic features, 64.2% (p = 0.003) for CENT, and 57.6% (p = 0.3) for clinical variables. Our results suggest that the proposed GMM-CNN features used with a RF classifier can significantly improve the capacity to prognosticate PDAC patients prior to surgery via routinely-acquired imaging data.
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http://dx.doi.org/10.1109/JBHI.2020.3025901DOI Listing
September 2020

Combined radiotherapy and immunotherapy in urothelial bladder cancer: harnessing the full potential of the anti-tumor immune response.

World J Urol 2020 Sep 11. Epub 2020 Sep 11.

Department of Radiation Oncology, Jewish General Hospital, Montreal, QC, Canada.

Purpose: Radiotherapy (RT), as part of trimodal therapy, is an attractive alternative treatment in patients with urothelial muscle-invasive bladder cancer (MIBC). There is accumulating evidence suggesting the immunomodulatory effects of RT and its potential synergy when combined with immunotherapy. The aim of this review was to report on the most recent advances on this combination, including the mechanisms of RT immunomodulation, practical approach to combining RT and immunotherapy, and ongoing clinical trials in bladder cancer.

Methods: Using the PubMed database, we identified articles published between March 2004 and April 2020 on the combination of RT with immunotherapy in localized or metastatic MIBC. A search of the Clinicaltrials.gov and Clinicaltrialsregister.eu/ retrieved ongoing clinical trials on the topic as well.

Results: Combination of RT with immunotherapy leads to immunogenic cell death and an increase in immune markers thus leading to improved tumor control. For localized MIBC, there are safety concerns related to the use of concurrent immunotherapy with hypofractionated RT, thus neoadjuvant or adjuvant immunotherapy is preferred. In the metastatic setting, the combination of multi-site RT with SBRT-like doses (≥ 6 Gy per fraction) and concurrent immunotherapy seems most efficacious at harnessing the abscopal effect. At least 25 clinical trials combining immunotherapy and RT in MIBC are currently ongoing and will answer pending questions on safety, efficacy, and practical considerations on RT scheduling, fractionation, and targets volumes.

Conclusion: RT has the potential to synergize with immunotherapy to improve oncological outcomes in patient with localized or metastatic MIBC. Clinical trials results are eagerly awaited.
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http://dx.doi.org/10.1007/s00345-020-03440-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484608PMC
September 2020

Impact of tumor size on the oncological outcome of high-grade nonmuscle invasive bladder cancer - examining the utility of classifying Ta bladder cancer based on size.

Urol Oncol 2020 11 29;38(11):851.e19-851.e25. Epub 2020 Jul 29.

Department of Urology, Ruhr-University Bochum, Marien Hospital, Herne, Germany. Electronic address:

Purpose: To examine survival rates and to calculate the risk of disease recurrence, progression, overall, and cancer-specific mortality in patients diagnosed with high-risk NMIBC using a multi-institutional dataset to evaluate differences between the guidelines of the European Association of Urology and the guidelines of the National Comprehensive Cancer Network (NCCN) with regard to tumor size in risk stratification.

Methods And Material: In total 1,116 individuals diagnosed with high-risk NMIBC between 2001 and 2013 were included in the analysis. Patients were stratified to NCCN guideline recommendations (high-grade T1, high-grade Ta ≤ 3 cm, and high-grade Ta > 3 cm). Recurrence and progression rates were calculated. Kaplan-Meier curves were fitted to examine differences in recurrence-free (RFS) and progression-free survival (PFS). Multivariable Cox proportional hazards regression models were employed to calculate differences in the RFS, PFS, overall, and cancer-specific survival (CSS).

Results: The majority of patients were diagnosed with high-grade T1 disease (N = 576, 51.6%), while 34.2% and 14.2% of patients were diagnosed with high-grade Ta ≤ 3 cm and Ta > 3 cm NMIBC, respectively. The 1- and 5-year RFS (1-year: 80.5% vs. 64.9%; 5-year: 58.6% vs. 48.3%, P = 0.048) and PFS (1-year: 99.1% vs. 98.6%; 5-year: 97.7% vs. 92.4%, P = 0.054) rates were higher in patients with Ta ≤ 3 cm. Patients diagnosed with high-grade Ta > 3 cm experienced unfavorable progression-free, and cancer-specific survival compared to high-grade Ta ≤ 3 cm, respectively (PFS: 2.41, 95% confidence interval [CI] 1.05-5.56, P = 0.038; CSS: hazard ratios [HR] 2.22, 95% CI 1.02-4.89, P = 0.048).

Conclusion: Patients diagnosed with high-grade Ta NMIBC ≤3 cm demonstrated a favorable progression-free, and cancer-specific survival compared to patients diagnosed with high-grade Ta > 3 cm and high-grade T1 NMIBC.
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http://dx.doi.org/10.1016/j.urolonc.2020.06.034DOI Listing
November 2020

Corrigendum to 'EAU-ESMO Consensus Statements on the Management of Advanced and Variant Bladder Cancer-An International Collaborative Multistakeholder Effort Under the Auspices of the EAU-ESMO Guidelines Committees' [European Urology 77 (2020) 223-250].

Authors:
J Alfred Witjes Marek Babjuk Joaquim Bellmunt H Maxim Bruins Theo M De Reijke Maria De Santis Silke Gillessen Nicholas James Steven Maclennan Juan Palou Tom Powles Maria J Ribal Shahrokh F Shariat Theo Van Der Kwast Evanguelos Xylinas Neeraj Agarwal Tom Arends Aristotle Bamias Alison Birtle Peter C Black Bernard H Bochner Michel Bolla Joost L Boormans Alberto Bossi Alberto Briganti Iris Brummelhuis Max Burger Daniel Castellano Richard Cathomas Arturo Chiti Ananya Choudhury Eva Compérat Simon Crabb Stephane Culine Berardino De Bari Willem De Blok Pieter J L De Visschere Karel Decaestecker Konstantinos Dimitropoulos Jose L Dominguez-Escrig Stefano Fanti Valerie Fonteyne Mark Frydenberg Jurgen J Futterer Georgios Gakis Bogdan Geavlete Paolo Gontero Bernhard Grubmüller Shaista Hafeez Donna E Hansel Arndt Hartmann Dickon Hayne Ann M Henry Virginia Hernandez Harry Herr Ken Herrmann Peter Hoskin Jorge Huguet Barbara A Jereczek-Fossa Rob Jones Ashish M Kamat Vincent Khoo Anne E Kiltie Susanne Krege Sylvain Ladoire Pedro C Lara Annemarie Leliveld Estefania Linares-Espinós Vibeke Løgager Anja Lorch Yohann Loriot Richard Meijer M Carmen Mir Marco Moschini Hugh Mostafid Arndt-Christian Müller Christoph R Müller James N'Dow Andrea Necchi Yann Neuzillet Jorg R Oddens Jan Oldenburg Susanne Osanto Wim J G Oyen Luís Pacheco-Figueiredo Helle Pappot Manish I Patel Bradley R Pieters Karin Plass Mesut Remzi Margitta Retz Jonathan Richenberg Michael Rink Florian Roghmann Jonathan E Rosenberg Morgan Rouprêt Olivier Rouvière Carl Salembier Antti Salminen Paul Sargos Shomik Sengupta Amir Sherif Robert J Smeenk Anita Smits Arnulf Stenzl George N Thalmann Bertrand Tombal Baris Turkbey Susanne Vahr Lauridsen Riccardo Valdagni Antoine G Van Der Heijden Hein Van Poppel Mihai D Vartolomei Erik Veskimäe Antoni Vilaseca Franklin A Vives Rivera Thomas Wiegel Peter Wiklund Peter-Paul M Willemse Andrew Williams Richard Zigeuner Alan Horwich

Eur Urol 2020 Jul 21;78(1):e48-e50. Epub 2020 May 21.

Emeritus Professor, The Institute of Cancer Research, London, UK.

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http://dx.doi.org/10.1016/j.eururo.2020.03.017DOI Listing
July 2020

The impact of treatment modality on survival in patients with clinical node-positive bladder cancer: results from a multicenter collaboration.

World J Urol 2021 Feb 30;39(2):443-451. Epub 2020 Apr 30.

Department of Urology, Luzerner Kantonsspital, Lucerne, Switzerland.

Purpose: To assess the impact of perioperative chemotherapy on survival in cN+ BCa patients and analyze it according to the pN status.

Methods: A retrospective analysis was conducted on 639 BCa patients with cTanyN1-3M0 BCa treated with radical cystectomy (RC) and bilateral lymph node dissection (LND) with or without perioperative chemotherapy in ten tertiary referral centers from 1990 to 2017. Selected cN+ patients received induction chemotherapy (IC), whereas adjuvant chemotherapy (ACT) was delivered to selected pN+ patients. Univariable and multivariable Cox regression analyses were used to predict overall mortality (OM) after surgery, adjusting for clinicopathological confounders. Kaplan-Meier analyses assessed OM according to the treatment modality.

Results: Overall, 356 (56%) patients were treated with surgery alone, 155 (24%) with IC followed by surgery, and 128 (20%) with ACT following surgery. Over a median follow-up of 25 months, 316 deaths were recorded. At univariable analysis, patients treated with IC and surgery had lower OM both considering cN+ [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.87, p = 0.004] and cN+pN- patients (HR 0.61, 95% CI 0.37-0.99, p = 0.05) compared to those treated with surgery alone. cN+pN+ patients treated with ACT experienced lower OM compared to those treated with IC or surgery alone at multivariable analysis (HR 0.40, 95% CI 0.22-0.74, p = 0.003).

Conclusion: Patients with cTany cN+ cM0 BCa benefit more in terms of OS when treated with IC followed by RC + LND compared to RC + LND alone, regardless of LNMs at final histopathology examination. More data are needed to assess the role of ACT in the management of cN+ patients.
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http://dx.doi.org/10.1007/s00345-020-03205-zDOI Listing
February 2021

Postoperative Radiation Therapy in Patients with Extracranial Chondrosarcoma: A Joint Study of the French Sarcoma Group and Rare Cancer Network.

Int J Radiat Oncol Biol Phys 2020 07 11;107(4):726-735. Epub 2020 Apr 11.

Department of Radiation Oncology, Centre Baclesse/ARCHADE-Normandie Université, Caen, France; Laboratoire de Physique Corpusculaire, Caen, France; Unicaen-Normandie Université, Caen, France. Electronic address:

Purpose: Postoperative radiation therapy (poRT) of intracranial/skull base chondrosarcomas (CHSs) is standard treatment. However, consensus is lacking for poRT in extracranial CHS (eCHS) owing to their easier resectability and intrinsic radioresistance. We assessed the practice and efficacy of poRT in eCHS.

Methods And Materials: This multicentric retrospective study of the French Sarcoma Group/Rare Cancer Network included patients with eCHS who were operated on between 1985 and 2015. Inverse propensity score weighting (IPTW) was used to minimize poRT allocation biases.

Results: Of 182 patients, 60.4% had bone and 39.6% had soft-tissue eCHS. eCHS were of conventional (31.9%), myxoid (28.6%; 41 extraskeletal, 11 skeletal), mesenchymal (9.9%), or other subtypes. En-bloc surgery with complete resection was performed in 52.6% and poRT in 36.8% of patients (median dose, 54 Gy). Irradiated patients had unfavorable initial characteristics, with higher grade and incomplete resection. Median follow-up time was 61 months. Five-year incidence of local relapse was 10% with poRT versus 21.6% without (P = .050). Using the IPTW method, poRT reduced the local relapse risk (hazard ratio, 0.27; 95% confidence interval, 0.14-0.52; P < .001). Five-year disease-free survival (DFS) was 71.8% with poRT and 64.2% without (P = .680). Using the IPTW method, poRT improved DFS (hazard ratio, 0.51; 95% confidence interval, 0.30-0.85; P = .010). The benefit of poRT on local relapse and DFS was confirmed after exclusion of the extraskeletal subtype. There was no difference in overall survival. Prognostic factors of poorer DFS in multivariate analysis were deeper location, higher grade, incomplete resection, and no poRT.

Conclusions: poRT should be offered in patients with eCHS and high-grade or incomplete resection, regardless of the histologic subtype.
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http://dx.doi.org/10.1016/j.ijrobp.2020.03.041DOI Listing
July 2020

Combined Long-Term Androgen Deprivation and Pelvic Radiotherapy in the Post-operative Management of Pathologically Defined High-Risk Prostate Cancer Patients: Results of the Prospective Phase II McGill 0913 Study.

Front Oncol 2020 12;10:312. Epub 2020 Mar 12.

Department of Radiation Oncology, Jewish General Hospital, Montreal, QC, Canada.

Following radical prostatectomy, prostate bed radiotherapy (PBRT) has been combined with either long-term androgen deprivation therapy (LT-ADT) or short-term ADT with pelvic lymph node radiotherapy (PLNRT) to provide an oncological benefit in randomized trials. McGill 0913 was designed to characterize the efficacy of combining PBRT, PLNRT, and LT-ADT. It is the first study to do so prospectively. In a single arm phase II trial conduced from 2010 to 2016, 46 post-prostatectomy prostate cancer patients at a high-risk for relapse (pathological Gleason 8+ or T3) were assessed for treatment with combined LT-ADT (24 months), PBRT, and PLNRT. Patients received PLNRT and PBRT (44 Gy in 22 fractions) followed by a PBRT boost (22 Gy in 11 fractions). The primary endpoint was progression-free survival (PFS). Toxicity and quality of life (QoL) were evaluated using CTCAE V3.0 and EQ-5D-3L questionnaires, respectively. Among the 43 patients were treated as per protocol, median PSA was 0.30 μg/L. On surgical pathology, 51% had positive margins, 40% had Gleason 8+ disease, 42% had seminal vesicle involvement, and 19% had lymph node involvement. At a median follow-up of 5.2 years, there were no deaths or clinical progression. At 5 years, PFS was 78.0% (95% Confidence Interval 63.7-95.5%). Not including erectile dysfunction, patients experienced: 14% grade 2 endocrine toxicity while on ADT, one incident of long-term gynecomastia, 5% grade 2 acute urinary toxicity, 5% grade 2 late Urinary toxicity, and 24% long-term hypogonadism. No comparison between the average or minimum self-reported QoL at baseline, during ADT, nor after ADT demonstrated a statistically significant difference. Combining PBRT, PLNRT, and LT-ADT had an acceptable PFS in patients with significant post-operative risk factors for recurrence. While therapy was well-tolerated, long-term hypogonadism was a substantial risk. Further investigations are needed to determine if this combination is beneficial. NCT01255891.
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http://dx.doi.org/10.3389/fonc.2020.00312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080953PMC
March 2020

Assessment of Safety and Efficacy of Combined Trabectedin and Low-Dose Radiotherapy for Patients With Metastatic Soft-Tissue Sarcomas: A Nonrandomized Phase 1/2 Clinical Trial.

JAMA Oncol 2020 04;6(4):535-541

TERABIS Group, IBiS (Instituto de Biomedicina de Sevilla), Sevilla, Spain.

Importance: Active therapeutic combinations, such as trabectedin and radiotherapy, offer potentially higher dimensional response in second-line treatment of advanced soft-tissue sarcomas. Dimensional response can be relevant both for symptom relief and for survival.

Objective: To assess the combined use of trabectedin and radiotherapy in treating patients with progressing metastatic soft-tissue sarcomas.

Design, Setting, And Participants: Phase 1 of this nonrandomized clinical trial followed the classic 3 + 3 design, with planned radiotherapy at a fixed dose of 30 Gy (3 Gy/d for 10 days) and infusion of trabectedin at 1.3 mg/m2 as the starting dose, 1.5 mg/m2 as dose level +1, and 1.1 mg/m2 as dose level -1. Phase 2 followed the Simon optimal 2-stage design. Allowing for type I and II errors of 10%, treatment success was defined as an overall response rate of 35%. This study was conducted in 9 sarcoma referral centers in Spain, France, and Italy from April 13, 2015, to November 20, 2018. Adult patients with progressing metastatic soft-tissue sarcoma and having undergone at least 1 previous line of systemic therapy were enrolled. In phase 2, patients fitting inclusion criteria and receiving at least 1 cycle of trabectedin and the radiotherapy regimen constituted the per-protocol population; those receiving at least 1 cycle of trabectedin, the safety population.

Interventions: Trabectedin was administered every 3 weeks in a 24-hour infusion. Radiotherapy was required to start within 1 hour after completion of the first trabectedin infusion (cycle 1, day 2).

Main Outcomes And Measures: The dose-limiting toxic effects of trabectedin (phase 1) and the overall response rate (phase 2) with use of trabectedin plus irradiation in metastatic soft-tissue sarcomas.

Results: Eighteen patients (11 of whom were male) were enrolled in phase 1, and 27 other patients (14 of whom were female) were enrolled in phase 2. The median ages of those enrolled in phases 1 and 2 were 42 (range, 23-74) years and 51 (range, 27-73) years, respectively. In phase 1, dose-limiting toxic effects included grade 4 neutropenia lasting more than 5 days in 1 patient at the starting dose level and a grade 4 alanine aminotransferase level increase in 1 of 6 patients at the +1 dose level. In phase 2, among 25 patients with evaluable data, the overall response rate was 72% (95% CI, 53%-91%) for local assessment and 60% (95% CI, 39%-81%) for central assessment.

Conclusions And Relevance: The findings of this study suggest that the recommended dose of trabectedin for use in combination with this irradiation regimen is 1.5 mg/m2. The trial met its primary end point, with a high overall response rate that indicates the potential of this combination therapy for achieving substantial tumor shrinkage beyond first-line systemic therapy in patients with metastatic, progressing soft-tissue sarcomas.

Trial Registration: ClinicalTrials.gov Identifier: NCT02275286.
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http://dx.doi.org/10.1001/jamaoncol.2019.6584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042948PMC
April 2020

EAU-ESMO Consensus Statements on the Management of Advanced and Variant Bladder Cancer-An International Collaborative Multistakeholder Effort: Under the Auspices of the EAU-ESMO Guidelines Committees.

Authors:
J Alfred Witjes Marek Babjuk Joaquim Bellmunt H Maxim Bruins Theo M De Reijke Maria De Santis Silke Gillessen Nicholas James Steven Maclennan Juan Palou Tom Powles Maria J Ribal Shahrokh F Shariat Theo Van Der Kwast Evanguelos Xylinas Neeraj Agarwal Tom Arends Aristotle Bamias Alison Birtle Peter C Black Bernard H Bochner Michel Bolla Joost L Boormans Alberto Bossi Alberto Briganti Iris Brummelhuis Max Burger Daniel Castellano Richard Cathomas Arturo Chiti Ananya Choudhury Eva Compérat Simon Crabb Stephane Culine Berardino De Bari Willem De Blok Pieter J L De Visschere Karel Decaestecker Konstantinos Dimitropoulos Jose L Dominguez-Escrig Stefano Fanti Valerie Fonteyne Mark Frydenberg Jurgen J Futterer Georgios Gakis Bogdan Geavlete Paolo Gontero Bernhard Grubmüller Shaista Hafeez Donna E Hansel Arndt Hartmann Dickon Hayne Ann M Henry Virginia Hernandez Harry Herr Ken Herrmann Peter Hoskin Jorge Huguet Barbara A Jereczek-Fossa Rob Jones Ashish M Kamat Vincent Khoo Anne E Kiltie Susanne Krege Sylvain Ladoire Pedro C Lara Annemarie Leliveld Estefania Linares-Espinós Vibeke Løgager Anja Lorch Yohann Loriot Richard Meijer M Carmen Mir Marco Moschini Hugh Mostafid Arndt-Christian Müller Christoph R Müller James N'Dow Andrea Necchi Yann Neuzillet Jorg R Oddens Jan Oldenburg Susanne Osanto Wim J G Oyen Luís Pacheco-Figueiredo Helle Pappot Manish I Patel Bradley R Pieters Karin Plass Mesut Remzi Margitta Retz Jonathan Richenberg Michael Rink Florian Roghmann Jonathan E Rosenberg Morgan Rouprêt Olivier Rouvière Carl Salembier Antti Salminen Paul Sargos Shomik Sengupta Amir Sherif Robert J Smeenk Anita Smits Arnulf Stenzl George N Thalmann Bertrand Tombal Baris Turkbey Susanne Vahr Lauridsen Riccardo Valdagni Antoine G Van Der Heijden Hein Van Poppel Mihai D Vartolomei Erik Veskimäe Antoni Vilaseca Franklin A Vives Rivera Thomas Wiegel Peter Wiklund Andrew Williams Richard Zigeuner Alan Horwich

Eur Urol 2020 02 19;77(2):223-250. Epub 2019 Nov 19.

Emeritus Professor, The Institute of Cancer Research, London, UK.

Background: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.

Objective: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management.

Design: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference.

Setting: Online Delphi survey and consensus conference.

Participants: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management.

Outcome Measurements And Statistical Analysis: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), and 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus).

Results And Limitations: Overall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease.

Conclusions: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach.

Patient Summary: This report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available.
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http://dx.doi.org/10.1016/j.eururo.2019.09.035DOI Listing
February 2020

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.

Lancet Oncol 2019 12 16;20(12):1740-1749. Epub 2019 Oct 16.

Biostatistics Unit, Clinical Research and Innovation Department, Léon Bérard Cancer Centre, Lyon, France.

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.
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http://dx.doi.org/10.1016/S1470-2045(19)30486-3DOI Listing
December 2019

Use of metrics to quantify IMRT and VMAT treatment plan complexity: A systematic review and perspectives.

Phys Med 2019 Aug 9;64:98-108. Epub 2019 Jul 9.

Department of Radiotherapy, Institut Bergonié, Comprehensive Cancer Centre, F-33000 Bordeaux, France.

Purpose: Fixed-field intensity modulated radiation therapy (FF-IMRT) or volumetric modulated arc therapy (VMAT) beams complexity is due to fluence fluctuation. Pre-treatment Quality Assurance (PTQA) failure could be linked to it. Several plan complexity metrics (PCM) have been published to quantify this complexity but in a heterogeneous formalism. This review proposes to gather different PCM and to discuss their eventual PTQA failure identifier abilities.

Methods And Materials: A systematic literature search and outcome extraction from MEDLINE/PubMed (National Center for Biotechnology Information, NCBI) was performed. First, a list and a synthesis of available PCM is made in a homogeneous formalism. Second, main results relying on the link between PCM and PTQA results but also on other uses are listed.

Results: A total of 163 studies were identified and n = 19 were selected after inclusion and exclusion criteria application. Difference is made between fluence and degree of freedom (DOF)-based PCM. Results about the PCM potential as PTQA failure identifier are described and synthesized. Others uses are also found in quality, big data, machine learning and audit procedure.

Conclusions: A state of the art is made thanks to this homogeneous PCM classification. For now, PCM should be seen as a planning procedure quality indicator although PTQA failure identifier results are mitigated. However limited clinical use seems possible for some cases. Yet, addressing the general PTQA failure prediction case could be possible with the big data or machine learning help.
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http://dx.doi.org/10.1016/j.ejmp.2019.05.024DOI Listing
August 2019

Review of hypo-fractionated radiotherapy for localized muscle invasive bladder cancer.

Crit Rev Oncol Hematol 2019 Oct 16;142:76-85. Epub 2019 Jul 16.

Department of Radiation Oncology, Institut Bergonié, 33076, Bordeaux Cedex, France. Electronic address:

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http://dx.doi.org/10.1016/j.critrevonc.2019.06.010DOI Listing
October 2019

Long-term androgen deprivation, with or without radiotherapy, in locally advanced prostate cancer: updated results from a phase III randomised trial.

BJU Int 2020 06 2;125(6):810-816. Epub 2020 Mar 2.

Department of Radiation Oncology, Institut Bergonié, Bordeaux, France.

Objectives: To report the long-term oncological outcomes of a randomised trial comparing androgen-deprivation therapy (ADT) combined with external beam radiation therapy (EBRT) and ADT alone in patients with locally advanced prostate cancer.

Patients And Methods: In this multicentre phase III trial, patients were randomly assigned to ADT alone or ADT+EBRT. Leuprorelin 11.25 mg was administered for 3 years. The whole pelvis was treated at a dose of 46 Gy and the prostate with a boost from 20 to 28 Gy. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), disease-specific survival (DSS), locoregional PFS (LRPFS), metastasis-free survival (MFS), biochemical PFS (BPFS), and tolerance.

Results: With a median follow-up of 7.3 years, 263 patients were included. The 8-year PFS rate was significantly higher in the ADT+EBRT arm than in the ADT arm (48% vs 7%; hazard ratio [HR] 0.27, 95% confidence interval [CI] 0.17-0.39; P < 0.001); in patients with a baseline PSA level ≥50 ng/mL (HR 0.10, 95% CI 0.05-0.20; P < 0.001) and in patients with a baseline PSA level <50 ng/mL (HR 0.28, 95% CI 0.19-0.40; P < 0.001). The risk of death from prostate cancer was significantly reduced in the ADT+EBRT arm (sub-HR [SHR] 0.48, 95% CI 0.25-0.91; P = 0.02). The 8-year OS rate was 57% in the ADT arm and 65% in the ADT+EBRT arm (no significant difference). LRPFS was significantly in favour of the ADT+EBRT arm (SHR 0.61, 95% CI 0.42-0.89; P = 0.01). MFS was comparable between both arms (P = 0.88). Analysis of toxicities revealed acute lower tolerance in the ADT+EBRT arm, with a gradual decrease in intensity from 6 months after the end of EBRT.

Conclusions: These long-term results confirm the oncological benefit of combining EBRT with ADT in the treatment of locally advanced prostate cancer.
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http://dx.doi.org/10.1111/bju.14768DOI Listing
June 2020

A propensity analysis comparing definitive chemo-radiotherapy for muscle-invasive squamous cell carcinoma of the bladder vs. urothelial carcinoma of the bladder using the National Cancer Database.

Clin Transl Radiat Oncol 2019 Feb 12;15:38-41. Epub 2018 Dec 12.

Washington University in St. Louis, Department of Radiation Oncology, St. Louis, MO, United States.

Introduction: Squamous cell carcinoma (SqCC) is the second most common histology of primary bladder cancer, but still very limited information is known about its treatment outcomes. Most bladder cancer trials have excluded SqCC, and the current treatment paradigm for localized SqCC is extrapolated from results in urothelial carcinoma (UC). In particular, there is limited data on the efficacy of definitive chemo-radiotherapy (CRT). In this study, we compare overall survival outcomes between SqCC and UC patients treated with definitive CRT.

Materials/methods: We queried the National Cancer Database (NCDB) for muscle-invasive (cT2-T4 N0 M0) bladder cancer patients diagnosed from 2004 to 2013 who underwent concurrent CRT. Propensity matching was performed to match patients with SqCC to those with UC. OS was analyzed using the Kaplan-Meier survival method, and the log-rank test and Cox regression were used for analyses.

Results: 3332 patients met inclusion criteria of which 79 (2.3%) had SqCC. 73.4% of SqCC patients had clinical T2 disease compared to 82.5% of UC patients. Unadjusted median OS for SqCC patients was 15.6 months (95% CI, 11.7-19.6) versus 29.1 months (95% CI, 27.5-30.7) for those with UC (P < 0.0001). On multivariable analysis, factors associated with worse OS included: SqCC histology [HR: 1.53 (95% CI, 1.19-1.97); P = 0.001], increasing age [HR: 1.02 (95% CI, 1.02-1.03); P < 0.0001], increasing clinical T-stage [HR: 1.21 (95% CI, 1.13-1.29); P < 0.0001], and Charlson-Deyo comorbidity index [HR: 1.26 (95% CI, 1.18-1.33); P < 0.0001]. Seventy-seven SqCC patients were included in the propensity-matched analysis (154 total patients) with a median OS for SqCC patients of 15.1 months (95% CI, 11.1-18.9) vs. 30.4 months (95% CI, 19.4-41.4) for patients with UC (P = 0.013).

Conclusions: This is the largest study to-date assessing survival outcomes for SqCC of the bladder treated with CRT. In this study, SqCC had worse overall survival compared to UC patients. Histology had a greater impact on survival than increasing T-stage, suggesting that histology should be an important factor when determining a patient's treatment strategy and that treatment intensification in this subgroup may be warranted.
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http://dx.doi.org/10.1016/j.ctro.2018.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304339PMC
February 2019

Radiation Therapy in Resectable Intrathoracic Sarcomas. A Rare Cancer Network Study.

Int J Radiat Oncol Biol Phys 2019 04 20;103(5):1175-1181. Epub 2018 Dec 20.

Department of Radiation Oncology, Clinica IRAM, Santiago, Chile; Faculty of Medicine, Universidad Diego Portales, Santiago, Chile. Electronic address:

Purpose: Intrathoracic sarcomas (ITS) are considered rare tumors and have a dismal prognosis. We investigated outcomes and risk factors for local control (LC), disease-free survival (DFS), and overall survival (OS) in patients with resected nonmetastatic ITS treated with or without adjuvant radiation therapy (RT) and/or chemotherapy.

Methods And Materials: Patients from the Rare Cancer Network database were studied. A Kaplan-Meier estimate was used to assess survival curves, and Cox proportional hazards regression was used to assess risk factors for LC, DFS, and OS.

Results: Between 2000 and 2017, 121 patients met inclusion criteria. The primary site was lung in 30%, mediastinum in 34%, and pleura in 36%. Thirty-nine percent and 32% received RT and chemotherapy. Median follow-up was 34 months (range, 2-141). LC, DFS, and OS at 10 years were 52%, 18.7%, and 7.2%, respectively. In multivariate analysis, RT (P = .003) and R1 margin status (P = .041) retained a significant association with LC. Only R1 resection (P = .002) remained associated with an increased risk of death in multivariate analysis. Overall, 7 patients (6%) developed grade 3 treatment-related chronic toxicity events.

Conclusions: This joint analysis revealed that OS remains modest in this group of patients, mainly given by the high risk of local and distant failure. Our results suggest that resected ITS can benefit from adjuvant RT.
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http://dx.doi.org/10.1016/j.ijrobp.2018.12.022DOI Listing
April 2019

Early Toxicity of a Phase 2 Trial of Combined Salvage Radiation Therapy and Hormone Therapy in Oligometastatic Pelvic Node Relapses of Prostate Cancer (OLIGOPELVIS GETUG P07).

Int J Radiat Oncol Biol Phys 2019 04 14;103(5):1061-1067. Epub 2018 Dec 14.

Department of Radiation Oncology, Institut de Cancérologie de l'Ouest, Nantes, St-Herblain, France; Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), UMR 1232 Inserm - 6299 CNRS, Institut de Recherche en Santé de l'Université de Nantes, Nantes, France. Electronic address:

Purpose: Limited pelvic nodal relapse of prostatic cancer is a paramount challenge for locoregional salvage treatments. Salvage whole pelvis radiation therapy as considered in the BLINDED trial is an attractive option, but there are concerns about its toxicity. This article describes early toxicity with the technique.

Methods And Materials: BLINDED was a prospective multicenter phase 2 trial investigating high-dose salvage pelvic irradiation with an additional dose to the fluorocholine-based positron emission tomography-positive pelvic lymph nodes, combined with 6-month androgen blockade. The prescribed dose was 54 Gy in 1.8 Gy fractions with up to 66 Gy in 2.2 Gy fractions to the pathologic pelvic lymph nodes. Early toxicity was defined as toxicity until 1 year after radiation therapy. Patients quality of life was assessed using the European Organisation for Research and Treatment of Cancer questionnaires (QLQ-C30 and QLQ-PR25).

Results: Seventy-four patients were recruited in 15 French radiation oncology departments between August 2014 and July 2016. Seven were excluded before treatment because of violation of the inclusion criteria. The intention-to-treat analysis therefore included 67 patients. Half had received prior prostatic irradiation. Median age was 67.7 ± 6.5 years. Grade 2 acute urinary toxicity was observed in 9 of 67 patients (13.4%), and grade 2 1-year toxicity occurred in 4 of 67 patients (6%). Three patients (4.4%) had grade 3 urinary toxicity. Grade 2 acute digestive toxicity was observed in 10 of 67 patients (14.9%), and grade 2 1-year toxicity occurred in 4 of 67 patients (6%). Patients with prior prostate bed irradiation did not exhibit increased urinary or digestive toxicity. The European Organisation for Research and Treatment of Cancer questionnaire scores at 1 year did not worsen significantly.

Conclusions: The acute and 1-year toxicity of the BLINDED protocol was satisfactory, even in patients with a history of prostatic irradiation.
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http://dx.doi.org/10.1016/j.ijrobp.2018.12.020DOI Listing
April 2019

Management of non-metastatic castrate-resistant prostate cancer: A systematic review.

Cancer Treat Rev 2018 Nov 21;70:223-231. Epub 2018 Sep 21.

Department of Oncology, Antoine-Lacassagne Center, Nice, France.

Management of non metastatic castrate resistant prostate cancer is challenging for clinicians due to the heterogeneity of the disease and to the scarce clinical data available in this setting. Recent results obtained with the new generation hormone therapies (NGHT) apalutamide and enzalutamide bring a new perspective for the treatment strategy. The authors present here a systematic review of the treatment options.
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http://dx.doi.org/10.1016/j.ctrv.2018.09.006DOI Listing
November 2018

Localized Myxofibrosarcomas: Roles of Surgical Margins and Adjuvant Radiation Therapy.

Int J Radiat Oncol Biol Phys 2018 10 2;102(2):399-406. Epub 2018 Jun 2.

Department of Surgery, Curie Institute, Paris, France.

Purpose: The objective of this study was to describe the outcome and prognostic factors for adults treated for localized myxofibrosarcoma.

Methods And Materials: We conducted a retrospective multicenter study of 425 nonmetastatic patients who underwent surgery between January 1996 and December 2015 in French National Group and were enrolled in the Conticabase. Pathologic diagnosis was systematically reviewed by expert pathologists. The endpoints were relapse-free and metastasis-free survival. Log-rank tests and Cox models have been used to identified prognostic factors.

Results: Median age was 66 years; 53% were males; 85% of cases occurred in limbs or superficial trunk; median size was 60 mm; 47% and 39% were grades 2 and 3, respectively; 66% had R0 resection and 34% R1 resection. Adjuvant radiation therapy was given to 65% of patients, neoadjuvant radiation therapy to 3%, neoadjuvant chemotherapy to 7%, and adjuvant chemotherapy to 13%. The median follow-up was 51 months. The 5-year local relapse-free survival was 67%; independent prognostic factors for local relapse were R1 resection (hazard ratio [HR] = 1.26; P = .001) and adjuvant radiation therapy (HR = 0.35; P = .0001) (ie, R1 resection and no adjuvant radiation therapy increase the hazard ratio). In stratified analysis, adjuvant radiation therapy was beneficial after R0 resection (P = .0020) and after R1 resection (P = .0001). The 5-year overall survival was 80%. The 5-year metastasis-free survival was 83%. Independent prognostic factors for metastatic relapse were grade 3 disease (HR = 1.975; P = .0001) and tumor size (HR = 1.006; P = .001).

Conclusions: This large series of myxofibrosarcoma confirms the high rate of local relapse. Combination of R0 resection and adjuvant radiation therapy provided the best local control. In parallel with an increasing rate of R0 resection and adjuvant radiation therapy, we observed a constant improvement in both metastatic and local relapse-free survival during the study.
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http://dx.doi.org/10.1016/j.ijrobp.2018.05.055DOI Listing
October 2018

Risk factors for loco-regional recurrence after radical cystectomy of muscle-invasive bladder cancer: A systematic-review and framework for adjuvant radiotherapy.

Cancer Treat Rev 2018 Nov 21;70:88-97. Epub 2018 Jul 21.

Department of Urology, Centre Hospitalier Universitaire de Reims, F-51092 Reims, France.

Background: Radical cystectomy (RC) associated with pelvic lymph node dissection (PLND) is the most common local therapy in the management of non-metastatic muscle invasive bladder cancer (MIBC). Loco-regional recurrence (LRR), however, remains a common and important therapeutic challenge associated with poor oncologic outcomes. We aimed to systematically review evidence regarding factors associated with LRR and to propose a framework for adjuvant radiotherapy (RT) in patients with MIBC.

Methods: We performed this systematic review in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. We searched the PubMed database for articles related to MIBC and associated treatments, published between January 1980 and June 2015. Articles identified by searching references from candidate articles were also included. We retrieved 1383 publications from PubMed and 34 from other sources. After an initial screening, a review of titles and abstracts, and a final comprehensive full text analysis of papers assessed for eligibility, a final consensus on 32 studies was obtained.

Results: LRR is associated with specific patient-, tumor-, center- or treatment-related variables. LRR varies widely, occurring in as many as 43% of the cases and is strongly related to survival outcomes. While perioperative treatment does not impact on LRR, pathological factors such as pT, pN, positive margins status, extent of PLND, number of lymph nodes removed and/or invaded are correlated with LRR. Patients with pT3-T4a and/or positive lymph-nodes and/or limited pelvic lymph-node dissection and/or positive surgical margins have been distributed in LRR risk groups with accuracy.

Conclusions: LRR patterns are well-known and for selected patients, adjuvant treatments could target this event. Intrinsic tumor subtype may guide future criteria to define a personalized treatment strategy. Prospective trials evaluating safety and efficacy of adjuvant RT are ongoing in several countries.
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http://dx.doi.org/10.1016/j.ctrv.2018.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441580PMC
November 2018

Systemic treatments for high-risk localized prostate cancer.

Nat Rev Urol 2018 08;15(8):498-510

Department of Oncology, Antoine-Lacassagne Center, Nice, France.

The majority of patients with prostate cancer who later develop lethal metastatic disease have high-risk localized disease at presentation, emphasizing the importance of effective treatment strategies at this stage. Multimodal treatment approaches that combine systemic and local therapies offer a promising strategy for improving the clinical outcomes of patients with high-risk localized prostate cancer. Combinations of neoadjuvant and adjuvant chemotherapy, hormonal therapy, or chemohormonal therapy are considered to be the standard of care in most solid tumours and should be investigated in the future for the treatment of prostate cancer to improve patient outcomes. However, although the combination of androgen deprivation therapy and radiotherapy is a standard of care in high-risk localized or locally advanced prostate cancer, the benefit of chemotherapy or chemohormonal therapy has yet to be demonstrated outside of the metastatic setting. Moreover, the benefit of neoadjuvant and/or adjuvant systemic therapies in combination with radical prostatectomy has not been proved. The development of next-generation hormonal agents, which have been approved for the treatment of castration-resistant prostate cancer, offers further therapeutic possibilities that are being assessed in early-phase clinical trials.
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http://dx.doi.org/10.1038/s41585-018-0017-xDOI Listing
August 2018

[Radiation therapy in patients with inflammatory bowel disease. A review].

Bull Cancer 2018 May 10;105(5):517-522. Epub 2018 Apr 10.

Université Paris Est Créteil (UPEC), AP-HP, hôpitaux universitaires Henri-Mondor, service d'oncologie-radiothérapie & centre sein Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France; Inserm unité 955 EQ 07, 94010 Créteil, France. Electronic address:

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, are multifactorial diseases characterized by a chronic intestinal inflammation. Abdominal and pelvic irradiation can result in acute or chronic digestive toxicity. A few old studies on small population samples have suggested an increase of gastro-intestinal toxicities in patients with IBD in case of irradiation. Nevertheless, the physiopathology is unknown. More recent studies, including new irradiation techniques, have shown less toxicity events in these patients with IBD. There are no recommendations for irradiation in patients with IBD. This review aims to report recent data on this topic and discuss them regarding radiation parameters.
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http://dx.doi.org/10.1016/j.bulcan.2018.02.005DOI Listing
May 2018

Loco-regional treatment for castration-resistant prostate cancer: Is there any rationale? A critical review from the AFU-GETUG.

Crit Rev Oncol Hematol 2018 Feb 30;122:144-149. Epub 2017 Dec 30.

Department of Radiation therapy, Institut Bergonié, Bordeaux, France. Electronic address:

Emerging evidence from population-based and retrospective series suggests a potential improvement of clinical outcomes in metastatic prostate cancer. Moreover, metastasis-directed treatment has shown encouraging results in this setting. There is an increasing interest in exploring the potential of local therapies in advanced prostate cancer, but this has rarely been specifically addressed in the castration-resistant state, whether non-metastatic or metastatic. A review of relevant articles was performed on the oncologic benefit of local treatment of the primary tumor or metastasis-targeted treatment in castration-resistant prostate cancer patients. The main goal of this strategy is to delay introduction of a new systemic agent to maintain quality of life and potentially to limit resistance. Further investigation is required to provide high-level evidence for the oncologic benefit of this treatment modality.
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http://dx.doi.org/10.1016/j.critrevonc.2017.12.012DOI Listing
February 2018

Manual vs. automated implantation of seeds in prostate brachytherapy: Oncologic results from a single-center study.

Brachytherapy 2018 Jan - Feb;17(1):214-220

Department of Radiation Oncology, Institut Bergonié, Comprehensive Cancer Center, Bordeaux Cedex, France.

Purpose: The objective of this study was to study survival and tolerance of prostate cancer patients treated with I permanent interstitial brachytherapy by automated vs. manual implantation of seeds.

Methods And Materials: Between 2002 and 2010, 349 selected patients were treated with I brachytherapy by the same team: from 2002 to April 2005, 65 patients with linked seeds and then 284 patients treated using Nucletron First System automated implantation. We analyzed biochemical recurrence-free survival (bRFS) rates and toxicities (univariate and multivariate analyses).

Results: Two hundred seventy-seven (79.4%) and 69 patients (19.8%) with low- and intermediate-risk disease were treated, respectively (median follow-up: 64 months). The 5-year bRFS rate was 93.1% (95% confidence interval 89.3-95.6) for the entire cohort. The 5-year bRFS rates were 93.4% and 91.7% for patients with low- and intermediate-risk disease, respectively (p = 0.42). In univariate and multivariate analyses, there was no statistically significant difference in the 5-year bRFS rate depending on the implantation technique (93.1% vs. 91.8%, respectively, for automated and linked seeds; p = 0.53). In univariate analysis, only D prostate (dose delivered to 90% of the prostate) <140 Gy (p = 0.01), lack of prostate-specific antigen bounce (p = 0.008), and nadir prostate-specific antigen >0.11 (p = 0.01) were predictive factors for bRFS. We observed Grade 3 urethritis in 7 patients (2%), urinary incontinence in 2 patients (0.7%), and Grade 4 proctitis in 2 patients (0.7%).

Conclusions: In this large single-center series, brachytherapy for selected localized prostate cancer achieved excellent rates of biochemical control at 5 years (93.1%) with an acceptable toxicity profile, irrespective of the implantation technique used.
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http://dx.doi.org/10.1016/j.brachy.2017.09.013DOI Listing
July 2018