Publications by authors named "Laurence Collette"

141 Publications

Predicting Outcomes in Men With Metastatic Nonseminomatous Germ Cell Tumors (NSGCT): Results From the IGCCCG Update Consortium.

J Clin Oncol 2021 Apr 6:JCO2003296. Epub 2021 Apr 6.

University Department of Medical Oncology, Inselspital, University Hospital, University of Bern, Bern, Switzerland.

Purpose: The classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) plays a pivotal role in the management of metastatic germ cell tumors but relies on data of patients treated between 1975 and 1990.

Materials And Methods: Data on 9,728 men with metastatic nonseminomatous germ cell tumors treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Europe, North America, and Australia. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS). The survival estimates were updated for the current era. Additionally, a novel prognostic model for PFS was developed in 3,543 patients with complete information on potentially relevant variables. The results were validated in an independent data set.

Results: Compared with the original IGCCCG publication, 5-year PFS remained similar in patients with good prognosis with 89% (87%-91%) versus 90% (95% CI, 89 to 91), but the 5-year OS increased from 92% (90%-94%) to 96% (95%-96%). In patients with intermediate prognosis, PFS remained similar with 75% (71%-79%) versus 78% (76%-80%) and the OS increased from 80% (76%-84%) to 89% (88%-91%). In patients with poor prognosis, the PFS increased from 41% (95% CI, 35 to 47) to 54% (95% CI, 52 to 56) and the OS from 48% (95% CI, 42 to 54) to 67% (95% CI, 65 to 69). A more granular prognostic model was developed and independently validated. This model identified a new cutoff of lactate dehydrogenase at a 2.5 upper limit of normal and increasing age and presence of lung metastases as additional adverse prognostic factors. An online calculator is provided (https://www.eortc.org/IGCCCG-Update).

Conclusion: The IGCCCG Update model improves individual prognostication in metastatic nonseminomatous germ cell tumors. Increasing age and lung metastases add granularity to the original IGCCCG classification as adverse prognostic factors.
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http://dx.doi.org/10.1200/JCO.20.03296DOI Listing
April 2021

Survival and New Prognosticators in Metastatic Seminoma: Results From the IGCCCG-Update Consortium.

J Clin Oncol 2021 Mar 17:JCO2003292. Epub 2021 Mar 17.

Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.

Purpose: The classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major advance in the management of germ-cell tumors, but relies on data of only 660 patients with seminoma treated between 1975 and 1990. We re-evaluated this classification in a database from a large international consortium.

Materials And Methods: Data on 2,451 men with metastatic seminoma treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Australia, Europe, and North America. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS) calculated from day 1 of treatment. Variables at initial presentation were evaluated for their prognostic impact. Results were validated in an independent validation set of 764 additional patients.

Results: Compared with the initial IGCCCG classification, in our modern series, 5-year PFS improved from 82% to 89% (95% CI, 87 to 90) and 5-year OS from 86% to 95% (95% CI, 94 to 96) in good prognosis, and from 67% to 79% (95% CI, 70 to 85) and 72% to 88% (95% CI, 80 to 93) in intermediate prognosis patients. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good prognosis patients with LDH above 2.5× upper limit of normal had a 3-year PFS of 80% (95% CI, 75 to 84) and a 3-year OS of 92% (95% CI, 88 to 95) versus 92% (95% CI, 90 to 94) and 97% (95% CI, 96 to 98) in the group with lower LDH.

Conclusion: PFS and OS in metastatic seminoma significantly improved in our modern series compared with the original data. The original IGCCCG classification retains its relevance, but can be further refined by adding LDH at a cutoff of 2.5× upper limit of normal as an additional adverse prognostic factor.
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http://dx.doi.org/10.1200/JCO.20.03292DOI Listing
March 2021

Correcting the bias of the net benefit estimator due to right-censored observations.

Biom J 2021 Apr 22;63(4):893-906. Epub 2021 Feb 22.

Neurobiology Research Unit, Rigshospitalet, Copenhagen, Denmark.

Generalized pairwise comparisons (GPCs) are a statistical method used in randomized clinical trials to simultaneously analyze several prioritized outcomes. This procedure estimates the net benefit (Δ). Δ may be interpreted as the probability for a random patient in the treatment group to have a better overall outcome than a random patient in the control group, minus the probability of the opposite situation. However, the presence of right censoring introduces uninformative pairs that will typically bias the estimate of Δ toward 0. We propose a correction to GPCs that estimates the contribution of each uninformative pair based on the average contribution of the informative pairs. The correction can be applied to the analysis of several prioritized outcomes. We perform a simulation study to evaluate the bias associated with this correction. When only one time-to-event outcome was generated, the corrected estimates were unbiased except in the presence of very heavy censoring. The correction had no effect on the power or type-1 error of the tests based on the Δ. Finally, we illustrate the impact of the correction using data from two randomized trials. The illustrative datasets showed that the correction had limited impact when the proportion of censored observations was around 20% and was most useful when this proportion was close to 70%. Overall, we propose an estimator for the net benefit that is minimally affected by censoring under the assumption that uninformative pairs are exchangeable with informative pairs.
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http://dx.doi.org/10.1002/bimj.202000001DOI Listing
April 2021

Diagnostic and prognostic factors in patients with prostate cancer: a systematic review protocol.

BMJ Open 2021 Feb 11;11(2):e040531. Epub 2021 Feb 11.

Translational Oncology and Urology Research (TOUR), King's College London, London, UK.

Introduction: As part of the PIONEER (Prostate Cancer Diagnosis and Treatment Enhancement Through the Power of Big Data in Europe) Consortium, we will explore which diagnostic and prognostic factors (DPFs) are currently being researched to previously defined clinical and patient-reported outcomes for prostate cancer (PCa).

Methods And Analysis: This research project will follow the following four steps: (1) a broad systematic literature review of DPFs for all stages of PCa, covering evidence from 2014 onwards; (2) discussion of systematic review findings by a multidisciplinary expert panel; (3) risk of bias assessment and applicability with Prediction model Risk Of Bias Assessment Tool criteria, Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) and the Quality In Prognosis Studies tool (QUIPS) and (4) additional quantitative assessments if required.

Ethics And Dissemination: We aim to develop an online tool to present the DPFs identified in this research and make them available across all stakeholders. There are no ethical implications.
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http://dx.doi.org/10.1136/bmjopen-2020-040531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880102PMC
February 2021

Repeatability and reproducibility of ADC measurements: a prospective multicenter whole-body-MRI study.

Eur Radiol 2021 Jan 6. Epub 2021 Jan 6.

Institut de Recherche Expérimentale & Clinique (IREC) - Radiology Department, Université Catholique de Louvain (UCLouvain) - Cliniques Universitaires Saint Luc, Avenue Hippocrate 10, B-1200, Brussels, Belgium.

Objectives: Multicenter oncology trials increasingly include MRI examinations with apparent diffusion coefficient (ADC) quantification for lesion characterization and follow-up. However, the repeatability and reproducibility (R&R) limits above which a true change in ADC can be considered relevant are poorly defined. This study assessed these limits in a standardized whole-body (WB)-MRI protocol.

Methods: A prospective, multicenter study was performed at three centers equipped with the same 3.0-T scanners to test a WB-MRI protocol including diffusion-weighted imaging (DWI). Eight healthy volunteers per center were enrolled to undergo test and retest examinations in the same center and a third examination in another center. ADC variability was assessed in multiple organs by two readers using two-way mixed ANOVA, Bland-Altman plots, coefficient of variation (CoV), and the upper limit of the 95% CI on repeatability (RC) and reproducibility (RDC) coefficients.

Results: CoV of ADC was not influenced by other factors (center, reader) than the organ. Based on the upper limit of the 95% CI on RC and RDC (from both readers), a change in ADC in an individual patient must be superior to 12% (cerebrum white matter), 16% (paraspinal muscle), 22% (renal cortex), 26% (central and peripheral zones of the prostate), 29% (renal medulla), 35% (liver), 45% (spleen), 50% (posterior iliac crest), 66% (L5 vertebra), 68% (femur), and 94% (acetabulum) to be significant.

Conclusions: This study proposes R&R limits above which ADC changes can be considered as a reliable quantitative endpoint to assess disease or treatment-related changes in the tissue microstructure in the setting of multicenter WB-MRI trials.

Key Points: • The present study showed the range of R&R of ADC in WB-MRI that may be achieved in a multicenter framework when a standardized protocol is deployed. • R&R was not influenced by the site of acquisition of DW images. • Clinically significant changes in ADC measured in a multicenter WB-MRI protocol performed with the same type of MRI scanner must be superior to 12% (cerebrum white matter), 16% (paraspinal muscle), 22% (renal cortex), 26% (central zone and peripheral zone of prostate), 29% (renal medulla), 35% (liver), 45% (spleen), 50% (posterior iliac crest), 66% (L5 vertebra), 68% (femur), and 94% (acetabulum) to be detected with a 95% confidence level.
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http://dx.doi.org/10.1007/s00330-020-07522-0DOI Listing
January 2021

Timing to achieve the highest rate of pCR after preoperative radiochemotherapy in rectal cancer: a pooled analysis of 3085 patients from 7 randomized trials.

Radiother Oncol 2021 Jan 20;154:154-160. Epub 2020 Sep 20.

UOC Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario "A. Gemelli" IRCCS - Roma, Italy; Istituto di Radiologia, Università Cattolica del Sacro Cuore - Roma, Italy.

Purpose: Optimal timing of surgery after neoadjuvant chemoradiotherapy (Nad-CRT) is still controversial in locally advanced rectal cancer (LARC). The primary goal of this study was to determine the best surgical interval (SI) to achieve the highest rate of pathological complete response (pCR) and secondly to evaluate the effect on survival outcomes according to the SI.

Patients And Methods: Patients data were extracted from the international randomized trials: Accord12/0405, EORTC22921, FFCD9203, CAO/ARO/AIO-94, CAO-ARO-AIO-04, INTERACT and TROG01.04. Inclusion criteria were: age≥ 18, cT3-T4 and cN0-2, no clinical evidence of distant metastasis at diagnosis, Nad-CRT followed by surgery. Pearson's Chi-squared test with Yates' continuity correction for categorical variables, the Mann-Whitney test for continuous variables, Mann-Kendall test, Kaplan-Meier curves with log-rank test, univariate and multivariate logistic regression model was used for data analysis.

Results: 3085 patients met the inclusion criteria. Overall, the pCR rate was 14% at a median SI of 6 weeks (range 1-31). The cumulative pCR rate increased significantly when SI lengthened, with 95% of pCR events within 10 weeks from Nad-CRT. At univariate and multivariate logistic regression analysis, lengthening of SI (p< 0.01), radiotherapy dose (p< 0.01), and the addition of oxaliplatin to Nad-CRT (p< 0.01) had a favorable impact on pCR. Furthermore, lengthening of SI was not impact on local recurrences, distance metastases, and overall survival.

Conclusion: This pooled analysis suggests that the best time to achieve pCR in LARC is at 10 weeks, considering that the lengthening of SI is not detrimental concerning survival outcomes.
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http://dx.doi.org/10.1016/j.radonc.2020.09.026DOI Listing
January 2021

A new measure of treatment effect in clinical trials involving competing risks based on generalized pairwise comparisons.

Biom J 2021 Feb 16;63(2):272-288. Epub 2020 Sep 16.

CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Université Lyon 1, Villeurbanne, France.

In survival analysis with competing risks, the treatment effect is typically expressed using cause-specific or subdistribution hazard ratios, both relying on proportional hazards assumptions. This paper proposes a nonparametric approach to analyze competing risks data based on generalized pairwise comparisons (GPC). GPC estimate the net benefit, defined as the probability that a patient from the treatment group has a better outcome than a patient from the control group minus the probability of the opposite situation, by comparing all pairs of patients taking one patient from each group. GPC allow using clinically relevant thresholds and simultaneously analyzing multiple prioritized endpoints. We show that under proportional subdistribution hazards, the net benefit for competing risks settings can be expressed as a decreasing function of the subdistribution hazard ratio, taking a value 0 when the latter equals 1. We propose four net benefit estimators dealing differently with censoring. Among them, the Péron estimator uses the Aalen-Johansen estimator of the cumulative incidence functions to classify the pairs for which the patient with the best outcome could not be determined due to censoring. We use simulations to study the bias of these estimators and the size and power of the tests based on the net benefit. The Péron estimator was approximately unbiased when the sample size was large and the censoring distribution's support sufficiently wide. With one endpoint, our approach showed a comparable power to a proportional subdistribution hazards model even under proportional subdistribution hazards. An application of the methodology in oncology is provided.
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http://dx.doi.org/10.1002/bimj.201900354DOI Listing
February 2021

Event-Free Survival, a Prostate-Specific Antigen-Based Composite End Point, Is Not a Surrogate for Overall Survival in Men With Localized Prostate Cancer Treated With Radiation.

J Clin Oncol 2020 09 18;38(26):3032-3041. Epub 2020 Jun 18.

Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA.

Purpose: Recently, we have shown that metastasis-free survival is a strong surrogate for overall survival (OS) in men with intermediate- and high-risk localized prostate cancer and can accelerate the evaluation of new (neo)adjuvant therapies. Event-free survival (EFS), an earlier prostate-specific antigen (PSA)-based composite end point, may further expedite trial completion.

Methods: EFS was defined as the time from random assignment to the date of first evidence of disease recurrence, including biochemical failure, local or regional recurrence, distant metastasis, or death from any cause, or was censored at the date of last PSA assessment. Individual patient data from trials within the Intermediate Clinical Endpoints in Cancer of the Prostate-ICECaP-database with evaluable PSA and disease follow-up data were analyzed. We evaluated the surrogacy of EFS for OS using a 2-stage meta-analytic validation model by determining the correlation of EFS with OS (patient level) and the correlation of treatment effects (hazard ratios [HRs]) on both EFS and OS (trial level). A clinically relevant surrogacy was defined a priori as an ≥ 0.7.

Results: Data for 10,350 patients were analyzed from 15 radiation therapy-based trials enrolled from 1987 to 2011 with a median follow-up of 10 years. At the patient level, the correlation of EFS with OS was 0.43 (95% CI, 0.42 to 0.44) as measured by Kendall's tau from a copula model. At the trial level, the was 0.35 (95% CI, 0.01 to 0.60) from the weighted linear regression of log(HR)-OS on log(HR)-EFS.

Conclusion: EFS is a weak surrogate for OS and is not suitable for use as an intermediate clinical end point to substitute for OS to accelerate phase III (neo)adjuvant trials of prostate cancer therapies for primary radiation therapy-based trials.
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http://dx.doi.org/10.1200/JCO.19.03114DOI Listing
September 2020

Impact of acute kidney injury on anticancer treatment dosage and long-term outcomes: a pooled analysis of European Organisation for Research and Treatment of Cancer trials.

Nephrol Dial Transplant 2020 Apr 26. Epub 2020 Apr 26.

European Organisation for Research and Treatment of Cancer, Brussels, Belgium.

Background: The impact of kidney dysfunction on long-term outcomes of patients with advanced cancer remains unclear.

Methods: Patients with advanced cancer included in trials conducted by the European Organisation for Research and Treatment of Cancer were eligible for this retrospective analysis. Acute kidney injury (AKI) was identified using serum creatinine levels and using adverse events reported by investigators. The impact of baseline estimated glomerular filtration rates (eGFRs) on progression-free survival (PFS) and overall survival (OS) was investigated. Pooled estimates of the impact of AKI on dose intensity, treatment duration, PFS and OS were obtained following a meta-analytic process.

Results: Nine trials were included in this study, totalling 2872 metastatic patients with various tumour types and various systemic treatment types. Baseline eGFR had homogeneously no impact on PFS or OS. Most Risk, Injury, Failure, Loss of kidney function and End-stage kidney disease (RIFLE) events occurred early during the course of the treatment. AKI was not associated with an increased rate of treatment discontinuation, while it decreased the study treatment dose intensity. Occurrence of a first RIFLE event significantly and homogeneously reduced PFS (pooled hazard ratio = 1.18, 95% confidence interval 1.07-1.30; P = 0.0012), while its impact on OS was more heterogeneous across trials.

Conclusion: AKI is associated with reduced treatment dose intensity and reduced PFS. Therefore, close monitoring of the kidney function during the first months of treatment should be included in clinical trial protocols and probably also in daily practice to enable early AKI diagnosis and management. Collaboration between oncologists and nephrologists is needed to reduce the risk of undertreatment of patients experiencing AKI.
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http://dx.doi.org/10.1093/ndt/gfaa049DOI Listing
April 2020

Proportional odds assumption for modeling longitudinal ordinal multiple toxicity outcomes in dose finding studies of targeted agents: A pooled analysis of 54 studies.

Contemp Clin Trials Commun 2020 Mar 25;17:100529. Epub 2020 Jan 25.

INSERM U1018, CESP, Université Paris-Saclay, UVSQ, Villejuif, F-94805, France.

Background: Data generated by phase I trials is richer than the classical binary DLT measured at the first cycle used as primary endpoints. Several works developed designs for more informative endpoints, e.g. ordinal toxicity grades and/or longitudinal data which relied however on strong assumptions, in particular the proportional odds (PO) assumption.

Methods: We evaluated this PO assumption for the dose and cycle on a large database of individual patient data from 54 phase I clinical trials of molecularly targeted agents. The PO model is a specific case of the continuation ratio logit model (CRLM) with null parameters. We compared the PO and CRLM models using the widely applicable information criterion (WAIC). We considered a longitudinal multivariate ordinal toxicity outcome (cutaneous, digestive, hematological, general disorders, and other toxicities).

Results: WAIC suggested that the CRLM model (WAIC = 30911.58) outperformed the PO model (WAIC = 31432.10). Deviance from PO assumption for dose was observed for digestive and general disorder toxicities. There was moderate cycle effect with slight deviance from PO assumption for the other type of toxicity.

Conclusions: Designs based on PO for dose should be a useful tool for drug with low expected digestive or general disorder toxicity dose-related incidence.
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http://dx.doi.org/10.1016/j.conctc.2020.100529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005415PMC
March 2020

International standards for the analysis of quality-of-life and patient-reported outcome endpoints in cancer randomised controlled trials: recommendations of the SISAQOL Consortium.

Lancet Oncol 2020 02;21(2):e83-e96

European Organisation for Research and Treatment of Cancer, Brussels, Belgium.

Patient-reported outcomes (PROs), such as symptoms, function, and other health-related quality-of-life aspects, are increasingly evaluated in cancer randomised controlled trials (RCTs) to provide information about treatment risks, benefits, and tolerability. However, expert opinion and critical review of the literature showed no consensus on optimal methods of PRO analysis in cancer RCTs, hindering interpretation of results. The Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data Consortium was formed to establish PRO analysis recommendations. Four issues were prioritised: developing a taxonomy of research objectives that can be matched with appropriate statistical methods, identifying appropriate statistical methods for PRO analysis, standardising statistical terminology related to missing data, and determining appropriate ways to manage missing data. This Policy Review presents recommendations for PRO analysis developed through critical literature reviews and a structured collaborative process with diverse international stakeholders, which provides a foundation for endorsement; ongoing developments of these recommendations are also discussed.
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http://dx.doi.org/10.1016/S1470-2045(19)30790-9DOI Listing
February 2020

Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation.

Lancet Oncol 2020 01;21(1):e18-e28

Department for Radiation Oncology, Ghent University Hospital and Ghent University, Ghent, Belgium.

Oligometastatic disease has been proposed as an intermediate state between localised and systemically metastasised disease. In the absence of randomised phase 3 trials, early clinical studies show improved survival when radical local therapy is added to standard systemic therapy for oligometastatic disease. However, since no biomarker for the identification of patients with true oligometastatic disease is clinically available, the diagnosis of oligometastatic disease is based solely on imaging findings. A small number of metastases on imaging could represent different clinical scenarios, which are associated with different prognoses and might require different treatment strategies. 20 international experts including 19 members of the European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer OligoCare project developed a comprehensive system for characterisation and classification of oligometastatic disease. We first did a systematic review of the literature to identify inclusion and exclusion criteria of prospective interventional oligometastatic disease clinical trials. Next, we used a Delphi consensus process to select a total of 17 oligometastatic disease characterisation factors that should be assessed in all patients treated with radical local therapy for oligometastatic disease, both within and outside of clinical trials. Using a second round of the Delphi method, we established a decision tree for oligometastatic disease classification together with a nomenclature. We agreed oligometastatic disease as the overall umbrella term. A history of polymetastatic disease before diagnosis of oligometastatic disease was used as the criterion to differentiate between induced oligometastatic disease (previous history of polymetastatic disease) and genuine oligometastatic disease (no history of polymetastatic disease). We further subclassified genuine oligometastatic disease into repeat oligometastatic disease (previous history of oligometastatic disease) and de-novo oligometastatic disease (first time diagnosis of oligometastatic disease). In de-novo oligometastatic disease, we differentiated between synchronous and metachronous oligometastatic disease. We did a final subclassification into oligorecurrence, oligoprogression, and oligopersistence, considering whether oligometastatic disease is diagnosed during a treatment-free interval or during active systemic therapy and whether or not an oligometastatic lesion is progressing on current imaging. This oligometastatic disease classification and nomenclature needs to be prospectively evaluated by the OligoCare study.
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http://dx.doi.org/10.1016/S1470-2045(19)30718-1DOI Listing
January 2020

MRI versus F-FDG-PET/CT for detecting bone marrow involvement in multiple myeloma: diagnostic performance and clinical relevance.

Eur Radiol 2020 Apr 16;30(4):1927-1937. Epub 2019 Dec 16.

Department of Haematology, IREC, Cliniques Universitaires Saint Luc, UCLouvain, Brussels, Belgium.

Purpose: To compare the diagnostic performance of MRI and F-FDG-PET/CT in detecting bone marrow involvement (BMI) in patients with multiple myeloma (MM).

Materials And Methods: This retrospective study was approved by our Institutional Review Board. Two radiologists and two nuclear medicine specialists independently and blindly reviewed 84 pairs of MRI and PET/CT scans obtained in 73 MM patients. Readers assessed the presence and patterns of BMI. The best valuable comparator (BVC) for BMI was established by a panel review of all baseline and follow-up imaging, and biological and pathological information. Intra- and inter-reader agreement and correlation between MRI and PET/CT were assessed using the prevalence-adjusted bias-adjusted kappa (k) coefficient. Diagnostic performance of MRI and PET/CT in detecting BMI was evaluated from ROC characteristics. Association between imaging and biological, pathological, and clinical findings was assessed using Wilcoxon rank-sum and chi-square tests.

Results: Intra- and inter-reader agreement was very good for MRI (k = 0.90 [0.81; 1.00] and 0.88 [0.78; 0.98]). Intra- and inter-reader agreement was good for PET/CT (k = 0.80 [0.69; 0.91] and 0.71 [0.56; 0.86]). The sensitivity of MRI to detect BMI (97% [90%; 100%]) was significantly superior to that of PET/CT (76% [64%; 85%]) (p < 0.001). The specificity of MRI (86% [57%; 98%]) was lower than that of PET/CT (93% [66%; 100%]), without reaching statistical significance (p = 0.32). There was a strong correlation between decisions regarding patient management and PET/CT findings (p < 0.001).

Conclusion: MRI is significantly more sensitive than PET/CT to detect BMI in MM. Patient management is more strongly correlated with PET/CT findings.

Key Points: • MRI and PET/CT have very close diagnostic value for the detection of bone marrow involvement in multiple myeloma. • MRI has a significantly higher sensitivity and better reproducibility. • PET/CT findings appear to have a higher impact on clinical decisions.
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http://dx.doi.org/10.1007/s00330-019-06469-1DOI Listing
April 2020

Overall Survival in Men With Bone Metastases From Castration-Resistant Prostate Cancer Treated With Bone-Targeting Radioisotopes: A Meta-analysis of Individual Patient Data From Randomized Clinical Trials.

JAMA Oncol 2020 02;6(2):206-216

Université Paris Sud, Orsay, France.

Importance: Both α-emitting and β-emitting bone-targeted radioisotopes (RIs) have been developed to treat men with metastatic castration-resistant prostate cancer (CRPC). Only 1 phase 3 randomized clinical trial has demonstrated an overall survival (OS) benefit from an α-emitting RI, radium 223 (223Ra), vs standard of care. Yet no head-to-head comparison has been done between α-emitting and β-emitting RIs.

Objective: To assess OS in men with bone metastases from CRPC treated with bone-targeted RIs and to compare the effects of α-emitting RIs with β-emitting RIs.

Data Sources: PubMed, Cochrane Library, ClinicalTrials.gov, and meeting proceedings between January 1993 and June 2013 were reviewed. Key terms included randomized trials, radioisotopes, radiopharmaceuticals, and prostate cancer. Data were collected, checked, and analyzed from February 2017 to October 2018.

Study Selection: Selected trials included patients with prostate cancer, recruited more than 50 patients from January 1993 to June 2013, compared RI use with no RI use (placebo, external radiotherapy, or chemotherapy), and were randomized. Patients were diagnosed with histologically proven prostate cancer and disease progression after both surgical or chemical castration and have evidence of bone metastasis. Nine randomized clinical trials were identified as eligible, but 3 were excluded for insufficient data.

Data Extraction And Synthesis: Individual patient data were requested for each eligible trial, and all data were checked with a standard procedure. The log-rank test stratified by trial was used to estimate hazard ratios (HRs), and a similar fixed-effects (FE) model was used to estimate odds ratios (ORs). The between-trial heterogeneity of treatment effects was evaluated by Cochran test and I2 and was accounted by a random-effects (RE) model.

Main Outcomes And Measures: Overall survival; secondary outcomes were symptomatic skeletal event (SSE)-free survival and adverse events.

Results: Based on 6 randomized clinical trials including 2081 patients, RI use was significantly associated with OS compared with no RI use (HR, 0.86; 95% CI, 0.77-0.95; P = .004) with high heterogeneity (χ25 = 24.46; P < .001; I2 = 80%), but this association disappeared when using an RE model (HR, 0.80; 95% CI, 0.61-1.06; P = .12; τ2 = 0.08). The heterogeneity is explained both by the type of RI and by the inclusion of 2 outlier trials that included 275 patients; the OS benefit was significantly higher with the α-emitting RI 223Ra (HR, 0.70; 95% CI, 0.58-0.83) but not significant with the β-emitting RI strontium-89 (HR, 0.96; 95% CI, 0.84-1.10) (P for interaction = .004). Excluding the outlier trials led to an overall HR of 0.82 (95% CI, 0.73-0.92; P < .001) (between-trial heterogeneity: χ23 = 6.51; P = .09; I2 = 54%) using an FE model and an HR of 0.80 (95% CI, 0.65-0.99; P = .04; τ2 = 0.02) using an RE model. The HR for SSE-free survival was 0.81 (95% CI, 0.69-0.93; P = .004) (between-trial heterogeneity: χ23 = 6.71; P = .08; I2 = 55%) when using an FE model and was 0.76 (95% CI, 0.58-1.01; P = .06; τ2 = 0.04) when using an RE model. There were more hematological toxic effects with RI use compared with no RI use (OR, 1.48; 95% CI, 1.17-1.88; P = .001).

Conclusions And Relevance: In metastatic CRPC, a significant improvement of OS and SSE-free survival was obtained with bone-targeted α-emitting but not β-emitting RIs. Caution is necessary for generalizability of these results, given the between-trial heterogeneity.
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http://dx.doi.org/10.1001/jamaoncol.2019.4097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990736PMC
February 2020

Local Failure and Survival After Definitive Radiotherapy for Aggressive Prostate Cancer: An Individual Patient-level Meta-analysis of Six Randomized Trials.

Eur Urol 2020 02 10;77(2):201-208. Epub 2019 Nov 10.

Department of Radiation Oncology, Cedars Sinai, Los Angeles, CA, USA.

Background: The importance of local failure (LF) after treatment of high-grade prostate cancer (PCa) with definitive radiotherapy (RT) remains unknown.

Objective: To evaluate the clinical implications of LF after definitive RT.

Design, Setting, And Participants: Individual patient data meta-analysis of 992 patients (593 Gleason grade group [GG] 4 and 399 GG 5) enrolled in six randomized clinical trials.

Outcome Measurements And Statistical Analysis: Multivariable Cox proportional hazard models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), and distant metastasis (DM)-free survival (DMFS) and LF as a time-dependent covariate. Markov proportional hazard models were developed to evaluate the impact of specific transitions between disease states on these endpoints.

Results And Limitations: Median follow-up was 6.4 yr overall and 7.2 yr for surviving patients. LF was significantly associated with OS (hazard ratio [HR] 1.70 [95% confidence interval {CI} 1.37-2.10]), PCSS (3.10 [95% CI 2.33-4.12]), and DMFS (HR 1.92 [95% CI 1.54-2.39]), p < 0.001 for all). Patients who had not transitioned to the LF state had a significantly lower hazard of transitioning to a PCa-specific death state than those who transitioned to the LF state (HR 0.13 [95% CI 0.04-0.41], p < 0.001). Additionally, patients who transitioned to the LF state had a greater hazard of DM or death (HR 2.46 [95% CI 1.22-4.93], p = 0.01) than those who did not.

Conclusions: LF is an independent prognosticator of OS, PCSS, and DMFS in high-grade localized PCa and a subset of DM events that are anteceded by LF events. LF events warrant consideration for intervention, potentially suggesting a rationale for upfront treatment intensification. However, whether these findings apply to all men or just those without significant comorbidity remains to be determined.

Patient Summary: Men who experience a local recurrence of high-grade prostate cancer after receiving upfront radiation therapy are at significantly increased risks of developing metastases and dying of prostate cancer.
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http://dx.doi.org/10.1016/j.eururo.2019.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008470PMC
February 2020

Pooled Analysis of external-beam RADiotherapy parameters in phase II and phase III trials in radiochemotherapy in Anal Cancer (PARADAC).

Eur J Cancer 2019 11 28;121:130-143. Epub 2019 Sep 28.

Department of Radiation Oncology, La Pitié Salpêtrière - Charles Foix University Hospital, Sorbonne University, Paris, France.

Purpose: Concomitant external-beam radiochemotherapy (5-fluorouracil-mitomycin C) has become the standard of care in anal cancer since the '90s. A pooled analysis of individual patient data from 7 major trials was performed quantifying the effect of radiation therapy (RT)-related parameters on the outcome of patients with anal cancer.

Materials And Methods: Pooling databases from combined modality trials, the impact of RT parameters (total dose, gap duration, OTT: overall treatment time) on outcome including locoregional failure (LRF), 5-year progression free survival (PFS) and toxicities were investigated. Individual patient data were received for 10/13 identified published studies conducted from 1987 to 2008 (n = 3031). A Cox regression model was used (landmark = 3 months after RT for first follow-up).

Results: After data inspection indicating severe heterogeneity between trials, only 1343 patients from 7/10 studies received were analysed (the most recent ones, since 1994; median follow-up = 4.1 years). A higher overall 5-year LRF rate [22.8% (95% confidence interval [CI] 22.3-27.3%)] significantly correlated with longer OTT (p = 0.03), larger tumour size (p < 0.001) and male gender (p = 0.045). Although significant differences were not observed, subset analyses for LRF (dose range: 50.4-59 Gy) seemed to favour lower doses (p = 0.412), and when comparing a 2-week gap versus 3 (dose: 59.4 Gy), results suggested 3 weeks might be detrimental (p = 0.245). For a 2-week gap versus none (dose range: 55-59.4 Gy), no difference was observed (p = 0.89). Five-year PFS was 65.7% (95% CI: 62.8-68.5%). Higher PFS rates were observed in women (p < 0.001), smaller tumour sizes (p < 0.001) and shorter OTT (p = 0.025). Five-year overall survival [76.7% (95% CI: 73.9%-79.3%)] correlated positively with female gender (p < 0.001), small tumour size (p = 0.027) and short OTT (p = 0.026). Descriptive toxicity data are presented.

Conclusion: For patients receiving concurrent external-beam doublet chemoradiation, a longer OTT seems detrimental to outcome. Further trials involving modern techniques may better define optimal OTT and total dose.
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http://dx.doi.org/10.1016/j.ejca.2019.08.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924923PMC
November 2019

A Systematic Review and Recommendation for Reporting of Surrogate Endpoint Evaluation Using Meta-analyses.

JNCI Cancer Spectr 2019 Mar 6;3(1):pkz002. Epub 2019 Feb 6.

Background: Meta-analysis of randomized controlled trials (RCTs) has been widely conducted for the evaluation of surrogate endpoints in oncology, but little attention has been given to the adequacy of reporting and interpretation. This review evaluated the reporting quality of published meta-analyses on surrogacy evaluation and developed recommendations for future reporting.

Methods: We searched PubMed through August 2017 to identify studies that evaluated surrogate endpoints using the meta-analyses of RCTs in oncology. Both individual patient data (IPD) and aggregate data (AD) meta-analyses were included for the review.

Results: Eighty meta-analyses were identified: 22 used IPD and 58 used AD from multiple RCTs. We observed variability and reporting deficiencies in both IPD and AD meta-analyses, especially on reporting of trial selection, endpoint definition, study and patient characteristics for included RCTs, and important statistical methods and results. Based on these findings, we proposed a checklist and recommendations to improve completeness, consistency, and transparency of reports of meta-analytic surrogacy evaluation. We highlighted key aspects of the design and analysis of surrogate endpoints and presented explanations and rationale why these items should be clearly reported in surrogacy evaluation.

Conclusions: Our reporting of surrogate endpoint evaluation using meta-analyses (ReSEEM) guidelines and recommendations will improve the quality in reporting and facilitate the interpretation and reproducibility of meta-analytic surrogacy evaluation. Also, they should help promote greater methodological consistency and could also serve as an evaluation tool in the peer review process for assessing surrogacy research.
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http://dx.doi.org/10.1093/jncics/pkz002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649812PMC
March 2019

Sample size computation in phase II designs combining the A'Hern design and the Sargent and Goldberg design.

J Biopharm Stat 2020 03 22;30(2):305-321. Epub 2019 Jul 22.

EORTC Headquarters, Statistics Department, Brussels, Belgium.

This work focuses on the modification of two classical phase II trials designs, the A'Hern design, a single-arm single-stage design, and the Sargent and Goldberg design introduced in the context of flexible screening designs. In the first part of the paper, we have proposed a drift-adjusted A'Hern design, a hybrid design combining the A'Hern design and the Sargent and Goldberg design. Indeed, classical single-arm phase II designs such as the A'Hern design are still widely used in oncology. Conducting randomized comparative phase II trials may be challenging in many settings due to the increased sample size and this despite larger type 1 errors. Randomized non-comparative phase II designs first introduced by Herson and Carter include a simultaneous randomized standard-treatment reference arm to detect any drift in the reference arm assumption, but the trial is analyzed against historical controls as if it were a single-arm study. However, not incorporating at all an internal control arm in the trial design has been criticized in the literature. Our new design takes into account the observed response rate in a non-comparative reference arm to reduce the trial's risk of a false-positive conclusion. In the second part, we have proposed an alternative strategy to determining the sample size of the screened selection design. The latter, introduced in recent years by Yap et al. and Wu et al., extended the Sargent and Goldberg design to include a comparison to a historical control. However, their sample size computations may have potential weaknesses, which motivated us to revisit the existing approaches. A detailed simulation study has been carried out to evaluate the operating characteristics of the drift-adjusted A'Hern design and the different sample size strategies of the screened selection designs.
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http://dx.doi.org/10.1080/10543406.2019.1641817DOI Listing
March 2020

Surgical Safety of Cytoreductive Nephrectomy Following Sunitinib: Results from the Multicentre, Randomised Controlled Trial of Immediate Versus Deferred Nephrectomy (SURTIME).

Eur Urol 2019 10 18;76(4):437-440. Epub 2019 Jun 18.

The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Urology, The Royal Free Hospital and University College London, London, UK. Electronic address:

The European Organisation for Research and Treatment of Cancer SURTIME trial explored timing of sunitinib, a tyrosine kinase inhibitor (TKI), and cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma. Previous retrospective studies suggest increased surgery-related adverse events (AEs) after presurgical TKI. We report surgical safety from a randomised comparison of CN before or after sunitinib. In-hospital mortality, 30-d readmission rate, and intraoperative and 30-d postoperative AEs according to Common Terminology Criteria for Adverse Events version 4 and Clavien-Dindo (CD) were analysed. Patients were randomised 1:1 to immediate CN followed by sunitinib versus sunitinib followed by deferred CN 24h after the last dose of sunitinib. None of the tumours in the deferred arm became unresectable, and only two patients had a sunitinib-related delay of CN of >2wk. AEs related to surgery (all grades) in the immediate and deferred arms occurred in 52% and 53% after CN, respectively, although the number of intraoperative surgery-related AEs was higher in the immediate arm. Postoperative AEs (CD ≥3), 30-d readmission, and in-hospital mortality rates were 6.5%, 13%, and 4.3% in the immediate arm and 2.5%, 7.5%, and 2.5% in the deferred arm, respectively. There were no differences in surgery time, blood loss, and hospital stay. PATIENT SUMMARY: Patients with metastatic kidney cancer do not have more surgical complications irrespective of whether they are treated with systemic therapy before or after surgery.
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http://dx.doi.org/10.1016/j.eururo.2019.06.006DOI Listing
October 2019

ESMO-MCBS: setting the record straight - Authors' reply.

Lancet Oncol 2019 04;20(4):e193

Department of Clinical Oncology, Guy's & St Thomas' NHS Trust, London, UK; Institute of Cancer Policy, King's College London, London, UK.

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http://dx.doi.org/10.1016/S1470-2045(19)30166-4DOI Listing
April 2019

Cumulative Toxicity in Targeted Therapies: What to Expect at the Recommended Phase II Dose.

J Natl Cancer Inst 2019 11;111(11):1179-1185

Background: In the era of molecularly targeted agents (MTAs), it is recommended to account for toxicity over several cycles to identify the recommended phase II dose (RP2D). We investigated the relationship between the risk of toxicity at cycle 1 and the cumulative incidence of toxicity over subsequent cycles in trials of single MTAs.

Methods: On individual patient data from 26 phase I clinical trials of single MTAs provided by the National Cancer Institute, we estimated the probability of first-severe toxicity per treatment cycle as well as the cumulative incidence at, below, and above the maximum tolerated dose (MTD). Toxicity was further subclassified into nonhematologic and hematologic. A prediction table was developed to estimate the cumulative incidence up to six cycles based on the toxicity rate observed in the first cycle.

Results: Overall, 942 patients were included. For patients treated at the MTD, the probability of first-severe toxicity decreased from 24.8% (95% prediction interval [PI] = 20.3% to 32.9%) to 2.2% (95% PI = 0.1% to 7.7%) from cycle 1 to 6, whereas the cumulative incidence of toxicity reached 51.7% (95% PI = 40.5% to 66.3%) after six cycles. Toxicity rates ranging from 20.0% to 30.0% in the first cycle were associated with 46.8% (95% PI = 39.5% to 54.2%) and 65.8% (95% PI = 57.7% to 73.1%) cumulative incidence after six cycles.

Conclusion: This study examined the risk of severe toxicity over time of single MTAs. The cumulative incidence of toxicity at the MTD was higher than the usually accepted toxicity targets, challenging the definition of the RP2D of MTAs. The prediction table may help calibrate the target rate at the RP2D.
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http://dx.doi.org/10.1093/jnci/djz024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855968PMC
November 2019

Towards an evidence-informed value scale for surgical and radiation oncology: a multi-stakeholder perspective.

Lancet Oncol 2019 02;20(2):e112-e123

Department of Clinical Oncology, Guy's & St Thomas' NHS Trust, London, UK; Institute of Cancer Policy, King's College London, London, UK.

Surgery and radiotherapy, two locoregional cancer treatments, are essential to help improve cancer outcomes, control, and palliation. The continued evolution in treatment processes, techniques, and technologies-often at substantially increased costs-demands for direction on outcomes that are most valued by patients, and the evidence that is required before clinical adoption of these practices. Three recently introduced frameworks-the European Society for Medical Oncology Magnitude of Clinical Benefit Scale, the American Society of Clinical Oncology Value Framework, and the National Comprehensive Cancer Network Blocks-which all help define the value of oncology treatments, were appraised with a focus on their methods and definition of patient benefit. In this Review, we investigate the applicability of these frameworks to surgical and radiotherapy innovations. Findings show that these frameworks are not immediately transferable to locoregional cancer treatments. Moreover, the lack of emphasis on patient perspective and the reliance on traditional, trial-based endpoints such as survival, disease-free survival, and safety, calls for a new framework that includes real-world evidence with focus on the whole spectrum of patient-centred endpoints. Such an evidence-informed value scale would safeguard against the proliferation of low-value innovation while simultaneously increasing access to treatments that show significant improvements in the outcomes of cancer care.
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http://dx.doi.org/10.1016/S1470-2045(18)30917-3DOI Listing
February 2019

A multinational, multi-tumour basket study in very rare cancer types: The European Organization for Research and Treatment of Cancer phase II 90101 'CREATE' trial.

Eur J Cancer 2019 03 14;109:192-195. Epub 2019 Jan 14.

Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium; Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1016/j.ejca.2018.12.013DOI Listing
March 2019

Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients With Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib: The SURTIME Randomized Clinical Trial.

JAMA Oncol 2019 02;5(2):164-170

The Netherlands Cancer Institute, Amsterdam, the Netherlands.

Importance: In clinical practice, patients with primary metastatic renal cell carcinoma (mRCC) have been offered cytoreductive nephrectomy (CN) followed by targeted therapy, but the optimal sequence of surgery and systemic therapy is unknown.

Objective: To examine whether a period of sunitinib therapy before CN improves outcome compared with immediate CN followed by sunitinib.

Design, Setting, And Participants: This randomized clinical trial began as a phase 3 trial on July 14, 2010, and continued until March 24, 2016, with a median follow-up of 3.3 years and a clinical cutoff date for this report of May 5, 2017. Patients with mRCC of clear cell subtype, resectable primary tumor, and 3 or fewer surgical risk factors were studied.

Interventions: Immediate CN followed by sunitinib therapy vs treatment with 3 cycles of sunitinib followed by CN in the absence of progression followed by sunitinib therapy.

Main Outcomes And Measures: Progression-free survival was the primary end point, which needed a sample size of 458 patients. Because of poor accrual, the independent data monitoring committee endorsed reporting the intention-to-treat 28-week progression-free rate (PFR) instead. Overall survival (OS), adverse events, and postoperative progression were secondary end points.

Results: The study closed after 5.7 years with 99 patients (80 men and 19 women; mean [SD] age, 60 [8.5] years). The 28-week PFR was 42% in the immediate CN arm (n = 50) and 43% in the deferred CN arm (n = 49) (P = .61). The intention-to-treat OS hazard ratio of deferred vs immediate CN was 0.57 (95% CI, 0.34-0.95; P = .03), with a median OS of 32.4 months (95% CI, 14.5-65.3 months) in the deferred CN arm and 15.0 months (95% CI, 9.3-29.5 months) in the immediate CN arm. In the deferred CN arm, 48 of 49 patients (98%; 95% CI, 89%-100%) received sunitinib vs 40 of 50 (80%; 95% CI, 67%-89%) in the immediate arm. Systemic progression before planned CN in the deferred CN arm resulted in a per-protocol recommendation against nephrectomy in 14 patients (29%; 95% CI, 18%-43%).

Conclusions And Relevance: Deferred CN did not improve the 28-week PFR. With the deferred approach, more patients received sunitinib and OS results were higher. Pretreatment with sunitinib may identify patients with inherent resistance to systemic therapy before planned CN. This evidence complements recent data from randomized clinical trials to inform treatment decisions in patients with primary clear cell mRCC requiring sunitinib.

Trial Registration: ClinicalTrials.gov identifier: NCT01099423.
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http://dx.doi.org/10.1001/jamaoncol.2018.5543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439568PMC
February 2019

Comparison of Local Control of Brain Metastases With Stereotactic Radiosurgery vs Surgical Resection: A Secondary Analysis of a Randomized Clinical Trial.

JAMA Oncol 2019 02;5(2):243-247

Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Importance: Brain metastases are a common source of morbidity for patients with cancer, and limited data exist to support the local therapeutic choice between surgical resection and stereotactic radiosurgery (SRS).

Objective: To evaluate local control of brain metastases among patients treated with SRS vs surgical resection within the European Organization for the Research and Treatment of Cancer (EORTC) 22952-26001 phase 3 trial.

Design, Setting, And Participants: This unplanned, exploratory analysis of the international, multi-institutional randomized clinical trial EORTC 22952-26001 (conducted from 1996-2007) was performed from February 9, 2017, through July 25, 2018. The EORTC 22952-26001 trial randomized patients with 1 to 3 brain metastases to whole-brain radiotherapy vs observation after complete surgical resection or before SRS. Patients in the present analysis were stratified but not randomized according to local modality (SRS or surgical resection) and treated per protocol with 1 to 2 brain metastases and tumors with a diameter of no greater than 4 cm.

Interventions: Surgical resection or SRS.

Main Outcomes And Measures: The primary end point was local recurrence of treated lesions. Cumulative incidence of local recurrence was calculated according to modality (surgical resection vs SRS) with competing risk regression to adjust for prognostic factors and competing risk of death.

Results: A total of 268 patients were included in the analysis (66.4% men; median age, 60.7 years [range, 26.9-81.1 years]); 154 (57.5%) underwent SRS and 114 (42.5%) underwent surgical resection. Median follow-up time was 39.9 months (range, 26.0-1982.0 months). Compared with the SRS group, patients undergoing surgical resection had larger metastases (median 28 mm [range, 10-40 mm] vs 20 mm [range, 4-40 mm]; P < .001), more frequently had 1 brain metastasis (112 [98.2%] vs 114 [74.0%]; P < .001), and differed in location (parietal, 21 [18.4%] vs 61 [39.6%]; posterior fossa, 30 [26.3%] vs 12 [7.8%]; P < .001). In adjusted models, local recurrence was similar between the SRS and surgical resection groups (hazard ratio [HR], 1.15; 95% CI, 0.72-1.83). However, when stratified by interval, patients with surgical resection had a much higher risk of early (0-3 months) local recurrence compared with those undergoing SRS (HR, 5.94; 95% CI, 1.72-20.45), but their risk decreased with time (HR for 3-6 months, 1.37 [95% CI, 0.64-2.90]; HR for 6-9 months, 0.75 [95% CI, 0.28-2.00]). At 9 months or longer, the surgical resection group had a lower risk of local recurrence (HR, 0.36; 95% CI, 0.14-0.93).

Conclusions And Relevance: In this exploratory analysis, local control of brain metastases was similar between SRS and surgical resection groups. Stereotactic radiosurgery was associated with improved early local control of treated lesions compared with surgical resection, although the relative benefit decreased with time.

Trial Registration: ClinicalTrials.gov Identifier: NCT00002899.
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http://dx.doi.org/10.1001/jamaoncol.2018.4610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439566PMC
February 2019

Responding to the challenges of international collaborations between the east and the west - report of the first JCOG-EORTC symposium and a perspective from young JCOG and EORTC investigators.

Jpn J Clin Oncol 2019 Jan;49(1):96-99

JCOG Data Center/operations office, National Cancer Center.

International/intercontinental collaboration is necessary to set up new innovative clinical trials for cancer treatment. However, the infrastructure, especially Asia-Europe academic partnerships, to enable such collaboration has not been fully structured and differences and similarities between the research groups have not been well studied. In 2015, collaboration started between the biggest cancer research organizations in Asia and EU, Japan Clinical Oncology Group (JCOG) and European Organisation for Research and Treatment of Cancer (EORTC). Following the first pilot collaboration study, the first scientific symposium took place in December 2017 in Tokyo. Before the symposium, a working visit for EORTC investigators from the Early Career Investigator initiative (ECI), willing to develop projects within the JCOG-EORTC partnership, was held. In addition to the digest of the working visit and symposium, we aimed to describe the differences and similarities between the two groups and to identify key factors for collaboration from the perspective of the young investigators of the networks. These findings are described in this article.
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http://dx.doi.org/10.1093/jjco/hyy155DOI Listing
January 2019

Association of Gleason Grade With Androgen Deprivation Therapy Duration and Survival Outcomes: A Systematic Review and Patient-Level Meta-analysis.

JAMA Oncol 2019 01;5(1):91-96

Department of Radiation Oncology, University of California, Los Angeles, Los Angeles.

Importance: Androgen deprivation therapy (ADT) improves survival outcomes in patients with high-risk prostate cancer (PCa) treated with radiotherapy (RT). Whether this benefit differs between patients with Gleason grade group (GG) 4 (formerly Gleason score 8) and GG 5 (formerly Gleason score 9-10) disease remains unknown.

Objective: To determine whether the effectiveness of ADT duration varies between patients with GG 4 vs GG 5 PCa.

Design, Setting, And Participants: Traditional and network individual patient data meta-analyses of 992 patients (593 GG 4 and 399 GG 5) who were enrolled in 6 randomized clinical trials were carried out.

Main Outcomes And Measures: Multivariable Cox proportional hazard models were used to obtain hazard ratio (HR) estimates of ADT duration effects on overall survival (OS) and distant metastasis-free survival (DMFS). Cause-specific competing risk models were used to estimate HRs for cancer-specific survival (CSS). The interaction of ADT with GS was incorporated into the multivariable models. Traditional and network meta-analysis frameworks were used to compare outcomes of patients treated with RT alone, short-term ADT (STADT), long-term ADT (LTADT), and lifelong ADT.

Results: Five hundred ninety-three male patients (mean age, 70 years; range, 43-88 years) with GG 4 and 399 with GG 5 were identified. Median follow-up was 6.4 years. Among GG 4 patients, LTADT and STADT improved OS over RT alone (HR, 0.43; 95% CI, 0.26-0.70 and HR, 0.59; 95% CI, 0.38-0.93, respectively; P = .03 for both), whereas lifelong ADT did not (HR, 0.84; 95% CI, 0.54-1.30; P = .44). Among GG 5 patients, lifelong ADT improved OS (HR, 0.48; 95% CI, 0.31-0.76; P = .04), whereas neither LTADT nor STADT did (HR, 0.80; 95% CI, 0.45-1.44 and HR, 1.13; 95% CI, 0.69-1.87; P = .45 and P = .64, respectively). Among all patients, and among those receiving STADT, GG 5 patients had inferior OS compared with GG 4 patients (HR, 1.25; 95% CI, 1.07-1.47 and HR, 1.40; 95% CI, 1.05-1.88, respectively; P = .02). There was no significant OS difference between GG 5 and GG 4 patients receiving LTADT or lifelong ADT (HR, 1.21; 95% CI, 0.89-1.65 and HR, 0.85; 95% CI, 0.53-1.37; P = .23 and P = .52, respectively).

Conclusions And Relevance: These data suggest that prolonged durations of ADT improve survival outcomes in both GG 4 disease and GG 5 disease, albeit with different optimal durations. Strategies to maintain the efficacy of ADT while minimizing its duration (potentially with enhanced potency agents) should be investigated.
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http://dx.doi.org/10.1001/jamaoncol.2018.3732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440243PMC
January 2019

Use of modern imaging methods to facilitate trials of metastasis-directed therapy for oligometastatic disease in prostate cancer: a consensus recommendation from the EORTC Imaging Group.

Lancet Oncol 2018 10 1;19(10):e534-e545. Epub 2018 Oct 1.

Cancer Research UK Imaging Centre, The Institute of Cancer Research and Royal Marsden Hospital-Sutton, UK.

Oligometastatic disease represents a clinical and anatomical manifestation between localised and polymetastatic disease. In prostate cancer, as with other cancers, recognition of oligometastatic disease enables focal, metastasis-directed therapies. These therapies potentially shorten or postpone the use of systemic treatment and can delay further metastatic progression, thus increasing overall survival. Metastasis-directed therapies require imaging methods that definitively recognise oligometastatic disease to validate their efficacy and reliably monitor response, particularly so that morbidity associated with inappropriately treating disease subsequently recognised as polymetastatic can be avoided. In this Review, we assess imaging methods used to identify metastatic prostate cancer at first diagnosis, at biochemical recurrence, or at the castration-resistant stage. Standard imaging methods recommended by guidelines have insufficient diagnostic accuracy for reliably diagnosing oligometastatic disease. Modern imaging methods that use PET-CT with tumour-specific radiotracers (choline or prostate-specific membrane antigen ligand), and increasingly whole-body MRI with diffusion-weighted imaging, allow earlier and more precise identification of metastases. The European Organisation for Research and Treatment of Cancer (EORTC) Imaging Group suggests clinical algorithms to integrate modern imaging methods into the care pathway at the various stages of prostate cancer to identify oligometastatic disease. The EORTC proposes clinical trials that use modern imaging methods to evaluate the benefits of metastasis-directed therapies.
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http://dx.doi.org/10.1016/S1470-2045(18)30571-0DOI Listing
October 2018

Statistical analysis of patient-reported outcome data in randomised controlled trials of locally advanced and metastatic breast cancer: a systematic review.

Lancet Oncol 2018 09;19(9):e459-e469

European Organisation for Research and Treatment of Cancer, Brussels, Belgium.

Although patient-reported outcomes (PROs), such as health-related quality of life, are important endpoints in randomised controlled trials (RCTs), there is little consensus about the analysis, interpretation, and reporting of these data. We did a systematic review to assess the variability, quality, and standards of PRO data analyses in advanced breast cancer RCTs. We searched PubMed for English language articles published in peer-reviewed journals between Jan 1, 2001, and Oct 30, 2017. Eligible articles were those that reported PRO results from RCTs of adult patients with advanced breast cancer receiving anti-cancer treatments with reported sample sizes of at least 50 patients-66 RCTs met the selection criteria. Only eight (12%) RCTs reported a specific PRO research hypothesis. Heterogeneity in the statistical methods used to assess PRO data was observed, with a mixture of longitudinal and cross-sectional techniques. Not all articles addressed the problem of multiple testing. Fewer than half of RCTs (28 [42%]) reported the clinical significance of their findings. 48 (73%) did not report how missing data were handled. Our systematic review shows a need to improve standards in the analysis, interpretation, and reporting of PRO data in cancer RCTs. Lack of standardisation makes it difficult to draw robust conclusions and compare findings across trials. The Setting International Standards in the Analyzing Patient-Reported Outcomes and Quality of Life Data Consortium was set up to address this need and develop recommendations on the analysis of PRO data in RCTs.
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http://dx.doi.org/10.1016/S1470-2045(18)30418-2DOI Listing
September 2018