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Local Failure Events in Prostate Cancer Treated with Radiotherapy: A Pooled Analysis of 18 Randomized Trials from the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium (LEVIATHAN).
Ma, Ting Martin; Chu, Fang-I; Sandler, Howard; Feng, Felix Y; Efstathiou, Jason A; Jones, Christopher U; Roach, Mack; Rosenthal, Seth A; Pisansky, Thomas; Michalski, Jeff M; Bolla, Michel; de Reijke, Theo M; Maingon, Philippe; Neven, Anouk; Denham, James; Steigler, Allison; Joseph, David; Nabid, Abdenour; Souhami, Luis; Carrier, Nathalie; Incrocci, Luca; Heemsbergen, Wilma; Pos, Floris J; Sydes, Matthew R; Dearnaley, David P; Tree, Alison C; Syndikus, Isabel; Hall, Emma; Cruickshank, Clare; Malone, Shawn; Roy, Soumyajit; Sun, Yilun; Zaorsky, Nicholas G; Nickols, Nicholas G; Reiter, Robert E; Rettig, Matthew B; Steinberg, Michael L; Reddy, Vishruth K; Xiang, Michael; Romero, Tahmineh; Spratt, Daniel E; Kishan, Amar U.
Affiliation
  • Ma TM; Depart of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA.
  • Chu FI; Depart of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA.
  • Sandler H; Department of Radiation Oncology, Cedars Sinai, Los Angeles, CA, USA.
  • Feng FY; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
  • Efstathiou JA; Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Jones CU; Department of Radiation Oncology, Sutter Medical Group, Roseville, CA, USA.
  • Roach M; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
  • Rosenthal SA; Department of Radiation Oncology, Sutter Medical Group, Roseville, CA, USA.
  • Pisansky T; Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
  • Michalski JM; Department of Radiation Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
  • Bolla M; Department of Radiation Therapy, CHU Grenoble, Grenoble, France.
  • de Reijke TM; Department of Urology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
  • Maingon P; Department of Radiation Oncology, Centre Georges François Leclerc, University of Burgundy, Dijon, Burgundy, France.
  • Neven A; Luxembourg Institute of Health, Competence Center for Methodology and Statistics, Strassen, Luxembourg.
  • Denham J; School of Medicine and Public Health, Faculty of Health and Medicine University of Newcastle, Newcastle, NSW, Australia.
  • Steigler A; School of Medicine and Public Health, Faculty of Health and Medicine University of Newcastle, Newcastle, NSW, Australia.
  • Joseph D; Department of Surgery, University of Western Australia.
  • Nabid A; Department of Radiation Oncology, Centre Hospitaler Universitaire de Sherbrooke, Sherbrooke, QC, Canada.
  • Souhami L; Department of Radiation Oncology, McGill University Health Centre, Montreal, QC, Canada.
  • Carrier N; Centre de recherche clinique, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada.
  • Incrocci L; Department of Radiation Oncology, Erasmus Medical Center, Rotterdam, The Netherlands.
  • Heemsbergen W; Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Pos FJ; Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Sydes MR; MRC Clinical Trials Unit at UCL, University College London, London, UK.
  • Dearnaley DP; Academic Urology Unit, Royal Marsden Hospital, London, UK; The Institute of Cancer Research, London, UK.
  • Tree AC; The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, London, UK.
  • Syndikus I; Clatterbridge Cancer Centre, Wirral, UK.
  • Hall E; The Institute of Cancer Research, London, UK.
  • Cruickshank C; The Institute of Cancer Research, London, UK.
  • Malone S; The Ottawa Hospital Cancer Centre, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Roy S; Department of Radiation Oncology, Rush University Medical Center, Chicago, IL, USA.
  • Sun Y; Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
  • Zaorsky NG; Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
  • Nickols NG; Depart of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA.
  • Reiter RE; Department of Urology, University of California Los Angeles, Los Angeles, CA, USA.
  • Rettig MB; Department of Urology, University of California Los Angeles, Los Angeles, CA, USA; Division of Hematology/Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
  • Steinberg ML; Depart of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA.
  • Reddy VK; Depart of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA.
  • Xiang M; Depart of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA.
  • Romero T; Department of Medicine Statistics Core, University of California Los Angeles, Los Angeles, CA, USA.
  • Spratt DE; Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
  • Kishan AU; Depart of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA. Electronic address: Aukishan@mednet.ucla.edu.
Eur Urol ; 82(5): 487-498, 2022 11.
Article in En | MEDLINE | ID: mdl-35934601
CONTEXT: The prognostic importance of local failure after definitive radiotherapy (RT) in National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa) patients remains unclear. OBJECTIVE: To evaluate the prognostic impact of local failure and the kinetics of distant metastasis following RT. EVIDENCE ACQUISITION: A pooled analysis was performed on individual patient data of 12 533 PCa (6288 high-risk and 6245 intermediate-risk) patients enrolled in 18 randomized trials (conducted between 1985 and 2015) within the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium. Multivariable Cox proportional hazard (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), distant metastasis-free survival (DMFS), and local failure as a time-dependent covariate. Markov PH models were developed to evaluate the impact of specific transition states. EVIDENCE SYNTHESIS: The median follow-up was 11 yr. There were 795 (13%) local failure events and 1288 (21%) distant metastases for high-risk patients and 449 (7.2%) and 451 (7.2%) for intermediate-risk patients, respectively. For both groups, 81% of distant metastases developed from a clinically relapse-free state (cRF state). Local failure was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06-1.30), PCSS (HR 2.02, 95% CI 1.75-2.33), and DMFS (HR 1.94, 95% CI 1.75-2.15, p < 0.01 for all) in high-risk patients. Local failure was also significantly associated with DMFS (HR 1.57, 95% CI 1.36-1.81) but not with OS in intermediate-risk patients. Patients without local failure had a significantly lower HR of transitioning to a PCa-specific death state than those who had local failure (HR 0.32, 95% CI 0.21-0.50, p < 0.001). At later time points, more distant metastases emerged after a local failure event for both groups. CONCLUSIONS: Local failure is an independent prognosticator of OS, PCSS, and DMFS in high-risk and of DMFS in intermediate-risk PCa. Distant metastasis predominantly developed from the cRF state, underscoring the importance of addressing occult microscopic disease. However a "second wave" of distant metastases occurs subsequent to local failure events, and optimization of local control may reduce the risk of distant metastasis. PATIENT SUMMARY: Among men receiving definitive radiation therapy for high- and intermediate-risk prostate cancer, about 10% experience local recurrence, and they are at significantly increased risks of further disease progression. About 80% of patients who develop distant metastasis do not have a detectable local recurrence preceding it.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Neoplasm Recurrence, Local Type of study: Observational_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limits: Humans / Male Language: En Journal: Eur Urol Year: 2022 Document type: Article Affiliation country: United States Country of publication: Switzerland
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Neoplasm Recurrence, Local Type of study: Observational_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limits: Humans / Male Language: En Journal: Eur Urol Year: 2022 Document type: Article Affiliation country: United States Country of publication: Switzerland