Ting Martin Ma1, Fang-I Chu1, Howard Sandler2, Felix Y Feng3, Jason A Efstathiou4, Christopher U Jones5, Mack Roach3, Seth A Rosenthal5, Thomas Pisansky6, Jeff M Michalski7, Michel Bolla8, Theo M de Reijke9, Philippe Maingon10, Anouk Neven11, James Denham12, Allison Steigler12, David Joseph13, Abdenour Nabid14, Luis Souhami15, Nathalie Carrier16, Luca Incrocci17, Wilma Heemsbergen18, Floris J Pos18, Matthew R Sydes19, David P Dearnaley20, Alison C Tree21, Isabel Syndikus22, Emma Hall23, Clare Cruickshank23, Shawn Malone24, Soumyajit Roy25, Yilun Sun26, Nicholas G Zaorsky27, Nicholas G Nickols1, Robert E Reiter28, Matthew B Rettig29, Michael L Steinberg1, Vishruth K Reddy1, Michael Xiang1, Tahmineh Romero30, Daniel E Spratt27, Amar U Kishan31. 1. Depart of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA. 2. Department of Radiation Oncology, Cedars Sinai, Los Angeles, CA, USA. 3. Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA. 4. Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. 5. Department of Radiation Oncology, Sutter Medical Group, Roseville, CA, USA. 6. Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA. 7. Department of Radiation Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA. 8. Department of Radiation Therapy, CHU Grenoble, Grenoble, France. 9. Department of Urology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands. 10. Department of Radiation Oncology, Centre Georges François Leclerc, University of Burgundy, Dijon, Burgundy, France. 11. Luxembourg Institute of Health, Competence Center for Methodology and Statistics, Strassen, Luxembourg. 12. School of Medicine and Public Health, Faculty of Health and Medicine University of Newcastle, Newcastle, NSW, Australia. 13. Department of Surgery, University of Western Australia. 14. Department of Radiation Oncology, Centre Hospitaler Universitaire de Sherbrooke, Sherbrooke, QC, Canada. 15. Department of Radiation Oncology, McGill University Health Centre, Montreal, QC, Canada. 16. Centre de recherche clinique, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada. 17. Department of Radiation Oncology, Erasmus Medical Center, Rotterdam, The Netherlands. 18. Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. 19. MRC Clinical Trials Unit at UCL, University College London, London, UK. 20. Academic Urology Unit, Royal Marsden Hospital, London, UK; The Institute of Cancer Research, London, UK. 21. The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, London, UK. 22. Clatterbridge Cancer Centre, Wirral, UK. 23. The Institute of Cancer Research, London, UK. 24. The Ottawa Hospital Cancer Centre, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. 25. Department of Radiation Oncology, Rush University Medical Center, Chicago, IL, USA. 26. 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. 27. Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA. 28. Department of Urology, University of California Los Angeles, Los Angeles, CA, USA. 29. 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. 30. Department of Medicine Statistics Core, University of California Los Angeles, Los Angeles, CA, USA. 31. Depart of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA. Electronic address: Aukishan@mednet.ucla.edu.
Abstract
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.
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.