TY - JOUR
T1 - Local Failure Events in Prostate Cancer Treated with Radiotherapy
T2 - A Pooled Analysis of 18 Randomized Trials from the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium (LEVIATHAN)
AU - Ma, Ting Martin
AU - Chu, Fang I.
AU - Sandler, Howard
AU - Feng, Felix Y.
AU - Efstathiou, Jason A.
AU - Jones, Christopher U.
AU - Roach, Mack
AU - Rosenthal, Seth A.
AU - Pisansky, Thomas
AU - Michalski, Jeff M.
AU - Bolla, Michel
AU - de Reijke, Theo M.
AU - Maingon, Philippe
AU - Neven, Anouk
AU - Denham, James
AU - Steigler, Allison
AU - Joseph, David
AU - Nabid, Abdenour
AU - Souhami, Luis
AU - Carrier, Nathalie
AU - Incrocci, Luca
AU - Heemsbergen, Wilma
AU - Pos, Floris J.
AU - Sydes, Matthew R.
AU - Dearnaley, David P.
AU - Tree, Alison C.
AU - Syndikus, Isabel
AU - Hall, Emma
AU - Cruickshank, Clare
AU - Malone, Shawn
AU - Roy, Soumyajit
AU - Sun, Yilun
AU - Zaorsky, Nicholas G.
AU - Nickols, Nicholas G.
AU - Reiter, Robert E.
AU - Rettig, Matthew B.
AU - Steinberg, Michael L.
AU - Reddy, Vishruth K.
AU - Xiang, Michael
AU - Romero, Tahmineh
AU - Spratt, Daniel E.
AU - Kishan, Amar U.
AU - Meta-analysis of Randomized trials in Cancer of the Prostate MARCAP Consortium investigators
N1 - Funding Information:
Financial disclosures: Alison Tree acknowledges support from Cancer Research UK (C33589/A28284 and C7224/A28724) and the National Institute for Health Research (NIHR) Cancer Research Network. This project represents independent research supported by the National Institute for Health research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. Amar U. Kishan certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Amar U. Kishan reports funding support from grant P50CA09213 from the Prostate Cancer National Institutes of Health Specialized Programs of Research Excellence, grant W81XWH-22-1-0044 from the Department of Defense, grant RSD1836 from the Radiological Society of North America, the STOP Cancer Organization, the Jonsson Comprehensive Cancer Center, and the Prostate Cancer Foundation; personal fees from Varian Medical Systems, Inc., ViewRay Inc., and Intelligent Automation, Inc.; and research support from ViewRay, Inc., the American Society for Radiation Oncology (ASTRO), the Prostate Cancer Foundation, and the Jonsson Comprehensive Cancer Center, all outside the submitted work. Nicholas G. Zaorsky is supported by the National Institutes of Health Grant LRP 1 L30 CA231572-01 and the American Cancer Society – Tri State CEOs Against Cancer Clinician Scientist Development Grant CSDG-20-013-01-CCE, and received remuneration from the American College of Radiation Oncology for prostate cancer chart review and accreditation of radiation oncology facilities nationally, all outside the submitted work. Daniel E. Spratt declares personal fees from Janssen, AstraZeneca, and BlueEarth, outside the submitted work. All other authors have no conflict of interest to declare.
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/11
Y1 - 2022/11
N2 - 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.
AB - 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.
KW - Distant metastasis
KW - Local control
KW - Local failure
KW - Pooled analysis
KW - Prostate cancer
KW - Radiation therapy
UR - http://www.scopus.com/inward/record.url?scp=85136062470&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/35934601
U2 - 10.1016/j.eururo.2022.07.011
DO - 10.1016/j.eururo.2022.07.011
M3 - Review article
C2 - 35934601
SN - 0302-2838
VL - 82
SP - 487
EP - 498
JO - European Urology
JF - European Urology
IS - 5
ER -