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)

Meta-analysis of Randomized trials in Cancer of the Prostate MARCAP Consortium investigators, Ting Martin Ma, Fang I. Chu, Howard Sandler, Felix Y. Feng, Jason A. Efstathiou, Christopher U. Jones, Mack Roach, Seth A. Rosenthal, Thomas Pisansky, Jeff M. Michalski, Michel Bolla, Theo M. de Reijke, Philippe Maingon, Anouk Neven, James Denham, Allison Steigler, David Joseph, Abdenour Nabid, Luis SouhamiNathalie Carrier, Luca Incrocci, Wilma Heemsbergen, Floris J. Pos, Matthew R. Sydes, David P. Dearnaley, Alison C. Tree, Isabel Syndikus, Emma Hall, Clare Cruickshank, Shawn Malone, Soumyajit Roy, Yilun Sun, Nicholas G. Zaorsky, Nicholas G. Nickols, Robert E. Reiter, Matthew B. Rettig, Michael L. Steinberg, Vishruth K. Reddy, Michael Xiang, Tahmineh Romero, Daniel E. Spratt, Amar U. Kishan*

*Corresponding author for this work

Research output: Contribution to journalReview articleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)487-498
Number of pages12
JournalEuropean Urology
Volume82
Issue number5
DOIs
Publication statusPublished - Nov 2022

Bibliographical note

Funding/Support and role of the sponsor: Funding support for this study comes from the Prostate Cancer Foundation and ASTRO to Amar U. Kishan. Amar U. Kishan also thanks generous donations from the DeSilva, McCarrick, and Bershad families.

Publisher Copyright: © 2022 The Author(s)

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