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).
Date
2022-10-14Author
Ma, TM
Chu, F-I
Sandler, H
Feng, FY
Efstathiou, JA
Jones, CU
Roach, M
Rosenthal, SA
Pisansky, T
Michalski, JM
Bolla, M
de Reijke, TM
Maingon, P
Neven, A
Denham, J
Steigler, A
Joseph, D
Nabid, A
Souhami, L
Carrier, N
Incrocci, L
Heemsbergen, W
Pos, FJ
Sydes, MR
Dearnaley, DP
Tree, AC
Syndikus, I
Hall, E
Cruickshank, C
Malone, S
Roy, S
Sun, Y
Zaorsky, NG
Nickols, NG
Reiter, RE
Rettig, MB
Steinberg, ML
Reddy, VK
Xiang, M
Romero, T
Spratt, DE
Kishan, AU
Meta-analysis of Randomized trials in Cancer of the Prostate MARCAP Consortium investigators,
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Distant metastasis
Local control
Local failure
Pooled analysis
Prostate cancer
Radiation therapy
Research team
Clinic Acad RT Dearnaley
Clin Trials & Stats Unit
Language
eng
Date accepted
2022-07-14
License start date
2022-08-04
Citation
European Urology, 2022, 82 (5), pp. S0302-2838(22)02523-4 -
Publisher
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