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),European Urology

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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)
European Urology ( IF 23.4 ) Pub Date : 2022-08-05 , DOI: 10.1016/j.eururo.2022.07.011
Ting Martin Ma ₁ , Fang-I Chu ₁ , Howard Sandler ₂ , Felix Y Feng ₃ , Jason A Efstathiou ₄ , Christopher U Jones ₅ , Mack Roach ₃ , Seth A Rosenthal ₅ , Thomas Pisansky ₆ , Jeff M Michalski ₇ , Michel Bolla ₈ , Theo M de Reijke ₉ , Philippe Maingon ₁₀ , Anouk Neven ₁₁ , James Denham ₁₂ , Allison Steigler ₁₂ , David Joseph ₁₃ , Abdenour Nabid ₁₄ , Luis Souhami ₁₅ , Nathalie Carrier ₁₆ , Luca Incrocci ₁₇ , Wilma Heemsbergen ₁₈ , Floris J Pos ₁₈ , Matthew R Sydes ₁₉ , David P Dearnaley ₂₀ , Alison C Tree ₂₁ , Isabel Syndikus ₂₂ , Emma Hall ₂₃ , Clare Cruickshank ₂₃ , Shawn Malone ₂₄ , Soumyajit Roy ₂₅ , Yilun Sun ₂₆ , Nicholas G Zaorsky ₂₇ , Nicholas G Nickols ₁ , Robert E Reiter ₂₈ , Matthew B Rettig ₂₉ , Michael L Steinberg ₁ , Vishruth K Reddy ₁ , Michael Xiang ₁ , Tahmineh Romero ₃₀ , Daniel E Spratt ₂₇ , Amar U Kishan ₁ ,

Affiliation

Depart of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA.
Department of Radiation Oncology, Cedars Sinai, Los Angeles, CA, USA.
Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Department of Radiation Oncology, Sutter Medical Group, Roseville, CA, USA.
Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
Department of Radiation Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
Department of Radiation Therapy, CHU Grenoble, Grenoble, France.
Department of Urology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
Department of Radiation Oncology, Centre Georges François Leclerc, University of Burgundy, Dijon, Burgundy, France.
Luxembourg Institute of Health, Competence Center for Methodology and Statistics, Strassen, Luxembourg.
School of Medicine and Public Health, Faculty of Health and Medicine University of Newcastle, Newcastle, NSW, Australia.
Department of Surgery, University of Western Australia.
Department of Radiation Oncology, Centre Hospitaler Universitaire de Sherbrooke, Sherbrooke, QC, Canada.
Department of Radiation Oncology, McGill University Health Centre, Montreal, QC, Canada.
Centre de recherche clinique, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada.
Department of Radiation Oncology, Erasmus Medical Center, Rotterdam, The Netherlands.
Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
MRC Clinical Trials Unit at UCL, University College London, London, UK.
Academic Urology Unit, Royal Marsden Hospital, London, UK; The Institute of Cancer Research, London, UK.
The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, London, UK.
Clatterbridge Cancer Centre, Wirral, UK.
The Institute of Cancer Research, London, UK.
The Ottawa Hospital Cancer Centre, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Department of Radiation Oncology, Rush University Medical Center, Chicago, IL, USA.
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.
Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Department of Urology, University of California Los Angeles, Los Angeles, CA, USA.
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.
Department of Medicine Statistics Core, University of California Los Angeles, Los Angeles, CA, USA.

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.

中文翻译：

前列腺癌放射治疗的局部失败事件：来自前列腺癌联合会 (LEVIATHAN) 随机试验荟萃分析的 18 项随机试验的汇总分析

语境

国家综合癌症网络中高风险前列腺癌 (PCa) 患者根治性放疗 (RT) 后局部失败的预后重要性仍不清楚。

客观的

评估局部失败的预后影响和放疗后远处转移的动力学。

取证

在前列腺癌随机试验的荟萃分析中，对参加 18 项随机试验（在 1985 年至 2015 年间进行）的 12533 名 PCa（6288 名高风险和 6245 名中等风险）患者的个体患者数据进行了汇总分析财团。开发了多变量 Cox 比例风险 (PH) 模型来评估总生存期 (OS)、PCa 特异性生存期 (PCSS)、无远处转移生存期 (DMFS) 和作为时间依赖性协变量的局部失败之间的关系。马尔可夫 PH 模型的开发是为了评估特定过渡态的影响。

证据综合

中位随访时间为 11 年。高危患者有 795 例（13%）局部失败事件和 1288 例（21%）远处转移，中危患者分别有 449 例（7.2%）和 451 例（7.2%）。对于两组，81% 的远处转移是从临床无复发状态（cRF 状态）发展而来的。局部失败与 OS（风险比 [HR] 1.17，95% 置信区间 [CI] 1.06–1.30）、PCSS（HR 2.02，95% CI 1.75–2.33）和 DMFS（HR 1.94，95% CI 1.75）显着相关–2.15，页数 < 0.01 全部）在高危患者中。局部失败也与 DMFS 显着相关（HR 1.57，95% CI 1.36–1.81），但与中危患者的 OS 无关。与局部失败的患者相比，没有局部失败的患者转变为 PCa 特异性死亡状态的 HR 显着较低（HR 0.32，95% CI 0.21–0.50，p < 0.001）。在稍后的时间点，在两组的局部失败事件后出现了更远的转移。