Local Failure and Survival After Definitive Radiotherapy for Aggressive Prostate Cancer: An Individual Patient-level Meta-analysis of Six Randomized Trials

Amar U Kishan; Fang-I Chu; Christopher R King; Wendy Seiferheld; Daniel E Spratt; Phuoc Tran; Xiaoyan Wang; Stephanie E Pugh; Kiri A Sandler; Michel Bolla; Philippe Maingon; Theo De Reijke; Nicholas G Nickols; Matthew Rettig; Alexandra Drakaki; Sandy T Liu; Robert E Reiter; Albert J Chang; Felix Y Feng; Dipti Sajed; Paul L Nguyen; Patrick A Kupelian; Michael L Steinberg; Paul C Boutros; David Elashoff; Laurence Collette; Howard M Sandler

doi:10.1016/j.eururo.2019.10.008

Local Failure and Survival After Definitive Radiotherapy for Aggressive Prostate Cancer: An Individual Patient-level Meta-analysis of Six Randomized Trials

Eur Urol. 2020 Feb;77(2):201-208. doi: 10.1016/j.eururo.2019.10.008. Epub 2019 Nov 10.

Authors

Amar U Kishan¹, Fang-I Chu², Christopher R King², Wendy Seiferheld³, Daniel E Spratt⁴, Phuoc Tran⁵, Xiaoyan Wang⁶, Stephanie E Pugh³, Kiri A Sandler², Michel Bolla⁷, Philippe Maingon⁸, Theo De Reijke⁹, Nicholas G Nickols¹⁰, Matthew Rettig¹¹, Alexandra Drakaki¹², Sandy T Liu¹², Robert E Reiter¹³, Albert J Chang², Felix Y Feng¹⁴, Dipti Sajed¹⁵, Paul L Nguyen¹⁶, Patrick A Kupelian², Michael L Steinberg², Paul C Boutros¹⁷, David Elashoff⁶, Laurence Collette¹⁸, Howard M Sandler¹⁹

Affiliations

¹ Department of Radiation Oncology, University of California, Los Angeles, CA, USA; Department of Urology, University of California, Los Angeles, CA, USA. Electronic address: aukishan@mednet.ucla.edu.
² Department of Radiation Oncology, University of California, Los Angeles, CA, USA.
³ NRG Oncology Statistics and Data Management Center, Philadelphia, PA, USA.
⁴ Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
⁵ Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Department of General Internal Medicine and Health Services Research, University of California, Los Angeles, CA, USA.
⁷ Department of Radiation Oncology, Centre Hospitalier Universitaire de Grenoble, Grenoble, France.
⁸ Centre Georges-François Leclerc, Dijon, France; Sorbonne Université Paris, Paris, France.
⁹ Department of Urology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
¹⁰ Department of Radiation Oncology, University of California, Los Angeles, CA, USA; Department of Radiation Oncology, Veteran Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
¹¹ Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Division of Hematology and Oncology, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
¹² Division of Hematology and Oncology, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
¹³ Department of Urology, University of California, Los Angeles, CA, USA.
¹⁴ Departments of Radiation Oncology, Urology, and Medicine, University of California, San Francisco, CA, USA.
¹⁵ Department of Pathology, University of California, Los Angeles, CA, USA.
¹⁶ Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
¹⁷ Department of Urology, University of California, Los Angeles, CA, USA; Department of Human Genetics, University of California, Los Angeles, CA, USA.
¹⁸ European Organization for Research and Treatment of Cancer Headquarters, Brussels, Belgium.
¹⁹ Department of Radiation Oncology, Cedars Sinai, Los Angeles, CA, USA.

Abstract

Background: The importance of local failure (LF) after treatment of high-grade prostate cancer (PCa) with definitive radiotherapy (RT) remains unknown.

Objective: To evaluate the clinical implications of LF after definitive RT.

Design, setting, and participants: Individual patient data meta-analysis of 992 patients (593 Gleason grade group [GG] 4 and 399 GG 5) enrolled in six randomized clinical trials.

Outcome measurements and statistical analysis: Multivariable Cox proportional hazard models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), and distant metastasis (DM)-free survival (DMFS) and LF as a time-dependent covariate. Markov proportional hazard models were developed to evaluate the impact of specific transitions between disease states on these endpoints.

Results and limitations: Median follow-up was 6.4 yr overall and 7.2 yr for surviving patients. LF was significantly associated with OS (hazard ratio [HR] 1.70 [95% confidence interval {CI} 1.37-2.10]), PCSS (3.10 [95% CI 2.33-4.12]), and DMFS (HR 1.92 [95% CI 1.54-2.39]), p < 0.001 for all). Patients who had not transitioned to the LF state had a significantly lower hazard of transitioning to a PCa-specific death state than those who transitioned to the LF state (HR 0.13 [95% CI 0.04-0.41], p < 0.001). Additionally, patients who transitioned to the LF state had a greater hazard of DM or death (HR 2.46 [95% CI 1.22-4.93], p = 0.01) than those who did not.

Conclusions: LF is an independent prognosticator of OS, PCSS, and DMFS in high-grade localized PCa and a subset of DM events that are anteceded by LF events. LF events warrant consideration for intervention, potentially suggesting a rationale for upfront treatment intensification. However, whether these findings apply to all men or just those without significant comorbidity remains to be determined.

Patient summary: Men who experience a local recurrence of high-grade prostate cancer after receiving upfront radiation therapy are at significantly increased risks of developing metastases and dying of prostate cancer.

Keywords: High grade; Local failure; Radiotherapy.

Publication types

Meta-Analysis

MeSH terms

Humans
Male
Neoplasm Grading
Prostatic Neoplasms / mortality*
Prostatic Neoplasms / pathology
Prostatic Neoplasms / radiotherapy*
Randomized Controlled Trials as Topic
Treatment Failure

Abstract

Publication types

MeSH terms

Grants and funding