Meta-Analysis

. 2020 Feb;77(2):201-208.

doi: 10.1016/j.eururo.2019.10.008. Epub 2019 Nov 10.

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

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.

PMID: 31718822
PMCID: PMC7008470
DOI: 10.1016/j.eururo.2019.10.008

Meta-Analysis

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

Amar U Kishan et al. Eur Urol. 2020 Feb.

. 2020 Feb;77(2):201-208.

doi: 10.1016/j.eururo.2019.10.008. Epub 2019 Nov 10.

Authors

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.

PMID: 31718822
PMCID: PMC7008470
DOI: 10.1016/j.eururo.2019.10.008

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.

PubMed Disclaimer

Conflict of interest statement

Financial disclosures: 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: None.

Figures

**Fig. 1 –**
Schematic depiction of the (A) four-state and (B) three-state models developed to evaluate various disease states experienced and traversed by patients with high-grade localized prostate cancer. The four-state model was designed to evaluate the outcomes PCSS and OS; patients who did not experience a PCa-specific mortality event were coded as “censored” for PCSS. OS = overall survival; PCa = prostate cancer; PCSS = PCa-specific survival.

**Fig. 2 –**
Hazard rate of distant metastasis development in 2-yr intervals in patients with local control (LC, blue) and local failure (LF, red). Here, these are treated as time-independent variables, meaning that all patients with LF at any point (before or after distant metastasis development) are included in the LF group, whereas patients in the LC group never had an LF event. ADT = androgen deprivation therapy; DM = distant metastasis; LTADT = long-term ADT; RT = radiotherapy; STADT = short-term ADT.

See this image and copyright information in PMC

Comment in

Local Failure in High-grade Prostate Cancer: An Elusive but Important Outcome and Target for Clinical Trials.
Alibhai SMH, Warde P. Alibhai SMH, et al. Eur Urol. 2020 Feb;77(2):209-210. doi: 10.1016/j.eururo.2019.11.013. Epub 2019 Nov 29. Eur Urol. 2020. PMID: 31787428 No abstract available.
Local control matters.
Levitin RB, Hamstra DA. Levitin RB, et al. Transl Androl Urol. 2020 Jun;9(3):991-996. doi: 10.21037/tau-2020-06. Transl Androl Urol. 2020. PMID: 32676381 Free PMC article. No abstract available.
Implications of local failure on overall prognosis in aggressive prostate cancer.
Mula-Hussain L, Roy S, Malone S. Mula-Hussain L, et al. Transl Androl Urol. 2020 Jun;9(3):1001-1005. doi: 10.21037/tau-2020-04. Transl Androl Urol. 2020. PMID: 32676383 Free PMC article. No abstract available.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

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Medical