Androgen deprivation therapy use and duration with definitive radiotherapy for localised prostate cancer: an individual patient data meta-analysis

Amar U Kishan; Yilun Sun; Holly Hartman; Thomas M Pisansky; Michel Bolla; Anouk Neven; Allison Steigler; James W Denham; Felix Y Feng; Almudena Zapatero; John G Armstrong; Abdenour Nabid; Nathalie Carrier; Luis Souhami; Mary T Dunne; Jason A Efstathiou; Howard M Sandler; Araceli Guerrero; David Joseph; Philippe Maingon; Theo M de Reijke; Xavier Maldonado; Ting Martin Ma; Tahmineh Romero; Xiaoyan Wang; Matthew B Rettig; Robert E Reiter; Nicholas G Zaorsky; Michael L Steinberg; Nicholas G Nickols; Angela Y Jia; Jorge A Garcia; Daniel E Spratt; MARCAP Consortium group

doi:10.1016/S1470-2045(21)00705-1

Androgen deprivation therapy use and duration with definitive radiotherapy for localised prostate cancer: an individual patient data meta-analysis

Lancet Oncol. 2022 Feb;23(2):304-316. doi: 10.1016/S1470-2045(21)00705-1. Epub 2022 Jan 17.

Authors

Amar U Kishan¹, Yilun Sun², Holly Hartman², Thomas M Pisansky³, Michel Bolla⁴, Anouk Neven⁵, Allison Steigler⁶, James W Denham⁶, Felix Y Feng⁷, Almudena Zapatero⁸, John G Armstrong⁹, Abdenour Nabid¹⁰, Nathalie Carrier¹¹, Luis Souhami¹², Mary T Dunne⁹, Jason A Efstathiou¹³, Howard M Sandler¹⁴, Araceli Guerrero¹⁵, David Joseph¹⁶, Philippe Maingon¹⁷, Theo M de Reijke¹⁸, Xavier Maldonado¹⁹, Ting Martin Ma²⁰, Tahmineh Romero²¹, Xiaoyan Wang²¹, Matthew B Rettig²², Robert E Reiter²³, Nicholas G Zaorsky²⁴, Michael L Steinberg²⁰, Nicholas G Nickols²⁵, Angela Y Jia²⁶, Jorge A Garcia²⁷, Daniel E Spratt²⁸; MARCAP Consortium group

Affiliations

¹ Department of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA; Department of Urology, University of California Los Angeles, Los Angeles, CA, USA. Electronic address: [email protected].
² Department of Population 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.
³ Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
⁴ Radiotherapy Department, University Hospital, Grenoble, France.
⁵ Statistics Department, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium.
⁶ School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia.
⁷ Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
⁸ Hospital Universitario de la Princesa, Madrid, Spain.
⁹ Cancer Trials Ireland and St Luke's Radiation Oncology Network, Dublin, Ireland.
¹⁰ Department of Radiation Oncology, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada.
¹¹ Clinical Research Center, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada.
¹² Department of Radiation Oncology, McGill University Health Centre, Montréal, QC, Canada.
¹³ Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.
¹⁴ Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁵ Hospital Son Espases, Palma de Mallorca, Spain.
¹⁶ Department of Medicine and Surgery, University of Western Australia, Perth, WA, Australia.
¹⁷ Department of Oncology, Hematology, and Supportive Care, Sorbonne University, Paris, France.
¹⁸ Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
¹⁹ Hospital Universitari Vall d'Hebron, Barcelona, Spain.
²⁰ Department of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA.
²¹ Division of General Internal Medicine and Health Services Research, University of California Los Angeles, Los Angeles, CA, USA.
²² Department of Urology, University of California Los Angeles, Los Angeles, CA, USA; Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
²³ Department of Urology, University of California Los Angeles, Los Angeles, CA, USA.
²⁴ Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
²⁵ Department of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA; Department of Urology, University of California Los Angeles, Los Angeles, CA, USA.
²⁶ Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²⁷ Division of Oncology, Seidman Cancer Center, Cleveland, OH, USA.
²⁸ Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA. Electronic address: [email protected].

PMID: 35051385
DOI: 10.1016/S1470-2045(21)00705-1

Abstract

Background: Randomised trials have investigated various androgen deprivation therapy (ADT) intensification strategies in men receiving radiotherapy for the treatment of prostate cancer. This individual patient data meta-analysis of relevant randomised trials aimed to quantify the benefit of these interventions in aggregate and in clinically relevant subgroups.

Methods: For this meta-analysis, we performed a systematic literature search in MEDLINE, Embase, trial registries, the Web of Science, Scopus, and conference proceedings to identify trials with results published in English between Jan 1, 1962, and Dec 30, 2020. Multicentre randomised trials were eligible if they evaluated the use or prolongation of ADT (or both) in men with localised prostate cancer receiving definitive radiotherapy, reported or collected distant metastasis and survival data, and used ADT for a protocol-defined finite duration. The Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium was accessed to obtain individual patient data from randomised trials. The primary outcome was metastasis-free survival. Hazard ratios (HRs) were obtained through stratified Cox models for ADT use (radiotherapy alone vs radiotherapy plus ADT), neoadjuvant ADT extension (ie, extension of total ADT duration in the neoadjuvant setting from 3-4 months to 6-9 months), and adjuvant ADT prolongation (ie, prolongation of total ADT duration in the adjuvant setting from 4-6 months to 18-36 months). Formal interaction tests between interventions and metastasis-free survival were done for prespecified subgroups defined by age, National Comprehensive Cancer Network (NCCN) risk group, and radiotherapy dose. This meta-analysis is registered with PROSPERO, CRD42021236855.

Findings: Our search returned 12 eligible trials that provided individual patient data (10 853 patients) with a median follow-up of 11·4 years (IQR 9·0-15·0). The addition of ADT to radiotherapy significantly improved metastasis-free survival (HR 0·83 [95% CI 0·77-0·89], p<0·0001), as did adjuvant ADT prolongation (0·84 [0·78-0·91], p<0·0001), but neoadjuvant ADT extension did not (0·95 [0·83-1·09], p=0·50). Treatment effects were similar irrespective of radiotherapy dose, patient age, or NCCN risk group.

Interpretation: Our findings provide the strongest level of evidence so far to the magnitude of the benefit of ADT treatment intensification with radiotherapy for men with localised prostate cancer. Adding ADT and prolonging the portion of ADT that follows radiotherapy is associated with improved metastasis-free survival in men, regardless of risk group, age, and radiotherapy dose delivered; however, the magnitude of the benefit could vary and shared decision making with patients is recommended.

Funding: University Hospitals Seidman Cancer Center, Prostate Cancer Foundation, and the American Society for Radiation Oncology.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Age Factors
Aged
Aged, 80 and over
Androgen Antagonists / therapeutic use*
Humans
Male
Middle Aged
Prostatic Neoplasms / mortality
Prostatic Neoplasms / pathology
Prostatic Neoplasms / therapy*
Radiotherapy Dosage
Time Factors

Substances

Androgen Antagonists