Trials comparing moderately hypofractionated radiotherapy (MHFRT) to conventionally-fractionated radiotherapy (CFRT) for prostate cancer have varied considerably in intent (non-inferiority vs superiority) and MHFRT dose. We compare the efficacy and toxicity profiles of isodose MHFRT and dose-escalated MHFRT.
This was an individual patient data meta-analysis that identified randomised phase 3 trials of CFRT versus MHFRT that had published individual patient-level data on efficacy and late toxicity. A systematic literature search using MEDLINE, Embase, trial registries, the Web of Science, Scopus, and relevant conference proceedings was initially conducted on Dec 15, 2023, and was re-conducted on Jan 8, 2025. Trials that did not publish efficacy data, did not publish late toxicity data, or did not use modern dose radiotherapy (≥70 Gy in 2 Gy equivalents) in the CFRT group were excluded. Individual patient data were provided to MARCAP by study investigators. Three separate meta-analyses were designed to compare efficacy (primary endpoint was progression-free survival), physician-scored late toxicity (co-primary endpoints were late grade 2 or higher genitourinary and late grade 2 or higher gastrointestinal toxic effects), and patient-reported outcomes (co-primary endpoints were clinically-significant decrements in patient-reported urinary or bowel quality of life) between patients receiving CFRT versus MHFRT.
We identified 1696 records for review. Seven phase 3 trials comparing MHFRT with CFRT were eligible for inclusion in our analysis. Individual patient data were obtained from these seven studies (3454 patients from three trials comparing CFRT with isodose MHFRT and 2426 patients from four trials comparing CFRT with dose-escalated MHFRT). At a median follow-up of 5·4 years (IQR 4·6-7·2) for isodose MHFRT and 7·1 years (5·7-8·4) for dose-escalated MHFRT, no differences in progression-free survival were detected (hazard ratio 0·92, 95% CI 0·81-1·05; p=0·21 and 0·94, 0·82-1·09; p=0·43 respectively). No increased odds of grade 2 or higher genitourinary toxic effects were identified for either isodose (odds ratio [OR] 1·16, 95 CI% 0·86-1·57; p=0·32) or dose-escalated MHFRT (1·20, 0·95-1·51; p=0·13). The odds of grade 2 or higher gastrointestinal toxic effects were significantly higher with dose-escalated (OR 1·48, 95% CI 1·14-1·92; p=0·0035) but not isodose MHFRT (1·30, 0·59-2·87; p=0·51). Isodose MHFRT was not found to show different odds of urinary quality-of-life decrement (OR 1·03, 95% CI 0·51-2·09; p=0·93) or bowel quality-of-life decrement (0·76, 0·40-1·43; p=0·39). Dose-escalated MHFRT was associated with greater odds of bowel quality-of-life decrement (OR 1·68, 95% CI 1·07-2·61; p=0·023), but no evidence of greater urinary quality-of-life decrement was found (1·57, 0·87-2·85; p=0·13).
Isodose MHFRT and dose-escalated MHFRT both have similar efficacy compared with CFRT, but dose-escalated MHFRT is associated with higher physician-scored and patient-reported bowel toxicity. Isodose regimens, eg, 60 Gy in 20 fractions, should be the standard MHFRT regimen for localised prostate cancer.
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The Lancet. Oncology. 2025 Mar 17 [Epub ahead of print]
Amar U Kishan, Yilun Sun, Alison C Tree, Emma Hall, David Dearnaley, Charles N Catton, Himanshu R Lukka, Gregory Pond, W Robert Lee, Howard M Sandler, Felix Y Feng, Paul L Nguyen, Luca Incrocci, Wilma Heemsbergen, Floris J Pos, Eric Horwitz, Jessica Karen Wong, Karen E Hoffman, Comron Hassanzadeh, Deborah A Kuban, Stefano Arcangeli, Giuseppe Sanguineti, Stephane Supiot, Gilles Crehange, Igor Latorzeff, Tahmineh Romero Kalbasi, Michael L Steinberg, Luca F Valle, Andrew Loblaw, John Nikitas, Soumyajit Roy, Nicholas G Zaorsky, Angela Y Jia, Daniel E Spratt
Department of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA. Electronic address: ., Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA., Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, Sutton, UK., Institute of Cancer Research, London, UK., Department of Radiation Oncology, Princess Margaret Cancer Centre and University of Toronto, Toronto, ON, Canada., Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, ON, Canada., McMaster University, Hamilton, ON, Canada., Department of Radiation Oncology, Duke University, Durham, NC, USA., Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA., Department of Radiation Oncology, Dana- Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA., Department of Radiotherapy, Erasmus Medical Center, Rotterdam, Netherlands., Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands., Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA., Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy., Department of Radiation Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy., Institut de Cancérologie de l'Ouest, Saint Herblain, Nantes, France., Department of Radiation Oncology, Institut Curie, Saint-Cloud, France., Department of Radiation Oncology, Oncorad Clinique Pasteur, Toulouse, France., Department of Medicine Statistical Core, University of California Los Angeles, Los Angeles, CA, USA., Department of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA., Department of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA; Greater Los Angeles VA Medical Center, Los Angeles, CA, USA., Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada., Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Department of Radiation Oncology, Rush University Medical Center, Chicago, IL, USA., Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.