Amar U Kishan1, Xiaoyan Wang2, Yilun Sun3, Tahmineh Romero2, Jeff M Michalski4, Ting Martin Ma5, Felix Y Feng6, Howard M Sandler7, Michel Bolla8, Philippe Maingon9, Theo De Reijke10, Anouk Neven11, Allison Steigler12, James W Denham12, David Joseph13, Abdenour Nabid14, Nathalie Carrier15, Luis Souhami16, Matt R Sydes17, David P Dearnaley18, Isabel Syndikus19, Alison C Tree18, Luca Incrocci20, Wilma D Heemsbergen20, Floris J Pos21, Almudena Zapatero22, Jason A Efstathiou23, Araceli Guerrero24, Ana Alvarez25, Carmen Gonzalez San-Segundo25, Xavier Maldonado26, Michael Xiang5, Matthew B Rettig27, Robert E Reiter28, Nicholas G Zaorsky29, Wee Loon Ong30, Robert T Dess31, Michael L Steinberg5, Nicholas G Nickols5, Soumyajit Roy32, Jorge A Garcia33, Daniel E Spratt29. 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: aukishan@mednet.ucla.edu. 2. Division of General Internal Medicine and Health Services Research, University of California Los Angeles, Los Angeles, CA, USA. 3. Department of Population Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA; Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA. 4. Department of Radiation Oncology, Washington University, St. Louis, MO, USA. 5. Department of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA. 6. Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA. 7. Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 8. Radiotherapy Department, University Hospital, Grenoble, France. 9. Department of Oncology, Hematology, and Supportive Care, Sorbonne University, Paris, France. 10. Department of Urology, Prostate Cancer Network in the Netherlands, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands. 11. Statistics Department, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium; Competence Center for Methodology and Statistics, Luxembourg Institute of Health, Strassen, Luxembourg. 12. School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia. 13. Department of Medicine and Surgery, University of Western Australia, Perth, WA, Australia. 14. Department of Radiation Oncology, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada. 15. Clinical Research Center, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada. 16. Department of Radiation Oncology, McGill University Health Centre, Montréal, QC, Canada. 17. Medical Research Council Clinical Trials Unit, University College London, London, UK. 18. The Institute of Cancer Research, London, UK. 19. Clatterbridge Cancer Centre, Birkenhead, UK. 20. Department of Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands. 21. Department of Radiation Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands. 22. Hospital Universitario de la Princesa, Madrid, Spain. 23. Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA. 24. Hospital Son Espases, Palma de Mallorca, Spain. 25. Hospital General Universitario Gregorio Marañón, Madrid, Spain. 26. Hospital Universitari Vall d'Hebron, Barcelona, Spain. 27. Department of Medical Oncology, University of California Los Angeles, Los Angeles, CA, USA. 28. Department of Urology, University of California Los Angeles, Los Angeles, CA, USA. 29. Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA. 30. Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia. 31. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. 32. Department of Radiation Oncology, Rush University, Chicago, IL, USA. 33. Division of Oncology, Seidman Cancer Center, Cleveland, OH, USA.
Abstract
BACKGROUND: The relative benefits of radiotherapy (RT) dose escalation and the addition of short-term or long-term androgen deprivation therapy (STADT or LTADT) in the treatment of prostate cancer are unknown. OBJECTIVE: To perform a network meta-analysis (NMA) of relevant randomized trials to compare the relative benefits of RT dose escalation ± STADT or LTADT. DESIGN, SETTING, AND PARTICIPANTS: An NMA of individual patient data from 13 multicenter randomized trials was carried out for a total of 11862 patients. Patients received one of the six permutations of low-dose RT (64 to <74 Gy) ± STADT or LTADT, high-dose RT (≥74 Gy), or high-dose RT ± STADT or LTADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Metastasis-free survival (MFS) was the primary endpoint. Frequentist and Bayesian NMAs were performed to rank the various treatment strategies by MFS and biochemical recurrence-free survival (BCRFS). RESULTS AND LIMITATIONS: Median follow-up was 8.8 yr (interquartile range 5.7-11.5). The greatest relative improvement in outcomes was seen for addition of LTADT, irrespective of RT dose, followed by addition of STADT, irrespective of RT dose. RT dose escalation did not improve MFS either in the absence of ADT (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.80-1.18) or with STADT (HR 0.99, 95% CI 0.8-1.23) or LTADT (HR 0.94, 95% CI 0.65-1.37). According to P-score ranking and rankogram analysis, high-dose RT + LTADT was the optimal treatment strategy for both BCRFS and longer-term outcomes. CONCLUSIONS: Conventionally escalated RT up to 79.2 Gy, alone or in the presence of ADT, does not improve MFS, while addition of STADT or LTADT to RT alone, regardless of RT dose, consistently improves MFS. RT dose escalation does provide a high probability of improving BCRFS and, provided it can be delivered without compromising quality of life, may represent the optimal treatment strategy when used in conjunction with ADT. PATIENT SUMMARY: Using a higher radiotherapy dose when treating prostate cancer does not reduce the chance of developing metastases or death, but it does reduce the chance of having a rise in prostate-specific antigen (PSA) signifying recurrence of cancer. Androgen deprivation therapy improves all outcomes. A safe increase in radiotherapy dose in conjunction with androgen deprivation therapy may be the optimal treatment.
BACKGROUND: The relative benefits of radiotherapy (RT) dose escalation and the addition of short-term or long-term androgen deprivation therapy (STADT or LTADT) in the treatment of prostate cancer are unknown. OBJECTIVE: To perform a network meta-analysis (NMA) of relevant randomized trials to compare the relative benefits of RT dose escalation ± STADT or LTADT. DESIGN, SETTING, AND PARTICIPANTS: An NMA of individual patient data from 13 multicenter randomized trials was carried out for a total of 11862 patients. Patients received one of the six permutations of low-dose RT (64 to <74 Gy) ± STADT or LTADT, high-dose RT (≥74 Gy), or high-dose RT ± STADT or LTADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Metastasis-free survival (MFS) was the primary endpoint. Frequentist and Bayesian NMAs were performed to rank the various treatment strategies by MFS and biochemical recurrence-free survival (BCRFS). RESULTS AND LIMITATIONS: Median follow-up was 8.8 yr (interquartile range 5.7-11.5). The greatest relative improvement in outcomes was seen for addition of LTADT, irrespective of RT dose, followed by addition of STADT, irrespective of RT dose. RT dose escalation did not improve MFS either in the absence of ADT (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.80-1.18) or with STADT (HR 0.99, 95% CI 0.8-1.23) or LTADT (HR 0.94, 95% CI 0.65-1.37). According to P-score ranking and rankogram analysis, high-dose RT + LTADT was the optimal treatment strategy for both BCRFS and longer-term outcomes. CONCLUSIONS: Conventionally escalated RT up to 79.2 Gy, alone or in the presence of ADT, does not improve MFS, while addition of STADT or LTADT to RT alone, regardless of RT dose, consistently improves MFS. RT dose escalation does provide a high probability of improving BCRFS and, provided it can be delivered without compromising quality of life, may represent the optimal treatment strategy when used in conjunction with ADT. PATIENT SUMMARY: Using a higher radiotherapy dose when treating prostate cancer does not reduce the chance of developing metastases or death, but it does reduce the chance of having a rise in prostate-specific antigen (PSA) signifying recurrence of cancer. Androgen deprivation therapy improves all outcomes. A safe increase in radiotherapy dose in conjunction with androgen deprivation therapy may be the optimal treatment.