Tolerance doses for late adverse events after hypofractionated radiotherapy for prostate cancer on trial NRG Oncology/RTOG 0415

Maria Thor, Joseph O. Deasy, Rebecca Paulus, W. Robert Lee, Mahul B. Amin, Deborah W. Bruner, Daniel A. Low, Amit B. Shah, Shawn C. Malone, Jeff M. Michalski, Ian S. Dayes, Samantha A. Seaward, Elizabeth M. Gore, Michele Albert, Thomas M. Pisansky, Sergio L. Faria, Yuhchyau Chen, Bridget F. Koontz, Gregory P Swanson, Stephanie L. PughHoward M. Sandler

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Purpose/objective: Hypofractionated radiotherapy (HRT) regimens for prostate cancer are emerging, but tolerance doses for late adverse events are scarce. The purpose of this study is to define dose–volume predictors for late gastrointestinal and genitourinary (GI and GU) toxicities after HRT in the multi-center NRG Oncology/RTOG 0415 low-risk prostate cancer trial (N = 521). Material/methods: Treatment in the studied HRT arm was delivered as 70 Gy at 2.5 Gy/fraction with 3D-CRT/IMRT (N = 108/413). At a median follow-up of 5.9 years, the crude late ≥Grade 2 GI and GU toxicities were 19% and 29%, respectively. For modeling, the complete HRT cohort was randomly split into training and validation (70% and 30%; preserved toxicity rates). Within training, dose–response modeling was based on dose–volume cut-points (EQD2Gy; bladder/rectum: α/β = 6 Gy/3Gy), age, acute ≥Grade 2 toxicity, and treatment technique using univariate and multivariate logistic regression on bootstrapping (UVA and MVA). Candidate predictors were determined at p ≤ 0.05, and the selected MVA models were explored on validation where model generalizability was judged if the area under the receiver-operating curve in validation (AUC validation ) was within AUC training ± SD with p ≤ 0.05, and with an Hosmer–Lemeshow p-value (p HL ) > 0.05. Results: Three candidate predictors were suggested for late GI toxicity: the minimum dose to the hottest 5% rectal volume (D5%[Gy]), the absolute rectal volume <35 Gy, and acute GI toxicity (AUC = 0.59–0.63; p = 0.02–0.04). The two generalizable MVA models, i.e., D5%[Gy] with or without acute GI toxicity (AUC validation = 0.64, 0.65; p = 0.01, 0.03; p HL = 0.45–0.56), suggest that reducing late GI toxicity from 20% to 10% would require reducing D5%[Gy] from ≤65 Gy to ≤62 Gy (logistic function argument: 17+(0.24D5%[Gy])). Acute GU toxicity showed only a trend to predict late GU toxicity (AUC training = 0.57; p = 0.07). Conclusion: Late GI toxicity, following moderate HRT for low-risk prostate cancer, increases with higher doses to small rectal volumes. This work provides quantitative evidence that limiting small rectal dose ‘hotspots’ in clinical practice of such HRT regimens is likely to further reduce the associated rates of GI toxicity.

Original languageEnglish (US)
Pages (from-to)19-24
Number of pages6
JournalRadiotherapy and Oncology
Volume135
DOIs
StatePublished - Jun 1 2019

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Prostatic Neoplasms
Radiotherapy
Area Under Curve
Rectum
Urinary Bladder
Logistic Models
Therapeutics

Keywords

  • Gastrointestinal
  • Genitourinary
  • Hypofractionation
  • Prostate cancer
  • Radiotherapy
  • Toxicity

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Radiology Nuclear Medicine and imaging

Cite this

Tolerance doses for late adverse events after hypofractionated radiotherapy for prostate cancer on trial NRG Oncology/RTOG 0415. / Thor, Maria; Deasy, Joseph O.; Paulus, Rebecca; Robert Lee, W.; Amin, Mahul B.; Bruner, Deborah W.; Low, Daniel A.; Shah, Amit B.; Malone, Shawn C.; Michalski, Jeff M.; Dayes, Ian S.; Seaward, Samantha A.; Gore, Elizabeth M.; Albert, Michele; Pisansky, Thomas M.; Faria, Sergio L.; Chen, Yuhchyau; Koontz, Bridget F.; Swanson, Gregory P; Pugh, Stephanie L.; Sandler, Howard M.

In: Radiotherapy and Oncology, Vol. 135, 01.06.2019, p. 19-24.

Research output: Contribution to journalArticle

Thor, M, Deasy, JO, Paulus, R, Robert Lee, W, Amin, MB, Bruner, DW, Low, DA, Shah, AB, Malone, SC, Michalski, JM, Dayes, IS, Seaward, SA, Gore, EM, Albert, M, Pisansky, TM, Faria, SL, Chen, Y, Koontz, BF, Swanson, GP, Pugh, SL & Sandler, HM 2019, 'Tolerance doses for late adverse events after hypofractionated radiotherapy for prostate cancer on trial NRG Oncology/RTOG 0415', Radiotherapy and Oncology, vol. 135, pp. 19-24. https://doi.org/10.1016/j.radonc.2019.02.014
Thor, Maria ; Deasy, Joseph O. ; Paulus, Rebecca ; Robert Lee, W. ; Amin, Mahul B. ; Bruner, Deborah W. ; Low, Daniel A. ; Shah, Amit B. ; Malone, Shawn C. ; Michalski, Jeff M. ; Dayes, Ian S. ; Seaward, Samantha A. ; Gore, Elizabeth M. ; Albert, Michele ; Pisansky, Thomas M. ; Faria, Sergio L. ; Chen, Yuhchyau ; Koontz, Bridget F. ; Swanson, Gregory P ; Pugh, Stephanie L. ; Sandler, Howard M. / Tolerance doses for late adverse events after hypofractionated radiotherapy for prostate cancer on trial NRG Oncology/RTOG 0415. In: Radiotherapy and Oncology. 2019 ; Vol. 135. pp. 19-24.
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title = "Tolerance doses for late adverse events after hypofractionated radiotherapy for prostate cancer on trial NRG Oncology/RTOG 0415",
abstract = "Purpose/objective: Hypofractionated radiotherapy (HRT) regimens for prostate cancer are emerging, but tolerance doses for late adverse events are scarce. The purpose of this study is to define dose–volume predictors for late gastrointestinal and genitourinary (GI and GU) toxicities after HRT in the multi-center NRG Oncology/RTOG 0415 low-risk prostate cancer trial (N = 521). Material/methods: Treatment in the studied HRT arm was delivered as 70 Gy at 2.5 Gy/fraction with 3D-CRT/IMRT (N = 108/413). At a median follow-up of 5.9 years, the crude late ≥Grade 2 GI and GU toxicities were 19{\%} and 29{\%}, respectively. For modeling, the complete HRT cohort was randomly split into training and validation (70{\%} and 30{\%}; preserved toxicity rates). Within training, dose–response modeling was based on dose–volume cut-points (EQD2Gy; bladder/rectum: α/β = 6 Gy/3Gy), age, acute ≥Grade 2 toxicity, and treatment technique using univariate and multivariate logistic regression on bootstrapping (UVA and MVA). Candidate predictors were determined at p ≤ 0.05, and the selected MVA models were explored on validation where model generalizability was judged if the area under the receiver-operating curve in validation (AUC validation ) was within AUC training ± SD with p ≤ 0.05, and with an Hosmer–Lemeshow p-value (p HL ) > 0.05. Results: Three candidate predictors were suggested for late GI toxicity: the minimum dose to the hottest 5{\%} rectal volume (D5{\%}[Gy]), the absolute rectal volume <35 Gy, and acute GI toxicity (AUC = 0.59–0.63; p = 0.02–0.04). The two generalizable MVA models, i.e., D5{\%}[Gy] with or without acute GI toxicity (AUC validation = 0.64, 0.65; p = 0.01, 0.03; p HL = 0.45–0.56), suggest that reducing late GI toxicity from 20{\%} to 10{\%} would require reducing D5{\%}[Gy] from ≤65 Gy to ≤62 Gy (logistic function argument: 17+(0.24D5{\%}[Gy])). Acute GU toxicity showed only a trend to predict late GU toxicity (AUC training = 0.57; p = 0.07). Conclusion: Late GI toxicity, following moderate HRT for low-risk prostate cancer, increases with higher doses to small rectal volumes. This work provides quantitative evidence that limiting small rectal dose ‘hotspots’ in clinical practice of such HRT regimens is likely to further reduce the associated rates of GI toxicity.",
keywords = "Gastrointestinal, Genitourinary, Hypofractionation, Prostate cancer, Radiotherapy, Toxicity",
author = "Maria Thor and Deasy, {Joseph O.} and Rebecca Paulus and {Robert Lee}, W. and Amin, {Mahul B.} and Bruner, {Deborah W.} and Low, {Daniel A.} and Shah, {Amit B.} and Malone, {Shawn C.} and Michalski, {Jeff M.} and Dayes, {Ian S.} and Seaward, {Samantha A.} and Gore, {Elizabeth M.} and Michele Albert and Pisansky, {Thomas M.} and Faria, {Sergio L.} and Yuhchyau Chen and Koontz, {Bridget F.} and Swanson, {Gregory P} and Pugh, {Stephanie L.} and Sandler, {Howard M.}",
year = "2019",
month = "6",
day = "1",
doi = "10.1016/j.radonc.2019.02.014",
language = "English (US)",
volume = "135",
pages = "19--24",
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TY - JOUR

T1 - Tolerance doses for late adverse events after hypofractionated radiotherapy for prostate cancer on trial NRG Oncology/RTOG 0415

AU - Thor, Maria

AU - Deasy, Joseph O.

AU - Paulus, Rebecca

AU - Robert Lee, W.

AU - Amin, Mahul B.

AU - Bruner, Deborah W.

AU - Low, Daniel A.

AU - Shah, Amit B.

AU - Malone, Shawn C.

AU - Michalski, Jeff M.

AU - Dayes, Ian S.

AU - Seaward, Samantha A.

AU - Gore, Elizabeth M.

AU - Albert, Michele

AU - Pisansky, Thomas M.

AU - Faria, Sergio L.

AU - Chen, Yuhchyau

AU - Koontz, Bridget F.

AU - Swanson, Gregory P

AU - Pugh, Stephanie L.

AU - Sandler, Howard M.

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Purpose/objective: Hypofractionated radiotherapy (HRT) regimens for prostate cancer are emerging, but tolerance doses for late adverse events are scarce. The purpose of this study is to define dose–volume predictors for late gastrointestinal and genitourinary (GI and GU) toxicities after HRT in the multi-center NRG Oncology/RTOG 0415 low-risk prostate cancer trial (N = 521). Material/methods: Treatment in the studied HRT arm was delivered as 70 Gy at 2.5 Gy/fraction with 3D-CRT/IMRT (N = 108/413). At a median follow-up of 5.9 years, the crude late ≥Grade 2 GI and GU toxicities were 19% and 29%, respectively. For modeling, the complete HRT cohort was randomly split into training and validation (70% and 30%; preserved toxicity rates). Within training, dose–response modeling was based on dose–volume cut-points (EQD2Gy; bladder/rectum: α/β = 6 Gy/3Gy), age, acute ≥Grade 2 toxicity, and treatment technique using univariate and multivariate logistic regression on bootstrapping (UVA and MVA). Candidate predictors were determined at p ≤ 0.05, and the selected MVA models were explored on validation where model generalizability was judged if the area under the receiver-operating curve in validation (AUC validation ) was within AUC training ± SD with p ≤ 0.05, and with an Hosmer–Lemeshow p-value (p HL ) > 0.05. Results: Three candidate predictors were suggested for late GI toxicity: the minimum dose to the hottest 5% rectal volume (D5%[Gy]), the absolute rectal volume <35 Gy, and acute GI toxicity (AUC = 0.59–0.63; p = 0.02–0.04). The two generalizable MVA models, i.e., D5%[Gy] with or without acute GI toxicity (AUC validation = 0.64, 0.65; p = 0.01, 0.03; p HL = 0.45–0.56), suggest that reducing late GI toxicity from 20% to 10% would require reducing D5%[Gy] from ≤65 Gy to ≤62 Gy (logistic function argument: 17+(0.24D5%[Gy])). Acute GU toxicity showed only a trend to predict late GU toxicity (AUC training = 0.57; p = 0.07). Conclusion: Late GI toxicity, following moderate HRT for low-risk prostate cancer, increases with higher doses to small rectal volumes. This work provides quantitative evidence that limiting small rectal dose ‘hotspots’ in clinical practice of such HRT regimens is likely to further reduce the associated rates of GI toxicity.

AB - Purpose/objective: Hypofractionated radiotherapy (HRT) regimens for prostate cancer are emerging, but tolerance doses for late adverse events are scarce. The purpose of this study is to define dose–volume predictors for late gastrointestinal and genitourinary (GI and GU) toxicities after HRT in the multi-center NRG Oncology/RTOG 0415 low-risk prostate cancer trial (N = 521). Material/methods: Treatment in the studied HRT arm was delivered as 70 Gy at 2.5 Gy/fraction with 3D-CRT/IMRT (N = 108/413). At a median follow-up of 5.9 years, the crude late ≥Grade 2 GI and GU toxicities were 19% and 29%, respectively. For modeling, the complete HRT cohort was randomly split into training and validation (70% and 30%; preserved toxicity rates). Within training, dose–response modeling was based on dose–volume cut-points (EQD2Gy; bladder/rectum: α/β = 6 Gy/3Gy), age, acute ≥Grade 2 toxicity, and treatment technique using univariate and multivariate logistic regression on bootstrapping (UVA and MVA). Candidate predictors were determined at p ≤ 0.05, and the selected MVA models were explored on validation where model generalizability was judged if the area under the receiver-operating curve in validation (AUC validation ) was within AUC training ± SD with p ≤ 0.05, and with an Hosmer–Lemeshow p-value (p HL ) > 0.05. Results: Three candidate predictors were suggested for late GI toxicity: the minimum dose to the hottest 5% rectal volume (D5%[Gy]), the absolute rectal volume <35 Gy, and acute GI toxicity (AUC = 0.59–0.63; p = 0.02–0.04). The two generalizable MVA models, i.e., D5%[Gy] with or without acute GI toxicity (AUC validation = 0.64, 0.65; p = 0.01, 0.03; p HL = 0.45–0.56), suggest that reducing late GI toxicity from 20% to 10% would require reducing D5%[Gy] from ≤65 Gy to ≤62 Gy (logistic function argument: 17+(0.24D5%[Gy])). Acute GU toxicity showed only a trend to predict late GU toxicity (AUC training = 0.57; p = 0.07). Conclusion: Late GI toxicity, following moderate HRT for low-risk prostate cancer, increases with higher doses to small rectal volumes. This work provides quantitative evidence that limiting small rectal dose ‘hotspots’ in clinical practice of such HRT regimens is likely to further reduce the associated rates of GI toxicity.

KW - Gastrointestinal

KW - Genitourinary

KW - Hypofractionation

KW - Prostate cancer

KW - Radiotherapy

KW - Toxicity

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