7/30/2018. Review of NTCP models for Thoracic radiotherapy: where are we? Maria Thor, PhD
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1 Review of NTCP models for Thoracic radiotherapy: where are we? Maria Thor, PhD Presentation outline Acute esophagitis (AE) Cardiac toxicity Presentation outline Acute esophagitis (AE) Cardiac toxicity 1
2 QUANTEC on AE: Dose/volume guidelines but no precise limit V 70 20% V 50 40% V 35 50% AE 30% Werner-Wasik M IJROBP 2010 QUANTEC on AE: Dose/volume guidelines but no precise limit V 70 20% V 50 40% V 35 50% AE 30% Other predisposing factors? Age Concurrent Dysphagia Tumor vol chemo Werner-Wasik M IJROBP 2010 AE post-quantec: Mean dose + Concurrent chemo N=374 (stage III: 62%), AE Grade 2=32% Stepwise cross-validated logistic regression (N variables =50) Huang EX IJROBP
3 AE post-quantec: Mean dose + Concurrent chemo (1.5ConChemo)+(0.07)-3.1 Good performance (calibration: right; AUC=0.83) AE=32% 15Gy 30Gy Huang EX IJROBP 2012 AE post-quantec: Mean dose + Concurrent chemo N=115 ( stage II: 75%), AE Grade 2=82% Validation of old model and generation of new model Huang EX Adv Radiat Oncol 2016 AE post-quantec: Mean dose + Concurrent chemo Old and new model similar (AUC=0.78, 0.78; p HL =0.54, 0.66) New model: (1.8ConChemo)+(0.09)-1.8 AE=82% 20Gy (old:25 Gy) 38Gy (old: 47Gy) Huang EX Adv Radiat Oncol
4 AE post-quantec: Mean dose + Concurrent chemo N=149 (stage II/III), AE Grade 2=36% Similar modeling approach as in the two Huang studies Wijsman R R&O 2015 AE post-quantec: Mean dose + Concurrent chemo (2.6ConChemo)+(0.12)+(1.2Female)+(0.99StageIII)-6.4 Good performance (AUC=0.82; p HL =0.13) AE=36% 9Gy 28Gy 48Gy 49Gy All risk factors Two risk factors One risk factor No risk factors Wijsman R R&O 2015 Presentation outline Cardiac toxicity 4
5 QUANTEC on RP: Recommended dose/volume limits MLD 20-23Gy RP 20% V % 1 NTCP = æ æ 1+ exp 4g MLD öö ç ç è è D 50 øø D 50 =30.8Gy γ 50 =0.97 Marks LB IJROBP 2010 QUANTEC on RP: Recommended dose/volume limits MLD 20-23Gy RP 20% V % 1 NTCP = æ æ 1+ exp 4g MLD öö ç ç è è D 50 øø D 50 =30.8Gy γ 50 =0.97 Other predisposing factors? Marks LB IJROBP 2010 RP post-quantec: Lung and heart dose interaction N=209, RP Grade 2=23% Stepwise cross-validated logistic regression (N variables >100) Huang EX Acta Oncol
6 RP post-quantec: Lung and heart dose interaction (0.02HeartD 10 )+(0.06MLD)-3.5 Good performance (calibration: lower right; AUC=0.72) Heart D 10 MLD Huang EX Acta Oncol 2011 RP post-quantec: Lung and heart dose interaction (0.02HeartD 10 )+(0.06MLD)-3.5 Good performance (calibration: lower right; AUC=0.72) No RP region: MLD 5Gy HeartD 10 25Gy Huang EX Acta Oncol 2011 RP post-quantec: Lung dose and predisposing factors QUANTEC s MLD response adjusted for predisposing factors ORs from meta-analysis - Mid/inferior tumor location: OR= Old age (63y): OR= Pulmonary comorbidity : OR= Sequential chemotherapy: OR= Smoking: OR=0.62, 0.69 (Current, Former) Vogelius I Acta Oncol 2012 Appelt AL Acta Oncol
7 RP post-quantec: Lung dose and predisposing factors QUANTEC D 50 =30.8Gy γ 50 =0.97 Appelt D 50 =34.4Gy γ 50 =1.19 Appelt AL Acta Oncol 2014 RP post-quantec: Lung dose and predisposing factors Validation (N=103, RP Grade 2=35%) Generalizable with respect to risk groups (QUANTEC was not) QUANTEC Appelt Appelt AL Acta Oncol 2014 Presentation outline Cardiac toxicity 7
8 Heart dose predicts survival First indications: RTOG 0617 MVA: Heart V 5 Bradley JD Lancet Oncol 2015 Heart dose and cardiac toxicity N=125, Grade 3 cardiac toxicity: 15% - Mean heart dose - Baseline cardiac disease Dess RT J Clin Oncol 2017 Heart dose and cardiac toxicity N=125, Grade 3 cardiac toxicity: 15% - Mean heart dose - Baseline cardiac disease N=112, Symptomatic cardiac events: 23% - Mean heart dose - Baseline coronary artery disease Dess RT J Clin Oncol 2017 Wang K J Clin Oncol
9 AUC AUC AUC Heart substructure dose and cardiac toxicity N=112, Arrhythmic/Ischemic/Pericardial: 11%/6%/8% Chambers, Heart, Pericardium (Mean dose, V 5, V 30, V 60 ) - Arrhythmic: Heart (V 5 ), RA (V 60 ) - Ischemic: Heart (V 5, V 30 ), LV (Mean, V 5, V 30 ) - Pericardial: Heart (all), LA (all), RA (all) Wang K R&O 2017 Heart substructure dose and cardiac toxicity N=112, Arrhythmic/Ischemic/Pericardial: 11%/6%/8% Chambers, Heart, Pericardium (Mean dose, V 5, V 30, V 60 ) - Arrhythmic: Heart (V 5 ), RA (V 60 ) - Ischemic: Heart (V 5, V 30 ), LV (Mean, V 5, V 30 ) - Pericardial: Heart (all), LA (all), RA (all) V x [Gy] V x [Gy] V x [Gy] Wang K R&O 2017 Presentation outline Cardiac toxicity 9
10 Model validation: Calibration + Discrimination = Detailed guidelines given in the TRIPOD statement Requirements: Published model equation, coefficients Calibration: How closely do predictions agree with observations - Calibration plot (ideal: data on identity line), Χ 2 -test, Hosmer-Lemeshow test Moons KGM Ann Intern Med 2015 Model validation: Calibration + Discrimination = Detailed guidelines given in the TRIPOD statement Requirements: Published model equation, coefficients Calibration: How closely do predictions agree with observations - Calibration plot (ideal: data on identity line), Χ 2 -test, Hosmer-Lemeshow test Discrimination: Prediction s ability to differentiate between event and non-event - C-statistics (AUC) Moons KGM Ann Intern Med 2015 Model validation: Calibration + Discrimination = Detailed guidelines given in the TRIPOD statement Requirements: Published model equation, coefficients Calibration: How closely do predictions agree with observations - Calibration plot (ideal: data on identity line), Χ 2 -test, Hosmer-Lemeshow test Discrimination: Prediction s ability to differentiate between event and non-event - C-statistics (AUC) Do NOT use a model for other purposes than for which it was developed! Moons KGM Ann Intern Med 2015 Marks LB IJROBP
11 Presentation outline Cardiac toxicity Validation of AE and RP models AE Models - (1.5ConChemo)+(0.07) (1.8ConChemo)+(0.09) (2.6ConChemo)+(0.12)+(1.2Female) +(0.99StageIII)-6.4 Huang EX IJROBP 2012 Huang EX Acta Oncol 2011 Wijsman R R&O 2015 RP models - NTCP. = 1 g 50 = 0.97 æ æ 1+ exp 4g MLD öö D 50 = 30.8Gy ç ç è è D 50 øø - (0.02HeartD 10 )+(0.06MLD) NTCP. 1 g = 50 risk = æ æ 1+ exp 4g 50 risk ç1- MLD öö 4 lnor ç è D æ è 50 risk øø D 50risk = 34.4D g lnor ö ç è 50 ø Marks LB IJROBP 2010 Huang EX Acta Oncol 2011 Appelt AL Acta Oncol 2014 Thor M 2018 (unpublished data) Validation of AE and RP models: Data and implementation 241 stage III NSCLC patients - IMRT to 64Gy (50-80Gy) AE, RP rates: 50%, 12% - Concurrent/sequential chemotherapy Thor M 2018 (unpublished data) 11
12 Validation of AE and RP models: Data and implementation 241 stage III NSCLC patients - IMRT to 64Gy (50-80Gy) AE, RP rates: 50%, 12% - Concurrent/sequential chemotherapy Model validation - Fractionation-corrected doses (AE/RP: α/β=10gy/3gy) - Equations and coefficients from published models - Calibration and discrimination (p HL, and AUC) over 1000 Bootstrap samples - Best model: Highest AUC with p HL ~0.50 Thor M 2018 (unpublished data) Validation of published AE and RP models: AE AUC=0.65 p HL=0.60 Huang EX IJROBP 2012 AUC=0.65 p HL=0.29 AUC=0.65 p HL=1.00 Thor M 2018 (unpublished data) Validation of published AE and RP models: RP AUC=0.65 p HL=0.90 Appelt AL Acta Oncol 2014 AUC=0.51 p HL=0.68 AUC=0.57 p HL=0.89 Thor M 2018 (unpublished data) 12
13 Presentation outline Cardiac toxicity Summary Cardiac toxicity Heart dose + Baseline heart function Potentially intra-heart sensitivity Calibration + Discrimination = Summary Cardiac toxicity Heart dose + Baseline heart function Potentially intra-heart sensitivity Calibration + Discrimination = AE: Concurrent chemotherapy + Mean esophageal dose RP: Mean lung dose + Individual characteristics 13
14 Summary Cardiac toxicity Heart dose + Baseline heart function Potentially intra-heart sensitivity Calibration + Discrimination = AE: Concurrent chemotherapy + Mean esophageal dose RP: Mean lung dose + Individual characteristics Jeong J Clin Cancer Res 2017 Thank you! Acknowledgments Joseph O Deasy Andrew Jackson Andreas Rimner Aditi Iyer Ellen Yorke Aditya Apte Jung Hun Oh Alexandra Hotca Ethan Bendau Funding NIH/NCI Cancer Support Grant P30 CA NIH R01 CA
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