Early Prediction of Acute Esophagitis for Adaptive Radiation Therapy

Abstract

Purpose: Acute esophagitis (AE) is a common dose-limiting toxicity in radiation therapy of locally advanced non-small cell lung cancer (LA-NSCLC). We developed an early AE prediction model from weekly accumulated esophagus dose and its associated local volumetric change.

Methods and materials: Fifty-one patients with LA-NSCLC underwent treatment with intensity modulated radiation therapy to 60 Gy in 2-Gy fractions with concurrent chemotherapy and weekly cone beam computed tomography (CBCT). Twenty-eight patients (55%) developed grade ≥2 AE (≥AE2) at a median of 4 weeks after the start of radiation therapy. For early ≥AE2 prediction, the esophagus on CBCT of the first 2 weeks was deformably registered to the planning computed tomography images, and weekly esophagus dose was accumulated. Week 1-to-week 2 (w1→w2) esophagus volume changes including maximum esophagus expansion (MEex%) and volumes with ≥x% local expansions (VEx%; x = 5, 10, 15) were calculated from the Jacobian map of deformation vector field gradients. Logistic regression model with 5-fold cross-validation was built using combinations of the accumulated mean esophagus doses (MED) and the esophagus change parameters with the lowest P value in univariate analysis. The model was validated on an additional 18 and 11 patients with weekly CBCT and magnetic resonance imaging (MRI), respectively, and compared with models using only planned mean dose (MED_Plan). Performance was assessed using area under the curve (AUC) and Hosmer-Lemeshow test (P_HL).

Results: Univariately, w1→w2 VE10% (P = .004), VE5% (P = .01) and MEex% (P = .02) significantly predicted ≥AE2. A model combining MED_W2 and w1→w2 VE10% had the best performance (AUC = 0.80; P_HL = 0.43), whereas the MED_Plan model had a lower accuracy (AUC = 0.67; P_HL = 0.26). The combined model also showed high accuracy in the CBCT (AUC = 0.78) and MRI validations (AUC = 0.75).

Conclusions: A CBCT-based, cross-validated, and internally validated model on MRI with a combination of accumulated esophagus dose and local volume change from the first 2 weeks of chemotherapy significantly improved AE prediction compared with conventional models using only the planned dose. This model could inform plan adaptation early to lower the risk of esophagitis.

FIGURE. 1.

Main workflow. MED _w1,w2=week 1 and week 2 accumulated Mean Esophagus Dose.

FIGURE. 2.

Calibration curves for the (A) proposed and (B) MED_plan model. Error bars denote 95% confidence interval. Dose-response curves for the (C) proposed and (D) MED_plan model where the dose-response predictions for ≥AE2 are given by the blue lines (gray ribbon is 95% CI). Orange quintiles denote observed ≥AE2 risk rate for each quintile (number of observed AE2/total number of patients) (error bars: 95% binomial confidence intervals); quintile-specific predicted/observed AE2 rates [%] are given above each quintile. ≥AE2 risk rate was calculated using the logistic function of [risk=1/1+exp(−x)] where x is the logistic regression argument (log-odds) for each model given below the dose-response curves.

FIGURE. 3.

≥AE2 predictability by dose-volume change parameters in CBCT and MRI cohorts for (A) MED_plan (B) MED_w2 and (C) w1→w2 VE10% (D) scatter plots showing the patient specific predictions using the (left) combination of MED_w2 and w1→w2 VE10% versus (right) only MED_plan. Symbol shapes represent observed ≥AE2 (circle) vs. Non-AE2 (<AE2, triangle) cases and continuous colors inside the symbols give prediction probabilities for each case. The annotated case (P1) is an outlier observed as an ≥AE2 case.

FIGURE. 4.

pCT, week1 and week2 images along with 3D view of w1→w2 expansions for two ≥AE2 cases from CBCT (top) and MRI (bottom) cohorts. (A) prescribed dose map overlaid on pCT. Green contour is the planning esophagus. (B) week1 CBCT/MRI. Green contour is ground-truth esophagus observed on week1. Red arrows depict expansion between week1 and week2 where Jacobian map inside the esophagus contour shows large expansion. (C) week2 CBCT/MRI. Green contour is esophagus on week2. Red filled color wash depicts w1→w2 VE10% inside the esophagus. (D) 3D view showing w1→w2 VE10% volume expanded (red structure) on week1 esophagus (green) and the small dark green structure inside VE10% is maximum esophagus expansion (MEex%). For each sub-figure, purple and blue contours are PTV and GTV, respectively.