Radiation-Induced Lung Injury Following Neoadjuvant Concurrent Chemoradiation Therapy for Locally-Advanced Breast Cancer

Abstract

Purpose/Objective(s)A phase I/II protocol was designed to evaluate the use of neoadjuvant concurrent chemoradiation therapy for locally advanced breast cancer (LABC). The trial was stopped due to a higher than expected rate of radiation pneumonitis (RP). The purpose of this study is to determine if baseline treatment, tumor, or patient factors are predictive of Radiation Induced Lung Injury (RILI) as measured by CT density changes, or RP.Materials/MethodsThirty-two patients with biopsy confirmed LABC were enrolled to receive protocol-based concurrent neoadjuvant chemoradiation therapy. Chemotherapy consisted of three cycles of IV 5- fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2) administered every three weeks. This was followed by concurrent weekly IV docetaxel (35 mg/m2) and 45 Gy in 25 fractions of external beam radiation therapy with a boost of 5.4-9 Gy in 3-5 fractions. A univariable logistic regression model was built to evaluate significant predictors of symptomatic RP (grade ≥2). To assess changes in lung density over time, serial post-treatment CT scans were contoured with isodose lines (<5, 10, 20, 30, >40 Gy) and co-registered with baseline CT scans using commercially available deformable registration algorithm. Density change values (Hounsfield Units) were generated for each isodose line, for each available follow-up scan, on 27 out of 32 patients. T-tests and ANOVAs (Analysis of Variance) were used to identify significant differences in density change stratified by various combinations of: (a) RP grade (≥2 versus <2), (b) radiation dose (5-10, 10-20, 20-30, 30-40, and >40 Gy), and (c) time (0-3, 3-6, 6-12, and >12 months).ResultsEighteen (56%) patients developed symptomatic RP, with eight (25%) experiencing grade 3 RP. On univariable analysis, no treatment, patient, or tumor factors were predictive for symptomatic RP, although there was an association with low left ventricular ejection fraction (p = 0.065). Radiation dose and time post-treatment were highly predictive of CT RILI (p < 0.001 and p = 0.021, respectively), with density changes peaking at 3-6 months. Patients who developed RP had significantly larger CT density changes than patients without RP at 6 months (p = 0.002) and at 12 months (p = 0.013). Density increases were most significant in regions receiving >30 Gy.ConclusionsIn this cohort of LABC receiving neoadjuvant concurrent chemoradiation therapy, there were strong correlations between radiation dose, follow-up time, and CT-measures of RILI. CT-based RILI measurements were also significantly associated with symptomatic RP. Further follow-up for the primary outcome of the trial is required to determine if the clinical benefits of concurrent chemoradiation therapy outweigh the risks. Purpose/Objective(s)A phase I/II protocol was designed to evaluate the use of neoadjuvant concurrent chemoradiation therapy for locally advanced breast cancer (LABC). The trial was stopped due to a higher than expected rate of radiation pneumonitis (RP). The purpose of this study is to determine if baseline treatment, tumor, or patient factors are predictive of Radiation Induced Lung Injury (RILI) as measured by CT density changes, or RP. A phase I/II protocol was designed to evaluate the use of neoadjuvant concurrent chemoradiation therapy for locally advanced breast cancer (LABC). The trial was stopped due to a higher than expected rate of radiation pneumonitis (RP). The purpose of this study is to determine if baseline treatment, tumor, or patient factors are predictive of Radiation Induced Lung Injury (RILI) as measured by CT density changes, or RP. Materials/MethodsThirty-two patients with biopsy confirmed LABC were enrolled to receive protocol-based concurrent neoadjuvant chemoradiation therapy. Chemotherapy consisted of three cycles of IV 5- fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2) administered every three weeks. This was followed by concurrent weekly IV docetaxel (35 mg/m2) and 45 Gy in 25 fractions of external beam radiation therapy with a boost of 5.4-9 Gy in 3-5 fractions. A univariable logistic regression model was built to evaluate significant predictors of symptomatic RP (grade ≥2). To assess changes in lung density over time, serial post-treatment CT scans were contoured with isodose lines (<5, 10, 20, 30, >40 Gy) and co-registered with baseline CT scans using commercially available deformable registration algorithm. Density change values (Hounsfield Units) were generated for each isodose line, for each available follow-up scan, on 27 out of 32 patients. T-tests and ANOVAs (Analysis of Variance) were used to identify significant differences in density change stratified by various combinations of: (a) RP grade (≥2 versus <2), (b) radiation dose (5-10, 10-20, 20-30, 30-40, and >40 Gy), and (c) time (0-3, 3-6, 6-12, and >12 months). Thirty-two patients with biopsy confirmed LABC were enrolled to receive protocol-based concurrent neoadjuvant chemoradiation therapy. Chemotherapy consisted of three cycles of IV 5- fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2) administered every three weeks. This was followed by concurrent weekly IV docetaxel (35 mg/m2) and 45 Gy in 25 fractions of external beam radiation therapy with a boost of 5.4-9 Gy in 3-5 fractions. A univariable logistic regression model was built to evaluate significant predictors of symptomatic RP (grade ≥2). To assess changes in lung density over time, serial post-treatment CT scans were contoured with isodose lines (<5, 10, 20, 30, >40 Gy) and co-registered with baseline CT scans using commercially available deformable registration algorithm. Density change values (Hounsfield Units) were generated for each isodose line, for each available follow-up scan, on 27 out of 32 patients. T-tests and ANOVAs (Analysis of Variance) were used to identify significant differences in density change stratified by various combinations of: (a) RP grade (≥2 versus <2), (b) radiation dose (5-10, 10-20, 20-30, 30-40, and >40 Gy), and (c) time (0-3, 3-6, 6-12, and >12 months). ResultsEighteen (56%) patients developed symptomatic RP, with eight (25%) experiencing grade 3 RP. On univariable analysis, no treatment, patient, or tumor factors were predictive for symptomatic RP, although there was an association with low left ventricular ejection fraction (p = 0.065). Radiation dose and time post-treatment were highly predictive of CT RILI (p < 0.001 and p = 0.021, respectively), with density changes peaking at 3-6 months. Patients who developed RP had significantly larger CT density changes than patients without RP at 6 months (p = 0.002) and at 12 months (p = 0.013). Density increases were most significant in regions receiving >30 Gy. Eighteen (56%) patients developed symptomatic RP, with eight (25%) experiencing grade 3 RP. On univariable analysis, no treatment, patient, or tumor factors were predictive for symptomatic RP, although there was an association with low left ventricular ejection fraction (p = 0.065). Radiation dose and time post-treatment were highly predictive of CT RILI (p < 0.001 and p = 0.021, respectively), with density changes peaking at 3-6 months. Patients who developed RP had significantly larger CT density changes than patients without RP at 6 months (p = 0.002) and at 12 months (p = 0.013). Density increases were most significant in regions receiving >30 Gy. ConclusionsIn this cohort of LABC receiving neoadjuvant concurrent chemoradiation therapy, there were strong correlations between radiation dose, follow-up time, and CT-measures of RILI. CT-based RILI measurements were also significantly associated with symptomatic RP. Further follow-up for the primary outcome of the trial is required to determine if the clinical benefits of concurrent chemoradiation therapy outweigh the risks. In this cohort of LABC receiving neoadjuvant concurrent chemoradiation therapy, there were strong correlations between radiation dose, follow-up time, and CT-measures of RILI. CT-based RILI measurements were also significantly associated with symptomatic RP. Further follow-up for the primary outcome of the trial is required to determine if the clinical benefits of concurrent chemoradiation therapy outweigh the risks.