Impact of residual setup errors after image guidance on heart dose in NSCLC patients

Abstract

Purpose or Objective A recent study of NSCLC patients showed small residual setup errors (shifts) in the direction of the heart following image-guidance were significantly related to overall survival. This study of the dosimetric effects of these residual shifts investigates the hypothesis that observed survival differences were related to a change in heart dose. Material and Methods Accumulated doses including shifts for each fraction were determined for 546 NSCLC patients treated with 55Gy in 20 fractions, assuming shift invariance (validated in a subset). Planning CTs and corresponding dose distributions were deformed to a reference case. Image-based datamining and permutation testing techniques were then applied to the difference between the planned and accumulated dose (Δdose) to determine where Δdose relates to 1-year survival. The significance of Δdose in the identified region was assessed using multivariable Cox analysis, correcting for age, sex, GTV, N stage and ECOGPS. The cohort was then split into octiles, based upon planned dose to the region, and multivariable Cox analysis performed for each sub-cohort to explore the dose response relationship. The identified dose threshold for damage was then tested in an independent validation cohort of 1482 NSCLC patients (treated with 55Gy in 20 fractions) from the same institution, based upon the planned dose to the region (as shifts were unavailable for this cohort). Results Permutation testing identified a small region in the heart base, near the right coronary artery, where Δdose correlated with 1-year survival (Figure 1). Δdose in this region showed no correlation with tested common clinical variables – meaning it is likely not confounded and thus is a sensitive test metric. Δdose was significant in multivariable Cox regression (p<0.001, HR 1.221/Gy), with increasing change in dose from plan resulting in greater risk of death. Octile analysis revealed Δdose to be significant only in the 7th octile, planning dose range 16.2– 23.4Gy, suggesting a steep dose-effect relation for heart damage in this range. Taking 16.2Gy as a conservative threshold dose, this result was successfully validated. Conclusion This study suggests the relation between residual setup errors and survival could be explained by changes in cardiac dose. It identifies an area at the heart base where dose is correlated with survival. Our results suggest the dose threshold for cardiac damage is between 16.2–23.4Gy in the base of the heart, which was validated in an independent cohort. This study provides further evidence supporting the use of stricter heart dose constraints, and explores what these constraints should be. The dose effect in other regions of the heart should also be investigated.