Mean Cardiopulmonary Dose and Vertebral Marrow Dose Differentially Predict Lineage-Specific Cytopenia Kinetics During Radiotherapy for Esophageal Cancer

Abstract

Lymphopenia is associated with poor outcomes in esophageal cancer (EC) patients (pts) undergoing chemoradiotherapy (CRT). While dose to vertebral marrow is implicated in lymphopenia, cytopenic effects of RT on non-marrow compartments are not well described. We hypothesized that dose to marrow (central) vs. circulating (peripheral) leukocytes (WBCs) has unique effects on WBC counts and clinical outcomes. We identified clinical and dosimetric factors associated with cytopenias in EC pts undergoing CRT, and temporally characterized dose-dependent effects on central and peripheral hematological compartments during therapy. Weekly and 90-day post-CRT cell counts (lymphocyte [Lym], neutrophil [Neu], hemoglobin [Hgb], and platelet [Plt]) were retrospectively collected for 49 pts treated with CRT (definitive or neoadjuvant) for locoregional EC. Dose volume histogram data for thoracic vertebral (TV) volumes receiving 10-40 Gy (TV10-4010-40 Gy (TVS10-40 Gy) was calculated by subtracting TV10-TV40 from total TV volume. Mean cardiopulmonary dose (mCPD) was calculated as mean dose to the volumetric sum of heart, lungs, and great vessels, excluding marrow, as a surrogate for circulating blood pool. We used linear and logistic regression to examine associations between absolute (Abs) and normalized (Nml) cell count nadirs and grade 3 (Gr3) and 4 (Gr4) cell count toxicities by CTCAE v5.0. Repeated measures ANOVA tested for associations between cell count trends and clinical predictors. WBC and Plt counts reached nadir at week 6 of CRT and Hgb at 90 days post-CRT. Abs WBC and Nml Lym declined more rapidly in diabetic pts (p=.02, p=.05); Nml Lym also declined more rapidly with age >66 (p=.047). mCPD was strongly associated with lower Abs and Nml WBC nadir (p=.0003, p=.0006), and Abs and Nml Neu nadir (p<0.01, p=.02), but not Lym nadirs (p>.27). In contrast, TVS10-30 and TV10-20 were associated with Abs Lym nadir (all p<.03, p≤.01) and Nml Lym nadir (all p≤.01, all p≤.001). mCPD was associated with Gr3+ leukopenia (p=.04) and Gr3+ neutropenia (p=0.01). In multivariate analysis, mCPD remained associated with Abs WBC nadir (p=.0018) Nml Neu nadir (p=.0392) and Abs Neu nadir (p=.0053), and TVS10-40 remained associated with Nml Lym nadir (all p≤.042). Mean cardiopulmonary dose and TV marrow dose differentially predict lineage-specific cytopenias during CRT for EC. mCPD is significantly associated with lower Abs and Nml nadirs of multiple cell lines, with the exception of Lym. In contrast, TV dose is significantly associated with lower Lym nadirs but not with other cytopenias. Diabetes and age are associated with a more rapid decline in WBC and Lym counts. Further studies are needed to confirm mechanisms of mCPD-associated count suppression, and to prospectively evaluate the influence of these factors on pt outcomes.