Dose-Dependent Association of Vertebral Body irradiation and Lymphopenia During Chemoradiation for Esophageal Cancer

Abstract

Lymphopenia during chemoradiation (CRT) for esophageal cancer (EC) can adversely affect clinical outcomes. Treatment related factors associated with lymphopenia in this population are not well defined. We hypothesized that radiation dose to vertebral bone marrow during chemoradiotherapy for EC was associated with lymphopenia. The goal of our study was to investigate the dosimetric relationship between vertebral irradiation and lymphopenia. We further sought to explore the association between missed chemotherapy events and hematological toxicity. With institutional review board approval, we retrospectively reviewed forty patients treated with either conventionally fractionated definitive or neoadjuvant CRT for EC. Patients were excluded if treated with palliative intent. Absolute lymphocyte count (ALC) was recorded weekly until two weeks following CRT and graded according to the common terminology of adverse events (CTCAE) version 4.0. Dose volume histogram (DVH) parameters were collected based on vertebral volume receiving between 10 and 40 Gy. Logistic regressions correlated Grade 4 toxicity with DVH parameters and linear regression analysis correlated absolute lymphocyte count nadir with DVH parameters. Receiver Operator Curves (ROC) were constructed to further define dose volume parameters associated with toxicity. Wilcoxon rank sum test and chi-squared analyses tested the association between missed chemotherapy for both Grade 4 lymphopenia and absolute lymphocyte nadir. There were a total of 21 (52.5%) Grade 3 (ALC <0.5 x 109/L) and 17 (42.5%) Grade 4 (ALC <0.2 x 109/L) lymphopenic events. Vertebral volume (VVERT) receiving ≥10 Gy (OR 1.015, p=0.02), ≥20 Gy (OR 1.018, P = 0.025), and ≥30 Gy (OR 1.012, p = 0.026) were correlated with Grade 4 lymphopenia on multivariable logistic regression. Multivariable linear regression correlated lymphopenia nadir with VVERT receiving ≥20 Gy (OR 0.99, P = 0.01), ≥30 Gy (OR 0.99, P = 0.01), and ≥40 Gy (OR 0.99, P = 0.01). Dosimetric parameters on ROC most predictive of Grade 4 toxicity included vertebral volume receiving 10 Gy (VVERT10) ≥291 cc, VVERT20 ≥278 cc, and VVERT30 ≥193 cc. Grade 4 lymphopenia, and lymphocyte nadir were associated with missed chemotherapy (p = 0.01 and p < 0.002, respectively). Lymphopenia, a known negative prognostic factor for EC, is associated with greater volume of vertebral bodies receiving radiation during CRT. Dosimetric sparing of the vertebral bodies may result in less immunosuppression, better tolerance of CRT, and improved clinical outcomes, warranting further investigation.