Lymphopenia Association with Planning Target Volume and Lung V5 and its effect on survival of esophageal cancer receiving neoadjuvant chemo-radiation with Dutch CROSS regime

Abstract

Background: Radiation has a strong lympholytic effect. This effect has been overlooked for decades until recently. As immunotherapy is becoming one of the main systemic treatment of various cancer, it is important to adopt best radiation technique to preserve lymphocyte numbers. Radiation-induced lymphopenia has been reported to be adversely associated with overall survival and recurrence free survival in various cancers including lung, pancreatic and head and neck cancer. Data of lymphopenia effect on esophageal cancer is lacking. We therefore sought to study the association of lymphopenia and overall survival in esophageal cancer patients who have undergone neoadjuvant chemo-radiation according to Dutch CROSS trial regime. One of the possible mechanism of severe lymphopenia in radiotherapy is the large volume of low dose bath killing large number of circulating lymphocytes in both systemic and pulmonary circulation. As there is report of relationship of low dose lung dosimetry parameters with lymphopenia in NSCLC, we also aim to study this relationship in esophageal cancer. Methods: All esophageal cancer patients from June 2012 to April 2015 in our tertiary university hospital who have received neoadjuvant chemo-radiation according to Dutch CROSS trial regime has been retrospectively reviewed. Total subjects eligible for review is 51. One subject has died before the start of chemo-radiation and thus was excluded from analysis. Lymphocyte nadir was defined as the minimum lymphocyte value measured between the start of neoadjuvant chemo-radiation and the operation date. Relationships between lymphocyte nadirs with overall survival (OS) and recurrence free survival (RFS) were evaluated with Cox-regression analysis. Association between Planning Target volume (PTV) and lung dose- volume histogram (DVH) parameters were analysed with Pearson correlation coefficients. Results: 48 out of 50 subjects have normal baseline lymphocyte counts. Low lymphocyte nadir is found to have negative effect on patient's overall survival (OS). On multi-variable Cox regression with backward elimination analysis, patients with higher lymphocyte nadirs exhibited significantly improved OS (hazard ratio [HR] Z=0.656 per 0.1 x 10^9 lymphocytes/L, p=0.009). Of note, No significant relationships with OS were seen in baseline total white cell count, lymphocyte count and neutrophil count. Analyses of lung DVH parameters revealed significant correlations at lower doses (lung V1-V15: P<0.001). The absolute value Pearson correlation coefficient incrementally decreased and became nonsignificant at higher doses (lung V25: P>.05). For instance, the correlation coefficient of V1, V5 and V10 were -0.566, -0.495 and -0.419 respectively. Larger PTV was also associated with lower lymphocyte nadir ( r= -0.367 P= 0.008). Conclusion(s): Lower lymphocyte nadir is associated with poorer overall survivial in this group of patients. Higher low dose lung DVH and larger PTV are associated with lower lymphocyte nadir. These findings shall be confirmed with prospective data in future studies. This also suggests immune preserving radiation strategy in radiation by suppressing low dose lung DVH may improve OS in this group of patients.