Severe lymphopenia predicts poorer survival in patients with rectal cancer undergoing neoadjuvant chemoradiation.
Authors: Kim Daniel W , Lee Grace , Weekes Colin D. , Ryan David P. , Parikh Aparna Raj , Allen Jill N. , Giantonio Bruce J. , Berger David L. , Kunitake Hiroko , Ricciardi Rocco , Cusack James C. , Hwang William L. , Hong Theodore S. , Wo Jennifer Y 
Published: January 2021

138

Background: Chemoradiation (CRT) induced lymphopenia is common and associated with poorer survival in multiple solid malignancies. The objective of this study was to evaluate the prognostic impact of lymphopenia in patients with rectal cancer undergoing neoadjuvant CRT. We hypothesized that severe lymphopenia would correlate with worse survival. Methods: The inclusion criteria for this single-institution retrospective study were: 1) biopsy-proven diagnosis of rectal adenocarcinoma, 2) receipt of neoadjuvant CRT followed by surgery, and 3) absolute lymphocyte count (ALC) available prior to and within 12 weeks of CRT. In general, CRT consisted of 5-fluorouracil or capecitabine and RT with 50.4 Gy over 28 fractions. Lymphopenia was graded according to CTCAE v5.0. The primary variable of interest was ALC nadir within 12 weeks of CRT, dichotomized by ALC of < 0.5 k/μl (Grade 3 lymphopenia). The primary endpoint was overall survival (OS). Cox modeling and Kaplan-Meier methods were used to perform survival analyses. Results: 193 patients were identified. Median follow-up for the entire cohort was 68 months. Median age was 58. 62% were male, 82% were Caucasian, and 90% had ECOG ≤1. Median tumor distance from anal verge was 8 cm. Overall clinical stage was 1 or 2 in 23% and 3 in 77%. Median baseline CEA was 3.2 ng/ml. 83% received chemotherapy following RT. Following CRT, 70% underwent low anterior resection and 30% underwent abdominoperineal resection. Median baseline ALC for the entire cohort was 1.7 k/ul. ALC nadir within 12 weeks of initiating CRT was < 0.5 k/ul among 110 (57%) patients. Patients who developed severe lymphopenia with CRT had a lower baseline hemoglobin (median 13.3 vs. 14.0 g/dl, p = 0.022) and lower baseline ALC (median 1.6 vs. 1.8 k/ul, p = 0.010) compared to those who did not develop severe lymphopenia. There were no differences in disease and treatment characteristics between the two groups. On multivariable Cox model, severe lymphopenia was significantly associated with increased hazards of death (HR = 3.52 [95% CI 1.47-8.44], p = 0.005). Receipt of chemotherapy post-CRT (HR = 0.22 [95% CI 0.09-0.54], p = 0.001) predicted better OS while higher pathologic T (HR = 8.01 [95% CI 2.98-17.21], p < 0.001) and N stage (HR = 9.43 [95% CI 3.19-27.86], p < 0.001) and positive surgical margin (HR = 3.77 [95% CI 1.13-12.62], p = 0.031) predicted worse OS. The 5-year OS was 79% vs. 92% in the cohort with vs. without severe lymphopenia, respectively (log-rank p = 0.001). Conclusions: CRT-induced lymphopenia is common and severe lymphopenia may be a prognostic marker of poorer survival in rectal cancer. Closer observation in high-risk patients and treatment modifications may be potential approaches to mitigating CRT-induced lymphopenia. Our findings also suggest an important role of the host immunity in rectal cancer outcomes, supporting the ongoing efforts of immunotherapy trials in rectal cancer.