Lymphocyte Trends During Neoadjuvant Chemoradiation Predict Pathologic Complete Response at Time of Surgical Resection of Locally Advanced Rectal Cancers

Abstract

While achieving complete pathologic tumor response (ypCR) following neoadjuvant chemoradiation (NCRT) is achievable in up to 25% of patients with locally-advanced rectal cancer, preoperative factors predicting which patients will achieve ypCR at time of definitive surgery are still poorly-elucidated. A number of studies have reported a correlation between peripheral lymphocyte counts and responses to various oncologic therapies and overall survival outcomes in patients with an array of malignancies including rectal cancer. The aim of this study is to determine whether lymphocyte trends at four weeks after initiation of NCRT are associated with complete treatment response in locally-advanced rectal cancers. Patient, tumor, and treatment data was abstracted on patients with T2 N1-2 and T3-4 N0-2 rectal cancers treated with NCRT and subsequent surgical resection at our institution from January 2009 through December 2013, allowing for two-year follow-up. Neoadjuvant chemoradiation for all patients consisted of completion of 4500 cGy to entire pelvis with boost to 5040 cGy to gross disease with concurrent 5-FU or capecitabine chemotherapy. Pathologic evaluation of final surgical specimens following NCRT was recorded as follows: complete response (ypCR), partial response (ypPR) or stable/progressive disease. Univariate analysis was performed to determine whether relative (%) lymphocyte counts at four weeks after initiation of NCRT (4wk RLC) and/or the ratio of 4wk total lymphocyte count (4wk TLC) to pre-treatment baseline total lymphocyte count (bTLC) were associated with the rates of ypCR. Frequencies were compared using the chi-square test. Thirty-one patients were identified who underwent NCRT followed by surgical resection for locally-advanced rectal cancer during the specified time period. Of the 31 post-NCRT surgical specimens reviewed, ypCR was observed in 10 patients (32%) and ypPR was found in 18 patients (58%). When analyzed as a continuous variable, greater 4wk RLC was predictive of ypCR (OR = 1.27, P = 0.065). Area under the ROC curve as a predictor for ypCR for 4wk RLC was 0.71 and for 4wk TLC: bTLC ratio was 0.69. Of patients with 4wk RLC ≤ 9, 3/19 (16%) achieved ypCR compared to 7/12 (58%) with RLC > 9 (P = 0.021). Of patients with 4wk TLC: bTLC ≤ 0.43, 3/17 (18%) achieved ypCR compared to 7/14 (50%) with 4wk TLC: bTLC > 0.43 (P = 0.055). When assessing lymphocyte trends at four weeks after initiation of NCRT, both RLC as well as percent decrease of TLC from baseline were associated with tumor ypCR at time of definitive surgery in patients with locally-advanced rectal cancers. This study underlines the importance of understanding the role of the host immune response in rectal tumor control. Further work characterizing which tumors have the highest response to immune modulation may guide patient selection in future studies investigating immune checkpoint inhibitors.