Predictors of Severe Chemoradiation-Related Lymphopenia in Patients With Anal Squamous Cell Carcinoma

Abstract

Treatment-related lymphopenia may be prognostic for poorer survival in anal squamous cell carcinoma (ASCC). With current randomized trials evaluating the potential role of immunotherapy in localized ASCC, the contribution of host immunity will become increasingly important. We sought to identify clinical, tumor, and dosimetric predictors for severe lymphopenia during chemoradiation (CRT) for ASCC.Patients who underwent CRT for ASCC from 2008-2020 at two Comprehensive Cancer Centers were identified and charts were reviewed. Only those who received 5-fluorouracil and mitomycin C concurrent with IMRT to 50.4-59.4 Gy were included. Lymphopenia was graded per CTCAE v5.0 with absolute lymphocyte count (ALC) nadir < 0.2×109/L indicating grade 4 toxicity. Logistic regression was used to distinguish the effects directly attributable to radiation exposure from contextual covariates. The outcome was presence of grade 4 lymphopenia. The primary predictors of interest were iliac crest V40 and total prescription dose (TPD). It was hypothesized that higher iliac crest V40 and higher TPD would be positively associated with severe lymphopenia. PTV total volume (PTVtv) and GTVp volume were also included and interactions with dose were examined for each. Lastly, covariates included history of malignancy, age, and pre-treatment ALC. These variables were selected because literature has identified them as relevant to lymphopenia in other samples.A total of 119 patients were identified with a median age of 59 years. Forty-seven patients (39%) had T3/4 disease and 57 patients (49%) had node positive disease. Fifty-eight patients (49%) developed grade 4 lymphopenia during CRT or within 1 month of completing treatment. On multivariate analysis pre-treatment ALC (P = 0.006, OR = 0.31), GTVp volume (P = 0.010, OR = 1.23), and iliac crest V40 (P = 0.013, OR = 1.08) were predictive of grade 4 lymphopenia. History of previous malignancy was associated with reduced risk of grade 4 lymphopenia (P = 0.030, OR = 0.04). TPD and PTVtv were not independently predictive of grade 4 lymphopenia, though patients with a higher TPD and smaller PTVtv were significantly more likely to develop grade 4 lymphopenia (P = 0.038) compared to those with both high TPD and PTVtv or both low TPD and PTVtv.Severe lymphopenia is common during CRT for ASCC and certain patients are at higher risk for developing this treatment-related toxicity. Pre-treatment lymphocyte count, larger tumor volume, and dose to the iliac crests are each independent predictors of grade 4 lymphopenia. Additionally, closer observation should be employed when treating patients with higher prescription doses and smaller PTV total volumes. With ongoing efforts to incorporate immunotherapy in the treatment of ASCC, using predictors to detect patients at risk for severe lymphopenia will be increasingly important.