Incidence and Impact of Lymphopenia Associated With Total Neoadjuvant Therapy for Low-Lying Rectal Tumors

Abstract

To assess incidence of lymphopenia and its association with outcomes in patients treated with total neoadjuvant therapy (TNT) for low-lying rectal tumors.Patients with Stage II-III, low rectal adenocarcinomas treated from 2015-2018 with TNT were retrospectively reviewed. All patients were candidates for an APR surgical resection, but were treated with intent to omit surgery if they had a clinical complete response. All patients received definitive radiation (median dose 54 Gy, range 50-56 Gy, at 1.8-2 Gy/fx) with concurrent capecitabine, with additional chemotherapy (CT) delivered either prior to or following chemoradiation (CRT). Institutional results on patient outcomes have previously been reported with a clinical complete response rate of 75%; with only 19% of those ultimately requiring surgery for local recurrence. Absolute lymphocyte counts (ALC) were collected prior to initiating CRT and at 3-month intervals following CRT and graded based on severity of lymphopenia (absolute lymphocyte count < 1000/mm3) using CTCAE v5.0. A Cox proportional hazards model was used to identify if degree of lymphopenia was associated with receipt of surgery (as surgery was only performed for either incomplete response or local recurrence).A total of 28 patients with low rectal cancers were treated with TNT during this period, with ALC analyzed for the 26 who had detailed lymphocyte data available. 7 patients were treated with CT followed by CRT, receiving a median of 8 (range 4-8) cycles of CT, and 18 patients were treated with CRT followed by CT, receiving a median of 6 cycles (range 1-9). One patient refused CT after CRT. Prior to initiating CRT, the median ALC was 1,665/mm3 (range, 710-3,060/mm3), with lymphopenia present in only 4 patients (1 neoadjuvant CT and 3 adjuvant CT). The median ALC nadir during CRT was 450/mm3 (range, 230-900/mm3), with all 26 patients experiencing lymphopenia during the course of CRT: 4% Grade 1, 35% Grade 2, 61% Grade 3, and 0% Grade 4. Rates of lymphopenia at 3-, 6-, and 12-months post CRT were 73%, 81%, and 42%, respectively. On Cox regression analysis, increased pre-CRT and 12-month post-CRT lymphocyte counts were associated with a decreased risk of need for surgery (P < 0.05) and remained significant when accounting for the sequencing of CT, while lymphocyte count nadir during CRT and 3-/6-month post-CRT levels were not (P > 0.05).Despite the frequency of lymphopenia during CRT, the degree of lymphopenia during and up to 6 months after CRT did not appear to predict future surgery. However, increased pre-CRT and 12-month post-CRT ALC were associated with decrease need of surgery. CRT produces both oxidative stress and immune response stimulation to kill cancer cells. Patients with higher pre-CRT and 12-month post-CRT ALC may represent a population with more robust immune systems, producing more favorable tumor responses. Additional studies are warranted.