Characterization and dosimetric predictors for absolute lymphocyte count changes during neoadjuvant chemoradiotherapy with or without pembrolizumab for esophageal squamous cell carcinoma: an analysis of a prospective cohort.

Aim: To characterize the differences of dynamic changes for absolute lymphocyte count (ALC) among esophageal squamous cell carcinoma (ESCC) patients treated with neoadjuvant chemoradiotherapy (nCRT) with or without pembrolizumab, as well as to investigate the clinical and lymphocyte-related organs dosimetric parameters that would impact ALC nadir during nCRT.

Materials and methods: A total of 216 ESCC patients who received nCRT (with pembrolizumab 144; without pembrolizumab: 72) were identified from a prospective cohort. Weekly and 1-month post-nCRT ALC were identified. lymphocyte-related organs at risk (LOARs) were delineated. linear and logistic regression analysis was used to analyze the association between G4 lymphopenia/lymphopenia nadir and clinical/DVHs factors. Receiver-operating characteristic curves were used to derive optimal dosimetric planning constraints. Grade 4 (G4) lymphopenia was defined as ALC < 0.2 × 10⁹/L during nCRT.

Results: G4 lymphopenia was observed in 35 ESCC patients (16.2%) during neoadjuvant treatment. Compared to nCRT alone, the addition of pembrolizumab to nCRT significantly improve lymphopenia recovery in the 1-months after nCRT (p = 0.0003), but the ALC at other time point during nCRT and ALC nadir was comparable between the two groups. A total of 198 patients finally received surgery. Of them, 98 patients archived pCR (49.5%), with 50.4% (68/135 patients) in nCRT with pembrolizumab and 47.6% (30/63) in nCRT alone(p = 0.94), respectively. The mean ALC nadir in the pCR group was significantly higher than those without (p = 0.0003). Multivariable linear and logistic regression analysis indicated that TVB mean dose, TVB V5, TVB V10, TVB V20, mean cardiopulmonary dose, mean ribs dose, mean whole body dose, mean spleen dose, V5, V10, and V20 of spleen dose were significantly associated with developing grade 4 lymphopenia. Dosimetric analysis showed that lymphocyte-sparing photon or proton irradiation was feasible while did not compromise clinically acceptable objectives.

Conclusion: The addition of pembrolizumab to nCRT improved lymphopenia recovery for ESCC after trimodality therapy. ALC nadir was significantly associated with pCR and RFS after nCRT. Sparing of LOARs using advanced radiation techniques might reduce the risk of developing lymphopenia and improve treatment response in the era of immunotherapy.