Impact of time-of-day administration of neoadjuvant chemoradiotherapy on pathologic complete response in esophageal cancer: A multi-site review over two decades.

Abstract

346 Background: Recent studies have consistently demonstrated associations between survival and time-of-day administration of oncologic treatments (i.e. immunotherapy and radiotherapy). However, the reported outcomes of OS and PFS are inextricably linked to confounding factors that also influence treatment appointments. We present the first report of surgical pathology as a more objective and unbiased measure of time-of-day related treatment efficacy in the neoadjuvant setting. Methods: We reviewed the medical records of all patients with non-metastatic esophageal cancer who underwent neoadjuvant chemoradiotherapy followed by esophagectomy within a multi-site academic hospital system between 2004 and 2024. Achievement of pathologic complete response (pCR) was correlated with receipt of at least 60% of radiotherapy (RT) fractions after 12:00 using both univariate and multivariable logistic regression, adjusted for clinicopathologic characteristics. Results: This study consisted of 789 patients with post-surgery median follow-up of 43 months (IQR 20–105). Patient characteristics were balanced between those who did and did not undergo at least 60% of RT fractions after 12:00 (Table, P>0.05), except for the use of proton therapy (P=0.001). Receipt of at least 60% of RT fractions after 12:00 was associated with significantly higher rate of pCR (25 vs. 13%, OR 2.10 [95% CI 1.22–3.60], P univar =0.007). This finding remained robust to multivariable adjustment for age, sex, ethnicity/race, smoking status, ECOG performance, tumor location, histology (type, grade, features), cancer stage, RT modality, and concurrent chemotherapy regimen (OR 2.22 [95% CI 1.20–4.08], P multivar =0.011). Patients who received at least 60% of RT fractions after 12:00 also had longer median OS (87 vs. 44 months, HR 0.75 [95% CI 0.58–0.98], P multivar =0.034). Time-of-day administration of chemotherapy infusions was not associated with pCR or OS. Conclusions: In neoadjuvant chemoradiotherapy for esophageal cancer, we found that receipt of more afternoon RT treatments was independently associated with improved outcomes as measured by both surgical pathology and OS. Additional mechanistic and prospective clinical studies of chronotherapy are warranted. Received ≥60% RT fractions after noon,N=622 (%) Received <60% RT fractions after noon,N=127 (%) P-value Median age [IQR] 62 [54–68] 62 [54–67] 0.656 Female 83 (13) 20 (16) 0.317 Never-smoker 176 (27) 26 (20) 0.183 ECOG 0–1 613 (93) 120 (94) 0.572 Adenocarcinoma histology 604 (91) 111 (87) 0.184 Signet ring cell features 99 (15) 26 (20) 0.144 Distal esophageal primary 606 (92) 114 (90) 0.495 Overall stage I–II / III / IVA 69 (10) / 435 (66) / 158 (24) 10 (8) / 81 (64) / 36 (28) 0.456 Received proton therapy 201 (30) 20 (16) 0.001