Early postoperative hospital exposome stress, multisystem recovery trajectories, and long-term oncologic outcomes after curative colorectal cancer surgery.

BACKGROUND: Postoperative recovery after colorectal cancer surgery is highly heterogeneous and incompletely explained by tumor stage or operative factors. Whether early postoperative inpatient stress exposure and subsequent multisystem recovery dynamics are associated with ctDNA-defined molecular residual disease and long-term oncologic outcomes remains unclear.

METHODS: In this prospective longitudinal cohort study, 1200 patients undergoing curative-intent resection for stage II-III colorectal cancer (2018-2020) were followed for up to 60 months. Early postoperative hospital exposome stress was quantified using a prespecified composite Hospital Exposome Stress Load (HESL) assessed during postoperative days 0-7. HESL was conceptualized as a composite inpatient recovery exposure based on routinely captured proxy indicators, rather than as a direct physical measurement of the ward environment. To address potential reverse causation, environmental/nocturnal disruption components were distinguished from care-process or clinical-intensity components in sensitivity analyses. Multisystem recovery trajectories were derived from repeated physiological and inflammatory measures using latent class mixed modeling. Trajectory classification was based on standardized recovery scores at POD3 and POD7 and did not include postoperative length of stay or downstream oncologic outcomes. Outcomes included clinically significant postoperative complications, ctDNA-defined molecular residual disease (MRD), and disease-free survival (DFS).

RESULTS: Higher HESL was associated with increased risk of postoperative complications and a greater likelihood of maladaptive recovery trajectories. MRD positivity increased stepwise across HESL tertiles (9.8%, 14.9%, and 22.4%, respectively), and both high HESL (adjusted OR 2.12, 95% CI 1.36-3.30) and maladaptive recovery phenotypes (adjusted OR 2.89, 95% CI 1.78-4.70) were associated with MRD positivity. Over long-term follow-up, elevated HESL (adjusted HR 1.68, 95% CI 1.32-2.14) and maladaptive recovery trajectories (adjusted HR 2.21, 95% CI 1.63-2.99) were associated with inferior DFS. Findings were robust across multiple sensitivity analyses.

CONCLISIONS: Early postoperative hospital exposome stress and multisystem recovery trajectories were associated with molecular residual disease and long-term oncologic outcomes after curative colorectal cancer surgery. Because HESL included both environmental/nocturnal disruption proxies and care-process intensity indicators, these findings should be interpreted as prognostic and hypothesis-generating rather than causal.