Restoring circadian homeostasis is associated with immune–metabolic recovery and medium-term oncologic outcomes after rectal cancer surgery: a prospective randomized trial

Mar 17, 2026Surgical endoscopy

Restoring daily body rhythms is linked to immune and metabolism recovery and medium-term cancer outcomes after rectal cancer surgery

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Abstract

Surgery significantly reduced the Circadian Rhythm Index from 83.5 ± 8.9 to 59.2 ± 11.8.

Lower baseline Circadian Rhythm Index was linked to higher peaks of interleukin-6 and increased complication risk.
Circadian reinforcement led to a decrease in interleukin-6 AUC₀-₇d from 518 ± 183 pg·day/mL to 362 ± 145 pg·day/mL.
This intervention also reduced inflammatory-nutritional deterioration, with a percent change from -30.8 ± 11.4% to -16.9 ± 10.3%.
Patients who received the intervention had a shorter hospital stay, averaging 9 days compared to 11 days.
The intervention was associated with improved 3-year disease-free survival, with a hazard ratio of 0.56.
Improvements in Circadian Rhythm Index accounted for nearly 28% of the reduction in interleukin-6 levels.

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BACKGROUND: Major surgery disrupts circadian homeostasis, amplifying inflammatory and metabolic stress. The clinical implications of restoring temporal alignment on perioperative immune-metabolic recovery and medium-term oncologic outcomes remain incompletely defined.

METHODS: A two-stage prospective study was conducted at the First Affiliated Hospital of Soochow University (2019-2021). Study A (n = 300) characterized perioperative circadian disruption using a multimodal Circadian Rhythm Index (CRI). Study B (n = 240) was a randomized trial comparing standard ERAS with an integrated circadian reinforcement protocol including timed feeding, controlled light exposure, and low-dose melatonin. Co-primary endpoints were serum interleukin-6 (IL-6) AUC₀-₇d and percent change in the Prognostic Inflammatory and Nutritional Index (ΔPINI).

RESULTS: Surgery markedly reduced CRI (83.5 ± 8.9 → 59.2 ± 11.8, p < 0.001). Lower baseline CRI predicted higher IL-6 peaks and increased complication risk. Circadian reinforcement reduced IL-6 AUC₀-₇d (362 ± 145 vs 518 ± 183 pg·day/mL; p < 0.001) and attenuated inflammatory-nutritional deterioration (ΔPINI -16.9 ± 10.3% vs -30.8 ± 11.4%; p < 0.001). Hospital stay was shorter (9 [8-11] vs. 11 [9-13] days; p = 0.002), and the intervention was associated with improved 3-year disease-free survival (HR 0.56 [0.35-0.89]; p = 0.014). Mediation analysis suggested that CRI improvement accounted for 27.8% of IL-6 reduction and 22.4% of ΔPINI benefit. No serious adverse events occurred.

CONCLUSIONS: Perioperative circadian disruption represents a measurable and modifiable component of surgical stress. Behavioral and environmental circadian reinforcement was associated with improved immune-metabolic recovery and favorable clinical trajectories. Integration of circadian-based strategies within ERAS warrants further multicenter validation.

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Restoring circadian homeostasis is associated with immune–metabolic recovery and medium-term oncologic outcomes after rectal cancer surgery: a prospective randomized trial

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