A Translational Randomized Trial of Perioperative Arginine Immunonutrition on Natural Killer Cell Function in Colorectal Cancer Surgery Patients

Ann Surg Oncol. 2022 Nov;29(12):7410-7420. doi: 10.1245/s10434-022-12202-y. Epub 2022 Jul 25.


Background: Surgery results in severe impairment of natural killer (NK) cell cytotoxicity (NKC) and activity (NKA, cytokine secretion), and a dramatic drop in arginine levels. Postoperative immunosuppression is associated with increased complications and recurrence. Perioperative arginine is reported to reduce postoperative complications. Because arginine modulates NK cell function, this study aimed to determine whether perioperative consumption of arginine-enriched supplements (AES) can improve NK cell function in colorectal cancer (CRC) surgery patients.

Methods: This study randomized 24 CRC patients to receive the AES or isocaloric/isonitrogenous control supplement three times a day for five days before and after surgery. The AES contained 4.2 g of arginine per dose (12.6 g/day). The primary objective was to determine whether AES improved NKC by 50 % compared with the control group after surgery.

Results: On surgery day (SD) 1, NKC was significantly reduced postoperatively in the control group by 50 % (interquartile range [IQR], 36-55 %; p = 0.02) but not in the AES group (25 % reduction; IQR, 28-75 %; p = 0.3). Furthermore, AES had no benefit in terms of NKA or NK cell number. Compliance was much greater preoperatively (>91 %) than postoperatively (<46 %). However, despite excellent preoperative compliance, arginine was rapidly cleared from the blood within 4 h after consumption and therefore, did not prevent the postoperative drop in arginine.

Conclusions: Oral consumption of arginine immunonutrition resulted in a modest improvement in NKC after surgery but was unable to prevent postoperative arginine depletion or the suppression of NKA (ClinicalTrials.gov NCT02987296).

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Arginine*
  • Colorectal Neoplasms* / surgery
  • Cytokines
  • Humans
  • Killer Cells, Natural
  • Postoperative Complications / prevention & control
  • Prospective Studies


  • Cytokines
  • Arginine

Associated data

  • ClinicalTrials.gov/NCT02987296