Abstract
BackgroundEven the best cancer surgery is usually associated with minimal residual disease. Whether these remaining malignant cells develop into clinical recurrence is at least partially determined by adequacy of host defense, especially natural killer cell function. Anesthetics impair immune defenses to varying degrees, but nitrous oxide appears to be especially problematic. We therefore tested the hypothesis that colorectal-cancer recurrence risk is augmented by nitrous oxide administration during colorectal surgery.MethodsWe conducted a 4- to 8-year follow-up of 204 patients with colorectal cancer who were randomly assigned to 65% nitrous oxide (n = 97) or nitrogen (n = 107), balanced with isoflurane and remifentanil. The primary outcome was the time to cancer recurrence. Our primary analysis was a multivariable Cox-proportional-hazards regression model that included relevant baseline variables. In addition to treatment group, the model considered patient age, tumor grade, dissemination, adjacent organ invasion, vessel invasion, and the number of nodes involved. The study had 80% power to detect a 56% or greater reduction in recurrence rates (i.e., hazard ratio of 0.44 or less) at the 0.05 significance level.ResultsAfter adjusting for significant baseline covariables, risk of recurrence did not differ significantly for nitrous oxide and nitrogen, with a hazard ratio estimate (95% CI) of 1.10 (0.66, 1.83), P = 0.72. No two-way interactions with the treatment were statistically significant.ConclusionColorectal-cancer recurrence risks were not greatly different in patients who were randomly assigned to 65% nitrous oxide or nitrogen during surgery. Our results may not support avoiding nitrous oxide use to prevent recurrence of colorectal cancer.Implications StatementThe risk of colorectal cancer recurrence was similar in patients who were randomly assigned to 65% nitrous oxide or nitrogen during colorectal surgery.Trial RegistrationCurrent Controlled Clinical Trials NCT00781352
Highlights
Even the best cancer surgery is usually associated with minimal residual disease
Cancer surgery is associated with release of tumor cells into the systemic circulation [1], and it is likely that minimal residual disease is present after even the best surgery
Though we did not expect any imbalance in these characteristics between the two groups due to randomized allocation of type of inhaled gas, patients in the nitrous-oxide group had slightly higher preoperative carcinoembryonic antigen (CEA) values than patients in the nitrogen group (3.4 [1.9, 7.5])
Summary
Even the best cancer surgery is usually associated with minimal residual disease. Whether these remaining malignant cells develop into clinical recurrence is at least partially determined by adequacy of host defense, especially natural killer cell function. Anesthetics impair immune defenses to varying degrees, but nitrous oxide appears to be especially problematic. Perioperative factors that impair host immunity are likely to facilitate local recurrence or establishment of metastatic tumor after cancer surgery [4]. The extent to which various anesthetic drugs depress natural killer cell and other immune functions related to countering malignancy varies considerably [5,7,8,9]. Nitrous oxide depresses neutrophil chemotaxis [14] and reduces proliferation of human peripheral blood mononuclear cells [14]
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