TY - JOUR
T1 - Intraoperative opioids are associated with decreased recurrence rates in colon adenocarcinoma
T2 - a retrospective observational cohort study
AU - Yuval, Jonathan B.
AU - Lee, Jasme
AU - Wu, Fan
AU - Thompson, Hannah M.
AU - Verheij, Floris S.
AU - Gupta, Hersh V.
AU - Irie, Takeshi
AU - Scarpa, Joseph R.
AU - McCormick, Patrick J.
AU - Smith, J. Joshua
AU - Shia, Jinru
AU - Weiser, Martin R.
AU - Sánchez-Vega, Francisco
AU - Tan, Kay See
AU - Fischer, Gregory W.
AU - Garcia-Aguilar, Julio
AU - Mincer, Joshua S.
N1 - Funding Information:
The National Institutes of Health/National Cancer Institute Memorial Sloan Kettering Cancer Center Support Grant (P30 CA008748). JBY's research fellowship at Memorial Sloan Kettering was funded in part by a grant from the National Cancer Institute ( T32 CA009501 ). Marie-Josée and Henry R. Kravis Center for Molecular Oncology.
Funding Information:
PJM's spouse has an equity interest in Johnson & Johnson. GWF is on the speaker's bureau and serves as a consultant for Edwards Lifesciences. JG-A has received support from Medtronic, Johnson & Johnson, and Intuitive Surgical. Dr Smith has served as a clinical advisor to Guardant Health Inc. (2019) and received travel support from Intuitive Surgical Inc. for fellow education (2015). JS is a consultant for Paige AI.The National Institutes of Health/National Cancer Institute Memorial Sloan Kettering Cancer Center Support Grant (P30 CA008748). JBY's research fellowship at Memorial Sloan Kettering was funded in part by a grant from the National Cancer Institute (T32 CA009501). Marie-Josée and Henry R. Kravis Center for Molecular Oncology.
Publisher Copyright:
© 2022 British Journal of Anaesthesia
PY - 2022/8
Y1 - 2022/8
N2 - Background: Opioid-induced immunomodulation may be important in colon adenocarcinoma, where tumour DNA mismatch repair (MMR) can determine the level of immune activation with consequences for therapeutic response and prognosis. We evaluated the relationship between intraoperative opioid exposure, MMR subtype, and oncological outcomes after surgery for colon adenocarcinoma. Methods: Intraoperative opioid use (standardised by calculating morphine milligram equivalents) during stage I–III colon adenocarcinoma resection was reviewed retrospectively. Tumours were classified as DNA mismatch repair deficient (dMMR) or proficient (pMMR) by immunohistochemistry. The primary outcome was local tumour recurrence, distant tumour recurrence, or both (multivariable analysis). The exposures of interest were intraoperative analgesia and tumour subtype. Opioid-related gene expression was analysed using The Cancer Genome Atlas Colon Adenocarcinoma transcriptomic data. Results: Clinical and pathological data were analysed from 1157 subjects (median age, 60 [51–70] yr; 49% female) who underwent curative resection for stage I–III colon adenocarcinoma. Higher intraoperative opioid doses were associated with reduced risk of tumour recurrence (hazard ratio=0.92 per 10 morphine milligram equivalents; 95% confidence interval [95% CI], 0.87–0.98; P=0.007), but not with overall survival. In tumours deficient in DNA MMR, tumour recurrence was less likely (HR=0.38; 95% CI, 0.21–0.68; P=0.001), with higher opioid dose associated with eightfold lower recurrence rates. Gene expression related to opioid signalling was different between dMMR and pMMR tumours. Conclusions: Higher intraoperative opioid dose was associated with a lower risk of tumour recurrence after surgery for stage I–III colon adenocarcinoma, but particularly so in tumours in which DNA MMR was deficient.
AB - Background: Opioid-induced immunomodulation may be important in colon adenocarcinoma, where tumour DNA mismatch repair (MMR) can determine the level of immune activation with consequences for therapeutic response and prognosis. We evaluated the relationship between intraoperative opioid exposure, MMR subtype, and oncological outcomes after surgery for colon adenocarcinoma. Methods: Intraoperative opioid use (standardised by calculating morphine milligram equivalents) during stage I–III colon adenocarcinoma resection was reviewed retrospectively. Tumours were classified as DNA mismatch repair deficient (dMMR) or proficient (pMMR) by immunohistochemistry. The primary outcome was local tumour recurrence, distant tumour recurrence, or both (multivariable analysis). The exposures of interest were intraoperative analgesia and tumour subtype. Opioid-related gene expression was analysed using The Cancer Genome Atlas Colon Adenocarcinoma transcriptomic data. Results: Clinical and pathological data were analysed from 1157 subjects (median age, 60 [51–70] yr; 49% female) who underwent curative resection for stage I–III colon adenocarcinoma. Higher intraoperative opioid doses were associated with reduced risk of tumour recurrence (hazard ratio=0.92 per 10 morphine milligram equivalents; 95% confidence interval [95% CI], 0.87–0.98; P=0.007), but not with overall survival. In tumours deficient in DNA MMR, tumour recurrence was less likely (HR=0.38; 95% CI, 0.21–0.68; P=0.001), with higher opioid dose associated with eightfold lower recurrence rates. Gene expression related to opioid signalling was different between dMMR and pMMR tumours. Conclusions: Higher intraoperative opioid dose was associated with a lower risk of tumour recurrence after surgery for stage I–III colon adenocarcinoma, but particularly so in tumours in which DNA MMR was deficient.
KW - DNA mismatch repair
KW - colon adenocarcinoma
KW - gene expression
KW - immunomodulation
KW - opioids
KW - surgery
UR - http://www.scopus.com/inward/record.url?scp=85132745371&partnerID=8YFLogxK
U2 - 10.1016/j.bja.2022.04.024
DO - 10.1016/j.bja.2022.04.024
M3 - Article
C2 - 35718564
AN - SCOPUS:85132745371
SN - 0007-0912
VL - 129
SP - 172
EP - 181
JO - British Journal of Anaesthesia
JF - British Journal of Anaesthesia
IS - 2
ER -