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Anesthesia Services of Wyoming

Effect of Anesthesia and Analgesia on Cancer Recurrence

Oncological surgery for tumor removal often serves as the first step in a patient’s cancer treatment plan. In the case of benign tumors, it may be the only course of treatment needed. However, the perioperative period includes several challenges for every surgical patient, since both surgery and anesthesia activate the body’s natural stress response, which involves the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). The HPA and SNS release neuroendocrine mediators, such as cytokines, catecholamines, and growth factors, which can promote tumor growth, angiogenesis, and micro-metastases. Anesthesiologists must carefully manage anesthesia and analgesia in cancer patients to ensure the drugs do not negatively influence immune response and cancer recurrence.1

Approximately 80% of cancer patients will receive anesthesia for analgesia, amnesia, sedation, or neuromuscular block, making it essential to understand the impacts of anesthetic drugs on recurrence.2 A 2003 preclinical study examined the effect of thiopental, ketamine, and propofol anesthesia on natural killer (NK) cell activity and resistance to experimental metastasis in lung tumors in rats. In this study, all anesthetics except propofol significantly increased tumor cell retention and metastasis, an effect that was attributed to reduced NK cell activity.3 On the other hand, another study found that ketamine is reported to decrease levels of proinflammatory cytokines, such as IL-6, and induce lymphocyte apoptosis via mitochondrial pathways.4 

Volatile anesthesia has also been found to have an effect on immune function and cancer recurrence. Halothane significantly decreases NK cell activity and is associated with accelerated tumor progression in mouse models of lung carcinoma and melanoma.3,5 Isoflurane may promote a pro-tumorigenic environment by upregulating hypoxia-inducible factor-1α (HIF1α), which is associated with aggressive cancer phenotypes and poorer health outcomes. The anesthetic has also been shown to promote tumor recurrence by increasing pro-tumorigenic cytokines and matrix metalloproteinases (MMPs), a group of enzymes involved in angiogenesis and linked to the progression of diseases such as cancer, arthritis, and ulcers.6,7

Local anesthetics work by blocking voltage-gated sodium channels (VGSCs), which impedes neural signal transmission. By inhibiting VGSCs, local anesthetics provide effective analgesia and reduce stress-induced immunosuppression, preserving the innate immune response. This mechanism can limit the potential negative effects of general anesthetics on cancer recurrence. Some cancers, such as breast, colon, and lung, express many VGSCs.1 By blocking these channels, local anesthetics like lidocaine, ropivacaine, and bupivacaine can have anti-tumor effects. Mesenchymal stem cells (MSC) are self-renewing clonal progenitor cells of tissues that spread to wounds and tumors. Local anesthetics reduce MSC proliferation, consistent with cell cycle delay or arrest at the G0/1-S phase transition. Microarray analyses in vitro revealed significant changes in lysosomal gene expression, indicating these anesthetics can impair phospholipid metabolism. In particular, ropivacaine negatively affected transcriptional programs related to tumorigenesis and metastasis.8 However, in a meta-analysis of 67,577 patients across 28 studies, there was no significant benefit of regional anesthesia in overall survival, recurrence-free survival, or biochemical recurrence-free survival. Nonetheless, the researchers conclude regional anesthetics are still quite beneficial in cancer treatment because their use reduces the clinical reliance on opioids. In addition, individual clinical studies show local anesthetics offer significant benefit over general anesthesia in terms of cancer recurrence.9

These findings suggest the effects of anesthesia on cancer outcomes and recurrence are influenced by the specific agents used and their unique interactions with the body’s immune system. Different anesthetic agents can have differential effects on immune response. Some, like volatile anesthetics, may promote tumor growth and cancer recurrence, while others, such as local anesthetics, may help mitigate these effects. The overall impact of anesthesia on cancer outcomes is highly complex. Further research can help elucidate the mechanisms through which different anesthetic agents influence cancer progression and establish evidence-based guidelines for anesthesia management in oncology.

References

  1. Karunarathna, I., et. al. “Effects of Anesthesia and Analgesia on Immunomodulation and Cancer Recurrence,” Oncological Surgery and Anesthesia, 2024. https://doi.org/10.13140/RG.2.2.15744.44809
  2. Horowitz, M., Neeman, E., Sharon, E., et. al., “Exploiting the Critical Perioperative Period to Improve Long-Term Cancer Outcomes.” Nature Reviews. Clinical Oncology, 12(4), 2015, 213–26. https://doi.org/10.1038/nrclinonc.2014.224
  3. Melamed, R., et. al. “Suppression of Natural Killer Cell Activity and Promotion of Tumor Metastasis by Ketamine, Thiopental, and Halothane, but Not by Propofol: Mediating Mechanisms and Prophylactic Measures.” Anesthesia & Analgesia, 2003, 1331–39. https://doi.org/10.1213/01.ANE.0000082995.44040.07
  4. Braun, S., et. al. “Ketamine Induces Apoptosis via the Mitochondrial Pathway in Human Lymphocytes and Neuronal Cells.” British Journal of Anaesthesia, 105(3), 2010, 347–54.  https://doi.org/10.1093/bja/aeq169
  5. Shapiro, J., et. al. “Anesthetic Drugs Accelerate the Progression of Postoperative Metastases of Mouse Tumors.” The Journal of Clinical Investigation, 68(3), 1981, 678–85. https://doi.org/10.1172/JCI110303
  6. Tavare, A.N., et. al. “Cancer Recurrence after Surgery: Direct and Indirect Effects of Anesthetic Agents.” International Journal of Cancer, 130(6), 2012, 1237–50.  https://doi.org/10.1002/ijc.26448
  7. Deegan, C.A., et. al. “Anesthetic Technique and the Cytokine and Matrix Metalloproteinase Response to Primary Breast Cancer Surgery:” Regional Anesthesia and Pain Medicine, 35(6), 2010, 490–95.  https://doi.org/10.1097/AAP.0b013e3181ef4d05
  8. Lucchinetti, E., et. al. “Antiproliferative Effects of Local Anesthetics on Mesenchymal Stem Cells: Potential Implications for Tumor Spreading and Wound Healing.” Anesthesiology, 116(4), 2012, 841–56.  https://doi.org/10.1097/ALN.0b013e31824babfe
  9. Grandhi, R.K., et. al. “The Relationship Between Regional Anesthesia and Cancer: A Metaanalysis.” Ochsner Journal, 17(4), 2017, 345–61. https://www.ochsnerjournal.org/content/17/4/345