The Amide Local Anesthetic Lidocaine in Cancer Surgery—Potential Antimetastatic Effects and Preservation of Immune Cell Function? A Narrative Review

Abstract

Surgical removal of the primary tumor in solid cancer is an essential component of the treatment. However, the perioperative period can paradoxically lead to an increased risk of cancer recurrence. A bimodal dynamics for early-stage breast cancer recurrence suggests a tumor dormancy-based model with a mastectomy-driven acceleration of the metastatic process and a crucial role of the immunosuppressive state during the perioperative period. Recent evidence suggests that anesthesia could also influence the progress of the disease. Local anesthetics (LAs) have long been used for their properties to block nociceptive input. They also exert anti-inflammatory capacities by modulating the liberation or signal propagation of inflammatory mediators. Interestingly, LAs can reduce viability and proliferation of many cancer cells in vitro as well. Additionally, retrospective clinical trials have suggested that regional anesthesia for cancer surgery (either with or without general anesthesia) might reduce the risk of recurrence. Lidocaine, a LA, which can be administered intravenously, is widely used in clinical practice for multimodal analgesia. It is associated with a morphine-sparing effect, reduced pain scores, and in major surgery probably also with a reduced incidence of postoperative ileus and length of hospital stay. Systemic delivery might therefore be efficient to target residual disease or reach cells able to form micrometastasis. Moreover, an in vitro study has shown that lidocaine could enhance the activity of natural killer (NK) cells. Due to their ability to recognize and kill tumor cells without the requirement of prior antigen exposure, NKs are the main actor of the innate immune system. However, several perioperative factors can reduce NK activity, such as stress, pain, opioids, or general anesthetics. Intravenous lidocaine as part of the perioperative anesthesia regimen would be of major interest for clinicians, as it might bear the potential to reduce the risk of cancer recurrence or progression patients undergoing cancer surgery. As a well-known pharmaceutical agent, lidocaine might therefore be a promising candidate for oncological drug repurposing. We urgently need clinical randomized trials assessing the protective effect of lidocaine on NKs function and against recurrence after cancer surgery to achieve a “proof of concept.”

Local anesthetics impair the growth and self-renewal of glioblastoma stem cells by inhibiting ZDHHC15-mediated GP130 palmitoylation

“…Amide local anesthetics act on nerve cells by blocking voltage-gated sodium channels, resulting in decreased depolarization and repolarization rates of excitatory nerve cell membranes [30,31]. It has been shown that common amide linked local anesthetics exhibit anticancer activity in a variety of cancers, including lung cancer, hepatocellular carcinoma, and thyroid cancer [32,33].…”

The Amide Local Anesthetic Ropivacaine Attenuates Acute Rejection After Allogeneic Mouse Lung Transplantation

“…The results of this study demonstrate beneficial effects of the amide-linked local anesthetic ropivacaine on AR 5 days after allogeneic lung transplantation in mice. Amide-linked local anesthetics such as ropivacaine and lidocaine have been demonstrated to possess profound anti-inflammatory properties [12][13][14]. As inflammatory signaling processes, leukocyte infiltration and subsequent damage to the transplanted organ are hallmarks of AR, we hypothesized that the drug would also be able to attenuate AR due to its antiinflammatory effects, e.g., by preserving endothelial barrier function [6].…”

<p>Effects of Anesthesia on Postoperative Recurrence and Metastasis of Malignant Tumors</p>

“…Lidocaine is an ideal adjuvant drug for cancer treatment given its major therapeutic advantages, strong anti-inflammatory effects, and protective effects on innate immune system surveillance. 91,92 In addition, it improves the prognosis of patients with cancer. However, its use in patients with cancer warrants further clarifications and clinical validation.…”

“…Moreover, regional anesthesia does not affect CMI and reduces surgeryinduced neuroendocrine response by weakening afferent nerve conduction in the HPA axis and the sympathetic nervous system. 85,91,104 Therefore, reducing opioid usage and inhaled anesthetic agents may reduce the risk of tumor recurrence.…”