Inhalational Anesthetics

Volatile anesthetics are the mainstay of anesthesia worldwide and are the most commonly used agents for maintenance of anesthesia. ^, Preclinical data have identified direct protumorigenic effects of volatile anesthetics across multiple cell lines.

In addition, volatile anesthetic agents have been shown to activate receptors on immune cells and have been shown in vitro to modulate the function of immune cells. ^, Impaired neutrophil, macrophage, and NK cell recruitment and activity has been shown in vitro in response to direct exposure to volatile anesthetics. ^, Conversely, exposure to propofol has been shown to preserve the function of immune cells. ^, Exploratory research is beginning to interrogate the clinical implications of these findings, in particular, to determine if the type of anesthesia used for surgery is indeed responsible for postoperative immune modulation and to assess the impact on postoperative outcomes. These data are presented elsewhere in this chapter.

Intravenous Anesthetics

Consistently, propofol has been shown to reduce proliferation, ^, increase cancer cell apoptosis, ^, reduce cancer cell viability, ^{, ,} and inhibit cancer cell migration and invasion, ^{, , , , , ,} in breast, endometrial, prostate, osteosarcoma, squamous cell carcinoma (SCC), lung, and glioblastoma cells. Interestingly, only one study found contradictory results with propofol increasing the velocity and migration of breast cancer cells.

To further understand the mechanism driving anesthetic agent modulation of tumor cell biology, in vitro data have implicated key target pathways. Propofol has been shown to increase apoptosis and inhibit tumor cell viability, epithelial-mesenchymal transition (EMT), invasion and migration via inhibition of the extracellular signal-related kinase 1/2 (ERK 1/2), protein kinase B-mammalian target of rapamycin (Akt-mTOR) and adenosine monophosphate-activated protein kinase (AMPK)/mTOR ⁴⁴ pathways, and programmed death ligand-1 (PD-L1). Expression of proteins required for EMT and invasion, MMPs, ^, VEGF, ^{, ,} e-cadherin, vimentin, and Snail has been shown to be reduced in cells treated with propofol. Similarly, induction of HIF-1α, crucial for angiogenesis in tumor cells, has been reduced with exposure to propofol in vitro in colorectal cancer and prostate cancer ^, and in ex vivo studies in head and neck SCC.

A small number of in vivo studies have examined the effects of anesthetic agents on tumor growth and metastasis, using varying experimental models ( Table 11.4 ). ­Treatment with volatile anesthesia increased pulmonary metastasis in a murine model of breast cancer, while treatment with propofol consistently reduced primary tumor growth, pulmonary metastasis, improved response to chemotherapy and improved overall survival in models of breast, chronic myeloid leukemia (CML), cervical, glioblastoma, and colorectal cancer.

Dexmedetomidine

Dexmedetomidine is a relatively new drug available to anesthetists and intensivists. Dexmedetomidine is a highly selective alpha-2-adrenoreceptor agonist with sedative, analgesic, and anxiolytic properties. It exerts its sedative effect through stimulation of the alpha-2-adrenoreceptor in the locus coeruleus, which blunts excitation of the central nervous system. The purported benefits of dexmedetomidine include a reduction in the surgical stress response, concurrent need for analgesia, and need for volatile anesthesia.

Laboratory evidence suggests that dexmedetomidine stimulates metastasis through stimulation of proliferation and invasion ^, of cancer cells. However, large retrospective studies have demonstrated no effect on cancer recurrence. ^, Dexmedetomidine has been shown to stimulate proliferation in human breast cancer cell lines through stimulation of alpha-2-adrenoreceptors. An in vivo study in mice has confirmed this finding. The alpha-2-adrenoreceptorextracellular receptor kinase (ERK) signaling pathway has been shown to promote proliferation, migration, and invasion of human breast cancer cells both in vitro and in vivo. Autocrine/paracrine prolactin signaling has also been shown to contribute to alpha-2-adrenoreceptor stimulation of breast cancer cell proliferation. Dexmedetomidine has also been shown to stimulate the upregulation of the antiapoptotic proteins Bcl-2 and Bcl-xL. A study involving the human osteosarcoma cell line MG63 found that dexmedetomidine inhibited cell proliferation and migration, and promoted apoptosis through upregulation of the miR-520a-3p, which directly targets AKT1 and represses the Akt/ERK pathway. These conflicting results might be explained due to the different tumor types studied; however, further research is needed to elucidate the reason for this difference. In vivo rodent models of breast, lung, and colon cancers have shown that short-term use of clinically relevant doses of dexmedetomidine promotes metastasis.

Dexmedetomidine may also affect tumorigenesis through immunomodulation. Dexmedetomidine has been shown in vivo in metastatic mouse models to expand monocytic myeloid-derived suppressor cells (M-MDSCs) in the postoperative period. These M-MDSCs were able to promote metastasis through increasing the production of the proangiogenic factor VEGF. These findings have been confirmed in lung cancer patients who were administered dexmedetomidine postthoracotomy. Subhypnotic doses of dexmedetomidine may downregulate antitumor immunity through decreasing the production of interleukin-12 (IL-12) from antigen-presenting cells, resulting in Th2 shift and increased cytotoxic T lymphocyte activity.

Midazolam

Midazolam is a benzodiazepine sedative drug that is used intraoperatively due to its rapid onset and short duration of action relative to other benzodiazepines. It also has significant anticonvulsant, amnesic, anxiolytic, and hypnotic properties that occur through modulation of GABA _A receptors in the central nervous system. Several studies have demonstrated the antitumor properties of midazolam; however, clinical trials establishing the effect of midazolam on cancer recurrence are yet to be conducted.

In vitro and in vivo evidence has demonstrated that midazolam inhibits cell proliferation and induces both apoptosis ^{, ,} and necrosis ^, in cancer cells. Midazolam’s antitumorigenic properties are partially mediated through the peripheral GABA _A receptor. Midazolam is thought to inhibit cell proliferation in FaDu human hypopharyngeal SCC cells partially through downregulating the expression of the EP300 gene, which controls the expression of numerous genes throughout the body and prevents tumor growth. ^{, ,} Midazolam has also been shown to exert its antiproliferative effect in FaDu cells through inhibition of transient receptor potential melastatin 7 (TRPM7). Similar results were also demonstrated in T-98-MG malignant glioblastoma cells.

Midazolam induces apoptosis in human lymphoma and neuroblastoma cell lines, and lung carcinoma cell lines in a concentration-dependent manner. ^, The activation of caspase-3, caspase-9, and PARP by midazolam indicates the induction of the intrinsic mitochondrial apoptosis pathway. Midazolam also inhibited pERK1/2 signaling causing activation of the pro-apoptotic protein Bid and downregulation of antiapoptotic proteins Bcl-XL and XIAP. Midazolam did not induce generation of apoptotic markers in oral squamous cell carcinoma (OSCC) cells but did induce mitochondrial swelling, vacuoles, and plasma membrane rupture. Another study demonstrated a switch from apoptotic cell death to necrotic cell death at high concentrations of midazolam.

Ketamine

Ketamine is a drug used for induction and maintenance of general anesthesia and for the treatment of pain. The main mechanism of action is through antagonism of NMDA receptors, which are associated with central ­sensitization. Ketamine also decreases presynaptic release of glutamate and interacts with opioid receptors. Ketamine has been shown to exert antitumor effects in vitro and in vivo through the suppression of cell proliferation and induction of apoptosis.

Ketamine has been shown to induce apoptosis in a lung adenocarcinoma cell line in a concentration-dependent manner through upregulation of CD69 expression. Downregulation of CD69 blocked the function of ketamine on inducing apoptosis. Another in vitro study of human embryonic stem cells revealed that ketamine induced neuronal apoptosis via a mitochondrial pathway as revealed through the activation of caspase 3 activity, loss of the mitochondrial membrane potential, and release of cytochrome c. Ketamine induced apoptosis in human hepatoma HepG2 cells through activation of a Bax-mitochondria-caspase protease pathway. Administration of Z-VEID-FMK, a caspase 6 inhibitor, prevented the ketamine-induced cellular apoptosis. Interestingly, one study found that ketamine facilitates breast cancer cell line MDA-MB-231 proliferation and invasion through increasing the expression of the antiapoptotic protein Bcl-2. Ketamine has been shown to inhibit the malignant potential of colorectal cancer cells via blockade of the NMDA receptor. NMDA blockade resulted in decreased phosphorylation of AKT, ERK, and Ca ²⁺ /calmodulin-dependent protein kinase II (CaMK II), decreased expression of HIF-1α, and a decrease in the intracellular Ca ²⁺ level. This resulted in decreased VEGF expression and migration of colorectal cancer cells.

Ketamine has been suggested to additionally affect tumor development through immunomodulation. Ketamine suppresses NK cell activity. Ketamine induces human lymphocyte apoptosis via the mitochondrial pathway and inhibits dendritic cell maturation. ^, Ketamine also decreases the production of proinflammatory cytokines, including tumor necrosis factor kappa B (NF-κB) and IL-6. Animal models have shown that ketamine increases lung and liver metastases with one study in a rat model showing that ketamine increased lung metastases via NK cell suppression. ^,

Volatile and Total Intravenous Anesthesia Anesthetics

A large body of literature has emerged investigating the association between choice of anesthetic agent and cancer outcomes in different populations ( Table 11.5 ). However, the studies are predominantly small and retrospective in nature, limiting the ability to delineate a clear association. The largest of the retrospective studies ^, have both shown a 5–10 percent-unit improvement in overall survival across multiple cancers with propofol compared with volatile anesthesia. Of note, Wigmore et al. found that the survival benefit of total intravenous anesthesia (TIVA) was predominantly due to its effect in gastrointestinal and urological cancers, and Enlund et al. attributed most of the reported survival benefit to the colorectal cancer cohort, suggesting a differential effect dependent on the biology of the cancer. Smaller retrospective studies have shown an improved recurrence-free survival with the use of TIVA in breast cancer and improved overall survival in oesophageal, glioma, gastric, and colorectal cancers.

Table 11.5

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