Volatile and Intravenous Anesthetics and Cancer





General Introduction: Anesthesia and Cancer Progression


Surgery remains a central treatment modality for patients with solid cancers, with more than 60% of cancer patients presenting for surgical resection, and more than 80% of cancer patients exposed to a surgical procedure during their treatment journey. , Together with a rapidly growing and aging population, it is estimated that in 2030 17.3 million cancer patients will need surgery as part of their oncologic treatment.


Accompanying surgical intervention is a perioperative stress response characterized by systemic release of inflammatory mediators, activation of cells of the innate and adaptive immune system, and prothrombotic responses. While evolutionarily appropriate to aid healing after surgical tissue damage, excessive and prolonged upregulation of these responses results in a period of prolonged postoperative immunosuppression and has the potential to alter the biological environment of tumor cells. The perioperative surgical response has thus been implicated in the progression of malignant disease.


Surgical intervention requires anesthesia and the role of anesthetic agents in modulating this perioperative stress response, cancer cell biology, and even long-term cancer outcomes is emerging. This chapter aims to provide a comprehensive overview of the current evidence supporting the impact of anesthetic agents on cancer progression.


Mechanisms of Cancer Development and Progression


Tumor cells have the ability to grow, proliferate, and spread within their host. In order to facilitate the tumor’s development, tumor angiogenesis is also established. This occurs when tumors are just 1 mm in size; therefore tumors have developed the potential to metastasize well before they are amenable to surgical resection. In addition, with surgical manipulation of tumors, cancer cells are released into circulation and can deposit in distant sites where they can develop into overt metastatic disease. However, not all patients who undergo surgery ultimately die from overwhelming metastatic disease, suggesting that not all tumor cells have the same propensity to spread into the blood stream or to establish themselves at distant sites as metastases.


The concept of immunoediting describes the role of the immune system in suppression and proliferation of oncologic disease. It recognizes the complex interplay between tumor cells and their environment, which is responsible for the removal of malignant cells (elimination) and control of disease (equilibrium), but also the unwanted progression of malignant disease (escape). , With this understanding, the importance of supporting an antitumorigenic immune state, particularly at times of physiologic perturbation such as during surgery, becomes increasingly significant. Macrophages, natural killer cells, and T cells play an important role in the survival, proliferation, and invasion of tumor cells within their host and are known to be suppressed in number and function after major surgical insult. It is- therefore- plausible that the immunosuppressive environment induced after major surgery has the potential to promote the growth and spread of potentially fatal disease.


Molecular Actions of Anesthetics and Cancers


While the complete mechanism of action of general anesthetic agents remains unclear, both volatile anesthetics and propofol exert their hypnotic and amnesic effects by positive modulation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), primarily through GABA A receptor activity , in the brain and spinal cord. Activity of anesthetic agents at other receptors has been identified, including potassium (K+) channels and N-methyl-d-aspartate (NMDA) receptors, and may be responsible for the secondary effects of anesthetic agents such as their effect on tumor and immune cells.


While these receptor interactions may explain the nonanesthetic (cardiovascular, respiratory, hepatic, and renal) side effects of commonly used anesthetic agents, it has been interestingly observed that affinity for these receptors explains the potential direct effect of anesthetic agents on cells of the immune system and tumor cells alike. ,


Preclinical In Vitro and In Vivo Studies of Cancer and Anesthetics


Studies have examined the effect of different anesthetic agents on tumor cell biology in vitro and in vivo, across a number of different tumor cell lines ( Tables 11.1 and 11.2 ). In addition to volatile anesthetics and propofol, studies of the most common intravenous agents studied have investigated the effect of other analgesic and hypnotic agents, including the NMDA-receptor antagonist ketamine, the alpha-2 adrenoreceptor agonist dexmedetomidine, and the benzodiazepine midazolam ( Table 11.3 ).



Table 11.1

Effect of Anesthetic Agents on Cancer Cell Biology

















































Mechanism Effect of Anesthetic Agent Cancer Type (Reference)
Proliferation ↓ Propofol Breast
Endometrial
Prostate
Osteosarcoma
Esophageal SCC
Ovarian
↑ Volatile
Hepatocellular
Apoptosis ↑ Propofol Nonsmall cell lung
Endometrial
Osteosarcoma
Lung
Esophageal SCC
Glioblastoma
Breast
NK-mediated cell apoptosis ↑ Propofol-paravertebral treated patient serum Breast
↓ Volatile anesthesia treated patient serum Breast
Cell viability ↓ Propofol Cervical
Endometrial
Lung
Glioma
Lung
Gastric
Metabolism ↓ Propofol Colorectal
Glioma
EMT ↓ Propofol Prostate
Invasion and migration ↓ Propofol
↑ Propofol (in esophageal SCC)
Endometrial
Lung
Glioma
Breast
Osteosarcoma
Lung
Esophageal SCC
↑ Volatile Ovarian


Table 11.2

Mechanistic Pathways Involved in Anesthetic Modulation of Tumor Cell Growth

































































































Mechanism Effect of Anesthetic Agent Reference
PD-L1 ↓ Propofol Breast
ERK1/2 ↓ Propofol Non–small cell lung
Colorectal
PUMA ↑ Propofol Non–small cell lung
AMPK/mTOR ↑ Propofol Cervical
HIF-1α ↓ Propofol
Colorectal
Prostate
Prostate
Squamous cell carcinoma
↑ Volatile Prostate
Renal cell
N-cadherin, vimentin and Snail expression (EMT) ↓ Propofol Lung
Akt/mTOR ↓ Propofol
Chronic myeloid leukemia
NF-κB signaling ↓ Propofol Gliosarcoma
Inflammatory cytokine production ↓ Propofol Gliosarcoma
CPAR-system-xc ↓ Propofol Glioma
Receptor target genes ↓ Propofol Prostate
Caspase-3 ↑ Propofol Lung
mIR-486
mIR-218
mIR-21
↑ Propofol Gliosarcoma
Lung
Pancreas
Slug-dependent PUMA and e-cadherin ↓ Propofol Pancreas
VEGF ↑ Volatile Ovarian
Renal
Ovarian
MMP-11 ↑ Volatile Ovarian
MMP-13 ↓Propofol Osteosarcoma
MMP-2, 7, 9 ↓Propofol
Glioblastoma
Lung
MMP-2, 9 ↑ Volatile Ovarian
Repair-associated genes ↓Propofol Leukemia
mTOR ↓Propofol Cervical


Table 11.3

Effect of Hypnotic Anesthetic Agents











































Mechanism Effect of Anesthetic Agent Cancer Type (Reference)
Proliferation ↑ Dexmedetomidine Breast
Colorectal
Lung
↓ Midazolam
Head and neck
Leukemia
Colorectal
↓ Ketamine
↑ Ketamine
Pancreas
Breast
Apoptosis ↓ Dexmedetomidine
↑ Dexmedetomidine
Lung
Neuroglioma
Bone
↑ Midazolam
Lung
Neuroglioma
Leukemia
Colorectal
Testicular
↑ Ketamine
Lung
Pancreas
Brain
Necrosis ↑ Midazolam
Oral squamous cell carcinoma
Lymphoma
Neuroblastoma
Invasion and migration ↑ Dexmedetomidine
↓ Dexmedetomidine
Breast
Lung
Neuroglioma
Osteosarcoma
↓ Ketamine Breast


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.


Sevoflurane


Sevoflurane is a widely used fluorinated methyl isopropyl ether anesthetic agent. Its effects on in vitro tumor cell mechanics have been investigated in hepatocellular carcinoma, breast, renal cell carcinoma, and ovarian cancer cell lines with consistent results.


Hepatocellular carcinoma cells treated with sevoflurane displayed increased proliferation compared to control, and the sera of patients who underwent surgical resection of breast cancer under propofol-paravertebral anesthesia showed increased apoptosis in HCC1500 breast cancer cells compared with sera from patients treated with sevoflurane-general anesthesia.


Exposure of ovarian cancer cells to the volatile anesthetics agents sevoflurane, isoflurane, and desflurane increased expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs), , factors known to support angiogenesis and epithelial-mesenchymal transformation, processes vital to the growth and spread of malignant cells.


Isoflurane


Induction of hypoxia-inducible factors (HIF-1α) is associated with increased tumor cell proliferation. Upregulation of HIF-1α via upregulation of PI-3K-Akt has been shown in prostate and renal cell carcinoma cells exposed to isoflurane. Increased invasion and expression of VEGF-A and MMP-11 was seen in ovarian cancer cells upon exposure to isoflurane.


Desflurane


Only one study in ovarian cancer has examined the effect of exposure to desflurane on tumor cell dynamics. Desflurane exposure led to the greatest expression of vascular endothelial growth factor-a (VEGF-A), matrix metalloproteinase-11 (MMP-11), C-X-C motif chemokine receptor-2 (CXCR2), and tumor growth factor-beta (TGF-β) expression compared with sevoflurane and isoflurane.


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.



Table 11.4

In Vivo Studies

































Mechanism Effect of Anesthetic Agent Cancer Type (Reference)
Pulmonary metastasis count ↓ Propofol
↑ Volatile
Breast
Osteosarcoma
Melanoma
Breast
Tumor size ↓ Propofol Cervical
CML
Gliosarcoma
Tumor growth ↓ Propofol (treated cells) Colorectal
Survival time ↑ Propofol Gliosarcoma
Lung tumor retention ↓ Propofol
↑ Volatile
Breast
Breast


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. ,


Clinical Studies


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.


Jun 26, 2022 | Posted by in ANESTHESIA | Comments Off on Volatile and Intravenous Anesthetics and Cancer
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