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 ).