*4.2.2.2 Propofol*

Propofol seems to have opposite effects to other general anesthetics as far as immunity is concerned. It seems that this drug does not suppress the immune system, but rather the opposite. It favors the cytotoxicity of NK cells, reduces the motility and invasiveness of tumor cells, inhibits COX and does not promote the synthesis of HIF (hypoxia-inducible factor), which is associated with a proven pro-angiogenic effect through the expression of vascular endothelial growth factor (VEGF) [28].

Different studies have observed beneficial anti-metastatic effects. It has been proposed that the inhibition of COX-2, and therefore of PGE2, could result in an improvement of the antitumor response of the immune system [38]. Other authors have proposed that propofol's weak β-adrenergic antagonist mechanism could be involved in its antitumor protection since many tumor cells have β-adrenergic receptors [39].

Zheng et al. [40] published 2018 a retrospective study of patients operated on for gastric cancer between 2007 and 2012, this study included 2856 individuals divided into 2 groups. Anesthetic maintenance was performed in one group based on total intravenous anesthesia (TIVA) with propofol plus remifentanil and the other with sevoflurane and remifentanil, showing greater survival in the group of patients that used TIVA.

Inada et al. [41] observed in patients undergoing craniotomy, how inhalational anesthesia with isoflurane compared with intravenous propofol produced a decrease in the ratio of Thr type 1 and 2 lymphocytes (Th1/Th2), which facilitates tumor progression, tilting the balance towards Th2 production; predominating therefore humoral immunity. On the other hand, Ren et al. [42] confirmed these findings with isoflurane versus propofol in lobectomy for lung cancer. They hypothesize that propofol promotes the activation and differentiation of peripheral Th cells to Th1, thereby favoring perioperative anti-metastatic cellular immunity.

In a study by Zhang Ye et al. [43] TIVA with propofol at therapeutic doses of 2–5 micrograms/milliliter (μg/ml) was found to inhibit tumor proliferation, induce apoptosis, and reduce invasion of osteosarcoma tumor cells (**Figure 5**).

### *4.2.2.3 Thiopental*

Thiopental reduces both the number and activity of NK cells in animal models [24].

### **Figure 5.**

*Propofol inhibits cell proliferation, promotes apoptosis, and reduces invasion. Propofol inhibits proliferation (A), promotes apoptosis (B-C), and reduces invasion (D) of MG63 osteosarcoma cell in a dose-dependent manner. \*P < 0.01 compared with the control group without propofol treatment. Image taken from the article by Zhang Ye et al. [43]. With permission of the author.*

### *4.2.2.4 Ketamine*

In a study in rats, Melamed et al. [44] determined that ketamine causes a significant decrease in the number and activity of NK cells, greater lung tumor progression as well as more numerous and aggressive lung metastases. Of the hypnotics analyzed in this study, ketamine showed the greatest immunosuppressive action, probably related to its potent adrenergic action. Recent studies support these conclusions and show not only decreased activity of neutrophils and NK cells, but also induces lymphocytic apoptosis in humans and inhibits the functional maturation of dendritic cells, interfering with other determinants of the immune reaction as in the production of cytokines that affect cellular immunity [44].

### *4.2.2.5 Benzodiazepines*

Commonly used as anxiolytics, sedatives, anticonvulsants, and in the context of alcohol withdrawal. Among them, midazolam, lorazepam, clonazepam, and diazepam, are useful in anesthetic practice due to their properties, especially midazolam, for being a safe drug with a short half-life. The immune changes produced by the use of benzodiazepines have shown disparate results, and it has not been determined that they are drugs that produce significant variations in immunity and, therefore, in cancer recurrence. Negative results were obtained with supraphysiological concentrations, where the chemotaxis capacity was diminished; in another context, Marino et al. [45] found that single doses of diazepam and midazolam induced neutrophil migration and phagocytosis. In general, they are useful drugs in the practice of anesthesia in patients with neoplasia.

### *4.2.2.6 Opiates*

One of the most frequent symptoms in cancer patients is pain, between 50 and 80% of patients experience some degree of pain. It is known that opiates are fundamental in the treatment of acute and chronic pain, as well as the perioperative period of oncological surgery. As the tumor progresses, it can cause severe pain related to the invasion of adjacent tissues, compromising nerves and bone structures [46].

The main concern regarding the effect that opiates may have; over the morphic in terms of oncological progression through the dissemination of tumor cells and the establishment of distant metastases, is mainly explained by 2 mechanisms; interactions with the immune system and stimulation of angiogenesis [47].

Impaired immune function is known to have a multifactorial etiology. On the one hand, the presence of uncontrolled pain generates activation of the SNS and the HPA axis with the consequent release of cortisol and catecholamines that determine immunosuppression [48]. On the other hand, there is both direct and indirect action of opioids on the immune system. Indirectly through the HPA axis and directly through specific receptors for opioids, such as μ3. These μ3 receptors and others such as OGFr (opioid growth factor receptor), are involved in cell signaling processes that mediate antibody production and NK cell-mediated cytotoxicity. The administration of opioids has been related to a decrease in the number and activity of NK cells, inhibition in the production of immunostimulatory cytokines such as IFN-γ and IL-2, less proliferation and activation of T lymphocytes, as well as less antibody production [49].

Opioids affect the integrity of the vascular endothelium, where they produce proliferation and migration of endothelial cells, a process known as angiogenesis [50]. Morphine administered in usual concentrations stimulates angiogenesis and proliferation of microvascular endothelial cells through a signaling pathway similar to that described for VEGF [51].

Binding to μ3 and OGF receptors by the synthetic opioids fentanyl and remifentanil occurs with much lower affinity [52].

Tramadol, in addition to its effect on the μ receptor, has adrenergic, serotonergic, and appears to preserve perioperative immune function compared to morphine. Studies have proposed that tramadol stimulates the activity of NK cells. Opioids with less structural similarity to morphine and less affinity for μ receptors are probably those that determine less immunosuppression [53].

Recent studies speak of a dual effect of morphine in the regulation of tumors, including its effects on proliferation, metastasis, angiogenesis, inflammation, and immunity.

In a review carried out in 2018; Tuerxun et al. [46] maintain that the main factors responsible for the dual role of morphine in terms of its activity on cancer lie in the dose and the type of tumor. In general terms; at high concentrations, morphine inhibits tumor cell growth, angiogenesis, invasion, and metastasis. However, low daily doses of morphine stimulate tumor cell proliferation, angiogenesis, and immunosuppression. Future studies will elucidate how true these claims are, but for now, they open a door to the analysis that will allow us to discuss how influential the use of morphine is in the perioperative period of cancer patients.

### *4.2.2.7 Non-steroidal anti-inflammatory drugs (NSAIDs)*

NSAIDs inhibit COX-1 and COX-2, a fundamental enzyme of the arachidonic acid cascade that ends with the synthesis of the different eicosanoids (prostaglandins, thromboxanes, and leukotrienes). Overexpression of the enzyme cyclooxygenase 2 (COX-2) has been found in about 90% of lung tumors, 71% of intestinal adenocarcinomas, and 56% of breast cancer neoplasms, among other types of cancer. The hyperfunctioning of this enzyme results in increased synthesis of PGE2, which inhibits NK cell activity, increases angiogenesis, and decreases cell apoptosis, favoring tumor progression [54].

The influence of prostaglandins on cancer seems to be mediated by two mechanisms. The first is an indirect mechanism through its interaction with the antitumor immune system. PGE2, synthesized by macrophages, produces a decrease in the number of NK cells with a reduction in cytotoxic activity, also affecting the response mediated by CD8+ T lymphocytes, favoring the secretion of Th2-type cytokines compared to Th1, a phenomenon that occurs in the perioperative period. The second is a direct mechanism of interaction with tumor growth and spread [55]. HIFs are intracellular proteins that coordinate the cell's adaptive response to hypoxemia, regulating genes that act to promote angiogenesis, cell proliferation, and metabolism. These proteins are closely linked to mechanisms of cellular adaptation to hypoxia, also known as hypoxic preconditioning. PGE2 has proangiogenic effects on tumor cells [56]. Taking into account the pro-tumor effects of prostaglandins, it seems logical to think that NSAIDs could have an antitumor effect [57].

### *4.2.2.8 Local anesthetics and regional anesthesia*

Both local anesthetics and regional anesthetic techniques seem to have a protective action against the progression of oncological disease. The justification for this statement is based on the attenuation of the endocrine-metabolic response to surgical stress and, consequently, on the reduction of the concentrations of glucocorticoids and endogenous catecholamines. On the other hand, local anesthetics favor the increased activity of CD8+ T lymphocytes and NK cells. In addition to regional anesthesia, less invasive surgical techniques reduce stress with the eventual decrease in SNS stimulation and decrease opioid requirements with the benefits that this entails. All of the above-mentioned favor the improvement of cellular immunity and could be associated with lower rates of cancer recurrence [58, 59].

Local anesthetics exert their effect by blocking voltage-gated sodium channels in the membrane of nerve cells, which are also found in the membrane of tumor cells and are thought to be involved in tumor cell invasion and metastasis [60].

In 2014 Scavonetto et al. [61] compared general anesthesia alone versus general anesthesia combined with epidural in a retrospective study in 1642 patients undergoing radical prostatectomy. This study demonstrated that supplementing general anesthesia with neuraxial analgesia for prostate cancer surgery was associated with decreased systemic cancer progression and improved overall survival compared with general anesthesia alone. This finding cannot be used to discriminate which element of anesthetic treatment (intrathecal opioids, local anesthetics) or mechanism (reduced stress response or systemic opioid reduction) may have contributed to the apparent benefit, but it is nevertheless a promising start for further research.

Recent studies have focused on the antitumor properties of local anesthetics; Wang HW et al. [60] in a study published in 2015, investigated the influence of local anesthetics on non-small cell lung cancer and found that lidocaine and ropivacaine can inhibit cell growth, invasion, and migration carcinogens, as well as induce their apoptosis. The antitumor properties of local anesthetics offer a potential opportunity for clinical application.

### *4.2.2.9 Glucocorticoids*

Corticosteroids are commonly used in anesthesia for the prophylaxis of postoperative nausea and vomiting. When administered in a single dose, after the start of surgery, they attenuate the inflammatory response and the pain associated with the surgical procedure [62].

Although it is known that the prolonged use of these drugs worsens the prognosis of cancer patients, it is questionable whether their use limited to the perioperative period influences tumor proliferation and the appearance of metastases. There are conflicting results. Some studies show a reduction in tumor angiogenesis, levels of VEFG, and circulating interleukins with the use of single-dose corticosteroids [63]. Singh et al. [62] showed an increase in distant metastases in colon cancer when dexamethasone was used in a single dose, concluding that further studies are still needed to define the role of these drugs in tumor recurrence.

### *4.2.2.10 β-adrenergic blockers*

β-adrenergic receptors have been associated with the progression of neoplasms; not only because of their presence in neoplastic cells and inducing changes in the

dynamics of the immune system and tumor microenvironment, but also because they are active components of the endocrine-metabolic response and inflammation associated with surgical trauma. In an observational study carried out by Hiller et al. [64] in 2015, it was possible to demonstrate a reduction in the incidence of tumor recurrence and greater survival in patients who had indicated the use of β-adrenergic blockers. Another study carried out by Wang HM et al. [65] in 2012 concluded that β-adrenergic blockers are associated with an improvement in metastasis-free survival, disease-free survival, and overall survival in this cohort of patients with non-small cell lung cancer, who were undergoing radiotherapy. Most of the patients who had a beneficial outcome in the study were taking cardioselective β-adrenergic (β1) blockers, which is consistent with other findings indicating that β1 receptors are responsible for negative outcomes in lung adenocarcinoma.

However, there is currently little scientific evidence to support the perioperative use of these drugs to reduce the catecholaminergic response and improve cellular immunity; Therefore, these findings should be verified in future studies that guarantee their efficacy, always taking into account risk–benefit in each particular patient.

## *4.2.2.11 α 2 adrenergic agonists*

Dexmedetomidine is a potent alpha 2 adrenergic agonist that exhibits sedative, hypnotic, analgesic, and sympatholytic effects. These characteristics make it possible to reduce the use of inhalation agents, opiates, and the sympathetic response in the perioperative period, with the consequent decrease in circulating catecholamine levels [66]. Based on the fact that both the sympathetic response and the pro-inflammatory state secondary to surgery, as well as the use of morphine, have been shown to accelerate tumor progression; It is believed that dexmedetomidine could reduce the progression of neoplastic disease secondary to the modulation of the inflammatory state typical of surgery, added to the reduction in the use of opiates and inhalational anesthetics [67].

It is known that surgery can determine immunosuppression, this is of vital importance in cancer patients.

Some studies have shown the role of dexmedetomidine in the immune response of cancer patients. Wang Y et al. [68] indicate that this drug maintains the Th1/Th2 ratio, which decreases the inflammatory response of patients who underwent gastric surgery with the consequent reduction in immunosurveillance alterations, which is of great importance in cancer patients. Due to the above, both in theory and in practice, dexmedetomidine is considered a very promising drug when it comes to the perioperative period of cancer patients. Unfortunately, recent studies show that this drug can promote tumor growth mainly secondary to direct stimulation of cancer cells. In an animal study, Lavon et al. [69] showed that dexmedetomidine at hypnotic doses may be related to the growth of metastases in the primary tumor of the breast, lung, and colon, although at sub hypnotic doses, that is, analgesic and sedative, the effect is not predictable; but not on all models. In addition, a study published by Gong et al. [70] showed that dexmedetomidine could negatively modulate human immunity by inhibiting the maturation and proliferation of dendritic cells, as well as by decreasing the activity and cytotoxicity of CD8+ T lymphocytes.

## *4.2.2.12 Statins*

They have anti-inflammatory, immunomodulatory, and anti-angiogenic effect. They reduce the incidence of colon, prostate, and skin cancer. In a study by Rubin et al. [71] in 2005, a relative reduction of 47% in the risk of colorectal cancer was demonstrated.
