Sie können Operatoren mit Ihrer Suchanfrage kombinieren, um diese noch präziser einzugrenzen. Klicken Sie auf den Suchoperator, um eine Erklärung seiner Funktionsweise anzuzeigen.
Findet Dokumente, in denen beide Begriffe in beliebiger Reihenfolge innerhalb von maximal n Worten zueinander stehen. Empfehlung: Wählen Sie zwischen 15 und 30 als maximale Wortanzahl (z.B. NEAR(hybrid, antrieb, 20)).
Findet Dokumente, in denen der Begriff in Wortvarianten vorkommt, wobei diese VOR, HINTER oder VOR und HINTER dem Suchbegriff anschließen können (z.B., leichtbau*, *leichtbau, *leichtbau*).
Several perioperative factors are responsible for the dysregulation or suppression of the immune system with a possible impact on cancer cell growth and the development of new metastasis. These factors have the potential to directly suppress the immune system and activate hypothalamic-pituitary-adrenal axis and the sympathetic nervous system with a consequent further immunosuppressive effect.
Anesthetics and analgesics used during the perioperative period may modulate the innate and adaptive immune system, inflammatory system, and angiogenesis, with a possible impact on cancer recurrence and long-term outcome. Even if the current data are controversial and contrasting, it is crucial to increase awareness about this topic among healthcare professionals for a future better and conscious choice of anesthetic techniques.
In this article, we aimed to provide an overview regarding the relationship between anesthesia and cancer recurrence. We reviewed the effects of surgery, perioperative factors, and anesthetic agents on tumor cell survival and tumor recurrence.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Introduction
Surgery represents one of the leading treatments for the therapeutic management of several kinds of tumors. However, at the same time, surgery can have a direct and an indirect effect on tumor cell survival leading to tumor recurrence. Surgery can lead to the release of cancer cells into the bloodstream during tumor manipulation with consequent metastatic spread to distant organs [1]. Furthermore, even with clear resected surgical margins, minimal residual disease may remain and flourish with consequent local or lymphatic spread [2]. Additionally, several perioperative factors, such as inflammatory response to surgery, hypothermia, blood transfusion, tissue hypoxia, hyperglycemia, post-operative pain, can create a state of relative immunosuppression [3, 4]. Stress factors also have the potential of activating the systemic inflammatory response and enhancing tumor growth, with consequential increasing the risk of metastatic recurrence [5]. Then, the aforementioned factors have also the potential of creating an appropriate microenvironment for tumor growth through the release of hormonal mediators (i.e., catecholamines, prostaglandins), cytokines (e.g., interleukin-6, IL-4 and IL-10, TGF-β) and the upregulated expression of the transcription factor hypoxia-inducible factor 1-alpha (i.e., HIF1A) with consequent enhancement of angiogenesis pathways, cell proliferation, and the metastatic ability of cancer cells [6‐8]. Not only, surgical stress can also trigger the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system which in turn also regulates the immune response with the consequent further suppression of cell immunity [9].
Likewise, anesthesia techniques may affect metastatic progression of tumor cells [10]. In fact, anesthetic drugs can play a modulatory effect on the immune system, on systemic inflammatory response, on neuroendocrine stress response and on cancer signaling pathways [11‐13]. The influence of the anesthetic technique on neuroendocrine, inflammatory, and immune responses during surgery can alter local and systemic immunity with consequent boosting the tumor growth factors production and loco-regional recurrence and metastasis [14]. Even more, anesthetic-analgesic drugs seemed also to mediate the expression of specific genes or molecular pathways involved in the control of differentiation, cell growth, and of tumor progression [11]. Interestingly, evidence suggested that propofol may have a potential antitumor effect due to the regulation of mRNA expression [15]. Several preclinical and clinical studies have already shown the potential impact of anesthetics and adjuvants on cancer recurrence and survival [10]. What seems to emerge from the existing literature is that opioids can suppress the humoral immune response and can have pro-angiogenic effects, whereas regional anesthesia techniques have been associated with lower rates of cancer recurrence [16‐18]. Even more, it seemed that total intravenous anesthesia (TIVA) was associated with improved recurrence-free survival in comparison to volatile anesthesia [19]. Thus, evidence is arising about the possible relation between anesthesia technique and cancer recurrence, however, a huge limitation to the current literature is represented by the impossibility of evaluating the effect of each single drug on cancer recurrence, since anesthesia requires a combination of different classes of anesthetics (i.e., hypnotic, analgesic). Consequently, further studies are needed on this topic.
Anzeige
Accordingly, it is crucial for healthcare personnel to consider the possible relation and implication between anesthesia, perioperative stress factors and cancer for a future better and conscious choice of anesthetic technique with the goal of improving cancer outcome. In this article, we aimed to provide an overview regarding the relationship between anesthesia and cancer recurrence. We reviewed the effects of surgery, perioperative factor, and anesthetic agents on tumor cell survival and tumor recurrence.
Perioperative metastasis
Perioperative stress factors trigger physiological responses that in turn can create an appropriate microenvironment for the growth of pre-existing micro-metastatic, for the formation of new ones and for their spread [20]. Several perioperative variables (i.e., the inflammatory response to surgery, hypothermia, and blood transfusion) represent important risk factors responsible for creating a state of relative immunosuppression and of increasing vulnerability to cancer recurrence.
Perioperative metastasis survival and growth are mediated through various mechanisms [21]:
Increase shedding of cancer cells due to mechanical manipulations of the tumor during surgery [1];
Triggering the neuroendocrine and paracrine stress responses [24];
Activation of pro-angiogenic signaling pathways [25];
Expression of specific genes and/or molecular pathways [26].
Metastasis can occur through transcoelomic, lymphatic, and/or hematogenous routes. Transcoelomic spread refers to the diffusion of cancer cells to the peritoneal cavity, due to the migration of a primary cancer of the abdomen/pelvis or due to the systemic spread of another kind of primary cancer [27]. During abdominal and pelvic operation, surgical manipulation can be responsible for intraperitoneal seeding [28]. Even more, lymphatic network is commonly increased in solid tumors, especially in tumor margin and peritumor area and lymph flow that drains tumors is often increased, with increased interstitial fluid pressure and consequent altered lymphatic drainage [29‐31]. Consequently, mechanical disruption and manipulation of the cancer during surgery may facilitate the dissemination of tumor cells also through lymphatic routes [32]. In fact, surgical incision may be responsible for endothelial disruption and consequent increase in the hydrostatic and oncotic pressures, thus favoring migration of cancer cells in the lymphatic network and subsequent dissemination. Additionally, physiological response to surgical stress led to an overexpression of lymphangiogenic factors (i.e., vascular endothelial growth factor (VEGF), prostaglandins, and platelet-derived growth factor (PDGF)) with consequent further enhance of tumor dissemination [33‐35]. Surgery may also increase the hematic release of circulating tumor cells (CTC); the levels of CTC were found to be increased during different kind of surgeries [36‐39]. Not all the CTC are able to seed with the consequent formation of distant metastasis. To accomplish this process, CTC have to escape circulating immune defenses and to migrate and invade fertile zone to colonize. Several inflammatory mediators and hypoxic conditions are responsible of creating vulnerable areas where CTC can migrate and proliferate: the so-called pre-metastatic niche [40].
Anzeige
The activation of inflammatory system due to surgical stress lead to the migration of macrophages, neutrophils, fibroblasts and mesenchymal stem cells on the site of the surgery [41]. These cells secrete several factors (e.g., VEGF, PDGF, epidermal growth factor-EGF, prostaglandin, matrix metalloproteinases (MMP)), responsible for promoting cancer growth, lymphangiogenesis, angiogenesis, and consequent dissemination [42]. Prostaglandins play an important role in increasing the metastatic invasiveness of cancer cells through the activation of several receptors (e.g., B2-adrenergic, and cyclooxygenase-2 receptors) [43, 44]. Even more, MMP and VEGF are responsible for favoring tumor cell adhesion, angiogenesis, and invasiveness of cancer cells [42, 45]. Interestingly, platelet seemed to play an important role in immune escaping of cancer cells [46]. In fact, micro-clot formation can protect CTC from natural killer (NK), from cell-mediated detection, and promotes CTC adhesion to the endothelium. Even more, activated platelets can release soluble mediators (i.e., transforming-growth factor beta -TGF-β, PDGF and adenosine triphosphate) with important effects on immune system: modulation of the NK activity and of the vascular permeability [47]. Furthermore, local and systemic immune responses to surgery lead to pro-inflammatory and immunosuppressive consequences with deeply suppression of cell-mediated immunity (CMI) [6]. The consequent immunosuppression is due to the release of several mediators such as cytokines (e.g., Interleukin-6), with an inhibitory effect on NK activity. Remarkably, several trials have found an increased level of Th2 lymphocytes and decrease level of Th1 lymphocytes with altered Th1/Th2 ratio during cancer surgery [48]. These responses may represent another important aspect to consider regarding the relation between perioperative stress response and immunosuppression.
The activation of neural signaling is induced not only by surgical tissue trauma but also by other stress factors (e.g., hypothermia, tissue hypoxia, and patient anxiety). The activation of neural signaling (i.e., the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis) led to the release of stress hormones (i.e., catecholamines, opioids, and glucocorticoids) with important consequences on cancer cell invasiveness [49]. The consequent hormonal storm stimulates inflammatory and immunologic response. Afferent nerves from the site of tissue damage triggers the activation of the HPA axis and sympathetic nervous system with consequent secretion of ACTH, cortisol, catecholamines, aldosterone, vasopressin, and glucagon. Cortisol are natural steroid hormones that bind the transcription factor glucocorticoid receptor (GR). The hypersecretion of cortisol lead to the upregulation of anti-inflammatory protein and downregulation of pro-inflammatory protein expression. Even more, cortisol influences the adaptive and innate immunity systems. Because of increased cortisol production, the number of circulating monocytes, macrophage and dendritic cells are reduced. Even more, another important consequence is represented by reduction of circulating T cells, with a shift from a pro-inflammatory Th1 phenotype to an anti-inflammatory Th2 phenotype. Glucocorticoids also effects the expression of genes that regulate the inflammatory response (i.e., NF-KB and AP-1) and inhibits the activation, proliferation, and production of immunoglobulins by B cell lymphocyte [50]. Even more, the activation of the neuroendocrine response is also responsible of changing tumor microenvironment, and remodeling lymphatic and blood vasculature [51]. All these processes are implied in tumor recurrence. Stress hormones were reported to downregulate NK, cytotoxic T lymphocytes activity, and macrophage motility/phagocytosis [52, 53]. Furthermore, catecholamine bind β-adrenoceptors on cell surface with activation of calcium-cAMP signaling and consequent enhancement of pro-metastatic factors transcription (e.g., HIF, VEGF, and MMP) [54]. Beta-adrenoreceptors have been found in several cancer cells (i.e., breast, prostate, lung, liver) [54]. The activation of these signaling pathways leads to increase tumor cell growth and their invasiveness.
Finally, another important aspect is represented by the possible correlation between stress response and expression of specific genes or molecular pathways with the consequent changes in the cell signaling [26, 55, 56]. The epigenetic modification of gene expression involved during surgery is due to DNA methylation, histone modifications, chromatin, and noncoding RNAs (ncRNAs) remodeling [57]. Furthermore, the disruption of local vasculature during surgery, lead to hypoperfusion, ischemia, and hypoxia. Hypoxia stimulates the upregulated expression of the transcription factor hypoxia-inducible factor 1-alpha (i.e., HIF1A) with consequent promotion of angiogenesis, cell proliferation, and metastasis [58]. Furthermore, HIF promotes the secretion of angiogenic factors (e.g., VEGF and angiopoietin 2) with a further effect on tumor progression and metastatic spread [59]. The level of HIF1A has been correlated with tumor progression, metastatic spread and outcome [60]. Hypoxic conditions lead also to increased production of reactive oxygen species (ROS). The consequent oxidative stress can trigger several transcription factors (i.e., NF-κB, AP-1, p53, HIF-1α, PPAR-γ, β-catenin/Wnt, and Nrf2) that in turn lead to the expression of growth factors, inflammatory cytokines and chemokines [61]. The effect of surgery and of anesthetic techniques on cancer recurrence are summarized in Tables 1 and 2. A schematic representation of perioperative metastasis due to surgical manipulation is presented in Fig. 1.
Table 1
Effects of surgery on cancer recurrence
Effects of surgery on cancer recurrence
Action
Consequences
Direct effect on tumor cell survival
Surgical tumor manipulation
Release of cancer cells into the bloodstream ➔ metastatic spread to distant organs
Surgical tumor manipulation
Intraperitoneal seeding➔ Transcoelomic spread
Surgical tumor manipulation and incision
Endothelial disruption ➔ increase hydrostatic and oncotic pressure➔dissemination of tumor cells through lymphatic routes
Minimal residual disease in surgical margins
Local or lymphatic spread
Action
Consequences
Indirect effect on tumor cell survival
Physiological response to perioperative stress factors
Activating the systemic inflammatory response➔ migration of macrophages, neutrophils, fibroblasts on the site of the surgery ➔ Release of cytokines, growth factors and prostaglandin➔ promoting cancer growth, lymphangiogenesis, angiogenesis, and consequent dissemination
Physiological response to perioperative stress factors
Activating the systemic inflammatory response➔ state of relative immunosuppression➔ immune escaping of cancer cells➔appropriate microenvironment for tumor growth
Physiological response to perioperative stress factors
Trigger the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system➔ release of hormonal mediators➔ enhance tumor growth
Physiological response to perioperative stress factors
Expression of specific genes and/or molecular pathways➔ promotion of angiogenesis, cell proliferation, and metastasis
Physiological response to perioperative stress factors
Activation of pro-angiogenic signaling pathways➔ increasing the metastatic invasiveness
Table 2
Effects of anesthetics on cancer recurrence
Effects of anesthetics on cancer recurrence
Type of anesthetics
Effects
Volatile anesthetics
-Pro-inflammatory and immunosuppressive action
-Reduces Th1/Th2 ratio
-Impairs NK cell activity
-Induces T cell and B cell apoptosis
-Upregulation of hypoxia-inducible factors (HIF-1α, HIF-2α,)
-Increase transcription of pro-metastatic factors (VEGF, angiopoietin-1, proteases MMP-2, and MMP-9)
-Enhanced tumor cell proliferation
-Increase angiogenesis, and cell migration
Intravenous anesthetics
-Anti-inflammatory and immunosuppression properties
-Suppression of prostaglandin and inflammatory cytokine production
-Inhibition of cyclooxygenase (COX) activity
-Stimulate the proliferation of NK cells
-Increase expression of granzyme B and IFNγ
-Increase cytotoxic T lymphocyte activity
-Does not affect the Th1/Th2 ratio
-Modulate genetic signaling pathways
-Inhibits histone acetylation
Ketamine, Thiopental
-Suppress the activity of NK cells
-Induce apoptosis in lymphocytes
-Inhibits the functional maturation of dendritic cells
-Reduce the synthesis of pro-inflammatory cytokines
Opioids
-Modulate wound healing
-Immunosuppression effects
-Inhibits natural killer cell activity
-Inhibits responses of T and B cells to mitogens
-Inhibits antibody production
-Promotes lymphocyte apoptosis,
-Reduces the differentiation of T cells
-Inhibits phagocytic activity
-Inhibits of the release of cytokine/ chemokine production
Local anesthetics
-Activates apoptotic pathway
-Inhibits tumor cell growth and migration
-Increases the activity of NK
-Increases the number of T-helper (Th) cells
-Preserves Th1/Th2 cells ratio
-Preserves IFN-gamma concentrations
-Modulates gene expression
-Increases IL-4 levels
-Decreases IL-10, IL-8, TNF-alfa production
NSAIDs and COX-2 inhibitors
-Inhibits the cyclooxygenase 1 and the cyclooxygenase 2
-Reduces prostaglandin synthesis
Paracetamol
-Inhibits prostaglandin endoperoxide H2 synthase and cyclooxygenase activity
Anesthetic agents
Volatile and intravenous anesthetics
The increasing interest in the impact of anesthetics and cancer progression has stimulated several in vivo and in vitro studies on the relation between different kinds of anesthetics used during surgery and cancer development and progression [48, 62]. Even if the evidence is conflicting, halogenated anesthetics seemed to present several pro-inflammatory and immunosuppressive effects that can have an important impact on enhancing metastasis formation [63]. Volatile anesthetic agents are implied in the upregulation of hypoxia-inducible factors [64]. Several trials are showed that the exposure of cancer cells to isoflurane and sevoflurane led to upregulation of HIF-1α, HIF-2α, growth factor and increase transcription of pro-metastatic factors (VEGF, angiopoietin-1, proteases MMP-2 and MMP-9, insulin-like growth factor IGF-1) which enhanced tumor cell proliferation, increased angiogenesis, and cell migration [65, 66]. Furthermore, halogenated anesthetics inhibit the activity of the immune system; reduces Th1/Th2 ratio, impairs NK cell activity, induces T cell and B cell apoptosis [67‐69]. Consequently, the volatile anesthetic may promote immunosuppression and the creation of a pro-malignant environment that supports the growth of residual cancer cells.
On the other hand, propofol presents anti-inflammatory and immunosuppression properties [70‐72]. Several studies have shown that propofol could inhibit adhesion, migration, invasiveness of cancer cells and induce apoptosis [73, 74]. Propofol presents anti-inflammatory properties through the suppression of prostaglandin and inflammatory cytokine production and the inhibition of cyclooxygenase (COX) activity [75]. Even more, propofol may prevent immunosuppression through the preservation of NK cell function. Not only propofol preserved NK activity, it seemed that propofol could also stimulate the proliferation of NK cells through the increased expression of granzyme B, IFN-γ, and activating surface receptors (e.g., CD16, NKp30, NKp44, and NKG2D) [76‐78]. In fact, increased NK cell infiltration of tumors is reported after the administration of propofol. Furthermore, propofol could increase cytotoxic T lymphocyte activity and does not affect the Th1/Th2 ratio [79].
Propofol may also modulate genetic signaling pathways with important consequences on carcinogenesis:
Inhibition of HIF-1α protein synthesis induced by hypoxia [80];
Inhibition of the mRNA expression of MMP-2 and MMP-9 and p38 MAPK signaling (signaling pathway regulating proliferation, cell motility, and survival) [81];
Noteworthy, signaling pathways are not usually independent and participate in a crosstalk to create a regulatory network. Consequently, propofol may affect several pathways with important regulation on genes expression. Propofol with its anti-inflammatory and pro-immunity effects has been suggested to have a positive impact on long-term survival and cancer outcome [87‐90]. However, no unified conclusion has been reached and further evidence is needed to come to a clear conclusion. In 2019, a randomized controlled trial was published comparing the incidence of metastatic breast cancer recurrence in patients who received regional anesthesia and propofol versus general anesthesia with volatile anesthetic sevoflurane and opioid analgesia [91]. The studies included 2108 women who underwent breast surgery. Cancer recurrence was similar between the groups. Contrarily, a 2019 meta-analysis by Yap et al. analyzed the effects of anesthetics on cancer recurrence and survival [19]. The study included ten trials. The authors found that TIVA was associated with improved recurrence-free survival.
In 2021, Ramirez et al. performed a review describing how drugs may regulate important function on immune and cancer cells [92]. The authors presented several preclinical and clinical studies and explained the effects of anesthetics on cancer cells. The authors presented 21 retrospective and 4 RCTs studies comparing the effects of TIVA versus volatile anesthesia. They also presented 28 retrospective and 9 RCTs studies assessing the effects of regional anesthesia on long-term outcome. Preclinical evidence showed that volatile anesthesia regulates important function in cancer cells and that they can directly modify intracellular signal involved in proliferation, migration and invasion. The authors concluded that “…whether volatile anesthetics have a deleterious effect on cancer recurrence and survival remains a controversial issue…”; however, Ramirez explained how “…volatile anesthesia regulate important function in cancer cells.”. This evidence suggested that anesthetics may play a potential impact on cancer recurrence, at least from a cellular point of view. Of course, we cannot speculate that the result of preclinical studies could be translated into clinical practices.
Finally, ketamine and thiopental present immune effects. Thiopental inhibits the function of neutrophils and NK [93]. Ketamine may suppress the activity of NK cells, induce apoptosis in lymphocytes and inhibits the functional maturation of dendritic cells [94]. Ketamine may also reduce the synthesis of pro-inflammatory cytokines, (e.g., IL-6, TNF-α) [95]. However, the evidence regarding the relation between ketamine and thiopental and cancer is scarce and far to be conclusive.
Opioids
Increasing evidence suggests that, beyond their primary analgesic function, opioids present several physiological effects. Opioids modulate wound healing and cancer progression through their endothelial action and through their influence on angiogenesis [17]. Furthermore, opioids are known to act on the immune system with immunosuppression effects [16, 96]. Through the mu-opioid receptor (MOR) or non-opioid receptors (toll-like receptors) expressed by immune cells, opioids play their direct effect on the immune system, inhibiting natural killer cell activity, inhibiting responses of T and B cells to mitogens and antibody production [97‐100]. Furthermore, opioids can inhibit several neutrophils and macrophages activity: inhibition of phagocytic activity and inhibition of the release of cytokine/chemokine production [101]. Moreover, opioids act indirect effects on the immune system through the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis [102, 103].
The interplay between opioids and cancer, however, is complex and far to be understood deeply. It was also observed that neutrophils, macrophages and T cells also release endogenous opioid peptides with consequent reduction of inflammation and pain through the binding of peripheral opioid receptors [96, 104]. Noteworthy, it is important to take into account that the control of pain may have a beneficial indirect effect on immunity. The balance between the immunosuppressive effect of the opioid and the reduction of immunosuppression of pain is difficult to foresee [105].
In brief, different kinds of opioids seemed to act different effects in in vitro/in vivo model:
Morphine: suppresses the activity of NK cells, promotes lymphocyte apoptosis, reduces the differentiation of T cells, and stimulates angiogenesis [99];
Fentanyl: decrease the activity of NK cells and increase the number of regulatory T cells [106];
Sufentanil: decrease the activity of NK cells, increase the number of regulatory T cells, inhibits leukocyte migration [107];
Alfentanil: decreases the activity of NK cells [108];
Remifentanil: suppress the activity of NK cells and lymphocytic proliferation [109].
Interestingly, methyl-naltrexone, an opioid antagonist, seemed to inhibit tumor cell invasion and implantation, while continuous infusion of MNTX decreases primary tumor growth and development of lung metastasis [110].
Local anesthetics
The implementation of regional anesthesia/analgesia techniques seemed to have a positive impact on reducing cancer recurrence via several mechanisms [111]:
Reduces the stress response to surgery (via pain control or sympathetic block) and reduces the levels of cortisol, β-endorphin, and epinephrine [112, 113];
Reduces the need for opioids or volatile agents (indirect effect);
Modulates gene expression, DNA demethylation [119];
Increases IL-4 and decreasing IL-10, IL-8, TNF-alfa [120].
Besides the possible beneficial mechanism triggered by regional anesthesia, there is no strong evidence regarding the effect of regional anesthesia on cancer recurrence. Xu et al. evaluated the effects of epidural anesthesia-analgesia on recurrence-free survival after lung cancer surgery. The authors compared two groups: general anesthesia versus general anesthesia and regional anesthesia groups [121]. The authors concluded that regional anesthesia did not improve recurrence-free survival compared with general anesthesia alone. In both groups, general anesthesia was induced with propofol, sufentanil, and rocuronium while anesthesia was maintained with propofol and/or sevoflurane (with or without nitrous oxide inhalation). Even more, dexmedetomidine was given at the discretion of anesthesiologists. Consequently, due to the high heterogeneity of drugs administered (propofol, sevoflurane, opioids, dexmedetomidine), it was not possible to come to any conclusion regarding general anesthesia. It was impossible of evaluating the effect of each single drug on cancer recurrence. Similarly, in Du et al., the authors concluded that regional anesthesia did not improve recurrence-free survival compared with general anesthesia alone [122]. Even more, general anesthesia was induced with midazolam, propofol, sufentanil, and rocuronium and maintained with either intravenous, inhalation, or combined. A 2015 meta-analysis including 10 studies showed improved overall survival when neuraxial analgesia was used in radical prostatectomy [123]. On the other hand, as aforementioned mentioned, in 2019 a randomized controlled trial did not find any difference in cancer recurrence between the groups receiving regional anesthesia and propofol versus general anesthesia with volatile anesthetic sevoflurane and opioid analgesia [91]. Several studies were conducted on this topic; however, due to the heterogeneity of the trials, it is difficult to draw any conclusion from the existing literature [118, 124‐126].
Other drugs commonly used in the perioperative period:
NSAIDs and COX-2 inhibitors: represented the most widely painkiller used for the management of perioperative analgesia. NSAIDs inhibit the cyclooxygenase 1 (COX-1) and the cyclooxygenase 2 (COX-2) enzymes with consequent anti-inflammatory, analgesic and antipyretic effects. Several trials have already shown the potential benefits of NSAIDs in the prevention of human cancer [127]. Above all, the long-term use of daily low-dose aspirin has been already related to the risk reduction of several kind of cancers: from colon, breast, lung, and prostate cancer [127, 128]. COX is frequently overexpressed in several cancers with important effects on cancer progression with an important contribution in tumorigenesis [127, 129‐131]: increased production of prostaglandins, inhibition of apoptosis and promotion of angiogenesis, increased cell motility and invasion and modulation of inflammation and immune function [132, 133]. NSAIDs inhibit cyclooxygenase enzymes, leading to reduction of prostaglandin synthesis (i.e., prostaglandin E2, PGE2) and promote immune responses [134]. In particular, PGE2 plays a crucial role in promoting cancer progression; enhancement of cellular proliferation, promotion of angiogenesis, inhibition of apoptosis, stimulation of invasion/motility, and suppression of immune response [44]. Nevertheless, NSAIDs can be administered in combination with opioids or with paracetamol to increase the analgesic efficacy and to reduce the daily consumption of opioids [135]. Consequently, the possible survival benefits of receiving NSAIDs may be also due to their opioid-sparing effects of the usage of multimodality therapy in the perioperative settings [136].
Paracetamol: inhibits prostaglandin endoperoxide H2 synthase and cyclooxygenase activity with pain-relieving and antipyretic properties. However, paracetamol has no anti-inflammatory effects. Paracetamol can be administered in combination with opioids or NSAIDs to increases the analgesic efficacy and reduce daily morphine consumption [137]. Analyzing the current literature, the relationship between paracetamol usage and cancer recurrence are conflicting: increased risks for urinary tract cancers and decreased risk for ovarian cancer [138, 139]. However, the results reached so far have been inconsistent.
Alpha-2 adrenoceptor agonists: dexmedetomidine and clonidine are alpha-2 adrenoceptor agonists mainly used for sedation and as part of multimodal opioid-sparing analgesia. Alfa-adrenoceptors are found to be expressed in breast cancer, both epithelial and stromal cells [140]. Consequently, alfa-modulators may affect cancer progression and recurrence. However, evidence is scarce regarding the relation between dexmedetomidine and/or clonidine and cancer recurrence and far to be conclusive [141‐143].
Discussion and conclusions
Overview articles represent a useful aid for addressing bias and concerns or to put light on the insufficiency of the current literature and to stimulate further research in a particular field. We decided to provide an overview only on the impact of anesthetic techniques and surgery on cancer recurrence because the current data are controversial and contrasting. Our aim was to summarize content from several articles and provide the reader with a general understanding of the possible relation between anesthetics and cancer.
It is also important to highlight that, up to now, the heterogeneity of the factors implied in cancer recurrence during surgery are high and the heterogeneity of the current literature on cancer and anesthesia would make impractical, or at least hard, to summarize and to come to any kind of conclusion. Not only the anesthetic technique but also several perioperative factors can influence immune surveillance and inflammatory responses and they may favor proliferation of metastasis. Furthermore, the impact of anesthetics technique depending on the type of cancer could make the discussion confusing considering the vast and divergent literature available on this topic. This would made even more difficult to come to any kind of conclusion.
Another important limitation is represented by the fact that it is impossible to evaluate the effect of each single drug on cancer recurrence, since anesthesia requires a combination of different classes of drugs (i.e., hypnotic, analgesic). The difference in baseline characteristics between groups (i.e., ASA), the different concentration of volatile anesthetics used in the clinical studies, the different duration of the surgery and the extension of surgical incision (minimally invasive vs. open surgery) represented important confounding factors. Even more, the majority of the data looking at the relationship of these techniques and cancer outcome in different kind of tumor originates from retrospective studies.
Surely, evidence is arising about the possible impact of anesthesia technique, perioperative period, cancer recurrence and long-term outcome. Even if the current data are controversial and contrasting, it is crucial to increase awareness about this topic among healthcare professionals for a future better and conscious choice of anesthetic techniques. Consequently, further trials are needed for a deeper understanding of the aforementioned mechanisms and on the actual impact of anesthetic techniques on the long-term survival. At this stage of the clinical research, we think that share awareness represents the major goal in an informative way.
Fig. 1
Schematic representation of perioperative metastasis due to surgical manipulation
The authors declare that they have no competing interests.
Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Tohme S, Simmons RL, Tsung A (2017) Surgery for cancer: a trigger for metastases. Cancer Res 77(7):1548–1552
2.
Pierik AS, Leemans CR, Brakenhoff RH Resection margins in head and neck cancer surgery: an update of residual disease and field cancerization. Cancers (Basel):132021
3.
Vallejo R, Hord ED, Barna SA, Santiago-Palma J, Ahmed S (2003) Perioperative immunosuppression in cancer patients. J Environ Pathol Toxicol Oncol 22(2):139–146PubMedCrossRef
4.
Peng YP, Qiu YH (2006) Surgical stress and immunosuppression. Sheng Li Ke Xue Jin Zhan 37(1):31–36PubMed
5.
Chen Z, Zhang P, Xu Y, Yan J, Liu Z, Lau WB et al (2019) Surgical stress and cancer progression: the twisted tango. Mol Cancer 18(1):132PubMedPubMedCentralCrossRef
6.
Alazawi W, Pirmadjid N, Lahiri R, Bhattacharya S (2016) Inflammatory and immune responses to surgery and their clinical impact. Ann Surg 264(1):73–80PubMedCrossRef
7.
Wu WK, Sung JJ, Lee CW, Yu J, Cho CH (2010) Cyclooxygenase-2 in tumorigenesis of gastrointestinal cancers: an update on the molecular mechanisms. Cancer Lett 295(1):7–16PubMedCrossRef
8.
Huang H, Benzonana LL, Zhao H, Watts HR, Perry NJ, Bevan C et al (2014) Prostate cancer cell malignancy via modulation of HIF-1α pathway with isoflurane and propofol alone and in combination. Br J Cancer 111(7):1338–1349PubMedPubMedCentralCrossRef
9.
Saito H (1996) Endocrine response to surgical stress. Nihon Geka Gakkai Zasshi 97(9):701–707PubMed
10.
Wall T, Sherwin A, Ma D, Buggy D (2019) Influence of perioperative anaesthetic and analgesic interventions on oncological outcomes: a narrative review. Br J Anaesth 123(2):135–150PubMedPubMedCentralCrossRef
11.
Ponferrada AR, Orriach JLG, Manso AM, Haro ES, Molina SR, Heredia AF et al (2020) Anaesthesia and cancer: can anaesthetic drugs modify gene expression? Ecancermedicalscience 14:1080. https://doi.org/10.3332/ecancer.2020.1080. eCollection 2020.
12.
Dang Y, Shi X, Xu W, Zuo M (2018) The effect of anesthesia on the immune system in colorectal cancer patients. Can. J Gastroenterol Hepatol 2018:7940603. https://doi.org/10.1155/2018/7940603. eCollection 2018.
13.
Schneemilch CE, Schilling T, Bank U (2004) Effects of general anaesthesia on inflammation. Best Pract Res Clin Anaesthesiol 18(3):493–507PubMedCrossRef
14.
Kurosawa S, Kato M (2008) Anesthetics, immune cells, and immune responses. J Anesth 22(3):263–277PubMedCrossRef
15.
Hamaya Y, Takeda T, Dohi S, Nakashima S, Nozawa Y (2000) The effects of pentobarbital, isoflurane, and propofol on immediate-early gene expression in the vital organs of the rat. Anesth Analg 90(5):1177–1183PubMedCrossRef
16.
Eisenstein TK (2019) The role of opioid receptors in immune system function. Front Immunol 10:2904PubMedPubMedCentralCrossRef
17.
Ondrovics M, Hoelbl-Kovacic A, Fux DA (2017) Opioids: modulators of angiogenesis in wound healing and cancer. Oncotarget 8:25783–25796PubMedPubMedCentralCrossRef
18.
Le-Wendling L, Nin O, Capdevila X (2016) Cancer recurrence and regional anesthesia: the theories, the data, and the future in outcomes. Pain Med 17(4):756–775PubMed
19.
Yap A, Lopez-Olivo MA, Dubowitz J, Hiller J, Riedel B (2019) Anesthetic technique and cancer outcomes: a meta-analysis of total intravenous versus volatile anesthesia. Can J Anaesth 66(5):546–561PubMedCrossRef
20.
Onuma AE, Zhang H, Gil L, Huang H, Tsung A (2020) Surgical stress promotes tumor progression: a focus on the impact of the immune response. Clin Med 9(12):4096. Published online 2020 Dec 18. https://doi.org/10.3390/jcm9124096
21.
Neeman E, Ben-Eliyahu S (2013) The perioperative period and promotion of cancer metastasis: New outlooks on mediating mechanisms and immune involvement. Brain Behav Immun 30(Suppl):S32–S40PubMedCrossRef
22.
Margraf A, Ludwig N, Zarbock A, Rossaint J (2020) Systemic inflammatory response syndrome after surgery: mechanisms and protection. Anesth Analg 131(6):1693–1707PubMedCrossRef
23.
Salo M (1992) Effects of anaesthesia and surgery on the immune response. Acta Anaesthesiol Scand 36(3):201–220PubMedCrossRef
24.
Okur H, Küçükaydin M, Ustdal KM (1995) The endocrine and metabolic response to surgical stress in the neonate. J Pediatr Surg 30:626–625PubMedCrossRef
25.
Kong B, Michalski CW, Friess H, Kleeff J (2010) Surgical procedure as an inducer of tumor angiogenesis. Exp Oncol 32(3):186–189PubMed
26.
Lirk P, Fiegl H, Weber NC, Hollmann MW (2015) Epigenetics in the perioperative period. Br J Pharmacol 172(11):2748–2755PubMedPubMedCentralCrossRef
Bahat G, Saka B, Yenerel M, Yilmaz E, Tascioglu C, Dogan O (2010) Peritoneal seeding and subsequent progression of mantle cell lymphoma after splenectomy for debulking. Curr Oncol 17:78–82PubMedPubMedCentralCrossRef
29.
Stacker SA, Williams SP, Karnezis T, Shayan R, Fox SB, Achen MG (2014) Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat Rev Cancer 14(3):159–172PubMedCrossRef
30.
Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P et al (2001) Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 7(2):192–198PubMedCrossRef
31.
Hoshida T, Isaka N, Hagendoorn J, di Tomaso E, Chen YL, Pytowski B et al (2006) Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications. Cancer Res 66:8065–8075PubMedCrossRef
32.
Tvedskov TF, Jensen MB, Kroman N, Balslev E (2012) Iatrogenic displacement of tumor cells to the sentinel node after surgical excision in primary breast cancer. Breast Cancer Res Treat 131(1):223–229PubMedCrossRef
33.
Hirakawa S, Kodama S, Kunstfeld R, Kajiya K, Brown LF, Detmar M (2005) VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med 201(7):1089–1099PubMedPubMedCentralCrossRef
34.
Abramovitch R, Marikovsky M, Meir G, Neeman M (1999) Stimulation of tumour growth by wound-derived growth factors. Br J Cancer 79(9-10):1392–1398PubMedPubMedCentralCrossRef
35.
Antonio N, Bønnelykke-Behrndtz ML, Ward LC, Collin J, Christensen IJ, Steiniche T et al (2015) The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer. EMBO J 34(17):2219–2236PubMedPubMedCentralCrossRef
36.
Skondra M, Gkioka E, Kostakis ID, Pissimissis N, Lembessis P, Pectasides D et al (2014) Detection of circulating tumor cells in breast cancer patients using multiplex reverse transcription-polymerase chain reaction and specific primers for MGB, PTHRP and KRT19 correlation with clinicopathological features. Anticancer Res 34(11):6691–6699PubMed
37.
Brown DC, Purushotham AD, Birnie GD, George WD (1995) Detection of intraoperative tumor cell dissemination in patients with breast cancer by use of reverse transcription and polymerase chain reaction. Surgery 117:95–101PubMedCrossRef
38.
Hashimoto M, Tanaka F, Yoneda K, Takuwa T, Matsumoto S, Okumura Y et al (2014) Significant increase in circulating tumour cells in pulmonary venous blood during surgical manipulation in patients with primary lung cancer. Interact Cardiovasc Thorac Surg 18(6):775–783PubMedCrossRef
39.
Peach G, Kim C, Zacharakis E, Purkayastha S, Ziprin P (2010) Prognostic significance of circulating tumour cells following surgical resection of colorectal cancers: a systematic review. Br J Cancer 102(9):1327–1334PubMedPubMedCentralCrossRef
40.
Peinado H, Zhang H, Matei IR, Costa-Silva B, Hoshino A, Rodrigues G et al (2017) Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer 17(5):302–317PubMedCrossRef
41.
Landén NX, Li D, Ståhle M (2016) Transition from inflammation to proliferation: a critical step during wound healing. Cell Mol Life Sci 73(20):3861–3885PubMedPubMedCentralCrossRef
42.
Dunn IF, Heese O, Black PM (2000) Growth factors in glioma angiogenesis: FGFs, PDGF, EGF, and TGFs. J Neurooncol 50(1-2):121–137PubMedCrossRef
43.
Wang D, DuBois RN (2008) Pro-inflammatory prostaglandins and progression of colorectal cancer. Cancer Lett 267(2):197–203PubMedPubMedCentralCrossRef
Im JH, Fu W, Wang H, Bhatia SK, Hammer DA, Kowalska MA et al (2004) Coagulation facilitates tumor cell spreading in the pulmonary vasculature during early metastatic colony formation. Cancer Res 64(23):8613–8619PubMedCrossRef
46.
Amo L, Tamayo-Orbegozo E, Maruri N, Eguizabal C, Zenarruzabeitia O, Riñón M et al (2014) Involvement of platelet-tumor cell interaction in immune evasion. Potential role of podocalyxin-like protein 1. Front Oncol 4:245PubMedPubMedCentralCrossRef
Ishikawa M, Nishioka M, Hanaki N, Miyauchi T, Kashiwagi Y, Ioki H et al (2009) Perioperative immune responses in cancer patients undergoing digestive surgeries. World J Surg Oncol 7:7PubMedPubMedCentralCrossRef
49.
Kim TH, Rowat AC, Sloan EK (2016) Neural regulation of cancer: from mechanobiology to inflammation. Clin Transl Immunol 5:e78CrossRef
50.
Rosenkrantz Hölmich E, Petring Hasselager R, Tvilling Madsen M, Orhan A, Gögenur I (2020) Long-term outcomes after use of perioperative glucocorticoids in patients undergoing cancer surgery: a systematic review and meta-analysis. Cancers (Basel) 12(1):76. Published online 2019 Dec 27. https://doi.org/10.3390/cancers12010076
51.
Dilley RJ, Schwartz SM (1989) Vascular remodeling in the growth hormone transgenic mouse. Circ Res 65(5):1233–1240PubMedCrossRef
52.
Mavoungou E, Bouyou-Akotet MK, Kremsner PG (2005) Effects of prolactin and cortisol on natural killer (NK) cell surface expression and function of human natural cytotoxicity receptors (NKp46, NKp44 and NKp30). Clin Exp Immunol 139(2):287–296PubMedPubMedCentralCrossRef
53.
Deitch EA, Bridges RM (1987) Stress hormones modulate neutrophil and lymphocyte activity in vitro. J Trauma 27(10):1146–1154PubMedCrossRef
54.
Mravec B, Horvathova L, Hunakova L (2020) Neurobiology of cancer: the role of β-adrenergic receptor signaling in various tumor environments. Int J Mol Sci 21(21):7958. https://doi.org/10.3390/ijms21217958
55.
Ilango S, Paital B, Jayachandran P, Padma PR, Nirmaladevi R (2020) Epigenetic alterations in cancer. Front Biosci (Landmark Ed) 25:1058–1109CrossRef
56.
Gibney ER, Nolan CM (2010) Epigenetics and gene expression. Heredity (Edinb) 105(1):4–13CrossRef
57.
Sadahiro R, Knight B, James F, Hannon E, Charity J, Daniels IR et al (2020) Major surgery induces acute changes in measured DNA methylation associated with immune response pathways. Sci Rep 10(1):5743PubMedPubMedCentralCrossRef
58.
Dengler VL, Galbraith M, Espinosa JM (2014) Transcriptional Regulation by Hypoxia Inducible Factors. Crit Rev Biochem Mol Biol 49(1):1–15PubMedCrossRef
59.
Ahn GO, Seita J, Hong BJ, Kim YE, Bok S, Lee CJ et al (2014) Transcriptional activation of hypoxia-inducible factor-1 (HIF-1) in myeloid cells promotes angiogenesis through VEGF and S100A8. Proc Natl Acad Sci U S A 111(7):2698–2703PubMedPubMedCentralCrossRef
60.
Masoud GN, Li W (2015) HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B 5:378–389PubMedPubMedCentralCrossRef
61.
Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB (2010) Oxidative stress, inflammation, and cancer: How are they linked? Free Radic Biol Med 49(11):1603–1616PubMedPubMedCentralCrossRef
62.
Yang W, Cai J, Zabkiewicz C, Zhang H, Ruge F, Jiang WG (2017) The effects of anesthetics on recurrence and metastasis of cancer, and clinical implications. World J Oncol 8(3):63–70PubMedPubMedCentralCrossRef
63.
Xu Y, Jiang W, Xie S, Xue F, Zhu X (2020) The Role of Inhaled Anesthetics in Tumorigenesis and Tumor Immunity. Cancer Manag Res 12:1601–1609PubMedPubMedCentralCrossRef
Benzonana LL, Perry NJ, Watts HR, Yang B, Perry IA, Coombes C et al (2013) Isoflurane, a commonly used volatile anesthetic, enhances renal cancer growth and malignant potential via the hypoxia-inducible factor cellular signaling pathway in vitro. Anesthesiology. 119(3):593–605PubMedCrossRef
66.
Zhang W, Shao X (2016) Isoflurane promotes non-small cell lung cancer malignancy by activating the Akt-mammalian target of rapamycin (mTOR) signaling pathway. Med Sci Monit 22:4644–4650PubMedPubMedCentralCrossRef
67.
Tazawa K, Koutsogiannaki S, Chamberlain M, Yuki K (2017) The effect of different anesthetics on tumor cytotoxicity by natural killer cells. Toxicol Lett 266:23–31PubMedCrossRef
68.
Ji FH, Wang YL, Yang JP (2011) Effects of propofol anesthesia and sevoflurane anesthesia on the differentiation of human T-helper cells during surgery. Chin Med J (Engl) 124(4):525–529
69.
Loop T, Dovi-Akue D, Frick M, Roesslein M, Egger L, Humar M et al (2005) Volatile anesthetics induce caspase-dependent, mitochondria-mediated apoptosis in human T lymphocytes in vitro. Anesthesiology. 102(6):1147–1157PubMedCrossRef
70.
Chen RM, Chen TG, Chen TL, Lin LL, Chang CC, Chang HC et al (2005) Anti-inflammatory and antioxidative effects of propofol on lipopolysaccharide-activated macrophages. Ann N Y Acad Sci 1042:262–271PubMedCrossRef
71.
Helmy SA, Al-Attiyah RJ (2001) The immunomodulatory effects of prolonged intravenous infusion of propofol versus midazolam in critically ill surgical patients. Anaesthesia 56:4–8PubMedCrossRef
72.
Li R, Liu H, Dilger JP, Lin J (2018) Effect of propofol on breast cancer cell, the immune system, and patient outcome. BMC Anesthesiol 18(1):77PubMedPubMedCentralCrossRef
73.
Wang H, Jiao H, Jiang Z, Chen R (2020) Propofol inhibits migration and induces apoptosis of pancreatic cancer PANC-1 cells through miR-34a-mediated E-cadherin and LOC285194 signals. Bioengineered 11:510–521PubMedPubMedCentralCrossRef
74.
Du Q, Liu J, Zhang X, Zhu H, Wei M, Wang S (2018) Propofol inhibits proliferation, migration, and invasion but promotes apoptosis by regulation of Sox4 in endometrial cancer cells. Braz J Med Biol Res 51(4):e6803. https://doi.org/10.1590/1414-431x20176803. Epub 2018 Feb 26
75.
Inada T, Kubo K, Shingu K (2011) Possible link between cyclooxygenase-inhibiting and antitumor properties of propofol. J Anesth 25(4):569–575PubMedCrossRef
76.
Zhou M, Dai J, Zhou Y, Wu J, Xu T, Zhou D et al (2018) Propofol improves the function of natural killer cells from the peripheral blood of patients with esophageal squamous cell carcinoma. Exp Ther Med 16:83–92PubMedPubMedCentral
77.
Ai L, Wang H (2020) Effects of propofol and sevoflurane on tumor killing activity of peripheral blood natural killer cells in patients with gastric cancer. J Int Med Res 48(3):300060520904861. https://doi.org/10.1177/0300060520904861.
78.
Brand JM, Schmucker P, Breidthardt T, Kirchner H (2001) Upregulation of IFN-gamma and soluble interleukin-2 receptor release and altered serum cortisol and prolactin concentration during general anesthesia. J Interferon Cytokine Res 21(10):793–796PubMedCrossRef
79.
Liu S, Gu X, Zhu L, Wu G, Zhou H, Song Y et al (2016) Effects of propofol and sevoflurane on perioperative immune response in patients undergoing laparoscopic radical hysterectomy for cervical cancer. Medicine (Baltimore) 95(49):e5479. https://doi.org/10.1097/MD.0000000000005479.
80.
Tanaka T, Takabuchi S, Nishi K, Oda S, Wakamatsu T, Daijo H et al (2010) The intravenous anesthetic propofol inhibits lipopolysaccharide-induced hypoxia-inducible factor 1 activation and suppresses the glucose metabolism in macrophages. J Anesth 24(1):54–60PubMedCrossRef
81.
Wu KC, Yang ST, Hsia TC, Yang JS, Chiou SM, Lu CC et al (2012) Suppression of cell invasion and migration by propofol are involved in down-regulating matrix metalloproteinase-2 and p38 MAPK signaling in A549 human lung adenocarcinoma epithelial cells. Anticancer Res 32:4833–4842PubMed
82.
Zhang L, Wang N, Zhou S, Ye W, Jing G, Zhang M (2012) Propofol induces proliferation and invasion of gallbladder cancer cells through activation of Nrf2. J Exp Clin Cancer Res 31(1):66PubMedPubMedCentralCrossRef
83.
Guo XG, Wang S, Xu YB, Zhuang J (2015) Propofol suppresses invasion, angiogenesis and survival of EC-1 cells in vitro by regulation of S100A4 expression. Eur Rev Med Pharmacol Sci 19:4858–4865PubMed
Ishikawa M, Iwasaki M, Sakamoto A, Ma D (2021) Anesthetics may modulate cancer surgical outcome: a possible role of miRNAs regulation. BMC Anesthesiol 21(1):71PubMedPubMedCentralCrossRef
86.
Gao X, Mi Y, Guo N, Luan J, Xu H, Hu Z et al (2020) The mechanism of propofol in cancer development: An updated review. Asia Pac J Clin Oncol 16(2):e3–e11PubMedCrossRef
87.
Xu Y, Pan S, Jiang W, Xue F, Zhu X (2020) Effects of propofol on the development of cancer in humans. Cell Prolif 53(8):e12867. Published online 2020 Jun 29. https://doi.org/10.1111/cpr.12867
88.
Enlund M, Berglund A, Andreasson K, Cicek C, Enlund A, Bergkvist L (2014) The choice of anaesthetic--sevoflurane or propofol--and outcome from cancer surgery: a retrospective analysis. Ups J Med Sci 119(3):251–261PubMedPubMedCentralCrossRef
89.
Lee JH, Kang SH, Kim Y, Kim HA, Kim BS (2016) Effects of propofol-based total intravenous anesthesia on recurrence and overall survival in patients after modified radical mastectomy: a retrospective study. Korean J Anesthesiol 69(2):126–132PubMedPubMedCentralCrossRef
90.
Lai HC, Lee MS, Lin C, Lin KT, Huang YH, Wong CS et al (2019) Propofol-based total intravenous anaesthesia is associated with better survival than desflurane anaesthesia in hepatectomy for hepatocellular carcinoma: a retrospective cohort study. Br J Anaesth 123(2):151–160PubMedPubMedCentralCrossRef
Ramirez MF, Cata JP (2021) Anesthesia techniques and long-term oncological outcomes. Front 11:788918. https://doi.org/10.3389/fonc.2021.788918. eCollection 2021.
93.
Nishina K, Akamatsu H, Mikawa K, Shiga M, Maekawa N, Obara H et al (1998) The inhibitory effects of thiopental, midazolam, and ketamine on human neutrophil functions. Anesth Analg 86(1):159–165PubMedCrossRef
94.
Forget P, Collet V, Lavand'homme P, De Kock M (2010) Does analgesia and condition influence immunity after surgery? Effects of fentanyl, ketamine and clonidine on natural killer activity at different ages. Eur J Anaesthesiol 27(3):233–240PubMedCrossRef
95.
Li Y, Shen R, Wen G, Ding R, Du A, Zhou J et al (2017) Effects of Ketamine on Levels of Inflammatory Cytokines IL-6, IL-1β, and TNF-α in the Hippocampus of Mice Following Acute or Chronic Administration. Front Pharmacol 8:139. https://doi.org/10.3389/fphar.2017.00139. eCollection 2017.
96.
Plein LM, Rittner HL (2018) Opioids and the immune system - friend or foe. Br J Pharmacol 175(14):2717–2725PubMedCrossRef
97.
Boland JW, Pockley AG (2018) Influence of opioids on immune function in patients with cancer pain: from bench to bedside. Br J Pharmacol 175(14):2726–2736PubMedCrossRef
98.
Beilin B, Martin FC, Shavit Y, Gale RP, Liebeskind JC (1989) Suppression of natural killer cell activity by high-dose narcotic anesthesia in rats. Brain Behav Immun 3(2):129–137PubMedCrossRef
99.
Pruett SB, Han YC, Fuchs BA (1992) Morphine suppresses primary humoral immune responses by a predominantly indirect mechanism. J Pharmacol Exp Ther 262(3):923–928PubMed
100.
Ninković J, Roy S (2013) Role of the mu opioid receptor in opioid modulation of immune function. Amino Acids 45(1):9–24PubMedCrossRef
101.
Roy S, Ninkovic J, Banerjee S, Charboneau RG, Das S, Dutta R et al (2011) Opioid drug abuse and modulation of immune function: consequences in the susceptibility to opportunistic infections. J Neuroimmune Pharmacol 6(4):442–465PubMedPubMedCentralCrossRef
102.
Hall DM, Suo JL, Weber RJ (1998) Opioid mediated effects on the immune system: sympathetic nervous system involvement. J Neuroimmunol 83(1-2):29–35PubMedCrossRef
103.
Mellon RD, Bayer BM (1998) Evidence for central opioid receptors in the immunomodulatory effects of morphine: review of potential mechanism(s) of action. J Neuroimmunol 83(1-2):19–28PubMedCrossRef
104.
Kelly E, Henderson G, Bailey CP (2018) Emerging areas of opioid pharmacology. Br J Pharmacol 175(14):2715–2716PubMedPubMedCentralCrossRef
105.
Page GG (2005) Immunologic effects of opioids in the presence or absence of pain. J Pain Symptom Manage 29(5 Suppl):S25–S31PubMedCrossRef
106.
Martucci C, Panerai AE, Sacerdote P (2004) Chronic fentanyl or buprenorphine infusion in the mouse: similar analgesic profile but different effects on immune responses. Pain. 110(1-2):385–392PubMedCrossRef
107.
Peng Y, Yang J, Guo D, Zheng C, Sun H, Zhang Q et al (2020) Sufentanil postoperative analgesia reduce the increase of T helper 17 (Th17) cells and FoxP3(+) regulatory T (Treg) cells in rat hepatocellular carcinoma surgical model: A randomised animal study. BMC Anesthesiol 20(1):212PubMedPubMedCentralCrossRef
Sacerdote P, Gaspani L, Rossoni G, Panerai AE, Bianchi M (2001) Effect of the opioid remifentanil on cellular immune response in the rat. Int Immunopharmacol 1(4):713–719PubMedCrossRef
110.
Janku F, Johnson LK, Karp DD, Atkins JT, Singleton PA, Moss J (2016) Treatment with methylnaltrexone is associated with increased survival in patients with advanced cancer. Ann Oncol 27(11):2032–2038PubMedPubMedCentralCrossRef
111.
Tedore T (2015) Regional anaesthesia and analgesia: relationship to cancer recurrence and survival. Br J Anaesth 115(Suppl 2):ii34–ii45PubMedCrossRef
112.
Hahnenkamp K, Herroeder S, Hollmann MW (2004) Regional anaesthesia, local anaesthetics and the surgical stress response. Best Pract Res Clin Anaesthesiol 18(3):509–527PubMedCrossRef
113.
O'Riain SC, Buggy DJ, Kerin MJ, Watson RWG, Moriarty DC (2005) Inhibition of the stress response to breast cancer surgery by regional anesthesia and analgesia does not affect vascular endothelial growth factor and prostaglandin E2. Anesth Analg 100:244–249PubMedCrossRef
114.
Chang YC, Hsu YC, Liu CL, Huang SY, Hu MC, Cheng SP (2014) Local anesthetics induce apoptosis in human thyroid cancer cells through the mitogen-activated protein kinase pathway. PLoS One 9(2):e89563PubMedPubMedCentralCrossRef
115.
Chamaraux-Tran TN, Mathelin C, Aprahamian M, Joshi GP, Tomasetto C, Diemunsch P et al (2018) Antitumor Effects of Lidocaine on Human Breast Cancer Cells: An In Vitro and In Vivo Experimental Trial. Anticancer Res 38(1):95–105PubMed
116.
Bar-Yosef S, Melamed R, Page GG, Shakhar G, Shakhar K, Ben-Eliyahu S (2001) Attenuation of the tumor-promoting effect of surgery by spinal blockade in rats. Anesthesiology. 94(6):1066–1073PubMedCrossRef
117.
Wada H, Seki S, Takahashi T, Kawarabayashi N, Higuchi H, Habu Y et al (2007) Combined spinal and general anesthesia attenuates liver metastasis by preserving TH1/TH2 cytokine balance. Anesthesiology 106:499–506PubMedCrossRef
118.
Grandhi RK, Lee S, Abd-Elsayed A (2017) The Relationship Between Regional Anesthesia and Cancer: A Metaanalysis. Ochsner J 17(4):345–361PubMedPubMedCentral
119.
Xuan W, Hankin J, Zhao H, Yao S, Ma D (2015) The potential benefits of the use of regional anesthesia in cancer patients. Int J Cancer 137(12):2774–2784PubMedCrossRef
120.
Piegeler T, Votta-Velis EG, Liu G, Place AT, Schwartz DE, Beck-Schimmer B et al (2012) Antimetastatic potential of amide-linked local anesthetics: inhibition of lung adenocarcinoma cell migration and inflammatory Src signaling independent of sodium channel blockade. Anesthesiology. 117(3):548–559PubMedCrossRef
Lee BM, Singh Ghotra V, Karam JA, Hernandez M, Pratt G, Cata JP (2015) Regional anesthesia/analgesia and the risk of cancer recurrence and mortality after prostatectomy: a meta-analysis. Pain Manag 5(5):387–395PubMedPubMedCentralCrossRef
124.
Biki B, Mascha E, Moriarty DC, Fitzpatrick JM, Sessler DI, Buggy DJ (2008) Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: a retrospective analysis. Anesthesiology. 109(2):180–187PubMedCrossRef
125.
Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI (2006) Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology. 105(4):660–664PubMedCrossRef
126.
Sessler DI, Ben-Eliyahu S, Mascha EJ, Parat MO, Buggy DJ (2008) Can regional analgesia reduce the risk of recurrence after breast cancer? Methodology of a multicenter randomized trial. Contemp Clin Trials 29(4):517–526PubMedCrossRef
127.
Harris RE, Beebe-Donk J, Doss H, Burr DD (2005) Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of non-selective COX-2 blockade (review). Oncol Rep 13(4):559–583PubMed
128.
Tsoi KKF, Ho JMW, Chan FCH, Sung JJY (2019) Long-term use of low-dose aspirin for cancer prevention: A 10-year population cohort study in Hong Kong. Int J Cancer 145(1):267–273PubMedCrossRef
129.
Tomozawa S, Tsuno NH, Sunami E, Hatano K, Kitayama J, Osada T et al (2000) Cyclooxygenase-2 overexpression correlates with tumour recurrence, especially haematogenous metastasis, of colorectal cancer. Br J Cancer 83(3):324–328PubMedPubMedCentralCrossRef
130.
Okajima E, Uemura H, Ohnishi S, Tanaka M, Ohta M, Tani M et al (2003) Expression of cyclooxygenase-2 in primary superficial bladder cancer tissue may predict risk of its recurrence after complete transurethral resection. Aktuelle Urol 34(4):256–258PubMedCrossRef
131.
Singh B, Berry JA, Shoher A, Ramakrishnan V, Lucci A (2005) COX-2 overexpression increases motility and invasion of breast cancer cells. Int J Oncol 26(5):1393–1399PubMed
132.
Schack A, Fransgaard T, Klein MF, Gögenur I (2019) Perioperative Use of Nonsteroidal Anti-inflammatory Drugs Decreases the Risk of Recurrence of Cancer After Colorectal Resection: A Cohort Study Based on Prospective Data. Ann Surg Oncol 26(12):3826–3837PubMedCrossRef
Moris D, Kontos M, Spartalis E, Fentiman IS (2016) The Role of NSAIDs in Breast Cancer Prevention and Relapse: Current Evidence and Future Perspectives. Breast Care (Basel) 11(5):339–344CrossRef
135.
Chen JY, Ko TL, Wen YR, Wu SC, Chou YH, Yien HW et al (2009) Opioid-sparing effects of ketorolac and its correlation with the recovery of postoperative bowel function in colorectal surgery patients: a prospective randomized double-blinded study. Clin J Pain 25:485–489PubMedCrossRef
136.
Bailard NS, Flores RA (2015) Could opioid sparing, rather than a direct non-steroidal anti-inflammatory drug effect, be responsible for improved survival after conservative breast surgery? Br J Anaesth 114:527PubMedCrossRef
137.
Wong I, St John-Green C, Walker SM (2013) Opioid-sparing effects of perioperative paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) in children. Paediatr Anaesth 23(6):475–495PubMedPubMedCentralCrossRef
138.
Friis S, Nielsen GL, Mellemkjaer L, McLaughlin JK, Thulstrup AM, Blot WJ et al (2002) Cancer risk in persons receiving prescriptions for paracetamol: a Danish cohort study. Int J Cancer 97(1):96–101PubMedCrossRef
139.
Weiss NS (2016) Use of acetaminophen in relation to the occurrence of cancer: a review of epidemiologic studies. Cancer Causes Control 27(12):1411–1418PubMedPubMedCentralCrossRef
140.
Bruzzone A, Piñero CP, Rojas P, Romanato M, Gass H, Lanari C et al (2011) α(2)-Adrenoceptors enhance cell proliferation and mammary tumor growth acting through both the stroma and the tumor cells. Curr Cancer Drug Targets 11(6):763–774PubMedCrossRef
141.
Cata JP, Singh V, Lee BM, Villarreal J, Mehran JR, Yu J et al (2017) Intraoperative use of dexmedetomidine is associated with decreased overall survival after lung cancer surgery. J Anaesthesiol Clin Pharmacol 33(3):317–323PubMedPubMedCentralCrossRef
142.
Forget P, Berlière M, Poncelet A, De Kock M (2018) Effect of clonidine on oncological outcomes after breast and lung cancer surgery. Br J Anaesth 121(1):103–104PubMedCrossRef
143.
Lavon H, Matzner P, Benbenishty A, Sorski L, Rossene E, Haldar R et al (2018) Dexmedetomidine promotes metastasis in rodent models of breast, lung, and colon cancers. Br J Anaesth 120(1):188–196PubMedCrossRef
Auf mögliche kardiale Auswirkungen postoperativer Schmerzen weist die Subgruppenanalyse des randomisierten kontrollierten HIP-ATTACK-Trials hin. Bei ausgeprägten Schmerzen im Zusammenhang mit einer Hüftoperation stiegen die Troponinspiegel signifikant an – ein Kausalzusammenhang ist damit allerdings noch nicht belegt.
Laut einer Querschnittstudie leiden rund 7% der in Deutschland lebenden über 16-Jährigen unter chronischen Schmerzen, die ihren Alltag stark beeinträchtigen. Außer biologischen scheinen auch psychische und soziale Faktoren mit sogenanntem High-Impact Chronic Pain assoziiert zu sein.
Ob nun Sonogerät, Praxiscomputer oder gar TI-Konnektor: Einfach zum nächsten Wertstoffhof sollten Praxisteams ausgediente Elektrogeräte nicht bringen. Was bei der Entsorgung zu beachten ist. Und wie die Teams sicher sensible Daten auf PC-Festplatte, externem Datenspeicher und TI-Komponenten löschen.
Im Fall einer Sepsis ist eine Körpertemperatur unter 36 °C bei älteren Menschen ein Warnsignal. In einer Studie aus Dänemark war bei Hypothermie, nicht aber bei Fieber das Mortalitätsrisiko deutlich erhöht.
Mit unserem e.Med Abo Anästhesiologie haben Sie jederzeit Zugriff auf aktuelles, praxisnahes Fachwissen – kompakt und einfach verfügbar. Jetzt CME-Punkte bequem online sammeln.
