The idea that surgery promotes local cancer recurrence and distant metastasis is not novel. In fact, >2 millennia ago, observations concerning the negative impact of surgical manipulation on cancer progression were documented. A. Cornelius Celsus, author of “De Medicina,” who established the first staging system of cancer, believed that only cacoethes (the first stage of cancer) should be removed, because other stages would be irritated by the treatment.1 Likewise, Alfred A.L.M. Velpeau (1795–1867) noticed that surgical removal of cancer was associated with the return of the disease and that the operation tended to accelerate tumor growth.1 Modern therapies such as chemotherapy and radiation have eliminated many cancer fatalities. Nevertheless, despite our advances in cancer treatment technique, metastatic recurrence still remains the leading cause of death from cancer.
Several theories have been advocated to explain the frequent incidence of cancer recurrence, most notably residual minimal disease,2 dissemination of tumor cells at the time of surgery,3,4 and possibly tumor dormancy5 (a period when cancer cells are quiescent before progressive growth). Also, surgery creates profound metabolic, neuroendocrine, inflammatory, and immunological stress.6–9 This surgical stress response includes the release of chemical mediators that have been directly and indirectly implicated in cancer growth. These mediators could cause an upregulation of major promalignant pathways, resulting in a disruption of normal tumor homeostasis, thus promoting local and distant metastasis. Importantly, the type of anesthesia may play a role in this process and could indirectly promote malignant cell development. In this article, we briefly review possible mechanisms involved in the effect of surgery on cancer recurrence and then discuss how anesthetic management could potentially influence these mechanisms, thereby affecting long-term patient outcome.
IMMUNITY AND CANCER
The idea that the immune system recognizes cancerous cells as “nonself” and thereby destroys them was first established by Paul Ehrlich a century ago and was fostered by Burnet and Thomas under the immunosurveillance hypothesis.10 They suggested that the immune system could actually eliminate cancer cells before they are clinically detectable. It was clear, however, that the immune system is unable to destroy cancer cells completely, as evidenced by the persistence of tumor despite a competent immune system. Subsequently, the concept of immunoediting was born.10 Under this theory, the immune system is believed to “inadvertently” promote tumor progression by clearing some tumor cells and thereby selecting for those cells most resistant to immune system clearance.
The process of immunoediting is divided into 3 steps. The first step represents the “elimination phase” where cells of the innate and adaptive immune system recognize and destroy tumor cells. The second step is the “equilibrium phase” where it is postulated that the immune system keeps cancer cells in check for a variable period of time. The third step is called “escape” whereby tumor cells evade immunity and become overt tumors.10 The mechanisms underlying these events are not entirely understood and include alteration in antigen presentation, secretion of immunosuppressive agents, and stimulation of inhibitory pathways. Thus, the immunosuppressant effects of surgery through the secretion of proinflammatory and antiinflammatory cytokines could shape the journey of residual minimal disease toward immune evasion and growth. This hypothesis remains without definitive support at this time.
THE SURGICAL STRESS RESPONSE AND CANCER
Although the primary role of the stress response after surgery is to augment the healing process, either overactivity or underactivity of host-defense mechanisms paradoxically may lead to negative consequences. For instance, the surgical stress response may provide optimal conditions for persistence of residual minimal malignant disease after surgery. Surgery has been suggested to accelerate the development of preexisting micro metastases and to promote the establishment of new metastases.4,11 It is believed that the postoperative period is the most vulnerable period for potential metastasis after surgery. This vulnerability is mostly attributed to suppression of cell-mediated immunity, the first-line defense mechanism against cancer.4 The depression of the immune system occurs within hours of surgery, lasts for several days, and is proportional to the extent of surgical trauma.12 For example, patients with low levels of natural killer (NK) cell activity undergoing primary cancer surgery have been shown to have a higher rate of cancer-related morbidity and mortality. This association has been demonstrated in patients with colorectal,13,14 gastric,15 lung,16 as well as head and neck cancer.17,18 The underlying mechanisms of postoperative immune suppression have not been completely established; however, existing data strongly suggest a role for the neuroendocrine system, inflammatory system, and the HPA (hypothalamic-pituitary-adrenal) axis.19
Role of the Neuroendocrine System
As early as 1919, scientists demonstrated that young students with pulmonary tuberculosis who were exposed to academic stress had reduced phagocytic capacity to eliminate the pathogen.20 This was an early demonstration of the effect stress has on the immune system. Likewise, stress has long been considered as a contributor to cancer development.21 Levels of stress biomarkers, primarily epinephrine and norepinephrine, are elevated in the perioperative period.19 These neurotransmitters are believed to be responsible for the relationship between stress and cancer progression.22 This is thought to happen via interaction with β1- and β2-adrenergic receptors expressed by tumor cells. Catecholamines have been shown to directly increase the invasive potential of ovarian cancer cells via β-adrenergic upregulation of matrix metalloproteinases23 and activation of STAT-3 (signal transducer of activation and transcription), a contributor to malignant cell proliferation and survival.24 Catecholamines also have been shown to increase the production of vascular endothelial growth factor in ovarian cancer cells,25 and to influence the migration of multiple cancer cell lines including breast, ovarian, and colon cancer.26 Catecholamines have been shown to influence cell migration and angiogenesis via stimulation of β1 and β2 receptors27–29 in addition to suppressing cell-mediated immunity (CMI).4
Role of the Inflammatory System
Cancer is often considered an anarchic cell replication process beyond any form of control or recognition; however, this is a profound oversimplification. In fact, cancer growth and metastasis are very complex processes with cell replication merely representing the tip of the iceberg. Within the tumor microenvironment lies a machinery of highly sophisticated malignant cascades where several products of the inflammatory system such as cytokines, chemokines, prostaglandins (PGs), and cyclooxygenase (COX) are believed to promote cancer progression through immunosuppression, resistance to apoptosis, and promotion of angiogenesis.30 This is true of the role of chronic inflammation for certain forms of cancer, but it is not clear whether acute inflammation, such as occurs in the perioperative period, results in the same outcomes. Nonetheless, Goldfarb and Ben-Eliyahu2 suggested that an increase in the level of cytokines (interleukins, IL-6 and IL-8), and PGE2 in combination with a decrease of T helper type 1 cell-induced cytokine production (IL-2, interferon γ), could account for the profound suppression of NK cytotoxic activity in the perioperative period.
Role of the HPA Axis
Pain, a potent stimulant of the HPA axis, has been implicated in causing immunosuppression, making pain management particularly important in the cancer surgery patient. Pain activates the HPA axis and the sympathetic nervous system, thus setting off a cascade of events that leads to immunosuppression. Acute pain has been shown to suppress NK cell activity31,32 and promote tumor development in animals.33 Not surprisingly, provision of pain relief has been shown to attenuate surgery-induced increases in metastatic susceptibility in animals.34
POSSIBLE TARGETS FOR METASTASIS PREVENTION BY THE ANESTHESIOLOGIST
Given that the surgical stress response seems to increase opportunities for cancer dissemination and metastasis at the exact time that cancer cells may be released into the circulation, is it possible to minimize these detrimental effects by an appropriate choice of anesthetics? The influence of anesthesia on the stress response to surgery has been investigated in depth. Our goal is to review the anesthetic interventions (Table 1) that affect pathways with a link to tumor progression (Fig. 1).
Opioids have long been the mainstay of treatment of cancer-related pain and are an important modality for the prevention of perioperative pain. As stated above, pain leads to CMI suppression, and its treatment is therefore particularly important. Unfortunately, it also has been established that opioids (morphine in particular) inhibit cellular and humoral immune function in humans.35–37 There are no data directly implicating opioids in cancer genesis in humans, but animal data strongly suggest that they may contribute to cancer recurrence in the clinical setting. For example, in rodent studies, it was demonstrated that morphine is proangiogenic and promotes breast tumor growth.38,39 This tumor-promoting effect of opiates was also demonstrated with fentanyl,40 although in other studies, synthetic opiates did not seem to exhibit immunosuppressive effects. Instead, fentanyl was shown in healthy volunteers to increase NK activity.41 Morphine has not been demonstrated to be tumor promoting in all models; e.g., it was found to promote apoptosis and cell death in an adenocarcinoma model42 and in Jurkat cells.43 Inhibitory effects of morphine on tumor growth have been found in human and animal models as well. For example, in a mouse model, the repeated administration of morphine resulted in decreased tumor cell–induced tissue destruction.44 This observation was verified in a series of clinical studies showing that pre- and postoperative administration of morphine reduced systemic dissemination of tumor cells.44–46 This potentially protective effect of morphine on tumor growth was attributed to enhanced T cell–mediated immune responses,47 physiologically active μ opioid receptor splice variant,48 inhibition of nuclear factor-κB,49 and nitric oxide release through the constitutive nitric oxide synthase pathway.50 Evidently, morphine-tumor interaction is complex, its mechanisms are not completely unraveled, and to a certain extent, contradictory. Further studies in this field are essential to elucidate this interaction. The effects of neuraxial administration of morphine on tumor progression have not been extensively studied. As much smaller doses are used for neuraxial administration, it seems likely that any effects of opioids would be less than after systemic administration.
Using a mouse model, Farooqui et al.51 demonstrated that the chronic use of morphine leads to a stronger expression of COX-2 in tumor cells that increased PG production, which impaired analgesia and increased tumor angiogenesis, growth, metastasis, and mortality.
In addition, they showed that inhibition of COX-2 by administration of celecoxib prevented morphine-induced tumor growth and metastasis and increased survival. This suggests that COX-2 inhibitors may be used in conjunction with opioid to decrease pain in cancer patients, while counterbalancing the negative effects of opioids on immune function. Even in the absence of opiates, COX-2 inhibitors show promise in preventing cancer growth and metastases in animal models. They have multiple effects, including inducing apoptosis,52–54 decreasing the levels of angiogenic factors,55–57 and decreasing tumor microvascular density.26,52
Indomethacin, a nonselective COX inhibitor, attenuated the metastasis-promoting effect of surgery in rats.11 Whereas the intraoperative use of indomethacin may be associated with increased blood loss because of COX-1 inhibition, a selective COX-2 inhibitor might be a feasible adjunct that can be used to attenuate perioperative immunosuppression.
In summary, some opiates and COX inhibitors can be used effectively in the cancer surgery patient. The use of celecoxib, a COX-2 inhibitor, is approved by the Food and Drug Administration for the prevention of colorectal cancer in high-risk patients with preexisting susceptibility such as familial adenomatous polyposis. Opioids are probably best used in conjunction with COX inhibitors or when administered via a neuraxial technique. COX inhibitors may prevent metastatic progression and, in addition to their synergistic analgesic properties, attenuate opioid-induced immunosuppression. Although both nonselective COX and selective COX-2 inhibitors are effective, it is recommended that the latter be used to minimize the chance of bleeding and chance of gastric irritation. The risk of cardiovascular complications should additionally be evaluated before their use.
Since the 1980s, clonidine, an antihypertensive drug with sedative properties, has been used as an adjuvant to local anesthetics in various regional techniques to extend the duration of the block.58 Dexmedetomidine is indicated for sedation in patients receiving mechanical ventilation in the intensive care unit. In 2006, Vázquez et al.59 published the first study to describe the presence of α2-adrenoceptors in human epithelial breast cell lines. In 2008, Bruzzone et al.60 demonstrated a significant enhancement of mouse mammary tumor growth induced by clonidine. In that study, incubation for 2 days with the α2-adrenoceptor agonists (clonidine 0.1 mg · kg−1 · d−1 and dexmedetomidine 0.05 mg · kg−1 · d−1) significantly enhanced proliferation of the mammary tumor cells. The α2-adrenoceptor antagonists yohimbine (0.5 mg · kg−1 · d−1) and rauwolscine (0.5 mg · kg−1 · d−1) completely reversed the enhancement of tumor growth of clonidine. These results suggest that the α2-agonist clonidine exerts its enhancement on tumor growth by enhancing cell proliferation and decreasing cell apoptosis, whereas the inverse agonist (i.e., an agent that exerts the opposite pharmacologic effect of an agonist) rauwolscine exerts its protective action both by enhancing apoptosis and reducing cell proliferation. However, the group receiving yohimbine alone showed a nonsignificant but constant increase in tumor growth, whereas rauwolscine alone diminished tumor growth significantly, behaving as a reverse agonist. Therefore, the possibility of blocking this α2-adrenoceptor–mediated tumor enhancement by hormones released during stress could be an interesting adjuvant therapy for breast cancer patients.60
Hasegawa and Saiki61 demonstrated a relationship among stress, tumor growth, and β-adrenergic activation independent of glucocorticoid levels in mice. They also showed that the administration of β-blockers abrogated this effect. A combination of β-blockers and COX-2 inhibitors improves immune competence and reduces the risk of tumor metastasis after surgery in animals.26 Palm et al.62 demonstrated that use of β-blockers in mice with prostate carcinoma inhibited lumbar lymph node metastases. It seems that β-blockers act by inhibition of catecholamine's induced signal transducer and activator of transcription 3 (STAT-3) activity. STATs are a family of transcription factors that regulate the expression of certain immune system genes. Given the available animal data on the effect of catecholamine on cancer progression and the chemopreventive effect of β-blockers, it seems possible that β-blockers may be beneficial in preventing metastatic progression in humans.
Anesthetic Induction Drugs and Volatile Anesthetics
Melamed et al.63 demonstrated in rats that ketamine, thiopental, and halothane reduced NK cell activity and increased lung tumor retention and metastasis. The number of circulating NK cells per milliliter of blood was reduced significantly by ketamine and thiopental. The effect of halothane was similar, but did not reach statistical significance.63 The authors suggested that a reduction in NK cell activity might have a major impact on the resistance to tumor development. The interaction of ketamine with α- and β-adrenoreceptors could be one reason for the suppression of NK activity and the promotion of metastasis.64 Although the mechanism for immune suppression induced by thiopental or volatile anesthetics remains to be elucidated, it is not related to the anesthetic state per se.63 Of interest, propofol did not exhibit these effects; instead, propofol seems to have protective effects through various mechanisms, including inhibition of COX-2,65 inhibition of PGE2, but also through enhancement of antitumor immunity.66 Ke et al.67 showed in patients undergoing open cholecystectomy that the combination of propofol and remifentanil resulted in an increase in antiinflammatory cytokines IL-10 (known to have antitumor activity and help with healing and repair), as compared with inhaled anesthesia with isoflurane. Inada et al.68 found in patients undergoing supratentorial tumor excision that propofol anesthesia mitigated the adverse effects of surgical stress-induced immune response better than isoflurane. It would be intuitive therefore to think that total IV anesthesia is preferable to an inhaled technique for patients undergoing cancer surgery.
Although less information is available on other drugs used for anesthesia induction, they may affect the immune system as well. For example, midazolam decreases IL-8 levels. This may contribute to immunosuppression because IL-8 is a chemotactic and activating factor that mediates neutrophil adhesion and margination and is essential for host defense.69
Regional anesthesia, including spinal and epidural anesthesia, reduces the stress response caused by surgery, which is believed to be a mediator of postoperative immunosuppression.70,71 Regional anesthesia attenuates the surgical stress response by blocking afferent neural transmission. This prevents noxious afferent input from reaching the central nervous system. The addition of regional anesthesia to general anesthesia also results in less overall use of opioids and volatile anesthetics. This association may be beneficial to patients undergoing cancer surgery, because it should theoretically result in less immunosuppression.
In a retrospective analysis of patients undergoing surgical treatment for breast cancer, Exadaktylos et al.72 demonstrated that the use of paravertebral nerve block in combination with general anesthesia was associated with a longer cancer-free interval and a lower incidence of recurrence. Similar results were shown in other retrospective studies of the use of epidural local anesthetics in prostate cancer and colon cancer surgery.73,74 Moreover, in a large-scale study in patients with melanoma, substitution of local anesthesia for general anesthesia independently predicted a decrease in tumor recurrence.75 Also, a recent study of the effect of paravertebral blocks and propofol on cytokine response during breast cancer surgery noted a decrease in tumorigenic cytokines IL-1β/IL-8 and an increase in IL-10, a known antitumor cytokine.76 The results of these studies should be interpreted cautiously, and there still is no clear evidence whether a simple change in anesthetic practice could affect patient survival. Several multicenter prospective randomized controlled trials are underway, which will test the hypothesis that local or metastatic recurrence after several types of cancer surgery will be decreased in patients randomized to a regional anesthetic technique in comparison to those receiving general anesthesia.77
Anemia and Perioperative Blood Transfusion
Anemia is an ominous sign for the cancer patient. Caro et al.78 conducted a systematic quantitative review and demonstrated that anemia is associated with increased postoperative morbidity and mortality in all forms of cancer, with decreased local control in surgically treated squamous cell carcinoma79 and decreased survival in non–small cell lung carcinoma.80 It may seem logical that transfusing the anemic cancer patient would lead to an increase in survival; however, evidence suggests that transfusion poses an independent risk to the cancer patient.
In 1973, Opelz et al.81 proposed the idea of transfusion-related immunomodulation (TRIM) after recognizing that kidney transplant recipients who received >10 U of allogenic blood had better allograft survival. The demonstration of TRIM has led many to hypothesize that patients undergoing surgery for cancer are at an increased risk for metastatic recurrence if they receive blood products. A recent meta-analysis conducted by Amato and Pescatori82 suggests this may be correct for patients with colorectal cancer. The authors reviewed 36 studies involving >12,000 patients and found a moderate association between perioperative blood transfusion and colorectal cancer recurrence with an odds ratio of 1.42 (95% confidence interval, 1.20–1.67). These findings call for carefully restricted indications for perioperative transfusions in colorectal cancer patients operated on for cure, and await the results of future studies addressing the role of surgery-related risk factors on the need for transfusion and disease recurrence.82 However, perioperative transfusion requirement and transfusion within 30 days of operation were not significant predictors of survival for patients with pancreatic ductal adenocarcinoma.83
There are >200 published reports on transfusion-related metastatic recurrence with no official consensus. In fact, the only consistency among published data is that cancer patients who receive blood transfusions during surgery tend to do worse. This is independent of whether the blood is allogenic, autogenic, or leukocyte reduced. We are still awaiting human data with regard to the age of the blood products; however, a link between cancer progression and aged erythrocytes was recently demonstrated in a rat model.84 Nevertheless, it seems that both anemia and blood transfusions are associated with poorer outcomes in cancer patients. Perhaps factors influencing the need for blood transfusion have a greater bearing on prognosis than the receipt of blood itself. For the anesthesiologist, it is important to ensure that the patient is medically optimized before surgery, that all attempts are made to perform minimal blood loss surgery, and that transfusions are used judiciously.
Perioperative hypothermia is associated with an increase in wound infections.85 In fact, maintaining normothermia is more effective than perioperative antibiotics in the prevention of wound infections.85 Hypothermia also causes increased blood loss and predisposes patients to blood transfusions.86 Additionally, hypothermia in combination with surgery and general anesthesia has been shown to lead to a reduction in CMI, particularly NK cells, and an increase in lung tumor retention and metastasis in rats.87 Although a retrospective analysis could not confirm this finding in humans,88 it seems important that the anesthesia provider maintains normothermia in cancer patients. This simple measure may lead to a reduction in cancer recurrence after surgery and will most assuredly lead to a reduction in perioperative infections, blood loss, and need for blood transfusion.
Statins first attracted interest for cancer prevention as an unexpected result of safety monitoring in large randomized controlled trials of statins' and other lipid-decreasing drugs' effectiveness in preventing cardiovascular disease. This monitoring was implemented because the randomized controlled trials showed consistent increases in statin-associated noncardiovascular disease mortality.89 The safety results, however, indicated that statins did not increase cancer incidence or cancer mortality. In fact, subsequent intensive clinical and observational studies and preclinical data showed significant statin-associated reduction in overall cancer incidence, the most promising of which are colorectal, prostate, breast, and skin cancers.90,91 This has been further highlighted by 2 large population-based studies that showed statin-associated reduction in the risk of colorectal and advanced prostate cancers.92
The effects of statins have been shown to occur through 3-hydroxy-3-methylglutaryl coenzyme A reductase-dependent or -independent pathways such as binding to lymphocyte function associated antigen 1, which has an important role in leukocyte migration and T cell activation.93 One study of ischemia and cancer indicated that statins augmented blood flow to the ischemic tissue but did not increase blood flow or capillary density in implanted colon tumors. In fact, the growth of these blood vessels was substantially delayed, suggesting an antiangiogenic effect of statins in carcinogenesis.94 The beneficial effects of statins on carcinogenesis have also been linked to their antiinflammatory and immunomodulatory effects on adhesion, inflammatory mediators, major histocompatibility complex II, T helper 1 and 2 cytokines, and C-reactive protein.95 Statins also seem to induce apoptosis and inhibit proliferation by regulating several signaling pathways in malignant cells.96 This pleiotropic aspect of statins indicates the broad impact that these drugs can have on public health, which should be defined by well-designed observational studies of cancer within large prospective cohorts.
It is much too early to write evidence-based guidelines for the anesthesiologist's role in the prevention of cancer recurrence. At this time, we have very interesting animal data (but do not know if these can be extrapolated to medical practice) and very limited, mostly retrospective, clinical studies. Many questions remain unanswered: How much anesthetic exposure is necessary? Do the type, grade, stage, and location of tumor matter? How can we optimally influence the inflammatory response in the postoperative period? As anesthesiologists, we render care to patients coming to the operating room for diverse and complex cancer operations. By this time, the tumor has already grown, micrometastases already exist, tumor manipulation will cause malignant cells to migrate, and in many patients recurrence will occur after a variable period of time. The possibility that perioperative management may alter the rate or incidence of recurrence is tremendously exciting, but much more research is needed in order for this possibility to be conclusively demonstrated.
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