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Review Articles

Operative Trauma and Blood Loss — Impact on Tumor Growth and Recurrence

Pretzsch, Elise∗,†; Bösch, Florian∗,†; Renz, Bernhard∗,†; Werner, Jens∗,†; Angele, Martin∗,†; Chaudry, Irshad H.∗,†

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doi: 10.1097/SHK.0000000000001656
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Abstract

INTRODUCTION

Major surgical injury may lead to an excessive inflammatory response followed by a systemic immunosuppression which is considered a significant risk factor for postoperative complications including sepsis and multiple organ failure. In cancer patients, surgical removal of the primary tumor is one of the most important steps within multimodal therapy approaches toward eradicating the disease or limiting further progression. In this regard, therapies such as chemotherapy, radiation, and targeted therapies may have immunosuppressive side effects themselves and add to the immunosuppression following major surgery. There is growing evidence that immunosuppression following surgical trauma might not only be a risk factor for postoperative complications but also a risk factor for metastatic growth and tumor recurrence (1). Several studies have assessed the pathophysiology of the immunoinflammatory response following surgical trauma and described the influence of different parameters mediating this response (2, 3). This article will focus on the impact of intraoperative blood loss and surgical injury on tumor growth and recurrence. Attempts to control for perioperative inflammation thereby avoiding the adverse effects of postoperative immunosuppression may exhibit positive effects on tumor growth, metastasis formation, and recurrence.

INTRAOPERATIVE BLOOD LOSS, RECURRENCE, AND SURVIVAL—CLINICAL OBSERVATIONS

In patients with tumors that require excessive surgical interventions concomitant with major surgical trauma and potential blood loss, i.e., liver surgery or upper gastrointestinal surgery, reports indicate a correlation between the extent of the surgical trauma, blood loss and consecutive haemorrhage, and tumor recurrence (4, 5).

The majority of studies have focused on the impact of perioperative blood transfusions due to hemorrhage on patient outcome (6, 7). However, only few studies have focused on the circumstances necessitating blood replacement in the first place, in this respect intraoperative blood loss (IBL), and investigated its association to long-term survival, tumor growth, and recurrence. Some studies have reported that blood transfusion is an adverse prognostic factor, probably due to immunosuppression, but the topic remains controversial and is beyond the scope of this article (8–13).

It has to be considered that advanced tumor stages require more complex surgery which in turn is associated with potentially more blood loss and enhanced surgical trauma. In this respect, studies demonstrate that tumor size is a predictor for intraoperative blood loss (5, 14, 15). Thus, negative effects on tumor progression due to intraoperative blood loss may be in part explained by more complex surgical procedures due to more advanced tumors. Nonetheless, this article will outline that other factors associated with blood loss and surgical trauma may affect tumor growth and recurrence and should be considered in the future clinically in oncological patients.

Apart from the immunological effects of blood transfusions, there is growing evidence suggesting an independent association of trauma-related hemorrhage, trauma-associated inflammation, and immunosuppression and tumor proliferation. In this respect, three tumor entities will be mentioned exemplarily and the impact of hemorrhage on survival and tumor recurrence will be further elucidated.

IBL has been shown to be an independent prognostic factor for overall survival in stage I to III gastric cancer patients following curative gastrectomy (4, 16). Patients with IBL ≥400 mL showed significantly worse 5-year survival rates and shorter disease-free survival than patients with IBL <400 mL (58% vs. 73% and 62% vs. 82%, respectively). After adjusting for other factors including receipt of blood transfusion, IBL still remained an independent prognostic factor (16). Of interest, patients with IBL ≥400 mL had a significantly higher prevalence of hepatic metastases as a type of initial recurrence than patients with IBL <400 mL (11% vs. 4% respectively) (16). Studies focusing on peritoneal carcinomatosis after gastrectomy, which is the most common type of recurrence after curative gastrectomy, report that intraoperative large hemorrhage correlates with a higher risk of peritoneal metastasis and represents an independent risk factor for peritoneal recurrence (16–18).

Furthermore, several studies could demonstrate that in patients with pancreatic invasive ductal adenocarcinoma receiving pancreatic resection, excessive IBL is associated with shorter overall- and recurrence-free survival. However, even though minimizing blood loss is of utter importance, IBL was not an independent prognostic factor as opposed to positive lymph node status and R-status (19, 20).

While there have been several studies on IBL and outcome after hepatic surgery, only few studies have investigated the impact of IBL on survival and recurrence in patients with hepatic resection of colorectal liver metastasis (CRLM). IBL >250 mL in CRLM resection has been reported to be an independent prognostic factor for overall survival (5). Similarly, in this respect Jiang et al. (14) reported a diminished long-term survival and also recurrence-free survival.

Although IBL seems to be a valuable and sensitive indicator for treatment outcome, prognosis, and tumor recurrence in all three mentioned types of gastrointestinal cancer, not too much light has been shed on possible underlying mechanisms. Furthermore, the referenced data suggests that there are discrepancies in literature with regard to whether IBL is an independent factor for patient prognosis and specifically tumor growth and recurrence. While some of the studies cited above support this hypothesis, other studies and clinical experience suggest that IBL is a tumor-related and surgery-related factor negatively affecting patient prognosis and tumor growth and recurrence and should be interpreted within the context of other associated factors such as extent and timeline of surgery, surgical approach (laparoscopic vs. open), tissue trauma, patient comorbidities, heart function, anesthesiologic management, etc (20–23).

This article will describe the immunoinflammatory response following IBL focusing on hemodynamic and cellular metabolic alterations, suppression of cell-mediated immunity and their impact on tumor recurrence and growth. Furthermore, clinical and surgical aspects related to IBL and their influence on tumor proliferation and recurrence will be elaborated. Finally, possible strategies to reduce the adverse effects of IBL on tumor growth and prognosis will be reviewed.

IMMUNOINFLAMMATORY RESPONSE AND PRO-TUMORIGENIC EFFECTS FOLLOWING SURGICAL TRAUMA AND INTRAOPERATIVE BLOOD LOSS

Surgical injury accompanied by hemorrhage is characterized by an excessive early inflammatory response and concomitant marked depression in the patient's immune function (2, 3, 24, 25).

Severe hemorrhage followed by hypovolemia and vasoconstriction, mediated by sympathetic reflexes and a surge in catecholamines, leads to decreased blood flow and insufficient oxygen delivery to peripheral tissue and end-organs. Subsequently, this hypoxic state might lead to anaerobic cell metabolism resulting in a decrease of cellular adenosine triphosphate levels, an in equilibrium in cellular calcium homeostasis, and an accumulation of deleterious lactic acid and oxygen radicals which may stimulate the release of inflammatory mediators such as cytokines and PEG2. This rise of inflammatory mediators is considered to be followed by a both direct and indirect depression of cell-mediated immunity affecting various cell types such as macrophages and lymphocytes, eventually resulting in a systemic immunosuppression (26, 27) (please see Fig. 1).

Fig. 1
Fig. 1:
Hypothesis of the cascade of events following major surgical trauma and hemorrhage. The postoperative inflammatory response is followed by a counter-regulatory anti-inflammatory response that can lead to a depression of cell-mediated immunity and systemic immunosuppression potentially promoting tumor growth and recurrence.

Hemodynamic and metabolic alterations—impact on immunosuppression and tumor growth

Hemodynamic alterations

Hemorrhage leads to decreased blood flow and arterial hypotension potentially resulting in circulatory shock. The number of hypotensive episodes has already been demonstrated to be an independent prognostic factor for tumor growth and recurrence (7). Hemorrhage has been shown to be a potent stimulator of catecholamine secretion, however, besides fluid resuscitation the additional administration of catecholamines is often required to counteract circulatory depression (24, 28). Apart from the hemodynamic effects, there is a growing evidence suggesting that catecholamines also exert a variety of non-hemodynamic functions (29). These include immunosuppressive effects, a promotion of proliferation, migration, and angiogenesis and an acceleration of tumor growth and metastasis formation (1).

The majority of immune cells express adrenergic receptors, mainly ß2, on their surface. While the receptor density varies between different cell types, natural killer cells present the highest density of adrenergic receptors (30, 31). Studies could show that binding of catecholamines can lead to an impairment of natural killer cell activity, reduced cytotoxicity, and overall suppression. This might not only result in immunodepression but can also compromise resistance to natural killer cell sensitive metastasis (31, 32). Furthermore, models could show that ß-adrenergic signaling promotes the recruitment of macrophages into the primary tumor. This may lead to an induction of a prometastatic gene expression signature and enhances M2 macrophage differentiation (33). In this respect, in an orthotopic mouse model of breast cancer, neuroendocrine activation had a negligible effect on the growth of the primary tumor but lead to a 30-fold increase in metastasis to distant tissues (33). Furthermore, studies could show that catecholamines can lead to an imbalance of Th1/Th2 cells with a shift toward Th2 cells (34). Briefly, Th1 cells regulate cellular immunity through secretion of IFNγ, transforming growth factor (TGF)ß, and IL-2 and activation of natural killer cells and macrophages. Th2 cells promote humoral immunity through production of IL-4 and IL-10 which in turn inhibit macrophage activation and T-cell proliferation as well as pro-inflammatory cytokine production (35–37). In this respect, upon ß-adrenergic stimulation, Th1 cell differentiation and function is reduced. There are discrepancies in literature with regard to the responsiveness of Th2 cells to ß-adrenergic stimulation. Whereas former studies have not demonstrated any direct effects of ß-adrenergic stimulation on Th2 cells and reported an imbalance of Th1/Th2 cells with a shift toward Th2 cells and a favored response due to lack of ß-adrenergic receptor expression on Th2 cells, Loza et al. for the first time reported that Th2 cells might also express ß2-receptors and might also be responsive to ß-adrenergic stimulation in a concentration-dependent manner resulting in a suppression of pro-inflammatory cytokines. Potentially the use of more sensitive detection methods may account for this divergent information. Studies suggest that responsible pathways include cyclic adenosine monophosphate signaling; however, further studies are required to further elucidate the exact underling mechanisms. As a result, an immunosuppressive state and a perioperative suppression of antitumoral and antimetastatic immunity is attained and according to recent literature this is rather due to ß-adrenergic stimulation of both Th1 and Th2 cells than due to a Th1/Th2 shift (29, 30).

Further cellular and molecular effects of catecholamines include an upregulation of proangiogenic factors such as vascular endothelial growth factor (VEGF) and neurotrophins thereby promoting tumor growth and a promotion of tumor invasion into the extracellular matrix (ECM) through upregulation of matrix metalloproteinases (38–41). Moreover, catecholamines may promote cell adhesion (42), mobilization, and motility (43, 44), and an increment of apoptosis- and anoikis-resistance (45).

In summary, apart from their hemodynamic effects, catecholamines have numerous non-hemodynamic properties and regulate processes critical for tumor growth and metastatic dissemination. Further support for the crucial role of catecholamines comes from recent studies that report a significantly improved overall survival in patients receiving perioperative ß-blocker treatment thereby potentially counteracting the protumorigenic effects of catecholamines (39). In view of this, further studies focussing on potential strategies such as ß-adrenergic blockage, to attenuate the deleterious effects of catecholamines during the perioperative phase, inhibit tumor growth, preclude metastatic spread, and ultimately improve treatment outcome, are needed (39, 43, 46).

Cellular metabolic alterations

Hemorrhage causes reduced regional blood flow, which results in regional hypoxia leading to several alterations in cell metabolism. Due to the decreased oxygen availability to the tissue, an increased demand is placed on anaerobic metabolism which leads to a decrease in ATP levels. A decrease in cellular ATP has been linked to a marked depression of splenocyte proliferation and lymphokine production (i.e., IL-2, TNF-α) immediately after hemorrhage (2, 47). Tissue hypoxia and the enhancement of anaerobic metabolic functions also lead to the release of lactic acid and an accumulation of oxygen radicals. This lactic acid, as well as tumor-derived lactic acid, has been demonstrated to have critical functions in cellular signalling and can lead to cell dysfunctions including altered macrophage responses and depressed antigen-presentation (27, 29, 48). The release of damage-associated molecular patterns, including mitochondrial DNA and formyl peptides, instigates a systemic inflammatory response reinforcing the association between trauma, blood loss, and inflammation. Hypoxia also promotes genomic instability, resulting in a variety of genetic changes that can promote the development of a more aggressive phenotype of residual tumor cells (49). Lastly, decreased ATP levels have also been shown to perturbate cellular calcium homeostasis. A dyshomeostasis in cellular calcium has been suggested to contribute to the suppression of cellular immunity following hemorrhage potentially by impairing macrophage antigen presentation function and splenocyte function (27). In summary, markedly decreased cellular ATP following hemorrhage and regional hypoxia might contribute to early immunosuppression after surgery.

Suppression of cell-mediated immunity

Cytokines

Surgical trauma and blood loss results in an inflammatory response reflected in an increased release of inflammatory mediators such as pro-inflammatory cytokines and acute-phase proteins. This state of systemic inflammation is accompanied by and intertwined with counter-regulatory anti-inflammatory reactions and reflected in the rise in anti-inflammatory cytokines and prostaglandins. This results in a highly vulnerable state with concurrent expression of pro- and anti-inflammatory cytokines alternately predominating.

Activation of the systemic inflammatory response is associated with acute multiple organ failure and early death after surgery. In contrast, an excessive anti-inflammatory response can induce a prolonged immunosuppressive state that could favor tumor growth (3, 27, 50).

TNF-α and IL-6 have been demonstrated to be important mediators of the inflammatory response following surgery. Only 30 to 45 min after the onset of hemorrhage, significant levels of TNF-α and IL-6 are measurable in the blood and remain so up to 4 to 6 h. Studies investigating the underlying mechanisms of the sudden rise in cytokines suggested that the release of TNF-α and IL-6 might be attributed to two partially independent mechanisms. Ayala et al. reported that surgical trauma alone does not lead to a significant increase in TNF-α levels. However, surgical trauma associated with hemorrhage leads to a marked release of TNF-α into the circulation, which suggests that hemorrhage is mainly responsible for the increase in TNF-α following surgery (51, 52). In contrast, the increase of IL-6 levels might be attributed more tightly to the surgical trauma and tissue injury than hemorrhage, as increased levels of IL-6 could be measured during surgery even before the onset of hemorrhage. However, the release of IL-6 was further enhanced by hemorrhage (24, 51, 53). In addition, studies demonstrated that IL-6 levels correlate with the extent of the surgical trauma as well as the duration of the procedure (51, 54). Of interest, even though IL-6 is considered to be one of the major mediators in the acute-phase response following hemorrhage and surgical trauma, IL-6 not only exerts pro-inflammatory functions but also shows anti-inflammatory properties by attenuating the activity of pro-inflammatory cytokines such as TNF-α and IL-1, thereby controlling the local and systemic inflammatory response (55). In several clinical and experimental studies chronic inflammation has been shown to induce tumorigenesis and proliferation, i.e., ulcerative colitis in colorectal cancer, hepatitis in hepatocellular carcinoma, and chronic pancreatitis in pancreatic cancer (56, 57). Moreover, prophylactic administration of aspirin (acetylsalicylic acid) as an anti-inflammatory agent can reduce the risk of developing colorectal cancer and cancer metastasis (58, 59). Whether acute temporary perioperative inflammation affects tumor progression is subject of current studies.

In an attempt to counter-regulate the inflammatory response following surgery, anti-inflammatory mediators such as anti-inflammatory cytokines (e.g., IL-10, TGF-ß) and prostaglandin E2 (PGE2) are released. IL-10 is a cytokine with diverse functions that acts as a modulator of proinflammatory cytokines such as TNF-α. Induction of IL-10 correlates with a reduction of TNF-α levels and its associated pro-inflammatory effects and has been shown to inhibit Th1 cell function and lymphokine release. In this respect, IL-10 has been demonstrated to attenuate the systemic inflammatory response during sepsis in mice (50, 60). About 24 h after the induction of hemorrhage, a rise in TGF-ß can be observed and elevated concentrations in the blood can be detected for up to 72 h (61). Several studies reported a correlation between elevated TGF-ß levels and an equally long lasting depression of splenocyte proliferation and function. Moreover, administration of neutralizing antibodies against TGF-ß could restore splenocyte function (61, 62). Taken these findings together, it appears that there is a direct link between increased levels of TGF-ß and splenocyte suppression and TGF-ß might play a key role in the protracted suppression of cell-mediated immunity after hemorrhage and surgical trauma. Furthermore, the aforementioned increased inflammatory cytokine release leads to an increased PGE2 synthesis which contributes to the depression of macrophage and lymphocyte functions, thereby promoting further immunosuppression and creating a pro-tumorigenic milieu (24, 63, 64). Prostaglandin synthesis is driven by cyclooxygenases (COX) COX-1, COX-2, and COX-3. COX-2, normally absent in most cells, is particularly induced by proinflammatory cytokines and growth factors and plays an important part in the regulation of inflammatory processes also linked to carcinogenesis (65). Furthermore, COX-2, which mainly produces PGE2, is upregulated in various malignancies and PGE2 has been demonstrated to be involved in tumorigenic processes including angioneogenesis (65, 66). Prostaglandins, in part released by tumor cells themselves or macrophages recruited by tumor cells, have been shown to suppress monocyte-macrophage functions, antigen presentation, and anti-inflammatory cytokine production (67, 68). Taking these findings together, prostaglandins can contribute to tumor growth and progression through their involvement in immunosuppressive processes and through direct pro-tumorigenic effects.

Although several other pro- and anti-inflammatory cytokines have been mentioned in the literature to possibly play a role in the immunoinflammatory response following surgical trauma and hemorrhage, this review focused on cytokines that to this date seem to play pivotal roles and exert key regulatory functions in the perioperative immune response. Of interest, patients with severe hemorrhage appear to show even higher levels of proinflammatory cytokines than patients with trauma alone (52).

Macrophages

One of the main functions of macrophages includes the ability to process and present foreign antigens on their surface. Association with major histocompatibility complex (MHC) class I antigens activates cytotoxic T lymphocytes whereas association with MHC class II antigens leads to recognition by T-helper lymphocytes. In response, activated T-helper lymphocytes induce lymphokine production and B-cell antibody production (69). In addition to antigen presentation, macrophages also release costimulatory cytokines (i.e., IL-1) (27). In this respect, several studies indicated that hemorrhage and a decrease in blood pressure lead to a profound depression in splenic and macrophage antigen presentation function possibly due to the inability to express MHC class II antigen Ia (24, 25, 70, 71). This paralysis of macrophage function has been shown to persist for several days after surgery despite adequate resuscitation, correlates with the extent of surgical trauma, and contributes majorly to the depression of cell-mediated immunity following hemorrhage (2, 70). Furthermore, macrophages have been reported to be critical regulators of tumor immunity (72). Tumor-associated macrophages (TAMs) can directly inhibit cytotoxic T lymphocyte responses through production of inhibitory cytokines and reactive oxygen species. Moreover, TAMs can indirectly inhibit T lymphocyte functions by controlling the immune microenvironment. This includes the inhibition of stimulatory cell populations (i.e., dendritic cells) and the recruitment of immunosuppressive cells (i.e., regulatory T cells). Through regulation of the ECM and the chemokine milieu, TAMs appear to be able to exclude T cells from intratumoral regions thereby indirectly inhibiting T-cell recruitment and responses (72). This overall inhibition of T-cell responses by TAMs can lead to an impairment in recognition and elimination of cancer cells commonly exerted by T lymphocytes. In this respect, TAMs might thereby promote tumor growth and dissemination (73). Overall, these studies indicate that macrophages are important for the control of tumors. Whether trauma or blood loss in oncological patients depress all macrophages or solely certain subtypes or alternatively stimulate TAMs remains to be elucidated in more detailed postoperative macrophage analyses.

Lymphocytes and natural killer cells

Several experimental and clinical studies could demonstrate that surgical injury and hemorrhage alter the ability of T-lymphocytes to respond to mitogenic activation by Concanavalin A and Phytohemagglutinin leading to a depression of lymphocyte proliferation. In this respect, the degree of lymphocyte depression correlates with the complexity of the surgical procedure (62, 71, 74, 75). An in vivo study showed that hemorrhage, despite adequate resuscitation, induced a significant depression of mitogen-stimulated T-lymphocyte blastogenesis on the day of surgery that lasted for about 9 days until T-lymphocyte responses returned back to normal (62). Taken together, these findings indicate that hemorrhage leads to a very early depression in cell-mediated immunity that lasts for a prolonged time period despite adequate resuscitation. Angele et al. suggested that macrophages might initiate the immunosuppression following surgical trauma and blood loss, whereas T-lymphocytes might play a critical role in maintaining the immunosuppressive state (76, 77). During the early postoperative period, T-lymphocytes are suppressed but still able to stimulate the release of cytokines from monocytes, whereas activated monocytes subsequently induce T-lymphocyte suppression (76, 77). In this respect, apart from the suppression of lymphocyte proliferation, the capacity of T-lymphocytes to secrete IL-2, IL-3, IL-6, IFN-γ, and TNF-α during the early postoperative period is severely reduced and associated with the decline in cellular ATP (2, 47, 78, 79). According to Zellweger et al. (75) the T-lymphocyte-related depression of these lymphokines persists for up to 5 days after surgery. In this respect, T-cell suppression in patients after solid organ transplantation is associated with a higher susceptibility for the development and the recurrence of tumors thereby further emphasizing the pivotal role of T-cells in tumor control (80). In addition, the importance of T-cells in anti-tumor immunity has been underscored by recent research on immune checkpoint receptors and inhibitors. In the context of persistent antigen exposure in cancer, T-cells become exhausted. T-cell exhaustion has been shown to be associated with defects in cytokine production, an upregulation of inhibitory receptors/immune checkpoints, and inefficient control of tumors. In this respect, through activation of immune checkpoint pathways with subsequent suppression of anti-tumor immune responses, tumors may evade immunosurveillance and progress. While these findings on the pivotal role of T-cells in anti-tumor immunity and suppression have led to the discovery of specific checkpoint inhibitors that are currently used in a palliative setting, it is still unclear, whether postoperative immunosuppression might additionally contribute to the dysfunction and exhaustion of T-cells and whether patients may benefit from the administration of checkpoint receptor agonists or antagonists during the perioperative period (81, 82).

As almost all types of leukocytes express receptors for catecholamines, studies could show that natural killer cells are another leukocyte subgroup that are inhibited by the rise of catecholamines following hemorrhage (83). Mediating cytotoxicity, natural killer cells may play a critical role in immune responses against tumor growth and metastasis (84). After identification of malignant cells, they can induce apoptosis through secretion of cytoplasmic granule toxins and activation of the death-receptor pathway (85). Animal studies and in vitro models could show that suppression of natural killer cell toxicity not only compromises resistance to tumor growth and metastasis, but is even associated with a higher incidence of tumors and metastases compared with a state of non-suppressed natural killer cell response (83, 86, 87).

In summary, the depression of various lymphocyte subgroups following hemorrhage reflects the broad systemic influence of intraoperative blood loss on the immune system and defines a state of impaired immune defence which can not only increase the susceptibility to infection but also favors tumor growth due to a decreased anti-tumor and anti-metastatic immunity. Nonetheless, the exact role of the individual immune cells in controlling tumor cell proliferation and their metastatic potential has not been exactly defined and needs to be elucidated in the future. This might open a new field for targeted therapies in oncological patients following surgery or systemic therapies with immunosuppressive side effects.

Oncology patients undergoing surgical treatment often receive additional treatment in the form of neoadjuvant or adjuvant chemotherapy. The immunosuppressive and cytotoxic side effects of chemotherapy are well known. Patients receiving neoadjuvant treatment have an increased risk of chronic anemia secondary to bone marrow suppression of certain chemotherapeutic drugs. Chronic anemia in turn has been demonstrated to have immunosuppressive effects and is associated with higher rates of perioperative blood transfusions which can lead to immunosuppression as discussed elsewhere (88, 89). However, as the effect of cytotoxic chemotherapy on different leukocyte subsets has mainly been analyzed in patients with hematological malignancies, it is not well understood how chemotherapeutic treatment affects leukocyte populations in patients with solid tumors. In this respect, the question arises whether the administration of chemotherapy enhances and adds to the immunosuppressive effects of surgical trauma and blood loss or represents an independent immunomodulatory factor which is the subject of current studies.

OUTLOOK ON POSSIBLE APPROACHES TO REDUCE THE ADVERSE EFFECTS OF INTRAOPERATIVE BLOOD LOSS

As indicated throughout this review, intraoperative blood loss and surgical trauma are associated with an increased risk for tumor growth and recurrence and it was the aim of this article to further elucidate potential underlying mechanisms. Accordingly, we will discuss how these insights could be used to develop perioperative therapeutic strategies that might limit or prevent increased tumor growth and recurrence following hemorrhage (please see Fig. 2).

Fig. 2
Fig. 2:
Outlook on possible approaches to reduce the deleterious effects of intraoperative blood loss and surgical trauma and control for perioperative immunosuppression to limit tumor growth and recurrence.

Optimization of surgical procedures

Optimizing surgical procedures and limiting surgical trauma is the first step to decrease intraoperative blood loss. Increased surgical experience through high surgeon's and hospital's annual caseloads has been demonstrated to be an independent prognostic factor for increased overall and disease-free survival and decreased recurrence incidence (90). Management of intraoperative blood loss requires an effective collaboration between the surgical and anesthesia team. Administration of anesthetic and analgesic agents as well as blood transfusions, fluid resuscitation, management of hypotensive episodes and hypothermia, pain, and the extent and duration of surgery have all been reported to influence the perioperative immune response and the degree of these factors correlates with the severity of the immunosuppression (1, 91, 92). To reduce tissue damage and accelerate recovery, laparoscopic procedures are increasingly performed. The immunoinflammatory response after laparoscopic surgery is less intense compared with conventional approaches. Systemic cytokine responses are less pronounced and cell-mediated immunity is less impaired (54, 93, 94). Patients after laparotomy show increased blood levels of VEGF, matrix-metalloproteinases (e.g., MMP9), interleukins (e.g., IL-6), and TNF-α, that have previously been described to promote tumor growth compared with patients after laparoscopy (54, 95, 96). Furthermore, several studies comparing the effect of laparoscopic versus open procedures on different lymphocyte subsets suggest a more severe and prolonged decline in total lymphocyte count in open procedures than in minimally invasive procedures (22). An animal study investigating the effects of the CO2 pneumoperitoneum on immune functions and absolute lymphocyte counts found that the proliferation of T lymphocytes was preserved following pneumoperitoneum but reduced following laparotomy (23). In addition, with regard to the Th1/Th2 balance, the reduction in Th1 cells and increase in Th2 cells is more pronounced in open surgery than minimally invasive surgery (97, 98). Moreover, due to their critical role in the local as well as systemic immune response, peritoneal macrophages have been studied under the influence of the pneumoperitoneum versus open surgery, however, with conflicting results. Some animal studies reported an enhanced bacterial clearance and increased secretion of hydrogen peroxide following pneumoperitoneum, while other studies report the opposite effects (99, 100). Moreover, the majority of studies and meta-analyses on different tumor entities report a reduction of intraoperative blood loss due to less tissue damage in laparoscopic procedures compared with open surgery (101, 102). Additionally, recent studies suggest that the pneumoperitoneum generated in laparoscopic surgery might have a beneficial procoagulatory effect. However, higher pressures also predispose for hypercoagulation and venous stasis leading to complications such as deep vein thrombosis (103, 104). Considering the potential immunosuppressive effects of blood transfusions, intraoperative cell salvage is an efficient way of reducing the need for allogenic blood transfusion (105). In this respect, it was hypothesized that reinfusion of lost blood might also increase the risk for systemic dissemination of malignant cells. The results of a comprehensive meta-analysis, however, did not support any association between the use of intraoperative cell salvage and development of metastases or increased recurrence rates (106).

Immunotherapy

As hemorrhage and intraoperative trauma induce severe immunosuppression, the perioperative period represents a good window of opportunity for immunomodulation.

Perioperative administration of immunomodulatory mediators such as IL-2, IL-7, interferons, and granulocyte-macrophage colony-stimulating factor has been demonstrated to be associated with a reduction in surgery-associated immunosuppression (107, 108). Those studies also showed that the numbers of immune cells and production of inflammatory mediators returned back to normal baseline and cells regained their antitumor cytotoxicity. IL-7 has become an attractive candidate for immunotherapy in various clinical situations. Among its diverse functions, recent preclinical and clinical studies have particularly highlighted its immune-enhancing properties with regard to the regulation and maintenance of T-cell homeostasis. A recent clinical trial could demonstrate that the administration of IL-7 could restore lymphocytes and mitigate adaptive immunosuppression in septic shock (109). In addition, another study suggested that the combination of IL-7 signaling with immune checkpoint inhibition could improve the efficacy of immunotherapy and potentially reverse immunosuppression and diminish tumor growth (110). In summary, a variety of immunomodulatory mediators have been demonstrated to avoid and counteract postoperative immunosuppression and the restoration of the immune response has been shown to promote antitumor cytotoxicity. The question of which one of these mediators is the best substance to improve the immune response needs to be determined in further studies. To date, none of the mentioned mediators have been introduced as a standard therapy in the clinical arena. However, clinical and experimental studies emphasize the importance of a functioning immune system postoperatively for adequate tumor control and show promising results with respect to the administration of immunomodulatory mediators in the perioperative period.

Toll-like receptor (TLR) agonists have recently been found to induce a balanced and effective cytokine response without significant adverse effects. Toll-like receptors are important components of the innate immunity and have been shown to be differentially expressed in critically ill patients developing sepsis compared with those with sterile inflammation (111). TLR9 agonist has been demonstrated to activate natural killer cells and B lymphocytes (112). In animal models it reduced metastatic progression and tumor growth (113). TLR4 was shown to activate T lymphocytes and dendritic cells potentially also associated with a reduction in cancer metastasis (114, 115). However, further studies are needed to investigate the effect and safety of such treatment in the perioperative setting.

Catecholamines and prostaglandins have also been discussed in this article with regards to their immunosuppressive effects. In animal models, administration of ß-blockers and selective COX2 inhibitors has been found to improve antitumor immunity and reduce the risk of tumor growth and metastasis (39, 46, 116). However, while chronic use of COX inhibitors and ß-blockers has widely been accepted to be an efficient measure to reduce the risk to develop various primary tumors, the perioperative use of these drugs and their effect on recurrence and metastasis formation has not been extensively studied yet but might bring promising results (58, 117).

The discovery of immune checkpoint receptors and subsequent development of checkpoint inhibitors to target and reduce tumor growth and recurrence via affecting the interaction between T-cells, macrophages, and tumor cells has been a great success for the immunotherapy of cancer. programmed cell death protein 1, Programmed cell death 1 ligand 1, and cytotoxic T-lymphocyte-associated Protein 4 inhibitors have been approved and are in use for various malignancies. Whether these substances may also be used in the perioperative setting may be elucidated in further clinical trials (118).

CONCLUSION

In cancer patients, surgical removal of the primary tumor is one of the main steps within multimodal therapy concepts to eliminate the disease and limit further progression. At the same time, surgical trauma is associated with an immunoinflammatory response counter-regulated by an anti-inflammatory response. Those changes result in a prolonged state of immunosuppression which may favor tumor growth, spread, and recurrence. Intraoperative blood loss has been shown to contribute and potentially even aggravate the perioperative immunosuppressive state. Moreover, hemorrhage can be an independent prognostic factor for tumor growth and recurrence. It was the aim of this article to provide an overview of the underlying mechanisms how surgical trauma and consecutive perioperative immunoinflammatory responses may affect tumor cell proliferation and growth. Better understanding of this critical perioperative phase might help to develop strategies to reduce the adverse effects of hemorrhage and postoperative immunosuppression and exhibit positive effects on tumor growth and recurrence.

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Keywords:

Hemorrhage; immunosuppression; surgical trauma; tumor growth; tumor recurrence

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