CHAPTER 2 Video-Assisted Thoracic Surgery Versus Thoracotomy
Impact on the Immune System
Introduction
Minimally invasive surgery is attractive to patients for many reasons, such as smaller scars, shorter hospital stays, and earlier recovery. Although the lower complication rates after minimally invasive surgery usually have been attributed to patients experiencing less pain, the lower complication rates may reflect a more intact immune system after minimally invasive surgery.1
Surgery causes immunosuppression by “hemodynamic changes in humoral agents, such as catecholamines, and by peptides, such as cytokines, produced at the site of injury and by various immune cells.”2 Immunosuppression can increase the likelihood of tumor metastasis formation and development of septic complications postoperatively.3 Lord Moynihan of Leeds said, “The cleaner and gentler the act of operation, the less the patient suffers, the smoother and quicker his convalescence, the more exquisite the wound heals.”4
Surgery, Cancer, and the Immune System
Human studies have shown that patients with compromised immune systems are at increased risk for developing cancer.11 In a prospective study over 11 years, the age-adjusted cancer risk was 0.63 for subjects with normal cytotoxic activity compared with patients with compromised cytotoxic activity.11
It is thought that a normally functioning human immune system regularly scavenges and removes aberrant cells.12 For example, despite the fact that cancer cells are found in the blood of patients after lung cancer surgery,13 many are cured by the operations, indicating that the immune system must control the circulating cancer cells.
The balance between the cancer burden and immune system status may affect the body’s ability to control the cancer. Surgical stress may lessen immunologic activity, and the type of procedure may affect tumor cell dissemination. For example, in a comparison of female C3H/He mice treated by laparotomy or laparoscopy, tumor nodules subsequently developed in 5%, 30%, and 83% (P <.01) of the control mice, laparoscopic resection mice, and open resection mice, respectively.14
Surgical Stress and Immunologic Function
In general, surgery has been shown to compromise the immune system.7 Surgery induces the release of acute-phase response mediators, such as C-reactive protein (CRP) and cytokines, whose concentration increases or decreases in response to inflammation.1 In an acute inflammatory and immunologic response to injury or trauma, neutrophil granulocytes and macrophages secrete molecules known as cytokines into the bloodstream. Important cytokines include interleukins IL-1, IL-6, and IL-8 and tumor necrosis factor (TNF).
The liver responds by producing a large number of acute-phase reactants, such as CRP, which inhibits the growth of microbes by binding to phosphorylcholine, assists in complement binding to foreign and damaged cells, and enhances phagocytosis by macrophages. CRP may increase 50,000-fold in response to acute inflammation and infection, initially. Because this occurs within 6 hours and peaks at 48 hours, measuring and charting CRP values can help to determine disease progress or the effectiveness of treatments.15
TNF, primarily produced by macrophages, can promote apoptotic cell death, cellular proliferation, differentiation, inflammation, tumorigenesis, and viral replication. TNF causes the hypothalamus to suppress appetite and induce fever. TNF causes the liver to stimulate an acute-phase response that increases CRP and other mediators and it attracts neutrophils to help them stick to endothelial cells for migration. TNF causes macrophages to stimulate phagocytosis and the production of IL-1 oxidants and inflammatory lipid prostaglandin E2 (PGE2). A locally increased concentration causes inflammation, including heat, swelling, redness, and pain. Overproduction and high concentrations of TNF may induce shocklike symptoms, and it has been implicated in a variety of human diseases, including cancer.16 Several laparoscopic procedures have provoked a smaller release of cytokines than open laparotomies.1,17
Immune effector cells (IECs) are short-lived, activated cells that defend the body in an immune response. Effector B and T cells, also known as plasma cells, secrete antibodies and cytotoxic (CD8) and helper (CD4) cells that carry out cell-mediated responses. Some IECs are less affected by minimally invasive surgery than open procedures. With compromised IECs, established tumors grew equally well after minimally invasive surgery and open surgery,14 but with intact IECs, tumor growth rate was significantly greater after an open procedure.18 In a male Wrister rat (350 to 380 g) model, the effects of stress (i.e., corticosteroid) and immunologic parameters (i.e., neopterin and IL-1β).18 were compared for laparoscopic and open surgery.
Anabolic parameters reflect the immunologic effect of surgical stress. Significant differences were found in postoperative stress (491 versus 609 ng/mL, P = .08) and immune parameters (neopterin: 0.225 versus 0.372 ng/mL, P = .01; IL-1β: 268 versus 754 pg/mL, P = .2). Seven days postoperatively, the rats lost 5.99% of their body weight after open surgery and only 2.4% after laparoscopic surgery. Weight loss is a reflection of the anabolic state of the rats.19
Insulin-like growth factor 1 (IGF-1) is another parameter of anabolism that may play an important role in malignant cell propagation; postoperative decreases in serum levels of IGF correlate with the degree of surgical trauma. Assisting in metabolism, growth, and regeneration, IGF-1 travels to extracellular tissue. In male rats of the inbred WAG strain (200 to 300 g), Bouvy and colleagues20 found significantly higher total peritoneal tumor load for conventional open small-bowel resection (P <.05) compared with higher postoperative IGF-1 levels for laparoscopic procedures (P <.02). However, these findings are not specific because there are other factors that influence the immune system and tumor growth. Operations may cause localized ischemia that reduces defense mechanisms, which makes the ischemic site vulnerable for tumor implantation and growth.20 This is a complex issue because even the type of insufflation used for laparoscopic procedures affects tumor growth. Because of a greater effect on hemodynamics, carbon dioxide (compared with helium) insufflation promotes tumor growth.21
There are much more data for abdominal operations than for thoracic operations. However, comparisons of the immune response to VATS with that for open thoracotomy suggest that minimally invasive procedures in the chest may also have immunologic benefits.7,8
The immune system response to surgical trauma is a complex interaction of several systems. Changes in the immune system may affect the immediate postoperative period. Cytokines trigger or enhance endothelial leukocyte activation.1,7,8 Although elevated IL-6 levels correlate with the degree of surgical trauma, they are more than a marker of the degree of trauma. Cytokines are the main mediators of the inflammatory response. IL-6 is the main inducer of liver synthesis of acute-phase proteins.22 IL-6 is also involved in rapid weight loss, which frequently accompanies short-term disease or injury such as sepsis, trauma, or burns.22 Hypermetabolism-associated malnutrition in liver transplant recipients is involved in the deterioration of perioperative energy metabolism and the exaggerated postoperative IL-6 response. IL-6 is an important mediator of experimental cancer cachexia in the murine adenocarcinoma cell line.7 Some human studies have shown an increased IL-6 response in nutritionally depleted cancer patients.23
Increased levels of certain proinflammatory cytokines, such as IL-6 and IL-8, caused by surgical trauma increase the risk of postoperative complications.1 Recruited by inflammation, primary macrophage cells process antigens and release chemokines to signal other cells. One such chemokine, IL-8, induces chemotaxis in its target cells, such as neutrophil granulocytes, to phagocytose the antigen, which triggers pattern toll-like receptors. Some studies comparing laparoscopy with open laparotomy for colectomy,24 hysterectomy,25 and Nissen fundoplication26 show that the minimally invasive procedure causes less release of CRP, whereas other studies did not show that laparoscopy had less impact on the immune system.27
Thoracic Surgery and the Immune System
In a prospective comparison of lobectomy patients undergoing VATS or thoracotomy for lung cancer, the postoperative levels of IL-6 and IL-8 were significantly lower in the VATS group.28 Previously, Yamada and colleagues showed that high IL-6 and IL-8 levels after thoracic surgical procedures were associated with an increased incidence of postoperative infections28 and respiratory failure.29,30 Szczesny and coworkers showed that elevated levels of IL-6 in pleural fluid was a marker for a higher risk of postoperative complications.31
The data about thoracic procedures and the immune system are not clear-cut. Sugi and coworkers32 found no difference in the IL-6 and IL-8 levels for VATS and thoracotomy patients,1 and Friscia and associates33 showed lower levels of IL-6 and IL-8 for VATS compared with open lung volume reduction surgery.
Cancer Development and the Immune System
Changes in the immune system may affect the body’s ability to fight cancer. Elevated IL-6 levels may encourage cell proliferation in certain subtypes of non–small-cell lung cancer.34 Because it promotes the activity of insulin growth factor (IGF) and inhibits IGF binding protein (IGFBP), IL-6 creates an environment that may promote tumor growth.32 IGF may cause progression of tumors because it stimulates tumor growth and reduces tumor apoptosis.35 Because IGFBP attenuates the activity of IGF, it inhibits tumorigenesis. Low circulating levels of IGFBP have been found in patients with advanced prostate cancer36 and patients at risk for colon cancer.32 The anti-oncogenic properties of IGFBP-3 include the induction of apoptosis in lung cancer37 and impairment of DNA synthesis in poorly differentiated tumor cells.32 IL-12, IL-17, and IL-23 are less affected by VATS than open procedures, but the significance of this is unknown.7
IGFBP-3 may be particularly important in lung cancer patients. Patients after lung cancer surgery have circulating cancer cells.13 In a prospective study, IGFBP-3 levels were higher on postoperative day 3 for patients after VATS than after thoracotomy. Conversely, levels of matrix metalloproteinase 9 (MMP-9), which cleaves and deactivates IGFBP-3, were lower in the VATS patients. Elevated MMP-9 levels facilitate tumor invasion and metastasis through its proteolytic properties against type IV collagen in the basement membrane.38,39 These data suggest that there may be an immunologic reason why VATS may provide better lung cancer survival than a thoracotomy.
Surgery and Cellular Immunity
Most operations diminish circulating lymphocytes and cell-mediated immunity, and minimally invasive procedures appear to have a smaller impact on the immune system. For abdominal surgery, laparoscopy has a smaller impact than a laparotomy.7
VATS produces less immunosuppression of lymphocytes and causes a smaller reduction in the total number of T cells and CD4 T cells. Natural killer (NK) cells are important for tumor immunosurveillance because they recognize, target, and kill tumor cells without prior sensitization.40 The number of NK cells is considerably lower after thoracotomy than after VATS.41 IL-10 is a cytokine that helps tumor cells escape from the immune system by inhibiting NK cell cytotoxicity, and in experiments, it increased tumor cell resistance to NK cells.42 After lobectomy, IL-10 levels are higher. Phagocytosis by neutrophils is less affected after VATS.8,32
Components of the cellular immune system may be affected less after a minimally invasive operation than after an operation through large traditional incisions. Compared with thoracotomy,1,7,8 VATS is associated with better cellular immunity (i.e., neutrophil and monocyte function) and less postoperative impact on CRP, causes fewer disturbances of chemokines, and produces a lower stress response. The degree of access trauma correlates with the degree of inflammation and immunosuppression. The reduced impact of VATS may translate into better survival for cancer patients who have minimally invasive surgery.
Experiments with a delayed-type hypersensitivity (DTH) assay, which evaluates the cellular immune system, have shown that laparotomy has a greater impact on the cellular immune system than laparoscopy. The DTH response starts with antigen injected into the skin. In the activation phase, antigen is presented to lymphocytes on the surface of antigen-presenting cells. In the inflammatory phase, antigen-stimulated CD4+ lymphocytes respond by proliferating and elaborating cytokines that act in an endocrine manner to cause endothelial cell leakage and fibrin deposition that creates swelling at the site of antigen challenge. In the effector phase, vascular endothelial cells, activated by cytokines, recruit effector cells to eliminate the intracellular pathogen. The size of the induration of the skin is directly proportional to the strength of the immune response. Anergy to DTH testing is associated with a significantly higher incidence of postoperative sepsis, wound infection, mortality, and even lower resectability rates and higher cancer recurrence rates.43
DTH testing has been used to assess the impact of open compared with minimally invasive abdominal surgery in animals. Gleason and colleagues43 studied three serial DTH challenges of phytohemagglutinin (PHA) in 100 5- to 6-week-old female C3H/H3N mice. PHA is a polyclonal stimulator that acts directly on immature CD4+ lymphocytes, stimulating cell proliferation and cytokine production. Measurements of footpad thickness showed a significantly lower DTH response in the sham laparotomy group compared with the laparoscopy group, indicating cellular immune suppression in the open group.43
Suppression of the cellular immune system increases susceptibility to sepsis. In two similar rat models testing cell-mediated immune function, Allendorf and colleagues44 compared laparotomy with pneumoperitoneum, and in another study, Allendorf and coworkers45 compared laparoscopy with laparotomy. They tested the susceptibility to bacterial infections by measuring the size of skin pustules after injection with Staphylococcus aureus 502A. Both groups showed better cellular immune function with the minimally invasive surgery, as demonstrated by smaller pustules and quicker healing. When researchers gauged immune function by evaluating DTH responses to phytohemagglutinin (PHA), a nonspecific T-cell mitogen, he found significantly smaller DTH response in the laparotomy group.18
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44 Allendorf J.D.F., Bessler M., Whelan R.L., et al. Better preservation of the immune fucntion after laparoscopic-assisted versus open bowl resection in a murine model. Dis Colon Rectum. 1996;39(Suppl):S67-S72.
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