Video-Assisted Thoracic Surgery Versus Thoracotomy: Impact on the Immune System

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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

Some surgeons theorize that minimally invasive surgery may increase cancer cure rates by reducing the impact of an operation on the immune system. This chapter explores that theory and compares the data on minimally invasive thoracic surgery (i.e., video-assisted thoracic surgery [VATS]) and on open thoracotomy for lung cancer surgery:

VATS has been associated with a reduced impact on measurable components of the immune system1,7,8 and possibly with higher cure rates for lung cancer surgery,9,10 leading to speculation about whether patient selection or the procedure’s diminished immunologic disturbance may account for improved outcomes.

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

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