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

In cancer patients, surgical removal of the primary tumor is one of the major steps within a multimodal therapy concept toward eliminating the disease and limiting further progression. In this respect, surgical trauma can have potent effects on the patient's immune system. Intraoperative blood loss associated with major surgical trauma leads to reduced blood flow, regional hypoxia, metabolic, and microenvironmental alterations stimulating an inflammatory response characterized by the release of pro-inflammatory cytokines (i.e., TNF-α, IL-6) and acute-phase proteins. The inflammatory state is accompanied by and intertwined with a counter-regulatory anti-inflammatory response reflected in the rise of anti-inflammatory cytokines (i.e., transforming growth factor-β) and prostaglandins (i.e., prostaglandin E2) which can lead to a depression of cell-mediated immunity and systemic immunosuppression. This results in a highly vulnerable state with concurrent expression of pro- and anti-inflammatory cytokines alternately predominating. The immunosuppressive state is characterized by a reduced antigen-presentation capacity of macrophages, alterations in lymphocyte proliferation, and activation as well as a shift of the Th1/Th2 (T helper cells 1 and 2) balance toward Th2 and a decrease in natural killer cell activity. The severity of the immunosuppression thereby correlates with the extent and the duration of the surgical procedure. Growing evidence suggests that the immunosuppressive state following hemorrhage and surgical trauma might not only be a risk factor for postoperative complications but also facilitate tumor proliferation, metastatic growth, and recurrence. This article provides an overview of the cascade of events and underlying mechanisms resulting in immunosuppression and describes the impact of hemorrhage and major surgical trauma on tumor growth and recurrence. Attempts to control for perioperative inflammation thereby reducing the adverse effects of postoperative immunosuppression could have positive effects on tumor growth, metastasis formation, and recurrence.