Perioperative granulocyte colony-stimulating factor does not prevent severe infections in patients undergoing esophagectomy for esophageal cancer: a randomized placebo-controlled clinical trial.

Despite improved surgical techniques and better perioperative management, postoperative complications remain a serious problem in patients undergoing esophagectomy for esophageal cancer. During the early postoperative course, infections occur in approximately 50% of patients,1–4 the majority of which relate to the lung. In larger series, pneumonia-associated postoperative mortality ranges between 5% and 10%.5–7 Possible reasons are the major surgical trauma, poor nutritional status, and reduced immune response. Impaired neutrophil function in patients with esophageal cancer has been reported as an additional putative cofactor for bacterial infections.8 Endogenous hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) enhance host defense against pathogens by mobilizing granulocytes and improving neutrophil function.9 In a recently published meta-analysis, G-CSF was shown to reduce the frequency and length of neutropenia in patients undergoing chemotherapy for malignant lymphoma10 and solid tumors.11 Currently, G-CSF is mainly used for the prevention of chemotherapy-induced neutropenia and neutropenia-associated infections, in clinical trials aimed at dose escalation of cytostatic drugs, as well as in high-dose chemotherapy and stem-cell selection. More recently, smaller studies have investigated the use of G-CSF to prevent bacterial infections in non-neutropenic patients.12–18 In a trial involving non-neutropenic postoperative/posttraumatic patients at high risk of sepsis, none of the G-CSF treated patients developed sepsis, whereas 3 patients in the control group died.14 Another trial involving patients with acute traumatic brain injury or cerebral hemorrhage reported that G-CSF was associated with a dose-dependent reduction in the frequency of bacteremia.15 One pilot study investigated the efficacy of G-CSF in preventing postoperative infections after radical vulvectomy.18 Compared with historic controls, the incidence of wound infection and wound breakdown was markedly decreased. Administration of G-CSF in these trials was safe and well tolerated. In addition, there is some evidence that G-CSF activates anti-inflammatory cytokines such as IL-1ra and soluble TNF-alpha-receptor (sTNFR) and reduces the levels of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF).19 Because G-CSF might improve impaired neutrophil function in patients undergoing esophagectomy for esophageal cancer, our group performed a phase-II study using a perioperative application schedule.20 We found a marked increase in neutrophil function despite the extensive surgical trauma as well as a low infection rate in 20 patients enrolled when compared with historic controls. To validate these data, we initiated a prospective placebo-controlled study with perioperative administration of G-CSF to reduce infection rates in patients after esophagectomy for esophageal cancer. Here, we report the results of this multicenter trial in a total of 155 randomized patients.