Syddansk Universitet The immune response is affected for at least three weeks after extensive surgery for ovarian cancer Brøchner,

IntroductIon: The treatment of women with ovarian can­ cer in advanced stages consists of extensive surgery fol­ lowed by chemotherapy initiated three weeks after surgery. In this study, selected immune parameters were investi­ gated to elucidate when the immune system is normalised following the operation. Methods: Ten women undergoing extensive surgery for ovarian cancer were compared with a control group of ten women undergoing abdominal hysterectomy for a benign diagnosis. Blood samples were collected over a period of 21 days post­operatively. The levels of interleukin­6, interleu­ kin­8, interleukin­10 and the activity and total frequency of natural killer cells were measured. results: Interleukin­6 and interleukin­10 were significantly elevated immediately after the operation and also after 21 days. The total population of natural killer cells and the to­ tal activity were reduced. The total activity of natural killer­ cells did not normalise within 21 days. conclusIons: The level of the cytokines interleukin­6 and interleukin­10 is increased 21 days after the operation, and the function of natural killer cells is not normalised at 21 days after surgery. FundIng: The study received funding from Odense Univer­ sity Hospital Free Research Fund. trIal regIstratIon: not relevant. The survival of women with ovarian cancer (OC) in ad­ vanced stages (stages IIIa­c and IV, according to The Inter­ national Federation of Gynaecology and Obstetrics) has improved considerably over the past ten years. The treat­ ment has changed from either traditional surgery or chemotherapy to a combination of both treatment op­ tions offering the affected women extensive surgery fol­ lowed by chemotherapy [1­3]. Extensive surgery includes hysterectomy and bilateral salpingo­oophorectomy, peri­ tonectomy, resection of parts of the colon or the small in­ testine and splenectomy in cases with macroscopic me­ tastasis visible on the spleen. All para­aortic and pelvic lymph nodes are removed if metastases are suspected. In Denmark, the treatment protocol dictates that chemotherapy should be initiated three weeks post­ operatively (PO) unless the white blood cell count (WBC) is reduced. Two theories have been proposed in relation to the effect of surgery followed by chemotherapy. The first theory is that resection diminishes the amount of tu­ mour cells which enhances the cytotoxicity of chemo­ therapy in relation to the residual cancer. The second theory is that the tumour cells induce immunosuppres­ sion and thus enhance a vicious circle with tumour growth suppressing the remaining immune system. Extensive surgery reduces the tumour burden and thus slows this vicious circle [4]. The effect observed after ex­ tensive surgery is probably a combination of both. In order to elucidate the changes in the immune system in women undergoing extensive surgery, we ana­ lysed their immune system and compared changes with changes encountered in women undergoing abdominal hysterectomy due to benign disease. The following immune parameters of special rele­ vance to the innate immune system were chosen to de­ scribe the immune profile: Interleukin (IL) 6, IL­8, IL­10 and natural killer (NK) cells. Il­6 is a pleiotropic cytokine that acts in a pro­in­ flammatory way by attracting neutrophils to the area where damage has occurred. Moreover, it promotes the upregulation of adhesion molecules and L­selectin. IL­6 also stimulates the hepatic acute­phase protein synthe­ sis with release of C­reactive protein and procalcitonin. Furthermore, Il­6 stimulates the production of prosta­ glandin E2 which, in turn, stimulates the secretion of IL­ 10 production. In addition, IL­6 has its own direct anti­ inflammatory properties. The secretion of IL­6 correlates with the magnitude of the trauma and the duration of surgery, and elevated levels of IL­6 increase the risk of post­operative complications. Elevated IL­6 serum levels in patients with OC are correlated with shorter relapse­ free periods and overall poor survival [5]. IL­8 plays an important role in inflammation as it re­ cruits T­cells and accelerates wound healing. In several studies, the presence of IL­8 in women with OC has been correlated with a poor outcome [6]. IL­8 is produced by monocytes, neutrophils and epithelial cells, but also by the tumour cells. IL­10 is responsible for T helper cell proliferation. IL­10 also hampers the maturation of dendritic cells and hinders the function of co­stimulatory molecules. the immune response is affected for at least three weeks after extensive surgery for ovarian cancer Anne Craveiro Brøchner1, Søren Mikkelsen1, Iørn Hegelund2, Marianne Hokland3, Ole Mogensen2 & Palle Toft1