Serum C-Reactive Protein as Independent PrognosticVariable in Patients with Ovarian Cancer
Purpose: To evaluate serum C-reactive protein (CRP) as prognostic variable in patients with epithelial ovarian cancer (EOC). Experimental Design: In a multicenter study, preoperative serum CRP was evaluated in 623 patients with EOC. Results were correlated with clinical data. Results:Mean (SD) preoperative serum CRPwas 3.6 (4.8) mg/dL. Serum CRPwas significantly associated with International Federation of Gynecologists and Obstetricians stage (P < 0.001) and postoperative residual tumor mass (P < 0.001) but not with histologic grade (P = 0.1) and type (P = 0.7), patients’age (Pearson’s correlation coefficient = 0.05; P = 0.2), and serumCA125 (Pearson’s correlation coefficient = 0.02; P = 0.6). Patients with platinum-resistant EOC had significantly higher CRP serum levels compared with patients with platinum-sensitive EOC [6.0 (6.6) mg/dL versus 2.8 (3.8) mg/dL; P < 0.001]. Higher International Federation ofGynecologists and Obstetricians stage (P < 0.001), presence of postoperative residual tumor mass (P < 0.001), tumor grade (P = 0.001), serum CA 125 (P = 0.03), and serum CRP (P = 0.001) were independently associated with overall survival. Patients with serum CRP V1mg/dL versus >1mg/dL had an overall 5-year survival of 82% versus 58.5% (P < 0.001). Conclusion: Serum CRP can be seen as a novel, widely available independent prognostic variable of ovarian cancer. C-reactive protein (CRP) is one of the most important acutephase proteins produced predominantly by hepatocytes rising rapidly in response to inflammation (1, 2). CRP has both proinflammatory and anti-inflammatory actions, and it is uncertain which is predominant. Proinflammatory effects include the induction of monocytes. Anti-inflammatory actions are reflected by the diminished accumulation of neutrophils at inflammatory sites due to reduced neutrophil adhesion to the endothelium and the noninflammatory clearance of apoptotic cells (1, 2). Circulating serum CRP is routinely measured in clinical laboratories as marker for various acute and chronic inflammatory diseases (3–5). The pathogenesis and development of ovarian cancer have also been closely linked to inflammatory processes (6, 7). The inflammatory response promotes carcinogenesis by damaging DNA, stimulating angiogenesis and cell proliferation, and inhibiting apoptosis (8, 9). Various proinflammatory cytokines, such as interleukin-1, interleukin-6, tumor necrosis factor-a, IFN-g, and tumor growth factor, all known to stimulate CRP production, influence survival, growth, mutation, proliferation, differentiation, and migration of tumor cells (6, 7, 10, 11). Serum CRP has been shown to parallel carcinogenesis possibly as an expression of the host defense reaction or as paraneoplastic syndrome (1, 3). Therefore, serum CRP has been investigated as risk factor and prognostic variable in various human malignancies, such as colon (12), esophageal (13), hepatocellular (14), and renal cell (15) cancer. Few data are available on the role of serum CRP in gynecologic malignancies. Preliminary data suggest a possible prognostic value in patients with ovarian cancer (16). Tumor stage and postoperative residual tumor mass at primary cytoreductive surgery have been shown to most reliably predict outcome in patients with ovarian cancer (17). Clinical decision making with respect to adjuvant therapy is largely based on International Federation of Gynecologists and Obstetricians (FIGO) stage and tumor grade, especially in earlystage disease. The standard concept of six cycles of a platinum/ taxane combination as adjuvant chemotherapy for ovarian Imaging, Diagnosis, Prognosis Authors’ Affiliations: Department of Obstetrics and Gynecology, Medical University ofVienna; Ludwig Boltzmann Institute of Gynecology and Gynecologic Oncology ; Department of Obstetrics and Gynecology, Wilhelminenspital, Vienna, Austria; Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria; Department of Obstetrics and Gynecology, Charite¤ / CampusVirchow-Klinikum, University Medicine of Berlin, Berlin, Germany; and Department of Obstetrics and Gynecology, Landeskrankenhaus Klagenfurt, Klagenfurt, Austria Received 5/1/07; revised 9/4/07; accepted10/24/07. Grant support: Ludwig Boltzmann Institute of Gynecology and Gynecologic Oncology,Vienna, Austria. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Requests for reprints: Lukas A. Hefler, Department of Obstetrics and Gynecology, Medical University of Vienna, Waehringer Gu« rtel 18-20, A-1090 Vienna, Austria. Phone: 43-1-40400-2962; Fax: 43-1-40400-2911; E-mail: lukas.hefler@meduniwien.ac.at. F2008 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-1044 www.aacrjournals.org Clin Cancer Res 2008;14(3) February1, 2008 710 Research. on July 16, 2017. © 2008 American Association for Cancer clincancerres.aacrjournals.org Downloaded from cancer has recently been challenged (18, 19). Omission of chemotherapy for adequately staged early-stage disease (20), a neoadjuvant chemotherapy approach for patients expected not to be optimally debulked at primary cytoreductive surgery (21), and consolidation chemotherapy for patients at high risk for recurrent disease have been advocated (22). Additional prognostic variables to more individually tailor adjuvant therapy would be of considerable clinical value. Therefore, the aim of the present study was to investigate the clinical value of serum CRP as independent prognostic variable in a large multicenter study of patients with ovarian cancer. Materials andMethods Patients. A total of 623 patients with epithelial ovarian cancer were included in the present retrospective multicenter study (Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria: n = 208; Department of Obstetrics and Gynecology, Innsbruck Medical University, Innsbruck, Austria: n = 192; Department of Obstetrics and Gynecology, Charité/Campus Virchow-Klinikum, University Medicine of Berlin, Berlin, Germany: n = 99; Landeskrankenhaus Klagenfurt, Klagenfurt, Austria: n = 64; Wilhelminenspital, Vienna, Austria: n = 29; Sozialmedizinisches Zentrum Süd, KFJ, Vienna, Austria: n = 31). The respective Institutional Review Boards approved the present study. Data were collected with chart review. Before elective surgery, an acute infection was ruled out by a physical examination, measuring body temperature, and respective blood tests. Patients were treated according to standards of the respective institution with hysterectomy, bilateral salpingo-oophorectomy, pelvic and/or paraaortic lymphadenectomy, appendectomy, and omentectomy. All patients with tumor stages Ic to III and all patients with clear cell carcinoma received a platinum-based chemotherapy. All patients were followed up in 3-month intervals, including vagino-rectal palpation, abdominal ultrasound examination, and serum tumor marker evaluation. In cases of clinically doubtful findings and/or tumor marker elevation, computed tomography was done. The mean duration of follow-up was 25.5 (24.1) months. Patient charts were reviewed to obtain clinical data about age, FIGO tumor stage, tumor grade, amount of postoperative residual tumor mass after primary surgery, histologic type, preoperative serum CA 125, and time of death or time of last follow-up. Mean patient’s age at diagnosis, distribution of tumor stage, amount of postoperative residual tumor mass, and tumor grade were not different between study centers. Patients with platinum-resistant and platinum-sensitive tumors were defined as having a time with no evidence of disease V6 months versus >6 months after completion of primary chemotherapy. CRP measurement. Patients’ blood was obtained before surgery by peripheral venous puncture. CRP serum levels were measured as part of the clinical routine by a modified latex-enhanced immunoturbidimetric assay using a CRP Latex kit (Olympus Life and Material Science Europe) according to the manufacturer’s instructions (23). Serum levels V1 mg/dL were defined as normal. The manufacturer claims an intraassay variability between 1.64% and 3.34%. Serum CRP levels were not assessed expressly as part of the study but were ascertained as part of clinical routine. Of note, serum CRP levels were not assayed at one central laboratory to better reflect clinical practice, but all clinical laboratories used the same assay kit. Table 1. Patients’ characteristics and CRP serum levels in patients with ovarian cancer broken down by clinicopathologic variables Variable n or mean (SD) Mean (SD) CRP serum levels (mg/dL) P Patients with epithelial ovarian cancer 623 — — Age at first diagnosis (y) 60.5 (13.7) — — Tumor stage FIGO I 143 1.9 (3.0) <0.0001* FIGO II 44 2.1 (2.6) FIGO III 346 4.3 (5.3) FIGO IV 90 4.7 (5.6) Postoperative residual tumor mass after surgery (cm) V2 459 2.9 (4.5) <0.0001c >2 164 5.7 (5.3) Tumor grade G1 89 2.7 (5.2) 0.1* G2 218 3.4 (4.7) G3 316 3.9 (4.7) Histologic type Serous 401 3.6 (4.7) 0.7c Mucinous 68 Endometrioid 89 Others 65 Mucinous, endometrioid, and all others combined 222 3.5 (5.0) Length of follow-up (mo) 25.5 (24.1) — — Status at last observation Alive with no evidence of disease 342 — — Alive with stable disease 66 — — Progressive disease 64 — — Dead as a result of disease 131 — — Dead as a result of other causes 15 — — Lost to follow-up 5 — — *One-way ANOVA. ct test. SerumCRPand Prognosis in Ovarian Cancer www.aacrjournals.org Clin Cancer Res 2008;14(3) February1, 2008 711 Research. on July 16, 2017. © 2008 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Statistics. Values are given as means (SD). Variables were compared using Pearson’s correlation coefficient, t test, and one-way ANOVA. Survival probabilities were calculated by univariate Kaplan-Meier a