OBJECTIVE: To evaluate whether C-reactive protein (CRP) serum levels are associated with prognosis in surgically treated endometrial cancer.
METHODS: In the present multicenter study, CRP serum levels were measured preoperatively in 403 surgically staged patients with endometrioid endometrial cancer. Results were correlated to clinical data.
RESULTS: The mean (standard deviation) serum CRP level in patients with endometrial cancer was 1.0 (1.8) mg/dL. Serum CRP levels were associated with tumor stage (P=.01), but not with tumor grade (P=.8), lymph node involvement (P=.8), and age at diagnosis (P=.9). In a univariable survival analysis, serum CRP levels, tumor stage, tumor grade, and age at diagnosis were associated with disease-free and overall survival (all P <.001). In a multivariable Cox regression model, serum CRP levels (P=.001, P=.004), tumor stage (P <.001, P <.001), tumor grade (P=.02, P=.009), and age at diagnosis (P=.002, P=.001) were independent prognostic factors for disease-free and overall survival.
CONCLUSION: Our results suggest that elevated serum CRP levels are associated with a less favorable prognosis in patients with surgically treated endometrial cancer.
LEVEL OF EVIDENCE: II
C-reactive protein serum levels are associated with prognosis in patients with endometrial cancer.
From the Departments of Obstetrics & Gynecology, 1 Medical University of Vienna, Vienna, Austria; 2 Innsbruck Medical University, Innsbruck, Austria; and 3 Landeskrankenhaus Klagenfurt, Klagenfurt, Austria.
Supported by Ludwig Boltzmann Institute of Gynecology and Gynecologic Oncology, Vienna, Austria.
Corresponding author: Lukas Hefler MD, Department of Obstetrics & Gynecology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria; e-mail: email@example.com.
Financial Disclosure The authors have no potential conflicts of interest to disclose.
C-reactive protein (CRP) is a pentameric protein consisting of five noncovalently bonded identical subunits, with an overall molecular weight of approximately 118,000 d. It is predominantly synthesized by hepatocytes.1,2 C-reactive protein is an acute-phase reactant that has traditionally been used as a serologic marker of acute and chronic inflammation.1,2 C-reactive protein is normally present in trace levels in serum, but increases rapidly and dramatically in response to proinflammatory cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factor.1–5
In inflammatory processes, CRP binds to specific molecular configurations that are typically expressed on the surface of various pathogens.6 CRP undergoes calcium-dependent binding to choline phosphatides, such as lecithin, lysolecithin, sphingomyelin, polysaccharides, and peptopolysaccharides present on bacteria, parasites, and fungi.5 The functional properties of CRP include the ability to activate the classic complement pathway, and the ability to modulate the function of phagocytic cells.1,5 Although the exact functions of CRP in vivo are not yet known, these properties suggest that CRP has a role in opsonization of infectious agents.5
Besides its role in inflammation, CRP has also been shown to be involved in cell death, known to be a crucial factor in the pathogenesis and development of malignant diseases. The inflammatory response promotes carcinogenesis by damaging DNA,7,8 stimulating angiogenesis and cell proliferation, and inhibiting apoptosis.9 Various proinflammatory cytokines, such as IL-1, IL-6, tumor necrosis factor-α, interferon-γ, and tumor growth factor, all known to stimulate CRP production, influence survival, growth, mutation, proliferation, differentiation, and migration of tumor cells.10–12 Furthermore, they regulate the communication between tumor and stromal cells, as well as tumor interaction with the extracellular matrix.12 Serum CRP has been shown to parallel carcinogenesis, possibly as an expression of the host-defense reaction or as paraneoplastic syndrome.13,14
Therefore, CRP serum levels have been investigated in various malignancies, both as predictive and prognostic factors.15–23 Preoperatively, elevated CRP serum levels have been shown to be a significant prognostic factor in patients with espohageal,21 hepatocellular,22 and colorectal18,23 cancer. However, little is known about the possible prognostic value of CRP serum levels in gynecologic tumors.24 Therefore, the aim of the present study was to evaluate the possible association of preoperative CRP serum levels with prognosis in patients with surgically treated endometrial cancer.
MATERIALS AND METHODS
Clinical data were obtained retrospectively from files at the Medical University of Vienna, Department of Obstetrics and Gynecology, the Landeskrankenhaus Klagenfurt, Department of Obstetrics and Gynecology, and the Innsbruck Medical University, Department of Obstetrics and Gynecology. Four hundred three consecutive patients (Medical University of Vienna, n=189; Landeskrankenhaus Klagenfurt, n=77; Innsbruck Medical University, n=137) with histologically confirmed endometrioid endometrial cancer undergoing surgery between December 1995 and January 2005 were included in our study. Other histologic types of endometrial cancer were excluded form the present study. Approval for this study was obtained by the respective institutional review boards.
Diagnosis of endometrial cancer was established by dilation and curettage. Subsequently, patients were treated by hysterectomy, bilateral salpingo-oophorectomy, and pelvic and in selected cases paraaortic lymphadenectomy (n=145). In cases of lymph node metastases, postoperative radiotherapy was provided according to standardized treatment protocols. A regimen of adjuvant chemotherapy using carboplatin/paclitaxel was used in patients with advanced disease (n=46). Histologic staging and grading was performed according to the current International Federation of Gynecology and Obstetrics (FIGO) classification.
Patients were followed up at regular intervals after surgery, including inspection, vaginorectal, and screening for serum tumor marker evaluation. In cases of clinically suspicious findings and/or tumor marker elevation, computed tomography was performed.
Patients' blood was obtained 48 hours or less before surgery by peripheral venous puncture. C-reactive protein serum levels were measured routinely in the clinic before surgery by a modified latex-enhanced immunoturbidimetric assay25 using a CRP Latex kit (OSR6199, Olympus Life and Material Science Europa GmbH [Irish Branch], Lismeehan, Ireland) according to the manufacturer's instructions. The manufacturer claims an intraassay variability between 1.64% and 3.34%.
Serum levels of 0.5 mg/dL or less are considered as normal in this assay. Additionally, CA 125 serum levels were measured in 143 patients treated at the Medical University of Vienna, Department of Obstetrics and Gynecology. Cancer antigen 125 serum levels were measured using an enzyme immunologic test (Ezymun-Test, CA 125 II, Boehringer Mannheim, Mannheim, Germany). The specificity at 35 units/mL is 95%. The serum assay was performed by certified technicians blind to the clinical outcomes of patients.
Values are given as means (standard deviation) for evenly distributed values or medians (interquartile range) for values not evenly distributed. Metric measures were compared using Student t test. Pearson's correlation analysis was performed when two metric measures were compared. Survival probabilities were calculated by a univariable Cox regression analysis (metric variables) or a product limit method of Kaplan and Meier using the log rank test (categorical variables). A multivariable Cox regression model was performed comprising tumor stage, tumor grade, age at diagnosis, and CRP serum levels. The results were analyzed for the endpoint of disease-free and overall survival. Survival times of patients disease-free or still alive were censored with the last follow-up date. P<.05 was considered statistically significant. We used the statistical software SPSS 11.0 for Windows (SPSS Inc., Chicago, IL) for statistical analysis.
Characteristics of patients with no evidence of disease at last observation and patients with progressive disease/cancer-related deaths at last observation are shown in Table 1. C-reactive protein serum levels broken down by the evaluated clinicopathologic measures FIGO tumor stage, tumor grade, lymph node involvement, and age at diagnosis are shown in Table 2. C-reactive protein serum levels were associated with tumor stage, but not with tumor grade, lymph node involvement, and age at diagnosis (Table 2). A significant correlation was found between serum CRP levels and FIGO tumor stage (P=.001, Pearson's correlation coefficient=0.2) using correlation analysis.
In a univariable survival analysis, CRP serum levels, tumor stage, tumor grade, and age at diagnosis were associated with disease-free and overall survival (Table 3). Kaplan-Meier curves for normal (0.5 mg/dL or less) compared with abnormal (more than 0.5 mg/dL) CRP serum levels for all FIGO stages are shown in Figure 1 (disease-free survival, P=.3) and Figure 2 (overall survival, P=.2). For the subgroup of patients with advanced disease, ie, FIGO III/IV, the respective Kaplan-Meier curves are shown in Figure 3 (disease-free survival, P=.9) and Figure 4 (overall survival, P=.5). Based on the relatively low number of patients in this subgroup (n=53), statistical significance was not reached (P=.9 and P=.5, respectively).
In a multivariable Cox regression model, higher CRP serum levels, tumor stage, tumor grade, and age at diagnosis were associated with a shortened disease-free and overall survival (Table 3). Cancer antigen 125 serum levels were available for 143 patients treated at the Medical University of Vienna, Department of Obstetrics and Gynecology. Serum CRP levels and serum CA 125 levels were closely correlated overall (all FIGO stages, P <.001, Pearson's correlation coefficient=0.3) and also in the subgroup of FIGO stage III/IV (P=.02, Pearson's correlation coefficient=0.5). In a univariate Cox regression analysis, CA 125 serum levels were not associated with survival (Table 3).
We present data on the prognostic value of CRP serum levels in a large series of patients with endometrial cancer. In parallel with other malignancies,18–24 the results of this multicenter study suggest that elevated preoperative CRP serum levels are associated with a less favorable prognosis in affected patients.
Prognosis of endometrial cancer is currently mainly determined by tumor stage, grade of differentiation and histologic subtype.26–28 Other nonsurgical or histologic markers are not yet in widespread use. With respect to serum tumor markers, assessment of CA 125 is so far the only more commonly used test in endometrial cancer before surgery and has been shown to be predictive for extrauterine spread.29 Measurement of CRP serum levels is a standard test in most clinical laboratories as a marker of inflammation. C-reactive protein serum levels are relatively easy and inexpensive to measure and would therefore be a good candidate to serve as an additional prognostic factor.
Compared with other gynecologic cancers, the overall prognosis for patients with endometrial cancer is relatively good, yielding a low number of events, because the disease is usually diagnosed clinically at an early stage. Therefore, we performed the present multicenter study and included a relatively high number of patients. In our series, CRP serum levels were associated with the length of disease-free and overall survival, whereas the clinically established prognostic factors tumor stage, tumor grade, and age at diagnosis were confirmed in the same analysis.
Our sample size is large, making our results statistically valid, because, in addition to CRP serum levels, all commonly accepted prognostic factors were found to be independently associated with survival. Although the majority of recurrences and subsequent cancer-related deaths occur within 36 months after primary treatment, the relatively short follow-up must be seen as a possible shortcoming of our study. A longer follow-up time might influence the predictive value of serum CRP levels in patients with endometrial cancer.
Of note, the aim of the present study was to analyze the association between serum CRP levels as continuous factor and survival. This study was not designed to determine a cutoff value of serum CRP levels to classify patients into prognostic categories. The usefulness of CRP serum levels as prognostic factor for endometrial cancer in patients with coexisting acute inflammatory conditions remains questionable. In the present study, an acute infection as a potential cofounder was ruled out before elective surgery by a physical examination and blood tests.
We provide interesting data on serum CRP levels in patients with endometrial cancer. Preoperative CRP serum levels are independently associated with survival in patients with surgically treated endometrial cancer. However, it would not be prudent to recommend the use of serum CRP levels as routine tumor marker in endometrial cancer at this point.
1. Kolb-Bachofen V. A review on the biological properties of C-reactive protein. Immunobiology 1991;183:133–45.
2. Jupe D. The acute phase response and laboratory testing. Aust Fam Physician 1996;25:324–9.
3. Castell JV, Gomez-Lechon MJ, David M, Fabra R, Trullenque R, Heinrich PC. Acute-phase response of human hepatocytes: regulation of acute-phase protein synthesis by interleukin-6. Hepatology 1990;12:1179–86.
4. Gewurz H. Biology of C-reactive protein and the acute phase response. Hosp Pract (Hosp Ed) 1982;17:67–81.
5. Ballou SP, Kushner I. C-reactive protein and the acute phase response. Adv Intern Med 1992;37:313–36.
6. Black S, Kushner I, Samols D. C-reactive protein. J Biol Chem 2004;279:48487–90.
7. Fleming JS, Beaugie CR, Haviv I, Chenevix-Trench G, Tan OL. Incessant ovulation, inflammation and epithelial ovarian carcinogenesis: revisiting old hypotheses. Mol Cell Endocrinol 2006;247:4–21.
8. Jaiswal M, LaRusso NF, Burgart LJ, Gores GJ. Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Res 2000;60:184–90.
9. Jackson JR, Seed MP, Kircher CH, Willoughby DA, Winkler JD. The codependence of angiogenesis and chronic inflammation. FASEB J 1997;11:457–65.
10. Elliott RL, Blobe GC. Role of transforming growth factor Beta in human cancer. J Clin Oncol 2005;23:2078–93.
11. Mangi MH, Newland AC. Interleukin-3 in hematology and oncology: current state of knowledge and future directions. Cytokines Cell Mol Ther 1999;5:87–95.
12. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001;357:539–45.
13. Deodhar SD. C-reactive protein: the best laboratory indicator available for monitoring disease activity. Cleve Clin J Med 1989;56:126–30.
14. Marnell L, Mold C, Du Clos TW. C-reactive protein: ligands, receptors and role in inflammation. Clin Immunol 2005;117:104–11.
15. De Mello J, Struthers L, Turner R, Cooper EH, Giles GR. Multivariate analyses as aids to diagnosis and assessment of prognosis in gastrointestinal cancer. Br J Cancer 1983;48:341–8.
16. Raynes JG, Cooper EH. Comparison of serum amyloid A protein and C-reactive protein concentrations in cancer and non-malignant disease. J Clin Pathol 1983;36:798–803.
17. McMillan DC, Wotherspoon HA, Fearon KC, Sturgeon C, Cooke TG, McArdle CS. A prospective study of tumor recurrence and the acute-phase response after apparently curative colorectal cancer surgery. Am J Surg 1995;170:319–22.
18. Nozoe T, Matsumata T, Kitamura M, Sugimachi K. Significance of preoperative elevation of serum C-reactive protein as an indicator for prognosis in colorectal cancer. Am J Surg 1998;176:335–8.
19. Nozoe T, Saeki H, Sugimachi K. Significance of preoperative elevation of serum C-reactive protein as an indicator of prognosis in esophageal carcinoma. Am J Surg 2001;182:197–201.
20. Gockel I, Dirksen K, Messow CM, Junginger T. Significance of preoperative C-reactive protein as a parameter of the perioperative course and long-term prognosis in squamous cell carcinoma and adenocarcinoma of the oesophagus. World J Gastroenterol 2006;12:3746–50.
21. Shimada H, Nabeya Y, Okazumi S, Matsubara H, Shiratori T, Aoki T, et al. Elevation of preoperative serum C-reactive protein level is related to poor prognosis in esophageal squamous cell carcinoma. J Surg Oncol 2003;83:248–52.
22. Hashimoto K, Ikeda Y, Korenaga D, Tanoue K, Hamatake M, Kawasaki K, et al. The impact of preoperative serum C-reactive protein on the prognosis of patients with hepatocellular carcinoma. Cancer 2005;103:1856–64.
23. Nielsen HJ, Christensen IJ, Sorensen S, Moesgaard F, Brunner N. Preoperative plasma plasminogen activator inhibitor type-1 and serum C-reactive protein levels in patients with colorectal cancer. The RANX05 Colorectal Cancer Study Group. Ann Surg Oncol 2000;7:617–23.
24. Kodama J, Miyagi Y, Seki N, Tokumo K, Yoshinouchi M, Kobashi Y, et al. Serum C-reactive protein as a prognostic factor in patients with epithelial ovarian cancer. Eur J Obstet Gynecol Reprod Biol 1999;82:107–10.
25. Otsuji S, Shibata H, Umeda M. Turbidimetric immunoassay of serum C-reactive protein. Clin Chem 1982;28:2121–4.
26. Creasman WT, Odicino F, Maisonneuve P, Beller U, Benedet JL, Heintz AP, et al. Carcinoma of the corpus uteri. J Epidemiol Biostat 2001;6:47–86.
27. Kodama S, Kase H, Tanaka K, Matsui K. Multivariate analysis of prognostic factors in patients with endometrial cancer. Int J Gynaecol Obstet 1996;53:23–30.
28. Morrow CP, Bundy BN, Kurman RJ, Creasman WT, Heller P, Homesley HD, et al. Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol 1991;40:55–65.
© 2007 The American College of Obstetricians and Gynecologists
29. Dotters DJ. Preoperative CA 125 in endometrial cancer: is it useful? Am J Obstet Gynecol 2000;182:1328–34.