Original Article Gynecol Obstet Invest 2015;79:25–33 DOI: 10.1159/000365477
Received: November 19, 2013 Accepted after revision: June 25, 2014 Published online: September 27, 2014
Prognostic Significance of Pretreatment Plasma Fibrinogen and Platelet Levels in Patients with Early-Stage Cervical Cancer Kelei Zhao a Huan Deng b Yan Qin c Wenjun Liao a Weijiang Liang a a c
Department of Oncology, Nanfang Hospital, b Department of Oncology, The Third Affiliated Hospital, and Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
Key Words Cervical cancer · Platelet · Fibrinogen · Prognosis factor
Abstract Background: Hyperfibrinogenaemia and thrombocytosis, which usually occur in cancer patients, have been shown to contribute to cancer cell growth, progression, and metastasis. The aims of the present study were to assess the prognostic significance of pretreatment plasma fibrinogen and platelet levels in early-stage cervical cancer patients. Methods: The present study was a retrospective analysis of 220 cervical cancer patients with stage I–IIA disease. The pretreatment plasma fibrinogen and platelet levels were investigated along with clinicopathological findings and survival data. Results: The incidences of hyperfibrinogenaemia and thrombocytosis were 11.8 and 25.5%, respectively. Elevated fibrinogen levels were associated with advanced tumour stage, older age, large tumour size, deep stromal invasion, and tumour recurrence, whereas higher platelet levels correlated significantly with advanced tumour stage, large tumour size, and tumour recurrence. Kaplan-Meier analysis showed that hyperfibrinogenaemia and thrombocytosis were significantly associated with shorter disease-free and overall survival. Furthermore, patients with hyperfibrinoge-
© 2014 S. Karger AG, Basel 0378–7346/14/0791–0025$39.50/0 E-Mail [email protected] www.karger.com/goi
naemia and thrombocytosis may suffer from a higher risk of recurrence. Multivariate survival analyses showed that fibrinogen levels, but not platelet levels, were an independent prognostic factor for poor survival in early-stage patients. Conclusion: Hyperfibrinogenaemia and thrombocytosis may be valuable biomarkers for predicting recurrence in patients with early-stage cervical cancer. © 2014 S. Karger AG, Basel
Introduction
Cervical cancer is the third most commonly diagnosed cancer and the fourth leading cause of cancer death in females worldwide. More than 85% of these cases and deaths occur in developing countries [1]. Conventionally, radical surgery has been the mainstay treatment of earlystage cervical cancer, yielding a relatively favourable prognosis [2]. However, patients who experience recurrence have a poor prognosis because there are few feasible treatment options [3]. Therefore, identifying the unique biological characteristics that can predict recurrence is very important, as this enables the development of an optimal treatment plan. To better predict recurrence, numerous tumour markers have been evaluated as potential Weijiang Liang, MD, PhD Department of Oncology, Nanfang Hospital Southern Medical University, 1838 North Guangzhou Ave Guangzhou 510515 (PR China) E-Mail wjliang2 @ sina.com
prognostic predictors, such as squamous cell carcinoma antigen, tissue polypeptide antigen, carcinoembryogenic antigen, cancer antigen-125, and cytokeratin fragment 21-1 [4]. Unfortunately, it is still difficult to estimate the recurrence risk and outcome in patients with early-stage cervical cancer. The cancer-related coagulopathy commonly referred to as Trousseau’s syndrome was first described as an association between cancer and venous thromboembolism by Armand Trousseau in 1865. Since then, the hypercoagulable state has been widely acknowledged as being associated with malignancy, with a 50% reported incidence in cancer patients [5, 6]. Fibrinogen and platelets, which are essential coagulation parameters during the coagulation cascade, are also closely linked to several pathophysiological processes, such as cell adhesion, inflammatory processes, and wound healing. In recent years, a substantial number of studies have supported the hypothesis that fibrinogen and platelets play vital roles in tumourigenesis, contributing to angiogenesis, stroma formation, and haematogenous metastasis of tumour cells [7–10]. In clinical studies, Polterauer et al. [11] demonstrated that the pretreatment plasma fibrinogen level was an independent prognostic parameter for stage I–IV cervical cancer. However, to our knowledge, few studies have reviewed the prognostic value of pretreatment fibrinogen levels in early-stage cervical cancer. Regarding the relationship between cervical cancer and platelets, there is insufficient evidence available to evaluate the correlation between thrombocytosis and survival in patients with stage I–II cancer [12]. Furthermore, several studies involving locally advanced cancer stages have reported contradictory results [12]. In the present study, we combined the plasma fibrinogen and platelet levels to investigate the correlations between the two coagulation parameters and clinicopathological parameters in cervical cancer. Furthermore, we attempted to answer the question of whether hyperfibrinogenaemia and thrombocytosis could serve as prognostic factors to guide treatment in early-stage cervical cancer.
Materials and Methods Patients This study was approved by the Nanfang Hospital Ethics Review Board. In the present study, 220 operable patients with invasive cervical cancer treated at the Department of Gynecologic Oncology (Nanfang Hospital, Guangzhou, PR China) from January 2004 to December 2009 were enrolled. All patients were newly
26
Gynecol Obstet Invest 2015;79:25–33 DOI: 10.1159/000365477
confirmed to have cervical cancer and had not previously received treatment. Patients with liver disease, blood coagulation disorders, preoperative chemotherapy or radiotherapy, or oral administration of anticoagulants or acetylsalicylic acids within 1 month before the treatment were excluded from our study. Clinical data were extracted from patient files. Blood samples were obtained by peripheral venous puncture 24–48 h prior to treatment. Fibrinogen plasma levels were determined by the Clauss method using a Sysmex CA-1500 automated coagulometer (Sysmex, Kobe, Japan) [13]. Plasma platelet levels were obtained by an automated complete blood count. The reference ranges for plasma fibrinogen and platelet levels were defined as 1.9–3.9 g/l and 100–300 × 109/l, respectively. Plasma fibrinogen and platelet levels higher than 3.9 g/l and 300 × 109/l indicated hyperfibrinogenaemia and thrombocytosis, respectively. Clinical Management All of the cases had been diagnosed as cervical cancer at Nanfang Hospital, and tumour staging was defined according to the International Federation of Gynecology and Obstetrics criteria (FIGO 2009). All patients underwent surgery. Patients with stage IA microinvasive cervical cancer were treated by simple hysterectomy. Stage IB1–IIA patients were managed by radical hysterectomy and pelvic lymphadenectomy. Through postoperative pathological examinations, we obtained the clinicopathological features of the patients. Patients were scheduled for the first follow-up visit 3 months after completion of the therapy. Patients were instructed to be reassessed every 3–6 months for the next 5 years and once a year thereafter. Once recurrence occurred, the time to recurrence would be recorded. At the conclusion of the study, the vital status was recorded for all patients. Disease-free survival was defined as the period from the date of radical surgery to the date of recurrence or censoring. Overall survival was calculated as the time from radical surgery to death or censoring. The results were analysed for the endpoints of disease-free and overall survival. The last followup was performed in April 2013, with a median observation period of 53 (6–111) months. Statistics Statistical analysis was performed using the SPSS 13.0 statistical software package. Values are presented as the means (±SD) where appropriate. The t test or one-way analysis of variance (ANOVA) was used to compare continuous variables and clinicopathological parameters. Categorical variables were compared using the χ2 test. The correlation between fibrinogen and platelet levels was determined through Pearson’s correlation coefficient analysis. Survival curves were plotted according to the KaplanMeier method, and differences between groups were tested using the log-rank test. Uni- and multivariate Cox regression models were used to assess disease-free and overall survival. In the univariate analysis, age (vs. ≤43), FIGO tumour stage (I vs. IA1 vs. IA2 vs. IIA1 vs. IIA2), histological grade (G1 vs. G2 vs. G3), histopathological type (vs. squamous carcinoma), depth of stromal invasion (vs. ≤8 mm), lymphatic metastasis (vs. positive), tumour size (vs. ≤4 cm), and plasma fibrinogen and platelet levels were included. All the statistically significant variables observed in the univariate analysis were included in the multivariate survival analysis. p values 43 Stage I II Pathology type Squamous carcinoma Other types Histologic grade G1 G2 G3 Depth of invasion ≤8 mm >8 mm Not evaluated Lymphatic metastasis Negative Positive Tumour size ≤4 cm >4 cm Recurrence No Yes
220
2.89±0.84
p
Mean platelet levels, /μl
p
262.0±74.4 0.039
121 (55.0) 99 (45.0)
2.79±0.78 3.02±0.90
148 (67.3) 72 (32.7)
2.63±0.60 3.44±0.98
211 (95.9) 9 (4.1)
2.85±0.76 3.73±1.72
44 (16.8) 144 (65.4) 32 (17.8)
2.67±0.58 2.93±0.81 3.03±1.15
104 (47.3) 90 (40.9) 26 (11.8)
2.70±0.63 3.12±0.93
191 (85.2) 33 (14.8)
2.89±0.82 3.04±0.98
173 (77.6) 50 (22.4)
2.73±0.70 3.46±1.01
156 (70.9) 64 (29.1)
2.74±0.70 3.26±1.02
0.579 259.5±81.3 265.1±65.3
Received: November 19, 2013 Accepted after revision: June 25, 2014 Published online: September 27, 2014
Prognostic Significance of Pretreatment Plasma Fibrinogen and Platelet Levels in Patients with Early-Stage Cervical Cancer Kelei Zhao a Huan Deng b Yan Qin c Wenjun Liao a Weijiang Liang a a c
Department of Oncology, Nanfang Hospital, b Department of Oncology, The Third Affiliated Hospital, and Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
Key Words Cervical cancer · Platelet · Fibrinogen · Prognosis factor
Abstract Background: Hyperfibrinogenaemia and thrombocytosis, which usually occur in cancer patients, have been shown to contribute to cancer cell growth, progression, and metastasis. The aims of the present study were to assess the prognostic significance of pretreatment plasma fibrinogen and platelet levels in early-stage cervical cancer patients. Methods: The present study was a retrospective analysis of 220 cervical cancer patients with stage I–IIA disease. The pretreatment plasma fibrinogen and platelet levels were investigated along with clinicopathological findings and survival data. Results: The incidences of hyperfibrinogenaemia and thrombocytosis were 11.8 and 25.5%, respectively. Elevated fibrinogen levels were associated with advanced tumour stage, older age, large tumour size, deep stromal invasion, and tumour recurrence, whereas higher platelet levels correlated significantly with advanced tumour stage, large tumour size, and tumour recurrence. Kaplan-Meier analysis showed that hyperfibrinogenaemia and thrombocytosis were significantly associated with shorter disease-free and overall survival. Furthermore, patients with hyperfibrinoge-
© 2014 S. Karger AG, Basel 0378–7346/14/0791–0025$39.50/0 E-Mail [email protected] www.karger.com/goi
naemia and thrombocytosis may suffer from a higher risk of recurrence. Multivariate survival analyses showed that fibrinogen levels, but not platelet levels, were an independent prognostic factor for poor survival in early-stage patients. Conclusion: Hyperfibrinogenaemia and thrombocytosis may be valuable biomarkers for predicting recurrence in patients with early-stage cervical cancer. © 2014 S. Karger AG, Basel
Introduction
Cervical cancer is the third most commonly diagnosed cancer and the fourth leading cause of cancer death in females worldwide. More than 85% of these cases and deaths occur in developing countries [1]. Conventionally, radical surgery has been the mainstay treatment of earlystage cervical cancer, yielding a relatively favourable prognosis [2]. However, patients who experience recurrence have a poor prognosis because there are few feasible treatment options [3]. Therefore, identifying the unique biological characteristics that can predict recurrence is very important, as this enables the development of an optimal treatment plan. To better predict recurrence, numerous tumour markers have been evaluated as potential Weijiang Liang, MD, PhD Department of Oncology, Nanfang Hospital Southern Medical University, 1838 North Guangzhou Ave Guangzhou 510515 (PR China) E-Mail wjliang2 @ sina.com
prognostic predictors, such as squamous cell carcinoma antigen, tissue polypeptide antigen, carcinoembryogenic antigen, cancer antigen-125, and cytokeratin fragment 21-1 [4]. Unfortunately, it is still difficult to estimate the recurrence risk and outcome in patients with early-stage cervical cancer. The cancer-related coagulopathy commonly referred to as Trousseau’s syndrome was first described as an association between cancer and venous thromboembolism by Armand Trousseau in 1865. Since then, the hypercoagulable state has been widely acknowledged as being associated with malignancy, with a 50% reported incidence in cancer patients [5, 6]. Fibrinogen and platelets, which are essential coagulation parameters during the coagulation cascade, are also closely linked to several pathophysiological processes, such as cell adhesion, inflammatory processes, and wound healing. In recent years, a substantial number of studies have supported the hypothesis that fibrinogen and platelets play vital roles in tumourigenesis, contributing to angiogenesis, stroma formation, and haematogenous metastasis of tumour cells [7–10]. In clinical studies, Polterauer et al. [11] demonstrated that the pretreatment plasma fibrinogen level was an independent prognostic parameter for stage I–IV cervical cancer. However, to our knowledge, few studies have reviewed the prognostic value of pretreatment fibrinogen levels in early-stage cervical cancer. Regarding the relationship between cervical cancer and platelets, there is insufficient evidence available to evaluate the correlation between thrombocytosis and survival in patients with stage I–II cancer [12]. Furthermore, several studies involving locally advanced cancer stages have reported contradictory results [12]. In the present study, we combined the plasma fibrinogen and platelet levels to investigate the correlations between the two coagulation parameters and clinicopathological parameters in cervical cancer. Furthermore, we attempted to answer the question of whether hyperfibrinogenaemia and thrombocytosis could serve as prognostic factors to guide treatment in early-stage cervical cancer.
Materials and Methods Patients This study was approved by the Nanfang Hospital Ethics Review Board. In the present study, 220 operable patients with invasive cervical cancer treated at the Department of Gynecologic Oncology (Nanfang Hospital, Guangzhou, PR China) from January 2004 to December 2009 were enrolled. All patients were newly
26
Gynecol Obstet Invest 2015;79:25–33 DOI: 10.1159/000365477
confirmed to have cervical cancer and had not previously received treatment. Patients with liver disease, blood coagulation disorders, preoperative chemotherapy or radiotherapy, or oral administration of anticoagulants or acetylsalicylic acids within 1 month before the treatment were excluded from our study. Clinical data were extracted from patient files. Blood samples were obtained by peripheral venous puncture 24–48 h prior to treatment. Fibrinogen plasma levels were determined by the Clauss method using a Sysmex CA-1500 automated coagulometer (Sysmex, Kobe, Japan) [13]. Plasma platelet levels were obtained by an automated complete blood count. The reference ranges for plasma fibrinogen and platelet levels were defined as 1.9–3.9 g/l and 100–300 × 109/l, respectively. Plasma fibrinogen and platelet levels higher than 3.9 g/l and 300 × 109/l indicated hyperfibrinogenaemia and thrombocytosis, respectively. Clinical Management All of the cases had been diagnosed as cervical cancer at Nanfang Hospital, and tumour staging was defined according to the International Federation of Gynecology and Obstetrics criteria (FIGO 2009). All patients underwent surgery. Patients with stage IA microinvasive cervical cancer were treated by simple hysterectomy. Stage IB1–IIA patients were managed by radical hysterectomy and pelvic lymphadenectomy. Through postoperative pathological examinations, we obtained the clinicopathological features of the patients. Patients were scheduled for the first follow-up visit 3 months after completion of the therapy. Patients were instructed to be reassessed every 3–6 months for the next 5 years and once a year thereafter. Once recurrence occurred, the time to recurrence would be recorded. At the conclusion of the study, the vital status was recorded for all patients. Disease-free survival was defined as the period from the date of radical surgery to the date of recurrence or censoring. Overall survival was calculated as the time from radical surgery to death or censoring. The results were analysed for the endpoints of disease-free and overall survival. The last followup was performed in April 2013, with a median observation period of 53 (6–111) months. Statistics Statistical analysis was performed using the SPSS 13.0 statistical software package. Values are presented as the means (±SD) where appropriate. The t test or one-way analysis of variance (ANOVA) was used to compare continuous variables and clinicopathological parameters. Categorical variables were compared using the χ2 test. The correlation between fibrinogen and platelet levels was determined through Pearson’s correlation coefficient analysis. Survival curves were plotted according to the KaplanMeier method, and differences between groups were tested using the log-rank test. Uni- and multivariate Cox regression models were used to assess disease-free and overall survival. In the univariate analysis, age (vs. ≤43), FIGO tumour stage (I vs. IA1 vs. IA2 vs. IIA1 vs. IIA2), histological grade (G1 vs. G2 vs. G3), histopathological type (vs. squamous carcinoma), depth of stromal invasion (vs. ≤8 mm), lymphatic metastasis (vs. positive), tumour size (vs. ≤4 cm), and plasma fibrinogen and platelet levels were included. All the statistically significant variables observed in the univariate analysis were included in the multivariate survival analysis. p values 43 Stage I II Pathology type Squamous carcinoma Other types Histologic grade G1 G2 G3 Depth of invasion ≤8 mm >8 mm Not evaluated Lymphatic metastasis Negative Positive Tumour size ≤4 cm >4 cm Recurrence No Yes
220
2.89±0.84
p
Mean platelet levels, /μl
p
262.0±74.4 0.039
121 (55.0) 99 (45.0)
2.79±0.78 3.02±0.90
148 (67.3) 72 (32.7)
2.63±0.60 3.44±0.98
211 (95.9) 9 (4.1)
2.85±0.76 3.73±1.72
44 (16.8) 144 (65.4) 32 (17.8)
2.67±0.58 2.93±0.81 3.03±1.15
104 (47.3) 90 (40.9) 26 (11.8)
2.70±0.63 3.12±0.93
191 (85.2) 33 (14.8)
2.89±0.82 3.04±0.98
173 (77.6) 50 (22.4)
2.73±0.70 3.46±1.01
156 (70.9) 64 (29.1)
2.74±0.70 3.26±1.02
0.579 259.5±81.3 265.1±65.3
