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Annals of Surgical Oncology 10:355-362 (2003)
© 2003 Society of Surgical Oncology

ORIGINAL ARTICLES

Prognostic Significance of Vascular Endothelial Growth Factor, Basic Fibroblast Growth Factor, and Angiogenin in Patients With Resectable Hepatocellular Carcinoma After Surgery

Yee Chao, MD, PhD, Chung-Ping Li, MD, Gar-Yang Chau, MD, Chih-Ping Chen, MD, Kuang-Liang King, MD, Wing-Yiu Lui, MD, PhD, Sang-Hue Yen, MD, Full-Young Chang, MD, Wing-Kai Chan, MD and Shou-Dong Lee, MD

From the Cancer Center (YC, S-HY, W-KC), Division of Gastroenterology (C-PL, C-PC, F-YC, S-DL), Department of Medicine, and Division of General Surgery (G-YC, K-LK, W-YL), Department of Surgery, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Correspondence: Address correspondence and reprint requests to: Yee Chao, MD, PhD, Cancer Center, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, 112, Taiwan; Fax: 88-62-28-74-9425; E-mail: ychao{at}vghtpe.gov.tw


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Hepatocellular carcinoma (HCC) is a hypervascular malignancy. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiogenin (ANG) are important angiogenic factors of neoangiogenesis. This study investigated the predictive value of serum VEGF, bFGF, and ANG in tumor recurrence, disease-free survival (DFS), and overall survival (OS) in HCC patients.

Methods: Preoperative serum VEGF, bFGF, and ANG were measured in 98 patients with resectable HCC and in 15 healthy controls. The median follow-up time was 43 months.

Results: Preoperative serum VEGF was increased in patients with resectable HCC compared with healthy controls (P < .05). Increased serum VEGF was correlated with tumor recurrence (P = .001). Univariate analysis showed that serum VEGF, tumor-node-metastasis stage, tumor size and number, macroscopic portal vein invasion, and microscopic vascular invasion were correlated with OS and DFS. Serum bFGF and ANG were not associated with survival. Multivariate analysis showed that serum VEGF was the most significant predictor of DFS (relative risk, 2.35; 95% confidence interval, 1.26–4.39; P = .007) and OS (relative risk, 3.44; 95% confidence interval, 1.81–6.57; P < .001) in HCC patients after surgical resection.

Conclusions: Preoperative serum VEGF is a significant independent predictor of tumor recurrence, DFS, and OS in patients with resectable HCC.

Key Words: Angiogenin • Basic fibroblast growth factor • Hepatocellular carcinoma • Vascular endothelial growth factor


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, with an incidence of approximately 1 million new cases annually.1 HCC is characterized by intrahepatic spread, recurrence, and systemic metastasis, and the prognosis of advanced HCC remains poor.1,2 Surgery is the potentially curative treatment for patients with resectable HCC. The long-term survival results of surgery are still unsatisfactory because of frequent tumor recurrence after resection.3–7 Identification of a biological marker of HCC recurrence and metastasis may help to improve the management of HCC. It may also provide new avenues for rational drug design against specific molecular targets for HCC therapy. The search for a serum biological marker of tumor invasiveness and prognosis in HCC is of clinical importance, because no such marker is currently available. Preoperative serum alfa-fetoprotein is not predictive of the recurrence of HCC.8

HCC is a hypervascular tumor.9 Tumor angiogenesis may be essential for HCC growth, invasion, or metastasis. Tumor expressions of vascular endothelial growth factor (VEGF) are upregulated in HCC.8,10–20 Increased tumor expressions of VEGF may be associated with adverse clinicopathologic features in HCC patients.8,10,12,14,17–19,21,22 The clinical significance of other angiogenic factors in HCC is uncertain. Data regarding tumor expression of basic fibroblast growth factor (bFGF) or angiogenin (ANG) in HCC are limited.12

Increased plasma VEGF has been reported in HCC patients with metastasis.23 High serum VEGF was related to portal vein emboli, poorly encapsulated tumors,24 microscopic venous invasion, and recurrence in HCC patients.25 However, the prognostic value of circulating VEGF in the disease-free survival (DFS) and overall survival (OS) in HCC patients is uncertain. The survival significance of circulating bFGF in HCC patients is uncertain because of limited data. The clinical significance of ANG in HCC patients is unknown. The aim of this study was to evaluate the predictive value of preoperative serum VEGF, bFGF, and ANG in the DFS and OS of 98 patients with resectable HCC who received curative resection.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Preoperative serum VEGF, bFGF, and ANG were measured in 98 unselected consecutive patients diagnosed with resectable HCC who received curative resection at the Department of Surgery, Taipei Veterans General Hospital, from June 1994 to June 1998 and for whom frozen serum taken at the time of diagnosis and before cancer treatment was available. The criteria for resectability were absence of metastasis, no portal vein thrombosis, anatomically resectable disease, and adequate liver function reserve. Curative resection was defined as macroscopic complete removal of the tumor; this was performed by one experienced surgical team in our institution. No patient received any neoadjuvant or adjuvant treatment. The study was approved by the hospital ethics committee. Informed consent was obtained from all participants. In addition, this study conformed to the provisions of the World Medical Association Declaration of Helsinki.

Staging of patients was performed according to the American Joint Committee on Cancer. Pathologic findings of tumor size, number, grade, and encapsulation; microscopic vascular invasion; and macroscopic portal vein invasion were studied. Patients were followed up every 3 months regarding tumor recurrence and survival. Clinical examination, complete blood count, serum biochemistry, alfa-fetoprotein, chest x-ray, and abdominal sonogram and/or computed tomographic scan were performed. Serum samples from 15 healthy volunteers with informed consent were used as controls.

Analyses of Serum Angiogenic Factors
All serum samples were centrifuged at 2000 x g for 15 minutes at 4°C and stored at -80°C until tested in December 2000. Serum VEGF, bFGF, and ANG concentrations were measured by using commercially available enzyme-linked immunoabsorbent assay kits (R&D Systems Inc., Minneapolis, MN) according to the manufacturer’s instructions. Standard curves were constructed by using serial dilutions of recombinant VEGF, bFGF, and ANG. Optical densities were determined by using a microtiter plate reader (Bio-Kinetics Reader; Bio-Tek Instruments, Winooski, VT). Tests were performed in duplicate. The intra- and interassay variations of these assays were <10%.

Statistical Methods
Unpaired Student’s t-tests or one-way analysis of variance was used to analyze serum levels of VEGF, bFGF, and ANG between groups. Pearson’s correlation coefficient was used to determine the relationship between numerical variables, such as VEGF and platelet count. Cutoff values were determined for each serum angiogenic factor according to the best discrimination between patients with or without tumor recurrence regarding optimal values of sensitivity and specificity by using the receiver operating characteristic curve analysis. Survival was estimated with the Kaplan-Meier method and was compared by use of the log-rank test. The relative influence of different variables on survival was evaluated by multivariate analysis with Cox’s proportional hazards model after VEGF levels of platelet count were standardized. Logistic regression was used to assess the relationship of independent variables to the microscopic vascular invasion after VEGF levels of platelet count were standardized. Statistical analyses were performed with the SPSS software (SPSS, Inc., Chicago, IL). Results were considered statistically significant at P < .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Characteristics of 98 patients with resectable HCC who received curative surgical resection are listed in Table 1. The median follow-up time was 43 months (range, 24–72 months).


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  		TABLE 1. Patient characteristics
 
Serum Angiogenic Factors in Patients With Resectable HCC
Serum VEGF, bFGF, and ANG results in patients with resectable HCC are listed in Table 2. Serum VEGF was increased in patients with resectable HCC compared with healthy controls (P < .05).


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  		TABLE 2. Serum levels of VEGF, bFGF, and ANG
 
Serum Angiogenic Factors and Clinicopathologic Features
Serum VEGF, bFGF, and ANG results and clinicopathologic features in 98 patients with resectable HCC are listed in Table 1. Serum VEGF levels were significantly correlated with the platelet count (r= .68; P < .001).

Serum Angiogenic Factors and Tumor Recurrence After Resection
Serum VEGF was increased in 61 HCC patients with tumor recurrence compared with 37 patients without recurrence (242 ± 29 pg/mL vs. 125 ± 14 pg/mL; P = .001). Serum VEGF was also higher in 37 patients with early HCC recurrence (within 1 year of resection) compared with 24 patients with recurrence after 1 year of resection (295 ± 43 pg/mL vs. 163 ± 29 pg/mL; P = .014). Serum bFGF was 7.8 ± 1.3 pg/mL versus 9.4 ± 3.2 pg/mL (P = .57) and ANG was 252 ± 12 ng/mL versus 237 ± 9 ng/mL (P = .3) in patients with or without HCC recurrence, respectively.

Univariate Analysis of Serum Angiogenic Factors and Survival
Univariate analysis of factors correlated with DFS and OS in patients with resectable HCC by using Cox’s proportional hazards model is shown in Table 3. The cutoff values of 203 pg/mL for VEGF, 2.1 pg/mL for bFGF, and 273 ng/mL for ANG obtained by the receiver operating characteristic curve analysis were used in the univariate analysis. Serum VEGF, pathologic tumor-node-metastasis stage, tumor size and number, macroscopic portal vein invasion, and microscopic vascular invasion were associated with DFS and OS. Serum bFGF and ANG were not associated with DFS or OS.


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  		TABLE 3. Univariate analysis of prognostic factors
 
Serum VEGF was strongly correlated with the DFS (P = .0005) and OS (P < .0001) of patients with resectable HCC, as shown in Figs. 1 and 2. The predictive values of serum VEGF for OS were the following: sensitivity, 49%; specificity, 84%; positive predictive value, 78%; and negative predictive value, 58%.



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  		FIG. 1. Disease-free survival curve. Disease-free survival for patients with resectable hepatocellular carcinoma with higher serum vascular endothelial growth factor (VEGF) levels (VEGF >=203 pg/mL; ) is significantly poorer than for those with lower serum VEGF levels (VEGF <203 pg/mL; ).

 


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  		FIG. 2. Overall survival curve. Overall survival for patients with resectable hepatocellular carcinoma with higher serum vascular endothelial growth factor (VEGF) levels (VEGF >=203 pg/mL; ) is significantly poorer than for those with lower serum VEGF levels (VEGF <203 pg/mL; ).

 
Multivariate Analysis of Serum Angiogenic Factors and Survival
Multivariate analysis with Cox’s proportional hazards model showed that serum VEGF was the most independent predictive factor of DFS (P = .007) or OS (P < .001) in patients with resectable HCC, as shown in Table 4.


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  		TABLE 4. Multivariate analysis of prognostic factors of disease-free survival and overall survival
 
Serum Angiogenic Factors and Microscopic Vascular Invasion
Univariate logistic regression showed that increased serum VEGF was associated with microscopic vascular invasion (relative risk, 4.8; 95% confidence interval, 1.65–13.98; P = .004). Serum bFGF (P = .9) and ANG (P = .22) were not associated with microscopic vascular invasion. Multivariate logistic regression after adjusting for the platelet count showed that serum VEGF was the only significant independent predictor of microscopic vascular invasion (relative risk, 4.1; 95% confidence interval, 1.11–14.93; P = .03).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, we evaluated the preoperative serum concentration and the prognostic significance of a panel of angiogenic factors in patients with resectable HCC. We found significantly increased serum levels of VEGF and bFGF and reduced ANG in HCC patients compared with healthy controls. Increased serum VEGF was correlated with tumor recurrence and decreased DFS and OS. Multivariate analysis indicated that preoperative serum VEGF was the most significant independent predictor of microscopic vascular invasion, tumor recurrence, DFS, and OS in HCC patients after surgical resection. Serum bFGF or ANG was not associated with survival in HCC patients.

Increased plasma VEGF has been reported in patients with metastatic HCC.23 High serum VEGF was associated with portal vein emboli, poorly encapsulated tumors,24 microscopic venous invasion, and recurrence in HCC patients.25 Serum VEGF may be a biomarker of invasive tumor, recurrence, or metastasis, but the correlation with survival in HCC patients is uncertain. This is the first study that demonstrates that preoperative serum VEGF level is the most significant independent predictor of tumor recurrence, DFS, and OS in patients with resectable HCC. Thus, in comparison with standard clinicopathologic predictors of outcome in HCC3–7—such as tumor-node-metastasis stage; tumor size, number, and encapsulation; microscopic venous invasion; or macroscopic portal vein invasion—preoperative serum VEGF may be the best predictor of outcome in HCC patients. If the prognostic value of serum VEGF in HCC is confirmed by future studies, it may have important clinical implications.

Surgery is the potentially curative treatment for patients with HCC. The long-term survival results of surgery are still not satisfactory because of frequent tumor recurrence after resection.3–7 The use of preoperative serum VEGF before surgical resection may help the selection of HCC patients with a high risk of recurrence for more aggressive therapy or investigational therapy. Wider surgical margins may be associated with increased DFS after surgical resection of HCC.26 Neoadjuvant or adjuvant therapy as investigational treatment may be considered. Previously, reliable information about the prediction of prognosis might not be available until after histopathology of the resected specimen. The advantages of serum VEGF as a prognostic marker in HCC are that it can be performed in all HCC patients without surgical or biopsy materials and can be repeated serially. The enzyme-linked immunosorbent assay method commonly used is quantitative and precise and seems to be reliable and reproducible.

Liver transplantation has been accepted as curative treatment for patients with small HCC, but the presence of microscopic venous invasion is associated with unfavorable outcomes.27–29 The results of this study show that preoperative serum VEGF is also predictive of microscopic venous invasion in HCC. It has been suggested that the use of molecular markers may assist in the selection of patients with HCC for liver transplantation.29 Preoperative serum VEGF may be a candidate for such a biological marker.25

HCC is a highly vascular tumor. If serum VEGF is predictive of outcome in HCC patients, it may be reasonable to speculate that angiogenesis may be important in the pathogenesis or potential therapy of HCC. Tumor expressions of VEGF are upregulated in HCC patients.8,10–20 Increased tumor expressions of VEGF8,10,12,14,17–19,21,22 or increased circulating VEGF23–25 may be associated with increased vascularity and adverse clinicopathologic features in HCC patients. Antiangiogenic agents were reported to suppress the growth of metastasis of HCC in animals30,31 and in humans.32

A large number and great diversity of antiangiogenic agents are being evaluated in current phase I, II, and III clinical trials, with some encouraging results.33,34 Most antiangiogenic agents are cytostatic. Theoretically, antiangiogenic drugs are more likely to work best in adjuvant settings rather than with end-stage bulky disease, and DFS or OS end points may be better than tumor-response end points.33,34 HCC patients after curative surgical resection may represent the best adjuvant settings for antiangiogenic agents. In the future, effective antiangiogenic agents may be available for therapy of cancer patients. Preoperative serum VEGF may allow the selection of HCC patients with high angiogenic activity and high risk of early recurrence for neoadjuvant and/or adjuvant antiangiogenic therapies. Whether anti-VEGF agents should be the choice of antiangiogenic drugs for HCC therapy awaits future investigations.

Although evidence of circulating VEGF as a prognostic marker in cancer patients is strong, serum VEGF as a potential surrogate marker of angiogenic activity in cancer patients is regarded as uncertain. There are not yet any accepted reliable potential surrogate markers of angiogenic activity in cancer patients.33 Serum VEGF as a potential surrogate marker of angiogenic activity in HCC patients needs further investigation. This may have important clinical implications regarding the potential use of serum VEGF to predict or monitor the response to antiangiogenic therapy for HCC patients in the future.

The data from this study and another report23,25 showed that the lower range of circulating VEGF levels of early-stage HCC patients overlapped considerably with those of normal controls and patients with chronic hepatitis or cirrhosis. Therefore, serum VEGF may not be useful for early cancer detection in HCC or for diagnosis of HCC. The potential role of serial serum VEGF monitoring of HCC patients after surgical resection to detect early recurrence is important and is currently being investigated.

Hepatitis B or C virus infection was not correlated with VEGF levels of HCC in our study. This is in accordance with previous reports.35 Hepatitis B or C virus was not an independent predictor of DFS or OS of HCC patients in this study. This is in agreement with reports from Hwang et al.36 and Fong et al.37 However, others reported that hepatitis C is a strong independent predictor of survival for HCC patients.38 Whether hepatitis serology is an independent predictor of survival for HCC patients remains controversial.

A positive correlation was also found between the serum VEGF level and the platelet count. This result is in accordance with findings reported by others.23,25,39 The storage and release of VEGF by circulating platelets may have an important role in tumor invasion.40 Fast-growing tumors may release thrombopoietic cytokines in addition to angiogenic factors, such as VEGF.39 Although there was a positive correlation between the serum VEGF level and the platelet count, there was no significant association between platelet count and DFS and OS in this study. Serum VEGF level was an independent predictor of survival.

The release of bFGF from tumor cells has been demonstrated to be associated with an angiogenic switch in cancer development.41 In addition, bFGF acts synergistically with VEGF.42 Although serum bFGF was increased in HCC patients compared with controls in this study and in two other reports,43,44 the results of this study showed that serum bFGF has no prognostic significance in the DFS or OS of HCC patients. A recent report also indicated that serum bFGF did not have prognostic significance independently of tumor stage in the DFS of HCC patients.45

ANG is another potent angiogenic factor found to be expressed in tumor cells.46 To the best of our knowledge, no clinical study of circulating ANG has been performed in HCC patients. Results from this study indicate that serum ANG was decreased and has no prognostic significance in the survival of HCC patients. These results are consistent with the report that tumor ANG gene expressions were not detectable in four human HCCs and that ANG may not play a major role in the tumor angiogenesis of HCC.46


   Acknowledgments
 
The authors appreciate Rei-Hwa Lu’s laboratory and Pui-Ching Lee’s statistical assistance. Supported by Grant 90-422 from the Taipei Veterans General Hospital.

The acknowledgments are available online at www.annalssurgicaloncology.org.


   Footnotes
 
Preoperative serum vascular endothelial growth factor (VEGF) was increased in patients with resectable hepatocellular carcinoma (HCC). Preoperative serum VEGF is a significant independent predictor of tumor recurrence, disease-free survival, and overall survival in HCC patients after surgical resection.

Received for publication October 1, 2002. Accepted for publication December 20, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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A. X. Zhu, C. S. Fuchs, J. W. Clark, A. Muzikansky, K. Taylor, S. Sheehan, K. Tam, E. Yung, M. H. Kulke, and D. P. Ryan
A Phase II Study of Epirubicin and Thalidomide in Unresectable or Metastatic Hepatocellular Carcinoma
Oncologist, June 1, 2005; 10(6): 392 - 398.
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 RadiologyHome page
P. V. Pandharipande, G. A. Krinsky, H. Rusinek, and V. S. Lee
Perfusion Imaging of the Liver: Current Challenges and Future Goals
Radiology, March 1, 2005; 234(3): 661 - 673.
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P. P. Claudio, G. Russo, C. A. C. Y. Kumar, C. Minimo, A. Farina, S. Tutton, G. Nuzzo, F. Giuliante, G. Angeloni, V. Maria, et al.
pRb2/p130, Vascular Endothelial Growth Factor, p27(KIP1), and Proliferating Cell Nuclear Antigen Expression in Hepatocellular Carcinoma: Their Clinical Significance
Clin. Cancer Res., May 15, 2004; 10(10): 3509 - 3517.
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 JCOHome page
J.-N. Vauthey and J. A. Ajani
Liver Transplantation and Hepatocellular Carcinoma Biology: Beginning of the End of the Era of Educated Guesses
J. Clin. Oncol., December 1, 2003; 21(23): 4265 - 4267.
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S. Ferrero and N. Ragni
Prognostic Value of Plasma and Serum VEGF Levels in Patients With Resectable Hepatocellular Carcinoma
Ann. Surg. Oncol., November 1, 2003; 10(9): 1123 - 1123.
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