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Obstetrics & Gynecology 2000;96:721-726
© 2000 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Vascular Endothelial Growth Factor and Prognosis of Cervical Carcinoma

WEN-FANG CHENG, MD, PhD, CHI-AN CHEN, MD, CHIEN-NAN LEE, MD, LIN-HUNG WEI, MD, FON-JOU HSIEH, MD and CHANG-YAO HSIEH, MD, MSPH

From the Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan

Address reprint requests to: Chang-Yao Hsieh, MD, MSPH National Taiwan University Hospital Department of Obstetrics and Gynecology No. 7, Chung-Shan South Road Taipei Taiwan, Republic of China E-mail: cyhsieh{at}ha.mc.ntu.edu.tw


   Abstract
Top
Abstract
Patients and Methods
 Results
 Discussion
 References
 
Objective: To evaluate vascular endothelial growth factor (VEGF) as a marker for predicting lymph node metastasis and an independent prognostic factor of early-stage cervical carcinoma.

Methods: One hundred thirty-five women with stage IB–IIA cervical carcinoma had radical abdominal hysterectomies and pelvic lymph node dissections. Intratumoral cytosol VEGF concentrations were assayed with enzyme immunoassay. Histopathologic items and cytosol VEGF-influencing clinical outcomes were compared.

Results: Twenty-two women (16.3%) who had disease recurrence had higher levels of cytosol VEGF (1020 versus 112 pg/mg protein, P < .001) than those without recurrence. Using a cutoff value of 400 pg/mg protein resulted in best sensitivity of 75%, best specificity of 70%, positive predictive value of 41%, and negative predictive value of 92%. Only overexpressed cytosol VEGF (hazard ratio 6.44, P < .001) was an independent prognostic factor of disease-free survival. The overexpressed cytosol VEGF (hazard ratio 4.50, P = .021) and positive lymphovascular emboli (hazard ratio 4.11, P = .045) were independent prognostic factor of overall survival.

Conclusion: Cytosol VEGF might be a biomarker for the status of pelvic lymph nodes in early-stage cervical carcinoma and an independent prognostic indicator of its outcome.

Although cervical cancer rates have declined significantly in Western countries during the past several decades, it remains one of the most common forms of cancer in women in developing countries.1,2 With receding incidence of invasive cervical cancer is the frequent diagnosis of the disease in its early stages.3 Most women are first seen with stage I disease, implying favorable outcomes. Tumor size, depth of stromal invasion, lymphovascular emboli, parametrial invasion, and pelvic lymph node metastasis are prognostic factors of early-stage cervical cancer.4–7

Radical hysterectomy with pelvic lymphadenectomy is used frequently to treat stage IB and IIA cervical cancer.8 The knowledge of pelvic lymph node metastasis is crucial for treatment planning. Five-year survival is 70–90% in patients without lymph node involvement and decreases to 40–60% with metastasis.9,10 Hence, women with positive pelvic lymph nodes are considered at risk of recurrence and are treated more aggressively.11 Nodal status does not fully account for clinical outcomes, in fact 10–15% of women without pelvic lymph node involvement have tumor recurrence, and approximately half with involvement are cured of disease after adjuvant radiotherapy.12 More accurate prognostic parameters that correlate with outcome allow for the improved understanding of the biologic behavior of the tumor, and could help define a subgroup of women at risk of recurrence, which makes it possible to individualize treatment.

The growth of solid tumors and their metastatic spread were believed to be angiogenesis-dependent, as confirmed by several studies.13,14 Vascular endothelial growth factor (VEGF), which induces growth of a capillary network around a tumor and acts as a highly specific mitogen on endothelial cells, is an important factor in tumor angiogenesis.15 It was associated with disease-free and overall survivals in ovarian cancer.16 We evaluated the correlation between VEGF, microvessel density, and clinicopathologic parameters in cervical cancer,17 however, the quantitation of VEGF and its correlation with disease-free and overall survival rates are still unclear in cervical carcinoma.

The purposes of this study were 1) to determine if intratumoral cytosol VEGF could be a marker for predicting pelvic lymph node metastasis, and 2) to evaluate whether intratumoral cytosol VEGF is important in outcomes of early stage cervical carcinoma.


   Patients and Methods
Top
Abstract
 Patients and Methods
Results
 Discussion
 References
 
From January 1994 to June 1999, 135 subjects were enrolled with stage Ib-IIa cervical carcinoma who had radical abdominal hysterectomies and pelvic lymph node dissections. Women treated with conization, radiotherapy, or chemotherapy before surgery were excluded. The operation method used was the standard type III Wertheim hysterectomy, plus dissection of common iliac and pelvic lymph nodes en bloc. Clinicopathologic characteristics such as demographics, stage, tumor size, histologic type, depth of cervical stromal invasion, parametrial involvement, lymphovascular emboli, and status of pelvic lymph nodes were also recorded. Fifty of the 135 patients received postoperative adjuvant radiotherapy because of one or more risk factors such as lymph node metastasis, parametrial invasion, section margin involvement, full thickness of stromal invasion, lymphovascular emboli, or bulky tumors of 4 cm or greater. Irradiation was with a standard portal of the whole pelvis and anterior-posterior—posterior-anterior portals. The total radiation doses were 40 Gy to the pelvis and low para-aortic lymph node area in 20 fractions, plus a 10-Gy booster dose in four fractions to bilateral parametrial regions, and 20-Gy intracavitary radiotherapy with vaginal mold in two fractions. No extended field radiation was applied.

Periodic examinations during follow-up comprised history-taking, pelvic and rectal examinations, and lymph node palpation every 3 months for 2 years, and every 6 months thereafter. A Papanicolaou smear of the vaginal cuff was done at each visit. A chest X-ray was taken at 6-month intervals for 2 years, and yearly thereafter. Tumor markers including squamous cell carcinoma-associated antigen, and carcinoma antigen 125 were checked every 3 months for 2 years, and every 6 months thereafter. A complete blood count and biochemistry profile were done annually. Computerized tomography (CT) was done when recurrence was suspected. Abnormal results of CT scan, aspiration cytology from ascites, or tissue proved from biopsy, if possible, were defined as recurrence. Disease-free survival was measured as the period from operation to the date of confirmed recurrence, or the date of investigators’ last contact with disease-free women.

Part of each tissue specimen was collected during surgery, immediately frozen in liquid nitrogen, and stored at -70C until analyzed. The remaining tissue specimens were sent for pathologic examination. Cancer tissue preparation was done as reported.17,18 Tissue samples were thawed on ice and placed in 10 vol of ice-cold cell lysis buffer and homogenized. The lysate was centrifuged and the supernatant recovered and stored at -70C until analysis. Total protein in the prepared supernatant was measured by protein assay (Bio-Rad, Hercules, CA), and VEGF levels of the extract were determined by enzyme immunoassay with a commercially available kit (Quantikine Human VEGF Immunoassay; R&D Systems, Minneapolis, MN). Measurement of total protein and VEGF in the extract was duplicated and the average value of each sample recorded as pg/mg protein.

Statistical analyses were done with Statistical Package of Social Studies 6.0 (SPSS Inc., Chicago, IL) for Windows, which involved Student t test, {chi}2 test, one-way analysis of variance, Fisher exact test, Mann-Whitney U test, and the Kruskal-Wallis test. Patterns of disease-free survival were estimated by Kaplan-Meier product-limit survival curves. Cytosol VEGF concentrations were assessed as both continuous and categorical variables. Because of the skewed distribution of cytosol VEGF values, the 75% quantile was defined as the cutoff level. The effect of each prognostic variable on disease-free and overall survival was analyzed by the Cox regression model. P < .05 was considered statistically significant.


   Results
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Abstract
 Patients and Methods
 Results
Discussion
 References
 
Patients’ ages ranged from 29–71 years with a mean age of 50.6 years. Sixty-four (47.4%) were postmenopausal. One hundred twenty-two (90.4%) had stage IB and 13 (9.6%) had stage IIA cervical cancer. Pathologic examination showed 103 (76.3%) squamous cell carcinomas, 25 (18.5%) adenocarcinomas, five (3.7%) adenosquamous cell carcinomas, and two (1.5%) small cell carcinomas. Pelvic lymph node metastases were found in 28 of the 135 women (20.7%). Tumor size ranged from 0.3–6.0 cm (mean 2.6). Fifty women (37.3%) received postoperative adjuvant radiotherapy. The cytosol VEGF concentration ranged from 0–3050 pg/mg (median 154.0). Disease-free intervals of recurrence were from 2–41 months (median 12.5) and nonrecurrence from 12–70 months (median 23).

There were 22 women (16.3%) with delayed disease recurrence. Demographic characteristics between recurrent and nonrecurrent groups are listed in Table 1Go, with no significant differences between groups. Women with recurrence had a higher median cytosol VEGF protein level (1020 versus 112 pg/mg protein, P < .001) compared with those without. As listed in Table 2Go, significantly higher median cytosol VEGF concentrations were noted in tumors larger than 4 cm (775.0 versus 111.0 pg/mg protein, P = .013), with deep cervical stromal invasion (more than half thickness) (423.0 versus 86.5 pg/mg protein, P < .001), lymphovascular emboli (770.0 versus 111.5 pg/mg protein, P = .003), parametrial invasion (423.0 versus 114.5 pg/mg protein, P = .01), pelvic lymph node metastasis (807.5 versus 116.0 pg/mg protein, P = .003) compared with tumors less than 4 cm, with superficial stromal invasion, no lymphovascular emboli, no parametrial invasion, or no pelvic node metastasis. Other clinicopathologic characteristics such as stage of disease and menopausal status showed no significant difference in the cytosol VEGF concentrations.


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  		Table 1. Demographic Characteristics and Cytosol Vascular Endothelial Growth Factor According to Recurrence
 

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  		Table 2. Median Vascular Endothelial Growth Factor Concentrations in Clinicopathologic Characteristics
 
The diagnostic efficacy of cytosol VEGF for evaluating lymph node metastasis was analyzed. The receiver operating characteristics (ROC) curve illustrating the performance characteristics of VEGF for predicting lymph node metastasis is shown in Figure 1Go. A VEGF cutoff value of 400 pg/mg resulted in the best sensitivity with 75%, the best specificity of 70%, positive predictive value of 41%, and negative predictive value of 92% (Table 3Go).



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  		Figure 1. Receiver operating characteristic curve for cytosol vascular endothelial growth factor for predicting lymph node metastases of cervical carcinoma.

 

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  		Table 3. Vascular Endothelial Growth Factor Concentration for Predicting Lymph Node Metastasis
 
Table 4Go lists the results of assessment of risk factors of recurrence for those patients with disease-free survival, with overexpressed cytosol VEGF (hazard ratio 6.44 (2.37, 13.54), P < .001) being the only independent prognostic factor (Figure 2Go). Table 5Go lists the results of multivariable proportional hazards model analyses on risk factors that might influence the overall survival. The cytosol VEGF [hazard ratio 4.50 (1.25, 16.22), P = .021] (Figure 3Go) and lymphovascular emboli [hazard ratio 4.11 (1.05, 16.34), P = .045] are independent prognostic factors by multiple regression analysis.


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  		Table 4. Multivariable Proportional Hazards Model on the Disease-Free Survival
 


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  		Figure 2. The disease-free survival curves according to expression of vascular endothelial growth factor (log-rank test, P < .001).

 

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  		Table 5. Multivarible Proportional Hazards Model on the Overall Survival
 


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  		Figure 3. Overall survival curves show significantly poorer survival in women with overexpressed cytosol vascular endothelial growth factor (log-rank test, P = .002).

 

   Discussion
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Abstract
 Patients and Methods
 Results
 Discussion
References
 
Tumor angiogenesis is a complex process that involves endothelial cell proliferation, digestion of the extracellular matrix surrounding capillaries, endothelial cell migration, and differentiation into functioning capillaries. Evidence supports the concept that tumors can induce angiogenesis through many angiogenic molecules. VEGF is the most potent angiogenic molecule at present, not only inducing endothelial cell proliferation, but increasing vascular permeability. Our previous studies showed that VEGF could indicate disease severity and had a positive correlation with microvessel density in cervical cancer.17,18 This study confirmed our previous reports in that tumors with deep stromal invasion, parametrial invasion, lymphovascular emboli, and lymph node metastasis had higher cytosol VEGF than those with superficial stromal invasion, and without parametrial invasion, lymphovascular emboli, or lymph node metastasis. The results suggested that VEGF concentration indicates local invasive activity and metastatic potential of cervical carcinoma.

Prognostic factors of early-stage cervical carcinoma include tumor size, depth of stromal invasion, parametrial invasion, and lymph node metastasis. The dominant prognostic factor that affects survival after radical hysterectomy is lymph node status.19 Adjuvant radio-therapy or systemic chemotherapy is administered after surgery to women at high risk of relapse, with indications of positive pelvic node, positive section margin, parametrial invasion, or bulky tumors.8,20 Adjuvant radiation can reduce the incidence of local recurrence, which is beneficial to patients with positive surgical margins or parametrial invasions. For women with lymph node metastasis, adjuvant radiotherapy might reduce pelvic recurrence rates, but survival benefit is still unclear. Complication rates are higher in patients treated with surgery and adjuvant radiotherapy, so it is better to treat women with known lymph node metastasis by radiotherapy alone or concurrent chemoradiation. Preoperative evaluation of lymph node status is therefore important, because lymph node metatsasis will change the course of treatment for early-stage cervical carcinoma patients. Noninvasive diagnostic tools such as sonography, CT, or magnetic resonance imaging (MRI) are used to evaluate the lymph node status. We found that cytosol VEGF could be a marker for evaluating possible lymph node metastasis and might be used for treatment palnning in early-stage patients. When cytosol VEGF is higher than 400 pg/mg, we believe that pelvic lymph node metastasis should be suspected. Radiation therapy with or without concurrent chemotherapy seems to be better for women who have higher than 400 pg/mg cytosol VEGF protein levels.

Identification of factors that correlate with survival can give clinically relevant information to physicians and elucidate the basic biology of the disease. This study showed that VEGF affects prognoses of women with cervical cancer in stage IB and IIA. By Cox proportional hazards model, VEGF showed the only prognostically relevant information independent of other established prognostic factors of stage IB and IIA cervical cancer. Status of lymph node metastasis, parametrial invasion, lymphovascular emboli, and tumor size were not prognostic factors in this study. Our explanation is that because those factors always had close correlations with each other, they could not be independent factors in our survey.

There is abundant evidence that tumor angiogenesis influences prognosis of various cancers. Tumor angiogenesis, measured by microvessel density, has been reported as a prognostic factor in cervical carcinoma,21 and seems to be a new factor of disease severity and prognosis.20,22 Microvessel density influences the disease-free and overall survival of patients;21 however, methodologic problems such as inter- and intraobserver variability, heterogenicity of tumors, and selection of the area of most intense neovascularization (hot spot), remain unsolved. Quantitation of angiogenic molecules from urine, serum, or tumor tissues provides alternative methods. We tried to evaluate if VEGF, an angiogenic factor, could be a prognostic factor for cervical cancer patients. Those with overexpressed VEGF had poorer disease-free and overall survival rates. Chiarotto and Hill reported that VEGF could be upregulated in the presence of hypoxia,23 which may explain why cervical cancer patients who receive adjuvant radio- or chemotherapy continue to have higher recurrence rates. We suggest that cervical cancer patients with overexpressed cytosol VEGF, instead of other risk factors, be closely monitored to detect the early disease recurrence even if they are receiving postoperative adjuvant radiation or chemotherapy.

Chemotherapeutic cytotoxic agents act directly against tumor cells, whereas antiangiogenic molecules target the stromal component of tumors, which might be why some clinical trials report high response rates to antiangiogenic therapy in many solid tumors, including those that commonly either do not respond or respond poorly to conventional chemotherapy.24 The value of adjuvant chemotherapy for preventing relapse of cervical cancer has not been proved, and our data showed that growth, spread, and outcome of cervical carcinoma are angiogenesis related. We therefore, also stress the need for clinical trials to study the therapeutic effect of antiangiogenic substances on carcinoma of the uterine cervix.


   Footnotes
 
PII S0029-7844(00)01025-5

Received February 2, 2000. Received in revised form June 22, 2000. Accepted July 20, 2000.


   References
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 Patients and Methods
 Results
 Discussion
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1. Ponten J, Adami HO, Bergstrom R, Dillner J, Friberg LG, Gustafsson L, et al. Strategies for global control of cervical cancer. Int J Cancer 1995;60:1–26.[Medline]

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3. Pettersson F. Annual report on the results of treatment in gynecological cancer. Stockholm: International Federation of Gynecology and Obstetrics, 1994.

4. Gallion HH, van Nagell JR, Donaldson ES, Hanson MB, Powell DE, Maruyama Y, et al. Combined radiation therapy and extrafascial hysterectomy in the treatment of stage IB barrel-shaped cervical cancer. Cancer 1985;56:262–5.[Medline]

5. Fuller AF Jr, Elliott N, Kosloff C, Hoskins WJ, Lewis JL Jr. Determinants of increased risk for recurrence in patients undergoing radical hysterectomy for stage IB and IIA carcinoma of the cervix. Gynecol Oncol 1989;33:34–9.[Medline]

6. Sevin BU, Nadji M, Lampe B, Lu Y, Hilsenbeck S, Koechi OR, et al. Prognostic factors of early stage cervical cancer treated by radical hysterectomy. Cancer 1995;76:1978–86.[Medline]

7. Matsuyama T, Inoue I, Tsukamoto N, Kashimura M, Kamura T, Saito T, et al. Stage IB, IIA, IIB cervix cancer, postsurgical staging and prognosis. Cancer 1984;54:3072–7.[Medline]

8. Lin HH, Cheng WF, Chan KW, Chang DY, Chen CK, Huang SC. Risk factors for recurrence in patients with stage IB, IIA, and IIB cervical carcinoma after radical hysterectomy and postoperative pelvic irradiation. Obstet Gynecol 1996;88:274–9.[Abstract]

9. Burghardt E, Pickel H, Haas J, Lahousen M. Prognostic factors and operative treatment of stage IB to IIB cervical cancer. Am J Obstet Gynecol 1987;156:988–96.[Medline]

10. Martimbeau PW, Kjorstad KE, Iversen T. Stage Ib carcinoma of the cervix, The Norwegian Radium Hospital. II: Results when pelvic nodes are involved. Obstet Gynecol 1982;60:215–8.[Abstract/Free Full Text]

11. van Bommel PFJ, van Lindert ACM, Kock HCLV, Leers WH, Neijt JP. A review of prognostic factors in early stage carcinoma of the cervix (FIGO Ib and IIa) and implication for treatment strategy. Eur J Obstet Gynecol Reprod Biol 1987;26:69–84.[Medline]

12. Thomas GM, Dembo AJ. Is there a role for adjuvant pelvic radiotherapy after radical hysterectomy in early stage cervical cancer? Int J Gynecol Cancer 1991;1:1–8.

13. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 1990;82:4–6.[Free Full Text]

14. Cheng WF, Lee CN, Chu JS, Chen CA, Chen TM, Huang KT, et al. Vascularity index as a new parameter for the in vivo assessment of angiogenesis for cervical carcinoma. Cancer 1999;58:561–7.

15. Obermair A, Kucera E, Mayerhofer K, Speiser P, Seifert M, Czerwenka K, et al. Vascular endothelial growth factor (VEGF) in human breast cancer: Correlation with disease-free survival. Int J Cancer 1997;74:455–8.[Medline]

16. Chen CA, Cheng WF, Lee CN, Chen TM, Kung CCS, Hsieh FJ. Serum vascular endothelial growth factor in epithelial ovarian neoplasms: Correlation with patient survival. Gynecol Oncol 1999; 74:235–40.[Medline]

17. Cheng WF, Chen CA, Lee CN, Chen TM, Hsieh FJ, Hsieh CY. Vascular endothelial growth factor in cervical carcinoma. Obstet Gynecol 1999;93:761–5.[Abstract/Free Full Text]

18. Cheng WF, Lee CN, Chen CA, Chu JS, Kung CCS, Hsieh CY, et al. Comparison of in vivo and in vitro methods for evaluating angiogenesis and their clinical application in cervical carcinoma. Angiogenesis. In press.

19. Alvarez RD, Soong SJ, Kinney WK, Reid GC, Schray MF, Podratz KC, et al. Identification of prognostic factors and risk groups in patients found to have nodal metastases at the time of radical hysterectomy. Gynecol Oncol 1989;35:130–5.[Medline]

20. Cheng WF, Wei LH, Su YN, Cheng SP, Chu JS, Lee CN. The possible use of colour flow Doppler in planning treatment in early invasive carcinoma of the cervix. Br J Obstet Gynaecol 1999;106: 1137–42.[Medline]

21. Obermair A, Wanner C, Bilgi S, Speiser P, Kaider A, Reinthaller A, et al. Tumor angiogenesis in stage IB cervical cancer: Correlation of microvessel density with survival. Am J Obstet Gynecol 1998;178: 314–9.[Medline]

22. Iwasaka T, Kamura T, Yokoyama M, Natsuo N, Nakano H, Sugimori H. Adjuvant chemotherapy after radical hysterectomy for cervical carcinoma: A comparison with effects of adjuvant radiotherapy. Obstet Gynecol 1998;91:977–81.[Abstract]

23. Chiarotto JA, Hill RP. A quantitative analysis of the reduction in oxygen levels required to induce up-regulation of vascular endothelial growth factor (VEGF) mRNA in cervical cancer cell lines. Br J Cancer 1999;80:1518–24.[Medline]

24. Hawkins MJ. Clinical trials of angiogenic agents. Curr Opin Oncol 1995;7:90–3.[Medline]




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