Journal of Cancer Therapy, 2013, 4, 1478-1484
Published Online December 2013 (
Open Access JCT
Association between Pretreatment Levels of Serum
Vascular Endothelial Growth Factor (VEGF) and Survival
Outcomes in Locally Advanced Cervical Cancer Patients*
Kanyarat Katanyoo#, Kanisa Rongsriyam, Marisa Chongtanakon
Radiation Oncology Section, Department of Radiology, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bang-
kok, Thailand.
Received November 18th, 2013; revised December 8th, 2013; accepted December 15th, 2013
Copyright © 2013 Kanyarat Katanyoo et al. This is an open access article distributed under the Creative Commons Attribution Li-
cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In
accordance of the Creative Commons Attribution License all Copyrights © 2013 are reserved for SCIRP and the owner of the intel-
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Objective: To evaluate the association between pretreatment levels of serum vascular endothelial growth factor (VEGF)
and long-term treatment outcomes in patients with locally advanced cervical cancer (LACC). Methods: Thirty-nine
patients diagnosed with LACC (stage IIB-IVA) and obtaining blood for serum VEGF were identified. All patients re-
ceived complete treatment as radical radiotherapy with or without concurrent chemotherapy. Surveillance for all pa-
tients was every 3 months during the first 2 years, and every 6 months later. Results: Mean age of 39 patients was 52.3
± 10.8 years old. Twenty-three patients (59.0%) had stage IIB, and 16 patients (41.0%) had stage IIIB. Histological cell
type was mostly squamous cell carcinoma (89.7%). The median and 75th percentile level of serum VEGF were 610.2
pg/ml (0.0 - 4067.2 pg/ml) and 825.6 pg/ml, respectively. At median follow-up of 37.0 months (range, 26.8 - 46.3
months), the 3-year OS rate was 78.6%. Clinical stage (p = 0.04) and 75th percentile of VEGF level (p = 0.04) were im-
pacted on OS in univariable analysis. The 3-year OS of patients in stage IIB with serum VEGF of 825.6 pg/ml and of
> 825.6 pg/ml was slightly different, 94.4% and 80.0% respectively (p = 0.34), whereas there were many differences in
stage IIIB, 71.4% and 25.0% in patients with serum VEGF of 825.6 pg/ml and of >825.6 pg/ml respectively (p =
0.05). Conclusion: High pretreatment serum VEGF level has an influence on OS for LACC. It is potentially used as a
predictive factor, especially in patients stage IIIB, in order to provide efficient treatment and improve survival outcomes
in the future.
Keywords: Serum VEGF; Locally Advanced Cervical Cancer; Overall Survival
1. Introduction
Although screening program is well known for preven-
tion in cervical cancer, the incident rate of this cancer is
still high. In developing countries including Thailand,
cervical cancer is the second most common cancer in
women [1]. For locally advanced stage (IIB-IVA), con-
current chemoradiation (CCRT) is the standard treatment.
However, the treatment outcome is fair, which is just
60% - 65% in terms of 5-year overall survival [2]. An
important meta-analysis study found that CCRT had less
influence on advanced stages, while distant failure was
still the major problem of these patients [3]. Several me-
chanisms are involved in that failure which seems
unlikely to be controlled by CCRT.
New blood vessels have the significant role for tumor
cell proliferation and metastasis to distant organs. When
hypoxia has occurred in tumor cell, it can stimulate hy-
poxia-inducible transcription factors (HIFs) and signalise
to secret angiogenic factors [4]. One of the important
angiogenic factors is vascular endothelial growth factor
(VEGF), which has been determined to be considerable
protein for complicated mechanisms of tumor vessel
formation [4,5]. For cervical cancer, several literatures
were interested in the correlation of serum VEGF with
clinicopathological findings [6-14]. According to those
*Conflict of interest: All authors declared no conflict of interest.
#Corresponding author.
Association between Pretreatment Levels of Serum Vascular Endothelial Growth Factor
(VEGF) and Survival Outcomes in Locally Advanced Cervical Cancer Patients
results, serum VEGF was related with staging or advance
of disease [6,8-12,14]. However, some conflictions of
results were shown from two Asian studies [7,13]. For
the association of this serum with long-term treatment
outcomes in regard to progression-free survival (PFS)
and overall survival (OS), few studies had reported these
issues with inconsistent conclusions [8,9,11].
In 2011, we reported a prospective study which fo-
cused on the association of pretreatment serum VEGF
with clinicopathology and response of treatment by radi-
cal radiotherapy with or without concurrent chemother-
apy in stage IIB-IVA cervical cancer patients. The results
showed no correlation of serum VEGF level with stage
and tumor size, but patients who had persistent disease
had a trend of higher level of this serum than patients
who had complete response to disease after complete
treatment [13]. The objective of this study is to report the
relationship of pretreatment serum VEGF in those pa-
tients with long-term treatment outcomes in terms of
3-year PFS and OS.
2. Material and Methods
2.1. Patients
After an approval from the Institutional Review Board
(IRB) of Faculty of Medicine Vajira Hospital, Navamin-
dradhiraj University, we enrolled patients who were di-
agnosed as locally advanced stage (stage IIB-IVA) of
cervical cancer, and had squamous or adenocarcinoma as
cell type. Between January 2009 and June 2010, 40 pa-
tients were included with obtaining inform consent for
the first time. Blood specimens for serum VEGF were
taken before starting radical radiotherapy about 24 hours.
All detail of measurement of serum VEGF was shown in
our previous study [13]. Radical radiation therapy with or
without concurrent chemotherapy were performed for 39
patients, while one patient refused to receive treatment.
The median and 75th percentile of pretreatment level of
serum VEGF for those rest patients who were partici-
pated in present study were 610.2 pg/ml (0.0 - 4067.2
pg/ml) and 825.6 pg/ml, respectively.
2.2. Treatments
Radical radiotherapy composed of external beam pelvic
radiotherapy at a total dose of 54 - 60 Gy applied in daily
fractions of 1.8 - 2.0 Gy. Three to five fractions of intra-
cavitary (ICRT) high dose-rate brachytherapy were ap-
plied on weekly fractions of 6.0 - 7.2 Gy each to point A,
depending on tumor volume. Using weekly cisplatin or
carboplatin in a concurrent setting depended on each
physician. Weekly dosages of cisplatin or carboplatin
were 40 mg/m2 and 2AUC, respectively, with appropriate
pre-medications were given. Follow-up for all patients
was based on physical examination. At last time of ICRT,
all patients were follow-up at one month and two months
afterwards to evaluate response of treatment. Tumor or
suspected diseases that were still seen at cervix in the
third month were defined as persistent disease and taken
biopsy. Surveillance for all patients was every 3 months
during the first 2 years, and every 6 months after that.
PFS and OS which were the main objectives in this study
were ascertained. PFS was defined as interval from the
first date of radical radiotherapy to the time of disease
recurrence in pelvis, metastasis to other organs, or death.
For the patients who were lost to follow-up, PFS data
was right censored at the time of the last evaluation, or
contact when the patients were known to be progression-
free. OS was defined as time from the first date of treat-
ment to the date of death. For patients who were alive at
the end of study, survival data were right-censored at the
date of last follow-up visit. Written inform consent was
provided by all patients whose data were used to analyze
2.3. Statistical Analysis
Data were analyzed by using SPSS statistical software,
version 11.5 (SPSS Inc., Chicago, IL). Descriptive statis-
tic was used to analyze clinicopathological data, which
was summarized as number and percentage. Normal dis-
tribution of serum VEGF levels was tested using the
Kolmogorov-Smirnov test. OS and PFS were analyzed
by the Kaplan-Meier method. Univariable analysis was
used to compare between groups with log-rank test. A
two sided P-value <0.05 were considered statistically sig-
3. Results
Mean age of 39 patients was 52.3 ± 10.8 years. Twenty-
three patients (59.0%) had stage IIB, and 16 patients
(41.0%) had stage IIIB. Histological cell type was mostly
squamous cell carcinoma (89.7%). Except two patients
who were got treatment as radical radiotherapy alone,
almost of all patients received concurrent chemoradiation
(CCRT). Twenty-three patients from 37 patients (62.2%)
had weekly carboplatin for concurrence with external
radiation therapy, while weekly cisplatin was used for 14
remaining patients. All patients received complete treat-
ment as plan and were assessed response rate at 3 months
after the last fraction of ICRT. Nearly 95.0% of patients
had achieved complete response. All other details of
clinicopathology and correlation with pretreatment serum
VEGF level were demonstrated at our prior study [13].
From a median follow-up of 37.0 months (range, 26.8
- 46.3 months), eight patients (20.5%) died from disease
and one patient (2.6%) was alive with disease. Disease
Open Access JCT
Association between Pretreatment Levels of Serum Vascular Endothelial Growth Factor
(VEGF) and Survival Outcomes in Locally Advanced Cervical Cancer Patients
Open Access JCT
point was noted in patients in stage IIIB with serum
VEGF > 825.6 pg/ml. We found that patients in this
group had poor survival outcome, 3-year OS was 25.0%,
while 3-year OS of patients in the same stage with serum
825.6 pg/ml was 71.4%. Moreover, median survival of
patients who had serum VEGF > 825.6 pg/ml was 14.0
months (95% confidence interval [CI] = 7.0 - 21.0
months). Three out of 4 patients in this group developed
distant metastasis and died from disease. While median
survival of another group (serum VEGF 825.6 pg/ml)
had not been reached yet. The difference of survival
outcome from this using cut-off value in patients with
stage IIIB was quite remarkable. Due to small number of
patients, the statistic difference was reached marginally
significant (p = 0.05) (Figure 2).
progression were identified as local recurrence in one
(2.6%), distant metastasis in three (7.7%), and both pel-
vic and distant failure in four (10.2%). Lung (3 patients,
7.7%) and paraaortic node (3 patients, 7.7%) were the
most common sites of distant failure. The other sites of
distant organ metastasis were supraclavicular lymph
node (one patient, 2.6%), bone (one patient, 2.6%) and
inguinal lymph node (one patient, 2.6%). When the me-
dian of pretreatment serum VEGF (610.2 pg/ml) was
used for being the cut-off level, 6/9 patients (66.7%) who
had disease progression had VEGF levels higher than
that level. However, 14/30 patients (46.7%) who were
still alive without any evidence of disease also had
VEGF levels higher than the median level. There was no
significant difference of this cut-off level (p = 0.45). On
the one hand, when we used the 75th percentile of pre-
treatment level of serum VEGF (825.6 pg/ml) to be the
cut-off value, 4/9 patients (44.4%) with recurrence of
diseases and 5/30 patients (16.7%) with no evidence of
disease had serum VEGF levels more than this level. The
value of 75th percentile had a trend of association with
status of disease, but there was no statistically signify-
cance (p = 0.08).
4. Discussion
In current study, we found that serum VEGF at pretreat-
ment time in locally advanced cervical cancer has some
correlations with survival outcomes. The first point need
to be emphasized is an appropriate cut-off value. To date,
there is no standard level or recommendation for this
At the time of analysis, median PFS and OS had not
been reached. The 3-year PFS and OS rates were 76.9%
and 78.6%, respectively. In univariable analysis, clinical
stage was the only significant factor on 3-year PFS rate
(p = 0.02), whereas serum VEGF at cut-off value of 75th
percentile had a high tendency to be an influential factor
(p = 0.06). For 3-year OS, the 75th percentile of VEGF
level became to be one of two important factor (p = 0.04)
besides clinical stage (Figure 1). However, the cut-off
point at median VEGF level did not show any correlation
with both PFS and OS (Table 1). When we classified the
75th percentile of VEGF level by each clinical stage, 3-
year OS of patients in stage IIB with serum VEGF
825.6 pg/ml and >825.6 pg/ml was 94.4% and 80.0%,
respectively. This difference did not reach statistical sig-
nificance (p = 0.34). Kaplan-Meier curve could not be
done, because there was only one event in each group of
two different VEGF levels in stage IIB. The interesting
Figure 1. Overall survival when stratified by the 75th per-
centile of serum VEGF for all clinical stages (39 patients).
Table 1. Univariable analysis of prognostic factors for survival outcomes in locally advanced cervical cancer patients.
Prognostic factor 3-yr PFS (%) p-value 3-yr OS (%) p-value
Tumor size (4 cm vs >4 cm) 85.7 vs 66.7 0.13 88.9 vs 66.7 0.06
Histological cell type (SCCA vs ACA) 77.1 vs 75.0 0.89 79.1 vs 75.0 0.79
Clinical stage (IIB vs IIIB) 91.3 vs 56.2 0.01* 91.3 vs 60.1 0.04*
Median of serum VEGF (610.2 pg/ml vs >610.2 pg/ml) 84.2 vs 70.0 0.23 87.4 vs 70.0 0.12
75th percentile of serum VEGF (825.6 pg/ml vs >825.6 pg/ml) 83.3 vs 55.6 0.06 85.3 vs 55.6 0.04*
Abbreviation: PFS, progression-free survival; OS, overall survival; SCCA, squamous cell carcinoma; ACA, adenocarcinoma; VEGF, vascular endothelial
rowth factor. g
Association between Pretreatment Levels of Serum Vascular Endothelial Growth Factor
(VEGF) and Survival Outcomes in Locally Advanced Cervical Cancer Patients
Figure 2. Overall survival when stratified by the 75th per-
centile of serum VEGF in stage IIIB disease (16 patients).
issue. Therefore, we used two different levels in our
study. The first selected level was the median of serum
VEGF level (610.2 pg/ml), that was used in study of
Bachtiary [9] and Zusterzeel [11]. However, our finding
of this cut-off level did not show any relationship with
PFS and OS. The difference of our results from two pre-
vious studies was observed. Bachitary et al. demon-
strated that when serum VEGF level was more than 244
pg/ml (median point of serum VEGF in their study), tu-
mor radioresistance from radiation therapy were showed
and had the effect on survival outcomes. However, they
did not describe the detail in regard to area of treatment
failure [9]. The Landmark study of serum VEGF in cer-
vical cancer came from the Netherlands. They reported
that serum VEGF at median level in their study (540
pg/ml) was a prognostic factor to predict both PFS and
OS. The majority of their patients were in early stage
(100 of stage IB and 32 of stage IIA). While the number
of patients in stage IIB-IV which was the targeted group
in our study was 35 patients (19 of stage IIB, 11 of stage
III, and 5 of stage IV). As a consequence of these small
numbers, they could not demonstrate statistical differ-
ence when analyses were taken place in each stage [11].
The second challenging point was the level of the 75th
percentile of serum VEGF (825.6 pg/ml). This level was
used in the study of Lebrecht [8]. At this level, there was
a significant difference in 3-year OS between patients
who had serum VEGF level 825.6 vs >825.6 pg/ml (p
= 0.04). Due to our previous study, we found that there
were no any associations of serum VEGF level with tu-
mor stage [13]. Therefore, in order to evaluate that
whether those results still existed, we stratified level of
the serum VEGF (825.6 vs >825.6 pg/ml) by clinical
stage (stage IIB vs stage IIIB). The notable issue was
seen in patients in stage IIIB with serum VEGF higher
than 825.6 pg/ml. Patients in this group had the deterio-
ration of 3-year OS which was approximately three times
lower when compared with another group (25.0% vs
71.4%). Although statistical significance could not be
reached, the vast difference should be emphasized. The
effect of using this level to be the cut-off value did not
produce results in the same way as seen in Lebrecht et al.
who chose the 75th percentile of serum VEGF level
(319.4 pg/ml) for cut-off value [8]. They found no corre-
lation between high serum level at that value with PFS
and OS.
The problem concerning the proper cut-off value of
serum VEGF remains to be obscure and debated. Nowa-
days, our study was the fourth study which reported se-
rum VEGF with long term treatment outcomes including
PFS and OS in cervical cancer (Table 2). There is high
diversity of serum VEGF levels observed among four
studies. Some reasonable explanations may include va-
rious stages of disease (stage I - IV) and proportion of
each stage included in each study. Previous three studies
had enrolled patients in all stages, and that might deliver
wide range of VEGF level. Although the cut-off level
used in all studies was the same level, median or 75th
percentiles, the real figures among those four studies
showed wide distribution as well as inconsistence. The
median value of serum VEGF in our study was the high-
est value amongst all studies, because we included only
advanced stage. Therefore, there was no dilutional effect
of this serum from early disease like previous three stud-
We concern that the limitation in this study was the
number of patients which was not enough to make the
difference for statistical analysis, especially in stage IIIB.
However, the potential advantage of serum VEGF in that
stage is rather explicit. Patients who had two poor prog-
nostic factors, both stage IIIB and serum VEGF level of
>825.6 pg/ml, had a higher chance of distant metastasis
and death rate than patients in the same stage with serum
VEGF level 825.6 pg/ml. At the recent year, Chemora-
diotherapy for Cervical Cancer Meta-analysis Collabora-
tion (CCCMAC) concluded that CCRT had the benefit
over RT in all stages. However, they found that the bene-
fit of 5-year OS was compromised from CCRT when
increasing stage of disease was appeared, 7% in stage IIB
and only 3% in stage IIIB. Moreover, area that CCRT
had fewer efficacies was distant organs and affected on
distant metastasis [3]. However, patients in stage IIIB
who did not gain much benefit from CCRT, we did not
know that whether it would have association with serum
VEGF. These evidences suggest that for patients in lo-
cally advanced stage, they should get more aggressive
treatment than CCRT to salvage some occult metastatic
Open Access JCT
Association between Pretreatment Levels of Serum Vascular Endothelial Growth Factor
(VEGF) and Survival Outcomes in Locally Advanced Cervical Cancer Patients
Table 2. Studies of serum VEGF with survival outcomes.
Author [ref] Stage Number of
patients (%)
(pg/ml) (range) Cut-off value Outcomes Median FU
time (months)
1. Lebrecht [8]
9 (10.7%)
23 (27.4%)
6 (7.1%)
33 (39.3%)
11 (13.1%)
2 (2.4%)
(59.5 - 1849.1)
The 75th percentile
(581.7 pg/ml) No difference on PFS and OS 21.3
2. Bachitary [9] IB - II
18 (64.3%)
5 (21.7%)
(31.9 - 817.6) Median Difference in PFS
(p = 0.003) 25.0
3. Zusterzeel [11]
100 (59.9%)
32 (19.1%)
19 (11.4%)
16 (9.6%)
(280.0 - 1260.0)
Early stage: 440.0
Advanced stage: 1040.0
Difference in
PFS (p = 0.010) and
OS (p= 0.006)
4. This study IIB
23 (59.0%)
16 (41.0%)
(0.0 - 4067.2)
The 75th percentile
(825.6 pg/ml)
- No difference on PFS (p = 0.234) and
OS (p = 0.116)
The 75th percentile
- No difference on 3-year PFS (p = 0.061)
- Difference in 3-year OS (p = 0.042)
Abbreviation: NA, Not available.
At the present time, there is no standard serologic tu-
mor marker in cervical cancer [15]. The most potential
serum assay to be used at follow-up may be squamous
cell carcinoma antigen (SCC) [15,16]. This marker has
been studies the most when compared to others such as:
cytokeratin fragment (CYFRA 21-1), CA 125 and VEGF.
However, one problem seen in using SCC antigen is
similar to serum VEGF. The wide range of rising rate
appeared, 28% - 88%, due to some differences of the
cut-off value chosen [15]. However, the important thing
which we should be concerned is whether these serums
can improve survival outcomes of patients. As a result of
recurrent or metastatic disease of cervical cancer patients,
there is no any curative treatment for them. All treat-
ments are aimed as palliation. Hence, in locally advanced
diseases which are known that CCRT is not adequate to
control occult distant metastasis, more suitable treat-
ments should add more in appropriate patients. The ac-
curate serum tumor marker for prediction survival out-
comes may be used to evaluate these patients for receiv-
ing more aggressive treatment than CCRT at the first
time of treatment.
During the past decade, role of VEGF targeted therapy
was mentioned in gynecologic malignancies [17]. Most
studies concentrated on ovarian cancer, while a few trials
of cervical cancer are ongoing. Two phase II studies in-
volved using VEGF inhibitor at concurrent time with RT
and platinum-based chemotherapy. Since it takes years to
achieve the final outcomes of cancer treatment in terms
of PFS or OS, all answers about the role of VEGF in-
hibitor in cervical cancer are still inconclusive. Moreover,
we do not know whether serum VEGF can be used as an
indicator to follow-up treatment outcomes after patients
have obtained anti-VEGF drug. In breast cancer, human
epidermal growth factor receptor type 2 (HER-2/neu) is
one of the predictive factors. Trastusumab is the well-
known targeted therapy for treatment in patients with
HER-2/neu positive. Currently, there are greatly ad-
vanced studies in the field of cost-analysis studies in this
cancer [18-20]. On the other hand, the third new cases of
cancer in females worldwide is cervical cancer [1], but
the knowledge concerning salvage treatment including
additional chemotherapy or targeted therapy still require
further investigation. Whether this treatment may have
some benefit, the cost-effectiveness of this targeted ther-
apy should also be considered as seen in the issue with
5. Conclusion
In conclusion, serum VEGF demonstrates some advan-
tages for using it in locally advanced cervical cancer.
Based on our results, the most benefit for this serum as a
predictive factor may be seen in patients with stage IIIB.
In this stage, patients with high serum VEGF level, >
825.6 pg/ml, have a higher chance of treatment failure
and death rate compared to patients in the same stage
with serum VEGF level 825.6 pg/ml. However, some
questions regarding this serum still exist. We need more
studies to confirm the role of serum VEGF as a predic-
tive factor as well as the role of VEGF targeted-therapy
in appropriate patients to improve the most efficient
treatment outcomes.
Open Access JCT
Association between Pretreatment Levels of Serum Vascular Endothelial Growth Factor
(VEGF) and Survival Outcomes in Locally Advanced Cervical Cancer Patients
6. Acknowledgements
The authors gratefully acknowledge the financial support
provided by the medical research fund of Faculty of
Medicine Vajira Hospital, Navamindradhiraj University.
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Open Access JCT
Association between Pretreatment Levels of Serum Vascular Endothelial Growth Factor
(VEGF) and Survival Outcomes in Locally Advanced Cervical Cancer Patients
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