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Int J Clin Exp Med 2016;9(10):20137-20144
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Original Article
Recombinant human endostatin combined with
definitive chemoradiotherapy for patients with
locally advanced esophageal carcinoma
Xiaoling Ge1*, Yuandong Wang1*, Wei Wen2*, Hongcheng Zhu1, Hongxun Ye3, Xi Yang1, Jiayan Chen1,
Yuandong Cao1, Sheng Zhang1, Qingxia Mu1, Hongyan Cheng4, Jianxin Ma5, Shenbin Dai6, Qing Guo6, Baixia
Yang7, Jing Cai7, Min Yang1, Xinchen Sun1
Departments of 1Radiation Oncology, 2Cardiothoracic Surgery, 4General Internal Medicine, The First Affiliated
Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China; 3Department of Radiation Oncology,
Taixin People’s Hospital, Taizhou 225499, Jiangsu, China; 5Department of Radiation Oncology, Lianyungang No.
2 People’s Hospital, Lianyungang 222023, Jiangsu, China; 6Department of Radiation Oncology, Taizhou People’s
Hospital, Taizhou 225300, Jiangsu, China; 7Department of Radiation Oncology, Nantong Tumor Hospital Affiliated
to Nantong University, Nantong 226361, Jiangsu, China. *Equal contributors.
Received December 15, 2015; Accepted September 7, 2016; Epub October 15, 2016; Published October 30,
2016
Abstract: Background: The efficacy and toxicity of recombinant human endostatin combined with docetaxel, cisplatin, and radiation therapies were evaluated in patients with locally advanced esophageal cancer. Methods: Between
August 2010 and December 2012, 32 patients with clinical stage II and III squamous cell carcinoma of the esophagus were included in this retrospective analysis. The patients received recombinant human endostatin combined
with definitive chemoradiotherapy. The Kaplan-Meier method was conducted to compute the survival time and progression-free survival time. Early and late toxicities were mainly scored based on the Common Terminology Criteria
for Adverse Events 3.0. Results: A total of 21 and 11 patients had locally advanced stage II and III esophageal
carcinoma, respectively. All patients received 60 Gy radiation. However, two only received one-cycle chemotherapy
because of hematological toxicities. Complete response, partial response, stable disease, and progressive disease
characteristics were observed in 17 (53.1%), 10 (31.3%), 3 (9.4%) and 2 (6.3%) patients, respectively, at 1 month
post-treatment. After a median follow-up of 30 months, the median survival time was 22.0 months. The one- and
three-year overall survival (OS) rates were 68.8% and 43.8%, respectively. The median progression-free survival
(PFS) time was 16.0 months. The one- and three-year PFS rates were 56.3% and 31.3%, respectively. Hematologic
toxicity, gastrointestinal toxicity, and treatment-related esophagitis were 16.1%, 10.7%, and 19.6%, respectively.
Late toxicities, including esophagostenosis, were observed in six (19.6%) patients. Conclusions: The combined
treatment modality can be a promising therapeutic option for patients with locally advanced esophageal squamous
cell carcinoma. Additional prospective randomized control studies are necessary to confirm this finding.
Keywords: Recombinant human endostatin, chemoradiation, esophageal cancer, IMRT
Introduction
Esophageal cancer is the fourth most common
cancer in China and has one of the highest
mortality rates. Approximately 95% of esophageal cancer cases are squamous cell carcinoma (ESCC) [1]. Similar to other solid tumors,
ESCC primarily occurs in the elderly, and most
patients diagnosed with advanced stages of
the disease are unsuitable for surgery. Definitive
chemoradiotherapy is a standard treatment for
patients with esophageal carcinoma who have
no indications for surgery based on randomized
clinical trial results [2, 3]. However, esophageal
cancer is not always sensitive to chemoradiotherapy. Its prognosis remains unsatisfactory,
with a 5-year survival rate of < 30% [4]. Alternative regimens, such as new chemotherapy
drugs and targeted therapy, must be developed
to improve both local and distant control in
patients with locally advanced ESCC. Docetaxel
and cisplatin combination therapy is an active,
rh-Endo combined with CRT in ESCC
well-tolerated regimen for metastatic esophageal cancer. Moreover, this therapy is effective
in combination with radiotherapy in patients
with locally advanced esophageal cancer, with
a median survival time (MST) of 7-16 months
[5, 6].
The density of blood and lymphatic vessels is
related to the malignancy and biological characteristics of the tumor. Thus, tumor development can be suppressed by inhibiting angiogenesis [7]. Vascular endothelial growth factor
(VEGF) expression is one of the most important
predictors of prognostic factors in patients with
ESCC. VEGF may be a potential target for anticancer therapy in ESCC, and depressing VEGF
may be a promising method to delay tumor progression [8]. Substantial experimental and clinical evidence has indicated that radiotherapy
combined with angiogenesis inhibitors can be
beneficial to improving the tumor response to
radiotherapy [9]. Winkler et al. found that VEGF-R antibody enables the normalization of the
tumor vasculature over a period of time to
relieve tumor hypoxia in mouse brain tumor
models. Normalization of the tumor vasculature is temporary and often occurs over 1 week
of radiotherapy. Therapy yields its best results
during this period [10]. The preliminary results
of a phase II clinical study of chemoradiation
plus bevacizumab for locally advanced nasopharyngeal carcinoma suggested that bevacizumab prolongs progression-free survival [11].
Endostatin is a 20-kDa internal fragment of the
C-terminus of collagen XVIII. In a Phase III clinical study, recombinant human endostatin significantly improved the overall and progressionfree survival when used in combination with
the first-line chemotherapy regimen in patients
with advanced non-small-cell lung cancer [12].
A study has indicated that endostatin significantly sensitizes tissue to the anti-tumor and
anti-angiogenesis functions of radiation in human nasopharyngeal carcinoma xenografts by
increasing the apoptosis of endothelial and
tumor cells, improving tumor cell hypoxia, and
altering the proangiogenic factors [13]. In the
present study, we used recombinant human
endostatin combined with definitive chemoradiotherapy to treat esophageal carcinoma with
long-term follow-up and described the clinical
outcomes, including survival and the early and
late toxicity profiles.
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Patients and methods
Patients
A total of 32 patients with locally advanced
ESCC were admitted to receive recombinant
human endostatin combined with definitive chemoradiotherapy in the Department of Radiation Oncology of The First Affiliated Hospital of
Nanjing Medical University between August
2010 and December 2012. This time period
was selected to allow a sufficient follow-up interval and reveal late toxicities. The following
are the criteria for the inclusion of patients in
this study: histologically proven ESCC; age ≥ 18
years with clinically confirmed stage II-III carcinoma of the esophagus and without distant
metastasis by computed tomography (CT) or
positron emission computed tomography at the
time of diagnosis; and initially treated with
intensity-modulated radiotherapy (IMRT) and
recombinant human endostatin. All patients
also had an Eastern Cooperative Oncology
Group (ECOG) performance status score of 0 or
1. The required laboratory parameters for inclusion were an absolute neutrophil count (ANC) ≥
1×109/L, a platelet count ≥ 75×109/L, a total
bilirubin level ≤ 1.5 mg/dL, creatinine ≤ 1.5
mg/dL, serum glutamic oxaloacetic transaminase ≤ 2.5× the upper limit of normal (ULN),
and alkaline phosphatase ≤ 5× the ULN.
Patients with a break in treatment lasting > 3
days, prior thoracic cancer, thoracic radiation,
or disease recurrence were excluded. Patients
with metastases to distant organs or nonregional lymph nodes, biopsy-proven invasion
into the tracheobronchial tree, tracheo-esophageal fistula, malignant pleural effusion, pericardial effusion, or ascites were ineligible. Individuals with other active malignancy or significantly uncontrolled co-morbidity, making chemoradiation inadvisable, were also ineligible
for the study. All patients who refused surgery
voluntarily joined this study with informed consent, which was approved by the Ethical Board
of The First Affiliated Hospital of Nanjing Medical University. Thirty-two patients who met
the selection criteria were included in the analysis. Tumor evaluation was based on esophagoscopy, esophagography, chest/abdominal contrast-enhanced CT, chest contrast-enhanced
MRI, and endoscopic ultrasound of the esophagus. Tumor baseline characteristics (TNM stage, location, size, and histopathology) were re-
Int J Clin Exp Med 2016;9(10):20137-20144
rh-Endo combined with CRT in ESCC
Table 1. Clinical characteristics of the patients (n = 32)
Characteristics
Number of patients
Median (range) age, yrs
Gender
Male
Female
Performance status
0
1
Length (cm)
< 5 cm
≥ 5 cm
Tumor site
Upper
Middle
Lower
Histologic type
Squamous cell carcinoma
Clinical stage
II
III
Value
32
66 (45-82)
23 (71.9%)
9 (28.1%)
25 (78.1%)
7 (21.9%)
12 (37.5%)
20 (62.5%)
4 (12.5%)
17 (53.1%)
11 (34.4%)
32 (100%)
21
11
corded. Tumor staging was based on the International Union Against Cancer Tumor length
was defined by esophagoscopy and/or barium
esophagography and tumor diameter by CT
scan.
Treatments radiotherapy
Patients were immobilized in a supine position.
Planning CT scans, with a 3-mm slice thickness, were performed using a dedicated helical
CT scanner (Siemens) throughout the entire
neck and thorax. The CT images were transferred to and registered in the treatment planning system. The gross tumor volume (GTV) included all macroscopic tumors and enlarged
lymph nodes determined using available resources, including data from PET/CT fusion scans, endoscopic ultrasonography images, diagnostic CT images, and chest contrast-enhanced
MRI. The GTV was expanded to the CTV by
extending the radiation coverage to 3 cm superiorly, 3 cm inferiorly and 1 cm laterally. The PTV
was then generated using a uniform 0.3-cm
expansion beyond the borders of the CTV. The
organs at risk (lung and spinal cord) were outlined. All radiation treatments were delivered
as IMRT. Treatment plans were generated using
the Monaco System. The PTV irradiation dose
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was prepared at 60 Gy with 2.0 Gy per fraction
and 5 fractions per week. The prescription dose
covered at least 95% of the PTV volume, and
the hot point was limited within 105% of the
prescription dose. The spinal cord had a dose
constraint maximum of < 45 Gy, whereas for
the lungs, the mean dose and V20 were limited
to 15 Gy and 28%, respectively. IMRT plans
were generated using five or seven coplanar
beams with a 6-MV linear accelerator.
Chemotherapy
The concurrent chemotherapy regimen started
on the first day of radiotherapy. The patients
received two cycles of cisplatin-based doublets
with docetaxel. The regimens consisted of 75
mg/m2 docetaxel and 75 mg/m2 DDP on day 1
per 4 weeks. Dose modification for hematological toxicity was based on a full blood count
before the start of each chemotherapy cycle.
Full-dose chemotherapy was given if the ANC
(absolute neutrophil count) was 1×109/L or
higher and the platelet count was 75×109/L or
higher. If the ANC was 0.5×109/L to less than
1×109/L or the platelet count was 50×109/L to
less than 75×109/L, chemotherapy was stopped until the counts were recovered. Therapy
was restarted with a 25% dose reduction of cisplatin and docetaxel. Chemotherapy was restarted with a 50% dose reduction if the ANC
dropped below 0.5×109/L or the platelet count
was below 50×109/L. Cisplatin was withheld if
the renal function did not return to normal by
the time of the next scheduled dose. For other
grade 2 or higher non-hematological toxicities,
chemotherapy was withheld until the toxicities
resolved to grades 0 to 1.
Recombinant human endostatin
Recombinant human endostatin was used with
3-4 h continuous infusion at a dose of 15 mg
once a day for 14 days, with a second course
repeated after a 1-week interval. The first
course began on the first day of radiotherapy.
All toxicities related to the treatment were evaluated using the National Cancer Institute
Common Toxicity Criteria (NCI CTC, version 3.0).
Follow-up
Follow-up visits were scheduled for 1 month
after radiation and at 3-month intervals thereafter. Visits were more frequent for those
patients who received chemoradiotherapy,
experienced severe treatment-related compliInt J Clin Exp Med 2016;9(10):20137-20144
rh-Endo combined with CRT in ESCC
Figure 1. Overall survival of included patients.
from any cause. The progression-free survival (PFS) interval was defined as the time
from treatment to any type of
recurrence. Locoregional recurrence was defined as recurrence at the primary or nodal
site. Statistical analyses were
performed using SPSS 13.0
software. Differences between groups were analyzed with
Student’s t test, and a value of
P < 0.05 was considered significant. Survival curves were
calculated with the KaplanMeier method to compute the
survival time and the progression-free survival time, and a
one-sided logrank test was
performed for the hazard ratio
(HR).
Results
Patient and tumor characteristics
Figure 2. Progression-free survival of included patients.
cations, or were found to have disease progression. Follow-up examinations included basic laboratory studies, liver and renal function tests,
esophagography, chest CT scan, and PET/CT
scans when needed.
Statistical analysis
Overall survival (OS) duration was defined as
the time from treatment completion to death
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The patient and tumor characteristics are listed in Table 1.
Thirty-two patients were admitted from August 2010 and
December 2012. The median
age at admission was 66 years. The majority of the patients were male (71.9%), and
all had squamous cell carcinoma (100%). The most common site of the primary tumor
was the middle esophagus
(53.1%). At the time of presentation, 65.6% and 34.4% of
patients were clinically confirmed with stages II and III
cancer, respectively.
Clinical outcomes
April 30, 2014 was the date of the last followup, with a median follow-up time of 30 months
(range 26-36 months). At 1 month post-treatment, 17 (53.1%) of the patients attained a
complete response (CR) and 10 (31.3%) achieved a partial response (PR), whereas 3 (9.4%)
and 2 (6.3%) patients showed stable disease
(SD) and progressive disease, respectively. The
Int J Clin Exp Med 2016;9(10):20137-20144
rh-Endo combined with CRT in ESCC
Table 2. Response, recurrence rate and distant metastasis rate result
CR rate
PR rate
SD rate
PD rate
1-y OS
3-y OS
1-y PFS
3-y PFS
Recurrence rates
Distant metastasis rates
Value
17 (53.1%)
10 (31.3%)
3 (9.4%)
2 (6.3%)
22 (68.8%)
14 (43.8%)
18 (56.3%)
10 (31.3%)
13 (40.6%)
9 (28.1%)
MST was 22.0 months, and the median PFS
was 16.0 months. The 1- and 3-year OS rates
were 68.8% and 43.8% (Figure 1), and the corresponding PFS rates were 56.3% and 31.3%,
respectively (Figure 2). Local recurrence and
distant metastases were observed in 13
(40.6%) and 9 (28.1%) patients, respectively.
Four metastases were detected in the lungs,
one in the bones, three in the liver, and one in
a distant lymph node (Table 2).
Toxicities
The most common acute and late toxicities are
shown in Table 3. Esophagitis, hematologic,
and gastro-intestinal complications were common acute toxicities during treatment. Two patients refused to receive the second cycle of
chemotherapy because of grade 3 platelet toxicity. Other toxicities included acute cerebral
infarction (1/32), herpes virus infection (1/32),
pulmonary infection (2/32), severe fatigue
(3/32), fever (3/32), tracheoesophageal fistula
(1/32), and endostatin-related mild allergic
rash (1/32). One patient died of radiation pneumonia. All patients received 60 Gy of irradiation, except for one who received only 42 Gy for
acute cerebral infarction. Late toxicities after
the treatment included radiation pneumonia
(2/32), esophageal stenosis (6/32), and heart
injury (1/32). Serious late radiation toxicities,
such as radiation-induced myelitis and pericarditis, were not observed.
Discussion
Esophageal cancer is the most common thoracic cancer. Surgery or radiotherapy can achieve satisfactory results in the early stages of
20141
the disease, and a multidisciplinary treatment
is needed in the late stages [14]. Definitive
chemoradiotherapy can improve the survival
rate of patients with esophageal cancer. Recent
studies confirmed that concurrent radiotherapy
and chemotherapy in advanced esophageal
cancer are safe and feasible [15, 16]. However,
esophageal cancer is not always sensitive to
chemoradiotherapy. As a result, local invasion
could not be controlled, and relapses, lymph
node metastasis, and distant metastasis occur.
Most patients with esophageal cancer presenting with advanced inoperable disease have an
extremely poor prognosis. With combination
chemotherapy, MSTs of 9 and 14 months are
reported for patients with metastatic and locally advanced inoperable diseases, respectively
[17].
New molecular-targeted drugs are potential
future treatment options to improve the therapeutic effect. In many cancers, proangiogenic
pathways have been established as important
and effective therapeutic targets because they
are essential for tumor growth, progression,
and metastasis [18]. The research on antiangiogenic therapy for cancer began in 1971 with
the publication of Folkman’s imaginative hypothesis that tumor growth and progression depend on tumor angiogenesis [19]. The proof of
principle for VEGF inhibition in NSCLC has been
demonstrated in clinical trials of bevacizumab
in combination with platinum-based chemotherapy. Combination treatment improved survival versus chemotherapy alone in a first-line
setting in patients with non-squamous NSCLC
[20]. The pivotal AVF2107g trial proved that
adding bevacizumab to irinotecan, fluorouracil,
and leucovorin resulted in a statistically significant and clinically meaningful improvement in
the primary end point, OS (median OS, 20.3 mo
vs. 15.6 mo, HR = 0.66, P < 0.001) and the secondary end point, PFS (median PFS, 10.6 mo
vs. 6.2 mo, HR = 0.54, P < 0.001) [21].
Endostatin is one of the most potent endothelial cell inhibitors of angiogenesis and tumor
growth without displaying toxic side effects and
drug resistance. Endostatin suppresses endothelial cell proliferation and migration, thereby
inhibiting tumor angiogenesis [22]. In vitro experimental results showed that radiotherapy
combined with endostatin can significantly inhibit tumor growth and induce tumor regression, which may be related to the improvement
Int J Clin Exp Med 2016;9(10):20137-20144
rh-Endo combined with CRT in ESCC
attributed to the fact that the
majority of cases in this study
Grade 1
Grade 2
Grade 3 Grade 4
were in stage II (65.6%). A previAcute toxicities
ous study of concurrent chemoEsophagitis
13 (40.6%) 11 (34.4%) 2 (6.3%)
0
radiotherapy for locally advanced
Hematologic
17 (53.1%) 9 (28.1%) 2 (6.3%)
0
esophageal cancer patients shoGastrointestinal
18 (56.3%) 6 (18.8%) 4 (12.5%)
0
wed that the 2- and 3-year OS
Late toxicities
rates were 38.5% and 18.5%, reRadiationpneumonia 1 (3.1%)
0
0
1 (3.1%)
spectively [25]. Endostatin can
potentially cause cardiovascular
Esophagealstenosis 4 (12.5%)
2 (6.3%)
0
0
toxicities; thus, we applied intenHeart injury
1 (3.1%)
0
0
0
sity-modulated radiotherapy to reEndostatin-related
1 (3.1%)
0
0
0
duce the doses to the heart and
lungs. Despite adding a targeted
of tumor hypoxia and the inhibition of radiationdrug to the chemoradiotherapy regimen, definiinduced tumor angiogenesis in human xenotive CRT was not reduced. This result suggestgraft tumor models [23]. Zhou reported that
ed that combination with endostatin seems
endostatin combined with radiotherapy can sigtolerable for patients with locally advanced esonificantly improve antitumor activity. The tumor
phageal cancer. The primary toxicities observed
inhibition rates of endostatin, radiation, and
were associated with CRT. The present study is
endostatin plus radiation were 27.1%, 60.5%,
limited by the small number of cases analyzed.
and 86.1%, respectively. VEGF levels in the
Future studies with a larger number of cases
tumor tissue in the endostatin plus radiation
need to be conducted.
group were lower than those in the radiation
Conclusions
and control groups [24]. The results of the present study are important because they verified
We conclude that combining endostatin with
that endostatin can create a vascular normalCRT in treating primary unresectable carcinoization time window after treatment in lung canma of the esophagus may be a promising treatcer xenografts. Moreover, the results verified
ment for patients with unresectable esophathat the anti-tumor effect of irradiation is engeal cancer without systemic metastases, with
hanced during the normalization time induced
no observable increase in adverse effects and
by delivering endostatin. Zhong studied the
tolerable toxicity. Further prospective randomcombination of endostatin with definitive chemized controlled studies are needed to confirm
oradiotherapy for patients with advanced esothis finding.
phageal cancer. CRT combined with endostatin
resulted in a marked improvement in the comAcknowledgements
plete response rates (44.4% vs. 30.0%) and an
increase in the 1- and 3-year OS rates (72.0%
This work was supported by the Natural Science
vs. 50.0% and 32.0% vs. 22.0%, respectively).
Foundation of China (No. 81272504, No. 8147The median time to progression was extended
2809), Innovation Team [No. LJ201123 (EH11)],
to 11.3 months in the combination group vs.
A Project Funded by the Priority Academic Pr8.1 months in the CRT-alone group. Treatmentogram Development of Jiangsu Higher Educarelated toxicities that could be attributed spetion Institutions (PAPD) (JX10231801), grants
cifically to endostatin were not observed [8]. In
from Key Academic Discipline of Jiangsu Provin
our study of patients with esophageal cancer,
ce “Medical Aspects of Specific Environments”,
endostatin combined with chemoradiotherapy
the Six Major Talent Peak Project of Jiangsu
was well tolerated. The incidence of grade 3
Province (2013-WSN-040), Jiangsu Provincial
toxicity was 12.5%, and no grade 4 toxicity
Science and Technology Projects [BK2011854
occurred. The 1- and 3-year OS rates were
(DA11)], and the “333” Project of Jiangsu
68.8% and 43.8%, respectively, and the correProvince [BRA2012210 (RS12)].
sponding PFS rates were 56.3% and 31.3%.
The CR rate was 53.1%. These results are more
Disclosure of conflict of interest
favorable than those reported previously for
chemoradiotherapy alone, which may be partly
None.
Table 3. The most common acute toxicities and late toxicities
20142
Int J Clin Exp Med 2016;9(10):20137-20144
rh-Endo combined with CRT in ESCC
Address correspondence to: Min Yang and Xinchen
Sun, Department of Radiation Oncology, The First
Affiliated Hospital of Nanjing Medical University,
Nanjing 210029, Jiangsu, China. Tel: (086) 25-68135701; E-mail: [email protected] (MY); Tel: (086)
25-68135700; E-mail: [email protected]
(XCS)
[8]
[9]
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