Int J Clin Oncol (2011) 16:444–446
DOI 10.1007/s10147-010-0148-4
CASE REPORT
Pulmonary embolism due to internal jugular vein thrombosis
in a patient with non-small cell lung cancer receiving bevacizumab
Yosuke Togashi • Young Hak Kim •
Katsuhiro Masago • Koji Tamai • Yuichi Sakamori •
Tadashi Mio • Michiaki Mishima
Received: 13 August 2010 / Accepted: 1 November 2010 / Published online: 30 November 2010
Ó Japan Society of Clinical Oncology 2010
Abstract Internal jugular vein thrombosis is much less
common than deep venous thrombosis of lower limbs and
is generally caused by an indwelling venous catheter or
otological infection. Several cases of internal jugular vein
thrombosis associated with malignancy have been also
reported. Bevacizumab, a monoclonal neutralizing anti-
body against vascular endothelial growth factor, has shown
benefits in the treatment of many types of malignancy and
its use is increasing. Serious adverse effects, however, are
associated with the use of bevacizumab, including venous
thromboembolism. In this article, we present a rare case of
non-small cell lung cancer complicated by pulmonary
embolism due to internal jugular vein thrombosis associ-
ated with bevacizumab.
Keywords Non-small-cell lung cancer
Bevacizumab

Internal jugular vein thrombosis
Pulmonary embolism
Introduction
Bevacizumab, a recombinant humanized monoclonal neu-
tralizing antibody against vascular endothelial growth
factor (VEGF), has shown benefits in the treatment of
many types of malignancy including colorectal cancer,
non-small cell lung cancer (NSCLC), renal cell carcinoma,
and breast cancer. Serious adverse effects are associated
with the use of bevacizumab, including gastrointestinal
Y. Togashi
Y. H. Kim (&)
K. Masago
K. Tamai

Y. Sakamori
T. Mio
M. Mishima
Department of Respiratory Medicine,
Graduate School of Medicine, Kyoto University,
54 Shogoin-Kawaracho, Sakyo-ku, Kyoto 606-8507, Japan
e-mail: ekim@kuhp.kyoto-u.ac.jp
123
tract perforation, hemorrhage, arterial thromboembolism,
hypertensive crisis, reversible posterior leukoencephalop-
athy syndrome, neutropenia and infection, nephrotic syn-
drome, and congestive heart failure [1]. In addition, a
recent meta-analysis showed that the use of bevacizumab
has also been associated with a significantly increased risk
of venous thromboembolism (VTE) in cancer patients [2].
Deep venous thrombosis (DVT) of lower limbs is
widely recognized as a leading cause of pulmonary
embolism (PE) [3]. However, internal jugular vein
thrombosis is much less common and is generally caused
by an indwelling venous catheter or otological infection
[4]. In this article, we present a rare case of NSCLC
complicated by PE due to internal jugular vein thrombosis
associated with bevacizumab.
Case report
A 55-year-old male visited our hospital due to dyspnea. He
was diagnosed with NSCLC, with the primary lesion a
15-mm nodule in the left upper lobe, and the disease stage
cT4N3M1b, stage IV with bilateral mediastinal lymph
nodes metastases, left supraclavicular lymph node meta-
stasis, pleural dissemination, bilateral multiple pulmonary
metastases, and left adrenal metastasis. He received first-
line chemotherapy [carboplatin (AUC, 5) and paclitaxel
(175 mg/m2) plus bevacizumab (15 mg/kg)] and achieved
stable disease after 2 courses. However, he developed
dyspnea 10 days after the 3rd course of first-line chemo-
therapy and the symptom was getting worse.
He had Eastern Cooperative Oncology Group perfor-
mance status of 1 and weight loss of 10 kg per 6 months.
Physical examination showed that he had a blood pressure of
100/70 mmHg, a heart rate of 90/min, and decreased left
Int J Clin Oncol (2011) 16:444–446
Fig. 1 Chest contrast computed tomography (CT) after 2 courses of
first-line chemotherapy (carboplatin and paclitaxel plus bevacizumab)
revealed no thrombosis in the right internal jugular vein (a). The chest
respiratory sound on auscultation. There was no swelling
of his neck and lower extremities. Laboratory tests showed
peripheral white blood cells 5,600/mm3, hemoglobin
9.6 g/dl, and platelets increased to 434,000/mm3. Serum
D-dimer value was increased to 4.7 lg/ml. Arterial
blood gas analysis at room air showed pH 7.459, PaCO2
33.9 mmHg, and PaO2 69.5 mmHg. The chest X-ray
revealed left pleural effusion whose cytological examination
showed class V.His disease status was therefore evaluated as
progressive disease. Although pleurodesis was performed,
his symptom was unchanged. The chest contrast computed
tomography (CT) revealed right internal jugular vein
thrombosis and PE (Fig. 1). He was categorized as non-
massive PE by echocardiographic signs of normal right
ventricular function in spite of elevated plasma brain natri-
uretic peptide level (103.7 pg/ml) [5]. Additional blood
sample tests showed almost normal protein C, protein S,
antithrombin III, plasminogen, and a2-plasmin inhibitor.
Lupus anticoagulant and anti-cardiolipin antibody tests were
negative. Thereafter, anticoagulant therapy was started and
the symptom improved. He subsequently received second-
line chemotherapy (docetaxel).
Discussion
Angiogenesis, a process involving the proliferation of new
vessels, plays a crucial role in the growth and metastasis of
cancer [6]. This process is mainly driven by VEGF, whose
signaling pathway has been a target of many new anti-
neoplastic agents including bevacizumab, sorafenib, suni-
tinib, and others. Survival benefit by adding bevacizumab
445
contrast CT after 3 courses of first-line chemotherapy revealed right
internal jugular vein thrombosis (b, arrow) and pulmonary embolism
(c, arrow)
was reported when a combination of carboplatin and pac-
litaxel was used as a first-line treatment for advanced lung
cancer [7].
The toxicities observed with bevacizumab include gas-
trointestinal tract perforation, decreased wound healing,
hemorrhage, arterial thromboembolism, hypertension,
neutropenia and infection, nephrotic syndrome, and con-
gestive heart failure [1]. A recent meta-analysis which
included 7,956 patients with a variety of advanced solid
tumors from 15 randomized controlled trials in which
standard chemotherapy was used with or without beva-
cizumab showed that the use of bevacizumab has been
associated with a significantly increased risk of VTE [rel-
ative risk (RR) 1.33; 95% confidence interval (CI)
1.13–1.56; P \ 0.01] [2]. The risk of development of VTE
following the use of bevacizumab differed among tumor
types. For patients with NSCLC, the incidence of high-
grade VTE was 6.5% (95% CI 5.3–8.1). In addition, the
influence of the dose of bevacizumab was investigated in
this meta-analysis and the result was that both high and low
doses were associated with a significantly increased risk of
VTE [2].
The development of VTE may result from the anti-
VEGF effect of bevacizumab: (1) it may expose suben-
dothelial procoagulant phospholipids leading to thrombosis
by inhibiting VEGF-induced endothelial regeneration;
(2) it may reduce the production of nitric oxide and pros-
tacyclin, thus predisposing to thromboembolism; (3) inhi-
bition of VEGF may also increase the risk of thrombosis by
increasing hematocrit and blood viscosity via overproduc-
tion of erythropoietin; (4) it may increase the release of
procoagulant from the tumor into the bloodstream due to
123
446
an enhanced cytotoxic effect; and (5) it may increase
expression of proinflammatory cytokines causing damage
and in situ thrombus formation [2, 8].
The cancer population has an overall increased risk of
thrombosis [9, 10], and patients with idiopathic venous
thrombosis have an increased risk of harboring an occult
malignancy [11]. Some malignancies including lung cancer
are associated with a higher risk of VTE than others.
Additional risk factors include hospitalization, immobili-
zation, surgery, advanced age, widespread or metastatic
disease, presence of a central venous catheter, active che-
motherapy, presence of thrombophilia, first few months
after diagnosis, and so on [9, 10]. Internal jugular vein
thrombosis is commonly related to an indwelling venous
catheter or otological infection [4]. Several cases of inter-
nal jugular vein thrombosis associated with malignancy
have been also reported [12]. The incidence of PE due to
non-catheter-related thrombosis of the internal jugular vein
is not fully known. From the RIETE registry, 512 (4.4%) of
all DVT patients (11,564) had arm DVT. Of the 512
patients with arm DVT, 196 patients (38%) had cancer and
228 patients (45%) had catheter-related DVT. They pre-
sented less often with clinically overt PE than those with
lower-limb DVT (9.0 vs. 29%), but their 3-month outcome
was similar. Therefore, those authors recommended
appropriate therapy for patients with arm DVT as well as
lower-limb DVT [13]. In the article, however, there was no
description of internal jugular vein thrombosis.
In our case, although there was no indwelling catheter, the
patient had hypercoagulable state due to malignancy. He
also had additional risk factors including metastatic disease,
active chemotherapy, presence of thrombophilia, and first
few months after diagnosis. Then, he developed complica-
tions of PE due to internal jugular vein thrombosis after
receiving bevacizumab. Considering the biological effect of
bevacizumab and his clinical history, its use was thought to
be associated with internal jugular vein thrombosis and PE.
To the best of our knowledge, this is the first report of PE due
to internal jugular vein thrombosis associated with beva-
cizumab. Similar cases can be underdiagnosed because
patients with internal jugular vein thrombosis are sometimes
asymptomatic, as here. Since the use of bevacizumab is
increasing recently, we should be aware of this condition.
123
Int J Clin Oncol (2011) 16:444–446
Although the American Society of Clinical Oncology’s
guidelines do not recommend routine prophylaxis of
ambulatory cancer patients [9], future studies are required to
investigate the prevention and management of VTE asso-
ciated with bevacizumab.
Conflict of interest We declare that we have no potential conflict of
interest related to the article.
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