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\begin{document}

\title{Role of Anticoagulation in the Management of Tumor Thrombus: A 10 year
single center experience}



\author[1]{Shreya Agarwal}%
\author[2]{Dolores Mullikin}%
\author[2]{Valeria Smith}%
\author[1]{Michael  Scheurer}%
\author[1]{Bindi Naik-Mathuria}%
\author[1]{Paul Guillerman}%
\author[1]{Jennifer Foster}%
\author[1]{Rosa Diaz}%
\author[2]{Sarah Sartain}%
\affil[1]{Texas Children's Hospital}%
\affil[2]{Baylor College of Medicine}%


\vspace{-1em}



  
  \date{June 07, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Background: Children with cancer diagnosis are overall at a higher risk
of thrombosis. For a newly diagnosed bland thrombus, patients are
commonly started on anticoagulants to prevent further extension and
embolization of the clot. In the rare instance that a pediatric patient
has a tumor thrombus, the role of anticoagulation is less clear.
Procedure/Methods: Patients under 21 years of age with a finding of
tumor thrombus on imaging from 2010-2020 at Texas Children's Hospital
were identified and their medical records were reviewed. Results: A
total of 50 patients were identified. Most thrombi were incidental
findings at diagnosis; however, there were two patients who presented
with pulmonary embolism (PE). Inferior Vena Cava extension was noted in
36\% of the patients and 24\% patients had an intracardiac tumor
thrombus. Hepatoblastoma (26\%) was the most common malignancy
associated with tumor thrombus. Anticoagulation was initiated in 10
patients (20\%). Only 2 of these 10 patients showed response to
anticoagulation. However, 40\% (4/10) patients in the anticoagulation
cohort were noted to have bleeding complications (p \textless{}.05).
Conclusion: Children with intravascular extension of solid tumors were
not commonly started on anticoagulation at the time of diagnosis,
irrespective of the extent of tumor thrombus. Furthermore, we observed a
significant trend toward higher incidence of bleeding complications
after initiation of anticoagulation. There is inadequate evidence at
this time to support routine initiation of anticoagulation in pediatric
patients with intravascular extension of solid tumors.%
\end{abstract}%



\sloppy


\emph{Role of Anticoagulation in the Management of Tumor Thrombus: A 10
year single center experience}

\emph{Shreya Agarwal, MD\textsuperscript{1}, Dolores Mullikin,
MD\textsuperscript{1}, Michael E. Scheurer, PhD,
MPH\textsuperscript{1,2} , Valeria Smith, MD\textsuperscript{1}, Bindi
Naik-Mathuria, MD MPH\textsuperscript{3}, Robert P. Guillerman,
MD\textsuperscript{4}, Jennifer H. Foster, MD\textsuperscript{1}, Rosa
Diaz, MD\textsuperscript{1}, Sarah E. Sartain, MD\textsuperscript{1}}

\textsuperscript{1} Texas Children's Cancer and Hematology Center,
Baylor College of Medicine, Houston Tx

\textsuperscript{2} Center for Epidemiology and Population Health, Texas
Children's Hospital, Baylor College of Medicine, Houston Tx

\textsuperscript{3} Department of Surgery, Texas Children's Hospital,
Baylor College of Medicine, Houston Tx

\textsuperscript{4} Department of Radiology, Texas Children's Hospital,
Baylor College of Medicine, Houston Tx

Corresponding Author: Shreya Agarwal, MD

Texas Children's Hospital

Hematology and Cancer Center

6701 Fannin Suite 1510

Houston, Texas

sa9@bcm.edu

Word Count: Abstract- 235, Main text- 2896

Number of Tables: 2

Number of Figures: 1

Supplementary date: None

Running Title: Anticoagulation role in management of tumor thrombus

Keywords: Tumor thrombus, vascular metastasis, Wilms tumor,
osteosarcoma, anticoagulation, malignancy, bleeding, enoxaparin,
pulmonary embolism

Abstract:

\emph{Background\textbf{:}} Children with cancer diagnosis are overall
at a higher risk of thrombosis. For a newly diagnosed bland thrombus,
patients are commonly started on anticoagulants to prevent further
extension and embolization of the clot.~ In the rare instance that a
pediatric patient has a tumor thrombus, the role of anticoagulation is
less clear.\emph{~~}

\emph{Procedure/Methods} : Patients under 21 years of age with a finding
of tumor thrombus on imaging from 2010-2020 at Texas Children's Hospital
were identified and their medical records were reviewed.

\emph{Results:} A total of 50 patients were identified. Most thrombi
were incidental findings at diagnosis; however, there were two patients
who presented with pulmonary embolism (PE). Inferior Vena Cava extension
was noted in 36\% of the patients and 24\% patients had an intracardiac
tumor thrombus. Hepatoblastoma (26\%) was the most common malignancy
associated with tumor thrombus. Anticoagulation was initiated in 10
patients (20\%). Only 2 of these 10 patients showed response to
anticoagulation. However, 40\% (4/10) patients in the anticoagulation
cohort were noted to have bleeding complications (p \textless{}.05).

\emph{Conclusion:} Children with intravascular extension of solid tumors
were not commonly started on anticoagulation at the time of diagnosis,
irrespective of the extent of tumor thrombus.~Furthermore, we observed a
significant trend toward higher incidence of bleeding complications
after initiation of anticoagulation.~There is inadequate evidence at
this time to support routine initiation of anticoagulation in pediatric
patients with intravascular extension of solid tumors.

INTRODUCTION:

Children with cancer are at increased risk for venous thrombosis (VT) or
venous thromboembolism (VTE). ~This complication can manifest as bland
thrombus or tumor thrombus\textsuperscript{1,2}. Tumor thrombus is
defined as the extension of the tumor into the vessel lumen, typically a
vein. Incidence of tumor thrombus varies depending upon the type of
cancer\textsuperscript{3}. In children, it is most widely reported to be
associated with Wilms tumor\textsuperscript{4,5}. Although pathologic
exam is the reference standard, imaging is very reliable and helps in
early detection of tumor thrombus, without the use of any invasive
technique\textsuperscript{6}.

Bland thrombus on the other hand, is a fibrin clot without neoplastic
cells which may occur in patients with or without an underlying
malignancy. Bland thrombus is thought to result from the interaction of
various factors such as cancer type, presence of central venous
catheters, chemotherapy and acquired or inherited prothrombotic defects,
among others\textsuperscript{1}. Cancer can also contribute to the
development of bland thrombus by mechanical effects on the venous flow,
as in those with solid tumors\textsuperscript{2}. It is unknown if
intravascular extension or tumor thrombus increase the risk for bland
thrombus formation. Anticoagulation is sometimes administered in
conjunction with cancer-directed therapy to this group of patients.

Available literature describing the treatment characteristics and
outcomes of pediatric patients with solid tumor-associated tumor
thrombus is limited, and there are no evidence-based studies to guide
management. The purpose of this study is to describe the role of
anticoagulation in patients with tumor thrombus. We performed a
retrospective review at a large pediatric tertiary care center to
evaluate the clinical and treatment characteristics of patients with
tumor thrombus, indications for starting anticoagulation, and rate of
bland tumor formation and bleeding events for those treated with and
without anticoagulation.

METHODS:

Ethics approval, including waiver of consent, was obtained from the BCM
Institutional Review Board prior to data collection. We conducted a
retrospective review of consecutive patients with tumor thrombus between
January 2010 to May 2020 at Texas Children's Hospital (TCH)/Baylor
College of Medicine (BCM).

\textbf{Data collection:}

Imaging studies, including computed tomography (CT), magnetic resonance
imaging (MRI), ultrasonography (US) and echocardiography, for all
patients who were seen at TCH Cancer Center during the study period were
pulled from the electronic medical record using the keywords ``TUMOR''
and ``THROMBUS'' in the final impression. Epic Clarity reporting
database, based on the Oracle relational database management system, was
used. Pulled data was written in the Oracle SQL Developer tool.
Exclusion criteria included patients with age above 21 years or no
finding of tumor thrombus on imaging. For patients meeting the criteria,
the electronic medical records were comprehensively reviewed and
following data collected: patient demographics, tumor type, imaging
findings, treatment including chemotherapy, surgery, radiation,
anticoagulation- dose, duration, rationale, and complications.

\textbf{Definitions:}

Therapeutic anticoagulation was defined as low molecular weight heparin
(LMWH) dosed as 1 mg/kg subcutaneously (SQ) every 12 hours to attain
anti-FXa levels between 0.5 to 1, or unfractionated heparin (UFH)
administered intravenously to attain anti-FXa levels of 0.3 to 0.7
and/or PTT of 70 to 110 seconds. Prophylactic anticoagulation was
defined as LMWH 0.5 mg/kg SQ every 12 hours to attain anti-FXa level
between 0.2 to 0.4 or adult dose of 40 mg SQ daily.

Bleeding was defined per International Society on Thrombosis and
Hemostasis (ISTH) guidelines. Non major or minor bleeding was defined as
overt bleeding requiring blood product transfusion (not directly
attributable to the patient's underlying condition), bleeding requiring
medical or surgical intervention to restore hemostasis other than in the
operating room, other bleeding for which medical attention has been
sought and/or any overt macroscopic evidence of bleeding not fulfilling
above criteria for major bleeding\textsuperscript{7}. Major bleeding
defined as fatal bleeding, symptomatic bleeding in a critical area or
organ (like intracranial, intraocular, pericardial), and/or bleeding
causing a fall in hemoglobin by 2 g/dL or more requiring transfusion of
2 or more units of while blood or red blood cells\textsuperscript{8}.

\textbf{Outcomes:}

Our primary outcomes were the percent of patients with tumor thrombus
who received anticoagulation in combination with cancer-directed
therapies and the rate of bland tumor formation in patients treated with
or without anticoagulation.

Our secondary outcomes were all-cause mortalities; and the rate of
clinically relevant, non-major or minor bleeding, and/or major bleeding.

\textbf{Statistics:}

Descriptive statistics were used to compare demographic and clinical
characteristics between patients who did and did not experience a
bleeding event at the end of our follow up period. The Chi squared test
or Fisher's exact test, if less than 5 patients were in any given cell
of the contingency table, was used to compare categorical variables. A
two-sided p-value of 0.05 was used for statistical significance.

RESULTS:

On initial search of the medical records, 100 patients were identified.
Of these, only 50 met the study criteria. A total of 50 patients were
included in the final analyses. The remaining patients either did not
meet the age criteria (below 21 years) or on further detailed review of
the imaging, did not have a tumor thrombus. Patient characteristics are
summarized in Table 1. Most patients (n=13, 26\%) had hepatoblastoma,
followed by osteosarcoma (n=7, 14\%) (Figure 1). Eighteen patients
(36\%) had tumor thrombus confined to the inferior vena cava (IVC) and
12 patients (24\%) had tumor thrombus extending beyond the IVC to the
heart. For the remaining patients, tumor thrombus was limited to the
invasion of local draining vessels. The diagnostic imaging modalities
most frequently identifying tumor thrombus were CT (48\%) and MRI
(40\%). Echocardiogram was performed for all patients who had an IVC or
intracardiac tumor thrombus. Seventy percent (35/50) of tumor thrombus
cases on imaging were confirmed by pathological examination. 31 of these
35 patients underwent surgical resection, and for the remaining
patients, tissue for pathology was obtained on tumor biopsy (n=3) or
during thrombectomy (n=1).

Overall, 5 patients received upfront surgery and 6 did not receive any
cancer-directed therapy due to relapsed terminal disease. All others
received pre-operative chemotherapy (n=39, 78\%). Cardiac bypass was
required in 5 of the 12 patients with intracardiac tumor thrombus at the
time of surgical resection of the primary tumor and tumor thrombus.

\textbf{OVERALL OUTCOMES}

\textbf{Anticoagulation use and rate of bland thrombus}

A total of 10 (20\%) patients with tumor thrombus received
anticoagulation in combination with cancer-directed therapies. Patient
and tumor thrombus characteristics are summarized in Table 2. Six
patients received therapeutic doses of anticoagulation and 4 received
prophylactic doses of anticoagulation. The rationale for starting
anticoagulation was symptomatic tumor thrombus in 4 patients: pulmonary
embolism (PE, n=2), renal vein thrombus (RVT, n=1) and lower extremity
pain and swelling (n=1) concomitant to tumor thrombus diagnosis. Patient
6 was a teenager who relapsed with a right atrial thrombus identified on
routine surveillance imaging after completing therapy and achieving
complete remission of osteosarcoma. Despite therapeutic anticoagulation,
she developed a symptomatic PE 1 week later which required urgent
mechanical thrombectomy. Tissue specimen confirmed relapsed osteosarcoma
and the anticoagulant was discontinued. She subsequently died of another
PE. Patient 7 had newly diagnosed Ewing sarcoma treated with upfront
radical nephrectomy and IVC tumor thrombectomy, which was confirmed by
pathology. Routine scans obtained 2 weeks later, showed possible
residual tumor thrombus in IVC surgical site and pulmonary infarcts with
confirmation of PE via CT angiography. She was started on chemotherapy
following the surgery. The finding of thrombus on repeat imaging was
concerning for tumor thrombus vs a component of bland thrombus that
might have developed post thrombectomy. Hence, she was started
therapeutic anticoagulation in addition to chemotherapy for Ewings
sarcoma. After 6 months of therapeutic anticoagulation and chemotherapy,
repeat imaging studies showed complete resolution of IVC thrombus and
PE. She ultimately died due to relapsed disease. Patient 8 had clear
cell sarcoma with extensive tumor thrombus extending from IVC to common
iliac and femoral veins. Chemotherapy was initiated soon after
diagnosis, but anticoagulation was not started at that time. However, he
presented a few weeks later with left lower leg pain and swelling.
Repeat imaging showed the same extensive tumor thrombus and a new
separate small occlusive thrombus in the superficial femoral vein which
could be tumor thrombus vs bland thrombus. Given the patient was
symptomatic, he was started on therapeutic anticoagulation. Leg pain and
swelling resolved after 4 days and anticoagulation was discontinued at
that point. Patient underwent surgical resection and IVC thrombectomy
later and pathology confirmed the finding of tumor thrombus. Finally,
patient 10 was started on therapeutic anticoagulation for occlusive
renal vein tumor thrombus causing elevated creatinine, concerning for
acute kidney injury. He received three months of therapeutic
anticoagulation along with chemotherapy for metastatic embryonal
carcinoma and repeat imaging at the end of three months showed improved
blood flow through the renal vein. The other six patients had an
asymptomatic tumor thrombus. Rationale for initiating anticoagulation in
these patients was to prevent further progression and possible embolism
of the bland thrombus component of the tumor from high risk locations
(IVC and/or right atrium).

The follow up period for the cohort was a median of 13.5 months (range 1
month to 7 years). Of the patients with or without anticoagulation, none
developed a subsequent bland thrombus and/or embolization secondary to
tumor thrombus, although there was uncertainty about one patient:
Patient 7 developed another thrombus post-surgical resection, but
without pathologic exam, it was unknown if this was bland thrombus or a
remnant of the previous tumor thrombus. A single patient developed a
clearly catheter-associated deep vein thrombus not related to tumor
thrombus 1 month after his cancer diagnosis.

\textbf{Mortality and bleeding events}

The all-cause mortality was 38\% (19/50). The mortality rate for the
anticoagulation and no anticoagulation groups was 30\% (n=3) and 40\%
(n=16), respectively, and this was not statistically significant (p
=.7222). These deaths were mostly related to cancer progression and one
patient died of pulmonary embolism (patient 6).

A larger percentage of patients on anticoagulation had bleeding
complications than patients who did not receive anticoagulation (p
\textless{}.05) (Anticoagulation cohort: n=4, 40\%; no anticoagulation
cohort: n=2, 5\%). Of the 4 anticoagulated patients who bled, 3 had
gastrointestinal bleeding. One with massive post-op intra-abdominal
bleeding requiring exploratory laparotomy, two with bloody stool with no
notable drop in hemoglobin. One patient had mild epistaxis and gingival
bleeding. Two of the 40 patients who did not receive anticoagulation had
bleeding complications, including one with intra-operative hemorrhagic
shock due to intra-tumoral bleeding. No statistical difference was noted
for bleeding events based on gender, ethnicity, or the type of tumor.

DISCUSSION:

The major focus of this study was to review the role of anticoagulation
in the treatment of tumor thrombus. Our study showed that a minority
(20\%) of patients with tumor thrombus at a large tertiary center
received anticoagulation with the purpose of preventing bland thrombus
formation and/or embolization. Furthermore, there was no significant
difference in the rate of bland thrombus formation and/or embolization
or in overall survival in pediatric patients with intravascular
extension of a solid tumor or tumor thrombus treated with or without
anticoagulation. Patients who received anticoagulation experienced a
statistically significant increase in bleeding events.

Tumor thrombus is overall an uncommon clinical entity. However, its
presence can complicate the management plan. Hence, early and accurate
detection is helpful in surgical planning and in some cases, tumor
staging \textsuperscript{9,10}. Imaging is critical for early detection
and differentiation from bland thrombus \textsuperscript{11}. In adults,
renal cell carcinoma, hepatocellular carcinoma, and adrenocortical
carcinoma are the malignancies most frequently associated with tumor
thrombus\textsuperscript{12}; while in children, Wilms tumor has a
tendency for vascular invasion \textsuperscript{3,13}. In Wilms tumor,
20-35\% patients have renal vein involvement, while extension into the
IVC is reported in 4-10\% of patients \textsuperscript{4,13}. There are
isolated case reports reporting vascular invasion and tumor thrombus in
patients with Ewing sarcoma, osteosarcoma, neuroblastoma, and
hepatoblastoma \textsuperscript{14--17}. In our study, the most common
malignancy associated with tumor thrombus was hepatoblastoma, followed
by osteosarcoma and Wilms tumor.

Most of the patients were asymptomatic and tumor thrombus was detected
on routine imaging, similar to the observation in previous
studies\textsuperscript{5,13}. However, two of our patients presented
with PE and one with lower extremity pain and swelling. PE has been
previously reported as a presenting sign of primary or relapsed
osteosarcoma associated with tumor thrombus \textsuperscript{18,19}.
Yeduluri et al speculated that this could be attributable to the
predilection of metastatic spread by vascular invasion in
osteosarcoma\textsuperscript{20}. Our patient with Ewing sarcoma had
tumor thrombus-related PE, similar to a report by Dotson et al
describing a patient with Ewing sarcoma who developed systemic emboli
and myocardial infarction from tumor thrombus located in the left
atrium\textsuperscript{21}.

Although chemotherapy, surgery, and/or radiation form the backbone of
management of primary tumor and potentially, tumor thrombus, there is a
risk of tumor rupture or spread with potential complications such as PE
or systemic emboli of bland thrombus components. This risk is
particularly high in cases where tumor thrombus is located in the IVC or
extending to the heart. Hence considering anticoagulation, either by
prophylactic or therapeutic dosing, is not unreasonable. However, the
use of anticoagulation for patients with tumor thrombus is inconsistent.
While all Wilms tumor patients with intracardiac extension of the tumor
received anticoagulation post-resection for a minimum of 3 months in a
study by Cox et al \textsuperscript{22}, anticoagulation was not
attempted in some other similar studies \textsuperscript{4,13,23} and
the results were comparable in terms of survival and response to
treatment. In a review assessing OS patients with cardiovascular
involvement, the authors reported one patient was on anticoagulation
before the diagnosis of tumor thrombus was correctly established, but
otherwise almost all patients received chemotherapy and/or surgery with
no adjuvant anticoagulation with good outcomes \textsuperscript{20}. In
a study of patients with renal cell carcinoma, the most common tumor
associated with tumor thrombus in adults, presenting with PE, 5 of the 7
patients received anticoagulation with either unfractionated heparin or
enoxaparin; anticoagulation was held in the remaining two patients due
to bleeding \textsuperscript{24}. The authors' rationale was that
patients with malignancy are already at a high risk for thrombosis and
in the presence of an IVC tumor thrombus, there is additional
disturbance of flow through the IVC, further increasing their risk of
bland thrombosis or thromboembolism. In our patient cohort, we noted a
similar approach by the providers in that most of patients did not
receive anticoagulation, but it was initiated in 20\% of the patients
for management of signs or symptoms and/or to prevent further
complications from progression of bland components of the tumor thrombus
or thromboembolism. However, we want to emphasize that although
anticoagulation could be helpful, the backbone of treatment of tumor
thrombus is surgical with or without chemotherapy and radiation (when
indicated) for the underlying malignancy \textsuperscript{3}. This is
supported by findings in our patient cohort. Our patient with relapsed
osteosarcoma continued to have worsening tumor thrombus despite
therapeutic anticoagulation until thrombectomy was performed, and
despite initial improvement, had another episode of PE in the absence of
cancer-directed therapy. In contrast, our patient with Ewing sarcoma
received anticoagulation in conjunction with chemotherapy and surgery
and had a complete resolution of the tumor thrombus. The underlying
characteristics of tumor thrombus are different than bland thrombus
making it more likely to resolve with chemotherapy and respond minimally
to anticoagulation.

The benefits of anticoagulation must be weighed against the risks of
bleeding. Malignancy itself places patients at a high risk of bleeding
and thrombosis. In our dataset, 40\% patients on anticoagulation
developed bleeding, while this percentage was only 5\% for the group not
on anticoagulation. This difference in bleeding was statistically
significant, which is not surprising given the use of anticoagulation in
one group, but further underscores the importance of considering
anticoagulation on a case-by-case basis.

There are some limitations of this study. The design is retrospective
with subjects being identified by reported imaging findings. It is
possible that some patients may not have been included if tumor thrombus
was diagnosed intra-operatively but not appreciated on imaging, leading
to underreporting of the finding in our study. This could possibly
explain why there was a lower proportion of Wilms tumor thrombus in our
study compared to other pediatric reports. Pathological confirmation was
not made for all the suspected tumor thrombus cases, raising the
possibility that some tumor thrombi may have a component of bland
thrombus and hence, may have responded in part to anticoagulation. As a
single center study, our sample size is small, limiting the statistical
power to draw conclusions. Hence, further larger multi-center studies
are to needed to confirm these findings.

In conclusion, this study reports the largest case series of pediatric
tumor thrombus treated with or without anticoagulation in combination
with cancer-directed therapy. An important advantage of our study over
previous reports is that we focused on the role of anticoagulation in
lessening the potential risk of bland thrombus formation and/or
embolization in this cohort of patients since data is limited on this
subject. We found no difference in rate of bland thrombus formation
and/or embolization or survival in patients who did or did not receive
anticoagulation. However, we did find a significantly higher rate of
bleeding events in the anticoagulation group. Our study provides some
practical information and guidance for clinicians considering the use of
anticoagulation in these complicated patients both at risk for bleeding
and clotting. While we found no clear evidence that anticoagulation
administered in conjunction with cancer-directed therapies improves
outcomes in pediatric patients with tumor thrombus, further studies are
indicated to identify subgroups that may benefit from
thromboprophylaxis.

\textbf{Conflict of Interest:} Authors have no conflict of interest to
disclose.

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Figure 1: Distribution of solid tumor malignancies with tumor thrombus
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