Review articles
Herz
https://doi.org/10.1007/s00059-019-4833-4
Received: 17 March 2019
Revised: 7 June 2019
Accepted: 14 June 2019
© Springer Medizin Verlag GmbH, ein Teil von
Springer Nature 2019
Background
Malignant tumors are a common cause
of pericardial effusion. The most com-
mon cancer is lung cancer, followed by
breast cancer and lymphoma [1]. Pri-
mary cardiac tumors are rare since can-
cer begins in epithelial tissue, and the
heart is mainly composed of mesenchy-
mal tissue (the only epithelial tissue is
the endocardium and pericardium); the
most common cardiac tumor is mesothe-
lioma [2]. Malignant tumors are a com-
mon cause of pericardial effusion and in
some cases of malignant pericardial ef-
fusion; usually, a pericardial tamponade
that is life-threatening can be the first
symptom [3]. However, in most cases,
the symptoms progress from an asymp-
tomatic state to nonspecific symptoms,
such as dyspnea and tachycardia [4].
Malignant pericardial effusion is as-
sociated with poor prognosis in patients
with cancer and is the main cause of peri-
cardial tamponade [5]. Therefore, treat-
ment aims to relieve symptoms, maintain
hemodynamic stability, and prevent re-
currence of fluid. However, owing to the
diverse causes of malignant pericardial
effusion and the complexity of symptoms
[6], there are numerous challenges for the
treatment of malignant pericardial effu-
sion. This article reports on the latest
developments in the treatment of neo-
plastic pericardial effusion, especially the
clinical application of immunotherapy in
the treatment of neoplastic pericardial ef-
fusion (. Table 1).
J. Zhang1 · Q. Zhang2 · X. Chen2 · N. Zhang1
1
Department of Cardiology, the Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
2
Department of Clinical Medicine, Basic Medical College of Seven Years (2014), Hebei Medical University,
Shijiazhuang, Hebei Province, China
Management of neoplastic
pericardial disease
Surgical method
Pericardiocentesis
Pericardiocentesis is the removal of fluid
from the pericardial space between the
fibrous pericardium and the surface of
the heart, and may be performed as
a diagnostic or a therapeutic procedure
[7]. Pericardial puncture is an emer-
gency operation that is most commonly
performed in cases where a tamponade
threatens the patient’s life. In emergency
pericardial puncture, the pericardial fluid
is aspirated to restore normal heart func-
tion and peripheral perfusion. Although
ultrasound guidance is the preferred
method for pericardial puncture [8],
electrocardiogram (ECG) monitoring is
also used to indicate when the needle is
in contact with the myocardium. Peri-
cardial puncture is usually performed
through the transthoracic approach at
the fifth left intercostal space or the
xiphoid approach between the sternum
and the costal margin [9]. In the event
of a life-threatening situation where im-
mediate ECG monitoring or ultrasound
is not possible, a blind pericardial punc-
ture may be performed. However, this
method has unacceptably high recur-
rence rates and mortality (50% and 6%,
respectively) compared with methods in-
volving ECG or ultrasound monitoring
[10]. The main complications of peri-
cardial puncture are arrhythmia, cardiac
puncture, pneumothorax, and coronary
vascular injury. Other complications
associated with pericardial puncture
include peritoneal puncture, liver or
stomach injury, and diaphragmatic in-
jury (under the xiphoid approach); the
main complication of the parasternal ap-
proach is thoracic artery puncture [11].
For diagnosis with pericardial puncture,
Volk et al. performed cytological and
pathological analyses of 145 patients with
pericardial effusion. In the cytological
diagnosis, only 4.8% (N = 7) of patients
were diagnosed, while the cytological
and pathological diagnosis rate was only
6%. Therefore, the diagnostic value of
pericardial puncture is limited compared
with its therapeutic value [12].
Percutaneous catheter drainage
The pericardial cavity usually contains
25–50 ml of liquid [13]. Accumulation
of exudates or an exudate volume of
>50 ml is considered abnormal and may
cause cardiac compression, leading to sig-
nificant hemodynamic effects and im-
paired heart filling. For patients with
hemodynamic instability, percutaneous
catheter drainage under ultrasound guid-
ance is preferred [14]. Furthermore, pro-
gressive percutaneous catheter drainage
can reduce the abnormal hemodynamic
deterioration of the postoperative para-
doxical hemodynamic instability (PHI;
usually hypotension and shock within
24–48 h of drainage) for a large num-
ber of patients with pericardial effusions
and even those with pericardial tampon-
ade [15]. El Haddad et al. performed
extended catheter drainage on 212 pa-
tients with malignant pericardial effu-
sion. The recurrence rate of pericar-
dial effusion was 10–14%, and the maxi-
mum benefit was observed when catheter
drainage was within 3–5 days [16]. In
cases of pericardial tamponade, patients
are prone to fatal hyponatremia, which
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 Review articles

Table 1 Indications for different treatments of PBP is between the xiphoid and the
Treatment Indications left rib; given that the left rib is prone
to fatal complications such as pneumo-
Surgical method
thorax, the xiphoid process is preferred
Pericardiocentesis Pericardial tamponade
[27]. Several reports have shown that
Percutaneous catheter drainage Patients with hemodynamic instability
for patients with recurrent pericardial ef-
Pericardial window Recurrent large effusion or cardiac tamponade fusion and hemodynamic abnormalities,
Thoracoscopic pericardial Patients with hemodynamic stability PBP complications and effusion recur-
window (TPW) rence rates are lower than in traditional
Balloon pericardiectomy (PBP) Patients with pericardial tamponade or hemodynamic surgery [28–30]. Given that PBP is sim-
deterioration
ple, rapid, and safe, it can replace tradi-
Surgical pericardiectomy Patient life expectancy is very limited due to severe tional surgical xiphoid incision in some
complications or hemodynamic instability
cases, becoming the preferred treatment
Antineoplastic treatment for pericardial tamponade or clinical or
Systemic chemotherapy Malignant pericardial effusion caused by lymphoma and hemodynamic deterioration [31].
small cell lung cancer
Local injection of cytostatic or Malignant pericardial effusion caused by most tumors
sclerosing agent
Surgical pericardiectomy (under
Radiotherapy Malignant pericardial effusion caused by lymphoma,
the xiphoid or thoracic incision)
leukemia, and mediastinal tumors
The most commonly used approach for
Immunotherapy
surgical pericardiectomy is under the
Immunomodulatory monoclonal Advanced cancer patients xiphoid or thoracic incision. When
antibodies
the patient is hemodynamically stable,
Immune adoptive therapy Advanced cancer patients, especially melanoma patients
there is no significant difference in post-
operative complications and effusion
may be improved by pericardial drainage xiphoid, lateral, or anterior thoracotomy recurrence rate for either TPW or PBP
[17]. However, ultrasound-guided peri- [21]. However, an anterior sternal ap- compared with invasive surgery [24].
cardial puncture or catheter drainage may proach is more effective for obese pa- Therefore, in circumstances whereby the
have additional limitations/risks when tients, women with larger breasts, and life expectancy of the patient may be
the pericardial fluid is not free and is patients with ascites [22]. very limited owing to severe complica-
located in the lateral or posterior posi- The most common method for PW tions or hemodynamic instability, the
tion. Therefore, the surgical method may is the thoracoscopic pericardial window subclavian pericardial incision is the
be safer for patients who are difficult to (TPW) or balloon pericardiectomy (PBP) preferred method for PE surgery [32].
discharge or are considered at risk of re- to create the pericardial window. Thora- However, extended catheter drainage is
lapse [18]. coscopic pericardial window has to be the preferred treatment for hemodynam-
performed under conditions of single ically stable patients [33]. In the event
Pericardial window lung ventilation and general anesthesia; that a pericardial biopsy is required to
therefore, TPW is only suitable for pa- confirm the diagnosis, a less traumatic
The most common surgical treatment is tients with hemodynamic stability [23]. TPW or PBP approach is preferable.
pericardial window (PW). This involves Furthermore, for pericardial tamponade Patients with pericardial effusion,
creating a real window by a partial peri- and PHI patients, TPW is absolutely con- regardless of the type of drainage, may
cardiectomy, thereby creating a channel traindicated. Therefore, the application suffer pericardial decompression syn-
to allow for long-term drainage to an benefit of TPW is relatively limited. How- drome (PDS), a rare complication with
adjacent space, usually the pleural cav- ever, forspecific indications, itcanbe very extremely high mortality [34]. Although
ity [19]. The advantage of a PW is that beneficial [24]. The postoperative com- there is no uniform clinical manifestation
it prevents the risk of a second pericar- plications and recurrence rate of peri- or definition of PDS, it usually manifests
dial effusion and cardiac tamponade; the cardial tamponade are also lower than as PHI and/or pulmonary edema [35].
main mechanism is thought to involve those of traditional pericardial incision Furthermore, patients with pulmonary
the infiltration of pericardial fluid into [25]. Generally, PBP is performed un- embolism and neutropenia are more
the mediastinum and pleural cavity or der local anesthesia. By exchanging the prone to PHI [36]. Therefore, following
fluid discharge after the epicardium and guide wire and introducer, an expansion pericardial drainage, it is important to
pericardia inflammation [20]. The main balloon is placed for the parietal peri- be aware of the risks of PDS.
indication for a PW is recurrent large ef- cardium, and manual inflation is used
fusion or cardiac tamponade. The most to create the pericardial window, allow-
commonly used surgical approaches for ing for the pericardial effusion into the
creating a PW are through either a sub- chest [26]. The most common approach

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Antineoplastic treatment
Three major physiological conditions
have greatly limited the efficacy of tu-
mor chemotherapy. From blood to
cancer cells, therapeutic drugs must pass
through: (a) the vessel wall, (b) the
interstitial space, and (c) the cancer cell
membrane [37]. These barriers render
the penetration of anticancer drugs very
low, leading to the lack of sensitivity of
most tumors to treatment [38]. However,
it has also been reported that systemic
chemotherapy is more effective in ma-
lignant pericardial effusion caused by
lymphoma and small cell lung cancer
[39]. Topical delivery of a chemother-
apeutic drug is a method of delivering
a drug to a target site with minimal sys-
temic exposure. Systemic administration
of chemotherapeutic drugs can cause se-
vere toxicity, and therefore local delivery
of these drugs to pathological tissues is an
important means of improving the safety
and efficacy of cancer chemotherapy [40].
Furthermore, studies in animals have
demonstrated that sustained drug deliv-
ery systems at the tumor site enhance
the antitumor effects of the drug [41].
For common tumors that are transferred
to the pericardium, pericardial infusion
in the pericardium for the treatment
of pericardial disease caused by lung
cancer, pericardial injection of triammo-
nium for the treatment of breast cancer
pericardial metastases, for malignant
blood diseases such as lymphoma and
leukemia, consider using radiation ther-
apy [42]. For other tumors that metas-
tasize to the pericardium, local injection
of a cytostatic or sclerosing agent—such
as 5-fluorouracil, bleomycin, cisplatin,
interleukins, and other conventional
chemotherapy drugs—into the pericar-
dial cavity is routinely used. However,
most of these treatments only relieve
symptoms and are not successful in
curing the disease. Additionally, many
studies have shown that radiotherapy
has pericardial toxicity and, as such, this
treatment modality is not recommended
[43–45]. The best indication for radiation
therapy is extensive pericardial infiltra-
tion of cardiac tumor-encapsulated or
unresectable tumors, such as mediastinal
tumors [46]. Therefore, owing to the
Abstract · Zusammenfassung
Herz https://doi.org/10.1007/s00059-019-4833-4
© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2019
J. Zhang · Q. Zhang · X. Chen · N. Zhang
Management of neoplastic pericardial disease
Abstract
At present, there is no accurate and effective
method for treating neoplastic pericardial
effusion. This study analyzed the current
literature on the treatment of neoplastic
pericardial effusion to provide advice and
guidance for clinical treatment. Surgical
treatments include pericardial puncture,
extension of catheter drainage, pericardial
window, and surgical pericardiotomy. Each
surgical procedure has a corresponding
indication, and the best treatment is selected
according to the patient’s specific conditions.
Systemic chemotherapy is effective in
lymphoma and small cell lung cancer that
are sensitive to chemotherapeutic drugs.
Behandlung neoplastisch bedingter Erkrankungen des Perikards
Zusammenfassung
Gegenwärtig gibt es keine genaue und
wirksame Methode zur Behandlung eines
neoplastisch bedingten Perikardergusses. Für
die vorliegende Arbeit wurde die neueste
Literatur zur Behandlung neoplastischer
Perikardergüsse analysiert, um Hinweise und
Anleitungen für die klinische Behandlung zu
geben. Chirurgische Behandlungsansätze
umfassen die Perikardpunktion, länger ausge-
dehnte Katheterdrainage, Perikardfensterung
und chirurgische Perikardiotomie. Jeder
chirurgische Eingriff hat eine entsprechende
Indikation, und die am besten geeignete
Behandlung wird entsprechend den
spezifischen Bedingungen des Patienten
ausgewählt. Systemische Chemotherapie
ist gegen Lymphome und kleinzellige
Lungenkarzinome wirksam, wenn diese auf
limitations of chemotherapeutic drugs
and radiotherapy, researchers are forced
to develop new drugs or new routes of
administration to enhance the efficacy
and reduce the side effects and adverse
reactions of treatment. For example, an
inhalable powder formulation contain-
ing 5-fluorouracil micro-nanoparticles
has been developed for use in the treat-
ment of metastatic melanoma [47] and
a photothermal control system with syn-
ergistic chemical photothermotherapy
has been applied in the treatment of
multidrug-resistant cancer [48]. Fur-
Although pericardial injection of drugs is
effective for pericardial tamponade and
recurrent pericardial effusion, these methods
can only temporarily relieve symptoms and
cannot prolong the life of patients. In recent
years, immunotherapy, especially adoptive
immunotherapy, has achieved good results
in the treatment of neoplastic pericardial
effusion, thus providing a novel treatment
option for neoplastic pericardial effusion.
Keywords
Neoplastic pericardial disease · Pericardi-
um · Treatment management · Cancer ·
Immunotherapy
Chemotherapeutika ansprechen. Obwohl die
perikardiale Injektion von Medikamenten
bei Perikardtamponade und rezidivierendem
Perikarderguss wirksam ist, können diese
Verfahren die Symptome nur vorübergehend
lindern und die Lebensdauer der Patienten
nicht verlängern. In den letzten Jahren wur-
den durch die Immuntherapie, insbesondere
die adoptive Immuntherapie, gute Ergebnisse
bei der Behandlung des neoplastischen
Perikardergusses erzielt, wodurch eine
neuartige Behandlungsmöglichkeit für
den neoplastisch bedingten Perikarderguss
geschaffen wurde.
Schlüsselwörter
Neoplastisch bedingter Perikarderguss ·
Perikard · Behandlung · Krebs · Immuntherapie
thermore, the use of microbubbles as
a drug delivery vehicle effectively trans-
ports curcumin to cervical cancer cells,
reducing cytotoxicity and increasing
bioavailability [49].
New treatments for malignant
pericardial diseases
Immunotherapy
Immunotherapy is based on the idea
that cancer exhibits immunosuppressive
up-regulation of co-repressor receptors
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 Review articles
and ligands that reduce the activity of
tumor-infiltrating lymphocytes (TILs);
these include cytotoxic T lymphocyte-
associated protein-4 (CTLA-4), pro-
grammed death ligand-1 (PD-L1), and
T cell immunoglobulin and ITIM do-
main (TIGIT) or immunological evasion
of recognition and elimination [50, 51].
Generally, the clinical application of
immunotherapy is divided into four
categories: immunomodulatory mono-
clonal antibodies [52], oncoviruses [53],
administration of antibodies or recom-
binant proteins that either costimulate
immune cells or block immune in-
hibitory pathways (so-called immune
checkpoints; [54]), and adoptive cellular
therapy (ACT; [55]). Immunotherapy
can induce the body to produce a sys-
temic immune response to the tumor
and significantly improve the survival
rate of patients with metastasis. How-
ever, immune checkpoint inhibitors have
side effects including those that cause
pericardial effusion during the treat-
ment of patients with advanced cancer
[56]. There is also no vaccine to prevent
malignant pericardial effusion, and in
recent years, monoclonal antibodies and
adoptive immunotherapy have made
new progress in the treatment of malig-
nant pericardial effusion. Here, we focus
on the progress of immunomodulatory
monoclonal antibodies and adoptive im-
munotherapy therapy in the treatment
of malignant pericardial effusion.
Immunomodulatory monoclonal
antibodies
The tumor vasculature provides nutrients
for the growth of tumor cells, and the vas-
cular endothelial growth factor receptor
(VEGFR) present on tumor angiocytes is
a target for immunotherapy [57]. Its lig-
and, vascular endothelial growth factor
(VEGF), is a 34–42-kDa homodimeric
protein produced by both inflammatory
and malignant cells [58]. Vascular en-
dothelial growth factor plays an impor-
tant role in the development of malig-
nant serous cavity effusion; VEGF mRNA
is synthesized in all tumors, and VEGF
is also secreted by tumor cell lines in
vitro [59]. Bevacizumab, an anti-an-
giogenesis agent, is a kind of recom-
Herz
binant humanized monoclonal antibody
directed against VEGF-A [60]. Several
recent studies have reported that in pa-
tients with malignant pericardial effu-
sion, bevacizumab seems to be more ef-
fective than conventional chemothera-
peutics such as platinum and sclerosing
agents [61–64]. Chen et al. administered
bevacizumab in seven patients, and re-
ported that only one of the seven pa-
tients had recurrent fluid accumulation
before death. The median survival time
of these patients was 168 days (range,
22–224 days; [62]). A similar study using
intrapericardial cisplatin reported a me-
dian survival time of 120 ± 71 days (range,
68–268 days; [65]). These results suggest
that intrapericardial bevacizumab may
be more effective than other traditional
therapies in treating malignant pericar-
dial effusion.
Adoptive immunotherapy
Immunotherapy of patients with autolo-
gous reactive cell populations expanded
in vitro is known as ACT [66]. Tu-
mor cells are frequently antigenic, but
not immunogenic; these tumor-specific
antigens are expressed by malignant cells
and recognized by antitumor T cells [67].
Thus, T-cell-infiltrated tumors may op-
timally respond to therapies targeting
immune system inhibitory mechanisms
[68]. This view is supported by the
promising results achieved by tumor-in-
filtrating lymphocyte (TIL) adoptive cell
therapy in the treatment of patients with
metastatic melanoma [69]. The earliest
use of immunological adoptive ther-
apy for malignant pericardial effusion
was by Toh et al., who used autologous
interleukin-2(IL-2)-activated TILs for
local adoptive immunotherapy to treat
carcinomatous pericarditis arising in ad-
vanced cancer [70]. They administered
adoptive immunotherapy of pericardial
TILs to four patients with advanced can-
cer with malignant pericardial effusion
and demonstrated the presence of HLA
class-I-restricted tumor-specific CTLs in
IL-2-activated TILs in malignant peri-
cardial effusions. Although only four
patients were evaluated, one patient sur-
vived for 15 months, one patient had
no distant metastasis >11 months after
treatment, and the only adverse reac-
tion to treatment was a grade 1 fever.
These results confirm the safety and
efficacy of adoptive immunotherapy for
malignant pericardial effusion. In recent
years, much attention has been paid to
the cytokine-induced killer (CIK) cells
owing to their non-MHC-restricted tu-
moricidal effect on natural killer cells
and the antitumor activity of T lympho-
cytes [71]. Wang et al. used dendritic
cells in combination with CIK cells to
treat malignant pericardial effusion. In
their study, 31 patients with malignant
pericardial effusion were randomized
into a control group (N = 16) and a treat-
ment group (N = 15). The results showed
a statistically significant difference in the
control of pericardial effusion, treatment
side effects, and the quality of life of pa-
tients. Adoptive immunotherapy using
dendritic cells combined with CIK cells
has therefore been demonstrated to be
highly efficient with minimal toxicity
[72, 73].
Conclusion
Neoplastic pericardial effusion is a se-
rious complication in patients with ad-
vanced cancer. There is currently no
standard effective treatment. Pericar-
dial puncture is the best treatment for
patients with acute pericardial tampon-
ade. Systemic chemotherapy is effective
in lymphoma and small cell lung can-
cers that are sensitive to chemothera-
peutic drugs. Intracardiac injection of
drugs is beneficial to patients without
recurrence. However, the invasiveness
and high recurrence rate of surgical
treatment, as well as the low sensi-
tivity and high toxicity of chemother-
apy drugs to most tumors, do not aid
in improving the survival and qual-
ity of life of patients with neoplastic
pericardial effusion. The recent clini-
cal application of immunotherapy for
cancer patients—e.g., the treatment of
melanoma by PD-1—provides us with
a new treatment option for patients
with neoplastic pericardial effusion.
However, the effectiveness and safety of
future chemotherapeutic drugs and im-
munotherapy, combined with multiple
immunotherapies, must be thoroughly
assessed in clinical trials.
Corresponding address
N. Zhang
Department of Cardiology, the Fourth Affiliated
Hospital of Hebei Medical University
050011 Shijiazhuang, Hebei Province, China
zhangning127@126.com
Compliance with ethical
guidelines
Conflict of interest J. Zhang, Q. Zhang, X. Chen
and N. Zhang declare that they have no competing
interests.
For this article no studies with human participants or
animals were performed by any of the authors.
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