Noncardiogenic Pulmonary Edema: An Unusual and

Serious Complication of Anticancer Therapy

EVANGELOS BRIASOULIS, NICHOLAS PAVLIDIS
Department of Medical Oncology, University of Ioannina, Ioannina, Greece
Key Words. Chemotherapy Interleukin-2 Pulmonary toxicity NCPE ARDS Noncardiogenic pulmonary edema Acute lung injury
Cytarabine Gemcitabine All-trans retinoic acid Arsenic trioxide (As203).

A BSTRACT
Noncardiogenic pulmonary edema (NCPE) is a rare
and less well-recognizable pulmonotoxic syndrome of
anticancer therapy than pneumonitis/fibrosis. NCPE is
a clinical syndrome characterized by simultaneous presence of severe hypoxemia, bilateral alveolar infiltrates
on chest radiograph, and no evidence of left atrial
hypertension/congestive heart failure. The diagnosis of
drug-related NCPE relies upon documented exclusion
of any infectious, metabolic, or cancer-related causes.
The time proximity to therapy with drugs that are
known to precipitate NCPE, any preceding episodes of
flu-like symptoms during previous chemotherapy
courses and possible response to corticosteroids may
further support such a diagnosis. Cancer therapeutic
agents clearly associated with NCPE are cytarabine,

gemcitabine, and interleukin-2, as well as all-trans

retinoic acid in acute promyelocytic leukemia patients,
while a few other compounds have rarely or occasionally
been implicated. The pathophysiology of lung injury in
drug-induced NCPE remains unclear. There are indications suggesting that both a direct cytotoxic insult to the
lung epithelial cells and induction of a cytokine-triggered inflammatory response may be involved in its
pathogenesis. By distinction to drug-induced pulmonary
pneumonitis that may lead to permanent pulmonary
fibrosis, NCPE if not fatal, can be reversed upon prompt
recognition, following immediate discontinuation of the
offensive drug and start of intensive supportive treatment and intravenous corticosteroids. The Oncologist
2001;6:153-161

INTRODUCTION
Several cancer therapeutic drugs are known to induce
pulmonary damage, which may result in a variety of clinicopathologic syndromes with minor to severe clinical consequences [1]. Clinical syndromes associated with drug-induced
pulmonary toxicity include pneumonitis/fibrosis, hypersensitivity lung disease, and noncardiogenic pulmonary edema
(NCPE)/acute respiratory distress syndrome (ARDS). These
syndromes share a similar symptomatology but differ in regard
to the time-relation to cancer treatment, the radiographic findings, the duration of pulmonary damage, and the long-term
outcome [2]. Non-specific symptomatology of cough, progressive dyspnea, and often a low-grade fever alert clinicians
confronted with the diagnostic challenge to recognize subclinical syndromes and differentiate fully developed drug-induced
pulmonary reactions from lung injuries caused by infectious,
cardiac, and neoplastic causes.

The most common chemotherapy-associated lung

injury is drug-induced pneumonitis. This type of pulmonary
toxicity has extensively been studied and attributed to a
majority of the pulmonotoxic antineoplastic agents, of
which bleomycin is the prototype and nitrosoureas rank
second [3-7]. Major concern with this pulmonary toxicity is
the potential to progress to irreversible chronic pulmonary
fibrosis.
Noncardiogenic pulmonary edema is a rarely cited and
less well-recognizable pulmonotoxic syndrome of anticancer therapy. Our recent experience with NCPE that
complicated gemcitabine plus docetaxel combination
chemotherapy [8] prompted us to investigate existing medical literature in regard to this unusual pulmonary toxicity
of anticancer therapy. To our knowledge, this is the first
review on anticancer-therapy-associated noncardiogenic
pulmonary edema.

Correspondence: Evangelos Briasoulis, M.D., Medical Oncology Department, Ioannina University, Ioannina, 45110, Greece.
Telephone and Fax: 30-651-99394; e-mail: ebriasou@otenet.gr. Received August 15, 2000; accepted for publication
November 30, 2000. AlphaMed Press 1083-7159/2001/$5.00/0

The Oncologist 2001;6:153-161 www.TheOncologist.com

Briasoulis, Pavlidis
METHODS
A computerized Internet PubMed search of English and
non-English language medical literature was conducted by
using Reference Manager Version 9.5 (ISI ResearchSoft;
PA; http://www.risinc.com/RShome.html) for the period
1965 to 2000, and manually for the period 1960 to 1965.
For our search, we used as all-field parameters the generic
names of pharmacologic anticancer agents, the words
chemotherapy, immunotherapy, and biotherapy, and the
key phrases anticancer treatment and drug-induced, combined with the words or key phrases noncardiogenic or primary pulmonary edema, NCPE, pulmonary toxicity,
pulmonary disease, respiratory distress syndrome, and
acute lung injury.
Reports of drug-induced pulmonary disease related to
anticancer treatment had to fit the most accepted definitions
for NCPE and ARDS in order to be considered for this
review [9-11]. NCPE, also termed as Acute Lung Injury
(ALI), is a clinical syndrome characterized by simultaneous
presence of severe hypoxemia, bilateral alveolar infiltrates
on chest radiograph, and no evidence of left atrial hypertension. The term ARDS is applied to the most severe cases
of acute respiratory failure. According to the criteria set by
the American-European Consensus Conference on ARDS,
a 200 mmHg value of quotient PaO2/FIO2 (arterial oxygen-tension/fractional inspired-oxygen) defines ARDS,
while 300 mmHg characterizes ALI.
ANTICANCER THERAPY-INDUCED NONCARDIOGENIC
PULMONARY EDEMA
Clinical PresentationDiagnosis
NCPE is a rare but major complication of anticancer
therapy. This typically presents as a sub-acute clinical syndrome characterized by severe dyspnea, cough, tachypnea,
fatigue, and a low-grade fever that occurs shortly after or
within a few days following the administration of the offensive pharmaceutical agent or agents [8, 12, 13]. Patients
with drug-induced NCPE are usually markedly hypoxemic,
with crackles on auscultation and chest radiography showing confluent alveolar consolidations almost identical to
those seen in congestive heart failure, and a normal-size
heart [14].
Diagnosing drug-induced NCPE is actually an exercise
of exclusion, as there is no diagnostic test available.
Diagnosis relies upon typical radiograph findings [15] and
the documented exclusion of heart dysfunction and any
infectious, metabolic, or cancer-related causes. The time
proximity to administration of drugs known to precipitate
NCPE, any preceding episodes of flu-like symptoms during
previous chemotherapy courses, and possible response to

154

corticosteroids may further support such a diagnosis. By distinction from drug-induced pulmonary pneumonitis that
potentially may evolve to pulmonary fibrosis, NCPE if not
fatal, can be fully reversed upon prompt recognition, following discontinuation of offensive drugs and immediate start of
intensive support treatment and intravenous corticosteroids.
Cancer therapeutic agents that clearly precipitate NCPE
are cytarabine, gemcitabine, and interleukin 2 (IL-2), and the
all-trans retinoic acid and arsenic trioxide (As2O3) in acute
promyelocytic leukemia patients, while a few more compounds have rarely or occasionally been implicated (Table 1).
Biotherapeutic Agents
Among biological agents, recombinant IL-2 (rIL-2) has
been clearly associated with the induction of NCPE toxicity,
while there is some weak evidence for a similar pulmonotoxic
potential of white blood cell growth-stimulating factors.
IL-2, a glycoprotein naturally produced by human T cells
during immune response, was introduced in cancer therapeutics 15 years ago as a novel approach to the treatment of solid
tumors [16, 17]. This biological response modifier is currently employed in the management of metastatic melanoma
and renal cell carcinoma, alone or in combination with
chemotherapy or biotherapy [18-21].
Unfortunately, the clinical development of rIL-2 has been
compromised by frequently associated toxicities and a narrow
therapeutic index [22-24]. Regarding pulmonary toxicity, rIL2 given intravenously is commonly complicated by NCPE.
This occurs in the context of a vascular leak syndrome, the
most frequent complication of IL-2, and is mediated via a
mechanism of increased microvascular permeability [25, 26].
It is now clear that rIL-2-induced pulmonary toxicity is a doserelated phenomenon that tends to resolve within a few days
upon treatment discontinuation [27].
Initial clinical testing identified malaise and weight gain
as the dose-limiting toxicities of systemic administration of
rIL-2 [28], whereas further clinical experience revealed a significant incidence of NCPE in patients treated with high-dose
intravenous rIL-2 [29]. The incidence rate as recorded in the
first large cohorts of treated patients ranged from 10%-20%,
with a considerable number of treated patients requiring intubation [27, 30, 31]. Interestingly, newest clinical data show a
decline in rIL-2-related pulmonary toxicity, obviously due to
improvement in key safety issues such as eligibility screening
and optimization of therapeutic conditions. Kammula et al.
reviewed safety data of high-dose bolus rIL-2 (720,000 IU/kg
every 8 h) administered in 1,241 cancer patients over a 12year period and found a clear improvement in rIL-2 safety
profile with a remarkable drop from 12% to 3% in the incidence of NCPE [32]. The feasibility and the safety of longterm administration of subcutaneous rIL-2 at conventional

Cancer-Therapy-Related Noncardiogenic Pulmonary Edema

155

Table 1. Cancer therapeutic agents associated with the development of noncardiogenic pulmonary edema
Therapy/agent

Reportedestimated
incidence

Cytarabine
(high dose)

high

Characteristics/comments

Ref.

Potentially fatal toxicity described in leukemia patients treated with moderate to high
[47-49, 104]
cytarabine doses (1-1.5 g/m2/continuous infusion, or >3 g/m2 as 2 h IV infusion per 12 h)
over 3 to 4 days. It develops 1-2 weeks post chemotherapy usually at initial course.
Pathophysiology: increased alveolar capillary permeability

Recombinant IL-2
3%-20%
(high dose intravenous)

Described in renal cancer and melanoma patients, usually in the context of generalized
vascular leak syndrome. Severe but reversible on discontinuation of IL-2. An incidence
decline is being recorded over the last decade reflecting an improvement in safety keys
as the screening of eligible patients and the optimization of therapeutic conditions.
Pathophysiology: a damaging effect on vascular endothelial cells by cytokines

[23, 27, 32]

Bone marrow
transplantation

moderate

Bone marrow transplant patients may develop NCPE in the context of systemic capillary [75]
leak syndrome 1-2 months following high-dose chemotherapy. A pivotal contribution by
circulating leukocytes is suggested.

All-trans-retinoic
acid (ATRA)

12%

It occurs in the context of ATRA syndrome that may develop in acute promyelocytic
leukemia patients undergoing remission induction treatment with ATRA and is
characterized by fever, respiratory distress, peripheral edema and pleural or
pericardial effusions. Treatment with corticosteroids effective if started early.

[82]

Arsenic trioxide
(As203)

15%

Same as with ATRA.

[83]

Gemcitabine

0.1%

It is usually building up over a number of courses, but it may also occur after a single
administration. Life-threatening but also reversible upon treatment discontinuation and
start of intensive supportive therapy and IV corticosteroids.

[54, 56-60]

Gemcitabine plus
docetaxel

rare

In patients with solid tumors. Similar clinical features and outcome as with single
gemcitabine.

[8, 66]

Vinblastine

anecdotal

Mitomycin plus
vinblastine

2%

It tends to occur shortly after chemotherapy administration.

[69, 71]

Intrathecal
methotrexate

occasional

Three cases have been reported of rapidly developing respiratory distress following
the administration of methotrexate into the cerebrospinal fluid.

[73, 74]

G-CSF

occasional

Dacarbazine plus
fotemustine

anecdotal

[68]

[38-40]
Reported at a sequential administration regimen.

[105]

Note: Characterizations high, moderate, rare, occasional, and anecdotal are given in cases of lack of clear incidence data and must be loosely interpreted.

doses of 4.5 million IU/day, three times weekly, has been

well established [33] while novel locoregional administration
strategies, such as the inhalation of nebulized rIL-2, are being
investigated with the aim of improving its therapeutic index
[34]. The more favorable toxicity profile of subcutaneous,
compared with intravenous, bolus administration of rIL-2, is
possibly attributed to a lower systemic absorption (30% of
the injected dose) and a better pharmacokinetic profile (sustained systemic exposure and lower peak levels) associated
with this route [22].
Hematopoietic growth factors G-CSF and GM-CSF
have both been associated as causative or contributing factors with the development of pulmonary toxicity. G-CSF
administered during bleomycin-containing chemotherapy

regimens may enhance subclinical bleomycin pulmonary

toxicity [35, 36], while a possible pulmonotoxic synergy
has been suggested for the combination of GM-CSF with
chemoradiotherapy in small cell lung cancer patients who
received this treatment [37]. Regarding pulmonary edema,
G-CSF and GM-CSF have occasionally been implicated
with the development of true NCPE, as a small number of
published case reports indicate, not all of them well documented [38-40]. It is most possible that the underlying
pathophysiological machinery in NCPE cases is the same as
with the capillary-leak syndrome that has more commonly
been associated with the clinical use of these hematopoietic
factors [41-43]. It should be recognized that a definite association of G-CSF and GM-CSF with pulmonary toxicity in

Briasoulis, Pavlidis
most of the clinical studies is rather poorly documented, but
the pulmonotoxic potential of G-CSF has been highlighted
in a single preclinical study. Hierholzer et al. have shown
that installing G-CSF into the lungs of rats by intratracheal
injection resulted in recruitment of neutrophils, lung injury,
and impaired pulmonary function [44].
Cytotoxic Drugs
Two cytotoxic antimetabolites, cytarabine, and gemcitabine, both analogues of the nucleoside cytidine, have clearly
been associated with the development of pulmonary toxicity of
the NCPE type. Cytarabine is used in the chemotherapy of
leukemia and lymphoma, and gemcitabine is used in the
chemotherapy of solid tumors. These agents compete with
deoxycytidine triphosphate for incorporation into the C sites of
the growing DNA strand and halt DNA synthesis in progress,
inducing cell apoptosis primarily at the S phase [45, 46].
Treatment of leukemia patients with high or moderate
doses of cytarabine has been associated with the development
of NCPE at a relatively high rate. Andersson et al. reported a
12.5% incidence of fatal pulmonary edema in 103 relapsed
leukemia patients at a median time of 16 days from the initiation of high-dose cytarabine therapy. Postmortem findings
in seven patients who died of ARDS showed a massive pulmonary edema with a highly proteinaceous intra-alveolar
infiltrate, and in one case diffuse alveolar damage. No inflammatory changes were detected [47]. Similar toxicity has also
been seen in pediatric patients. Shearer et al. described a fatal
pulmonary insufficiency in 5 of 22 pediatric patients treated
with high-dose cytarabine and G-CSF support for relapsed
acute myelogenous leukemia. Postmortem examination disclosed profound pulmonary edema [48]. In another study,
Haupt reviewed clinical and pathologic features of 181
patients with leukemia who had been autopsied at the Johns
Hopkins Hospital. They found a highly significant increase in
the frequency of pulmonary edema in 51 patients (it was massive in 24 patients) who were treated with cytarabine within
the last 30 days prior to their death as compared with noncytarabine-treated patients. These investigators failed to detect
any other cause possibly related to the observed pulmonary
edema in 67% of the cases [49]. An interesting syndrome characterized by pulmonary edema, fever, and diarrhea was
reported in 4 of 23 lymphoma patients who were treated with
high-dose cytarabine. High concentrations of tumor necrosis
factor-alpha and platelet activating factor activity were found
in the serum of two of those patients [50]. Finally, a review of
radiography findings in patients treated with cytarabine who
developed pulmonary complications demonstrated diffuse
consolidations of the alveolar pattern in both lungs that
regressed within 3 to 7 days in the majority of patients who
recovered [15].

156

Gemcitabine is currently employed in the treatment of

solid tumors, as a drug of a particularly modest toxicity profile with a low incidence of the side effects normally associated with cytotoxics [51]. In regard to pulmonary toxicity a
self-limiting dyspnea has been reported in 5%-8% of patients
treated with this agent [52] while true NCPE was recorded in
clinical trials at an incidence of about 0.1% [53]. Interestingly,
flu-like symptoms and fever have also been reported in 20%35%, and peripheral edema in up to 20% of the patients
treated with gemcitabine [51]. Gemcitabine-induced pulmonary toxicity usually upsurges after a number of repeated
drug administrations gradually building up, although occasionally it has also been reported to occur after a single-dose
administration [54-56]. A small number of NCPE cases associated with the gemcitabine administration have been reported
so far. In the first published report Pavlakis et al. presented
three cases of cancer patients who developed NCPE/ARDS
while being treated with gemcitabine. Two patients died, after
being repeatedly challenged with gemcitabine despite persistent episodes of dyspnea following first chemotherapy
courses. Corticosteroids provided maximum benefit in a third
patient in whom they were commenced early at diagnosis and
were coupled with discontinuation of gemcitabine [54].
Following this report, two fatal and three successful corticosteroid-managed cases were reported [57-60]. In most of
these cases a diffuse alveolar damage consistent with acute
respiratory distress syndrome was found and systemic
corticosteroids seemed to help if started early at diagnosis.
There are also a few other cytotoxic compounds that have
occasionally been associated with NCPE. Those are docetaxel, vinblastine and intrathecal methotrexate. Docetaxel, a
novel mitotic spindle poison that acts as a microtubule stabilizer, has only infrequently been associated with the development of pulmonary toxicity, that is usually of the type of
hypersensitivity pneumonitis not meeting the criteria for
NCPE [61, 62]. Notably, a fluid retention syndrome is known
to occur in as many as 20%-60% of nonpremedicated patients
treated with the agent, but this is typically peripheral, with
pleural effusions reported only occasionally [63-65].
Although no NCPE has been attributed to docetaxel as a
single agent to date, several cases have been reported with
its combination with gemcitabine and radiotherapy [8, 66,
67]. Vinblastine as a single agent has anecdotally been
associated with the development of NCPE [68], but this
toxicity seems to occur more often when combined with
mitomycin [69-71].
Although the most common pulmonary disorder connected with methotrexate is a gradually developing interstitial pneumonitis in rheumatoid arthritis patients [72], three
cases of NCPE have been reported that were associated with
intrathecal methotrexate. The clinical course, radiology

157

findings, and in one patient, the pathology report favor the

diagnosis of NCPE in these cases [73, 74].
A high incidence of NCPE has been reported to occur in
allogeneic and autologous bone marrow transplant patients in
a single study. In those patients, NCPE presented in the context of a capillary leak syndrome and was accompanied by
generalized organ dysfunction in many cases [75]. It is
thought that induction chemotherapy may also play some role
in the development of lung toxicity in these patients. Data
suggest that standard-dose chemotherapy produces asymptomatic pulmonary dysfunction and inflammation, which may
prime the lungs for further injury by high-dose chemotherapy.
In a prospective study, high-risk breast cancer patients developed a 12.6% decrease of diffusing capacity of the lungs for
carbon monoxide (DL(CO)) after three cycles of induction
chemotherapy with CAF (cyclophosphamide, doxorubicin,
5-fluorouracil) and prior to high-dose chemotherapy with
autologous bone marrow or peripheral blood progenitor cell
support [76].
ATRA Syndrome
The vitamin A derivative all-trans-retinoic acid (ATRA)
and As203 are two drugs with the potential to induce granulocytic differentiation and promote apoptosis of leukemic
promyelocytes [77-79]. Currently used in the treatment of
acute promyelocytic leukemia [80, 81], these agents have
both been associated with the development of NCPE/ARDS
in the context of ATRA syndrome. This is a life-threatening
complication that occurs in a quarter of patients with acute
promyelocytic leukemia who undergo remission induction
treatment with ATRA or As203, with or without chemotherapy [82, 83]. The ATRA syndrome characterizes a loosely
defined constellation of signs and symptoms that primarily
consist of fever and respiratory distress, but also of weight
gain, peripheral edema, pleural or pericardial effusions, and
hypotension [84]. The pathophysiology of the ATRA syndrome is uncertain, but in vitro data provide evidence that
the induction of inflammatory cytokines in acute promyelocytic leukemia cells may play an important role in its pathogenesis [77].
Pathophysiology
The exact mechanism of lung injury in the case of
NCPE related to cancer therapeutic agents varies with each
class of drugs involved, but overall, it remains poorly
defined. It must be emphasized that comorbidities existing
in cancer patients potentially complicate the attempt to
identify an unequivocal explanation for these clinical findings. Furthermore, in combination chemotherapies or highdose chemotherapies with G-CSF support, it is quite
difficult to mark out the major offensive compound,

Cancer-Therapy-Related Noncardiogenic Pulmonary Edema

although lung toxicity can obviously be amplified when
pulmonotoxic agents are used concurrently.
Regarding cytotoxic agents, a direct insult by the offensive agent to the alveolar type I pneumocytes or pulmonary
vascular endothelial cells and the triggering of a cytokinemediated inflammatory response appear to be the most frequently involved pathogenic mechanisms. Findings from
leukemia patients who died of ARDS following treatment
with high-dose cytarabine revealed massive edema and
partly diffuse alveolar damage without inflammatory reaction, probably indicating that a direct cytocidal result was a
most contributing pathogenetic mechanism in those cases
[47]. The hypothesis for the involvement of a cytokinemediated inflammatory response is suggested by the drugrelated fever that occurs in almost half of the patients treated
with cytarabine or gemcitabine [85] and the rapid response
to corticosteroids reported by several investigators [60, 86].
Additional data provide evidence indicating the involvement of several cytokines, such as tumor necrosis factoralpha and platelet activating factor in the development of
lung injury [50, 87, 88]. Regarding a possible implication of
the dosage in the development of NCPE, a dose/pulmonarytoxicity relationship has only been documented for cytarabine, while this does not seem to be the case with gemcitabine
[89, 90]. Whatever the exact mechanism of pathogenesis of
the lung injury in the case of chemotherapy-induced NCPE,
the end-result is an increase in vascular permeability
accompanied by extravasation of fluids and proteins into
the air space [9]. This has been clearly documented by
autopsy findings [47, 54]. Interestingly, two cancer therapeutic agents with pulmonotoxic potential are also known
to induce a capillary leak syndrome [51, 91].
The pathogenesis of the lung injury that is related to
intravenous administration of high doses of recombinant
IL-2 has been investigated extensively. Initial preclinical
studies suggested that microvasculature damage, causing a
generalized increase of vascular permeability to albumin,
was the basic mechanism of rIL-2-induced NCPE [25].
Subsequent studies went into more detail and associated the
systemic administration of rIL-2 with lesions of venous and
capillary endothelia, alveolar basement membrane, and
type I epithelial cells in animals, while leukocyte or platelet
activation, generation of free radicals, and activation of the
complement system have also been suggested to be
involved in its pathogenesis [92-97]. Despite a widening
evidence of the involvement of various cytokines released
by activated lymphoid cells in the pathogenesis of rIL-2induced NCPE, the exact mechanism of the damaging
events that drive this clinical syndrome remain unclear [23,
33]. Recent demonstration of functional IL-2 receptors on
type II pneumocytes indicates that these cells may also

Briasoulis, Pavlidis
become involved in the pathogenesis of rIL-2-induced
NCPE [98].
Regarding NCPE that presents in the context of the
ATRA syndrome (see above), activation of production of
inflammatory cytokines by acute promyelocytic leukemia
cells after exposure to ATRA or As203 seems to play an
important role in its pathogenesis. In vitro data suggest that
acute promyelocytic leukemia cells may produce an
increased expression of IL-1 beta, tumor necrosis factoralpha, IL-8, L-selectin, and intercellular adhesion molecule-1 after induction of differentiation with ATRA, an
effect considered related to the progress of the differentiation [77, 99, 100]. The similarity of the clinical phenomena
that characterize the ATRA syndrome with those observed
after increased production or administration of exogenous
cytokines, the overexpression of which has been shown in
vitro to be activated after exposure of acute promyelocytic
leukemia cells to ATRA, suggests a link between the
ATRA syndrome/NCPE and increased production of cytokines and surface integrins during the process of induction
of differentiation.
Finally, research on systemic capillary leak syndrome
(SCLS) that is a distinct clinical entity characterized by
attacks of a marked shift of plasma from the intravascular
to the extravascular space may offer an additional theoretical basis for the interpretational approach of the pathophysiology underlining chemotherapy-related NCPE. There is

158

evidence for a complement-mediated injury that leads to a

breakdown of the endothelial barrier and plasma leakage in
SCLS [101-103].
Treatment
Awareness of early recognition of evolving lung toxicity and withdrawal of the possibly offensive drug or drugs
are suggested as the most important steps toward successful
management of drug-induced NCPE. Intravenous corticosteroids, if started early in the course of drug-induced
NCPE, diuretic therapy, and respiratory support with or
without mechanical ventilation have reportedly salvaged a
number of patients from this pulmonary toxicity.
CONCLUSION
It is important for practicing oncologists to realize that a
number of cancer-therapeutic agents can produce, or interact
with other drugs to produce, noncardiogenic pulmonary
edema. Prompt evaluation of any new respiratory symptoms
that occur in patients who are treated with pharmaceutical
agents potentially inducing NCPE is important for early detection of this severe complication. Patients with pulmonary compromise should be hospitalized and can successfully be
managed with high-dose corticosteroids, diuretics, and oxygen
supplementation. Immediate discontinuation of chemotherapy
is recommended upon suspicion of lung toxicity, and in disputed cases, a lung biopsy should be taken into consideration.

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