Interstitial Lung Disease Other than UIP
Moderators: Brian Chiu and William D. Travis
Section 6 -
Update on Drug Toxicities Affecting the Lung
Douglas B. Flieder
Fox Chase Cancer Center
Philadelphia, PA, USA
With an ever-increasing number of therapeutic and illicit drugs available for use, the list of
drugs responsible for untoward and oftentimes severe pulmonary disease also grows. Although criteria for
a definitive diagnosis are strict and most cases are considered either probable or possible rather than
more than 150 agents are known to cause adverse pulmonary reactions . Since most drug
reactions are not biopsied, the surgical pathologist's perspective is far from complete.
Histomorphologic findings ascribed to many antimicrobials, anti-inflammatory agents, cancer
chemotherapeutic agents, cardiovascular drugs, and recreational agents are not specific.
Standard pathology texts have historically taken a double-barreled approach toward the classification
of drug–induced lung disease compiling lists according to the implicated drug and lists describing
patterns of lung injury caused by particular agents. While the former method may serve our clinical
colleagues well, recognizing patterns of drug effect are better suited to the pathologic interpretation
of non-neoplastic lung disease. Histologic patterns associated with pulmonary drug reactions involve all
anatomic compartments and include pulmonary edema, alveolar hemorrhage, alveolar proteinosis-like
reaction, diffuse alveolar damage, organizing pneumonia, usual interstitial pneumonia-like pattern,
diffuse cellular interstitial infiltrates with or without granulomas, nonspecific interstitial pneumonia,
lymphocytic interstitial pneumonia, eosinophilic pneumonias, small vessel angiitis, pulmonary arterial
hypertension and veno-occlusive disease . Once a pattern is recognized, one can easily correlate the
findings with exhaustive lists of therapeutic agents in either texts or at the online database www.pneumotox.com.
Major advances in molecular-targeted therapies have led to the introduction of a wide range of new
anti-cancer agents. Recently approved protein kinase inhibitors for leukemia, gastrointestinal stromal
tumors (GIST) and carcinomas have greatly expanded the medical oncologist's armamentarium against
traditional chemotherapy-refractory malignancies. Not surprisingly, these agents are responsible for
many adverse reactions affecting many organ systems including the lungs
Gefitinib (Iressa; ZD1839) is a member of a new class of oral signal induction inhibitors that target
receptor tyrosine kinases (TKs) including the epidermal growth factor receptor (EGFR)-TK. While the
precise anticancer mechanism of action has not been established and gefitinib is referred to as a
"specific" or "selective" inhibitor of EGFR, this agent inhibits the activity of other intracellular
transmembrane TKs at concentrations similar to those at which it inhibits the epidermal growth factor
signal. On the basis of phase II trials, gefitinib is only approved by the United States Food and Drug
Administration (US FDA] as a third-line monotherapeutic agent  while in Japan the drug is used as a
second-line monotherapy for individuals who have failed platinum- and docetaxel-based regimens. A
dose-response effect is not seen and 250 mg is the dose of choice.
Gefitinib is considered a "safe" drug at 250 mg or 500 mg doses and is metabolized by hepatic enzyme
CYP3A4. Common adverse events include diarrhea (in 48% of patients receiving 250 mg daily), rash (43%),
and acne (25%). Dry skin, nausea, vomiting, pruritus, anorexia, asthenia and weight loss have also been
reported in at least 5% of patients along with transaminase increases. These relatively acceptable
(grade 1 or 2) toxicities required dose delays and reductions in only 15% and 1% of patients,
Pulmonary toxicity was apparent at the drug's inception with a worldwide incidence of 1%. In Japan,
toxicity rates of up to 5.4% were noted yet only 0.3% of Americans and other Westerners treated were
reported to have presumed pulmonary toxicity
A genetic component appears to play a role since in
randomized trials vs placebo in largely Western cohorts, the incidence is not significantly higher than
baseline or placebo groups. The initial alarming reports from Japan described an ARDS syndrome with
patients presenting with acute onset dyspnea with or without cough or fever within six weeks of starting
Almost one-third of stricken individuals received prior radiation therapy
and many had been treated for radiation pneumonitis with low-dose steroids. Practically two-third of
patients had received prior chemotherapy. One individual developed pulmonary toxicity after re-exposure
to the drug. Most significant, most one-third of cases were fatal despite discontinuation of the drug,
corticosteroid therapy and best supportive care
Not surprisingly, patients with
idiopathic pulmonary fibrosis had an increased mortality rate, approaching 80% . AstraZeneca suggests
that these figures are not unreasonable given these patients' underlying diseases, prior therapies and
comorbidities related to tobacco use; however, the true safety of this drug in susceptible patients is
Radiologic findings of bilateral ground-glass opacities correlate with histologic findings of diffuse
alveolar damage (DAD). Although clinicians often make empirical diagnoses of drug effect, patients who
are given gefitinib should undergo some sort of tissue sampling to ensure the exclusion of infection as
well as tumor emboli, a rare complication of lung cancer .
Acute lung injury is associated with various precipitating factors and is
ascribed to complex interactions between damaged endothelial and epithelial cells. The actions of EGFR
signaling in this complex process are unknown. Since EGFR is up-regulated in response to acute lung
injury and epidermal growth factor family members have been implicated in the repair of pulmonary damage,
it is possible that inhibition of EGFR-mediated signaling by gefitinib impairs the repair process and
exacerbates the destructive cascade .
Residual lung damage from prior chemotherapy or radiation therapy may be additional risk factors for
drug-induced lung injury.
Women with adenocarcinomas and with good performance status as well as those who manifest skin or
gastrointestinal toxicity respond best to gefitinib therapy
Molecular research appears to
have identified particular mutations associated with better response rates and it will be very
interesting to chart the incidence of pulmonary toxicity as the agent is eventually offered to a smaller
subset of NSCLC patients .
Of note, only one clinical (without histologic sampling) report of
erlotinib (Tarceva)-induced lung disease
following gefitinib therapy has been published .
Imatinib mesylate (Gleevec; STI571) is another protein-tyrosine kinase inhibitor that is remarkably
effective in the treatment of Philadelphia chromosome positive chronic myeloid leukemia (CML), and GIST.
This targeted therapy inhibits the TKs of the bcr-abl fusion oncoprotein specific to CML, the
c-transmembrane receptor KIT relatively specific to GIST and stem cell factor. The drug also blocks the
TK of the platelet-derived growth factor receptor (PDGFR) and its associated pathways.
Imatinib is generally well tolerated. While the treatment doses of 400 to 600 mg and pharmacokinetics
are similar in CML and GIST patients and the drug is metabolized by CYP3A4 with minor contributions from
other cytochrome P450 enzymes, side effects may differ in the different tumor treatment groups. Grade 3
and 4 neutropenia, thrombocytopenia and anemia head the list of toxicities, yet most patients experience
mild to moderate (grades 1 to 2) nausea with vomiting (43 to 73% of patients), diarrhea (30 to 60%),
abdominal pain (23 to 27%), muscle cramps (28 to 62%), rashes (26 to 47%), and superficial edema (54-76%)
(22-24). Respiratory tract complications, namely cough and dyspnea, have been reported in 7 to 14% of
Although most cases were ascribed to pulmonary edema or pleural effusions, several
case reports documenting interstitial pneumonia have been observed. As with gefitinib, imatinib-related
interstitial lung disease afflicts mostly Asian patients.
A form of generalized fluid retention including but not limited to pulmonary edema and pleural
effusions affects up to 6% of patients , while 2% of patients in one phase II study experienced
either pulmonary edema or pleural effusion . These complications may be dose related and are more
common in the elderly. However, pediatric patients with Ewing's sarcoma and CML have been reported
. The pathologic fluid accumulations resolved after drug cessation. Edema and effusions may be
caused by drug inhibition of PDGFR, whose pathways regulate interstitial fluid homeostasis by modulating
the tension between cells and extracellular matrix structures .
The incidence of interstitial pneumonia is not known, although up to 7% of Westerners receiving the
agent for CML developed pneumonia, not otherwise specified . Interstitial pneumonia may develop
within ten days or after almost one year of therapy and manifests as shortness of breath and
nonproductive cough . Decreased diffusion capacity and oxygen saturation may precede radiographic
Computed tomograms demonstrate varied distributions of ground-glass opacities from diffuse homogeneous
to patchy infiltrates along the bronchovascular bundles. Peribronchiolar and/or subpleural
consolidations or diffuse fine nodular opacities along bronchovascular bundles are less frequent findings
Japanese studies suggest a predominance of hypersensitivity type pattern with fewer cases of
interstitial pneumonia or cryptogenic organizing pneumonia patterns .
Not unlike most drug-induced pneumonias, varied histopathologic findings have been reported with
imatinib. Alveolar septal edema with lymphoplasmacytic infiltrates is the most common finding while
eosinophils and foci of intraalveolar fibromyxoid connective tissue, i.e., organizing pneumonia, have
also been noted
Lavage samples feature a predominance of histiocytes, scattered
eosinophils and a decreased CD4:CD8 ratio
Granulomas have not been described and drug
stimulation lymphocyte tests against imatinib have all been negative
Almost 75% of patients improved or recovered after drug cessation. However, not all patients received
corticosteroids. One patient developed pulmonary fibrosis, not otherwise specified . Interestingly,
interstitial pneumonia recurred in several patients after readministration of imatinib at reduced doses;
however, the use of low-dose steroids at the time of imatinib reintroduction appears to prevent
recurrence of pulmonary disease
Whether imatinib-induced interstitial pneumonia is a hypersensitivity type reaction or pharmacological
effect is unclear. Although the clinical, radiographic and therapeutic response to steroids suggests a
hypersensitivity phenomenon, PDGF plays a significant role in acute lung injury
prolonged inhibition of PDGF leads to interstitial pneumonia, however, is not known.
In summary, EGFR-TKIs are effective drugs against particular neoplasms. While toxicities are in
general acceptable, potentially deadly pulmonary reactions prompt discontinuation of the agents. Ethnic
differences appear to play a large role in clinical response and the development of pulmonary
toxicities. Though molecular studies have begun to unravel mechanisms of action and particular
susceptibility factors, investigations into genetic factors associated with toxicities such as CYP3A4
polymorphisms, should be rigorously pursued.
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