Case Report A 61-year-old black woman with primary peritoneal
carcinoma was admitted to the hospital with dyspnea on exertion of
two weeks duration. Her symptoms were gradual in onset and
progressive in nature. She denied having any cough, fevers, chills,
or chest discomfort. Past treatment of her peritoneal carcinoma,
which was diagnosed one year prior to admission, included 6 cycles
of carboplatin and taxol followed by 6 additional cycles of taxol
alone. Topotecan (Hycamtin, GB/US) was first administered one month
prior to admission, and at the time of admission she was receiving
the second cycle of topotecan. Her past medical history was
significant for a pulmonary embolism in March 2001which occurred
status post open reduction and internal fixation of a fractured
right femoral neck, type 2 diabetes mellitus, and hypertension. She
was a 50 pack-year smoker and had quit in 1980. In addition to the
topotecan, her medications at the time of admission included
coumadin, lisinopril, torecan, paroxetine, and sustained release
oral morphine. Initial evaluation was notable only for mild hypoxia
(pulse oximetry of 87%) that improved with 4L of oxygen by nasal
cannulae to 96%. The physical examination was unremarkable to
include a normal pulmonary exam. Initial laboratory studies were
notable for hemoglobin of 11.1, a hematocrit of 33.3, a prothrombin
time of 28.9, and an arterial blood gas on 4L of oxygen by nasal
cannulae: pH 7.41, pO2 77, pCO2 28.9, oxygen saturation 95%, base
excess 3.6. The PA and lateral chest x-ray revealed no infiltrates
or effusions. A computed tomographic (CT) pulmonary angiogram was
performed to exclude pulmonary embolism. This study revealed
geographic areas of ground-glass attenuation, mainly in the upper
lobes with sparing of the bases. High resolution computed
tomography (HRCT) of the chest with inspiratory and expiratory
phase images revealed that the differences between the areas of
high and low attenuation were accentuated upon expiration. Within
the areas of lower attenuation the pulmonary vessels appeared
subtly attenuated, and several of the areas of lower attenuation
met criteria for air trapping. (FIG. 1. High resolution CT. A:
Inspiratory high resolution CT at the level of the carina shows a
mosaic pattern of lung attenuation consisting of geographic areas
of decreased lung attenuation and vascularity. Incidental
subsegmental atelectasis is seen. B: Expiratory high resolution CT
at the same level demonstrating air trapping in the areas of
decreased lung attenuation and vascularity.) A bronchial alveolar
lavage (BAL) from the right, middle lobe revealed 156 WBC/mm3
(normal < 100 WBC/mm3) with 87 macrophages/mm3, 13
lymphocytes/mm3, and 73 RBC/mm3. Pap and Diff Quik stains of the
BAL fluid revealed macrophages, bronchial epithelial cells, and
inflammatory cells. No organisms or malignant cells were seen. A
fluorescent smear was negative for acid fast bacteria as were
cultures at 8 weeks. Fungal cultures of the BAL fluid did not yield
any organisms. Bacterial cultures of the BAL fluid were negative
for pathologic quantities of bacteria. A transbronchial biopsy was
performed revealing lung parenchyma with mild interstitial fibrosis
and numerous intra-alveolar macrophages; no malignant cells were
identified. Pulmonary function tests revealed a mild to moderate
restrictive pattern: FVC 2.23 (68%), FEV1 1.89 (72%), DLCO 10.7
(43%), DLCO/VA 3.0 (76%), TLC 4.16 (73%). The patient was admitted
to the hospital and was treated supportively with oxygen. Topotecan
was discontinued, and the patient was discharged with home oxygen.
At follow up 1 month after hospitalization the patient noted
symptomatic improvement in her shortness of breath. Repeat PFT's
revealed improvement in all parameters: FVC 2.41 (74%), FEV1 2.04
(78%), DLCO 14.0 (56%), DLCO/VA 3.34 (87%). Home oxygen therapy was
discontinued.
Diagnosis
Topotecan-induced lung injury. Radiographic pattern consistent with
bronchiolitis.
Findings
A computed tomographic (CT) pulmonary angiogram was performed to
exclude pulmonary embolism. This study revealed geographic areas of
ground-glass attenuation, mainly in the upper lobes with sparing of
the bases. High resolution computed tomography (HRCT) of the chest
with inspiratory and expiratory phase images revealed that the
differences between the areas of high and low attenuation were
accentuated upon expiration. Within the areas of lower attenuation
the pulmonary vessels appeared subtly attenuated, and several of
the areas of lower attenuation met criteria for air trapping. (FIG.
1. High resolution CT. A: Inspiratory high resolution CT at the
level of the carina shows a mosaic pattern of lung attenuation
consisting of geographic areas of decreased lung attenuation and
vascularity. Incidental subsegmental atelectasis is seen. B:
Expiratory high resolution CT at the same level demonstrating air
trapping in the areas of decreased lung attenuation and
vascularity.)
Discussion
Discussion Topotecan HCL is an antitumor drug exhibiting
topoisomerase I-inhibitory activity. Topotecan is indicated for the
treatment of metastatic carcinoma of the ovary after failure of
initial or subsequent chemotherapy; and as second-line treatment of
small cell lung cancer. Investigational uses include the treatment
of non small cell lung cancer and pediatric sarcomas. Commonly
reported dose-limiting adverse reactions to topotecan include
neutropenia, thrombocytopenia and anemia. These adverse reactions
are primarily hematologic in nature and result from bone marrow
suppression. The authors have found only one other report of
topotecan induced lung injury. Specifically, toptecan-induced lung
injury is described in a 45-year-old woman with small cell lung
cancer by Rossi et al. The patient in this report underwent wedge
resection biopsy which revealed histopathologic findings consistent
with bronchiolitis obliterans with organizing pneumonia (BOOP.)
Drug-induced lung injury is a diagnosis of exclusion. Therefore it
is important to identify alternative insults that might cause the
observed pattern of injury, and to rule them out. The most striking
findings in this case, are those of the CT abnormalities. The
observed mosaic pattern, with areas of lower attenuation and
decreased vascularity, is a radiographic characteristic of
obliterative bronchiolitis. As seen in this case, this pattern is
accentuated with expiration, a phenomenon thought to result from
heterogenous airway involvement leading to patchy airway closure.
The areas of decreased attenuation are the result both of the
hyperinflation caused by airway obstruction as well as the shunting
of blood away from these hypoxemic areas. Conditions causing a
similar radiographic pattern include extrinsic allergic alveolitis
(EAA), asthma, bronchiectasis, and rarely pulmonary vascular
abnormalities such as hypertension secondary to chronic
thromboembolism. Our patient did not carry the diagnosis of either
EAA or asthma. Furthermore, HRCT failed to reveal bronchiectasis
and CT pulmonary angiogram failed to reveal emboli. To absolutely
confirm the presence of bronchiolitis an open-lung biopsy is
usually required. The histologic pattern that one expects to see in
obliterative bronchiolitis is that of fibrous tissue between the
epithelium and muscularis mucosa causing concentric narrowing of
the airway lumen. Bronchiolitis is uncommon in adults. The usual
causes of bronchiolitis in adults include infections, inhalational
lung injury, adverse drug reactions, connective tissue diseases,
and finally idiopathic causes. Infectious causes of bronchiolitis
are rare in adults but have been associated with Mycoplasma
pneumoniae, Legionella pneumophila, and several viruses. , Cultures
of the study patient's BAL fluid grew Pseudomonas aeruginosa in
non-pathologic quantities, an organism which has not been
associated with acute bronchiolitis and which likely represents a
colonizing organism. Whereas viral infections are commonly a cause
of bronchiolitis in children, rarely are they a cause of such
serious disease in adults. The patient examined in this report
suffered no inhalational lung injury and had no history, symptoms
or signs suggestive of a connective tissue disorder. Thus,
topotecan remains as the sole agent associated with the disease
findings. The abnormal pulmonary function tests (PFT) correlate
with the radiographic abnormalities. PFTs in patients with
bronchiolitis can also correlate with the histology of the lesion.
When marked bronchiolar pathology is found histologically, one may
see a restrictive pattern and gas-exchange impairment. The paradox
of such marked bronchiolar pathology without airflow obstruction
can be explained by completely non-functional areas of lung
parenchyma which do not contribute either to lung emptying or to
gas exchange. Alternatively, the bronchiolitis may be associated
with organizing pneumonia which leads to a restrictive pattern on
pulmonary function testing. The study patient performed PFTs
revealing just such a restrictive pattern with reduced
gas-exchange. The improvement in all PFT parameters after cessation
of topotecan therapy supports the causal relationship between
topotecan use and the observed lung injury. Many drugs have been
reported to cause bronchiolitis. Several agents are classically
associated with drug-induced bronchiolitis (Penacillimine,
hexamethonium, busulphan) while others have bronchiolitis listed as
an idiosyncratic reaction . Due to the often non-specific nature of
clinical findings, lung function tests, and radiological signs; the
hallmark of drug-induced bronchiolitis remains improvement upon
cessation of the causative agent. Resolution of this patient's
pulmonary symptoms, improvement in measured lung function, and
cessation of supplemental oxygen dependance after cessation of
Topotecan, without any other specific treatment, implicates
Topotecan as the etiologic agent. This case illustrates a newly
recognized and important adverse reaction to topotecan therapy.
Previously, serious adverse reactions to topotecan were thought to
be only hematologic in nature. This case, in combination with the
aforementioned report of topotecan-related BOOP, adds to a growing
understanding of the pulmonary toxicity of topotecan.
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