Topotecan-induced bronchiolitis.

Abstract: Topotecan HCI is an antitumor drug exhibiting topoisomerase I-inhibitory activity. Topotecan is used in the treatment of metastatic carcinoma of the ovary and as second-line treatment of small-cell lung cancer. Reported dose-limiting adverse reactions to topotecan are primarily hematologic in nature. To date, only one other case of lung toxicity in a patient taking topotecan has been reported. The authors describe the development of obliterative bronchiolitis, as evidenced by radiographic and pulmonary function testing abnormalities, in a 61-year-old woman who presented with dyspnea, and who was receiving topotecan for peritoneal carcinomatosis.

Key Words: bronchiolitis, chemotherapy, lung, topotecan

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Drug-induced lung injury is a problem more commonly encountered with antineoplastic agents than with any other pharmaceutical class. Classically, pulmonary toxicity has been reported with cytotoxic agents such as bleomycin, methotrexate, and cyclophosphamide. Long experience with the use of these agents has allowed for recognition of their various toxicities and the classification of injury into several stereotypical patterns. However, for many newer antineoplastic agents, sufficient experience of use does not exist to identify pulmonary toxicity, let alone recognize a pattern of injury. We report a case of pulmonary toxicity associated with the relatively new antineoplastic agent topotecan. Our patient developed dyspnea and hypoxia in addition to radiographic and pulmonary function testing abnormalities during topotecan therapy. All deficits resolved with discontinuation of topotecan, suggesting a causal relationship between topotecan therapy and lung injury.

Case Report

A 61-year-old black female with primary peritoneal carcinoma was admitted to the hospital with dyspnea on exertion that had lasted 2 weeks. 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 1 year before admission, included six cycles of carboplatin and paclitaxel, followed by six additional cycles of paclitaxel alone. Topotecan was first administered 1 month before admission, and at the time of admission the patient was receiving the second cycle of topotecan. Her past medical history was significant for a pulmonary embolism in March 2001 (which occurred after reduction and internal fixation of a femoral fracture), 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 warfarin, lisinopril, thiethylperazine, paroxetine, and sustained-release oral morphine. Initial evaluation was notable only for mild hypoxia (pulse oximetry of 87%) that improved with 4 L of oxygen by nasal cannulas to 96%. Pulmonary exam was normal to auscultation and percussion. Initial laboratory studies were notable for a hemoglobin of 11.1, a hematocrit of 33.3, a prothrombin time of 28.9, and an arterial blood gas on 4 L of oxygen by nasal cannuals: pH, 7.41; P[O.sub.2], 77; PC[O.sub.2], 28.9; oxygen saturation, 95%; and base excess, 3.6. The posteroanterior and lateral chest radiograph revealed no infiltrates or effusions.

A computed tomographic (CT) pulmonary angiogram was obtained 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 of the chest with inspiratory and expiratory phase images revealed that the differences between the areas of high and low attenuation were accentuated on 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). A bronchial alveolar lavage (BAL) from the right middle lobe revealed 156 white blood cells/[mm.sup.3] (normal, < 100 white blood cells/[mm.sup.3]) with 87 macrophages/[mm.sup.3], 13 lymphocytes/[mm.sup.3], and 73 red blood cells/[mm.sup.3]. Papanicolaou 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, which revealed lung parenchyma with mild interstitial fibrosis and numerous intra-alveolar macrophages; no malignant cells were identified. Pulmonary function tests (PFTs) revealed a mild to moderate restrictive pattern: forced vital capacity, 2.23 (68%); forced expiratory volume in 1 second, 1.89 (72%); diffusing capacity of the lungs for carbon dioxide (DLCO), 10.7 (43%); DLCO corrected for alveolar volume ([V.sub.A]), 3.0 (76%); and total lung capacity, 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 PFTs revealed improvement in all parameters: forced vital capacity, 2.41 (74%); forced expiratory volume in 1 second 2.04, (78%); DLCO, 14.0 (56%); and DLCO/[V.sub.A], 3.34 (87%). Home oxygen therapy was discontinued.

Discussion

Topotecan HCI 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. (1) 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, topotecan-induced lung injury is described in a 45-year-old woman with small-cell lung cancer by Rossi. (2) The patient in Rossi's report underwent wedge resection biopsy that revealed histopathologic findings consistent with bronchiolitis obliterans with organizing pneumonia.

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. 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. (3) 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, asthma, bronchiectasis, and, rarely, pulmonary vascular abnormalities such as hypertension secondary to chronic thromboembolism. (4) Our patient did not carry the diagnosis of either extrinsic allergic alveolitis or asthma. Furthermore, high-resolution computed tomography failed to reveal bronchiectasis, and CT pulmonary angiogram failed to reveal emboli. To absolutely confirm the presence of bronchiolitis, an open-lung biopsy is required. This procedure was not performed due to the observed clinical and PFT improvement after stopping topotecan. The histologic pattern seen in obliterative bronchiolitis is that of fibrous tissue between the epithelium and muscularis mucosa causing concentric narrowing of the airway lumen. (5)

[FIGURE 1 OMITTED]

Bronchiolitis is uncommon in adults, with the usual causes being infections, inhalational lung injury, adverse drug reactions, and connective tissue diseases. Infectious causes of bronchiolitis are rare in adults but have been associated with Mycoplasma pneumoniae, Legionella pneumophila, and several viruses. (6,7) Cultures of the study patient's BAL fluid grew Pseudomonas aeruginosa in nonpathologic quantities, an organism that has not been associated with acute bronchiolitis and that 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 the sole agent associated with the patient's disease findings.

The observed PFT abnormalities correlate with the radiographic abnormalities. PFTs in patients with bronchiolitis often correlate with the histology of the lesion. When marked bronchiolar pathology is found histologically, one may see a restrictive pattern and gas-exchange impairment. (8) The paradox of such marked bronchiolar pathology without airflow obstruction can be explained by completely nonfunctional areas of lung parenchyma that 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 (penicillamine, hexamethonium, busulphan), whereas others have bronchiolitis listed as an idiosyncratic reaction. (9,10) Due to the often nonspecific nature of clinical findings, lung function tests, and radiological signs, the hallmark of drug-induced bronchiolitis remains improvement on 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.

Conclusion

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 bronchiolitis obliterans with organizing pneumonia, adds to a growing understanding of the pulmonary toxicity of topotecan.

Accepted December 8, 2003.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9707-0699

References

1. Clarke-Pearson DL, Van Le L, Iveson T, et al. Oral topotecan as single-agent second-line chemotherapy in patients with advanced ovarian cancer. J Clin Oncol 2001; 19:3967-3975.

2. Rossi SE. Pulmonary drug toxicity: radiologic and pathologic manifestations. Radiographics 2000;20:1245-1259.

3. Lynch DA. Imaging of small airways diseases. Clin Chest Med 1993; 14:623-634.

4. Arakawa H, Kurihara Y, Niimi H, et al. Bronchiolitis obliterans with organizing pneumonia versus chronic eosinophilic pneumonia: high-resolution CT findings in 81 patients. AJR Am J Roentgenol 2001;176:1053-1058.

5. Murray JF, Nadel JA. Textbook of Respiratory Medicine. 3rd ed. Philadelphia, WB Saunders Company, 2000, pp 1362-1364.

6. Sato P, Madtes DK, Thorning D. Bronchiolitis obliterans caused by Legionella pneumophila. Chest 1985;87:840-842.

7. Coultas DB, Samet JM, Butler C. Bronchiolitis obliterans due to Mycoplasma pneumoniae. West J Med 1986;144:471-474.

8. King TE Jr, Mortenson RL. Cryptogenic organizing pneumonitis: the North American experience. Chest 1992;102(1 suppl):8S-13S.

9. Cooper JA, White DA, Matthay RA. Drug-induced pulmonary disease. Am Rev Respir Dis 1986;133:321-340.

10. Lehne G, Lote K. Pulmonary toxicity of cytotoxic and immunosuppressive agents. Acta Oncol 1990;29:113-124.

RELATED ARTICLE:Key Points

* Lung injury, in the form of bronchiolitis, is a newly recognized and important adverse reaction to topotecan therapy.

* Drug-induced lung injury is a problem more commonly encountered with antineoplastic agents than with any other pharmaceutical class.

* Due to the often nonspecific nature of clinical findings, lung function tests, and radiological signs, the hallmark of drug-induced lung injury remains improvement on cessation of the causative agent.

Colin C. Edgerton, MD, Matthew Gilman, MD and Bernard J. Roth, MD

From the Department of Internal Medicine and Department of Radiology, Madigan Army Medical Center, Tacoma, WA.

Reprint requests to Colin C. Edgerton, MD, Department of Internal Medicine, Madigan Army Medical Center, Bldg. 9040, Fitzsimmons Drive, Tacoma, WA 98431. Email: [e-mail]