Medical and Pediatric Oncology 6 :255-259 ( 1 9 7 9 )
Pulmonary Toxicity From Carmustine (BCNU): A Case Report Raymond B. Weiss, MD, Sheila Shah, MD, and Stanley R. Shane, MD Departments of Medicine and Pathology, West Virginia University Medical Center, Morgantown
A patient who had a pneumonectomy for lung carcinoma was treated with carmustine when brain metastases developed. His pulmonary function was mildly compromised prior to the pneumonectomy by many years of smoking. After six months of carmustine therapy [total dose: 2,250 mg (1,200 mg/m*)] he developed interstitial pulmonary fibrosis with histologic changes consistent with drug toxicity. With seven previously reported cases of this drug effect and the addition of our case, carmustine must be added t o the list of cancer chemotherapeutic agents that can cause pulmonary toxicity. Key words: carmustine, BCNU, pulmonary fibrosis
INTR OD UCT I0 N
Manifestations of pulmonary toxicity from long-term administration of cancer chemotherapeutic agents have been noted frequently with bleomycin, for example, and rarely with such other agents as cyclophosphamide, methotrexate, and busulfan [ l ] . The histologic changes in the lung include diffuse alveolar damage and organizing interstitial pneumonia and fibrosis [ 1 1 . Until a case report by Holoye et a1 [ 2 ] was published, it was not recognized that carmustine could also produce interstitial pulmonary fibrosis with similar histology. Subsequently, six other cases of this problem have been published [3-51. We report another case of presumed carmustine pulmonary toxicity in a patient who had a previous pneumonectomy. CASE REPORT
A 52-year-old salesman was first seen at West Virginia University Hospital in June 1975 for work-up of a right hilar mass found on chest roentgenogram. Pertinent history was that he had been a two-pack per day smoker for over 30 years, and he was genetically BCNU - 1,3-bis (2-chloroethyl)-l-nitrosourea.
Dr. Weiss is now at the Clinical Investigations Branch, Division of Cancer Treatment, National Cancer Institute, Landow Building, Room 8C03, Bethesda, MD 20205. Address reprint requests there.
0098-1532/79/0603-025551.40 0 1979 Alan R. Liss, Inc.
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heterozygous for cystic fibrosis. He had three children, two of whom have had cystic fibrosis; a daughter died at age six of cystic fibrosis, and a son age 19 is living with the disease. Bronchoscopy confirmed the presence of a tumor mass in the right middle lobe bronchus. A right pneumonectomy was performed, and the pathology was poorly differentiated adenocarcinoma. No further therapy was given, and he stopped-smoking. He was well until January 1977 when he presented with a focal motor seizure of the left side of the body. A brain scan and a carotid arteriogram confirmed the presence of a tumor mass in the right cerebral hemisphere which was presumed to be metastatic. Workup failed to demonstrate any other metastases, and his chest roentgenogram was negative except for the pneumonectomy. He was treated with 5,000 rad of 6o Co to the whole brain. Dexamethasone was given in a dose of 3 mg/day. He was also on diphenylhydantoin and phenobarbital. In May 1977 his seizures increased in frequency and weakness of his left hand progressed. A brain scan showed a larger area of radionuclide uptake. Carmustine was begun in a dose of 80 mg/m2 daily times three, every six weeks. Over the next six months, he received five courses of carmustine [total dose administered: 2.250 mg (1,200 mg/m*)]. Dexamethasone was continued throughout this period. There was no exposure to known pulmonary toxins. The lowest blood counts recorded during treatment were: platelets 88,000/mm3;white cells 4,300/mm3. In November 1977 the patient developed incapacitating exertional dyspnea. He had a mild cough, which had been present since the pneumonectomy and never changed. A chest film showed interstitial infiltrates in the left base (Fig. 1) that were not there on the previous chest film done in September (Fig. 2). A presumptive diagnosis of lymphangitic carcinomatosis was made.
Fig. 1. Chest roentgenogram showing the interstitial infiltrate in the left base after BCNU therapy. Fig. 2. Chest roentgenogram taken 2% months before Figure 1 showing no infiltrates in the left lung.
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Bronchoscopy disclosed no evidence of tumor, either grossly or by cytologic examination of bronchial washings. All cultures were negative. Two days later the patient became severely hypoxic (arterial blood gases: pOz 43, pCOz 21.2, and pH 7.46) and required ventilatory support. He deteriorated steadily and died four days later. At autopsy the left lung had prominent fibrous thickening of visceral pleura. Cut surfaces of the left lung were reddish-gray and revealed a patchy “honeycomb” appearance. Focal granularity of the parenchyma was present. No thromboemboli or infarcts were seen, and the major bronchi were patent. Multiple sections of the left lung were found to contain varying degrees of interstitial fibrosis, with abundant fibroconnective tissue within the alveolar septa (Fig. 3). Larger areas of fibrosis were seen around small pulmonary arteries. Some alveoli contained fibrinous fluid and desquamated macrophages, with occasional hyaline membranes. The interlobular septa were swollen, and some alveoli were lined by metaplastic cuboidal epithelium. The visceral pleura was thickened with extensive proliferation of fibroconnective tissue. There was no residual or metastatic carcinoma in the thorax or abdomen. DISCUSSION
We report a patient who developed fatal pulmonary fibrosis proven at autopsy which was temporally related t o his carmustine therapy. There were no other known precipitating factors for this condition, and he had the histologic findings typical of druginduced lung toxicity: alveolar lining cell dysplasia, interstitial pneumonia, and interstitial fibrosis [ 1 ] .
Fig. 3. Photomicrograph of lung showing diffuse interstitial fibrosis (hematoxylin and eosin, original magnification, X 200)
Web, Shah,a n d S h a n e
258
TABLE I. Comparison o f Treatment Information in Reported Cases o f amustine-Associated Pulmonary Toxicity
Authors
Malignancy
Total cumulative carmustine dose
Treatment duration (months)
Holoye et a1 [ 21 1 Patient : age 19
Cerebellar astrocytoma
3,330 mg (2,081 mg/m2)
35
Crit tenden et a1 [ 31 1 Patient: age 4 3
Metastatic melanoma
1.800 mg (mg/m2 dose not given)
2’
Selker et a1 141 4 Patients: all adults
4 Brain gliomas
Mean: 2,030 mg/mz
Not given
Bailey et a1 [ 5 ] 1 Patient: age 2
Medulloblastoma
775 mg (1550 mg/m2)
24
Weiss et a1 (this paper)
Brain metastases of lung adenocarcinoma
2,250 mp (1,200 mg/m2 )
6
The toxic effects of carmustine are mainly bone marrow suppression and vomiting [6]. Several rare and minor effects are conjunctival flushing, alopecia, elevation of liver function tests, and cerebral dysfunction [6]. Although BCNU has been under investigational use since 1964 and commercially available since 1977, until recently [2-51 . pulmonary toxicity was not observed as a toxic phenomenon in humans. A report in 1966 documented four cases of patients treated with carmustine who developed pulmonary infiltrates [7]. However. in one case there was a question of viral infection. two cases had a benign asymptomatic course with clearing of the infiltrates in two to three weeks, and one had 1,200 rad of bilateral whole-lung radiation which, of course, could cause pneumonitis. In other words, there was no clear-cut instance of carmustine-induced pulmonary toxicity with irreversible fibrosis in these cases. Four very recent reports have documented seven instances of carmustine-associated pulmonary fibrosis, all histologically proven [2-51. All patients had the drug administered over many months in large doses, and all but one were adults (Table I). Our patient received carmustine for only a short time (six months). He had only one lung, and its function was compromised by his many years of smoking. Also, he was heterozygous for cystic fibrosis. Whether either or both of these factors had any relationship to the development of the drug-induced pulmonary toxicity is conjecture. Carmustine has produced pulmonary toxicity in the preclinical animal toxicology investigations of the drug [8] . However, the pulmonary effects were acute (pleural effusion and pulmonary edema), and no animal was studied for chronic toxicity. Postmortem histologic examination did not demonstrate any pulmonary fibrosis [8]. The animal toxicology data did not predict the human pulmonary toxicity of the type now being seen. Drug-induced pulmonary fibrosis was not suspected in the differential diagnosis of our patient’s interstitial infiltrate. It is suggested that with more awareness of the possibility that among the cancer chemotherapeutic agents carmustine can also produce lung toxicity, other cases will be recognized earlier before irreversible and fatal fibrosis occurs, as it did in our patient. ACKNOWLEDGMENTS
Supported in part by US Public Health Service grants CA 07757 and CA 19530.
Pulmonary Toxicity From Carmustine
2 59
REFERENCES 1. Sostman HD, Matthay RA, Putnam CE: Cytotoxic drug-induced lung disease. Am J Med 62:608-615, 1977. 2. Holoye PY, Jenkins DE, Greenberg SD: Pulmonary toxicity in long-term administration of BCNU. Cancer Treat Rep 60:1691-1694, 1976. 3. Crittenden D, Tranum BL, Haut A: Pulmonary fibrosis after prolonged therapy with 1,3-bis (2chloroethy1)-1 -nitrosourea. Chest 72: 372 -3 73, 1977. 4. Selker RG, Jacobs SA, Moore P: Interstitial pulmonary fibrosis as a complication of 1,3-bis-(2chloroethy1)-1-nitrosourea (BCNU) therapy. Proc Am SOCClin Oncol 19:333, 1978 (abstr). 5. Bailey CC, Marsden Morris Jones PH: Fatal pulmonary fibrosis following 1,3-bis (2chloroethyl)-lnitrosourea (BCNU) therapy. Cancer 42:74-76, 1978. 6. Wasserman lH:The nitrosoureas: An outline of clinical schedules and toxic effects. Cancer Treat Rep 60:709-711,1976. 7. Iriarte PV, Hananian J, Cortner JA: Central nervous system leukemia and solid tumors of childhood. Treatment with 1.3-bis (2-chloroethyl)-l-nitrosourea(BCNU). Cancer 19:1187-1194, 1966. 8. Broder LE, Carter SK: 1,3-bis-(2-chloroethyI)-1-nitrosourea (BCNU). Clinical brochure. National Cancer Institute, 1970.
,
Pulmonary Toxicity From Carmustine (BCNU): A Case Report Raymond B. Weiss, MD, Sheila Shah, MD, and Stanley R. Shane, MD Departments of Medicine and Pathology, West Virginia University Medical Center, Morgantown
A patient who had a pneumonectomy for lung carcinoma was treated with carmustine when brain metastases developed. His pulmonary function was mildly compromised prior to the pneumonectomy by many years of smoking. After six months of carmustine therapy [total dose: 2,250 mg (1,200 mg/m*)] he developed interstitial pulmonary fibrosis with histologic changes consistent with drug toxicity. With seven previously reported cases of this drug effect and the addition of our case, carmustine must be added t o the list of cancer chemotherapeutic agents that can cause pulmonary toxicity. Key words: carmustine, BCNU, pulmonary fibrosis
INTR OD UCT I0 N
Manifestations of pulmonary toxicity from long-term administration of cancer chemotherapeutic agents have been noted frequently with bleomycin, for example, and rarely with such other agents as cyclophosphamide, methotrexate, and busulfan [ l ] . The histologic changes in the lung include diffuse alveolar damage and organizing interstitial pneumonia and fibrosis [ 1 1 . Until a case report by Holoye et a1 [ 2 ] was published, it was not recognized that carmustine could also produce interstitial pulmonary fibrosis with similar histology. Subsequently, six other cases of this problem have been published [3-51. We report another case of presumed carmustine pulmonary toxicity in a patient who had a previous pneumonectomy. CASE REPORT
A 52-year-old salesman was first seen at West Virginia University Hospital in June 1975 for work-up of a right hilar mass found on chest roentgenogram. Pertinent history was that he had been a two-pack per day smoker for over 30 years, and he was genetically BCNU - 1,3-bis (2-chloroethyl)-l-nitrosourea.
Dr. Weiss is now at the Clinical Investigations Branch, Division of Cancer Treatment, National Cancer Institute, Landow Building, Room 8C03, Bethesda, MD 20205. Address reprint requests there.
0098-1532/79/0603-025551.40 0 1979 Alan R. Liss, Inc.
256
Web, Shah, and Shane
heterozygous for cystic fibrosis. He had three children, two of whom have had cystic fibrosis; a daughter died at age six of cystic fibrosis, and a son age 19 is living with the disease. Bronchoscopy confirmed the presence of a tumor mass in the right middle lobe bronchus. A right pneumonectomy was performed, and the pathology was poorly differentiated adenocarcinoma. No further therapy was given, and he stopped-smoking. He was well until January 1977 when he presented with a focal motor seizure of the left side of the body. A brain scan and a carotid arteriogram confirmed the presence of a tumor mass in the right cerebral hemisphere which was presumed to be metastatic. Workup failed to demonstrate any other metastases, and his chest roentgenogram was negative except for the pneumonectomy. He was treated with 5,000 rad of 6o Co to the whole brain. Dexamethasone was given in a dose of 3 mg/day. He was also on diphenylhydantoin and phenobarbital. In May 1977 his seizures increased in frequency and weakness of his left hand progressed. A brain scan showed a larger area of radionuclide uptake. Carmustine was begun in a dose of 80 mg/m2 daily times three, every six weeks. Over the next six months, he received five courses of carmustine [total dose administered: 2.250 mg (1,200 mg/m*)]. Dexamethasone was continued throughout this period. There was no exposure to known pulmonary toxins. The lowest blood counts recorded during treatment were: platelets 88,000/mm3;white cells 4,300/mm3. In November 1977 the patient developed incapacitating exertional dyspnea. He had a mild cough, which had been present since the pneumonectomy and never changed. A chest film showed interstitial infiltrates in the left base (Fig. 1) that were not there on the previous chest film done in September (Fig. 2). A presumptive diagnosis of lymphangitic carcinomatosis was made.
Fig. 1. Chest roentgenogram showing the interstitial infiltrate in the left base after BCNU therapy. Fig. 2. Chest roentgenogram taken 2% months before Figure 1 showing no infiltrates in the left lung.
Pulmonary Toxicity From Carmustine
257
Bronchoscopy disclosed no evidence of tumor, either grossly or by cytologic examination of bronchial washings. All cultures were negative. Two days later the patient became severely hypoxic (arterial blood gases: pOz 43, pCOz 21.2, and pH 7.46) and required ventilatory support. He deteriorated steadily and died four days later. At autopsy the left lung had prominent fibrous thickening of visceral pleura. Cut surfaces of the left lung were reddish-gray and revealed a patchy “honeycomb” appearance. Focal granularity of the parenchyma was present. No thromboemboli or infarcts were seen, and the major bronchi were patent. Multiple sections of the left lung were found to contain varying degrees of interstitial fibrosis, with abundant fibroconnective tissue within the alveolar septa (Fig. 3). Larger areas of fibrosis were seen around small pulmonary arteries. Some alveoli contained fibrinous fluid and desquamated macrophages, with occasional hyaline membranes. The interlobular septa were swollen, and some alveoli were lined by metaplastic cuboidal epithelium. The visceral pleura was thickened with extensive proliferation of fibroconnective tissue. There was no residual or metastatic carcinoma in the thorax or abdomen. DISCUSSION
We report a patient who developed fatal pulmonary fibrosis proven at autopsy which was temporally related t o his carmustine therapy. There were no other known precipitating factors for this condition, and he had the histologic findings typical of druginduced lung toxicity: alveolar lining cell dysplasia, interstitial pneumonia, and interstitial fibrosis [ 1 ] .
Fig. 3. Photomicrograph of lung showing diffuse interstitial fibrosis (hematoxylin and eosin, original magnification, X 200)
Web, Shah,a n d S h a n e
258
TABLE I. Comparison o f Treatment Information in Reported Cases o f amustine-Associated Pulmonary Toxicity
Authors
Malignancy
Total cumulative carmustine dose
Treatment duration (months)
Holoye et a1 [ 21 1 Patient : age 19
Cerebellar astrocytoma
3,330 mg (2,081 mg/m2)
35
Crit tenden et a1 [ 31 1 Patient: age 4 3
Metastatic melanoma
1.800 mg (mg/m2 dose not given)
2’
Selker et a1 141 4 Patients: all adults
4 Brain gliomas
Mean: 2,030 mg/mz
Not given
Bailey et a1 [ 5 ] 1 Patient: age 2
Medulloblastoma
775 mg (1550 mg/m2)
24
Weiss et a1 (this paper)
Brain metastases of lung adenocarcinoma
2,250 mp (1,200 mg/m2 )
6
The toxic effects of carmustine are mainly bone marrow suppression and vomiting [6]. Several rare and minor effects are conjunctival flushing, alopecia, elevation of liver function tests, and cerebral dysfunction [6]. Although BCNU has been under investigational use since 1964 and commercially available since 1977, until recently [2-51 . pulmonary toxicity was not observed as a toxic phenomenon in humans. A report in 1966 documented four cases of patients treated with carmustine who developed pulmonary infiltrates [7]. However. in one case there was a question of viral infection. two cases had a benign asymptomatic course with clearing of the infiltrates in two to three weeks, and one had 1,200 rad of bilateral whole-lung radiation which, of course, could cause pneumonitis. In other words, there was no clear-cut instance of carmustine-induced pulmonary toxicity with irreversible fibrosis in these cases. Four very recent reports have documented seven instances of carmustine-associated pulmonary fibrosis, all histologically proven [2-51. All patients had the drug administered over many months in large doses, and all but one were adults (Table I). Our patient received carmustine for only a short time (six months). He had only one lung, and its function was compromised by his many years of smoking. Also, he was heterozygous for cystic fibrosis. Whether either or both of these factors had any relationship to the development of the drug-induced pulmonary toxicity is conjecture. Carmustine has produced pulmonary toxicity in the preclinical animal toxicology investigations of the drug [8] . However, the pulmonary effects were acute (pleural effusion and pulmonary edema), and no animal was studied for chronic toxicity. Postmortem histologic examination did not demonstrate any pulmonary fibrosis [8]. The animal toxicology data did not predict the human pulmonary toxicity of the type now being seen. Drug-induced pulmonary fibrosis was not suspected in the differential diagnosis of our patient’s interstitial infiltrate. It is suggested that with more awareness of the possibility that among the cancer chemotherapeutic agents carmustine can also produce lung toxicity, other cases will be recognized earlier before irreversible and fatal fibrosis occurs, as it did in our patient. ACKNOWLEDGMENTS
Supported in part by US Public Health Service grants CA 07757 and CA 19530.
Pulmonary Toxicity From Carmustine
2 59
REFERENCES 1. Sostman HD, Matthay RA, Putnam CE: Cytotoxic drug-induced lung disease. Am J Med 62:608-615, 1977. 2. Holoye PY, Jenkins DE, Greenberg SD: Pulmonary toxicity in long-term administration of BCNU. Cancer Treat Rep 60:1691-1694, 1976. 3. Crittenden D, Tranum BL, Haut A: Pulmonary fibrosis after prolonged therapy with 1,3-bis (2chloroethy1)-1 -nitrosourea. Chest 72: 372 -3 73, 1977. 4. Selker RG, Jacobs SA, Moore P: Interstitial pulmonary fibrosis as a complication of 1,3-bis-(2chloroethy1)-1-nitrosourea (BCNU) therapy. Proc Am SOCClin Oncol 19:333, 1978 (abstr). 5. Bailey CC, Marsden Morris Jones PH: Fatal pulmonary fibrosis following 1,3-bis (2chloroethyl)-lnitrosourea (BCNU) therapy. Cancer 42:74-76, 1978. 6. Wasserman lH:The nitrosoureas: An outline of clinical schedules and toxic effects. Cancer Treat Rep 60:709-711,1976. 7. Iriarte PV, Hananian J, Cortner JA: Central nervous system leukemia and solid tumors of childhood. Treatment with 1.3-bis (2-chloroethyl)-l-nitrosourea(BCNU). Cancer 19:1187-1194, 1966. 8. Broder LE, Carter SK: 1,3-bis-(2-chloroethyI)-1-nitrosourea (BCNU). Clinical brochure. National Cancer Institute, 1970.
,
