Pulmonary, Pleural, and Thoracic Changes Complicating Chemotherapy 1

Therapeutic Radiology

Arthur S. Tucker, M.D., Arthur J. Newman, M.D., and Carlos Alvorado, M.D. Chronic respiratory failure slowly developed in two pediatric patients following long-term cyclophosphamide therapy for lymphocytic malignancy. One patient survived 12 years after acute lymphocytic leukemia was diagnosed but died of respiratory failure at age 16 still in initial remission; the other, a 12-year survivor of Hodgkin disease, has progressive deterioration-of pulmonary function. Each patient received cyclophosphamide (less than 70 g) during the initial years of the disease. Autopsy of the first patient and lung biopsy in the second revealed severe pulmonary fibrosis. There was loss of compliance and a dramatic change in the shape of the thorax which produced a markedly reduced anteroposterior diameter in both patients, and recurrent pneumothoraces in one. INDEX TERMS: Chemotherapy. Hodgkin's disease, complications and sequelae. Hodgkin's disease, therapy • Leukemia, therapy • (Lung, complications of antimetabolite therapy, 6 [0] .643) • Lungs, diseases • Lungs, effects of drugs on, 6 [0] .640 • Lungs, fibrosis Radiology 125:805-809, December 1977

white girl in 1963. She was initially treated with 6-mercaptopurine and prednisone, and maintained for two years on alternating courses of both drugs. At 6 years of age her therapy was changed to cyclophosphamide, 50 mg/d, and increased to 75 mg/d at age 7. At age 8 dysuria appeared, culminating in explosive hemorrhagic cystitis at age 9. Her hemoglobin fell to 4.5 g/ 100 ml, and 35 units of packed cells were administered before the hemorrhage was brought under control. The bladder had by then sloughed out completely, and a urinary diversion was achieved by anastomosing the ureters to an isolated loop ileostomy. No further chemotherapy was administered and the patient's leukemia remained in remission for the remainder of her life (Fig. 1). The patient remained stable for the next two years. In 1971 her weight dropped slightly. In 1972, at age 13, the patient's mother became aware of a scoliosis, and the spine was fused to prevent further deformity. A prolonged bothersome cough developed at 14 years of age and chest images became disquietingly abnormal (Figs. 2 and 3). Pulmonary function revealed a vital capacity of 23 % of normal, and at age 15 it fell to 17 %. Prednisone therapy was instituted at age 15 in an attempt to arrest pulmonary fibrosis, but dyspnea persisted (Fig. 4). The patient became progressively withdrawn, sucidal, suffered severe hallucinations and delusions, and deteriorated until her death in 1975 at age 161/2' Autopsy disclosed no evidence of leukemia. The lungs were small and firm, with pronounced fibrosis and abundant collagen. The alveolar spaces were lined with hyaline membranes. There was no polymerphonuclear infiltration, and cultures of the lungs were negative.

is the incidence of drug-induced disease in W children? No one knows, despite the fact that inHAT

creasing numbers of such cases are being recognized in our practices. The importance of this subject is attested to by the lists of drugs known to cause untoward reactions (9). We are concerned specifically with a respiratory insufficiency which developed in two children receiving long-term chemotherapy for malignant disease (5). Various studies of hospital admissions in this country indicate that anywhere from 1 to 15 % of all patients were admitted because of an adverse drug reaction (13), or they experienced such a reaction during hospitalization. Ten to 18 % of hospital patients are reported to experience a drug reaction before they are discharged (3,6), and more than 3 % of all hospital deaths may be drug-related (11). However, more recent surveys show that these figures may be rnlsleadinq; 60 % to 70 % of adverse drug reactions (ADRs) may be of relatively minor importance (4). A study of 7,423 admissions to the inpatient medical service of the University of Florida over a 3 V2-year period revealed 1,318 ADRs. Among these 16 proved fatal, an incidence of 1.70/0. All 16 patients were either seriously or terminally ill, so the affected population was certainly one at high risk (2). A series of 26,462 patients studied in acute-disease hospitals in seven countries (more than half of the total population studied was in the United States) included in the Boston Collaborative Drug Surveillance Program revealed a total of 11 deaths clearly due to drugs, and another 13 deaths in which drugs were the probable cause. These 24 cases constitute an incidence of 0.9 drug-related deaths per 1000 patients (7).

CASE II. "Lumps on the jaw" which did not respond to tonsillectomy and adenoidectomy, oral Declomycin, or 41 injections of penicillin developed in a 3-year-old white boy. A cervical node biopsy was performed at 3 years, 8 months of age. Hodgkin disease, Stage II (Fig. 5), was diagnosed. Radiation therapy was administered in total air dosages to the right cervical region of 1600 R and to the mediastinum of 2200 R (Fig. 6), followed by 25 mg/d cyclophosphamide (Fig. 7). Five years later hematuria appeared, cystoscopy demonstrated hemorrhagic areas in the bladder, and the cyclophosphamide was discontinued. No evidence of Hodgkin lymphoma was noted during a 12-year follOW-Up period. However, frequent episodes of unremitting coughing led to hospitalizations for "pneumonia" during this time. At age 14 he

CASE REPORTS CASE I. Acute lymphatic leukemia was diagnosed in a 41/2-year-old

, 1 From the Departments of Radiology and Pediatrics, Case Western Reserve University and University Hospitals of Cleveland, Ohio. Revised edition accepted for publication in July 1977. emt

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was admitted for evaluation of his respiratory state . His vital capacity was 35 % of normal. A biopsy. performed through a bronchoscope from the right lower lobe, revealed marked interstital fibrosis and mild alveolar hypoplasia. The patient was placed on 1 mg/k prednisone therapy for six months without relief of symptoms (Fig. 8). Subsequent pulmonary function studies showed a slow progressive decrease in vital capacity.

December 1977

The patient tires easily with activity and his sleeping respiratory rate is elevated to 28 per minute .

DISCUSSION

The patient in CASE I had a chest deformity which was

Fig. 1. CASE I. Chest at age 91f2' considered normal. Fig. 2. CASE I. Chest at age 14% shows nondescript diffuse streaking in the pulmonary parenchyma. A small right hydropneumothorax is present (arrow points to fluid level). The thorax has a much smaller AP diameter than it had originally. A scoliosis to the right at T 10 was fused at age 13%. and a Harrington rod is apparent in the fusion.

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partly related to scoliosis, in spite of surgical fusion. It differed from any other chest deformity we have seen in scoliosis, in that the anteroposterior diameter of the thorax

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became progressively diminished. Furthermore, there was a chronic failure of the lungs to fill the available intrathoracic space; this was manifest in recurrent self-limited

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Fig. 3. CASE I. PA chest image obtained 22 days after Figure 2 demonstrates small bilateral pneumothoraces (arrows) . Fig. 4. CASE I. AP chest image obtained at age 16% shows no pneumothroax but conspicuous soft-tissue pleural densities (arrows) compressing both upper lung fields . The pulmonary parenchyma is noticeably streaked . Fig. 5. CASE II. PA chest image obtained at 3 years, 8 months of age when Hodgkin disease was diagnosed. A rounded parenchymal dense lesion is seen in the right lower lobe. Fig. 6. CASE II. Port image showing field of treatment by radiation to the mediastinum.

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pneumothoraces and apparent thickening of the pleura over the lung apices. Meanwhile, an accentuation of markings which we attributed to a progressive fibrosis or interstitial pneumonitis, or both, developed in the lungs. Autopsy showed a severe degree of pulmonary fibrosis. We felt that the patient's psychosis was probably a consequence of central nervous system anoxia.

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The patient in CASE II experienced a somewhat similar physical limitation based on diminishing respiratory sufficiency. After 12 years he is alive and apparently free of tumor, but his lungs show some evidence of fibrosis and his thorax manifests a mild degree of anteroposterior shrinkage. We found two common demonimators in these two

8L Fig. 7. CASE II. Chest images obtained at age 5 1/2 years are normal. Fig. 8. CASE II. Chest images obtained at age 15 years, 5 months show mild pulmonary fibros is and bilateral pleural densities surrounding the upper lobes . The AP thoracic dimension is proportionately less than it was 10 years earlier.

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histories of pulmonary disability: prednisone and cyclophosphamide therapy. However, prednisone was not given to the second patient during the first 10 years of treatment, although cyclophosphamide was administered relatively early to both patients over a period of years. Cyclophosphamide, an alkylating agent which has been widely used in the treatment of leukemia, lymphoma, and carcinoma, has been reported as a likely cause of diffuse alveolar injury to the lungs (1, 8, 12). It appears to be very similar to another alkylating agent, busulfan (Myleran), whose effects are more definitively documented (9). Other drugs which have been incriminated as causes of similar injury are hexamethonium, methysergide (Sansert), and bleomycin (Blenoxane) (10).

REFERENCES 1. Andre R, Rochant H, Dreyfus B, et al: Fibrose interstitielle diffuse du poumon au cours d'une maladie de Hodgkin traltee par des doses elevees d'endoxan. Bull Soc Moo HOp Paris 118:1133-1141, Nov 1967 2. Caranasos GJ, May FE, Stewart RS, et al: Drug-associated deaths of medical inpatients. Arch Intern Med 136:872-875, Aug 1976 3. Friedman GO, Collen MF, Harris LE, et al: Experience in monitoring drug reactions in outpatients. The Kaiser-Permanente Drug Monitoring System. JAMA 217:567-572, Aug 1971 4. Karch FE, Lasagna L: Adverse drug reactions: a critical review. JAMA 234:1236-1241, Dec 1975

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5. Newman AJ, Alvorado C, Gross S: Pulmonary fibrosis: a delayed complication of cyclophosphamide. To be published. 6. Ogilvie RI, Ruedy J: Adverse drug reactions during hospitalization. Canad Med Assoc J 97:1450-1457, Dec 1967 7. Porter J, Jick H: Drug-related deaths among medical inpatients. JAMA 237:879-881, 1977 8. Rodin AE, Haggard ME, Travis LB: Lung changes and chemotherapeutic agents in childhood. Report of a case associated with cyclophosphamide therapy. Am J Dis Child 120:337-340, Oct 1970 9. Rosenow EC, 3d: The spectrum of drug-induced pulmonary disease. Ann Intern Med 77:977-991, Dec 1972 10. Samuels ML, Johnson DE, Holoye PY, et al: Large-dose bleomycin therapy and pulmonary toxicity. A possible role of prior radiotherapy. JAMA 235:1117-1120, Mar 1976 11. Shapiro S, Slone D, Lewis GP, et al: Fatal drug reactions among medical inpatients. JAMA 216:467-472, Apr 1971 12. Topilow AA, Rothenberg SP, Cottrell TS: Interstitial pneumonia after prolonged treatment with cyclophosphamide. Am Rev Respir Dis 108:114-117, Jul 1973 13. Visconti JA, Smith MC: The role of hospital personnel in reporting adverse drug reactions. Am J Hosp Pharm 24:273-275, 1967

Arthur S. Tucker, M.D. University Hospitals of Cleveland University Circle Cleveland, Ohio 44106

Pulmonary, pleural and thoracic changes complicating chemotherapy.

Pulmonary, Pleural, and Thoracic Changes Complicating Chemotherapy 1 Therapeutic Radiology Arthur S. Tucker, M.D., Arthur J. Newman, M.D., and Carlo...
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