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Bleomycin-Induced Lung Toxicity and Pentoxifylline

McGill UniversityMontreal, Canada

To the Editor:A 45-year-old man was treated with three cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy for a stage IIIc seminoma. The pretreatment carbon monoxide diffusing capacity of the lungs (DL_CO; corrected for hemoglobin) was 100% predicted, with a forced expiratory volume in 1 second (FEV₁) of 117% predicted and a forced vital capacity (FVC) of 134% predicted.

Four weeks after treatment, a chest x-ray was performed for dyspnea and cough. Bilateral basilar infiltrates were seen, a 7-day course of Levaquin failed to help, and prednisone 50 mg/d was begun. The consolidation diminished, but prominent new bilateral ground-glass opacities became apparent on chest x-ray and computed tomography scan, despite continued prednisone use. Symptoms worsened, and the patient was found to desaturate to 79% on room air. Therefore, 10 weeks after completion of BEP, the patient was admitted and started on high-dose co-trimoxazole and intravenous methylprednisolone 40 mg every 6 hours. A thoracoscopic lung biopsy was performed, and the pathology report supported bleomycin-induced toxicity, with no evidence of fungal, mycobacterial, or PCP involvement. Additionally, the immunofluorescence study using antisera to antibody and complement was negative, confirming nonimmunologic alveolar damage. The patient did not improve after 1 week, and room air transcutaneous oxygen saturations remained near 86% at rest, with desaturation below 80% on exertion. After 1 week, pentoxifylline was added at a dose of 400 mg orally bid and then increased to 400 mg tid. Four days later, room air oxygen saturation was steady at 94%. At discharge, DL_CO was 28%, FEV₁ was 67%, and FVC was 57% of predicted.

The pentoxifylline was discontinued 41/2 months after discharge, and prednisone was tapered from 50 mg orally bid at intervals of 2 to 4 weeks, first to 75 mg orally daily, then to 50 mg, 40 mg, 30 mg, and finally 20 mg orally daily. At the most recent follow-up, 5 months after discharge, the patient was well and walked 1 hour daily without dyspnea. At almost 4 months after discharge, DL_CO was 65%, FEV₁ was 106%, and FVC was 115% of predicted. A chest x-ray at 5 months after discharge showed only a shrinking 4 x 2-cm right-sided filled cavity.

Bleomycin-induced lung toxicity has been reported to occur in 2% to 40% of patients, depending on criteria used and the presence of risk factors, and death occurs in about 2% of treated patients.¹ Patients typically present with cough and dyspnea and have variable radiographic findings, most frequently a bilateral basilar interstitial pattern.

Bleomycin probably induces lung toxicity through the induction of oxygen radicals, with recruitment of leukocytes and fibroblasts augmenting the early inflammatory and later fibrotic reactions.² In animal models, Entzian et al³ have found that pentoxifylline decreases neutrophil alveolitis and weight loss associated with bleomycin lung toxicity. Kremer et al,⁴ by contrast, found no benefit in a mouse lung injury model. In other studies, pentoxifylline has been shown to inhibit inflammatory cytokines and exerts in vitro inhibition of fibroblast proliferation and extracellular matrix production.⁵ Recently, Delanian et al⁶ demonstrated clinical benefit in a cohort of 43 patients with radiation-induced cutaneous fibrosis using a combination of pentoxifylline and vitamin E.

Our patient suffered clinical and radiographic progression of bleomycin-induced lung injury on prednisone and failed to improve after 1 week of high dose, intravenous methylprednisolone. Clinical symptoms and oxygen saturation improved 4 days after the addition of oral pentoxifylline to the patient’s regimen, and the patient experienced a progressive improvement in his symptoms, radiographic abnormalities, and, most notably, pulmonary function studies. White and Stover⁷ reported their experience with 10 patients who developed severe bleomycin-induced pneumonitis. Seven patients were treated with corticosteroids, and significant clinical and radiographic improvement was noted; however, results of pulmonary function tests remained abnormal. Prolonged therapy was required over several months to maintain improvement, and tapering of the corticosteroid dosage led to recurrence both clinically and radiographically in five of the seven patients. Mortality was 60% among the 10 patients, with three early deaths in untreated patients and three late deaths occurring 12 to 15 months after diagnosis. Van Barneveld et al⁸ reported their experience with eight patients with bleomycin-induced pneumonitis who were not treated with corticosteroids. In contrast to the series of White and Stover, the seven surviving patients had complete reversibility of clinical, radiographic, and pulmonary function abnormalities. The apparent discrepancy between these two small series may be related to the relative severity of the pneumonitis, as evidenced by the strikingly high mortality rate reported by White and Stover, and by the broad definition of bleomycin-induced pneumonitis and the lack of symptoms in two out of the eight patients in the Van Barneveld series.

Our patient clearly had severe, symptomatic, bleomycin-induced pneumonitis. He progressed while receiving corticosteroids, and improved on high-dose corticosteroids only after more than 1 week of treatment and the addition of pentoxifylline. Unlike the experience reported by White and Stover, our patient had significant improvements in his pulmonary function studies as well as his symptoms and radiographic abnormalities. He tolerated tapering of his corticosteroid dose well and remains asymptomatic. There are laboratory data to support a role for pentoxifylline in the treatment of inflammatory and fibrotic processes as well as clinical data in the setting of radiation-induced soft tissue fibrosis. The possibility that pentoxifylline contributed to the recovery of our patient cannot be completely excluded.

It is unlikely that a prospective study of pentoxifylline in this setting can be undertaken. We present this case with the hope that other clinicians faced with cases of severe bleomycin-induced pneumonitis with progression on corticosteroids might consider a trial of pentoxifylline and report their experience. As cases accumulate, the merits of pentoxifylline may be better assessed.

REFERENCES

1. Simpson AB, Paul J, Graham J, et al: Fatal bleomycin pulmonary toxicity in the west of Scotland 1991-95: A review of patients with germ cell tumours. Br J Cancer 78: 1061-1066, 1998[Medline]

2. Chandler DB: Possible mechanisms of bleomycin-induced fibrosis. Clin Chest Med 11: 21-30, 1990[Medline]

3. Entzian P, Zahringer U, Schlaak M, et al: Comparative study on effects of pentoxifylline, prednisolone and colchicine in experimental alveolitis. Int J Immunopharmacol 20: 723-735, 1998[Medline]

4. Kremer S, Breuer R, Lossos IS, et al: Effect of immunomodulators on bleomycin-induced lung injury. Respiration 66: 455-462, 1999[Medline]

5. Berman B, Duncan MR: Pentoxifylline inhibits the proliferation of human fibroblasts derived from keloid, scleroderma and morphoea skin and their production of collagen, glycosaminoglycans and fibronectin. Br J Dermatol 123: 339-346, 1990[Medline]

6. Delanian S, Balla-Mekias S, Lefaix JL: Striking regression of chronic radiotherapy damage in a clinical trial of combined pentoxifylline and tocopherol. J Clin Oncol 17: 3283-3290, 1999[Abstract/Free Full Text]

7. White DA, Stover DE: Severe bleomycin-induced pneumonitis: Clinical features and response to corticosteroids. Chest 86: 723-728, 1984[Abstract/Free Full Text]

8. Van Barneveld PW, Sleijfer DT, van der Mark TW, et al: Natural course of bleomycin-induced pneumonitis: A follow-up study. Am Rev Respir Dis 135: 48-51, 1987[Medline]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Goffin, J. Articles by Sandor, V. Search for Related Content PubMed PubMed Citation Articles by Goffin, J. Articles by Sandor, V. Social Bookmarking                            What's this?