Gemcitabine-induced Pulmonary Toxicity

Case Report

The patient is a 56-year-old man with a 50 pack/year smoking history diagnosed with stage IV (pT3, pN1, M1) poorly-differentiated adenocarcinoma of the pancreatic head with a single 1.8-cm hepatic metastasis. The patient underwent a pylorus-sparing Whipple procedure, followed by five cycles of adjuvant chemotherapy under a study protocol. The regimen comprised of gemcitabine (1000 mg/m² × 2.15 m² =2300 mg i.v.) and study drug or placebo p.o. on days 1-21 out of a 28-day cycle. Cycles were repeated every four weeks. The patient demonstrated a complete response by cycle 3 on magnetic resonance imaging (MRI), and the decision was made to continue under the study protocol. By cycle 5, the patient received a cumulative dose of 32,300 mg of gemcitabine. Upon presentation for cycle 6, the patient reported several days of progressive dypsnea on exertion, chest tightness, and palpitations. Oxygen saturation was 82-84% on room air by pulse oximetry, which improved to 92% on 2 L of supplemental oxygen by nasal cannula. The patient also had a low-grade fever of 100.3°F/37.9°C. CT angiography of the chest demonstrated new diffuse groundglass opacities in the bilateral lower lobes when compared to the CT of the chest without i.v. contrast, five weeks prior (Figure 1). Mild to moderate emphysema was also seen, but no pulmonary emboli were detected. Myocardial infarction was ruled-out by normal electrocardiogram and normal cardiac biomarkers.

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Figure 1.

Representative axial images from a computerized tomography (CT) angiography of the chest at the time of presentation.

The patient underwent an extensive infectious work-up including serial blood cultures, urine culture, Streptococcus pneumoniae urinary antigen, Legionella urinary antigen, cultures of expectorated sputum and bronchoalveolar lavage for bacterial and viral (influenza, respiratory syncytial virus, parainfluenza, adenovirus, rhinovirus, metapneumovirus), fungal (Pneuocystis, Asperillus) and acid-fast bacilli. The patient's HIV status was also confirmed as being negative. This work-up failed to identify an infectious etiology for dyspnea.

Bronchosopy was visually normal. Cytological analysis of brochoalveolar lavage showed no evidence of malignancy, but showed numerous pulmonary alveolar macrophages. An immunocytochemical stain for cytomegalovirus was also negative. Transbronchial biopsy showed a pattern of diffuse alveolar damage with intra-alveolar fibrinous exudates. Again, special stains of the biopsy specimen failed to reveal an infectious etiology.

Upon presentation, the patient was immediately started on high-dose corticosteroids and empiric broad-spectrum anti-infectives, including azithromycin, piperacillin-tazobactam, sulfamethoxazole/trimethoprim, vancomycin, tobramycin, and oseltamivir. All anti-infective medications were discontinued as infectious etiologies were ruled out and at the time of discharge, the patient was prescribed with only an oral corticosteroid.

During the first five days of hospitalization, the patient required increasing supplemental oxygen requirements to maintain oxygen saturation above 90%, but did not require endotracheal intubation, mechanical intubation, or bilevel positive airway pressure (BPAP). By hospital day 10, the patient was able to wean off nasal cannula, but still required supplemental oxygen up to 6 L on ambulation. At the time of discharge, the patient's ambulatory oxygen saturation was 84% on room air and 94% with 4 L supplemental oxygen by nasal cannula. The patient was discharged with home oxygen. At six weeks' follow-up after discharge, the patient completed slow steroid taper and no longer required supplemental oxygen. The patient had also noted an increase in his functional status and exercise tolerance. Follow-up imaging at five weeks showed improvement of ground-glass opacities.