Case report

A 74-year-old woman was a non-smoker. She had been previously healthy until adenocarcinoma in the right lower lung with ipsilateral malignant pleural effusion, and lung metastasis was diagnosed in November 2008. She received single-agent chemotherapy with oral vinorelbine 60 mg/m2/week for 6 courses. Disease progression on chest CT scan was recognized in April 2009. The patient then received gefitinib (250 mg/day) on May 22, 2009. However, fever, aggravated dry cough and dyspnea developed after 5 days of gefitinib treatment. On arrival to our clinic, she appeared acutely ill and dyspneic. The body temperature was 38.3°C; pulse rate was 115 beats/min; respiratory rate was 28 breaths/min and the blood pressure was 135/85 mmHg. Hypoxemia and a 90% of oxyhemoglobin saturation were measured by pulse oximetry. Chest X-ray revealed bilateral increased ground-glass opacity predominantly over left upper lung zone (Figs. 1, 2) compared to chest X-ray taken as baseline 5 days ago. The laboratory values on initial presentation were illustrated in Table 1. She was admitted under the impression of gefitinib-related interstitial pneumonitis. After admission, gefitinib was discontinued immediately and methylprednisolone 120 mg/day was started. No evidence of infection or pathological microorganism was found in either sputum or blood culture. The serology tests for Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella pneumophila were all negative. On the 3rd hospitalization day, the patient presented with progressive dyspnea and severe hypoxemia. Follow-up chest X-ray and high resolution of chest CT also revealed diffuse ground-glass opacity over left whole lung (Fig. 3). She was transferred to MICU and high-dose corticosteroid treatment with methylprednisolone 500 mg/day for three consecutive days was administered intravenously. Her dyspnea and hypoxemia improved significantly in 2 days. Significant resolution of left upper zone opacity was also noted on 6th day of initiating steroid pulse therapy. After 3 days of pulse therapy, systemic steroid was tapered to 80 mg/day prednisolone and then tailed off 3 weeks later. There was no specific complication except general weakness over bilateral legs that gradually improved. On the 13th hospitalization day, she was discharged without obvious complications. One month later, follow-up chest CT (Fig. 4) showed total resolution of ground-glass lesions.

Fig. 1
figure 1

Before receiving gefitinib treatment

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Fig. 2
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Chest X-ray revealed bilateral increased ground-glass opacity predominantly over left upper lung zone compared to chest X-ray taken as baseline 5 days ago

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Table 1 Laboratory values on initial presentation
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Fig. 3
figure 3

Main tumor sized 3 cm over right lower lobe near right pulmonary hilum (white arrow) with pleural effusion. Left lung zones diffuse ground-glass opacity (black arrows)

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Fig. 4
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Right lower lobe tumor showed slight regression, but an adjacent metastatic lesion (white arrow) and left lymphangitic spreading tumor was noted. Left lung zones ground-glass opacity disappeared after discontinuing use of gefitinib

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Discussion

Gefitinib, a selective epidermal growth family receptor tyrosine kinase inhibitor (EGFR-TKI), was first approved in treatment of non-operable NSCLC in Japan since July 2002. Significant survival benefit was established in subgroups of Asian origin and non-smoker (1). Currently, gefitinib is used as second- or third-line therapy for patients with locally advanced or metastatic non-small cell lung cancer after failure of platinum-based and docetaxel-based chemotherapies in several eastern Asian countries (2).

The most common gefitinib-related drug adverse effects are acneiform skin rashes, diarrhea and nausea which are usually mild in severity and manageable (3). In addition to the above adverse effects, acute interstitial pneumonia induced by gefitinib was an infrequent but potentially lethal entity (4).

The incidence of acute interstitial pneumonia during gefitinib treatment varied between different ethnics. In a large prospective cohort study, of 1872 Japanese patients, a cumulative incidence at 12 weeks of gefitinib treatment was 4.0% (5). However, the reporting rate of ILD-type events in patients receiving gefitinib treatment was only 0.23% in the rest of the world excluding Japan (6). In Taiwan, a 5.8% incidence of gefitinib-related interstitial pneumonia was ever reported from a small prospective study (7). The precise mechanism of interstitial pneumonitis induced by gefitinib remains unknown. Compared with conventional chemotherapy, the risk of developing acute interstitial lung disease was higher with gefitinib (odds ratios was 3.2, 95% confidence interval, 1.9–5.4) (5).

Clinical manifestation of gefitinib-induced acute interstitial pneumonia included dyspnea, non-productive cough and profound hypoxemia (8, 9). Establishment of definite diagnosis is usually difficult since the main pathohistological finding of gefitinib-induced interstitial pneumonia was non-specific diffuse alveolar damage (4). Most accurate diagnosis relied on clinical manifestation, characteristic findings on CT scan, exclusion of pulmonary infection and a progression of lung cancer and the prompt clinical response to drug discontinuation (7, 8). New onset of respiratory symptoms in the first 4 weeks of gefitinib treatment is a major clue to the diagnosis (5). Chest computer tomography is the most useful investigation, and the major radiographic patterns on CT scan were a non-specific area with ground-glass attenuation and extensive bilateral ground-glass attenuation or airspace consolidations with traction bronchiectasis (10).

There was no randomized controlled trial to guide the management of gefitinib-induced acute interstitial pneumonia. Immediate withdrawal of gefitinib, intravenous corticosteroid and oxygen therapy is current recommended management (8). Successful treatment with high-dose corticosteroids (MTP 1 g/day intravenously for 3 consecutive days, followed by 60 mg/day of oral prednisolone and decreased by 10 mg per week) had been reported (11). The case in this report also revealed that some gefitinib-induced interstitial pneumonia may be refractory to medium-dose corticosteroids and could be treated successfully with high-dose corticosteroids. Table 2 illustrated cases of gefitinib-related ILD treated with high-dose corticosteroids. Thioredoxin (Trx), a redox-active protein with antioxidative effects, may be used on gefitinib-induced interstitial lung disease by suppression of leukocyte infiltration (12).

Table 2 Cases of gefitinib-related interstitial lung disease and treatment
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Careful surveillance of acute pulmonary toxicity during gefitinib treatment is essential. Early recognition and intervention including immediate withdrawal of gefitinib and corticosteroids treatment may prevent a fatal outcome, and high-dose corticosteroids should be considered if clinically deteriorated even under the recommended approach.