Successful retreatment with erlotinib after erlotinib-related interstitial lung disease

Introduction

Erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) used in the treatment of advanced stage non-small cell lung cancer (NSCLC). Erlotinib improves survival and quality of life in patients with advanced stage NSCLC when used as a first- or second-line treatment following platinum-based chemotherapy. ¹

Despite the relatively common side effects (diarrhea, rashes, decreased appetite, and asthenia), EGFR TKIs are considered safe medicines. However, cases of fatal interstitial lung disease (ILD) associated with EGFR TKIs have been reported. The mechanism of ILD is unknown. ILD in patients with NSCLC administered gefitinib is better described and some of these cases are reported to be fatal. However, erlotinib-related ILD is not well-known.

Case description

A 54-year-old nonsmoking woman presented to the hospital with chest pain and mild headache. Chest computed tomography (CT) showed a mass in the lower lobe of the right lung and metastasis in thoracic vertebrae. Cranial CT also showed brain metastasis. Transthoracic biopsy revealed adenocarcinoma of the lung.

The patient received palliative radiotherapy to brain and thoracic 9–11 vertebrae. Following radiotherapy, six cycles of chemotherapy consisting of 75 mg/m² cisplatin and 500 mg/m² pemetrexed was administered. Progression was seen 2 months following chemotherapy and erlotinib 150 mg daily was initiated.

The patient was referred to the hospital with severe cough at the 45th day of erlotinib treatment. Her body temperature, blood pressure, heart rate, and respiration rate were within normal limits. Blood oxygen saturation measured with pulse oximetry was 90%. Breath sounds were decreased on the lower parts of right hemithorax. Complete blood count showed leukocytes 9.6/µL (normal, 4000–10,000), neutrophils 66.4%, hemoglobin 11.4 mg/dL, and platelets 288,000/µL (normal, 150,000–400,000). C-reactive protein was 9.8 mg/dL (normal <0.5) and liver and renal functions were normal. Chest CT showed decreased right pleural effusion when compared with previous scans. There was a new ground-glass opacity in the right upper lobe and diffusely in the left lung (Figure 1). Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophilia were serologically negative. Echocardiogram did not show any ventricular dysfunction. The patient was considered to have erlotinib-related ILD because of the new chest CT findings and the lack of any infection. Erlotinib was discontinued and dexamethasone 8 mg (bid), amoxicillin clavulanate 1000 mg (bid), and sulfamethoxazole-trimethoprim 800/160 mg (bid) were initiated.

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Figure 1.

Chest computed tomography reveals a new ground-glass opacity in the right upper lobe and diffusely in the left lung.

Chest CT scan 40 days after clinical diagnosis of ILD showed an increase in the right pleural effusion but decrease in the ground-glass opacity in the right upper lobe and left lung (Figure 2). After informed consent for the risk of recurrent ILD was obtained from the patient, we administered erlotinib 100 mg daily because of the initial response. Ten weeks after reinitiation of erlotinib 100 mg daily, CT scan showed no evidence of ILD and decreased right pleural effusion as a treatment response (Figure 3).

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Figure 2.

Chest computed tomography reveals increase in right pleural effusion but decrease in ground-glass opacity in the right upper lobe and left lung.

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Figure 3.

Ten weeks after retreatment with erlotinib, computed tomography shows no evidence of interstitial lung disease and decreased right pleural effusion.

Consent for case information and images to be published was provided by the patient.

Discussion

Noninferiority of gefitinib compared to docetaxel and increased survival advantage of erlotinib compared to best supportive care in relapsed NSCLC have been shown previously. Erlotinib was approved by the US Food and Drug Administration in locally advanced or metastatic NSCLC after a series of chemotherapy in 2004.

EGFR TKIs are generally considered safe medicines. However, rarely they may cause fatal ILD. ILD incidence in patients with NSCLC treated with gefitinib and erlotinib is expected to be 1% and 0.8%, respectively. Erlotinib-related fatal ILD was reported to be 0.6% in the TRIBUTE study. EGFR TKI–related ILD incidence differs by race. Cumulative incidence of gefitinib-related ILD was reported to be 4% in a Japanese prospective study with 1872 patients. ² The incidence was 0.23% when Japanese patients were excluded. Low incidence of ILD may be a result of its difficult diagnosis and being a relatively newly described complication.

Patients with ILD commonly complain of dry cough, dyspnea, and mild fever. These symptoms appear approximately 47 days (5 days to 9 months) after the initiation of erlotinib treatment. Erlotinib-related ILD risk factors are unknown. History of pulmonary fibrosis was reported as a risk factor for ILD in a retrospective study with 122 patients with NSCLC treated with gefitinib. A significant association between gefitinib-related ILD and history of smoking and male sex was reported in another retrospective study with 1976 patients with NSCLC treated with gefitinib. ³

Radiologic findings in EGFR TKI–related ILD are nonspecific. Nonspecific ground-glass attenuation, extensive bilateral ground-glass attenuation, or consolidation with bronchiectasis are among these findings. The most common histomorphologic finding in EGFR TKI–related ILD is diffuse alveolar damage, which is a nonspecific reaction. Thus it is difficult to diagnose ILD histologically. ILD is diagnosed with clinical and radiologic findings after excluding pulmonary infection and progression of lung cancer and response to corticosteroid treatment. New respiratory symptoms in the first weeks of EGFR TKI treatment may be the first signs of ILD.

Treatment of EGFR TKI–related ILD is discontinuing the EGFR TKI, initiating corticosteroid treatment, and supportive treatment. Despite resolution with the treatment in some, many patients with ILD die due to progressive respiratory insufficiency. Mortality rate in patients with gefitinib-related ILD was reported to be 33%–44%. ⁴ In some cases, high-dose corticosteroids may be considered. Rechallenge with EGFR TKIs in patients who developed ILD is underexplored. Some patients desire to use EGFR TKIs again after recovery from ILD because they hope for good response and reduced toxicity with treatment with EGFR TKIs. It is unknown whether corticosteroids should be given during retreatment with EGFR TKIs. Patients should be closely supervised during retreatment with EGFR TKIs.^5,6

We reviewed the literature in Medline and PubMed using the English keywords “erlotinib rechallenge” and “interstitial lung disease”; “treatment with EGFR TKIs” and “erlotinib-induced interstitial lung disease” and “lung adenocarcinoma”; “treatment with erlotinib” and “gefitinib-induced interstitial lung disease” and “lung adenocarcinoma” and show the results in Table 1.

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Table 1.

Search strategies used in electronic database searches (all Medline via PubMed).

Search terms	Results	Related results
Erlotinib rechallenge and interstitial lung disease	7	3
Treatment with EGFR TKIs and erlotinib-induced interstitial lung disease and lung adenocarcinoma	4	2
Treatment with erlotinib and gefitinib-induced interstitial lung disease and lung adenocarcinoma	6	4

EGFR TKI: epidermal growth factor receptor tyrosine kinase inhibitor.

Patients treated with EGFR TKIs should be closely followed up for acute pulmonary toxicity. Patients with chronic obstructive pulmonary disease, with pulmonary fibrosis, or who had received radiotherapy to the thorax should be closely followed up as well. Early diagnosis/description of ILD, discontinuing the EGFR TKI treatment immediately, and initiating corticosteroid treatment may prevent fatal results.