Alveolar hemorrhage due to erlotinib in non-small-cell lung cancer resistant to gefitinib

1. Case report 

A 75-year-old female was admitted to our hospital for third line chemotherapy with erlotinib on 15 January, 2008. She had initially been referred by a local doctor for massive right pleural effusion on 2 February, 2007 and diagnosed as having lung cancer T4N1M0 (stage IIIB) (Fig. 1(a)). She had received four courses of carboplatin and paclitaxel as first line chemotherapy. Cancer cells detected in right bloody pleural effusion indicated an adenocarcinoma showing in-frame deletion in exon 19 (E746-A750del) of epidermal growth factor receptor (EGFR) mutation. Therefore, gefitinib was administered from 12 June. The level of serum CEA was decreased from 255.0ng/ml to 17.5ng/ml on 10 September. Chest radiograph showed a right hilar mass and moderate amount of pleural effusion (Fig. 1(b)). However, the level of serum CEA increased again to 107.3ng/ml on 7 January, 2008. Therefore, she was hospitalized to begin erlotinib treatment as third line chemotherapy. Eight days after administration of erlotinib, hemoptysis of 20ml was noted. Hemoglobin and arterial partial oxygen pressure before admission did not change after administration, and the patient recovered by the administration of carbazochrome and tranexamic acid as hemostatics. We strictly observed her clinical course, judging that the bleeding had been due to the anticancer effect of erlotinib, although a small amount of bloody sputum persisted. On 18 March, she demonstrated massive hemoptysis of more than 50ml with fever of 38°C. On chest radiograph, bilateral diffuse infiltration was newly detected (Fig. 1(c)). Hemoglobin decreased remarkably from 7.4g/dl to 5.6g/ml over two days. Bleeding time was normal and the platelet count was 29.7×104/μl. CRP and LDH did not change from those at admission. The PR3-ANCA and MPO-ANCA were within normal ranges. Urinalysis did not show either macro or microhematuria. On bronchoscopy, there was massive bleeding from the bilateral bronchial tree. Erlotinib was stopped considering that erlotinib might have induced alveolar hemorrhage. Then 800ml of red blood cells was transfused. Methylprednisolone of 500mg was administered for three days and then 10mg of prednisolone was administered. After three days, the patient improved and she discharged on 1 April, 2008.

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Fig. 1 (a) Chest radiograph on 2 February 2007. (b) Chest radiograph on 10 September 2007 showing improvement of right pleural effusion. (c) Chest radiograph on the second admission newly showed bilateral infiltration.

2. Discussion 

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. The epidermal growth factor receptor (EGFR) mediates cancer cell growth, proliferation, invasion, and metastasis, and inhibits apoptosis.1 When ligands bind to the receptor, the molecule is phosphorylated by constitutive tyrosine kinases, causing activation of the downstream pathways.2 The EGFR inhibitors gefitinib and erlotinib have shown promising results in the treatment of NSCLC.3

The double-blind, randomized phase III Iressa Survival Evaluation in Lung (ISEL) cancer trial compared gefitinib 250mg plus best supportive care (BSC) with placebo plus BSC. There was no significant overall survival benefit for gefitinib in either the entire trial population or in the subgroup of patients with adenocarcinoma. A survival benefit in favor of gefitinib was observed among 22% of patients who had never smoked and among 20% of those of Asian origin.4 In 2004, two independent groups reported an association between somatic EGFR mutations and a dramatic clinical response to gefitinib.5, 6 The mutations consisted of small, in-frame deletions or substitutions clustered around the adenosine triphosphate-binding site on exons 18, 19, and 21 of the EGFR gene, and approximately 90% of patients with EGFR mutations have one of the two major mutations.7 One is a 15-base pair nucleotide in-frame deletion (E746-A750del) in exon 19 and the other is a point mutation involving the replacement of leucine with arginine at codon 858 (L858R) in exon 21.8 In this case, the patient was a Japanese woman who had never smoked and the cancer cells from right pleural effusion disclosed an adenocarcinoma with an in-frame deletion in exon 19 (E746-A750del) of EGFR. Therefore, we expected she would respond to administration of gefitinib and in fact the level of serum CEA decreased for 7 months. When the level of serum CEA increased again, we chose erlotinib based on reports describing two cases demonstrating a successful response to erlotinib after failing of gefitinib.9, 10 Kobayashi et al. reported a patient with EGFR-mutant, gefitinib-responsive, advanced NSCLC who had a relapse after two years of complete remission during treatment with gefitinib.11 The DNA sequence of the EGFR gene in the tumor biopsy specimen at relapse demonstrated the presence of a second point mutation, resulting in a threonine-to-methionine amino acid change at position 790 of EGFR. Our patient did not respond to erlotinib, but alveolar hemorrhage did occur and was suspected to have been the result of erlotinib administration. With gefitinib, severe alveolar hemorrhage was reported in the Japanese literature.12 Although the mechanism of alveolar hemorrhage following erlotinib administration was not determined, some reports in gefitinib have suggested some mechanisms underlying alveolar hemorrhage. Hirata et al. reported that gefitinib inhibited angiogenesis induced by EGF.13 Apoptosis in human cancer cells induced by treatment with EGFR-TKI, but venous endothelial cells also demonstrated apoptosis.14, 15 Erlotinib, although there were no previous reports of alveolar hemorrhage, bilateral subdural hemorrhage with exacerbation of radiodermatitis after whole brain irradiation combined with erlotinib was reported.16 In that report, gefitinib was replaced with erlotinib on the fifth day after whole brain irradiation. The standard doses of 250mg gefitinib and 150mg erlotinib were not biologically equivalent. Erlotinib was administered at the maximum-tolerated dose, whereas gefitinib was administrated at approximately one-third of its maximum-tolerated dose.17 Furthermore, erlotinib may have higher-affinity binding to the EGFR kinase domain than gefitinib has.18 Therefore, erlotinib has an effectively toxic dose.

We should consider that there might be a risk of alveolar hemorrhage due to erlotinib administration in non-small-cell lung cancer resistant to gefitinib.

Conflict of interest 

This case report has not been previously published, and is not concurrently being submitted to any other journals or the news media.

We declare that there are no conflicts of interest related to the article or the research described.