Hemorrhage of brain metastasis from non-small cell lung cancer post gefitinib therapy: two case reports and review of the literature

Gefitinib is one of the inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR TKIs), designed to offer targeted therapies for a variety of solid tumors including the lung cancer [1]. Clinical trials have demonstrated that gefitinib is effective or non-inferior to chemotherapy in the treatment of a subset of patients with advanced non-small cell lung cancer (NSCLC) [2–4]. Gefitinib has also been regarded as a relatively safe agent, with the most common adverse drug reactions being diarrhea and skin rash, which are generally mild in nature and reversible [5, 6]. Here we describe two cases of brain metastasis from NSCLC who developed brain hemorrhage post gefitinib therapy. To our knowledge, these are the first reported cases of brain hemorrhage that might be involved in the use of gefitinib. Recently, a few hemorrhagic events in other parts of the body have also been reported after gefitinib administration [7–9]. Thus, we speculate brain hemorrhage could be one possible adverse drug reaction of gefitinib treatment for NSCLC.

Epidermal growth factor receptor (EGFR) is a member of the HER tyrosine kinase growth factor receptor family that signals cellular differentiation, proliferation, invasion, metastasis, and survival. It is expressed in a variety of human cancers including NSCLC (40%-80%), colorectal (25%-77%), pancreatic (30%-50%), breast (15%-30%), ovarian (35%-70%), prostate (40%) and gastric (33%) cancers [1]. Among the above-mentioned cancers, NSCLC was one of the most frequently studied objects of EGFR-targeted therapy, as evidenced by such clinical trials as INTEREST, ISEL (for gefitinib), and BR21 and SATURN (for erlotinib, another EGFR-TKI) [2, 4, 10, 11].

Gefitinib (ZD1839, Iressa), a selective inhibitor of EGFR tyrosine kinase (EGFR-TKI) which is competitive with the combination of EGFR tyrosine kinase, acts through blocking the signal transduction pathway of epithelial growth factor and thereby inhibiting the proliferation and metastasis, and, promoting the apoptosis of tumor cells [1]. The orally administered gefitinib has achieved a great effect since its approval by FDA in 2003, for it has less toxicity compared with traditional cytotoxic chemotherapy. In addition to an extremely small number of fatal interstitial pneumonia reported [12], the common adverse drug reactions of gefitinib are diarrhea, skin rash, dry skin, nausea and vomiting. On most occasions these reactions are mild and reversible. Other less common adverse effects include pruritus, anorexia, asthenia, and weight loss [13]. For the above reasons, gefitinib has been used as the second or third line therapy for advanced and metastatic NSCLC, or even evaluated as the first line therapy (IPASS trial) for a subset of patients with NSCLC [14]. Our first case was administered gefitinib without prior cytotoxic therapies.

Targeted therapies also aim at other signal transduction pathways like vascular endothelium growth factor (VEGF). It was reported that anti-angiogenic therapy (AAT) had led to serious hemorrhagic events in NSCLC, particularly in those of squamous cell origin [15]. An early phase I trial of bevacizumab, an anti-VEGF monoclonal antibody, also detected a case of intracranial hemorrhage from a choriocarcinoma brain metastasis. However, a recent phase II trial, AVF3752g, showed safety of bevacizumab in patients with NSCLC and previously treated brain metastases [16]. On the other hand, anti-EGFR therapy has seldom been warned against increased risks of bleeding, except a few case reports of anecdotal experience.

There has been a case report in which severe alveolar hemorrhage occurred after four weeks' gefitinib therapy in a 56-year-old man of NSCLC in Japan [9]. Recently, another two reports on bilateral subdural hemorrhage (SDH) after oral gefitinib administration have been published [7, 8]. In one, a 75-year-old woman was diagnosed as stage IV NSCLC and was introduced to take gefitinib at a daily dose of 250 mg. About 7 months later, the patient gradually developed headache and weakness, and CT demonstrated bilateral SDH another 2 months later. Although there was no obvious evidence of CNS metastasis, the authors still thought that bilateral SDH might had resulted from obstruction of dural vessels by latent dural metastasis and was also suggested as a possible adverse event of gefitinib therapy. Notably, the above-described two cases developed hemorrhagic events without CNS metastasis. Huang et al [8] reported another case where a 57-year-old male developed bilateral SDH after WBRT combined with EGFR-TKIs for NSCLC with brain metastases. Gefitinib was replaced with erlotinib on the 5th day after WBRT. During a follow-up period with erlotinib alone after completing WBRT, the patient developed bilateral SDH. The authors did not make a clear explanation for the complication. Apart from the above reports of hemorrhagic events that might be related to gefitinib in NSCLC, there was also a recent phase III study showing gefitinib dose-dependently increased tumor hemorrhage-type events in recurrent squamous cell carcinoma of the head and neck [17].

In the current report, two patients developed brain metastasis hemorrhage after taking gefitinib. Though in our first case brain tumor hemorrhage developed one month after a combination of gefitinib and WBRT, it is still possible that gefitinib played a role. There were no comorbiditis such as thrombocytopenia, coagulation abnormalities or other underlying cerebrovascular diseases or head trauma, and our own experience and reports from other authors suggested that WBRT alone was unlikely to be the cause of tumoral hemorrhage of brain metastases, but rather could decrease the hemorrhagic events through blunting angiogenesis and normalizing tumor vasculature [18, 19]. As considerable studies have demonstrated gefitinib to be a radiation sensitizer in the treatment of a variety of tumors including NSCLC, head and neck, breast, and colorectal cancers [20, 21], we think EGFR-targeted therapy may have strengthened the role of radiation-induced vascular occlusion and subsequent post-ischemic hemorrhage. Furthermore, gefitinib in combination with WBRT might lead to rapid shrinkage of brain metastasis and avascular necrosis, and induce reconstruction of microvasculature and vascular abnormality, subsequently leading to tumoral bleeding. This is especially true for those with high expression or mutations of EGFR. Unfortunately, our two cases have not been performed that kind of test, though patients now in our institute are strongly encouraged to take such test before taking gefitinib or other TKIs.

In the second case, hemorrhagic brain metastasis was found 8 months after gefitinib monotherapy. Before that, the patients also experienced severe paronychia and underwent a nail arrachement three months after gefitinib administration. MRI showed evidence of both subacute (hyperintensities on T1-weighted image) and chronic (hypointensities on T2-weighted image) components of bleeding, with no obvious perilesional edema, which might accounted for the mild symptoms and signs of the patients. For the above reasons, the patient was not immediately administered WBRT until some new hemorrhagic metastases were detected in other parts of the brain. As reported in the literature, the incidence of spontaneous intracranial hemorrhage from NSCLC with brain metastasis seemed to be very low (about 1.2%), though higher than those without CNS metastasis [22, 23]. Furthermore, recent studies on EGFR inhibition with gefitinib also showed its influence on angiogenesis [24]. Hence, though whether the brain metastasis hemorrhages were just coincidence or as a result of gefitinib therapy remain to be further confirmed, it seems possible that gefitinib might be involved in the brain hemorrhage in our two cases. Interestingly, there is a study on treatment of brain metastasis from NSCLC with WBRT and gefitinib which showed acute side effects were generally well tolerated, and no hemorrhagic events were mentioned [6], our experience suggest that caution should be taken when gefitinib is used in combination with WBRT.

In summary, from our cases and others reported in the literature, we speculate that brain metastasis hemorrhage could be a possible adverse drug reaction of gefitinib for treatment of NSCLC. With increasing use of gefitinib, especially in those patients with EGFR over-expression or mutations, it is reasonable to suggest that clinicians be highly cautious about this possible complication.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.