Readministration of gefitinib in a responder after treatment discontinuation due to gefinitib-related interstitial lung disease: a case report
© Takamochi et al; licensee BioMed Central Ltd. 2007
Received: 29 August 2007
Accepted: 17 November 2007
Published: 17 November 2007
Gefitinib is a new molecular-targeted agent for the treatment of patients with advanced non-small cell lung cancer that fail to respond to conventional chemotherapy. Gefitinib is considered to be well tolerated and less toxic compared with conventional cytotoxic drugs. However, interstitial lung disease (ILD) has been reported as a serious adverse effect. The precise management of a gefitinib responder having severe adverse events remains unknown.
We report the case of gefitinib readministration in a patient with lung adenocarcinoma who had once responded but in whom treatment had to be discontinued owing to gefinitib-related ILD. A dramatic response was achieved both at the time of initial treatment (250 mg/day) and at readministration of gefitinib (125 mg/day). The effectiveness of gefitinib therapy in our patient could be explained in part by the presence of an activating mutation of epidermal growth factor receptor (EGFR) gene, L858R in exon 21, which was identified in the primary tumor.
A reduced dose of gefitinib might be sufficient for patients having tumors with EGFR gene mutations, and that the currently approved dose may be excessively potent in some of these patients, thus resulting in the onset of adverse events.
Gefitinib is a new molecular-targeted agent for the treatment of patients with advanced non-small cell lung cancer that fail to respond to conventional chemotherapy. Early clinical trial data demonstrated that gefitinib was well tolerated and was less toxic compared with conventional cytotoxic drugs[1, 2]. The most common adverse events were skin rash and diarrhea, which are reversible with discontinuation of treatment. However, gefitinib-related interstitial lung disease (ILD) has been reported as a serious adverse effect of gefitinib therapy [3, 4]. The largest retrospective study conducted by the West Japan Thoracic Oncology Group (WJTOG) showed an overall prevalence of 3.5% and a mortality of 1.6%  Although the precise mechanism of gefitinib-related ILD remains unknown, the WJTOG study showed in a multivariate analysis that male sex, a history of smoking, and the coexistence of interstitial pneumonia were all significant risk factors.
We herein report a thought-provoking case of readministration of gefitinib in a patient with lung adenocarcinoma who had previously responded and developed gefinitib-related ILD. Gefitinib readministration with 50% dose was successful in managing disease progression.
A 56-year-old male was referred to our hospital because of a lung nodule detected on population-based radiological screening. He was a current smoker with a smoking index of 15 pack-years. A chest computed tomography (CT) scan demonstrated a15 mm solid-density nodule with pleural indentation in the left lower lobe. Mediastinal lymph nodes were not swollen in the mediastinal setting images (clinical T1N0M0, stage IA). He underwent left lower lobectomy and systematic lymphadenectomy. He was diagnosed as having lung adenocarcinoma with multiple mediastinal lymph node metastases and solitary pulmonary metastasis (pathological T4N2M0, stage IIIB). He received two courses of postoperative adjuvant chemotherapy (carboplatin/paclitaxel).
Because he gave his written informed consent to let us use surgically resected specimens for genetic analyses before operation, a mutation analysis of the epidermal growth factor receptor (EGFR) gene was conducted at Mitsubishi Kagaku Bio-Clinical Laboratories, Inc. Genomic DNA was prepared from a paraffin-embedded section using macrodissection in a surgically resected primary tumor specimen. The peptide nucleic acid-locked nucleic acid PCR clamp protocol  was used to perform a mutation analysis. One of the most common activating mutations, L858R in exon 21, was identified.
The precise management of a gefitinib responder having severe adverse events remains unknown. There are only two case reports on readministration of gefitinib in responders following treatment discontinuation due to severe gefitinib-related hepatotoxicity [6, 7]. Although the resumption of gefitinib (250 mg/day) and concurrent steroid therapy  failed to control hepatotoxicity, intermittent schedule of gefitinib administration (250 mg/day once every 5 days)  not only successfully reduced hepatotoxicity but also induced disease regression.
To the best of our knowledge, this is the second report of readministration of gefitinib in a patient who had once developed gefinitib-related ILD. Yano et al  previously reported the readministration of gefitinib in a responder after discontinuation owing to ILD(alveolar hemorrhage). Starting with 250 mg/day, gefitinib was given every other day after blepharitis developed at the time of initial treatment. This intermittent schedule of gefitinib administration was effective both for the initial treatment and the resumed treatment.
The currently approved dose of gefitinib was determined based on the data from two large phase II trials (IDEAL 1 and 2). Similar efficacy but higher toxicity was observed with the 500 mg dose. Consequently, 250 mg has been the recommended dose [9, 10]. However, anti-tumor activity was not necessarily dependent on the dose of gefitinib in previous trials [1, 2, 9, 10]. Even when the dose of gefitinib was less than 250 mg/day, several responders were documented [1, 2]. However, the development of adverse effects other than ILD is usually dependent on the dose of gefitinib [1, 2]. Therefore, re-treatment by a reduced dose may be effective for patients who had previously responded to standard dose of gefitinib but had discontinued treatment due to the occurrence of severe adverse events other than ILD. Due to the low incidence of gefinitib-related ILD, it is difficult to show whether the same hypothesis fit to the gefinitib-related ILD based on the observational studies. Although there are no data indicating the dose-dependency of ILD, we could successfully manage a patient who had once developed ILD with a half dose of gefitinib.
Numerous studies suggest that gefitinib has fairly effective anti-tumor activity, especially for tumors with EGFR gene mutations [11, 12]. It is well-known that EGFR-mutated tumors respond dramatically to lower dose of EGFR-TKIs such as gefitinib in experimental studies [13, 14]. These findings may suggest that a reduced dose of gefitinib is sufficient for tumors with these molecular characteristics, and that the currently approved dose is excessively potent in some of these patients and results in adverse events.
The prognosis of patients with lymphangitis carcinomatosa is extremely poor, with approximately 50% of the patients dying within three months of their first respiratory symptoms . Fortunately, our patient was able to spend the rest of his life at home without the relapse of ILD for 16 months after readministration of gefitinib. Therefore, a resumption of gefitinib therapy would be clinically beneficial for him. However, secondary treatment with gefitinib for a patient who once developed gefinitib-related ILD is usually considered very risky. Therefore, at this time, alternative therapeutic modalities should be chosen, if available.
We herein presented the case of gefitinib readministration in a patient with lung adenocarcinoma who had once responded but in whom treatment had to be discontinued owing to gefinitib-related ILD. Gefitinib readministration with 50% dose was found to successfully control disease progression.
We believe clinical trials are warranted to evaluate gefitinib readministration with a dose reduction for patients who have once responded but later discontinued this treatment owing to severe adverse events including ILD. The appropriate dose and schedule of gefitinib readministration also should be determined in these trials.
Written informed consent was given for publication from the patient's next-of-kin.
epidermal growth factor receptor
ground glass opacity
interstitial lung disease
West Japan Thoracic Oncology Group
This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (17790944).
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