Phase II study of irinotecan and amrubicin in patients with relapsed non-small cell lung cancer: Okayama Lung Cancer Study Group Trial 0402.

BACKGROUND: The survival advantage achieved by existing anti-cancer agents as second-line therapy for relapsed non-small cell lung cancer (NSCLC) is modest and further improvement of treatment outcome is desired. Combination chemotherapy with irinotecan and amrubicin for advanced NSCLC has not been fully evaluated. METHODS: The primary endpoint of this phase II clinical trial was objective response. Patients with NSCLC who had been treated previously with one or two chemotherapy agents were enrolled. Irinotecan and amrubicin were both administered on Days 1 and 8 of a 21-day cycle, at doses of 100 mg/m(2) and 40 mg/m(2), respectively. RESULTS: Between 2004 and 2006, 31 patients received a total of 101 courses; the median number of courses administered was three (range, one to six). Objective response was obtained in nine of the 31 patients (29.0% response rate; 95% confidence interval (CI), 12.1-46.0%). With a median follow-up time of 43.9 months, median survival time and the median progression-free survival time were 14.2 and 4.0 months, respectively. Myelosuppression was the most frequently observed adverse event, with grade 3/4 neutropenia in 51% of patients. Febrile neutropenia developed after nine courses (9%) and resulted in one treatment-related death. Cardiac toxicity and diarrhea, possibly specific for both agents, were infrequent and manageable. CONCLUSION: Combination chemotherapy with irinotecan and amrubicin is effective in patients with NSCLC but showed moderate toxicities in second- or third-line settings.

Long-term follow-up of phase II trial of docetaxel and cisplatin with concurrent thoracic radiation therapy for locally advanced non-small cell lung cancer.

BACKGROUND: Chemoradiation improves survival for patients with locally advanced non-small cell lung cancer (NSCLC), but clinical outcomes beyond five years are rarely reported. The aim of the present study was to identify the long-term results of a phase II study of docetaxel and cisplatin with concurrent thoracic radiation. METHODS: We previously reported short-term outcomes from the phase II study, which enrolled 42 patients (aged ≤ 75 years) with unresectable stage III NSCLC. We continued to follow these patients for long-term clinical outcomes. RESULTS: At a median follow-up for all patients of 6.3 years (range: 5.2-7.1 years), the median survival time was 2.1 years and the actual five-year survival rate was 31%. Among 14 patients who were progression-free longer than two years, three patients died due to bacterial or fungal pneumonia and one died due to gall bladder cancer. CONCLUSIONS: Thirty-one percent of locally advanced patients having NSCLC treated with docetaxel and cisplatin and concurrent thoracic radiation survived beyond five years. Progression-free patients might be cautiously followed up taking precautions against emerging pneumonia.

Non-localized Mycobacterium avium lung disease successfully treated with lobectomy and chemotherapy.

A 17-year-old boy presented with a large cavity and bilateral nodular opacities on his chest roentgenogram. Mycobacterium avium was identified in his sputum. According to the recommendations of the American Thoracic Society, he was not strongly recommended to undergo surgery because of non-localized lesions. But since cavities can provide a means for disease to spread to other lobes, we decided to perform a lobectomy including the cavity combined with chemotherapy. Now he has been well for 4 years without exacerbation. There is a possibility of long-term remission with this combination treatment in cases a destructive lesion of airway such as a cavity which is localized to one lobe, even if other lesions such as nodular opacities exist in many other lobes.

[Evaluation of COBAS TaqMan: a real-time PCR-based diagnostic kit for mycobacteria].

The real-time PCR-based diagnostic kits, COBAS TaqMan MTB and COBAS TaqMan MAI (Roche Diagnostics, Tokyo, Japan), were developed to detect Mycobacterium tuberculosis (MTB) and M. avium (MAV)/M. intracellulare (MIN), respectively. The TaqMan kits simultaneously perform amplification and detection of mycobacterial DNA to reduce assay time. We evaluated the diagnostic accuracy of both TaqMan kits in 781 clinical specimens, and compared the results with those obtained from the AMPLICOR MTB and MAI kits. With smear-positive specimens, the TaqMan kits showed 100% concordance with AMPLICOR in MTB, MAV and MIN. With all specimens, the concordances of TaqMan with AMPLICOR were 99.1%, 99.0%, and 99.7% in MTB, MAV and MIN, respectively. Four specimens for MTB and one for MAV were AMPLICOR positive/TaqMan negative. Among them, two specimens were culture-positive for MTB and one for MAV. Three specimens for MTB, seven for MAV, and two for MIN were AMPLICOR negative/TaqMan positive. Among them, two specimens were culture-positive for MTB, seven for MAV, and one for MIN. In twelve out of 21 specimens in which AMPLICOR failed to activate PCR, TaqMan successfully determined the results which were in concordance with those of mycobacterial culture. Thus, our data suggest that the accuracy of TaqMan in detecting mycobacterial DNA is superior to that of AMPLICOR. We conclude that TaqMan, which is an easy and rapid DNA amplification test, is useful for detecting MTB, MAV and MIN.

Combination of SN-38 with gefitinib or imatinib overcomes SN-38-resistant small-cell lung cancer cells.

Irinotecan is one of the effective anticancer agents for small-cell lung cancer (SCLC) and 7-ethyl-10-hydroxy-campthothecin (SN-38) is an active metabolite of irinotecan. Gefitinib and imatinib are tyrosine kinase inhibitors which have clinical activities in several malignancies and they are also potent inhibitors of breast cancer resistance protein (BCRP) transporter, which confers the resistance of topoisomerase I inhibitors including SN-38 and topotecan. The cytotoxicity of SN-38, gefitinib and imatinib for the SN-38-resistant cells (SBC-3/SN-38) from human SCLC cells, SBC-3, was evaluated using AlamarBlue assay. The drug concentration required to inhibit the growth of tumor cells by 50% (IC50) for 96-h exposure was used to evaluate the cytotoxicity. BCRP expression was determined by Western blotting and immunofluorescence staining. Intracellular topotecan accumulation was evaluated by flow cytometry. No differences were observed in the IC50 values (mean +/- SD) of the tyrosine kinase inhibitors between the SBC-3 cells and the SBC-3/SN-38 cells: 15+/-1.6 and 12+/-2.8 microM of gefitinib, respectively; 15+/-0.51 and 14+/-3.9 microM of imatinib, respectively. The SBC-3/SN-38 was 9.5-fold more resistant to SN-38 than the parental SBC-3. The SBC-3/SN-38 restored sensitivity to SN-38 when combined with 8 microM gefitinib or 8 microM imatinib, even though the IC50 values of SN-38 combined with gefitinib or imatinib in the SBC-3 cells did not change. BCRP was equally overexpressed in the SBC-3/SN-38 with and without gefitinib or imatinib. In addition, the BCRP expression on the SBC-3/SN-38 cell membrane with and without gefitinib seemed to be equal. Gefitinib increased intracellular accumulation of topotecan in the SBC-3/SN-38 cells. Gefitinib or imatinib reversed SN-38-resistance in these SCLC cells, possibly due to intracellular accumulation of SN-38 without any change in BCRP quantity. Irinotecan with gefitinib or imatinib might be effective for SCLC refractory to irinotecan.

Comprehensive pulmonary rehabilitation according to severity of COPD.

A new classification for the severity of COPD was proposed at GOLD 2003: stage I: FEV(1) > or = 80% predicted; stage II: 50% < or = FEV(1)<80%; stage III: 30% < or = FEV(1)<50%; and stage IV: FEV(1) < 30%. To elucidate the acute effects of pulmonary rehabilitation (PR) on patients with different stages of COPD, data on pulmonary function, arterial blood gas analysis, the 6-min walk test, respiratory muscle strength, and activities of daily living were analyzed before and after our comprehensive 4- to 8-week inpatient PR program between 1992 and 2003. A total of 225 patients (201 men and 24 women; 21 with stage II, 79 with stage III, and 125 with stage IV COPD) was assessed. There were significant differences in FEV(1)% predicted and % residual volume in stages III and IV, in % vital capacity in stages II, III and IV, and in % total lung capacity in stage II when comparing the changes between pre- and post-PR. Significant differences of PaO(2) in stages III and IV and PaCO(2) in stage IV were found when comparing the changes between pre- and post-PR. The 6-min walk distance was significantly increased after PR by an average of approximately 50m for all staged patients. Respiratory muscle strength was also significantly increased in stages III and IV. Activities of daily living were significantly improved in all stages. These results showed that patients with COPD had benefited from PR regardless of disease severity. The effects included improvement in pulmonary function, arterial blood gas analysis, 6-min walk distance, respiratory muscle strength, and activities of daily living although there were some differences among the three stages.

Distance and oxygen desaturation in 6-min walk test predict prognosis in COPD patients.

The aim of the present study was to predict the prognosis of Chronic obstructive pulmonary disease (COPD) patients who underwent comprehensive pulmonary rehabilitation (PR). A total of 144 patients who performed PR between 1992 and 1999 was assessed. After PR, 67 patients underwent lung volume reduction surgery (LVRS). Baseline data before PR consisted of body mass index, serum albumin levels, use of supplement oxygen at home, pulmonary function, arterial blood gas analysis, and distance and fall of hemoglobin oxygen saturation (DeltaSpO(2)) in 6-min walk test. In addition to pre-PR factors, treatment with LVRS was taken into the analysis. The prognostic significance of variables influencing survival was determined by univariate analysis with Log rank test or multivariate analysis using Cox's proportional hazard model. By a median follow-up time of 8.4 years, the median survival time was 8.1 years (95% confidence interval: 6.9-9.4 years). Albumin level, PaCO(2), distance and DeltaSpO(2) were significant prognostic factors in univariate analysis. LVRS did not affect the prognosis. The multivariate analysis showed short distance and increase of DeltaSpO(2) as significant independent predictors of the risk of death. 6-min walk test was very useful for predicting the prognosis of the COPD patients.

A triplet chemotherapy with cisplatin, docetaxel and gemcitabine in patients with advanced non-small-cell lung cancer: a phase I/II study.

PURPOSE: We conducted a phase I/II study of triplet chemotherapy consisting of cisplatin (CDDP), docetaxel (DCT) and gemcitabine (GEM) in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Fifty-three untreated patients with stage IIIB or IV NSCLC were enrolled. All drugs were given on days 1 and 8. The doses of CDDP and DCT were fixed at 40 mg/m(2) and 30 mg/m(2), respectively. In the phase I portion, a dose escalation study of GEM with starting dose of 400 mg/m(2) was conducted and primary objective in the phase II portion was response rate. RESULTS: The maximally tolerated dose (MTD) and recommended dose (RD) of GEM were determined as 800 mg/m(2) because grade 3 non-hematological toxicity (liver damage, diarrhea, and fatigue) developed in three of nine patients evaluated at that dose level. In pharmacokinetic analysis, C (max) and AUC of dFdC and dFdU were increased along with the dose escalation of GEM. However, no relationship between pharmacokinetic parameters and toxicity or response was observed. Objective response rate was 34% and median survival time was 11.7 months. Though major toxicity was myelosuppression, there were no life-threatening toxicities. CONCLUSION: These results indicate that this triplet chemotherapy is feasible and effective in patients with advanced NSCLC.

A phase I and pharmacological study of amrubicin and topotecan in patients of small-cell lung cancer with relapsed or extensive-disease small-cell lung cancer.

Cisplatin-based chemotherapy is considered to be a standard treatment in patients with relapsed or extensive-disease (ED) small-cell lung cancer (SCLC), the survival benefit remains modest. Relapsed or ED-SCLC patients were enrolled. Topotecan and amrubicin were administered on Days 1-5 and on Days 3-5, respectively. Nine patients received a total of 24 cycles. Since all three patients experienced dose-limiting toxicity (grade 4 neutropenia lasting for more than 4 days, grade 3 febrile neutropenia, and grade 4 thrombocytopenia) at the third dose level (topotecan: 0.75 mg/m2, amrubicin 40 mg/m2), the maximum tolerated dose was determined to be this dose level. Objective response was observed in six patients (67%). The maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) of amrubicin increased in a dose-dependent manner. Amrubicin did not influence the pharmacokinetics of topotecan. The Cmax and AUC of amrubicin were correlated with the duration of grade 4 neutropenia. The mean Cmax of topotecan on day 2 in responders (22.9+/-3.6) was significantly higher than that in non-responders (10.9+/-0.4). This phase I study showed the safety and activity of two-drug combination of amrubicin and topotecan in patients with relapsed or ED-SCLC.

[Antimycobacterial susceptibility against nontuberculous mycobacteria using brothmic NTM].

PURPOSE: Recently the incidence of pulmonary nontuberculous mycobacteria infection has increased among patients not only implicated with AIDS, but also without predisposing conditions. However, an effective antimicrobial therapy for the disease has not been established yet, because of the absence of highly active therapeutic drugs. We compared the in vitro antimicrobial activities of five antituberculous drugs, clarithromycin and fluoroquinolones against 92 clinical isolates belonging to three species of slowly growing nontuberculous mycobacteria. MATERIAL AND METHODS: M. avium (31 strains), M. intracellulare (44 strains), and M. kansasii (17 strains), all of which were isolated from sputum specimens of previously untreated patients with pulmonary nontuberculous mycobacteria infection, were used. The eight agents tested were streptomycin, ethambutol, kanamycin, isoniazid, rifampicin, clarithromycin, levofloxacin and gatifloxacin. The drug susceptibility of these strains in terms of MIC (minimum inhibitory concentration) was determined by BrothMIC NTM. RESULTS: The MICs of rifampicin, clarithromycin, levofloxacin and gatifloxacin for all three species were low and gatifloxacin was more active than levofloxacin between two fluoroquinolones. Regarding clarithromycin, 100% of the strains were susceptible to 2 micrograms/ml or less and none of the strains were resistant on this level. In contrast, the MICs of ethambutol and isoniazid for M. avium and M. intracellulare were high and less active in vitro than the other antimicrobial agents. CONCLUSION: These MIC studies suggest that rifampicin, clarithromycin, levofloxacin, and gatifloxacin have excellent in vitro antimicrobial activities against M. avium, M. intracellulare and M. kansasii and especially clarithromycin may be very useful as a drug therapy for previously untreated patients. In the treatment of pulmonary nontuberculous mycobacterium infection, further studies are needed to evaluate the clinical effects of these drugs and to observe the drug resistance, on the basis of the results of the drug susceptibility test by BrothMIC NTM.

[In vitro antituberculous activity of ofloxacin and levofloxacin against multidrug-resistant tuberculosis and clinical outcomes].

OBJECTIVE: To investigate in vitro antituberculous activity of ofloxacin (OFLX) and levofloxacin (LVFX) against multidrug-resistant tuberculosis and to study the clinical outcomes. SUBJECTS AND METHODS: In vitro antituberculous activity of OFLX and LVFX against multidrug-resistant strains of Mycobacterium tuberculosis isolated from 46 patients with pulmonary tuberculosis and a retropective clinical analysis of 45 patients were investigated. RESULTS: In susceptibility testing, resistance rates to OFLX or LVFX were higher in intractable cases (7/20: 35%) and in cases with prior chemotherapy using new quinolones (5/12: 42 %). Sputum culture conversion was observed in 34 patients (76%), however 9 among them later reverted to positive culture. In a single variate proportional hazards model, risk factors related to poor outcomes (treatment failure or relapse) were resistance to OFLX or LVFX, advanced disease on chest radiograph, and the number of susceptible drugs four or less. In a multiple variate proportional hazards model, a risk factor was resistance to OFLX or LVFX. Eighteen patients (40%) died, and among them, 10 died of tuberculosis. Survival time of treatment failure patients was significantly shorter than patients with sputum culture conversion. CONCLUSION: Resistance to OFLX or LVFX was considered to be a risk factor related to treatment failure and relapse in multidrug-resistant tuberculosis.

Influence of altering administration sequence of docetaxel, gemcitabine and cisplatin in patients with advanced non-small cell lung cancer.

BACKGROUND: A phase II study of a triplet chemotherapy with the administration sequence of gemcitabine (GEM), docetaxel (DCT) and cisplatin (CDDP) (OLCSG9908) was previously conducted in patients with advanced non-small cell lung cancer (NSCLC). The objective response rate was 34% and the median survival time (MST) and 1-year survival rate were 11.7 months and 49%, respectively. In an in vitro study of different sequence exposures to GEM and DCT, it was reported that the synergistic effect was more prominent using the administration sequence of DCT followed by GEM compared with the reverse sequence. In order to estimate the effects of the administration sequence, a phase II study of the same triplet chemotherapy was conducted with the administration sequence of DCT, CDDP and GEM. PATIENTS AND METHODS: Patients with unresectable stage IIIB/IV NSCLC were eligible. All drugs were given intravenously on days 1 and 8, and repeated every 4 weeks for up to 4 cycles. DCT (30 mg/m2) was given first, followed by CDDP (40 mg/m2) and GEM (800 mg/m2). RESULTS: Thirty-four patients were enrolled on this study (OLCSG0101). The objective response rate was 38% (95% CI: 22-56%). As grade 3/4 hematological toxicities, neutropenia, thrombocytopenia and anemia were observed in 70%, 41% and 21%, respectively, and febrile neutropenia was observed in 12%. As grade 3/4 non-hematological toxicities, vomiting and liver dysfunction were observed in 15% and 18%, respectively. These toxicities were manageable by conventional therapy. The MST and 1-year survival rate were 13.3 months (95% CI: 7.8-18.7 months) and 55% (95% CI: 38-73%), respectively. These results were similar to those of OLCSG9908. CONCLUSION: This triplet chemotherapy is well tolerated and effective in patients with advanced NSCLC, however, the treatment outcome was not significantly influenced by the administration sequence of DCT and GEM.

The combination effect of amrubicin with cisplatin or irinotecan for small-cell lung cancer cells.

The single agent of amrubicin is active in untreated small-cell lung cancer (SCLC). Cytotoxicity of amrubicinol, the active form of amrubicin, was evaluated in a parent SCLC cell line (SBC-3); an active metabolite of irinotecan, 7-ethyl-10-hydroxy-camptothecin (SN-38)-resistant subline (SBC-3/SN-38); and cisplatin-resistant subline (SBC-3/CDDP) using AlamarBlue assay. Interaction of the combined drugs was evaluated by median-effect plot analysis, and the fraction of apoptotic cells was determined using flow cytometry. SBC-3/SN-38 was 34-fold more resistant to SN-38 and SBC-3/CDDP was 7.2-fold more resistant to cisplatin than parental SBC-3. However, these resistant sublines retained sensitivity to amrubicinol (1.8- and 1.7-fold, respectively). Simultaneous exposure of SBC-3/SN-38 cells to amrubicinol and cisplatin showed a synergistic effect. Simultaneous exposure of SBC-3/CDDP cells to amrubicinol and SN-38 displayed synergistic or additive effects. The two-drug combination produced an increase of apoptotic cells compared to each single agent alone in both resistant cells. These findings suggest that amrubicin alone and in combination with cisplatin or irinotecan is effective against SCLC refractory to irinotecan and/or cisplatin.

Successful treatment of a patient with severe Churg-Strauss syndrome by a combination of pulse corticosteroids, pulse cyclophosphamide, and high-dose intravenous immunoglobulin.

A 24-year-old woman with a 4-year history of bronchial asthma suffered from bloody sputum, numbness of the extremities, elevated eosinophil count, and hypoxemia. A diagnosis of alveolar hemorrhage was made by bronchoalveolar lavage. Echocardiogram revealed severe hypokinesis of the left ventricular wall. Her respiratory condition deteriorated despite administration of pulse corticosteroids. A second pulse corticosteroids and pulse cyclophosphamide followed by high-dose intravenous immunoglobulin brought about a dramatic improvement of alveolar hemorrhage, cardiac impairment, and peripheral neuropathy. Levels of antimyeloperoxidase-antineutrophil cytoplasmic antibodies, soluble thrombomodulin, soluble interleukin-2 receptor, eosinophil cationic protein were elevated and returned to the normal range in remission. The combination of pulse corticosteroids, pulse cyclophosphamide, and high-dose intravenous immunoglobulin seemed effective for the acute phase of severe Churg-Strauss syndrome.

Successful treatment of a patient with synchronous advanced non-small cell lung cancer and acute myeloid leukemia by a combination of gefitinib, low-dose cytarabine and aclarubicin.

There are few reports describing simultaneous occurrence of acute leukemia and lung cancer. We describe here an 83-year-old woman who simultaneously developed advanced adenocarcinoma of the lung and acute myeloid leukemia. She could not receive intensive chemotherapy due to poor performance status. This patient was treated with a combination of gefitinib, low-dose cytarabine and aclarubicin. This combination could be safely administered in the elderly patient with poor performance status and was effective for both lung cancer and acute myeloid leukemia.

Smoking history before surgery and prognosis in patients with stage IA non-small-cell lung cancer--a multicenter study.

The prognosis of lung cancer patients with surgically resected non-small-cell lung cancer (NSCLC) can be predicted generally from age, sex, histologic type, stage at diagnosis, and additional treatment. Nine studies have reported that a history of smoking before diagnosis influences the prognosis of the disease in lung cancer patients. In this study, a total of 3082 patients who underwent surgery and were diagnosed with primary pathological stage IA NSCLC at 36 national hospitals from 1982 to 1997 were analyzed for the effect of smoking on survival. Smoking history and other factors influencing either the overall survival or the disease-specific survival rates of patients were estimated with the Cox proportional hazards model. Multivariate analysis demonstrated significant associations between overall survival and age (P < 0.0001), sex (P = 0.0002), and performance status (PS) (P < 0.0001). Disease-specific survival was associated with age (P = 0.0063), sex (0.00161), and PS (P = 0.0029). In males, disease-specific survival was associated with age (P = 0.0120), PS (P = 0.0022), and pack-years (number of cigarette packs per day, and years of smoking) (P = 0.0463). These results indicate that smoking history (pack-years) is important clinical prognostic factor in estimating disease-specific survival, in male patients with stage IA primary NSCLC that has been surgically resected.

[Factors affecting the success or failure of smoking cessation using nicotine patches].

We identified the initial diagnostic factors that influenced the success or failure of patients trying to quit smoking using nicotine patches. In a smoking cessation treatment program at a smoking clinic, each patient received about 30 minutes of counseling in the initial diagnosis, then undertook a 2-month smoking cessation program using the nicotine patch. Between March 2000 and June 2002, 45 patients consulted the clinic. We attempted to monitor 30 patients whose smoking status we were able to observe. The patient group consisted of 5 women and 25 men who ranged in age from 22 to 75 years (mean age, 49 years). A follow-up survey by telephone was carried out (median follow-up time: 184.5 days). Actuarial smoking cessation curves were calculated according to the Kaplan-Meier method, and comparisons were made with the generalized Wilcoxon test. The Cox proportional hazards model was used for multivariate analysis. At the end of the two-month period, 86.3% of the patients had not resumed smoking; at one year after the program began, 56.7% had not resumed smoking. In the univariate analysis, the significant factors in the failure to maintain cessation were: a smoking start age of under 18 years, no affective disease, and smoking the day's first cigarette within 5 minutes after waking up (p < 0.05). In the multivariate analysis, the independent predictive factors in failure were: a starting smoking age of under 18 years and no affective disease (p < 0.05). Thus, patients who started smoking at a young age or who were free of affective disease were more likely to fail in their attempt to quit smoking. Attention to these factors is necessary as part of the guidance provided for smoking cessation.

[Pulmonary tuberculosis case with consistant findings of endobronchial spread in chest roentogenography for about three years: a case report].

We reported a case of pulmonary infection by Mycobacterium tuberculosis complicated by endobronchial spread. Chest roentogenography and CT for an 85-year-old male complaining of cough showed endobronchial spread in right upper lung field. His sputum culture for eight weeks showed 10-20 colonies of Mycobacterium tuberculosis. Transbronchial lung biopsy revealed granulomas with caseous necrosis. Findings in chest XP and CT after the therapy with INH, RFP and EB for six months showed much improvement.

[Interstitial pneumonia due to gefitinib followed in detail by high-resolution CT in a patient with adenocarcinoma of the lung].

We describe the case of a 69-year-old woman with advanced adenocarcinoma of the lung, in whom interstitial pneumonia was induced by gefitinib. The shadow was not clear on chest radiography, but diffuse ground-glass opacity was detected on high-resolution CT. Two treatments with pulse corticosteroids improved the lung injury temporarily. However, it became worse on reduction of the steroids. The improvement and deterioration of the pneumonia had been followed in detail by 8 examinations by high-resolution CT. The ground-glass opacity seen in the CT did not completely disappear or progress rapidly under steroid therapy. The patient died 46 days after the onset of the pneumonia. Autopsy disclosed marked cancerous invasion of the lung, and diffuse alveolar damage was also recognized in parts. The cause of death was considered to be respiratory failure due mainly to cancer progression and additionally to diffuse alveolar damage induced by gefitinib.