Case of bilateral pneumothorax observed during the administration of gefitinib for lung adenocarcinoma with multiple pulmonary metastases

A 61-year-old woman who had never smoked was given a diagnosis of adenocarcinoma of the lung with multiple pulmonary metastases. Systemic chemotherapy consisting of carboplatin and paclitaxel was not effective, thereafter daily oral administration of gefitinib was initiated. Six days later, bilateral pneumothorax was found. The extent of the pneumothorax was slight and she recovered without drainage within about one month although treatment of gefitinib was restarted. Gefitinib was effective for lung cancer in this case. Bilateral pneumothorax is a rare complication of chemotherapy for lung cancer. Only 3 such cases under treatment with gefitinib were reported in Japan.     

Acute lung injury as a possible adverse drug reaction related to gefitinib.

Gefitinib is a potent drug used in the treatment of nonsmall-cell lung cancer (NSCLC). Gefitinib acts by inhibition of the epidermal growth factor receptor tyrosine kinase. Clinical trials have confirmed the efficacy of gefitinib for NSCLC. Adverse drug reactions, although frequent, are mild, and include acne-like skin rash and diarrhoea. The present study describes the case of a 56-yr-old male with NSCLC who, 4 weeks after treatment with gefitinib, suffered from a severe alveolar haemorrhage diagnosed by bronchoalveolar lavage. This is the first case report of an acute life-threatening lung injury in a patient with nonsmall-cell lung cancer who had been given gefitinib.     

Gefitinib in advanced non-small cell lung cancer

BACKGROUND: Gefitinib is an oral, selective epidermal growth factor receptor (EGFR) inhibitor that has activity in non-small cell lung cancer (NSCLC). AIM: To evaluate the tolerability, safety-profile and response of single agent gefitinib in patients with advanced stage NSCLC. METHODS: Twenty-seven patients of good performance status with stage IIIB or IV NSCLC were entered on the study at the Sydney Cancer Centre. Gefitinib was prescribed at an oral dose of 250 mg daily, as a continuous dose. Radiological evaluation of indicator lesions occurred at baseline and were repeated every 2-3 months until disease progression. Toxicity was graded using standard measures at baseline and at every month. RESULTS: The response rate was 17% in the patients eligible for evaluation. Symptom improvement was observed in 75% of patients. No patients withdrew because of adverse events. Toxicity was observed in 15 patients and consisted mainly of rash (59%), which was usually mild in severity. CONCLUSION: Gefitinib is active in NSCLC. It is well tolerated with minimal side-effects. Symptomatic improvement was found in the majority of patients treated with gefitinib. There may be a role for gefitinib in the palliation of symptoms in patients with advanced NSCLC.     

吉非替尼与托瑞米芬在肺癌治疗中的临床价值

目的 旨在分析吉非替尼与托瑞米芬在肺癌治疗中的临床价值.方法 选取在我院进行治疗的肺癌患者87例,随机分为两组,分别使用吉非替尼与托瑞米芬.结果 吉非替尼治疗肺癌的有效率高于托瑞米芬,两组之间不良反应无统计学差异.结论 吉非替尼能较托瑞米芬有效地治疗肺癌.     

吉非替尼治疗老年非小细胞肺癌的临床研究

目的观察吉非替尼（gefitinib，ZD1839）治疗老年非小细胞肺癌（NSCLC）的治疗效果及不良反应。方法43例经病理学或细胞学确诊的老年NSCLC患者（≥60岁），应用吉非替尼（250mg，每日1次，口服）治疗直至病情进展或出现严重不良反应。结果43例可评价疗效患者：获得完全缓解（CR）2例（4．7％），部分缓解（PR）11例（25．6％），有效率（RR）为30．3％；稳定（SD）13例（30．2％）；进展（PD）17例（39．5％）。中位生存期（MST）10．3月，中位无疾病进展时间（TFP）8、1月。与药物相关的不良反应依次为：皮疹18例（41．9％），腹泻14例（32．6％），恶心10例（23．3％），关节痛9例（20．9％），肝功能异常8例（18．6％）。尚无因不良反应需停药者。结论吉非替尼治疗老年NSCLC疗效明确，不良反应较轻，耐受性较好。     

Recurrent gefitinib-induced interstitial lung disease

Gefitinib, the epidermal growth factor receptor tyrosine kinase inhibitor, is effective for patients with non-small cell lung cancer. However, a serious adverse effect, interstitial lung disease (ILD), has been reported. The re-administration of gefitinib might be considered when there is no other choice of treatment and a therapeutic effect can be expected; however, there is no published data on the safety of restarting gefitinib after its discontinuation in cases suspected of having gefitinib-induced ILD. We report a case with recurrent gefitinib-induced ILD, which suggests that re-administration of gefitinib should be considered cautiously in patients who have previously developed gefitinib-induced ILD.     

Remarkable effect of gefitinib retreatment in a patient with nonsmall cell lung cancer who had a complete response to initial gefitinib

Gefitinib is an orally active epidermal growth factor receptor tyrosine kinase inhibitor, and it shows favorable antitumor activity against chemorefractory nonsmall cell lung cancer (NSCLC). However, patients with NSCLC have few treatment options available if they are refractory to gefitinib. We describe a 49-year-old patient with NSCLC who had a complete response to initial gefitinib that lasted for 12 months. The tumor relapsed, and the patient received cytotoxic chemotherapy. However, despite chemotherapy, the patient had radiographic progression of lung metastases and we commenced retreatment with gefitinib, showing a remarkable effect. Epidermal growth factor receptor (EGFR) gene analysis showed deletion mutations in codon 745-750 in exon 19 and EGFR gene amplification. Our case shows that after retreatment with gefitinib, patients may show a remarkable response if they showed a remarkable response to initial gefitinib administration and if a certain time has elapsed since the previous gefitinib treatment.     

Late fatal recurrence in gefitinib-treated NSCLC patients

Gefitinib is a selective epidermal growth factor receptor tyrosine kinase inhibitor, which blocks signal transduction pathways implicated in proliferation and survival of cancer cells. Long-term survival in patients with metastatic non-small-cell lung carcinoma (NSCLC) treated with gefitinib has recently been reported. We showed herein two cases of fatal rapid recurrence after a long-term disease control by gefitinib. The biology of fatal aggressive recurrence of gefitinib-treated NSCLC is not well characterized. Regardless of the mechanism, however, physicians treating patients with gefitinib should be alert to the possibility of fatal rapid recurrence after a long-term disease control by this drug.     

Successful treatment of non-small cell lung cancer by gefitinib in an elderly patient with poor performance status

A 91-year-old woman was admitted to our hospital with dyspnea. A chest radiograph and chest CT films revealed a large amount of pleural effusion in the right side pleural cavity. After serial thoracentesis, chest CT films showed a mass shadow in the right S(6). Adenocarcinoma cells were found in the pleural effusion, leading to a diagnosis of non-small cell lung cancer (stage IIIB). After administration of gefitinib, the mass shadow and pleural effusion reduced and her performance status improved. Gefitinib may be a well-tolerated therapeutic strategy in elderly and poor performance status patients with advanced non-small cell lung cancer.     

吉非替尼治疗晚期非小细胞肺癌的临床观察

目的 观察吉非替尼单药治疗晚期非小细胞肺癌的疗效与不良反应.方法 24例Ⅲ～Ⅳ期非小细胞肺癌患者口服吉非替尼(易瑞沙)250 mg/d,1次顿服,不限疗程,直至出现严重不良反应或因经济问题或死亡而终止.观察临床症状改善情况、不良反应,通过CT扫描判断疗效.结果 24例患者中完全缓解2例,部分缓解12例,稳定6例,进展4例,有效率为58.3%,疾病控制率为83.3%,主要不良反应为腹泻.结论 吉非替尼应用于放、化疗失败或不能耐受放、化疗的非小细胞肺癌患者是安全的,患者耐受性好.     

Gefitinib-induced interstitial lung disease showing improvement after cessation: disassociation of serum markers

Gefitinib (ZD1839), a small-molecule epidermal growth factor receptor tyrosine kinase inhibitor, is an anticancer agent for patients with non-small cell lung carcinoma. Recently, however, as a result of accumulating evidence, it has been recognized that gefitinib can give rise to lethal lung toxicity. The authors report a case of interstitial lung disease (ILD) induced by gefitinib, which improved promptly following cessation of the administration of the agent. Clinical signs suggesting a good prognosis were noted, namely, findings similar to acute eosinophilic pneumonia on CT and a disassociation in the elevation of specific serum markers of ILD. At the time of onset of ILD, serum concentrations of surfactant protein (SP)-A and SP-D were significantly increased, whereas that of KL-6 was not increased. A previous study of three cases of lethal lung toxicity resulting from gefitinib administration revealed a significant and almost equal increase in KL-6, SP-A and SP-D. These results suggest that SP-A and SP-D may be indicators of gefitinib-induced ILD and that KL-6 is a predictor of outcome. Using a combination of these markers may help to establish a differential prognosis in patients with gefitinib-induced ILD.     

Miliary brain metastases in 2 cases with advanced non-small cell lung cancer harboring EGFR mutation during gefitinib treatment

Here we report 2 cases of non-small cell lung cancer (NSCLC) with sensitive epidermal growth factor receptor (EGFR) gene mutation that developed miliary brain metastases characterized by dementia and disorientation during gefitinib therapy. One patient's therapy was switched from gefitinib to chemotherapy followed by whole brain radiotherapy (WBRT), which resulted in disease progression with coma. Gefitinib reinitiation improved the patient's symptoms. The other patient continued gefitinib during WBRT and achieved complete remission of the miliary metastases and lived 18 months longer. These results suggest that gefitinib concomitant with WBRT is an optional strategy for the treatment of patients with EGFR-mutated NSCLC with miliary metastases to prevent disease flare.     

吉非替尼-线治疗晚期肺腺癌的临床观察

目的 探讨吉非替尼-线治疗晚期肺腺癌的疗效及不良反应.方法 选择住院及门诊确诊肺腺癌Ⅲb或Ⅳ期17例,每天一次口服吉非替尼250 mg,直至出现PD为止,根据WHO标准评价其疗效及毒性不良反应.结果 17例中1例达到完全缓解(CR),8例部分缓解(PR),3例病情稳定(SD),5例病情进展(PD),总有效率为52.9％,疾病控制率(PR+ CR+ SD)为70.6％.结论 吉非替尼对于晚期非小细胞肺腺癌具有较好的疗效和耐受性.     

吉非替尼在晚期非小细胞肺癌维持治疗的作用

目的 观察吉非替尼对既往化学治疗有效的晚期(Ⅳ期)非小细胞肺癌维持治疗的疗效和安全性.方法 在15例经病理学确诊的非小细胞肺癌经4～6个周期含铂类方案化疗后取得临床完全缓解和部分缓解患者中,随机选取2例Ⅳ期肺腺癌患者予以吉非替尼维持治疗,250 mg/次,1次/d,口服.结果 2例晚期非小细胞肺癌患者肺部肿瘤进一步缩小,胸腔积液、心包积液消失.病例1放射性核素骨显像示转移病灶放射性浓聚程度明显降低.病例2 MRI显示颅内多发转移病灶稳定.患者生活质量显著提高,KPS评分提高30,症状改善率达100%.不良反应为皮疹和腹泻(Ⅰ级),不需处理.结论 吉非替尼用于既往化疗显效的晚期非小细胞肺癌患者的维持治疗有较好的疗效和安全性.同时可改善患者的相关症状,提高生活质量.     

Radiation recall pneumonitis induced by Gefitinib (Iressa): a case report]

Gefitinib is a newly developed molecular-target drug with selective inhibitory activity for tyrosine kinase of the epidermal growth factor receptor and has an encouraging effect on non-small cell lung cancer in an advanced stage. The adverse drug reactions including diarrhea, skin eruptions and liver dysfunction have been considered mild. However, cases of severe acute lung injuries were reported after approval of the drug in Japan in July, 2002. We report a case of recurrent large cell carcinoma of the lung in a 73-year-old man who suffered from radiation recall pneumonitis induced by Gefitinib. Two months after radiation therapy to the mediastinal and right hilar lesions was completed, he started to take Gefitinib at a dose of 250 mg/day. Six weeks later, he complained acutely of a dry cough, slight fever and effort dyspnea, and his chest CT demonstrated ground-glass opacity corresponding to the previous radiation field. In administering Gefitinib, as well as other cytotoxic drugs, meticulous monitoring for acute lung injury and radiation recall reaction is required.     

Severe acute interstitial pneumonia and gefitinib

Gefitinib is an oral selective inhibitor of the epidermal growth factor receptor tyrosine kinase that is an effective treatment for patients with advanced non-small cell lung cancer who do not respond to platinum-based chemotherapy. We assessed four patients who had non-small cell lung cancer causing severe acute interstitial pneumonia in association with gefitinib. Although two patients recovered after treatment with steroids, the other two died from progressive respiratory dysfunction. On the basis of autopsies and bilateral distribution of diffuse ground-glass opacities in chest CTs, we diagnosed diffuse alveolar damage, which was consistent with acute interstitial pneumonia. Patients with interstitial pneumonia also had other pulmonary disorders such as previous thoracic irradiation and poor performance status. Physicians should be aware of the alveolar damage induced by gefitinib, especially for patients with these characteristic features.     

双靶向吉非替尼磷脂胶束纳米载体靶向肺癌干细胞和肺癌细胞研究

目的研究双靶向吉非替尼磷脂胶束纳米载体靶向肺癌干细胞和肺癌细胞方法制备吉非替尼纳米载体和双靶向吉非替尼磷脂胶束纳米载体,检测吉非替尼载药量、包封率、粒径及zeta电位,培养肺癌细胞和干细胞分选,测定不同载药纳米载体在肺癌细胞中的蓄积效率、对肺癌细胞克隆球生长的影响、对肺癌细胞杀伤作用。结果双靶向吉非替尼纳米载体组包封率、粒径均高于吉非替尼纳米载体组,载药量、zeta电位低于吉非替尼纳米载体组,具有统计学差异(P<0.05)。两组载药纳米载体中的吉非替尼在各时间点的释放量比较,无统计学差异(P>0.05)。双靶向吉非替尼纳米载体组在肺癌A549细胞、A431细胞中的蓄积效率均高于吉非替尼纳米载体组,具有统计学差异(P<0.05)。双靶向吉非替尼纳米载体组肺癌A549细胞、A431细胞克隆球形成率均低于吉非替尼纳米载体组,具有统计学差异(P<0.05)。双靶向吉非替尼纳米载体组肺癌A549细胞、A431细胞在各时间点的存活率均低于吉非替尼纳米载体组,具有统计学差异(P<0.05)。结论双靶向吉非替尼磷脂胶束纳米载体可双靶向杀伤肺癌细胞,具有较强的抗肿瘤作用。     

Targeting non-small cell lung cancer with epidermal growth factor tyrosine kinase inhibitors: where do we stand, where do we go

Cytotoxic chemotherapy has only yielded modest gains in survival in lung cancer in the past decade. However, the development of agents targeting specific signaling pathways that drive carcinogenesis has heralded a major paradigm shift in the approach to treatment of cancer. In non-small cell lung cancer (NSCLC), many researchers have focused on the epidermal growth factor receptor (EGFR) because this protein is present on a relatively high proportion of non-small cell lung cancers and its intracellular tyrosine kinase activates a signaling cascade that drives tumor growth. Blockade of the EGFR by small molecule inhibitors of the tyrosine kinase, such as gefitinib and erlotinib, causes tumor regressions in NSCLC. Phase II monotherapy trials of EGFR tyrosine kinase inhibitors in patients with previously treated advanced NSCLC demonstrated anti-tumor activity with objective response rates of 10–19% with acceptable toxicities and an associated improvement in lung cancer symptomatology. Gefitinib is now an FDA approved treatment for advanced NSCLC previously treated with platinum and docetaxel-based therapies. However, phase III trials of gefitinib and erlotinib in combination with chemotherapy doublets have failed to demonstrate a survival advantage when compared with chemotherapy alone. It remains unclear why these drugs work so effectively in certain patients and so poorly in combination with chemotherapy. The goal of ongoing and future investigation is to identify which patients may benefit from this new therapeutic approach.     

关于吉非替尼治疗晚期非小细胞肺癌副反应分析

目的观察吉非替尼单药对化疗失败的晚期非小细胞肺癌的毒性反应。方法 41例既往化疗失败的非小细胞肺癌患者,口服吉非替尼250mg,每日1次直到病情进展或出现不可耐受的不良反应停药,同时评价疗效及药物不良反应。结果 41例患者中皮疹发生率60.98%;腹泻发生率26.83%,其中一例发生严重间质性肺炎。结论吉非替尼治疗晚期非小细胞肺癌疗效好,但有皮疹、腹泻、肝肾功能损伤、间质性肺炎等副作用。     

Epithelial membrane protein-1 is a biomarker of gefitinib resistance

We describe a molecular resistance biomarker to gefitinib, epithelial membrane protein-1 (EMP-1). Gefitinib is a small-molecule inhibitor that competes for the ATP-binding site on EGF receptor (EGFR) and has been approved for patients with advanced lung cancers. Treatment with gefitinib has resulted in clinical benefit in patients, and, recently, heterozygous somatic mutations within the EGFR catalytic domain have been identified as a clinical correlate to objective response to gefitinib. However, clinical resistance to gefitinib limits the utility of this therapeutic to a fraction of patients, and objective clinical responses are rare. We aimed to assess the molecular phenotype and mechanism of in vivo gefitinib resistance in xenograft models and in patient samples. We generated in vivo gefitinib-resistance models in an adenocarcinoma xenograft model by serially passaging tumors in nude mice in presence of gefitinib until resistance was acquired. EMP-1 was identified as a surface biomarker whose expression correlated with acquisition of gefitinib resistance. EMP-1 expression was further correlated with lack of complete or partial response to gefitinib in lung cancer patient samples as well as clinical progression to secondary gefitinib resistance. EMP-1 expression and acquisition of gefitinib clinical resistance was independent of gefitinib-sensitizing EGFR somatic mutations. This report suggests the role of the adhesion molecule, EMP-1, as a biomarker of gefitinib clinical resistance, and further suggests a probable cross-talk between this molecule and the EGFR signaling pathway.