Gefitinib in patients with progressive high-grade gliomas: a multicentre phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO)

To investigate the role of gefitinib in patients with high-grade gliomas (HGGs), a phase II trial (1839IL/0116) was conducted in patients with disease recurrence following surgery plus radiotherapy and first-line chemotherapy. Adult patients with histologically confirmed recurrent HGGs following surgery, radiotherapy and first-line chemotherapy, were considered eligible. Patients were treated with gefitinib (250 mg day(-1)) continuously until disease progression. The primary end point was progression-free survival at 6 months progression-free survival at 6 months (PFS-6). Tissue biomarkers (epidermal growth factor receptor (EGFR) gene status and expression, phosphorylated Akt (p-Akt) expression) were assessed. Twenty-eight patients (median age, 55 years; median ECOG performance status, 1) were enrolled; all were evaluable for drug activity and safety. Sixteen patients had glioblastoma, three patients had anaplastic oligodendrogliomas and nine patients had anaplastic astrocytoma. Five patients (17.9%, 95% CI 6.1-36.9%) showed disease stabilisation. The overall median time to progression was 8.4 (range 2-104+) weeks and PFS-6 was 14.3% (95% CI 4.0-32.7%). The median overall survival was 24.6 weeks (range 4-104+). No grade 3-4 gefitinib-related toxicity was found. Gefitinib showed limited activity in patients affected by HGGs. Epidermal growth factor receptor expression or gene status, and p-Akt expression do not seem to predict activity of this drug.     

A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression, amplification and NF-kB activation

Interesting activity has been reported by combining chemotherapy with cetuximab. An alternative approach for blocking EGFR function has been the development of small-molecule inhibitors of tyrosine kinase domain such as gefitinib. We designed a multicentre phase II study in advanced colorectal cancer combining gefitinib+FOLFOX in order to determine the activity and to relate EGFR expression and gene amplification and NF-kB activation to therapeutic results. Patients received FOLFOX-4 regimen plus gefitinib as first-line treatment. Tumour samples were analysed for EGFR protein expression by immunohistochemical analysis and for EGFR gene amplification by fluorescence in situ hybridisation (FISH), chromogenic in situ hybridisation (CISH) and NF-kB activation. Forty-three patients were enrolled into this study; 15 patients experienced a partial response (response rate=34.9%), whereas other 12 (27.9%) had a stable disease. Median progression-free survival (PFS) was 7.8 months and median overall survival (OS) was 13.9 months. We did not find any relationship with EGFR overexpression, gene amplification, while NF-kB activation was associated with a resistance to therapy. Gefitinib does not seem to increase the activity of FOLFOX in advanced colorectal cancer even in patients overexpressing EGFR or with EGFR amplification. Furthermore, while NF-kB activation seems to predict resistance to chemotherapy as demonstrated 'in vitro' models, gefitinib does not overcome this mechanism of resistance, as reported for cetuximab.     

The EGFR mutation and its correlation with response of gefitinib in previously treated Chinese patients with advanced non-small-cell lung cancer.

BACKGROUND: The aim of the study was to evaluate the efficacy of gefitinib and the epidermal growth factor receptor (EGFR) mutation to gefitinib response in a series of Chinese patients with pretreated advanced non-small-cell lung cancer (NSCLC). METHODS: A total of 98 patients who had failed at least one platinum-based regimen received gefitinib 250 mg once daily. The mutation analysis of the EGFR kinase domain was performed for 30 patients using paraffin-embedded tumor tissue. RESULTS: The response rate was 31.6% and the disease control rate was 67.3%. Objective response was correlated with adenocarcinoma, female gender and non-smokers. Median progress free survival (PFS) was 7.0 months, median overall survival (OS) was 12.0 months and 1-year survival was 53.1%. The median PFS and OS were improved among patients with adenocarcinoma, gefitinib responders and non-smokers. Active gene mutation was detected in 12 patients. Mutation rates were higher among gefitinib responders, non-smokers, patients with adenocarcinoma and female patients. OS was longer for patients with gene mutation than for patients without mutation. CONCLUSION: Gefitinib demonstrated significant antitumor activity with a favorable toxicity profile for pretreated Chinese patients with advanced NSCLC. The active mutation of the EGFR kinase domain was strongly associated with response to gefitinib and prolonged overall survival.     

Single agent gefitinib as first line therapy in patients with advanced non-small cell lung cancer: Washington University experience

Gefitinib has modest activity with an overall response rate of 11-18% in patients with metastatic non-small cell lung cancer (NSCLC) who have had progressive disease following platinum containing chemotherapy. However, the efficacy of gefitinib in previously untreated metastatic NSCLC is not known. We retrospectively analyzed the efficacy of gefitinib as a first line therapy in 26 patients with advanced NSCLC enrolled in the expanded access program. Patients received gefitinib 250 mg a day orally if they had a poor performance status (PS) or if they refused cytotoxic chemotherapy. Treatment was continued as long as there was no evidence of disease progression or unacceptable treatment related toxicities. The characteristics of 25 evaluable patients enrolled between the period of May 2001 and August 2002 include: 15 women, 10 men; median age 73 years (range 56-86), 81% had an ECOG performance status of two. Only one patient had a partial response and 32% had stable disease as their best response for a disease control rate of 36%; 32% of patients had disease control lasting 5 months or longer. The median overall survival and progression-free survival (PFS) were 14.1 and 2.9 months, respectively. Toxicities were minimal and included rash and diarrhea. Gefitinib was well tolerated and had interesting activity in previously untreated patients with advanced NSCLC.     

E-cadherin expression and epidermal growth factor receptor mutation status predict outcome in non-small cell lung cancer patients treated with gefitinib

It is known that an epidermal growth factor receptor (EGFR) gene mutation(s) is present in a percentage of non-small cell lung cancers (NSCLCs). Gefitinib, an inhibitor of the tyrosine kinase activity of EGFR, is effective on most of them. The EGFR mutation status alone cannot fully predict the response to gefitinib and the prognosis for the patients. We hypothesized that information on the expression levels of phosphorylated-EGFR and -Akt, and E-cadherin, alone or in combination with information on the EGFR mutation, may refine our ability of prediction. We investigated 24 NSCLCs that had recurred after surgery and were treated with gefitinib. Specimens resected by surgery were subjected to the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp reaction to determine the EGFR mutation status, and to immunohistochemical staining of phosphorylated-EGFR and -Akt, and E-cadherin to determine their expression levels. The EGFR mutation status was predictive of responsive disease (complete response: CR + partial response: PR) and controlled disease (CR + PR + stable disease: SD). Positive E-cadherin staining was predictive of longer time to progression (12.4 vs. 5.9 months, p<0.05) and overall survival (OS) (18.4 vs. 13.0 months, p<0.05). Together the patients with an EGFR mutation and the patients with positive E-cadherin staining defined a patient group with a median OS of 18.4 months and excluded the patient group with the median OS of 3.7 months. Neither p-Akt nor p-EGFR staining was associated with the response and survival. In patients with surgically resected NSCLC tumors, the EGFR mutation status and E-cadherin staining can select patients who will benefit from gefitinib therapy.     

Phase II trial of gefitinib 250 mg daily in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

PURPOSE: An objective response rate of 11% was reported in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) treated with 500 mg daily gefitinib although the recommended dose in lung cancer is 250 mg. This study evaluated the efficacy and toxicity of 250 mg daily gefitinib in patients with recurrent and/or metastatic SCCHN. EXPERIMENTAL DESIGN: Phase II trial with objective response rate as the primary end point. Measurements of quality of life and levels of serum vascular endothelial growth factor and transforming growth factor-alpha were assessed before and during therapy. RESULTS: In 70 patients, 1 (1.4%) partial response was observed. Median progression-free survival and overall survival were 1.8 and 5.5 months, respectively. Quality of life scores improved transiently during the first weeks of therapy before returning to baseline. Median vascular endothelial growth factor and transforming growth factor-alpha levels were above the normal range but were not predictive of outcome. Four patients experienced grade 3 drug-related adverse events. Rash of any grade was observed in 64% of subjects. Correlation between disease control (partial response + stable disease), progression-free survival, and overall survival and grade of cutaneous toxicity was observed (P = 0.001, 0.001, and 0.008 respectively). CONCLUSIONS: Gefitinib monotherapy at 250 mg in recurrent and/or metastatic SCCHN seems to have less activity than was previously observed for 500 mg daily. A dose-response relationship may exist for this agent in SCCHN and grade of cutaneous toxicity attributable to gefitinib is a clinical predictor of better outcome.     

Outcomes of patients with advanced non-small cell lung cancer treated with gefitinib (ZD1839, "Iressa") on an expanded access study

PURPOSE: To investigate the anti-tumor activity and toxicity of the epidermal growth factor receptor (EGFR) inhibitor gefitinib (ZD1839 or Iressa; AstraZeneca Pharmaceuticals, Wilmington, DE), in patients with advanced non-small cell lung cancer (NSCLC). METHODS: This was an open label, expanded access program (EAP) of oral gefitinib administered at 250 mg per day continuously until evidence of undue toxicity or disease progression. RESULTS: Two hundred consecutive patients with advanced NSCLC were enrolled in this study. The median number of prior chemotherapy regimens was 2 (range 0-6). One hundred seventy-two patients were treated with gefitinib; 23 expired from disease progression prior to treatment and 5 withdrew their consent. One hundred fifty-four patients are evaluable for toxicity; 8 (5.2%) experienced grade 3/4 toxicity; 2 patients discontinued therapy for grade 3 rash and one for grade 3 nausea. Of 172 patients evaluable for efficacy, 7 (4.1%; 95% CI; 1.7-8.2%) experienced a partial response (PR); 60 patients (34.9%) had stable disease (SD) as their best response. Median survival for all patients was 4.5 months (95% CI; 4.1-4.9 months). One-year survival was 29%. Significant independent prognostic factors associated with improved survival were female gender, good performance status (0/1), and adenocarcinoma histology. CONCLUSION: Gefitinib has anti-tumor activity, in a heterogeneous population of NSCLC patients treated on the EAP study. Treatment with gefitinib in this population is associated with a longer survival in women, those with good performance status and in patients with adenocarcinomas. These findings need to be further validated in additional clinical studies.     

A Phase Ⅱ Trial of Gefitinib as Maintenance Therapy after First-Line Chemotherapy for Advanced Non-Small Cell Lung Cancer in China

Objective:To investigate the efficacy and safety of gefitinib as maintenance therapy for advanced non-small cell lung cancer (NSCLC) patients who obtained disease control (DC) after first-line chemotherapy in Chinese population. Methods:Chinese patients with advanced NSCLC treated with standard chemotherapy and obtained DC were assigned to receive gefitinib as maintenance treatment. The primary end point was overall survival time (OS), the second end point was disease control rate (DCR) and progression-free survival time (PFS). DCR included complete response (CR) plus partial response (PR) and plus stable disease (SD). The impact of epidermal growth factor receptor (EGFR) mutation status on the treatment as exploratory point was also evaluated by denaturing high-performance liquid chromatography (DHPLC). Results:Among 75 enrolled patients, the overall response rate was 37% and the DCR (CR + PR +SD) was 66%. The median PFS and OS were 17.13 months and 26.13 months respectively, with 1- and 2-year survival rates 89.3% and 34.7%. Patients harboring somatic EGFR mutations obtained a prolonged median PFS and OS compared with EGFR wide type (25.1 vs. 13.0 months, P=0.019 and 33.37 vs. 25.57 months, P=0.014, respectively). In COX regression model, only EGFR mutation status was the independently factor influencing both PFS and OS (P=0.029 and 0.017, respectively), however, rash status was the predictor in terms of PFS (P=0.027).Conclusion:Gefitinib produced encouraging survival when delivered as maintenance therapy in Chinese patients obtaining DC after first-line chemotherapy, especially for patients carrying somatic EGFR mutations. EGFR mutation is an independently predictive factor of survival.     

吉非替尼对于化疗失败的晚期肺腺癌的疗效及生存观察

目的：观察吉非替尼在化疗失败的晚期肺腺癌中的疗效、生存时间及影响因素。方法：收集２１例初始化疗失败的转移性肺腺癌,应用吉非替尼２５０ｍｇ口服,每日１次,直至出现有客观证据的病情进展,或出现不可耐受的不良反应。用Ｋａｐｌａｎ-Ｍｅｉｅｒ法拟定生存曲线,采用Ｌｏｇｒａｎｋ检验分析生存因素。结果：２１例患者中ＣＲ３例（１４.３％）,ＰＲ例８（３８.１％）,ＳＤ３例（１４.３％）,ＰＤ７例（３３.３％）。客观缓解率为５２.４％,疾病控制率为６６.７％。中位无进展生存时间（ＰＦＳ）为６个月,中位生存时间（ＯＳ）为８个月。１年生存率为３３.３％（７／２１）,２年生存率为９５％（２／２１）。好的ＰＳ评分与生存期延长显著相关（Ｐ＜０.０１）。结论：吉非替尼对既往化疗失败的晚期肺腺癌疗效好,能有效改善生存时间,体力状态评分与吉非替尼治疗的生存时间相关。     

Gefitinib in patients with malignant mesothelioma: a phase II study by the Cancer and Leukemia Group B.

PURPOSE: The Cancer and Leukemia Group B conducted a phase II study of gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, in patients with previously untreated malignant mesothelioma. EXPERIMENTAL DESIGN: Eligible patients had unresectable pleural or peritoneal mesothelioma, measurable disease, no prior therapy, and performance status 0-1 by Cancer and Leukemia Group B criteria. Gefitinib (500 mg p.o.) was administered once a day for 21 days. Patients underwent restaging after every two cycles. Therapy was continued until disease progression or unacceptable toxicity. RESULTS: The most common grade 3 toxicities were diarrhea (16%) and nausea (12%). Of 43 patients enrolled, 1 patient (2%) had a complete response, 1 patient (2%) had a partial response, 21 (49%) had stable disease lasting two to eight cycles, 15 (35%) had progressive disease, and 5 (12%) had early deaths. One-year survival was 32% [95% confidence interval (CI), 21-50%]. Median survival and failure-free survival were 6.8% (95% CI, 3.5-10.3) and 2.6 months (95% CI, 1.5-4.0), respectively. The 3-month failure-free survival was 40% (95% CI, 25-56%). EGFR expression score by immunohistochemistry done in 28 patients was categorized as low (EGFR 1+ or 2+) or high (EGFR 3+) expression: 97% had EGFR overexpression (2+ or 3+). The median and 3-month failure-free survival were 3.6 months and 40% for those patients with low EGFR expression compared with 8.1 and 40% for those with high EGFR expression. CONCLUSIONS: Although 97% of patients with mesothelioma had EGFR overexpression, gefitinib was not active in malignant mesothelioma. EGFR expression does not correlate with failure-free survival.     

Activity of a specific inhibitor, gefitinib (Iressa, ZD1839), of epidermal growth factor receptor in refractory non-small-cell lung cancer.

BACKGROUND: Gefitinib (Iressa(TM), ZD1839) is an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Phase I studies showed that it is well tolerated, with evidence of tumor regression in patients with advanced non-small-cell lung cancer (NSCLC). Therefore, we aimed to assess the antitumor activity and tolerability of gefitinib in a series of patients with previously treated, advanced NSCLC, as a part of a compassionate use program. PATIENTS AND METHODS: To be eligible, all patients were required to have histologically or cytologically proven advanced or metastatic NSCLC, prior chemotherapy with at least one cisplatin-containing chemotherapy regimen or contraindication to cytotoxic drugs, Eastern Cooperative Oncology Group performance status < or =2, and adequate hematological, renal and hepatic parameters. All patients provided signed informed consent. Patient re-evaluation was performed every 4-6 weeks. RESULTS: Seventy-three consecutive patients were enrolled. Response rate, including complete and partial response, was 9.6%; an additional 43.8% of patients achieved stable disease, for an overall disease control of 53.4%. EGFR1 status was evaluated by immunocytochemistry in 25 patients. According to EGFR1 immunoreactivity all responses were observed with medium/strong imunoreactivity while three out of four responses were observed in high expressive patients. Median survival for all patients was 4 months while it reached 6 months for patients with disease control. The 1-year survival rate was 13.1% for the entire series and 23.2% for patients with disease control. Non-hematological toxicity was generally mild. CONCLUSION: Gefitinib has promising activity with a good toxicity profile in patients with progressive NSCLC who have received one or two prior chemotherapy regimens. A possible relationship within response and EGFR1 expression is suggested.     

吉非替尼(Iressa)在晚期肺腺癌的靶向治疗疗效观察

背景与目的 吉非替尼是选择性表皮生长因子受体酪氨酸激酶抑制剂,用于治疗非小细胞肺癌,特别是腺癌.本研究的目的是探讨吉非替尼在晚期肺腺癌中的疗效、副反应及影响因素.方法 收集26例晚期肺腺癌,应用吉非替尼250 mg口服,每日1次,直至出现任何疾病进展的客观证据或发生不可耐受的不良事件.定期复查,并进行生存分析.结果 26例患者中CR 1例(3.8%),PR 11例(42.3%),SD 9例(34.6%),PD 5例(19.2%).客观缓解率为46.2%,疾病控制率为80.8%.其中位无进展生存期为8.2个月,中位总体生存期为10.4个月,1年生存率为31.6%.年龄(＜70岁)、产生皮疹及CEA降低与较好的预后有密切关系,吉非替尼治疗级别及化疗次数等因素与预后无明显关系.用药前平均PS(ECOG)为3.0,用药后平均为1.8.平均症状缓解时间为5.2天.结论 吉非替尼是一种疗效好、副作用少、可以明显提高肺腺癌患者生活质量的靶向治疗药物,对没有化疗条件的腺癌患者,可以作为一线治疗首选用药.     

Concurrent radiotherapy with gefitinib in elderly patients with esophageal squamous cell carcinoma: Preliminary results of a phase II study

The survival rate associated with esophageal cancer is very poor due to diagnosis at advanced stages of disease and insensitivity to chemotherapy. This study investigated the efficacy of gefitinib combination with radiation in 20 elderly patients with esophageal squamous cell carcinoma (ESCC) who were not eligible for platinum-based chemotherapy. Immunohistochemistry was performed to analyze epidermal growth factor receptor (EGFR) expression, and the amplified refractory mutation system was used to detect EGFR mutations. Treatment response was assessed by endoscopy and computed tomography. Treatment toxicity was evaluated using the National Cancer Institute''s Common Toxicity Criteria. The data showed that among these 20 patients, 5 experienced a complete response (CR), 13 a partial response (PR), and 2 had stable disease. The overall response rate (CR + PR) was 90%, the median overall survival (OS) was 14.0 months (95% confidence interval [CI]: 10.0–17.9 months), and the median progression-free survival was 7.0 months (95% CI: 0–17.2 months). Patients with good Eastern Cooperative Oncology Group performance status, never smoking, and EGFR mutated tumors had the best OS (14.0, 14.0, and 17.0 months, respectively). Treatment-related grade 3/4 toxicity occurred in five patients. No case of grade 3/4 impaired liver function or hematological toxicity was observed. Concurrent radiotherapy with gefitinib is effective and tolerable in elderly ESCC patients.     

Phase II prospective study of the efficacy of gefitinib for the treatment of stage III/IV non-small cell lung cancer with EGFR mutations, irrespective of previous chemotherapy

PURPOSE: Mutations in the epidermal growth factor receptor (EGFR) gene are associated with increased sensitivity of non-small cell lung cancer (NSCLC) to gefitinib, an EGFR tyrosine kinase inhibitor. The objective of this study was to prospectively evaluate the efficacy of gefitinib in patients with stage III/IV NSCLC whose tumors carried EGFR mutations, irrespective of previous chemotherapy. EXPERIMENTAL DESIGN: Genomic DNA was extracted from tumor specimens and EGFR mutations in exons 19 and 21 analyzed by direct sequencing. Patients with stage III/IV NSCLC whose tumors had the EGFR mutations received gefitinib (250 mg/day orally). Response, toxicity and survival data were assessed. RESULT: From November 2004-May 2006, 21 patients with EGFR mutations received gefitinib (median age: 59 years; 17 females; 19 non-smokers; all had adenocarcinomas). Two patients discontinued gefitinib and withdrew from the study 3 weeks after gefitinib initiation (interstitial pneumonitis, 1 patient; facial acne, 1 patient). Of 19 patients, 3 achieved complete response, 13 exhibited partial response and 3 had stable disease. Response and disease control rates were 76% (95% confidence interval [CI] 53-92) and 90% (95% CI 70-99), respectively. The most common adverse event was skin toxicity (67%); however, no grade 4 skin toxicities were seen. Ten patients relapsed and three died at a median follow-up period of 12.6 months (range 5.6-23.8 months); median progression-free survival was 12.9 months. CONCLUSION: Analysis of tumor EGFR mutations in patients with NSCLC could be used to identify patients suitable for treatment with gefitinib to obtain optimum response and disease control rates.     

Gefitinib as first-line, compassionate use therapy in patients with advanced non-small-cell lung cancer

PURPOSE: To evaluate the efficacy of single-agent gefitinib (Iressa, ZD1839), an oral, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, as first-line compassionate use therapy for advanced non-small-cell Lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-five patients who were unfit or refused chemotherapy received oral gefitinib 250mg daily as first-line therapy for the treatment of recurrent or metastatic NSCLC in a compassionate use program at a single institution. RESULTS: Four of 22 evaluable patients (18%), two with adenocarcinomas and two with bronchioloalveolar carcinomas, had an objective response and five patients (23%) had stable disease. Duration of response or stable disease was 3.5-22+ months. Median time to progression was 2.2 months, median survival was 12.6 months and 1-year survival 52%. The partial response plus stable disease rate by Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 4/5 for PS 0 patients; 3/6 for PS 1-2 patients; and 2/14 for PS 3-4 patients. The two patients with PS > 2 who derived benefit from gefitinib had PS 3 due to co-morbidities. Two patients discontinued therapy due to severe toxicities: one patient had severe liver dysfunction and hemorrhagic cystitis, and another patient developed diarrhea with hypotension. A correlation between rash and antitumor activity was noted. Of seven patients who received chemotherapy subsequent to gefitinib, one had a partial response, three had stable disease, two progressed, and one was non-evaluable for response. CONCLUSION: We report encouraging response and survival results with gefitinib as first-line treatment in unselected patients with advanced NSCLC. Gefitinib monotherapy should undergo further evaluation as first-line therapy in advanced NSCLC.     

加速康复外科理念在行腹腔镜膀胱根治性切除术患者围术期中应用的临床观察#br#

目的探讨加速康复外科（ERAS）理念在腹腔镜膀胱根治性切除中应用的有效性和安全性。 方法收集2015年6月至2017年6月潍坊市人民医院收治的58例膀胱癌患者,分为传统组（n=28）和ERAS组（n=30）。比较两组患者的手术时间、手术出血量、术后排气时间、术后重度疼痛的发生数、麻醉苏醒时间、盆腔引流时间、术后住院天数以及术后并发症的发生情况。 结果ERAS组和传统组手术时间分别为（1722±379）min和（1873±218）min;术中出血量分别为（1597±465）ml 和（1771±469）ml,差异均无统计学意义（P＞005）。ERAS组和传统组麻醉苏醒时间分别为（254±54）min和（417±98）min;术后排气时间分别为（16±07）d和（22±07）d;盆腔引流时间分别为（25±11）d和（50±16）d;术后住院天数分比为（76±14）d和（110±18）d;术后疼痛VAS评分＞7分发生率分别为100％（3／30）和429％（12／28）;两组差异均有统计学意义（P＜005）。ERAS组1例刀口液化,1例发生肾结石;传统组2例肠梗阻,1例发生坠积性肺炎,1例发生肾结石。两组患者中均无尿瘘患者。 结论加速康复外科理念在腹腔镜下膀胱根治性切除术患者中的临床应用是安全、有效的,可加速患者的术后康复,值得临床推广应用。     

Sequential administration of docetaxel followed by maintenance gefitinib, as salvage treatment in patients with advanced NSCLC: a multicenter phase II trial

PURPOSE: To evaluate the activity and toxicity of the sequential administration of docetaxel followed by gefitinib in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND TREATMENT: Forty-one patients pre-treated with at least one prior chemotherapy regimen (platinum- or taxane-based) for advanced/metastatic NSCLC received three cycles of docetaxel 30 mg/m2, administered as a 1-h IV infusion, on days 1, 8 and 15 of each 4-week cycle followed by gefitinib 250 mg daily po. Gefitinib treatment was continued until disease progression, development of unacceptable toxicity, or withdrawal of patients consent. RESULTS: Two (4.9%) patients achieved a partial response and 10 (24.4%) stable disease, for a disease control rate of 29.3% (95% CI: 15.3%-43.2%) while on weekly docetaxel treatment. Additionally, progressive disease (PD) was observed in 29 (70.7%). No objective responses were observed during the gefitinib maintenance therapy; however, 17 (41.5%) patients presented stable disease maintained for more than 2 months. Median time to progression was 3.0 months (range: 1-38.3 months; 95% CI: 2.4-3.6); median overall survival 6.9 months (range: 1.2-40.2 months; 95% CI: 5.34-8.52) while the 1-year survival was 28.8%. Therapy was generally well tolerated with diarrhea and rash being the most frequent toxicities. CONCLUSIONS: The sequential administration of docetaxel and gefitinib was well tolerated and moderately active against advanced pre-treated NSCLC.     

Multicenter phase II trial of gefitinib first-line therapy followed by chemotherapy in advanced non-small-cell lung cancer (NSCLC): SAKK protocol 19/03.

BACKGROUND: Gefitinib is active in patients with pretreated non-small-cell lung cancer (NSCLC). We evaluated the activity and toxicity of gefitinib first-line treatment in advanced NSCLC followed by chemotherapy at disease progression. PATIENTS AND METHODS: In all, 63 patients with chemotherapy-naive stage IIIB/IV NSCLC received gefitinib 250 mg/day. At disease progression, gefitinib was replaced by cisplatin 80 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1, 8 for up to six 3-week cycles. Primary end point was the disease stabilization rate (DSR) after 12 weeks of gefitinib. RESULTS: After 12 weeks of gefitinib, the DSR was 24% and the response rate (RR) was 8%. Median time to progression (TtP) was 2.5 months and median overall survival (OS) 11.5 months. Never smokers (n = 9) had a DSR of 56% and a median OS of 20.2 months; patients with epidermal growth factor receptor (EGFR) mutation (n = 4) had a DSR of 75% and the median OS was not reached after the follow-up of 21.6 months. In all, 41 patients received chemotherapy with an overall RR of 34%, DSR of 71% and median TtP of 6.7 months. CONCLUSIONS: First-line gefitinib monotherapy led to a DSR of 24% at 12 weeks in an unselected patients population. Never smokers and patients with EGFR mutations tend to have a better outcome; hence, further trials in selected patients are warranted.     

吉非替尼治疗91例晚期非小细胞肺癌疗效分析

目的 总结表皮生长因子受体酪氨酸激酶抑制剂吉非替尼治疗91例晚期非小细胞肺癌患者的疗效、中位肿瘤进展时间（TTP）、中位生存期和毒副反应,分析与疗效、生存期可能相关的因素。方法 91例化疗失败的晚期非小细胞肺癌患者,中位化疗周期数为6（1～17）周期,68例（74．7％）患者至少经过二线方案化疗,疾病仍进展;Ⅳ期76例（83．5％）,其中42例（46．2％）至少有2个转移部位。口服吉非替尼剂量为250mg／d。运用SPSS11．5统计软件进行统计分析。结果 全组客观有效率为20．9％（19／91）,疾病控制率为63．7％（58／91）,症状改善率为72．7％（40／55）,ECOG评分稳定及改善为71．4％（65／91）。腺癌、至少接受二线方案化疗及出现皮肤毒性者与疾病控制率呈明显正相关（P值分别为0．04、0．02及0．00）。中位TTP 5．0个月（95％CI为3．26～6．74）,中位随访7．5（1～18．5）个月,1年生存率为56．4％。目前仍存活56例（61．5％）,其中29例（51．8％）仍处于疾病控制中,20例生存期已超过1年（12～18．5个月）。对生存有益的单因素为不吸烟、疾病控制、出现皮肤毒性及吉非替尼治疗过程中控制转移灶。经Cox回归分析发现,不吸烟、疾病控制是独立预后因素（P值分别为0．01和0．00）。毒副反应主要为Ⅰ、Ⅱ度皮肤毒性。结论 靶向治疗药物吉非替尼对传统治疗失败的晚期难治性非小细胞肺癌患者有明显疗效,有改善症状及延长生存期作用,且耐受性好。     

吉非替尼一线治疗34例晚期非小细胞肺癌的疗效分析

背景与目的：分子靶向药物吉非替尼单药治疗晚期非小细胞肺癌具有较好的疗效和安全性。本文观察吉非替尼一线治疗晚期非小细胞肺癌的疗效和不良反应。方法：34例病理确诊的不愿或不能接受传统细胞毒性药物化疗的非小细胞肺癌患者,口服吉非替尼250rng,每目1次,持续用药直至肿瘤进展或出现不可耐受的小良反应。结果：吉非替尼的有效率为29．4％,疾病控制率为61．8％,症状改善率为47．1％,中位无进展生存期为3．0个月,中位生存期为10．2个月,1年生存率为35．3％。其中不吸烟患者客观缓解率高于吸烟患者（P=0．023）。出现皮疹患者疾病控制率高于无皮疹患者（P=0．005）,LogistiC回归提示皮疹是疾病控制的独立因素（P=0．003）。最常见的不良反应是皮疹和腹泻。结论：对于不愿或不能接受传统细胞毒性药物化疗的非小细胞肺癌患者,吉非替尼为这些患者提供了另一个选择。