Clinical Analysis Of Gefitinib Treating Advanced Non Small Cell Lung Cancer After Obtained Resistance

Background and Purpose: Lung cancer has became the leading cause ofcancer related death in China, and the incidence of lung cancer is increasingyear by year. NSCLC accounts for~85%of lung cancers, among that50%areadenocarcinoma. The appearance of epidermal growth factor receptor-tyrosinekinase inhibitors (EGFR-TKI) brings a revolutionary change for the NSCLCpatients’ treatment patterns. The NSCLCs harboring activating EGFRmutations or having advantage clinical characteristics (such as non-smoker,adenocarcinoma, female) can experience good clinical response to EGFR-TKI,however, the NSCLC patients who respond to EGFR-TKI initially willinevitably develop obtained resistance. This has became a intractable problemin clinical work. A great deal of fundamental and clinical research is beingcarried out to discover the molecular mechanisms underlying this resistancerecently. In comparison, few studies have been conducted to find out about theclinical characteristics of obtained resistance in the patients who hadresponded to an EGFR-TKI. Gefitinib is a selective EGFR-TKI. Herein, thisstudy retrospectively analyzed progress free survival (PFS), clinicalcharacteristics, sites of disease progression and post-progression survival (PPS)of advanced NSCLC patients who experienced obtained resistance duringgefitinib therapy, to help judging prognosis、guiding treatment and supplyingadvances for patients’ follow up during gefitinib therapy.Methods: We reviewed72advanced NSCLC patients who developedobtained resistance during initial gefitinib therapy. All clinical cases wereobtained from Affiliated Hospital of Jilin University from January1,2010toJanuary1,2014. Progress free survival (PFS), clinical characteristics, sites of disease progression and post-progression survival (PPS) were analyzedretrospectively. Statistical analysis was performed with SPSS version17.0.Comparisons of categorical variables between the different groups were madewith the χ2test. Clinical evaluation of PFS and PPS was estimated by theKaplan–Meier method. The Log-rank test was used to compare the survivaloutcome with different potential factors. Cox proportional hazard analysis wasperformed to explore the effect of each variable on PPS. P <0.05prompteddifference was statistically significant.Results: Patients’ characteristics were summarized as follows: Themedian age was64years (range28–83years). Patients included46(63.8%)female,48(66.7%) never-smokers,58(80.6%) with PS0–1,56(77.8%) withadenocarcinoma,57(79.2%) with stage IV disease. Metastases to multipleorgans were found in23patients (31.9%). Metastases to the lung, bone, centralnervous system (CNS), pleura, liver, and adrenal gland were found in28(38.9%),27(37.5%),15(20.8%),4(5.5%),4(5.5%)�'�4(5.5%)patients,respectively. Twenty-five patients (34.7%) received gefitinib as the first-linetherapy,23(31.9%) second-line,14(19.4%) third line, and10(13.9%) furtherlines. EGFR mutational analysis was performed in56(77.8%) patients.Mutations were identified in41(57.0%) of the56patients. Of the41mutations,23(56.1%) were in-frame deletions at exon19,15(36.6%) werearginine-for-leucine substitutions at amino acid858. For the rest,19(2.4%)patients had other single mutation and2(4.9%) patients had double mutations.Responses to gefitinib therapy were as follows: CR in0patients, PR in48(66.7%), and SD in24(33.3%). At the time of acquired resistance,47(65.3%)of the patients showed symptomatic deterioration, the most common symptomsare cough and dyspnea. Sites of disease progression were as follows: primarylung lesion in46(63.9%), previous metastasis in25(34.7%), and newmetastasis in41(56.9%). The most common new lesion was the lung (27.8%), follow by the CNS (16.7%), pleura (15.3%) and bone (11.1%). Patients withEGFR wild type showed a tendency of higher frequency in symptomaticdeterioration (wild type vs. mutation type,73.3%vs.58.5%, P=0.31)、newlydevelopment of CNS (wild type vs. mutation type,26.7%vs.12.2%, P=0.4) andliver (wild type vs. mutation type,13.3%vs.2.4%, P=0.19) metastasis,compared with patients with EGFR mutation. Median PFS was10.1months(95%CI,9.1-11.1). PFS showed a significant longer duration in female,non-smoker, and patients with adenocarcinoma. Median PPS was8.8months(95%CI,8.1-9.5). Smoking history and tumour histology were independentfactors for PPS.Conclusion:1. PFS shows a significant longer duration in female, non-smoker, andpatients with adenocarcinoma.2. Patients who acquire resistance during gefitinib therapy usually showsymptomatic deterioration. The most common symptoms are coughand dyspnea.3. Patients with EGFR wild type showed a tendency of higher frequencyin symptomatic deterioration、newly development of CNS and livermetastasis, compared with patients with EGFR mutation.4. Sites of disease progression after gefitinib failure are as follows:primary lung lesion, previous metastasis and new metastasis. The mostcommon new lesion is lung, follow by the CNS, pleura and bone.5. Smoking history and tumour histology are independent factors for PPS.