Efficiency And Safety Of Intercalated Treatment Of Icotinib With Chemotherapy In Patients Undergoing Resection Of EGFR Mutation-positive Non-small Cell Lung Cancer

BackgroundLung cancer currently is the leading cause of cancer-related mortality worldwide.Wherein the non-small cell lung cancer (non-small cell lung cancer, NSCLC) accounts for more than 85% of all lung cancer cases. As is pointed out in the Chinese Primary Lung Cancer Diagnostic and Treatment Practices (2015 edition), The multidisciplinary, comprehensive treatment pattern should be adopted according to the patient’s performance status, tumor pathological histology and molecular classification, invasion, and the progress tend. Lung cancer surgery can be divided into complete resection, incomplete resection and removal of uncertainty. Where complete resection (or radical surgery) indication is I, II stage and some IIIA period (T3N1-2M0; T1-2N2M0; T4N0-1M0) non-small cell lung cancer. NSCLC complete resection adjuvant chemotherapy to some extent, improved the 5-year survival of patients. For adjuvant chemotherapy, IA NSCLC patients after surgery to be followed up regularly; II-IIIA complete resection of non-small cell lung cancer after adjuvant chemotherapy is the use of a standard protocol. Recommended use of platinum-based doublet joint applications and third-generation anticancer drugs. IB negative margins on high-risk groups need adjuvant chemotherapy, the risk factors may include poorly differentiated tumors (including lung neuroendocrine tumors, with the exception of well-differentiated neuroendocrine tumor), vascular invasion by wedge resection, tumor size> 4cm, Invasion of the pleural and incomplete lymph node sampling (Nx), these indications may not be independent factors, but in deciding adjuvant chemotherapy should be considered.In recent years, chemotherapy for NSCLC efficacy of new drugs has asymptotically a platform can not meet the current needs of NSCLC treatment. Molecular targeting therapy has become one of the hotspots of global research. Which is mainly based on the biological characteristics of tumor development, tumor cells and normal use of the difference on cell biology, namely tumor cell-specific targets. Main applications of monoclonal antibodies targeted therapy, genes, antisense oligonucleotides, peptides, specifically acts on lung cancer cell growth factor receptors, signal transduction molecules in specific sites, receptors, as well as lung cancer cell proliferation, division, invasion and metastasis-related molecular targets, specific for the tumor cells to normal cells smaller role in the killing of tumor cells at the same time, greatly reduce host toxicity. Depending on the molecular targets can be divided into vascular targeting, targeting growth factors, signal transduction pathways related to molecular targeted, invasion and metastasis-related molecules targeting other categories. Current research on epidermal growth factor receptor (epidermal growth factor receptor, EGFR) as the starting point of the most in-depth molecular targeted drugs.EGFR (epidermal growth factor receptor, EGFR) and more than 70% of malignancies, non-small cell lung cancer, breast cancer, prostate cancer, gastrointestinal tumors were EGFR overexpression, especially non-small cell lung cancer obvious. EGFR ligands, such as after the EGF/TGFa binding activation, etc., then leading to intracellular region autophosphorylation, intracellular tyrosine kinase activation, so it causes the activation of downstream signaling molecules. For the above mechanism, the epidermal growth factor receptor tyrosine kinase inhibitor (epidermal growth factor receptor tyrosine kinase inhibitor, EGFR-TKI) drugs also will be available. EGFR-TKI mainly through competitive inhibition of ATP binding to EGFR intracellular targeting inhibition of tyrosine kinase activation, thereby blocking signal transduction pathway, blocking the cell cycle and promote apoptosis of tumor cells, prevent tumor growth and metastasis to achieve the purpose of anti-tumor therapy. Recent studies showed that 60% -85% of NSCLC with EGFR overexpression, taking more than tumor cells in tumor progression associated signal transduction pathway; cell proliferation division accelerated; immortalized tumor cells and invasion capacity strengthening; tumor angiogenesis is activated; tumor cells to chemotherapy, radiation tolerance and other factors. There are four types of mutation status are considered to increase the sensitivity to TKI drugs were exon 19 deletions (19del),21 exon mutation (L858R),21 exon mutation (L861Q),18 exons point mutation (G719A/C); another three mutation status was confirmed with TKI resistance-associated, respectively, a point mutation in exon 19 (D761Y),20 exon mutation (T790M),20 exons inserted.IPASS, FIRST SIGNAL, NEJ002, WJTOG3405 etc. Several randomized controlled studies [3-7] was confirmed line EGFR-TKI treatment of advanced NSCLC objective response rate level progression-free survival was significantly better than the treatment of platinum-containing bivalent currently EGFR-TKIs line treatment of advanced NSCLC with EGFR mutations status has been established, and researchers have begun to explore the chemotherapy and EGFR-TKIs different combinations of mode applications in advanced NSCLC patients.Is it possible that EGFR-TKIs be used for adjuvant therapy in NSCLC patients after radical operation? We explored the application of EGFR-TKIs in postoperative adjuvant therapy, trying to find a suitable treatment which can help further improve the therapeutic efficacy of postoperative NSCLC patients.ObjectiveThis research focuses on the staging of high-risk stage IB-IIIA NSCLC after radical operation adjuvant therapy in patients with EGFR mutations, to investigate the Efficiency and safety of intercalated treatment of icotinib with chemotherapy in patients undergoing resection of EGFR mutation-positive non-small cell lung cancerMethodsPatients after admission through any of the following means of checking radiographic assessment and cTMN stages:(1) whole body PET-CT; (2) enhanced chest CT+cranial MRI+Abdominal ultrasound and whole body bone scan; based on the specific circumstances to decide whether bronchoscopy an examination. Preoperative evaluation of patients is expected to complete resection line before surgery to improve an operation after preparation. Surgical procedures are one-way all-thoracoscopic anatomic lobectomy, systematic hilar and mediastinal lymph node dissection. Resected tumor specimens for histopathological examination to determine the extent of tumor differentiation and histologic subtype, and obtain accurate pTNM stage; at the same time EGFR genetic testing to clarify the molecular pathological type. Inclusion criteria for this study include:(1) has accepted anatomic lobectomy, systematic hilar and mediastinal lymph node dissection in patients with NSCLC, and intraoperative complete resection of the lesion, pathological staging high-risk stage IB～III A period; (2) EGFR mutations detected one or more sensitive mutation; (3) Age≥18 years; (4) hematological, liver and kidney function required in the normal range; (5) PS score of 0 or 1; (6) before the group had not received any anti-tumor chemotherapy or radiotherapy; not suffering from other types of malignant tumors (7) before the group or the group; (8) informed consent and adjuvant therapy. Exclusion criteria included:(1) a class of EGFR detected in any of the following resistance mutations that exon 19 point mutations (19 D761Y),20 exon mutation (20 T790M), 20 exon inserted; (2) suffering from other diseases and conditions is not yet stable; (3) pregnant or lactating women.The patients were randomly selected based on the inclusion criteria were divided into groups and intervening chemotherapy group. Chemotherapy paclitaxel (150 mg/ m2, day 1)+platinum (cisplatin 75mg/m2 or carboplatin 300mg/m2, day 1) from the fourth week after surgery, a period of 21 days for chemotherapy after a total of four regular review cycle. Intervening treatment group received the same chemotherapy program, taking joint Icotinib (125mg/time,3 times/day,8 to 21 days; Icotinib chemotherapy), relapse occurs, transfer, and produce intolerable when the withdrawal of toxicity. Treatment response was assessed by means of any of the following checks:(1) whole body PET-CT; (2) enhanced chest CT+cranial MRI++ Abdominal ultrasound whole body bone scan; the fourth line medical check-up before the start of chemotherapy, after chemotherapy ends four inspected once every six months. During the study of patient compliance follow-up, if the patient received adjuvant chemotherapy and less than four cycles (or) lack of oral Icotinib four courses, it will be deemed not completed as planned test program. Initial follow-up time was 18 months, or to terminate the patient died. The primary endpoint was disease-free survival (DFS), secondary endpoints included toxicity of chemotherapy and EGFR-TKIs after drug treatment side effects.Results34 patients were randomly assigned to chemotherapy group (18 cases) and intervening treatment group (16 cases).16 cases (45.7 had a smoking history; the group of 34 patients,19 males (54.3%) and 15 females (45.7%); pathological type was adenocarcinoma 32 cases (97.0%), squamous cell carcinoma in 1 case (3.0%)%), non-smoking 18 cases (54.3%); the degree of tumor differentiation as well-24 cases (14.7%), poorly differentiated 13 cases (29.4%); lymph node status NO total 19 cases (55.9%), Nl total 5 cases (14.7%), N2 total of 13 cases (30.4%); pTNM staging high-risk IB 16 cases (47.1%), ii 6 cases (17.6%), JRA 18 cases (35.3%); 34 patients sensitive EGFR mutations were detected, of which 16 cases (47.1%) detected 19delete mutation,18 cases (52.9%) detected 21 L858R mutation, patients are also sensitive to the presence of two or more mutations were found. Both groups were age, sex, smoking history, N stage, tumor differentiation, pTNM stage, EGFR mutation sites, etc. By comparison showed no significant differences.34 cases of patients enrolled good compliance, according to test plan to complete treatment programs. As of December 30,2015,34 patients were not lost, and the clinical data and follow-up data were included in the analysis.Two groups of patients at 12 months of chemotherapy group was 88.9%of DFS, intervening treatment group was 100%(P= 0.163); 18 months, DFS was 64.7%vs 87.5%(P= 0.129), the long-term survival data for further the results of the follow-up study. In multivariate analysis, Cox proportional hazards model, the treatment group, pTNM stage impact should be variable statistically significant. Treatment groups corresponding HR was 22.241,95% CI for the 1.093-452.698, P= 0.044; pTNM installments corresponding HR was 23.238,95% CI of 2.248-220.025, P= 0.006.34 patients enrolled were receiving paclitaxel plus platinum-based adjuvant chemotherapy, toxicity between the two groups showed more degrees and 0 degrees I gastrointestinal reactions and bone marrow suppression reaction, degree II reaction rarely occurs not observed iii degree above toxicity. Other adverse neurotoxic reactions, allergic reactions, liver and kidney dysfunction were not found. The statistical comparison, side effects of chemotherapy between the two groups was no significant difference. Intervening for the oral treatment group during Exeter Nepalese side effects rate was 25.0%, the drug does not appear due to intolerable side effects resulting from the reduction or suspension of medication.ConclusionsIn this study, intercalated treatment groups displayed a tendency of longer DFS, compared with the chemotherapy group, multivariate analysis comparing chemotherapy treatment intermediate interpolation reflect the advantages, and the mode of treatment did not increase the intolerable drug side effects. Interposed between the above-mentioned results suggest that treatment with EGFR mutations in NSCLC adjuvant therapy may be a worthwhile model. With a larger sample, fuller follow-up observation of clinical research or further validate the value of EGFR-TKIs in EGFR mutant NSCLC adjuvant therapy.