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

BackgroundsLung cancer currently is the leading cause of cancer-related mortality worldwide, of which non-small cell lung cancer (NSCLC) accounts for more than 85%. As is pointed out in the Chinese Primary Lung Cancer Diagnostic and Treatment Practices (2015 edition), a multidisciplinary team and individual therapy are both necessary in the treatment of NSCLC. 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. Applications of surgery, chemotherapy, radiation therapy and molecular targeted therapy should be applied in a planned, reasonable way in order to prolong the patients’ survival time, controlling the tumor progress and improving the patient’s quality of life in the greatest degree. Surgical resection is an important treatment way for early or interim stage of NSCLC whose effect is closely related to prognosis. Lung cancer surgery can be divided into complete resection, incomplete resection and uncertain resection. NSCLC staging Ⅰ,Ⅱ and part of Ⅲ A (T3N1-2M0; T1-2N2M0; T4N0-1M0) are possible to be completely resected.Based on the basic and clinical researches in decade years, it is confirmed that the postoperative adjuvant chemotherapy could make survival benefit in the NSCLC patients with stage IB (with high risk factors) to stage IIIA. Patients with stage II to III A NSCLC patients are recommended to receive postoperative adjuvant chemotherapy (category 1A); patients with stage IA NSCLC are not recommended to receive postoperative adjuvant chemotherapy (category IA); patients with margins negatively stage IB may consider chemotherapy if they are with high-risk factors (category 2B). Examples of high-risk factors may include poorly differentiated tumors (including lung neuroendocrine tumors, but excluding well-differentiated neuroendocrine tumors), vascular invasion, wedge resection, tumors>4 cm, visceral pleural involvement, and incomplete lymph node sampling (Nx). These factors independently may not be an indication and may be considered when determining a treatment with adjuvant chemotherapy.Along with the development of molecular biology and relevant clinical researches, molecularly targeted therapy has attracted great attention and is considered as the most promising strategy for lung cancer therapy in the 21st century. Capable of blocking the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth rather than by simply interfering with all rapidly dividing cells, targeted cancer therapies are expected to be more effective than current treatments and less harmful to normal cells. And epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is one of the most exploited areas.EGFR-TKIs can competitively inhibit the ATPs binding to the intracellular areas of EGFR, thus inhibiting its signaling pathway, promoting tumor cell apoptosis, blocking the cell cycle, preventing tumor growth and metastasis and achieving anti-tumor effect. EGFR-TKIs are promising therapeutic drugs for the effective in treatment of EGFR-mutated NSCLC because patients with EGFR activating mutations are notably sensitive to EGFR-TKIs. There are four drug-sensitive mutations, including point mutations in exon 18 (G719A/C),21 (L858R and L861Q) and in-frame deletions in exon 19. These sensitizing EGFR mutations are found in approximately 10% of Caucasian patients with NSCLC and up to 50% of Asian patients. Thus far, three kinase domain mutations are associated with drug resistance: an exon 19 point mutation (19 D761Y), an exon 20 point mutation (20 T790M) and an exon 20 insertion.A number of clinical trials have demonstrated that a significant survival benefit is associated with EGFR-TKI treatment in patients with EGFR mutant advanced NSCLC. It is pointed out in NCCN Guideline of NSCLC that EGFR-TKIs should be used as first-line systemic therapy in patients with EGFR mutations instead of first-line chemotherapy. Different combined model of chemotherapy and EGFR-TKIs used in advanced NSCLC are under research.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 trial aims to investigate the application of EGFR-TKIs as adjuvant therapy in NSCLC patients after radical operation. We assessed the efficacy and safety of chemotherapy with or without icotinib in patients undergoing the resection of stage IB to IIIA EGFR-mutated NSCLC.MethodsThe study was undertaken at Nanfang Hospital, Southern Medical University (Guangzhou, China). Clinical stage was assessed by:1) Positron emission tomography-computed tomography (PET-CT) or 2) X-ray computed tomography (CT) scan, brain magnetic resonance imaging (MRI), bone scan and abdominal ultrasound, whether a bronchoscopy need to take was depended. Patients would receive unidirectionally thoracoscopic lobectomy and lymphadenectomy if the lung lesion was considered to be removed completely in surgery. Tumor specimens were collected during surgery and used for pathology diagnosis to confirm the exact pathology classification, tumor differentiation and the pTNM stage. EGFR mutation was detected by the scorpion amplification refractory mutation system (ARMS method).Patients were considered eligible for study inclusion if they were over 18 years of age, received unidirectionally thoracoscopic lobectomy and lymphadenectomy to remove the lung lesion completely, and had histologically confirmed NSCLC between stage IB (with high risk factors) and stage ⅢA, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, adequate hematological, biochemical and organ function and more than one or more kinds of sensitive EGFR mutation being detected. Exclusion criteria included any resistant EGFR mutations, systemic anticancer therapy prior to surgery, other malignancies before or during the study, any unstable illness, pregnancy or lactation.Eligible patients were randomly assigned in a 1:1 ratio to the chemotherapy-only or chemotherapy plus icotinib treatment group by using a random digits table. All patients received four cycles of platinum-based doublet chemotherapy (150 mg/m2 paclitaxel plus 80 mg/m2 nedaplatin or 30mg/m2 lobaplatin on day one of a three-week cycle). Two weeks after chemotherapy completed, patients assigned to the consolidation therapy group began oral icotinib treatment (125 mg, thrice daily). Icotinib treatment continued for four to eight months, or until the occurrence of disease relapse, metastasis or unacceptable icotinib or chemotherapy toxicity.Treatment response was assessed by:1) Positron emission tomography-computed tomography (PET-CT) or 2) X-ray computed tomography (CT) scan, brain magnetic resonance imaging (MRI), bone scan and abdominal ultrasound at the beginning of the fourth chemotherapy cycle and every six months thereafter. The primary endpoint of this study was disease-free survival (DFS), which was defined as the time from surgery to the first confirmed occurrence of disease relapse or metastasis. The secondary endpoint concerned the acceptable toxicity of chemotherapy and oral icotinib treatment. The cutoff for the primary analysis was 24 months after the last patient randomly assigned. Those patients will be considered as not completed the planned treatment program who received less than 4 cycles of chemotherapy and (or) less than 4 months of oral icotinib.This study was performed in accordance with the Declaration of Helsinki. All patients provided written informed consent before participating in this study.Results41 patients were enrolled between Feb 9,2011 and Dec 17,2012.21 patients were assigned to the combined chemotherapy plus icotinib treatment group, while 20 patients received chemotherapy only. Two patients in the chemotherapy group did not receive any study treatment after random assignment and were removed from the analysis. The data cutoff for the primary analysis was Dec 30,2014. There were 27 males (69.2%) and 12 females 30.8%),20 (51.3%) were present or former smokers and 19 (48.7%) non-smokers. Among the enrolled patients,37 (94.9%) had adenocarcinoma and 2 (5.1%) had squamous cell carcinoma,19 (48.7%) had well differentiated tumor and 20 (51.3%) poor differentiated,17 had lymph node metastasis (5 (12.8%) were Ni and 12 (30.8%) were N2) and 22 did not,17 (43.6%) had high-risk stage IB,10 (25.6%) had stage Ⅱ, and 12 (30.8%) had stage Ⅲ NSCLC. Sensitive EGFR mutations were detected in all of the 39 enrolled patients, among those 16 (41.0%) had exon 19 delete mutation,22 (56.4%) had exon 21 L858R mutation and 1 was detected an uncommon mutation of 18 G719X. None of the 39 patients was detected to carry two or more kinds of EGFR mutation. All 39 patients recruited for the study have finished the scheduled treatment and were eligible for data analysis. Baseline demographics and disease characteristics were well balanced between the two treatment groups.Patient outcomes were followed for up to 24 months after either four cycles of platinum-based doublet chemotherapy or consolidation therapy (platinum-based doublet chemotherapy supplemented by oral icotinib treatment). Treatment response data showed that the DFS was 100% in the chemotherapy plus icotinib group vs. 88.9% in the chemotherapy only group at 12 months (P=0.122),95.2% vs.83.3% at 18 months (P=0.225) and 90.5% vs.66.7% at 24 months (P=0.066). A longer follow-up study is needed to assess the long-term treatment responses of these 39 patients. In the Cox proportional hazards model, the treatment groups and pTNM stage showed a statistically significant, the HR was 0.136 (95%CI:0.022-0.829) and 5.498 (95%CI:1.333-22.673) respectively.All of the 39 patients received four cycles of platinum-based doublet chemotherapy. In brief, treatment-related complications affecting the gastrointestinal tract and marrow suppression were the most common side effects observed during chemotherapy treatment. These side effects were relatively mild and were mainly assigned grades of 0 or 1 after assessment, with a small number receiving a grade of 2; however, no grade 3 side effects or occurrences of intolerable toxicity were observed. No significant differences were identified in the rates of adverse events occurring between the two treatment groups.In the combined chemotherapy plus icotinib treatment group, three patients presented with grade 1 diarrhea, six patients presented with grade 1 rashes on their skin and one case developed a grade 3 rash. These side effects were improved after appropriate therapy. Other side effects were rarely observed, including neurotoxicity, liver and kidney damage and allergic reactions. The patients who received oral icotinib tolerated the drug well and no dose reductions or dose interruptions were necessary during this trial, the incidence of icotinib-related adverse events was 47.6%.ConclusionsThe results suggest that, firstly, chemotherapy plus orally icotinib displayed a tendency of longer DFS compared with chemotherapy only in the log-rank test and a significantly better DFS in the Cox proportional hazards model, and secondly, patients receiving extra orally icotinib showed favorable tolerance without severe side effects. Our current study demonstrated the consolidation treatment of icotinib after adjuvant chemotherapy might be worthy of further research in patients undergoing resection of stage IB to IIIA EGFR-mutated NSCLC. Further studies of larger patient populations recruited from multiple centers and longer follow-up schedule will be needed to verify the findings reported here.