Original Article
Efficacy of icotinib versus traditional chemotherapy as first‑line treatment for preventing brain metastasis from advanced lung adenocarcinoma in patients with epidermal growth factor receptor‑sensitive mutation ABSTRACT Objective: This study aimed to investigate the potential use of icotinib as first‑line treatment to prevent brain metastasis from advanced lung adenocarcinoma. Patients and Methods: This investigation was designed as a retrospective nonrandomized controlled study. Enrolled patients received either icotinib or traditional chemotherapy as their first‑line treatment. The therapeutic efficacy was compared among patients with advanced (stages IIIB and IV) lung adenocarcinoma with epidermal growth factor receptor (EGFR)‑sensitive mutation. The primary endpoint was the cumulative incidence of brain metastasis, whereas the secondary endpoint was overall survival (OS). Death without brain metastasis was considered a competitive risk to calculate the cumulative risk of brain metastasis. Survival analysis was conducted using the Kaplan–Meier method and statistical significance were determined using the log‑rank test. Results: The present study included 396 patients with 131 in the icotinib group and 265 in the chemotherapy group. Among those with EGFR‑sensitive mutation, the cumulative risk of brain metastasis was lower in the icotinib group than in the chemotherapy group. However, no significant difference in OS was observed between the two groups. Conclusion: Icotinib can effectively reduce the incidence of brain metastasis and therefore improve prognosis in advanced lung adenocarcinoma patients with EGFR‑sensitive mutation. KEY WORDS: Brain metastasis, epidermal growth factor receptor mutation, icotinib, lung adenocarcinoma *Fang Li and Nan Du contribute equally to this work
INTRODUCTION Lung cancer is the most commonly diagnosed cancer worldwide, representing the most common cause of cancer‑related death.[1‑3] Approximately, 85% of all cases are of nonsmall cell lung cancer (NSCLC), with lung adenocarcinoma being the most common pathological subtype. Adenocarcinoma accounts for approximately 40% of all lung cancer cases and its diagnosis has been increasing recently.[4] The disease subtype presents a particularly high incidence of local recurrence and distant metastasis, most commonly to the brain.[5,6] Brain metastasis from lung adenocarcinoma is a significant cause of death due to the disease. Although multi‑modality treatment including chemotherapy, surgery, and radiotherapy has been reported to reduce the incidence of extra‑cranial distant recurrence, its
efficacy against brain metastasis is dismal. Therefore, 40–50% of lung adenocarcinoma patients die of brain metastasis within 3 years after treatment.[7] Previous studies have suggested that chemotherapeutic agents, despite their systemic effectiveness, could not decrease the risk of brain metastasis from lung adenocarcinoma, possibly due to their inability to efficiently cross the blood‑brain barrier. These results demonstrate the limited effects of traditional therapy in preventing and treating brain metastasis, prompting us to urgently explore new treatment options to improve the quality of life and prolong the survival of lung cancer patients.
Xiao Zhao, Guangqin Zhu1, Huoming Chen2, Ping Yang3, Fang Li4,*, Nan Du* Department of Medical Oncology, Affiliated Hospital of PLA General Hospital, 1 Department of Medical Oncology, General Hospital of the Air Force of People’s Liberation Army, 2Department of Medical Oncology, Second Artillery General Hospital of People’s Liberation Army, 3 Department of Medical Oncology, Navy General Hospital of People’s Liberation Army, 4 Department of Medical Oncology, General Hospital of People’s Liberation Army, Beijing, China For correspondence: Prof. Nan Du, Department of Medical Oncology, Affiliated Hospital of PLA General Hospital, No. 51 Fucheng Road, Beijing‑100 048, China. E‑mail: dunan05@ aliyun.com Pro. Fang Li, Cancer Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing-100853, China. Email: prlifang@163. com
Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.145851 PMID: *** Quick Response Code:
In recent years, with the advancement of research on cancer‑related cell receptors, as well as gene and molecular‑regulated mechanisms, development of targeted drugs directed at signal transduction
Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 2- 2014
C155
Zhao, et al.: icotinib vs chemotherapy for brain metastasis
has met with some degree of progress and these agents have gradually gained clinical attention. The epidermal growth factor receptor (EGFR), with its tyrosine kinase activity and abundant expression on lung adenocarcinoma cells, is a member of the type I growth factor family (also known as the ERBB family with other members being the human EGF receptor (HER‑2, HER‑3, and HER‑4). EGFR can regulate the transcription of various genes through different signaling pathways to control tumor cell proliferation, differentiation, and apoptosis. It is also involved in tumor metastasis. The introduction of tyrosine kinase inhibitors (TKIs) targeting EGFR brought a new hope for advanced NSCLC patients. Previous studies have shown that EGFR‑TKI drugs such as gefitinib and erlotinib offered favorable efficacy in NSCLC patients, especially those with EGFR‑sensitive mutation.[8‑10] More recently, gefitinib and erlotinib have been suggested to not only exert effects on brain metastasis in NSCLC patients with EGFR‑sensitive mutation, but also reduce the risk of brain metastasis in patients with advanced disease.[11] Icotinib is a new type of oral EGFR‑TKI. It has demonstrated similar efficacy, but less adverse effects compared to gefitinib in a phase III clinical trial (ICOGEN).[12] However, no study on the relationship between icotinib treatment and brain metastasis has been reported. Therefore, we performed a retrospective nonrandomized controlled study to investigate the role of icotinib as first‑line therapy on preventing brain metastasis in advanced lung adenocarcinoma patients with EGFR‑sensitive mutation. PATIENTS AND METHODS Clinical data We retrospectively reviewed the clinical data of patients with advanced (stage IIIB or IV) lung adenocarcinoma with EGFR‑sensitive mutation who received icotinib or traditional chemotherapy as first‑line treatment between March 2009 and March 2012.[13] Treatments were conducted in subordinate units of Chinese Army Lung Cancer Group Patients were excluded if they showed brain metastasis or had severe heart, liver, kidney, and hematologic system diseases. Clinical data, including sex, onset age, smoking history, Eastern Cooperative Oncology Group performance status score, tumor grade, treatment history, EGFR mutation status of the tumor, and complete laboratory and imaging examination results were collected. EGFR gene mutation status was tested using the amplification‑refractory mutation system (ARMS). Tumors were graded according to the International Association for the Study of Lung Cancer version 7 NSCLC tumor‑node‑metastasis (TNM) clinical staging standard. The histology of the tumor was classified according to the 2004 World Health Organization criteria. A total of 396 patients were included and divided into the icotinib group and the chemotherapy group according to their first‑line therapy regimen, which lasted for at least a month. There were 131 patients in the icotinib group and 265 patients in the chemotherapy group. All enrolled patients provided written informed consent.
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Epidermal growth factor receptor gene mutation test Chinese Army Lung Cancer Group conventionally adopted the Scorpions’ ARMS to evaluate EGFR mutation status in all tumor samples.[14] All procedures were performed strictly following the Scorpions’ ARMS kit manual from the manufacturing company (QIAGEN, Valencia, CA, USA). In this study, the following EGFR mutations were considered sensitive mutations: deletion, repetition, or insertion of exon 19, L858R and L861Q point mutations, and G719 missense mutation. Therapeutic regimen Patients in the icotinib group received 125 mg icotinib orally, 3 times a day for more than 30 days. Those in the chemotherapy group received standard first‑line platinum‑based chemotherapy regimens: 94 received a pemetrexed plus platinum combination, 79 received a docetaxel plus platinum combination, 47 received a gemcitabine plus platinum combination, 28 received an etoposide plus platinum combination, and 17 received a navelbine plus platinum combination. Evaluation of efficacy and toxicity Baseline assessment of all patients was completed within 1 week before systemic chemotherapy. The assessment included clinical evaluation, chest computed tomography (CT), enhanced magnetic resonance imaging (MRI) of the skull, and examination of critical organs such as the liver and bone. Efficacy was evaluated 3 weeks after systemic therapy in both groups. Patients with the response or stable disease (SD) underwent a comprehensive evaluation every 8 weeks. Efficacy was assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1 (StataCorp, College Station, TX, USA), as complete response (CR), partial response (PR), SD, or progressive disease (PD). The response rate (RR) included CR and PR. The disease‑control rate (DCR) included CR, PR, and SD. Drug‑related toxicity was graded according to the National Cancer Institute toxicity classification standard version 3.0.[15] Follow‑up and survival analysis The primary endpoint was the cumulative incidence of brain metastasis, whereas the secondary endpoint was overall survival (OS). Brain metastasis was assessed according to clinical signs and symptoms, and was confirmed by CT, MRI, or pathology. The time from diagnosis of lung adenocarcinoma to brain metastasis (here after referred to as the time to brain metastasis occurrence) was measured in months, from the day when lung adenocarcinoma was accurately diagnosed to the day when brain metastasis was diagnosed, with 30 days being considered as 1 month. OS was calculated as the time from the 1st day of treatment until death or the last outpatient follow‑up visit. Follow‑up was conducted from the day of treatment and was continued despite PD‑related therapy termination. OS of patients who neither progressed nor died by the last day of follow‑upon (May 1, 2013) was assessed as per the last tumor evaluation.
Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 2- 2014
Zhao, et al.: icotinib vs chemotherapy for brain metastasis
Statistical analysis All data were analyzed using Stata12.0 software (StataCorp, College Station, TX, USA). Baseline characteristics between groups were compared using the Chi‑square test or Fisher’s exact test. The Kaplan–Meier method and log‑rank test were used for survival analysis. The cumulative risk of brain metastasis was estimated using the cumulative incidence curve. Death without brain metastasis was used as a competitive risk for calculating the cumulative risk of brain metastasis. P
Efficacy of icotinib versus traditional chemotherapy as first‑line treatment for preventing brain metastasis from advanced lung adenocarcinoma in patients with epidermal growth factor receptor‑sensitive mutation ABSTRACT Objective: This study aimed to investigate the potential use of icotinib as first‑line treatment to prevent brain metastasis from advanced lung adenocarcinoma. Patients and Methods: This investigation was designed as a retrospective nonrandomized controlled study. Enrolled patients received either icotinib or traditional chemotherapy as their first‑line treatment. The therapeutic efficacy was compared among patients with advanced (stages IIIB and IV) lung adenocarcinoma with epidermal growth factor receptor (EGFR)‑sensitive mutation. The primary endpoint was the cumulative incidence of brain metastasis, whereas the secondary endpoint was overall survival (OS). Death without brain metastasis was considered a competitive risk to calculate the cumulative risk of brain metastasis. Survival analysis was conducted using the Kaplan–Meier method and statistical significance were determined using the log‑rank test. Results: The present study included 396 patients with 131 in the icotinib group and 265 in the chemotherapy group. Among those with EGFR‑sensitive mutation, the cumulative risk of brain metastasis was lower in the icotinib group than in the chemotherapy group. However, no significant difference in OS was observed between the two groups. Conclusion: Icotinib can effectively reduce the incidence of brain metastasis and therefore improve prognosis in advanced lung adenocarcinoma patients with EGFR‑sensitive mutation. KEY WORDS: Brain metastasis, epidermal growth factor receptor mutation, icotinib, lung adenocarcinoma *Fang Li and Nan Du contribute equally to this work
INTRODUCTION Lung cancer is the most commonly diagnosed cancer worldwide, representing the most common cause of cancer‑related death.[1‑3] Approximately, 85% of all cases are of nonsmall cell lung cancer (NSCLC), with lung adenocarcinoma being the most common pathological subtype. Adenocarcinoma accounts for approximately 40% of all lung cancer cases and its diagnosis has been increasing recently.[4] The disease subtype presents a particularly high incidence of local recurrence and distant metastasis, most commonly to the brain.[5,6] Brain metastasis from lung adenocarcinoma is a significant cause of death due to the disease. Although multi‑modality treatment including chemotherapy, surgery, and radiotherapy has been reported to reduce the incidence of extra‑cranial distant recurrence, its
efficacy against brain metastasis is dismal. Therefore, 40–50% of lung adenocarcinoma patients die of brain metastasis within 3 years after treatment.[7] Previous studies have suggested that chemotherapeutic agents, despite their systemic effectiveness, could not decrease the risk of brain metastasis from lung adenocarcinoma, possibly due to their inability to efficiently cross the blood‑brain barrier. These results demonstrate the limited effects of traditional therapy in preventing and treating brain metastasis, prompting us to urgently explore new treatment options to improve the quality of life and prolong the survival of lung cancer patients.
Xiao Zhao, Guangqin Zhu1, Huoming Chen2, Ping Yang3, Fang Li4,*, Nan Du* Department of Medical Oncology, Affiliated Hospital of PLA General Hospital, 1 Department of Medical Oncology, General Hospital of the Air Force of People’s Liberation Army, 2Department of Medical Oncology, Second Artillery General Hospital of People’s Liberation Army, 3 Department of Medical Oncology, Navy General Hospital of People’s Liberation Army, 4 Department of Medical Oncology, General Hospital of People’s Liberation Army, Beijing, China For correspondence: Prof. Nan Du, Department of Medical Oncology, Affiliated Hospital of PLA General Hospital, No. 51 Fucheng Road, Beijing‑100 048, China. E‑mail: dunan05@ aliyun.com Pro. Fang Li, Cancer Center, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing-100853, China. Email: prlifang@163. com
Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.145851 PMID: *** Quick Response Code:
In recent years, with the advancement of research on cancer‑related cell receptors, as well as gene and molecular‑regulated mechanisms, development of targeted drugs directed at signal transduction
Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 2- 2014
C155
Zhao, et al.: icotinib vs chemotherapy for brain metastasis
has met with some degree of progress and these agents have gradually gained clinical attention. The epidermal growth factor receptor (EGFR), with its tyrosine kinase activity and abundant expression on lung adenocarcinoma cells, is a member of the type I growth factor family (also known as the ERBB family with other members being the human EGF receptor (HER‑2, HER‑3, and HER‑4). EGFR can regulate the transcription of various genes through different signaling pathways to control tumor cell proliferation, differentiation, and apoptosis. It is also involved in tumor metastasis. The introduction of tyrosine kinase inhibitors (TKIs) targeting EGFR brought a new hope for advanced NSCLC patients. Previous studies have shown that EGFR‑TKI drugs such as gefitinib and erlotinib offered favorable efficacy in NSCLC patients, especially those with EGFR‑sensitive mutation.[8‑10] More recently, gefitinib and erlotinib have been suggested to not only exert effects on brain metastasis in NSCLC patients with EGFR‑sensitive mutation, but also reduce the risk of brain metastasis in patients with advanced disease.[11] Icotinib is a new type of oral EGFR‑TKI. It has demonstrated similar efficacy, but less adverse effects compared to gefitinib in a phase III clinical trial (ICOGEN).[12] However, no study on the relationship between icotinib treatment and brain metastasis has been reported. Therefore, we performed a retrospective nonrandomized controlled study to investigate the role of icotinib as first‑line therapy on preventing brain metastasis in advanced lung adenocarcinoma patients with EGFR‑sensitive mutation. PATIENTS AND METHODS Clinical data We retrospectively reviewed the clinical data of patients with advanced (stage IIIB or IV) lung adenocarcinoma with EGFR‑sensitive mutation who received icotinib or traditional chemotherapy as first‑line treatment between March 2009 and March 2012.[13] Treatments were conducted in subordinate units of Chinese Army Lung Cancer Group Patients were excluded if they showed brain metastasis or had severe heart, liver, kidney, and hematologic system diseases. Clinical data, including sex, onset age, smoking history, Eastern Cooperative Oncology Group performance status score, tumor grade, treatment history, EGFR mutation status of the tumor, and complete laboratory and imaging examination results were collected. EGFR gene mutation status was tested using the amplification‑refractory mutation system (ARMS). Tumors were graded according to the International Association for the Study of Lung Cancer version 7 NSCLC tumor‑node‑metastasis (TNM) clinical staging standard. The histology of the tumor was classified according to the 2004 World Health Organization criteria. A total of 396 patients were included and divided into the icotinib group and the chemotherapy group according to their first‑line therapy regimen, which lasted for at least a month. There were 131 patients in the icotinib group and 265 patients in the chemotherapy group. All enrolled patients provided written informed consent.
C156
Epidermal growth factor receptor gene mutation test Chinese Army Lung Cancer Group conventionally adopted the Scorpions’ ARMS to evaluate EGFR mutation status in all tumor samples.[14] All procedures were performed strictly following the Scorpions’ ARMS kit manual from the manufacturing company (QIAGEN, Valencia, CA, USA). In this study, the following EGFR mutations were considered sensitive mutations: deletion, repetition, or insertion of exon 19, L858R and L861Q point mutations, and G719 missense mutation. Therapeutic regimen Patients in the icotinib group received 125 mg icotinib orally, 3 times a day for more than 30 days. Those in the chemotherapy group received standard first‑line platinum‑based chemotherapy regimens: 94 received a pemetrexed plus platinum combination, 79 received a docetaxel plus platinum combination, 47 received a gemcitabine plus platinum combination, 28 received an etoposide plus platinum combination, and 17 received a navelbine plus platinum combination. Evaluation of efficacy and toxicity Baseline assessment of all patients was completed within 1 week before systemic chemotherapy. The assessment included clinical evaluation, chest computed tomography (CT), enhanced magnetic resonance imaging (MRI) of the skull, and examination of critical organs such as the liver and bone. Efficacy was evaluated 3 weeks after systemic therapy in both groups. Patients with the response or stable disease (SD) underwent a comprehensive evaluation every 8 weeks. Efficacy was assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1 (StataCorp, College Station, TX, USA), as complete response (CR), partial response (PR), SD, or progressive disease (PD). The response rate (RR) included CR and PR. The disease‑control rate (DCR) included CR, PR, and SD. Drug‑related toxicity was graded according to the National Cancer Institute toxicity classification standard version 3.0.[15] Follow‑up and survival analysis The primary endpoint was the cumulative incidence of brain metastasis, whereas the secondary endpoint was overall survival (OS). Brain metastasis was assessed according to clinical signs and symptoms, and was confirmed by CT, MRI, or pathology. The time from diagnosis of lung adenocarcinoma to brain metastasis (here after referred to as the time to brain metastasis occurrence) was measured in months, from the day when lung adenocarcinoma was accurately diagnosed to the day when brain metastasis was diagnosed, with 30 days being considered as 1 month. OS was calculated as the time from the 1st day of treatment until death or the last outpatient follow‑up visit. Follow‑up was conducted from the day of treatment and was continued despite PD‑related therapy termination. OS of patients who neither progressed nor died by the last day of follow‑upon (May 1, 2013) was assessed as per the last tumor evaluation.
Journal of Cancer Research and Therapeutics - Volume 10 - Special Issue 2- 2014
Zhao, et al.: icotinib vs chemotherapy for brain metastasis
Statistical analysis All data were analyzed using Stata12.0 software (StataCorp, College Station, TX, USA). Baseline characteristics between groups were compared using the Chi‑square test or Fisher’s exact test. The Kaplan–Meier method and log‑rank test were used for survival analysis. The cumulative risk of brain metastasis was estimated using the cumulative incidence curve. Death without brain metastasis was used as a competitive risk for calculating the cumulative risk of brain metastasis. P
