The epidermal growth factor receptor-tyrosine kinase inhibitor era has changed the causes of death of patients with advanced non-small-cell lung cancer : Journal of the Chinese Medical Association

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Original Article

The epidermal growth factor receptor-tyrosine kinase inhibitor era has changed the causes of death of patients with advanced non-small-cell lung cancer

Wu, Wen-Shuoa; Chen, Yuh-Mina,*; Tsai, Chun-Minga; Shih, Jen-Fua; Lee, Yu-China; Perng, Reury-Pernga; Whang-Peng, Jacquelineb

Author Information
Journal of the Chinese Medical Association: December 2013 - Volume 76 - Issue 12 - p 682-685
doi: 10.1016/j.jcma.2013.08.006


    1. Introduction

    Lung cancer is the leading cause of cancer mortality worldwide. Only a few patients with lung cancer present with early-stage disease that is suitable for surgical treatment. Most patients are diagnosed with metastatic and advanced disease and have a dismal prognosis that seldom reaches beyond 1–2 years. Conventional cytotoxic chemotherapy is associated with a response rate of 20–35% and a median survival time of 10–12 months among patients with advanced non-small cell lung cancer (NSCLC).1,2 The epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) improve the survival of lung cancer patients as a second-line or third-line therapy. A selective patient profile that included female gender, nonsmoker or light smoker, East Asian ethnicity, and adenocarcinoma was more beneficial than other profiles.3 Pooled analyses in different areas suggest particularly promising results with EGFR-TKI therapy among patients harboring EGFR mutations.4,5 The discovery of a mutation in the tyrosine kinase domain of the EGFR in NSCLC represents a dramatic step in developing a treatment strategy for lung cancer. Large-scale screenings for EGFR mutations have had a great influence on decision-making in regard to treatment.6 Recently reported prospective trials further define the role of EGFR-TKIs as a first-line therapy.7,8 Patients with a tumor with a EGFR-activating mutation (EGFRmu; i.e., exon 19 deletions or exon 21 L958R) had better survival than patients with EGFR wild-type tumors (EGFRwt).4,9 The optimal use of EGFR-TKIs to prolong the survival of patients with NSCLC is gradually coming into focus.

    An increased risk of central nervous system (CNS) metastasis such as leptomeningeal carcinomatosis (LM) has been reported among patients who achieved disease control with gefitinib or erlotinib.10–12 This has changed the cause of mortality from lung cancer, which was previously characterized primarily as respiratory failure. The purpose of this study was to evaluate the influence of EGFR-TKIs on the cause of death in patients with advanced NSCLC whose tumor EGFR mutation status is known and who were treated with EGFR-TKI.

    2. Methods

    We retrospectively reviewed the chart records of our patients with advanced NSCLC who had received diagnosis, treatment, supportive care, and hospice care in our hospital between July 2005 and June 2010. This study was approved by our Institutional Review Board (VGHIRB 2011-04-0151A). The patients were all documented as deceased prior to our data review. The tumor EGFR mutation status was analyzed by using a DNA sequence method. Lung cancer staging was evaluated in accordance with the sixth edition of the tumor node metastasis staging system for NSCLC (AJCC Cancer Staging Manual 6th edition; Chapter 19; p. 167–77).

    Analysis for the EGFR mutation was performed with nucleotide sequence analysis. The VariantSEQr Resequencing Primer Set (Life Technologies CO., Ltd., New York, USA) was selected for the mutational analysis of the tyrosine kinase domain and exons 18–21 of the EGFR gene. Genomic DNA was extracted from paraffin blocks, exons 18–21 were amplified, and uncloned polymerase chain reaction fragments were sequenced and analyzed (in the sense and antisense directions) for the presence of heterozygous mutations. Normal control DNA provided by the ABI Company (Columbia, MD, USA) was used for the wild-type control. All sequence variations were confirmed by multiple independent polymerase chain reaction amplifications and repeated sequencing reactions. The EGFR-activating mutations were defined as mutations with exon 19 deletions or exon 21 L858R.

    Survival was measured from the date of initiating EGFR-TKI treatment (with erlotinib or gefitinib) to the date of death or last follow-up examination. A CNS death was attributed to CNS progression, which resulted in the worsening of neurological symptoms. Extracranial diseases were in a stable condition, according to the medical records. Death unrelated to CNS metastases was attributed to extracranial metastases that caused a target organ failure-related death.

    The Kaplan-Meier method with a log-rank test and the Cox proportional hazard model were used for statistical analysis of survival. All statistical analyses were performed by using SPSS software (version 19) (SPSS Inc., Chicago, IL, USA).

    3. Results

    Ninety-four patients had documented tumor EGFR data, had received EGFR-TKI treatment, and were with or without previous or salvage chemotherapy. All patients were deceased prior to our data review. Of this group, 36 had EGFRwt and 58 had EGFRmu; 42 patients were male and 52 were female. The mean age of the entire study population was 60.5 years. Thirty-six (62%) patients had an exon 19 deletion and 22 (38%) patients had exon 21 L858R point mutations. Of the patients with EGFRmu who died of CNS metastases, 17 (65.3%) patients had additional LM detected by brain MRI examinations. All three (100%) patients with EGFRwt who died of CNS metastases also had LM. Table 1 shows the clinical characteristics of the patients.

    Table 1:
    Clinical characteristics of the 94 patients.

    The overall survival after starting EGFR-TKI treatment was significantly longer for patients with the EGFRmu than for patients with EGFRwt (median, 17.2 months vs. 11.6 months, respectively; p = 0.0058; Fig. 1). Twenty-nine patients died of CNS metastases and 65 patients died of organ failure (other than the CNS). Patients who died of CNS metastases had received EGFR-TKI treatment significantly longer than patients who died of other organ failure (median 8 months vs. 1.9 months, respectively; p = 0.0003) with a hazard ratio of 2.308 (95% C.I. 1.452–3.668; p = 0.0004). Only 3 of the 36 patients with EGFRwt died of CNS metastases. A significantly higher proportion of EGFRmu patients (26 of 58; 44.8%) died of CNS metastases, compared to EGFRwt patients (3 of 36; 8.3%; p < 0.001).

    Fig. 1:
    The survival curve of all 94 patients who received EGFR-TKI with and without EGFR mutation (median 17.2 months vs. 11.6 months; p = 0.0058).

    4. Discussion

    According to our results, patients with the EGFRmu who received EGFR-TKI treatment had a longer survival compared to patients with EGFRwt who received the same treatment. The cause of mortality was also different between patients with EGFRmu and patients with EGFRwt. The CNS is a frequent site of disease progression or recurrence in patients with NSCLC, even in patients who are responsive to EGFR-TKI treatment such as gefitinib.10 This is a major problem during the terminal stage of NSCLC because of the severe impact on the patients' quality of life.13 LM, one manifestation of CNS metastasis, is a difficult disease to treat. In the literature, major favorable prognostic factors of LM include a good Eastern Cooperative Oncology performance status, the absence of serious fixed neurologic deficits, normal cerebrospinal fluid flow scans, and absent or responsive systemic disease.14 Management options for LM, other than palliative measures, are limited and include intrathecal chemotherapy or whole brain and/or spinal axis irradiation, all of which usually do not prolong patient survival.15–17

    The high incidence of CNS metastases in EGFR-TKI-treated EGFRmu patients may be caused by the incomplete penetration of TKI into the CNS; this may result in brain metastases or even LM.18,19 Several studies demonstrate that the concentration of gefitinib was low in the CNS, when using the standard dose treatment.18,19 Increasing the dose of gefitinib in a subset of EGFRmu NSCLC patients can treat or prevent metastatic CNS disease.19 Other studies also report favorable results for gefitinib-treated patients with CNS progression that was salvaged with erlotinib treatment, probably because of the higher serum erlotinib concentrations and better CSF penetration than with gefitinib.18,20

    When patients experience disease progression with CNS metastasis or LM, they frequently suffer from headache, vomiting, memory loss, seizures, multiple neurological and sensory impairments such as diplopia, tinnitus, vertigo, hearing impairment; and vision loss. They finally became comatose. Higher doses or pulse therapy with EGFR-TKI has been tried20 and intrathecal chemotherapy has been tried for meningeal carcinomatosis.17,21,22 Whole brain radiation therapy also plays an important role in treating this kind of patient. However, the absolute benefit of whole brain radiotherapy for patients in the terminal stage of NSCLC who have CNS failure remains undetermined.16,22,23 Medical treatments with steroid and glycerol may also have only short-term effects. Patients with LM or hydrocephalus sometimes may need cerebrospinal fluid drainage for intracranial pressure release.

    Patients who died of extra-CNS failure died primarily because of respiratory failure. Profound metastasis in the lung parenchyma, central airway obstruction, and severe hemoptysis may lead to respiratory failure. Some palliative therapy regimens can be administered to relieve symptoms with the objective of enhancing the quality of life of patients in the terminal stage of lung cancer. Repeated drainage with thoracentesis or pleurodesis may be helpful in improving symptoms in patients with massive effusion or symptomatic pleural effusion.24,25 Malignant pericardial effusion is also a detrimental condition that may develop into cardiac tamponade. Urgent intervention is consequently required to provide rapid relief of symptoms. Severe bone pain, visceral pain, or neuropathy may have a great impact on a patient's quality of life. Opioids are useful and safe medications for terminally ill patients who experience severe pain and dyspnea during their last days.26

    It has been suggested that integrating palliative care with standard oncologic care earlier in the management of patients with advanced lung cancer improves the quality of life and mood.27,28 The change in the causes of death after an era of EGFR-TKI treatment will impact the strategies and management of supportive and hospice care for patients. A multidisciplinary approach for the palliative care needs of patients with CNS metastases is becoming more apparent and necessary as each new day passes.


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    adenocarcinoma; epidermal growth factor receptor; tyrosine kinase inhibitor

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