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Jen-Fu Shih a ... a Department of Chest Medicine, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC.
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ScienceDirect Journal of the Chinese Medical Association 76 (2013) 682e685 www.jcma-online.com

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 Wen-Shuo Wu a, Yuh-Min Chen a,*, Chun-Ming Tsai a, Jen-Fu Shih a, Yu-Chin Lee a, Reury-Perng Perng a, Jacqueline Whang-Peng b a

Department of Chest Medicine, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC b Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan, ROC Received January 10, 2013; accepted April 22, 2013

Abstract Background: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective against tumor EGFR-mutated non-small cell lung cancer (NSCLC). Patients with the tumor EGFR-activating mutation (EGFRmu) had superior survival, compared to patients with EGFR wild-type tumors (EGFRwt). Many patients with the EGFRmu have had disease progression with EGFR-TKI treatment because of central nervous system (CNS) metastases. The objective of this retrospective study was to compare the causes of death in patients with a known tumor EGFR mutation status who had been treated with EGFR-TKIs. Methods: We retrospectively reviewed the chart records of our patients with advanced NSCLC who had received diagnosis, treatment, and supportive and hospice care in our hospital between July 2005 and June 2010. The tumor EGFR mutation status was analyzed by using a DNA sequence method. All enrolled patients had a documented cause of death. Results: Ninety-four patients had documented tumor EGFR data, had received EGFR-TKI treatment (either erlotinib or gefitinib), and were with or without previous or salvage systemic chemotherapy. Of the 94 patients, 36 patients had EGFRwt and 58 patients had EGFRmu. The overall patient survival after starting EGFR-TKI treatment was significantly longer in the EGFRmu patients (median 17.2 months) than in the EGFRwt patients (median 11.6 months; p ¼ 0.0058). Twenty-nine patients died of CNS metastases and 65 died of organ failure (other than the CNS). Patients who died of CNS metastases had undergone EGFR-TKI treatment significantly longer than patients who died of other organ failure (median, 8 months vs. 1.9 months; p ¼ 0.0003) with a hazard ratio of 2.308 [95% confidence interval (C.I.), 1.452e3.668; p ¼ 0.0004]. A significantly higher proportion of EGFRmu patients (26 of 58 patients; 44.8%) than EGFRwt patients (3 of 36 patients; 8.3%) ( p < 0.001) died of CNS metastases. Conclusion: The EGFRmu NSCLC patients survived longer and had a significantly higher probability of mortality due to CNS metastases, compared to the EGFRwt patients. This change in the causes of death was noted after the era of EGFR-TKI treatment, and will have an important impact on the strategies and management of supportive and hospice care for patients. Copyright Ó 2013 Elsevier Taiwan LLC and the Chinese Medical Association. All rights reserved. Keywords: adenocarcinoma; epidermal growth factor receptor; tyrosine kinase inhibitor

1. Introduction

* Corresponding author. Dr. Yuh-Min Chen, Department of Chest Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan, ROC. E-mail address: [email protected] (Y.-M. Chen).

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 1e2

1726-4901/$ - see front matter Copyright Ó 2013 Elsevier Taiwan LLC and the Chinese Medical Association. All rights reserved. http://dx.doi.org/10.1016/j.jcma.2013.08.006

W.-S. Wu et al. / Journal of the Chinese Medical Association 76 (2013) 682e685

years. Conventional cytotoxic chemotherapy is associated with a response rate of 20e35% and a median survival time of 10e12 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.10e12 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 EGFRTKI. 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. 167e77). 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 18e21 of the EGFR gene. Genomic DNA was extracted from paraffin blocks, exons 18e21 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,

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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 EGFRTKI 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. The overall survival after starting EGFR-TKI treatment was significantly longer for patients with the EGFRmu than for

Table 1 Clinical characteristics of the 94 patients.

Patient, n (%) Sex Male Female Age, mean (range) Median duration of EGFR-TKI treatment, mo. (range) Median survival time, mo. (range) Cause of death CNS metastasis Non-CNS metastasis

Patients with EGFRmua

Patients with EGFRwt

Total

58 (61.7)

36 (38.3)

94

25 33 60.8 (32e85) 6.5 (0.1e35.1)

17 19 60.1 (36e87) 1.4 (0.2e9.9)

42 52 60.5 (32e87) 3.2 (0.1e35.1)

17.2 (0.5e78.5) 11.6 (1.6e47.6) 15.3 (0.5e78.5)

26 32

3 33

29 65

CNS ¼ central nervous system; EGFR ¼ epidermal growth factor receptor; EGFRmu ¼ EGFR-activating mutation; EGFRwt ¼ EGFR wild-type tumor; TKI ¼ tyrosine kinase inhibitor. a Includes 36 patients with exon 19 deletions and 22 patients with exon 21 L858R.

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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 ¼ 0.0058).

patients with EGFRwt (median, 17.2 months vs. 11.6 months, respectively; p ¼ 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 ¼ 0.0003) with a hazard ratio of 2.308 (95% C.I. 1.452e3.668; p ¼ 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). 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 EGFRTKI 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.15e17 The high incidence of CNS metastases in EGFR-TKItreated 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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References 1. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92e8. 2. Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, et al. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol 2007;18:317e23. 3. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947e57. 4. Morita S, Okamoto I, Kobayashi K, Yamazaki K, Asahina H, Inoue A, et al. Combined survival analysis of prospective clinical trials of gefitinib for non-small cell lung cancer with EGFR mutations. Clin Cancer Res 2009;15:4493e8. 5. Jackman DM, Miller VA, Cioffredi LA, Yeap BY, Ja¨nne PA, Riely GJ, et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin Cancer Res 2009;15:5267e73. 6. Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361:958e67. 7. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010;11:121e8. 8. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizmi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380e8. 9. Wu WS, Chen YM, Tsai CM, Shih JF, Chiu CH, Chou KT, et al. Erlotinib has better efficacy than gefitinib in adenocarcinoma patients without EGFR-activating mutations, but similar efficacy in patients with EGFRactivating mutations. Exp and Ther Med 2012;3:207e13. 10. Omuro AM, Kris MG, Miller VA, Franceschi E, Shah N, Milton DT, et al. High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer 2005;103:2344e8. 11. Eichler AF, Kahle KT, Wang DL, Joshi VA, Willers H, Engelman JA, et al. EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer. Neuro Oncol 2010;12:1193e9. 12. Heon S, Yeap BY, Britt GJ, Costa DB, Rabin MS, Jackman DM, et al. Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib. Clin Cancer Res 2010;16:5873e82. 13. Penel N, Brichet A, Prevost B, Duhamel A, Assaker R, Dubois F, et al. Prognostic factors of synchronous brain metastases from lung cancer. Lung Cancer 2001;33:143e54.

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14. Kim DY, Lee KW, Yun T, Park SR, Jung JY, Kim DW, et al. Comparison of intrathecal chemotherapy for leptomeningeal carcinomatosis of a solid tumor: methotrexate alone versus methotrexate in combination with cytosine arabinoside and hydrocortisone. Jpn J Clin Oncol 2003;33:608e12. 15. Park JH, Kim YJ, Lee JO, Lee KW, Kim JH, Bang SM, et al. Clinical outcomes of leptomeningeal metastasis in patients with non-small cell lung cancer in the modern chemotherapy era. Lung Cancer 2012;76:387e92. 16. Morris PG, Reiner AS, Szenberg OR, Clarke JL, Panageas KS, Perez HR, et al. Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy. J Thorac Oncol 2012;7:382e5. 17. Chen YM, Chen MC, Tsai CM, Perng RP. Intrathecal gemcitabine chemotherapy for non-small cell lung cancer patients with meningeal carcinomatosisda case report. Lung Cancer 2003;40:99e101. 18. Fan WC, Yu CJ, Tsai CM, Huang MS, Lai CL, Hsia TC, et al. Different efficacies of erlotinib and gefitinib in Taiwanese patients with advanced non-small cell lung cancer: a retrospective multicenter study. J Thorac Oncol 2011;6:148e55. 19. Yi HG, Kim HJ, Kim YJ, Han SW, Oh DY, Lee SH, et al. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for leptomeningeal metastasis from non-small cell lung cancer patients with sensitive EGFR mutation or other predictive factors of good response for EGFR TKI. Lung Cancer 2009;65:80e4. 20. Clarke JL, Pao W, Wu N, Miller VA, Lassman AB. High-dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J Neurooncol 2010;99:283e6. 21. Grewal J, Saria MG, Kesari S. Novel approaches to treating leptomeningeal metastases. J Neurooncol 2012;106:225e34. 22. Chuang TY, Yu CJ, Shih JY, Yang PC, Kuo SH. Cytologically proven meningeal carcinomatosis in patients with lung cancer: clinical observation of 34 cases. J Formos Med Assoc 2008;107:851e6. 23. Kim HJ, Kim YJ, Seo MD, Yi HG, Lee SH, Lee SM, et al. Patterns of palliative procedures and clinical outcomes in patients with advanced nonsmall cell lung cancer. Lung Cancer 2009;65:242e6. 24. Chen YM, Shih JF, Yang KY, Lee YC, Perng RP. Usefulness of pig-tail catheter for palliative drainage of malignant pleural effusions in cancer patients. Support Care Cancer 2000;8:423e6. 25. Gompelmann D, Eberhardt R, Herth FJ. Advanced malignant lung disease: what the specialist can offer. Respiration 2011;82:111e23. 26. Radha Krishna LK, Poulose JV, Tan BS, Goh C. Opioid use amongst cancer patients at the end of life. Ann Acad Med Singapore 2010;39:790e7. 27. Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, et al. Early palliative care for patients with metastatic nonsmall-cell lung cancer. N Engl J Med 2010;363:733e42. 28. Mitka M. Cancer experts recommend introducing palliative care at time of diagnosis. JAMA 2012;307:1241e2.