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Long-term survival in three patients with metastatic non-small cell lung cancer treated with gefitinib
Lung Cancer (2006) 52, 253—255
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/lungcan
CASE STORY
Long-term survival in three patients with metastatic non-small cell lung cancer treated with gefitinib Katsumi Nakatomi a,b, Hiroshi Soda b,∗, Takeshi Kitazaki b, Hirofumi Nakano b, Kanako Uchida c, Sou Urabe c, Yoichi Nakamura b, Tomayoshi Hayashi d, Kazuhiro Tsukamoto c, Shigeru Kohno b a
Internal Medicine, Nagasaki Prefectural Shimabara Hospital, Shimabara 855-0861, Japan Second Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan c Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8521, Japan d Department of Pathology, Nagasaki University Hospital, Nagasaki 852-8501, Japan b
Received 5 December 2005; accepted 10 January 2006
KEYWORDS Epidermal growth factor; Molecular-targeted therapy; Lung cancer; Survival
Summary Gefitinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), produces radiographic regression and symptom relief in patients with refractory advanced nonsmall cell lung cancer. However, it remains controversial whether gefitinib improves patient survival. We report three cases of refractory metastatic non-small cell lung cancer who have survived approximately 3 years since they first started gefitinib. These long-term survivors were Japanese female non-smokers with adenocarcinoma, who often had multiple lung metastases and were effectively re-treated with gefitinib. One patient had a surgical specimen available for DNA extraction and showed deletions in exon 19 of EGFR. Our experience suggests that gefitinib may improve long-term survival in selected patients. Further studies are required to identify biomarkers downstream of the EGFR mutations that are involved in multiple lung metastases and which could identify those patients who may benefit from gefitinib re-treatment. © 2006 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The overactivation of epidermal growth factor receptor (EGFR) is involved in proliferation and survival of cancer cells. Gefitinib, a selective EGFR tyrosine kinase
∗ Corresponding author. Tel.: +81 95 849 7274; fax: +81 95 849 7285. E-mail address: [email protected] (H. Soda).
inhibitor, produces radiographic regression and symptom relief in patients with refractory advanced non-small cell lung cancer (NSCLC). The anti-tumor activity is more frequently seen in female non-smokers with adenocarcinoma that appears to be associated with certain mutations in the tyrosine kinase domain of EGFR [1]. However, it remains controversial whether gefitinib improves survival of patients with advanced NSCLC [2]. Here, we report three cases of refractory metastatic NSCLC who have survived for approximately 3 years since the start of gefitinib treatment.
0169-5002/$ — see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2006.01.008
254
2. Case report
K. Nakatomi et al. and her pulmonary lesions again regressed. She is alive 3 years and 1 month since she first took gefitinib.
2.1. Case 1 2.3. Case 3 A 52-year-old Japanese female non-smoker was admitted to hospital because of a lung nodule detected on populationbased radiological screening. She underwent right upper lobectomy for stage I lung adenocarcinoma. Five years after the operation, multiple bilateral lung metastases developed, which were diagnosed by video-associated thoracic surgery. After DNA extraction from paraffin-embedded surgical specimens of the lung metastatic nodules, deletions in exon 19 of EGFR were detected by the polymerase chain reaction (PCR) method, but the missense mutation of L858R in exon 21 was not detected by the PCR-restriction fragment length polymorphism method. The patient was given three courses of carboplatin and irinotecan followed by two courses of paclitaxel, but no response was observed. Eighteen months after the first chemotherapy, she began to take gefitinib (250 mg daily), and a partial response was achieved. (Fig. 1). The response lasted for 2 years and 11 months. Thereafter, lung metastases progressed again, and treatment with gefitinib was discontinued. She has subsequently received chemotherapy, including docetaxel, and has survived for 3 years and 4 months since she first took gefitinib.
2.2. Case 2 A 54-year-old Japanese female non-smoker presented to the hospital complaining of persistent right chest pain. A chest radiograph showed a nodular lesion in the right upper lung lobe. Lung adenocarcinoma was cytologically diagnosed by transbronchial brushing, and a systemic survey revealed stage IV disease with multiple liver and bone metastases. She received one course of cisplatin and irinotecan followed by one course of carboplatin and docetaxel, but no response was observed. Three months after diagnosis, she started treatment with gefitinib (250 mg daily), and partial response was achieved. Nine months later, the patient’s bone metastases and pleural effusion progressed. Treatment with gefitinib was interrupted for 2 months. After radiotherapy for the bone lesions, re-treatment with gefitinib was initiated,
A 79-year-old Japanese female non-smoker was referred to the hospital because of multiple bilateral lung nodules on a chest radiograph. She was diagnosed as having lung adenocarcinoma by transbronchial biopsy. A systemic survey revealed stage IV disease with lung and brain metastases. She received stereotactic radiosurgery for the brain lesions and systemic chemotherapy, including two courses of carboplatin and irinotecan, but the pulmonary lesions progressed. Three months after the diagnosis was made, she was treated with gefitinib (250 mg daily), and partial response was obtained. One year and 4 months after starting gefitinib, the patient’s liver dysfunction worsened and she developed bone metastases. Treatment with gefitinib was interrupted for 5 months. After radiotherapy for the bone lesions, the patient was re-treated with gefitinib because her brain lesions had increased in size; with treatment the lesions again regressed. The patient is alive for 2 years and 8 months since she first took gefitinib.
3. Discussion We report three cases of refractory metastatic NSCLC who have survived for approximately 3 years since they first took gefitinib. Based on the results of a phase III trial of docetaxel and pemetrexed, patients with refractory advanced NSCLC rarely survive more than 2 years after the start of secondline chemotherapy [3]. However, after treatment with gefitinib, the long-term survivors presented in this report had a partial response and disease control was achieved. Thus, the long-term survival of the patients in the current report may be attributed to treatment with gefitinib and control of metastatic lesions. All of the long-term survivors were female non-smokers with adenocarcinoma. It is known that responsiveness to gefitinib in NSCLC varies among patients, with a higher response rate observed in Asian females, non-smokers, and those with adenocarcinoma [1]. EGFR mutations are more
Fig. 1 (A) Bilateral multiple lung nodules seen before treatment with gefitinib. (B) Remarkable improvement of nodules 1 month after treatment with gefitinib.
Long-term survivals treated with gefitinib frequently detected in those who have a clinical response to gefitinib [1]. Approximately 90% of EGFR mutations comprise either deletions in exon 19 or a missense mutation of L858R in exon 21. Although a phase III trial did not demonstrate a survival benefit of gefitinib in patients with refractory NSCLC [2], several studies suggest that EGFR mutations are predictive of a prolonged survival in patients treated with gefitinib [4—6]. In the current report, long-term survivors had multiple lung metastases. Although a response to gefitinib is more often observed in patients with this metastatic pattern [7], its association with EGFR mutations has not been investigated in detail. One patient with multiple lung metastases had a surgical specimen available for DNA extraction, which showed deletions in exon 19 of EGFR. In our concurrent screening of lung adenocarcinoma specimens, three other cases of multiple lung metastases also showed deletions of exon 19 (unpublished data). A recent study reveals that the EGFR signaling pathway activates the chemokine receptor of CXCR4, which might be responsible for lung metastases [8]. Further investigation into how EGFR mutations are implicated in multiple lung metastases is needed. Unfortunately, even in gefitinib responders, disease progression is inevitable and occurs within 1 year of therapy. Little is known about the mechanisms of acquired resistance to gefitinib. However, re-treatment with gefitinib is known to be effective in some patients who develop recurrence after successful treatment with gefitinib [9]. In two cases presented here, re-treatment with gefitinib led to tumor regression and long-term survival. Resistance to gefitinib might be, at least in part, acquired by the ability of the tumor cells to utilize alternative growth factor pathways in the presence of gefitinib, as well to restore the EGFR pathway in the absence of gefitinib. We reported three cases of metastatic lung cancer who survived for approximately 3 years since they first took gefitinib. All were Japanese female non-smokers with adenocarcinoma. Of note, multiple lung metastases, effective re-treatment with gefitinib, and exon 19 deletions of EGFR were observed. Our experience suggests that gefitinib may result in long-term survival in selected patients. Further studies are required to identify biomarkers downstream of the EGFR mutations which are involved in multiple lung
255 metastases and which could identify those patients who may benefit from gefitinib re-treatment.
References [1] Pao W, Miller VA. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol 2005;23:556—68. [2] Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomized, placebo-controlled, multicentre study (Iressa survival evaluation in lung cancer). Lancet 2005;366:1527—37. [3] Hanna N, Shephered FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589—97. [4] Mitsudomi T, Kosaka T, Endoh H, Horio Y, Hida T, Mori S, et al. Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol 2005;23:2513—20. [5] Han S, Kim T, Hwang PG, Jeong S, Kim J, Choi IS, et al. Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 2005;23:2493—501. [6] Takano T, Ohe Y, Sakamoto H, Tsuta K, Matsuno Y, Tateishi U, et al. Epidermal growth factor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol 2005;23:6829—37. [7] Goto K, Kim YH, Kubota K, Niho S, Kakinuma H, Ohmatsu K, et al. Association of multiple pulmonary metastases with response to gefitinib in patients with non-small cell lung cancer. Proc Am Soc Clin Oncol 2004:22 [abstract #7098]. [8] Phillips RJ, Mestas J, Gharaee-Kermani M, Burdick MD, Sica A, Belperio JA, et al. Epidermal growth factor and hypoxiainduced expression of CXC chemokine receptor 4 on non-small cell lung cancer cells is regulated by the phosphatidylinositol 3-kinase/PTEN/AKT/mammarian target of rapamycin signaling pathway and activation of hypoxia inducible factor-1 alpha. J Biol Chem 2005;280:22473—81. [9] Kurata T, Tamura K, Kaneda H, Nogami T, Uejima H, Asai G, et al. Effect of re-treatment with gefitinib (‘Iressa’, ZD1839) after acquisition of resistance. Ann Oncol 2004;15:173—7.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/lungcan
CASE STORY
Long-term survival in three patients with metastatic non-small cell lung cancer treated with gefitinib Katsumi Nakatomi a,b, Hiroshi Soda b,∗, Takeshi Kitazaki b, Hirofumi Nakano b, Kanako Uchida c, Sou Urabe c, Yoichi Nakamura b, Tomayoshi Hayashi d, Kazuhiro Tsukamoto c, Shigeru Kohno b a
Internal Medicine, Nagasaki Prefectural Shimabara Hospital, Shimabara 855-0861, Japan Second Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan c Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8521, Japan d Department of Pathology, Nagasaki University Hospital, Nagasaki 852-8501, Japan b
Received 5 December 2005; accepted 10 January 2006
KEYWORDS Epidermal growth factor; Molecular-targeted therapy; Lung cancer; Survival
Summary Gefitinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), produces radiographic regression and symptom relief in patients with refractory advanced nonsmall cell lung cancer. However, it remains controversial whether gefitinib improves patient survival. We report three cases of refractory metastatic non-small cell lung cancer who have survived approximately 3 years since they first started gefitinib. These long-term survivors were Japanese female non-smokers with adenocarcinoma, who often had multiple lung metastases and were effectively re-treated with gefitinib. One patient had a surgical specimen available for DNA extraction and showed deletions in exon 19 of EGFR. Our experience suggests that gefitinib may improve long-term survival in selected patients. Further studies are required to identify biomarkers downstream of the EGFR mutations that are involved in multiple lung metastases and which could identify those patients who may benefit from gefitinib re-treatment. © 2006 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The overactivation of epidermal growth factor receptor (EGFR) is involved in proliferation and survival of cancer cells. Gefitinib, a selective EGFR tyrosine kinase
∗ Corresponding author. Tel.: +81 95 849 7274; fax: +81 95 849 7285. E-mail address: [email protected] (H. Soda).
inhibitor, produces radiographic regression and symptom relief in patients with refractory advanced non-small cell lung cancer (NSCLC). The anti-tumor activity is more frequently seen in female non-smokers with adenocarcinoma that appears to be associated with certain mutations in the tyrosine kinase domain of EGFR [1]. However, it remains controversial whether gefitinib improves survival of patients with advanced NSCLC [2]. Here, we report three cases of refractory metastatic NSCLC who have survived for approximately 3 years since the start of gefitinib treatment.
0169-5002/$ — see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2006.01.008
254
2. Case report
K. Nakatomi et al. and her pulmonary lesions again regressed. She is alive 3 years and 1 month since she first took gefitinib.
2.1. Case 1 2.3. Case 3 A 52-year-old Japanese female non-smoker was admitted to hospital because of a lung nodule detected on populationbased radiological screening. She underwent right upper lobectomy for stage I lung adenocarcinoma. Five years after the operation, multiple bilateral lung metastases developed, which were diagnosed by video-associated thoracic surgery. After DNA extraction from paraffin-embedded surgical specimens of the lung metastatic nodules, deletions in exon 19 of EGFR were detected by the polymerase chain reaction (PCR) method, but the missense mutation of L858R in exon 21 was not detected by the PCR-restriction fragment length polymorphism method. The patient was given three courses of carboplatin and irinotecan followed by two courses of paclitaxel, but no response was observed. Eighteen months after the first chemotherapy, she began to take gefitinib (250 mg daily), and a partial response was achieved. (Fig. 1). The response lasted for 2 years and 11 months. Thereafter, lung metastases progressed again, and treatment with gefitinib was discontinued. She has subsequently received chemotherapy, including docetaxel, and has survived for 3 years and 4 months since she first took gefitinib.
2.2. Case 2 A 54-year-old Japanese female non-smoker presented to the hospital complaining of persistent right chest pain. A chest radiograph showed a nodular lesion in the right upper lung lobe. Lung adenocarcinoma was cytologically diagnosed by transbronchial brushing, and a systemic survey revealed stage IV disease with multiple liver and bone metastases. She received one course of cisplatin and irinotecan followed by one course of carboplatin and docetaxel, but no response was observed. Three months after diagnosis, she started treatment with gefitinib (250 mg daily), and partial response was achieved. Nine months later, the patient’s bone metastases and pleural effusion progressed. Treatment with gefitinib was interrupted for 2 months. After radiotherapy for the bone lesions, re-treatment with gefitinib was initiated,
A 79-year-old Japanese female non-smoker was referred to the hospital because of multiple bilateral lung nodules on a chest radiograph. She was diagnosed as having lung adenocarcinoma by transbronchial biopsy. A systemic survey revealed stage IV disease with lung and brain metastases. She received stereotactic radiosurgery for the brain lesions and systemic chemotherapy, including two courses of carboplatin and irinotecan, but the pulmonary lesions progressed. Three months after the diagnosis was made, she was treated with gefitinib (250 mg daily), and partial response was obtained. One year and 4 months after starting gefitinib, the patient’s liver dysfunction worsened and she developed bone metastases. Treatment with gefitinib was interrupted for 5 months. After radiotherapy for the bone lesions, the patient was re-treated with gefitinib because her brain lesions had increased in size; with treatment the lesions again regressed. The patient is alive for 2 years and 8 months since she first took gefitinib.
3. Discussion We report three cases of refractory metastatic NSCLC who have survived for approximately 3 years since they first took gefitinib. Based on the results of a phase III trial of docetaxel and pemetrexed, patients with refractory advanced NSCLC rarely survive more than 2 years after the start of secondline chemotherapy [3]. However, after treatment with gefitinib, the long-term survivors presented in this report had a partial response and disease control was achieved. Thus, the long-term survival of the patients in the current report may be attributed to treatment with gefitinib and control of metastatic lesions. All of the long-term survivors were female non-smokers with adenocarcinoma. It is known that responsiveness to gefitinib in NSCLC varies among patients, with a higher response rate observed in Asian females, non-smokers, and those with adenocarcinoma [1]. EGFR mutations are more
Fig. 1 (A) Bilateral multiple lung nodules seen before treatment with gefitinib. (B) Remarkable improvement of nodules 1 month after treatment with gefitinib.
Long-term survivals treated with gefitinib frequently detected in those who have a clinical response to gefitinib [1]. Approximately 90% of EGFR mutations comprise either deletions in exon 19 or a missense mutation of L858R in exon 21. Although a phase III trial did not demonstrate a survival benefit of gefitinib in patients with refractory NSCLC [2], several studies suggest that EGFR mutations are predictive of a prolonged survival in patients treated with gefitinib [4—6]. In the current report, long-term survivors had multiple lung metastases. Although a response to gefitinib is more often observed in patients with this metastatic pattern [7], its association with EGFR mutations has not been investigated in detail. One patient with multiple lung metastases had a surgical specimen available for DNA extraction, which showed deletions in exon 19 of EGFR. In our concurrent screening of lung adenocarcinoma specimens, three other cases of multiple lung metastases also showed deletions of exon 19 (unpublished data). A recent study reveals that the EGFR signaling pathway activates the chemokine receptor of CXCR4, which might be responsible for lung metastases [8]. Further investigation into how EGFR mutations are implicated in multiple lung metastases is needed. Unfortunately, even in gefitinib responders, disease progression is inevitable and occurs within 1 year of therapy. Little is known about the mechanisms of acquired resistance to gefitinib. However, re-treatment with gefitinib is known to be effective in some patients who develop recurrence after successful treatment with gefitinib [9]. In two cases presented here, re-treatment with gefitinib led to tumor regression and long-term survival. Resistance to gefitinib might be, at least in part, acquired by the ability of the tumor cells to utilize alternative growth factor pathways in the presence of gefitinib, as well to restore the EGFR pathway in the absence of gefitinib. We reported three cases of metastatic lung cancer who survived for approximately 3 years since they first took gefitinib. All were Japanese female non-smokers with adenocarcinoma. Of note, multiple lung metastases, effective re-treatment with gefitinib, and exon 19 deletions of EGFR were observed. Our experience suggests that gefitinib may result in long-term survival in selected patients. Further studies are required to identify biomarkers downstream of the EGFR mutations which are involved in multiple lung
255 metastases and which could identify those patients who may benefit from gefitinib re-treatment.
References [1] Pao W, Miller VA. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol 2005;23:556—68. [2] Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomized, placebo-controlled, multicentre study (Iressa survival evaluation in lung cancer). Lancet 2005;366:1527—37. [3] Hanna N, Shephered FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589—97. [4] Mitsudomi T, Kosaka T, Endoh H, Horio Y, Hida T, Mori S, et al. Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol 2005;23:2513—20. [5] Han S, Kim T, Hwang PG, Jeong S, Kim J, Choi IS, et al. Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 2005;23:2493—501. [6] Takano T, Ohe Y, Sakamoto H, Tsuta K, Matsuno Y, Tateishi U, et al. Epidermal growth factor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol 2005;23:6829—37. [7] Goto K, Kim YH, Kubota K, Niho S, Kakinuma H, Ohmatsu K, et al. Association of multiple pulmonary metastases with response to gefitinib in patients with non-small cell lung cancer. Proc Am Soc Clin Oncol 2004:22 [abstract #7098]. [8] Phillips RJ, Mestas J, Gharaee-Kermani M, Burdick MD, Sica A, Belperio JA, et al. Epidermal growth factor and hypoxiainduced expression of CXC chemokine receptor 4 on non-small cell lung cancer cells is regulated by the phosphatidylinositol 3-kinase/PTEN/AKT/mammarian target of rapamycin signaling pathway and activation of hypoxia inducible factor-1 alpha. J Biol Chem 2005;280:22473—81. [9] Kurata T, Tamura K, Kaneda H, Nogami T, Uejima H, Asai G, et al. Effect of re-treatment with gefitinib (‘Iressa’, ZD1839) after acquisition of resistance. Ann Oncol 2004;15:173—7.