- Email: [email protected]
Long-term survivors of more than 5 years in advanced non-small cell lung cancer
Lung Cancer 67 (2010) 120–123
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Long-term survivors of more than 5 years in advanced non-small cell lung cancer Kyoichi Kaira a , Toshiaki Takahashi a , Haruyasu Murakami a , Asuka Tsuya a , Yukiko Nakamura a , Tateaki Naito a , Masahiro Endo b , Nobuyuki Yamamoto a,∗ a b
Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan Division of Diagnostic Radiology, Shizuoka Cancer Center, 1007 Shimonagakubo Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan
a r t i c l e
i n f o
Article history: Received 19 January 2009 Received in revised form 13 March 2009 Accepted 17 March 2009 Keywords: Non-small cell lung cancer Long-term survivor Chemotherapy Molecular-targeted therapy Radiotherapy Multimodality
a b s t r a c t Background: The aim of this study is to evaluate the rate of long-term survival of more than 5 years in advanced non-small cell lung cancer (NSCLC). Methods: One-hundred and twenty-four patients with advanced NSCLC treated with chemotherapy from September 2002 to October 2003 were reviewed. Results: Ten (8%) patients survived for more than 5 years. The median survival time (MST) for the 10 patients was 61.5 months, ranging from 60.1 to 81.0 months. All of the 10 patients had performance status (PS) 0 or 1 and adenocarcinoma. As the initial treatment, 9 patients were treated with a platinumcontaining chemotherapy [median progressive free survival (PFS), 10.7 months] and 8 patients received gefitinib as the second or third line chemotherapy (median PFS, 28.7 months). Nine patients received cytotoxic agents after first line chemotherapy (median duration of the chemotherapy, 22.4 months). A mean regimen of chemotherapy was three (range, 1–8). Re-challenge of gefitinib was performed in 2 patients, and surgical resection of solitary brain metastasis was performed as the initial treatment in 2 patients. Conclusion: Our results suggest that good performance status, adenocarcinoma and EGFR-TKI therapy play an important role in the long-term survivors of more than 5 years. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer remains the most common cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancer patients [1]. Although surgery is the standard treatment, the tumor is inoperable at the time of diagnosis for the majority of patients with NSCLC. The meta-analysis of 16 randomized controlled trials have demonstrated that platinumbased chemotherapy may have a better potential for prolonging survival than the best supportive care for these patients [2]. Nowadays, doublet chemotherapies consisting of the platinum plus third-generation agent are currently the standard regimens and recommended as the first line chemotherapy [3]. However, the prognosis of patients with advanced NSCLC is still poor and recent phase III trials demonstrated a median survival time (MST) of from 8 to 10 months and 1-year survival rate of 30–35% [4]. In the several reports on long-term survivors among advanced NSCLC patients, only 4–6% of patients have been described to survive for more than 2 years [5–7]. Recently, some researchers
∗ Corresponding author. Tel.: +81 55 989 5222; fax: +81 55 989 5634. E-mail address: [email protected] (N. Yamamoto). 0169-5002/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2009.03.014
described that long-term survivors of pulmonary adenocarcinoma treated by gefitinib [8]. Approximately 70% of NSCLCs with epidermal growth factor receptor (EGFR) mutations respond to EGFR-tyrosine kinase inhibitors (TKIs), whereas only 10% of tumors without EGFR mutations respond to them [9]. Recent prospective phase II studies of gefitinib for patients with EGFR mutation demonstrated an objective response rate (RR) of 76.4%, a median progressive free survival (PFS) 9.7 months and MST of 24.3 months [10]. Thus, selected NSCLC patients may survive more than 2 years. However, there is still little detailed information about the clinical course of advanced NSCLC patients who survived more than 5 years. Here, we examined the clinical characteristics of advanced NSCLC patients who survived more than 5 years at our institution. 2. Material and methods Shizuoka Cancer Center was opened on September 2002. Between September 2002 and October 2003, 191 patients with primary lung cancer were treated at the Department of Thoracic Oncology of Shizuoka Cancer Center. One hundred seventy-four patients had NSCLC. Among them, 152 of NSCLC patients had advanced IIIB/IV disease and 124 received some kind of chemotherapy as the initial treatment. Sixty-four (51.6%) of 124 patients were treated by gefitinib.
61.5 81.0 67.3 73.6 75.1 61.2 60.1 60.2 60.1 61.5 6 2 5 6 6 8 2 1 3 6
Total regimens
13.0 4.3 21.2 5.4 44.1 47.0 25.6 – 22.4 24.7 18 3 20 4 18 23 23 – 4 19 36.0 63.1 40.2 17.1 3.6 10.2 – – 21.5 36.2 PR SD PR SD SD PR – – SD SD 6.5 9.3 7.1 25.4 19.2 3.0 35.2 12.2 12.3 3.0 PR SD SD SD PR SD SD SD SD SD CBDCA + PTX CDDP + GEM CBDCA + PTX CBDCA + GEM CDDP + GEM CBDCA + PTX CPT-11 CBDCA + PTX CBDCA + PTX CBDCA + PTX Positive Unknown Unknown Unknown Unknown Unknown Positive Unknown Unknown Unknown Yes No No No Yes Yes Yes Yes No No 1 0 0 0 0 1 0 0 0 0 IV IV IV IIIB IV IV IV IV IV IIIB 65/M 73/F 62/F 71/F 65/M 56/M 78/M 53/M 71/M 56/F 1 2 3 4 5 6 7 8 9 10
T4N1M1 T4N3M1 T2N3M1 T4N0M0 T2N3M1 T4N3M1 T4N0M1 T2N0M1 T4N3M1 T4N0M0
Total cycles PFS RR
PFS
Yes (brain) No Yes (brain) No No No No Yes (chest, brain) Yes (bone) No
Palliative radiation Cytotoxic agents Second line
Gefitinib PFS (month) RR
EGFR mutation Smoking history PS Stage TNM Age/sex
Table 1 Individual characteristics of the 10 patients with more than 5 years survival.
3.1. Long-term survivors of more than 5 years
No. of patients
3. Results
Fig. 1 is a survival curve of total 124 patients. The MST, 1-year, 2-year, 3-year, 4-year and 5-year survival rate were 11.3 months, 45%, 24%, 17%, 12% and 8%, respectively. Out of the 124 patients, 10 (6 men and 4 women) with a median age of 63 years (range, 53–78 years) survived for more than 5 years. The MST for the 10 patients was 61.5 months, ranging from 60.1 to 81.0 months. Table 1 shows the individual characteristics and survival status of the 10 patients. Patient’s characteristics are following: Performance status (PS), clinical stage and histology of the patients were as follows: 8 patients with PS 0; 2 patients with PS 1; 2 patients with stage IIIB; 8 patients with stage IV; 10 patients with adenocarcinoma. As the initial treatment, 9 patients were treated with a platinumcontaining chemotherapy. The response rate of first chemotherapy was 20% (partial response, 2 patients; stable disease, 8 patients), and the median PFS was 10.7 months. Eight out of the 10 patients received gefitinib as the second or third line chemotherapy. The response rate was 37.5% (partial response, 3 patients; stable disease, 5 patients), and the median PFS was 28.7 months. Nine patients received cytotoxic agents after first line chemotherapy. The median duration of the chemotherapy was 22.4 months, and a mean regimen of chemotherapy was three (range, 1–8). In 2 patients (patients 1 and 3), the re-challenge of gefitinib was performed after the failure of gefitinib therapy as the second or third line chemotherapy. The PFS of patients 1 and 3 after the re-challenge of gefitinib were
First line
Staging as performed for all the patients according to the TNM classification of the Union International Contre Cancer (UICC) [11]. For TNM staging, all patients underwent a computed tomography (CT) scan of the thorax and upper part of abdomen, a bone scintigram or PET scan, and a brain CT or MRI. The histological analysis of the tumor was based on the WHO classification for cell types [12]. Survival was recorded from the first day of treatment to the date of death or last follow-up, and the survival curves were calculated according to Kaplan–Meier method [13]. Probability values of ≤0.05 indicated a statistically significant difference. Fisher’s exact test was used to examine the association of two categorical variables. Survival difference was analyzed by the log-rank test. Multivariate analyses were performed using stepwise Cox proportional hazards model to identify independent prognostic factors. Statistical analysis was performed using JMP 8 (SAS, Institute Inc., Cary, NC, USA) for windows.
Regimen
Fig. 1. MST, 1-year, 2-year, 3-year, 4-year and 5-year survival rate for all of 124 patients were 11.3 months, 45%, 24%, 17%, 12% and 8%, respectively.
Abbreviation: PS, performance status; RR, response rate; PFS, progressive free survival (months); PR, partial response; SD, stable disease; CBDCA, carboplatin; PTX, paclitaxel; CDDP, cisplatin; GEM, gemcitabine; CPT-11, topotecin; EGFR, epidermal growth factor receptor.
121 Overall survival
K. Kaira et al. / Lung Cancer 67 (2010) 120–123
122
K. Kaira et al. / Lung Cancer 67 (2010) 120–123
Table 2 Differences of the characteristics between long-term survivors (LTS) of more than 2 years and non-LTS. CharacteristicsNon-LTS (n = 90)LTS of more than 2 years Total (n = 34)
From 2 to 5 years (n = 24)
More than 5 years (n = 10)
Age ≤65/>65 p-value
48/42 0.8420a
19/15
14/10 0.7175b
5/5
Gender Male/female p-value
62/28 0.0612
17/17
11/13 0.7079
6/4
PS 0-1/2-3 p-value
79/11 0.0314
34/0
24/10 1.0000
10/0
Smoking Yes/no p-value
60/30 0.0625
16/18
11/13 1.0000
5/5
Histology AC/non-AC p-value
62/28 0.0039
32/2
22/2 1.0000
10/0
Stage IIIB/IV p-value
20/70 1.0000
7/27
5/19 1.0000
2/8
T-stage T1, 2/T3, 4 p-value
32/58 0.3020
16/18
13/11 0.2700
3/7
N-stage N0, 1/N2, 3 p-value
23/67 0.1229
14/20
9/15 0.7041
5/5
28/6
20/4 1.0000
8/2
was performed. As the palliative radiotherapy, gefitinib was given and the patient has been disease-free. 3.2. Clinical characteristics and prognostic significance in long-term survivors We compared the clinical characteristics between long-term survivors (LTS) of more 2 years and the others (non-LTS) (Table 2). Good performance status, adenocarcinoma and gefitinib therapy were significantly predominant in the LTS of more 2 years. In the LTS of more than 2 years, we investigated the comparison of clinical characteristics between survivors (n = 10) of more than 5 years and those (n = 24) of from 2 to 5 years, but there were not any different factors in these groups. The prognostic factors in total 124 patients were evaluated by univariate analysis and it is shown in Table 3. Good performance status, adenocarcinoma and gefitinib therapy were shown to be favorable prognostic factors by univariate analysis. To identify independent prognostic factors, Cox’s proportional hazard model was used for analysis. The multivariate analysis demonstrated that these three variables were a significant independent factor to predict a favorable prognosis (Table 3). 4. Discussion
Gefitinib therapy Yes/no 39/51 p-value 0.0001
Note: PS, performance status; AC, adenocarcinoma. a Comparison between non-LTS (n = 90) and LTS of more than 2 years (n = 34). b Comparison between LTS of from 2 to 5 years (n = 20) and LTS of more than 5 years (n = 10).
13 and 8 months, respectively. Nine patients were alive and one patient died due to primary disease. Two patients (patients 1 and 8) have solitary brain metastases, and surgical resection of brain metastasis was performed as the initial treatment. In patient 1, whole brain radiation was performed after the surgery, and the patient were treated with first line chemotherapy. He was treated with gefitinib and repeated cytotoxic agents, and he is alive now. In patient 8, the patient was treated with first line chemotherapy after the resection of brain metastasis. Twelve months after the initial chemotherapy, the recurrence of lung cancer was found in the lung and chest radiation was given. The patient has been disease-free from the chest radiation. One patient (patient 9) was treated with a palliative radiation of bone metastases. However, the recurrence of bone metastases was observed in the incidence of seven frequencies. Repeated local radiotherapy
In the present study, all patients have good performance status and adenocarcinoma. The majority of the patients was given a platinum-containing chemotherapy as an initial treatment and received gefitinib as the second or third line chemotherapy. Although the response rate of our study was not high as compared with previous description [10,13], adequate treatment including prolonging administration of EGFR-TKI and cytotoxic agents, seems to play an important role in the long-term survivors. In this study, 80% of long-term survivors were observed in patients with response rate of stable disease (SD) as the initial treatment. Approximately 60% of the patients who received gefitinib, had a response rate of SD. The median PFS of initial treatment was 10.7 months. In pretreated patients, however, the median PFS of gefitinib and the median duration of cytotoxic agents were 28.7 and 22.4 months, respectively. In total 124 patients, good performance status, adenocarcinoma and gefitinib therapy were a significant independent factor to predict a favorable prognosis. The survival benefit of EGFR-TKI may be associated with the long-term survivors of more than 2 years. For the long-term survivor of more than 5 years, it may be necessary to be treated with not only EGFR-TKI but also repeated cytotoxic agents in pretreated NSCLC patients. Additionally, palliative radiation therapy may also contribute to prolonging survival. Some previous studies have reported long-term survivors among unresectable NSCLC [6,7,13,14]. Patients with stage III and IV disease were included in these studies, and they were mainly treated with initial chemotherapy followed by other treatments. Okamoto et al. reported that 17 (7.7%) of 222 NSCLC patients with
Table 3 Univariate and multivariate analysis of prognostic factors (n = 124). Prognostic factor
Univariate analysis (Log-rank test) (p value)
Age (≤65/>65) Gender (male/female) PS (0-1/2-3) Smoking (yes/no) Histology (AC/non-AC) Stage (IIIB/IV) Gefitinib therapy (yes/no)
0.9683 0.0984 0.0025 0.0757 0.0002 0.6244 0.0002
Multivariate analysis (Cox’s proportional hazards models) Hazard ratio
Note: PS, performance status; AC, adenocarcinoma.
1.3039 1.1244 0.2624 1.0007 0.4709 1.4968 0.5603
95% Confidence interval 0.8784–1.9419 0.6049–2.0981 0.1389–0.5324 0.5541–1.2206 0.2929–0.7681 0.9311–2.3346 0.3526–0.8891
p value 0.1879 0.7120 0.0005 0.9981 0.0029 0.0939 0.0140
K. Kaira et al. / Lung Cancer 67 (2010) 120–123
metastatic disease survived for more than 2 years [7]. In their study, the majority of long-term survivors of more than 2 years received multimodality therapies, and three patients who survived for more than 8 years, received surgery for the primary site. Sixteen (94%) of the 17 NSCLC patients have adenocarcinoma, and they concluded that an early N status, good performance status, single site of distant metastasis, and surgical treatment as initial treatment were significant prognostic factors in the long-term survival. However, the treatment history of EGFR-TKI was not included in their study. Recently, Satoh et al. also reported that 14 (12.8%) and 7 (6.4%) of 109 unresectable NSCLC patients survived for more than 2 or 3 years, respectively [6]. All patients were of good performance status and were given a platinum-based chemotherapy as an initial treatment (response rate, 42.8%). Out of the 14 patients, 13 (92.8%) have adenocarcinoma, and 8 (57.1%) were treated with gefitinib. They concluded that good performance status and gefitinib therapy were shown to be good prognostic factors. In the study of European Lung Cancer Working Party, 79% of the patients with unresectable NSCLC who survived more than 4 years were treated after chemotherapy by other therapeutic modalities [14]. However, there is some information about the clinical course of long-term survivors of more than 5 years. On July 2002, gefitinib was approved as the treatment of clinical practice for pretreated NSCLC patients in Japan. To our knowledge, there was no description of the analysis containing gefitinib therapy in the long-term survivors of more than 5 years. The present study is small number and preliminary, however this is the first retrospective study including gefitinib therapy in the analysis of the long-term survivors of more than 5 years. The survival benefit of third line chemotherapy is unknown. However, a mean regimen of chemotherapy was three in our study. If patients have good performance status, the administration of cytotoxic agents was performed as possible. In the future study, third line chemotherapy should be investigated whether it have a potential of prolonging survival. In this study, the repeated administration of cytotoxic agents may contribute to the long-term survival. There are many studies about local treatment for unresectable NSCLC and treatment for brain metastasis have been most frequently described. Local-control treatment using surgery or stereotactic radiosurgery (SRS) for the patients with solitary brain metastasis has a positive impact on prolonging survival [15,16]. In the present study, 2 patients received surgical resection for solitary brain metastasis before an initial chemotherapy, and 1 patient received whole brain radiotherapy after an initial chemotherapy. These patients have no recurrence of brain metastases. The limitation of our study must be addressed. Our study is small sample size and preliminary. The NSCLC patients who initially treated between September 2002 and October 2003, were eligible in this retrospective study. Our study had a heterogeneous group with T4No disease and resected brain metastases. Moreover, the mutation of EGFR was not investigated before the administration of gefitinib. Although the NSCLC patients with EGFR mutation might survive for more than 2 years with gefitinib therapy, it is unknown
123
whether they survive for more than 5 years. In the long-term survivors of more than 5 years, the prognostic markers including EGFR mutation should be investigated in future. In conclusion, our results suggest that good performance status, adenocarcinoma and EGFR-TKI therapy play an important role in the long-term survivors of more than 5 years. Adequate treatment including multimodality strategies might be considered for selected patients. Conflicts of interest statement We, all authors, have no financial or personal relationships with other people or organisations that could inappropriately influence our work. References [1] Novell S, Le Chevalier T. Chemotherapy for non-small cell lung cancer: Part 1. Early-stage disease. Oncology (Williston Park) 2003;17:357–64. [2] NSCLC Meta-Analysis Collaborative Group. Chemotherapy in addition to supportive care improves survival in advanced non-small cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomized controlled trials. J Clin Oncol 2008;26:4617–25. [3] Pfister DG, Johnson DH, Azzoli CG, Sause W, Smith TJ, Baker Jr, et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 2004;22:330–53. [4] Socinski MA, Morris DE, Masters GA, Lilenbaum R. American College of Chest Physicians. Chemotherapeutic management of stage IV non-small cell lung cancer. Chest 2003;123:226S–43S. [5] Albain KS, Crowley JJ, LeBlanc M, Livingston RB. Survival determinants in extensive-stage non-small cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol 1991;9:1618–26. [6] Satoh H, Ishikawa H, Ohara G, Kagohashi K, Kurishima K, Ohtsuka M, et al. Longterm survivors after chemotherapy in advanced non-small cell lung cancer. Anticancer Res 2007;27:4457–60. [7] Okamoto T, Maruyama R, Shoji F, Asoh H, Ikeda J, Miyamoto T, et al. Long-term survivors in stage IV non-small cell lung cancer. Lung Cancer 2005;47:85–91. [8] Nakatomi K, Soda H, Kitazaki T, Nakano H, Uchida K, Urabe S, et al. Long-term survival in three patients with metastatic non-small cell lung cancer treated with gefitinib. Lung Cancer 2006;52:253–5. [9] Mitsudomi T, Yatabe Y. Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci 2007;98:1817–24. [10] Morita S, Hirashima T, Hagiwara K, et al. Gefitinib combined survival analysis of the mutation positives from the prospective phase II trials (I-CAMP). J Clin Oncol 2008;26(May (suppl.)) [abstr. 8101]. [11] Cancer IUA. TNM classification of malignant tumors. 5th ed. New York: Wiley–Liss; 1997. [12] Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E.Histological typing of lung and pleural tumors, 3rd ed. World Health Organization International Histological Classification of tumors. Berlin: Springer Verlag; 1999. [13] Fikkelstein DM, Ettinger DS, Ruckdescel JL. Long-term survivors in metastatic non-small cell lung cancer: an Eastern Cooperative Oncology Group Study. J Clin Oncol 1986;4:702–9. [14] Sculier JP, Pasemans M, Libert P, Bureau G, Bureau G, Dabouis G, et al. Longterm survival after chemotherapy containing platinum derivatives in patients with advanced unresectable non-small cell lung cancer. European Lung Cancer Working Party. Eur J Cancer 1994;30A:1342–7. [15] Kondziolka D, Patel A, Lunsford LD, Kassam A, Flickinger JC. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 1999;45:427–34. [16] Pachell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990;322:494–500.
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Long-term survivors of more than 5 years in advanced non-small cell lung cancer Kyoichi Kaira a , Toshiaki Takahashi a , Haruyasu Murakami a , Asuka Tsuya a , Yukiko Nakamura a , Tateaki Naito a , Masahiro Endo b , Nobuyuki Yamamoto a,∗ a b
Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan Division of Diagnostic Radiology, Shizuoka Cancer Center, 1007 Shimonagakubo Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan
a r t i c l e
i n f o
Article history: Received 19 January 2009 Received in revised form 13 March 2009 Accepted 17 March 2009 Keywords: Non-small cell lung cancer Long-term survivor Chemotherapy Molecular-targeted therapy Radiotherapy Multimodality
a b s t r a c t Background: The aim of this study is to evaluate the rate of long-term survival of more than 5 years in advanced non-small cell lung cancer (NSCLC). Methods: One-hundred and twenty-four patients with advanced NSCLC treated with chemotherapy from September 2002 to October 2003 were reviewed. Results: Ten (8%) patients survived for more than 5 years. The median survival time (MST) for the 10 patients was 61.5 months, ranging from 60.1 to 81.0 months. All of the 10 patients had performance status (PS) 0 or 1 and adenocarcinoma. As the initial treatment, 9 patients were treated with a platinumcontaining chemotherapy [median progressive free survival (PFS), 10.7 months] and 8 patients received gefitinib as the second or third line chemotherapy (median PFS, 28.7 months). Nine patients received cytotoxic agents after first line chemotherapy (median duration of the chemotherapy, 22.4 months). A mean regimen of chemotherapy was three (range, 1–8). Re-challenge of gefitinib was performed in 2 patients, and surgical resection of solitary brain metastasis was performed as the initial treatment in 2 patients. Conclusion: Our results suggest that good performance status, adenocarcinoma and EGFR-TKI therapy play an important role in the long-term survivors of more than 5 years. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer remains the most common cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancer patients [1]. Although surgery is the standard treatment, the tumor is inoperable at the time of diagnosis for the majority of patients with NSCLC. The meta-analysis of 16 randomized controlled trials have demonstrated that platinumbased chemotherapy may have a better potential for prolonging survival than the best supportive care for these patients [2]. Nowadays, doublet chemotherapies consisting of the platinum plus third-generation agent are currently the standard regimens and recommended as the first line chemotherapy [3]. However, the prognosis of patients with advanced NSCLC is still poor and recent phase III trials demonstrated a median survival time (MST) of from 8 to 10 months and 1-year survival rate of 30–35% [4]. In the several reports on long-term survivors among advanced NSCLC patients, only 4–6% of patients have been described to survive for more than 2 years [5–7]. Recently, some researchers
∗ Corresponding author. Tel.: +81 55 989 5222; fax: +81 55 989 5634. E-mail address: [email protected] (N. Yamamoto). 0169-5002/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2009.03.014
described that long-term survivors of pulmonary adenocarcinoma treated by gefitinib [8]. Approximately 70% of NSCLCs with epidermal growth factor receptor (EGFR) mutations respond to EGFR-tyrosine kinase inhibitors (TKIs), whereas only 10% of tumors without EGFR mutations respond to them [9]. Recent prospective phase II studies of gefitinib for patients with EGFR mutation demonstrated an objective response rate (RR) of 76.4%, a median progressive free survival (PFS) 9.7 months and MST of 24.3 months [10]. Thus, selected NSCLC patients may survive more than 2 years. However, there is still little detailed information about the clinical course of advanced NSCLC patients who survived more than 5 years. Here, we examined the clinical characteristics of advanced NSCLC patients who survived more than 5 years at our institution. 2. Material and methods Shizuoka Cancer Center was opened on September 2002. Between September 2002 and October 2003, 191 patients with primary lung cancer were treated at the Department of Thoracic Oncology of Shizuoka Cancer Center. One hundred seventy-four patients had NSCLC. Among them, 152 of NSCLC patients had advanced IIIB/IV disease and 124 received some kind of chemotherapy as the initial treatment. Sixty-four (51.6%) of 124 patients were treated by gefitinib.
61.5 81.0 67.3 73.6 75.1 61.2 60.1 60.2 60.1 61.5 6 2 5 6 6 8 2 1 3 6
Total regimens
13.0 4.3 21.2 5.4 44.1 47.0 25.6 – 22.4 24.7 18 3 20 4 18 23 23 – 4 19 36.0 63.1 40.2 17.1 3.6 10.2 – – 21.5 36.2 PR SD PR SD SD PR – – SD SD 6.5 9.3 7.1 25.4 19.2 3.0 35.2 12.2 12.3 3.0 PR SD SD SD PR SD SD SD SD SD CBDCA + PTX CDDP + GEM CBDCA + PTX CBDCA + GEM CDDP + GEM CBDCA + PTX CPT-11 CBDCA + PTX CBDCA + PTX CBDCA + PTX Positive Unknown Unknown Unknown Unknown Unknown Positive Unknown Unknown Unknown Yes No No No Yes Yes Yes Yes No No 1 0 0 0 0 1 0 0 0 0 IV IV IV IIIB IV IV IV IV IV IIIB 65/M 73/F 62/F 71/F 65/M 56/M 78/M 53/M 71/M 56/F 1 2 3 4 5 6 7 8 9 10
T4N1M1 T4N3M1 T2N3M1 T4N0M0 T2N3M1 T4N3M1 T4N0M1 T2N0M1 T4N3M1 T4N0M0
Total cycles PFS RR
PFS
Yes (brain) No Yes (brain) No No No No Yes (chest, brain) Yes (bone) No
Palliative radiation Cytotoxic agents Second line
Gefitinib PFS (month) RR
EGFR mutation Smoking history PS Stage TNM Age/sex
Table 1 Individual characteristics of the 10 patients with more than 5 years survival.
3.1. Long-term survivors of more than 5 years
No. of patients
3. Results
Fig. 1 is a survival curve of total 124 patients. The MST, 1-year, 2-year, 3-year, 4-year and 5-year survival rate were 11.3 months, 45%, 24%, 17%, 12% and 8%, respectively. Out of the 124 patients, 10 (6 men and 4 women) with a median age of 63 years (range, 53–78 years) survived for more than 5 years. The MST for the 10 patients was 61.5 months, ranging from 60.1 to 81.0 months. Table 1 shows the individual characteristics and survival status of the 10 patients. Patient’s characteristics are following: Performance status (PS), clinical stage and histology of the patients were as follows: 8 patients with PS 0; 2 patients with PS 1; 2 patients with stage IIIB; 8 patients with stage IV; 10 patients with adenocarcinoma. As the initial treatment, 9 patients were treated with a platinumcontaining chemotherapy. The response rate of first chemotherapy was 20% (partial response, 2 patients; stable disease, 8 patients), and the median PFS was 10.7 months. Eight out of the 10 patients received gefitinib as the second or third line chemotherapy. The response rate was 37.5% (partial response, 3 patients; stable disease, 5 patients), and the median PFS was 28.7 months. Nine patients received cytotoxic agents after first line chemotherapy. The median duration of the chemotherapy was 22.4 months, and a mean regimen of chemotherapy was three (range, 1–8). In 2 patients (patients 1 and 3), the re-challenge of gefitinib was performed after the failure of gefitinib therapy as the second or third line chemotherapy. The PFS of patients 1 and 3 after the re-challenge of gefitinib were
First line
Staging as performed for all the patients according to the TNM classification of the Union International Contre Cancer (UICC) [11]. For TNM staging, all patients underwent a computed tomography (CT) scan of the thorax and upper part of abdomen, a bone scintigram or PET scan, and a brain CT or MRI. The histological analysis of the tumor was based on the WHO classification for cell types [12]. Survival was recorded from the first day of treatment to the date of death or last follow-up, and the survival curves were calculated according to Kaplan–Meier method [13]. Probability values of ≤0.05 indicated a statistically significant difference. Fisher’s exact test was used to examine the association of two categorical variables. Survival difference was analyzed by the log-rank test. Multivariate analyses were performed using stepwise Cox proportional hazards model to identify independent prognostic factors. Statistical analysis was performed using JMP 8 (SAS, Institute Inc., Cary, NC, USA) for windows.
Regimen
Fig. 1. MST, 1-year, 2-year, 3-year, 4-year and 5-year survival rate for all of 124 patients were 11.3 months, 45%, 24%, 17%, 12% and 8%, respectively.
Abbreviation: PS, performance status; RR, response rate; PFS, progressive free survival (months); PR, partial response; SD, stable disease; CBDCA, carboplatin; PTX, paclitaxel; CDDP, cisplatin; GEM, gemcitabine; CPT-11, topotecin; EGFR, epidermal growth factor receptor.
121 Overall survival
K. Kaira et al. / Lung Cancer 67 (2010) 120–123
122
K. Kaira et al. / Lung Cancer 67 (2010) 120–123
Table 2 Differences of the characteristics between long-term survivors (LTS) of more than 2 years and non-LTS. CharacteristicsNon-LTS (n = 90)LTS of more than 2 years Total (n = 34)
From 2 to 5 years (n = 24)
More than 5 years (n = 10)
Age ≤65/>65 p-value
48/42 0.8420a
19/15
14/10 0.7175b
5/5
Gender Male/female p-value
62/28 0.0612
17/17
11/13 0.7079
6/4
PS 0-1/2-3 p-value
79/11 0.0314
34/0
24/10 1.0000
10/0
Smoking Yes/no p-value
60/30 0.0625
16/18
11/13 1.0000
5/5
Histology AC/non-AC p-value
62/28 0.0039
32/2
22/2 1.0000
10/0
Stage IIIB/IV p-value
20/70 1.0000
7/27
5/19 1.0000
2/8
T-stage T1, 2/T3, 4 p-value
32/58 0.3020
16/18
13/11 0.2700
3/7
N-stage N0, 1/N2, 3 p-value
23/67 0.1229
14/20
9/15 0.7041
5/5
28/6
20/4 1.0000
8/2
was performed. As the palliative radiotherapy, gefitinib was given and the patient has been disease-free. 3.2. Clinical characteristics and prognostic significance in long-term survivors We compared the clinical characteristics between long-term survivors (LTS) of more 2 years and the others (non-LTS) (Table 2). Good performance status, adenocarcinoma and gefitinib therapy were significantly predominant in the LTS of more 2 years. In the LTS of more than 2 years, we investigated the comparison of clinical characteristics between survivors (n = 10) of more than 5 years and those (n = 24) of from 2 to 5 years, but there were not any different factors in these groups. The prognostic factors in total 124 patients were evaluated by univariate analysis and it is shown in Table 3. Good performance status, adenocarcinoma and gefitinib therapy were shown to be favorable prognostic factors by univariate analysis. To identify independent prognostic factors, Cox’s proportional hazard model was used for analysis. The multivariate analysis demonstrated that these three variables were a significant independent factor to predict a favorable prognosis (Table 3). 4. Discussion
Gefitinib therapy Yes/no 39/51 p-value 0.0001
Note: PS, performance status; AC, adenocarcinoma. a Comparison between non-LTS (n = 90) and LTS of more than 2 years (n = 34). b Comparison between LTS of from 2 to 5 years (n = 20) and LTS of more than 5 years (n = 10).
13 and 8 months, respectively. Nine patients were alive and one patient died due to primary disease. Two patients (patients 1 and 8) have solitary brain metastases, and surgical resection of brain metastasis was performed as the initial treatment. In patient 1, whole brain radiation was performed after the surgery, and the patient were treated with first line chemotherapy. He was treated with gefitinib and repeated cytotoxic agents, and he is alive now. In patient 8, the patient was treated with first line chemotherapy after the resection of brain metastasis. Twelve months after the initial chemotherapy, the recurrence of lung cancer was found in the lung and chest radiation was given. The patient has been disease-free from the chest radiation. One patient (patient 9) was treated with a palliative radiation of bone metastases. However, the recurrence of bone metastases was observed in the incidence of seven frequencies. Repeated local radiotherapy
In the present study, all patients have good performance status and adenocarcinoma. The majority of the patients was given a platinum-containing chemotherapy as an initial treatment and received gefitinib as the second or third line chemotherapy. Although the response rate of our study was not high as compared with previous description [10,13], adequate treatment including prolonging administration of EGFR-TKI and cytotoxic agents, seems to play an important role in the long-term survivors. In this study, 80% of long-term survivors were observed in patients with response rate of stable disease (SD) as the initial treatment. Approximately 60% of the patients who received gefitinib, had a response rate of SD. The median PFS of initial treatment was 10.7 months. In pretreated patients, however, the median PFS of gefitinib and the median duration of cytotoxic agents were 28.7 and 22.4 months, respectively. In total 124 patients, good performance status, adenocarcinoma and gefitinib therapy were a significant independent factor to predict a favorable prognosis. The survival benefit of EGFR-TKI may be associated with the long-term survivors of more than 2 years. For the long-term survivor of more than 5 years, it may be necessary to be treated with not only EGFR-TKI but also repeated cytotoxic agents in pretreated NSCLC patients. Additionally, palliative radiation therapy may also contribute to prolonging survival. Some previous studies have reported long-term survivors among unresectable NSCLC [6,7,13,14]. Patients with stage III and IV disease were included in these studies, and they were mainly treated with initial chemotherapy followed by other treatments. Okamoto et al. reported that 17 (7.7%) of 222 NSCLC patients with
Table 3 Univariate and multivariate analysis of prognostic factors (n = 124). Prognostic factor
Univariate analysis (Log-rank test) (p value)
Age (≤65/>65) Gender (male/female) PS (0-1/2-3) Smoking (yes/no) Histology (AC/non-AC) Stage (IIIB/IV) Gefitinib therapy (yes/no)
0.9683 0.0984 0.0025 0.0757 0.0002 0.6244 0.0002
Multivariate analysis (Cox’s proportional hazards models) Hazard ratio
Note: PS, performance status; AC, adenocarcinoma.
1.3039 1.1244 0.2624 1.0007 0.4709 1.4968 0.5603
95% Confidence interval 0.8784–1.9419 0.6049–2.0981 0.1389–0.5324 0.5541–1.2206 0.2929–0.7681 0.9311–2.3346 0.3526–0.8891
p value 0.1879 0.7120 0.0005 0.9981 0.0029 0.0939 0.0140
K. Kaira et al. / Lung Cancer 67 (2010) 120–123
metastatic disease survived for more than 2 years [7]. In their study, the majority of long-term survivors of more than 2 years received multimodality therapies, and three patients who survived for more than 8 years, received surgery for the primary site. Sixteen (94%) of the 17 NSCLC patients have adenocarcinoma, and they concluded that an early N status, good performance status, single site of distant metastasis, and surgical treatment as initial treatment were significant prognostic factors in the long-term survival. However, the treatment history of EGFR-TKI was not included in their study. Recently, Satoh et al. also reported that 14 (12.8%) and 7 (6.4%) of 109 unresectable NSCLC patients survived for more than 2 or 3 years, respectively [6]. All patients were of good performance status and were given a platinum-based chemotherapy as an initial treatment (response rate, 42.8%). Out of the 14 patients, 13 (92.8%) have adenocarcinoma, and 8 (57.1%) were treated with gefitinib. They concluded that good performance status and gefitinib therapy were shown to be good prognostic factors. In the study of European Lung Cancer Working Party, 79% of the patients with unresectable NSCLC who survived more than 4 years were treated after chemotherapy by other therapeutic modalities [14]. However, there is some information about the clinical course of long-term survivors of more than 5 years. On July 2002, gefitinib was approved as the treatment of clinical practice for pretreated NSCLC patients in Japan. To our knowledge, there was no description of the analysis containing gefitinib therapy in the long-term survivors of more than 5 years. The present study is small number and preliminary, however this is the first retrospective study including gefitinib therapy in the analysis of the long-term survivors of more than 5 years. The survival benefit of third line chemotherapy is unknown. However, a mean regimen of chemotherapy was three in our study. If patients have good performance status, the administration of cytotoxic agents was performed as possible. In the future study, third line chemotherapy should be investigated whether it have a potential of prolonging survival. In this study, the repeated administration of cytotoxic agents may contribute to the long-term survival. There are many studies about local treatment for unresectable NSCLC and treatment for brain metastasis have been most frequently described. Local-control treatment using surgery or stereotactic radiosurgery (SRS) for the patients with solitary brain metastasis has a positive impact on prolonging survival [15,16]. In the present study, 2 patients received surgical resection for solitary brain metastasis before an initial chemotherapy, and 1 patient received whole brain radiotherapy after an initial chemotherapy. These patients have no recurrence of brain metastases. The limitation of our study must be addressed. Our study is small sample size and preliminary. The NSCLC patients who initially treated between September 2002 and October 2003, were eligible in this retrospective study. Our study had a heterogeneous group with T4No disease and resected brain metastases. Moreover, the mutation of EGFR was not investigated before the administration of gefitinib. Although the NSCLC patients with EGFR mutation might survive for more than 2 years with gefitinib therapy, it is unknown
123
whether they survive for more than 5 years. In the long-term survivors of more than 5 years, the prognostic markers including EGFR mutation should be investigated in future. In conclusion, our results suggest that good performance status, adenocarcinoma and EGFR-TKI therapy play an important role in the long-term survivors of more than 5 years. Adequate treatment including multimodality strategies might be considered for selected patients. Conflicts of interest statement We, all authors, have no financial or personal relationships with other people or organisations that could inappropriately influence our work. References [1] Novell S, Le Chevalier T. Chemotherapy for non-small cell lung cancer: Part 1. Early-stage disease. Oncology (Williston Park) 2003;17:357–64. [2] NSCLC Meta-Analysis Collaborative Group. Chemotherapy in addition to supportive care improves survival in advanced non-small cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomized controlled trials. J Clin Oncol 2008;26:4617–25. [3] Pfister DG, Johnson DH, Azzoli CG, Sause W, Smith TJ, Baker Jr, et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 2004;22:330–53. [4] Socinski MA, Morris DE, Masters GA, Lilenbaum R. American College of Chest Physicians. Chemotherapeutic management of stage IV non-small cell lung cancer. Chest 2003;123:226S–43S. [5] Albain KS, Crowley JJ, LeBlanc M, Livingston RB. Survival determinants in extensive-stage non-small cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol 1991;9:1618–26. [6] Satoh H, Ishikawa H, Ohara G, Kagohashi K, Kurishima K, Ohtsuka M, et al. Longterm survivors after chemotherapy in advanced non-small cell lung cancer. Anticancer Res 2007;27:4457–60. [7] Okamoto T, Maruyama R, Shoji F, Asoh H, Ikeda J, Miyamoto T, et al. Long-term survivors in stage IV non-small cell lung cancer. Lung Cancer 2005;47:85–91. [8] Nakatomi K, Soda H, Kitazaki T, Nakano H, Uchida K, Urabe S, et al. Long-term survival in three patients with metastatic non-small cell lung cancer treated with gefitinib. Lung Cancer 2006;52:253–5. [9] Mitsudomi T, Yatabe Y. Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci 2007;98:1817–24. [10] Morita S, Hirashima T, Hagiwara K, et al. Gefitinib combined survival analysis of the mutation positives from the prospective phase II trials (I-CAMP). J Clin Oncol 2008;26(May (suppl.)) [abstr. 8101]. [11] Cancer IUA. TNM classification of malignant tumors. 5th ed. New York: Wiley–Liss; 1997. [12] Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E.Histological typing of lung and pleural tumors, 3rd ed. World Health Organization International Histological Classification of tumors. Berlin: Springer Verlag; 1999. [13] Fikkelstein DM, Ettinger DS, Ruckdescel JL. Long-term survivors in metastatic non-small cell lung cancer: an Eastern Cooperative Oncology Group Study. J Clin Oncol 1986;4:702–9. [14] Sculier JP, Pasemans M, Libert P, Bureau G, Bureau G, Dabouis G, et al. Longterm survival after chemotherapy containing platinum derivatives in patients with advanced unresectable non-small cell lung cancer. European Lung Cancer Working Party. Eur J Cancer 1994;30A:1342–7. [15] Kondziolka D, Patel A, Lunsford LD, Kassam A, Flickinger JC. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 1999;45:427–34. [16] Pachell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990;322:494–500.