Anticancer Section / Original Paper Chemotherapy 2015–16;61:41–50 DOI: 10.1159/000440941
Received: February 27, 2015 Accepted: September 7, 2015 Published online: November 1, 2015
Comparison of the Efficacy between Pemetrexed plus Platinum and Non-Pemetrexed plus Platinum as First-Line Treatment in Patients with Wild-Type Epidermal Growth Factor Receptor Nonsquamous Non-Small Cell Lung Cancer: A Retrospective Analysis Eun Joo Kang Kyung Hoon Min Gyu Young Hur Sung Yong Lee Jae Jeong Shim Kyung Ho Kang Sang Cheul Oh Jae Hong Seo Jun Suk Kim Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
Abstract Background: Despite the development of molecular research and targeted therapy, patients with wild-type epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) still receive platinum doublet chemotherapy as the standard first-line treatment. We investigated the efficacy of first-line regimens in patients with wild-type EGFR nonsquamous NSCLC. Methods: We retrospectively analyzed the efficacy of various platinum doublet regimens as first-line treatments. Between 2007 and 2013, a total of 165 patients with wild-type EGFR nonsquamous NSCLC were included in this study. Results: Seventy-one (43.0%) patients were treated with pemetrexed plus platinum (PP) and 94 (57.0%) with non-pemetrexed plus platinum (NPP). The overall response rate was not different between the PP- and NPP-treated groups (26.8 vs. 28.7%, respectively; p = 0.78). The median progression-free survival (PFS) and overall survival (OS) also
© 2015 S. Karger AG, Basel 0009–3157/15/0611–0041$39.50/0 E-Mail [email protected] www.karger.com/che
showed no differences between the two treatment groups (p = 0.12 for PFS, p = 0.42 for OS). The median PFS and OS for the PP group were 4.6 months (95% CI, 3.8–5.4) and 18.7 months (95% CI, 11.7–25.8), respectively, and for the NPP group, they were 4.2 months (95% CI, 3.4–5.0) and 12.2 months (95% CI, 10.3–14.1), respectively. In the subgroup analysis, most subgroups showed no significant difference in PFS and OS between the two treatment groups. Conclusion: Our data showed that the efficacy of various platinum doublet regimens was similar in patients with wild-type EGFR nonsquamous NSCLC. © 2015 S. Karger AG, Basel
Introduction
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. The use of chemotherapy has led to the prolonged survival of patients with advanced, metastatic NSCLC. A two-drug combination, also called ‘platinum doublet’, which includes platinum (e.g. cisplatin or carboplatin) and a non-platinum Sung Yong Lee, MD, PhD Department of Internal Medicine, Korea University Guro Hospital 148, Gurodong-ro, Guro-gu Seoul 152-703 (Republic of Korea) E-Mail dragonett @ naver.com
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Key Words Epidermal growth factor receptor · First-line chemotherapy · Non-small cell lung carcinoma · Wild type
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pemetrexed plus platinum (PP) for patients with wildtype EGFR nonsquamous NSCLC. Notably, we attempted to determine whether PP shows superior results in patients with wild-type EGFR nonsquamous NSCLC. Patients and Methods Patients Patients with wild-type EGFR nonsquamous NSCLC who received platinum doublet chemotherapy as the first-line treatment at the Korea University Guro Hospital between January 2007 and December 2013 were included in this retrospective study. All patients had to meet the following criteria: histologically confirmed nonsquamous NSCLC with distant metastases or recurrent disease after surgical resection, wild-type EGFR confirmed by direct sequencing or peptide nucleic acid (PNA) clamping method using the PNA ClampTM EGFR mutation detection kit (Panagene, Inc., Daejeon, Korea), platinum doublet chemotherapy as first-line treatment and no concurrent active malignancy other than NSCLC. Patients who received a single chemotherapeutic agent or platinum doublet combining targeted therapies with cetuximab or bevacizumab and patients who were enrolled in clinical trials as well as patients who received platinum doublet chemotherapy with concurrent chemoradiotherapy were excluded. Data were collected from the electronic medical records. This study was approved by the Institutional Review Boards of the Korea University Guro Hospital. Data Collection For each patient, the following data were collected and analyzed: age, sex, tumor histology, stage at diagnosis, site(s) of metastases and the number of organs in which a metastasis was found during the first-line chemotherapy, and performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) at the beginning of the first-line chemotherapy. In addition, we analyzed the following data: type of chemotherapy regimen, start and end date of chemotherapy, and response and best response to the first-line chemotherapy according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) guidelines. Patient responses were assessed at 2- to 3-month intervals with enhanced computed tomography. Magnetic resonance imaging, fluorodeoxyglucose positron emission tomography and bone scans were performed based on the physician’s decision. Chemotherapy Regimens Various platinum doublet regimens were used and classified into the following categories: (i) PP (all regimens combining pemetrexed and cisplatin or carboplatin); (ii) taxane + platinum (all regimens combining docetaxel or paclitaxel plus cisplatin or carboplatin); (iii) gemcitabine + platinum (all regimens combining gemcitabine plus cisplatin or carboplatin), and (iv) other agents + platinum (all regimens combining vinorelbine, etoposide or irinotecan plus cisplatin or carboplatin). Statistical Analyses All patients who received at least one cycle of first-line chemotherapy were included in the analysis of efficacy. Rates were compared using the χ2 test. The Kaplan-Meier method was used to estimate overall (OS) and progression-free survival (PFS). PFS was
Kang/Min/Hur/Lee/Shim/Kang/Oh/Seo/ Kim
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drug (e.g. pemetrexed, gemcitabine, taxane or vinorelbine) has been used as the standard first-line treatment in these patients for many years [1]. However, due to the vast development in molecular research and targeted therapy, the NSCLC treatment paradigm has changed. Notably, the use of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), such as erlotinib or gefitinib, resulted in improved response rates and prolonged survival in patients with EGFR mutation-positive NSCLC [2–5]. Therefore, EGFR TKI is approved as the first-line treatment for patients with EGFR mutationpositive NSCLC, and previous studies also demonstrated the favorable efficacy of TKI as second-line treatment in patients with NSCLC irrespective of the EGFR mutation status [6, 7]. Because EGFR mutations have been reported in 10–50% of lung adenocarcinoma cases [8, 9], more than half of the patients with adenocarcinoma and most patients with squamous cell carcinoma should be treated with platinum doublet chemotherapy as first-line treatment. While drug development for EGFR mutation-positive NSCLC progressed tremendously, only little progress has been made for the treatment of patients with wild-type EGFR NSCLC. Except for some trials that were performed only with patients with EGFR mutation-positive NSCLC for the efficacy of EGFR TKI, most clinical studies in NSCLC patients have not addressed the EGFR mutation status. Until now, no study has been conducted to compare the efficacy of various platinum doublet regimens in the treatment of patients with wild-type EGFR NSCLC. A randomized study that compared four platinum doublet regimens, paclitaxel plus cisplatin, gemcitabine plus cisplatin, docetaxel plus cisplatin or paclitaxel plus carboplatin, showed similar advantages over other regimens [10]. However, treatment response and survival were somewhat different according to the tumor histology in a phase III study comparing gemcitabine plus cisplatin with pemetrexed plus cisplatin in patients with NSCLC. Gemcitabine plus cisplatin showed superior results in squamous cell carcinomas, but pemetrexed plus cisplatin showed superior results in adenocarcinomas [11]. Since this study, several studies also reported superior survival results with the use of pemetrexed plus cisplatin in nonsquamous NSCLC. Thus, pemetrexed plus cisplatin is the preferred treatment for nonsquamous NSCLC [12, 13]. However, these results are also from studies conducted in patients with NSCLC regardless of EGFR mutation status. Thus, we performed this study to compare the efficacy of various platinum doublet regimens, including
Table 1. Patient characteristics
Characteristics
Total
PP
NPP
p value
Patients, n Age, years Range Sex Male Female Histology Adenocarcinoma Large cell carcinoma Other Smoking history Never-smoker Current/ex-smoker Stage at diagnosis Stage I–IIIA Stage IIIB–IV ECOG PS 0 1–2 Response CR + PR SD + PD Maintenance treatment Continuation Switch None After first-line treatment First line only ≥Second line Not known Metastatic organs 0–2 ≥3 Brain metastasis Yes No
165 (100.0) 66 29 – 85
71 (43.0) 63 31 – 85
94 (57.0) 68 29 – 81
0.44
118 (71.5) 47 (28.5)
44 (62.0) 27 (38.0)
74 (78.7) 20 (21.3)
151 (91.5) 5 (3.0) 9 (5.5)
66 (93.0) 3 (4.2) 2 (2.8)
85 (90.4) 2 (2.2) 7 (7.4)
62 (37.6) 103 (62.4)
30 (42.3) 41 (57.7)
32 (34) 62 (66)
20 (12.1) 145 (87.9)
11 (15.5) 60 (84.5)
9 (9.6) 85 (90.4)
54 (32.7) 111 (67.3)
29 (40.8) 42 (59.2)
25 (26.6) 69 (73.4)
46 (27.9) 119 (72.1)
19 (26.8) 52 (73.2)
27 (28.7) 67 (71.3)
12 (7.3) 3 (1.8) 150 (90.9)
12 (16.9) 0 59 (83.1)
0 3 (3.2) 91 (96.8)
38 (23.0) 121 (73.3) 6 (3.6)
19 (69.0) 49 (26.8) 3 (4.2)
19 (76.6) 72 (20.2) 3 (3.2)
132 (80) 33 (20)
59 (83.1) 12 (16.9)
73 (77.7) 21 (22.3)
28 (17) 137 (83)
15 (21.1) 56 (78.9)
13 (13.8) 81 (86.2)
0.02 0.33
0.28 0.18 0.05 0.78
0.00 0.55
0.39 0.22
Figures in parentheses are percentages. CR = Complete response; PR = partial response; SD = stable disease; PD = progressive disease.
Patient Characteristics Between January 2007 and December 2013, a total of 534 patients with NSCLC received chemotherapy at our institution, and 165 patients with wild-type EGFR nonsquamous NSCLC who received platinum doublet chemotherapy as the palliative first-line treatment were included in this analysis. The patient characteristics are listed in table 1. Median age was 66 years (range: 29–85). There were 118 males (71.5%) and 47 females (28.5%). Of
Several Platinum Doublet Combinations in EGFR Wild-Type NSCLC
Chemotherapy 2015–16;61:41–50 DOI: 10.1159/000440941
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Results
measured from the initiation of the first-line chemotherapy until the first occurrence of progressive disease, death from any cause or the last follow-up if none of the preceding events had occurred. OS was determined by the interval between the 1st day of first-line treatment and death or the last day of the follow-up. The difference between the curves was analyzed using the log-rank test. After univariate analyses using the Kaplan-Meier method, variables significantly associated with poor survival (variables with p < 0.05) were selected, and a Cox proportional hazard regression was conducted for multivariate analyses by the ‘ENTER’ method. The Statistical Package for the Social Sciences for Windows (version 20.0; SPSS Inc., Chicago, Ill., USA) was used for all statistical analysis. A value of p < 0.05 was considered statistically significant.
the 165 patients, 151 (91.5%) were diagnosed with adenocarcinoma, 5 (3.0%) with large-cell carcinoma, and 9 (5.5%) were diagnosed with another histology (4 with sarcomatoid carcinoma, 2 with undifferentiated carcinoma, 2 with adenosquamous cell carcinoma and 1 with pleomorphic carcinoma). Wild-type EGFR was detected using the PNA clamping method in 84 (50.9%) patients and by direct sequencing in 81 (49.1%) patients. At initial diagnosis, 145 (87.9%) patients were diagnosed with stage IIIB or IV disease and treated with chemotherapy as firstline treatment; 20 (12.1%) patients were diagnosed with stage I–IIIA at initial diagnosis and received chemotherapy due to recurrence after curative surgery. Sixty-two (37.6%) patients were never-smokers, 27 (16.4%) were ex-smokers, and 76 (46.1%) were current smokers. One
Table 2. First-line chemotherapeutic regimens
Regimens
n
Pemetrexed + platinum Pemetrexed + cisplatin Non-pemetrexed + platinum Gemcitabine + platinum Gemcitabine + cisplatin Gemcitabine + carboplatin Taxane + platinum Docetaxel + carboplatin Docetaxel + cisplatin Paclitaxel + carboplatin Paclitaxel + cisplatin Other agents + platinum Vinorelbine + cisplatin Etoposide + carboplatin Etoposide + cisplatin Irinotecan + carboplatin Total
%
71
43.0
17 35
10.3 21.2
1 11 18 7
0.6 6.7 10.9 4.2
2 1 1 1
1.2 0.6 0.6 0.6
165
100
hundred and twenty-one (73.3%) patients received at least second-line chemotherapy after failure of the firstline treatment. Thirty-one (18.8%) patients received third-line chemotherapy and 44 (26.7%) received more than fourth-line chemotherapy. Among the 165 patients, 71 (43%) were treated with PP, and all patients in this group were treated with cisplatin. Ninety-four (57.0%) patients were treated with non-pemetrexed plus platinum (NPP); the regimens are listed in table 2. In the NPP group, 52 (31.5%) patients were treated with gemcitabine plus platinum and 37 (22.4%) patients were treated with taxane plus platinum. Patients treated with PP were relatively young, and the proportion of female patients in this group was higher than that in the NPP group (p = 0.018). The median number of treatment cycles was 5 (range: 1–8) in the PP group and 4 (range: 1–10) in the NPP group. In Korea, some maintenance regimens are permitted and partially covered by health insurance since 2012; only 15 (9.1%) patients received treatment continuation or switched to maintenance treatment. Among the 71 patients in the PP group, 12 (16.9%) received continuation of pemetrexed maintenance after 4 cycles of pemetrexed plus cisplatin treatment. In the NPP group, 3 (3.2%) patients were switched to maintenance (2 used erlotinib and 1 used pemetrexed) treatment and none received continuation maintenance. Except for sex and maintenance treatment, there was no significant difference in the clinical characteristics of the patients between the two treatment groups. Efficacy of Platinum Doublet Regimens Of the 165 patients, the best responses were complete remission in 3 patients (1.9%) and partial remission in 39 patients (25.2%). The overall response rate (ORR), including complete and partial remissions, was 26.8% in the PP group and 28.7% in the NPP group; there was no statistical difference in ORR between the two treatment
Table 3. Efficacy analysis
CR
PR
SD
Pemetrexed + platinum Gemcitabine + platinum Taxane + platinum Other agents + platinum
1 (1.5) 0 2 (5.9) 0
18 (26.9) 13 (26.0) 8 (23.5) 0
40 (59.7) 30 (60.0) 20 (58.8) 4 (100.0)
Total
3 (1.9)
39 (39.0)
94 (60.6)
PD
NE
Total
8 (11.9) 7 (14.0) 4 (11.8) 0
4 2 3 1
71 52 37 5
19 (12.3)
10
165
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Figures in parentheses are percentages. CR = Complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = not evaluable.
groups (p = 0.78). ORR of the gemcitabine plus platinum group was 26.0% and ORR of the taxane plus platinum subgroup was 29.4%. The efficacy analysis of the platinum combinations is presented in table 3. No difference was also observed in median PFS and OS between the PP and the NPP group (p = 0.12 for PFS and p = 0.42 for OS). The median PFS and OS for all pa-
1.0
1.0
Pemetrexed + platinum Gemcitabine + platinum Taxane + platinum Other agents + platinum
0.8
OS p = 0.82
0.6
Pemetrexed + platinum
0.4
Non-pemetrexed + platinum
0.8 Cumulative survival
Cumulative survival
tients who received first-line platinum doublet were 4.3 months [95% confidence interval (CI), 4.0–4.6] and 14.3 months (95% CI, 9.7–18.9), respectively. The median PFS and OS of the PP group were 4.6 months (95% CI, 3.8–5.4) and 18.7 months (95% CI, 11.7–25.8), respectively, and those of the NPP group were 4.2 months (95% CI, 3.4–5.0) and 12.2 months (95% CI, 10.3–14.1), re-
OS p = 0.42 0.6
0.4
0.2
0.2
0
0 0
12
24
a
48
60
72
84
96
Time (months)
1.0
0
0.4
36
48
60
72
84
96
Time (months)
Pemetrexed + platinum Non-pemetrexed + platinum 0.8
0.2
PFS p = 0.12
0.6
0.4
0.2
0
0
10
20 Time (months)
30
40
0
12
d
24
36
Time (months)
Fig. 1. OS (a, b) and PFS (c, d) according to the chemotherapeutic regimens. a, c Various platinum doublet regimens. b, d PP and NPP groups.
Several Platinum Doublet Combinations in EGFR Wild-Type NSCLC
Chemotherapy 2015–16;61:41–50 DOI: 10.1159/000440941
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0
c
24
1.0
Cumulative survival
PFS p = 0.07
0.6
12
b
Pemetrexed + platinum Gemcitabine + platinum Taxane + platinum Other agents + platinum
0.8 Cumulative survival
36
HR (95% CI) Age >70 years Age 70 years Male Female Current/ex-smoker Never-smoker ECOG PS 0 ECOG PS 1–2 Stage at diagnosis: I–IIIA Stage at diagnosis: IIIB–IV Number of metastases: 3 Number of metastases: 0–2 Bone metastasis only Others Lung and/or pleural metastases only Other Brain metastasis No brain metastasis Second-line treament: TKI Second-line treatment: chemotherapy
0.84 (0.52–1.35) 1.04 (0.54–2.01) 0.89 (0.57–1.40) 1.21 (0.55–2.64) 0.90 (0.48–1.69) 0.88 (0.54–1.42) 3.38 (0.65–17.5) 1.00 (0.68–1.49) 0.87 (0.28–1.15) 1.11 (0.70–1.74) 0.87 (0.60–1.35) 1.13 (0.52–2.44) 1.32 (0.26–6.60) 0.83 (0.56–1.22) 0.69 (0.35–1.32) 0.89 (0.54–1.45) 1.14 (0.46–2.69) 0.80 (0.52–1.22) 0.76 (0.36–1.61) 0.88 (0.45–1.73) 0.5
a
50
5
Favors PP
Favors NPP HR (95% CI) 0.76 (0.51–1.13) 0.78 (0.44–1.38) 0.85 (0.58–1.24) 0.67 (0.36–1.24) 0.76 (0.50–1.14) 0.79 (0.46–1.35) 1.33 (0.95–1.88) 0.77 (0.28–2.22) 0.68 (0.40–1.18) 0.83 (0.55–1.23) 0.80 (0.56–1.14) 0.68 (0.31–1.50) 0.46 (0.12–1.84) 0.81 (0.58–1.13) 0.99 (0.61–1.60) 0.60 (0.38–0.96) 0.84 (0.37–1.88) 0.75 (0.53–1.06) 0.86 (0.47–1.56) 0.81 (0.49–1.35)
Age >70 years Age 70 years Male Female Current/ex-smoker Never-smoker ECOG PS 0 ECOG PS 1–2 Stage at diagnosis: I–IIIA Stage at diagnosis: IIIB–IV Number of metastases: 3 Number of metastases: 0–2 Bone metastasis only Other Lung and/or pleural metastases only Other Brain metastasis No brain metastasis Second-line treament: TKI Second-line treatment: chemotherapy 0
b
0.5 Favors PP
1.0
1.5
2.0
2.5
Favors NPP
spectively. In detail, the median PFS and OS of the taxane plus platinum subgroup were 4.2 months (95% CI, 2.4– 5.9) and 11.4 months (95% CI, 5.5–17.3), respectively. The median PFS and OS of the gemcitabine plus platinum subgroup were 3.7 months (95% CI, 2.4–5.0) and 46
Chemotherapy 2015–16;61:41–50 DOI: 10.1159/000440941
12.6 months (95% CI, 9.5–15.7), respectively. There was no statistical difference in median PFS and median OS according to the treatment regimens (p = 0.07 for PFS and p = 0.82 for OS). The survival curves for PFS and OS are shown in figure 1. Kang/Min/Hur/Lee/Shim/Kang/Oh/Seo/ Kim
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Fig. 2. a Subgroup analysis: OS (a) and PFS (b).
Table 4. Multivariate analysis for prognostic factors
Sex (male vs. female) Smoking history (current/ex- vs. never-smoker) ECOG PS (0 – 1 vs. 2) Stage at diagnosis (stage IIIB–IV vs. I–IIIA) Number of metastases (≥3 vs. 0 – 2) Metastatic organ (M1b vs. M1a) Treatment after first line (≥second-line vs. first-line treatment only)
PP
NPP
HR
95% CI
p value
HR
95% CI
p value
HR
95% CI
p value
– – 0.83 9.00 1.70 3.07
– – 0.40 to 1.75 2.00 to 40.37 0.76 to 3.81 1.40 to 6.72
– – 0.63 0.00 0.20 0.01
1.63 – – – 1.45 1.72
0.89 to 2.97 – – – 0.80 to 2.63 1.01 to 2.93
0.12 – – – 0.23 0.05
1.25 1.10 – 2.49 1.60 1.86
0.70 to 2.26 0.64 to 1.84 – 1.25 to 4.94 0.99 to 2.57 1.21 to 2.84
0.45 0.75 – 0.01 0.05 0.00
4.34
2.03 to 9.30
0.00
3.62
2.06 to 6.36
0.00
3.29
2.15 to 5.01
0.00
Subgroup Analysis for OS and PFS In order to find differences in PFS or OS according to the treatment groups, we conducted subgroup analysis between the PP and the NPP group using Cox regression analysis. As shown in figure 2, for PFS, patients who had metastases, excluding the lung and pleura at the time of first-line chemotherapy, showed superior results when they were treated with PP (p = 0.03). No statistical significance was found and no statistically significant results were observed for PFS and OS for most other subgroups. Clinical Parameters Related to Treatment Outcomes Univariate analysis showed that the OS for patients treated with PP was significantly associated with the following factors: stage at diagnosis (stage I–IIIA vs. stage IIIB–IV), ECOG PS (0 vs. 1–2), number of organs with metastases (0–2 vs. ≥3), metastatic organs (M1a vs. M1b) and treatment after failure of first-line chemotherapy (≥second-line chemotherapy vs. first-line treatment only). For patients who were treated with NPP, univariate analysis showed that OS was significantly associated with the following factors: gender (male vs. female), number of organs with metastases (0–2 vs. ≥3), metastatic organs (M1a vs. M1b) and treatment after failure of first-line chemotherapy (≥second-line chemotherapy vs. first-line treatment only). We then conducted multivariate analysis for each treatment group using a Cox proportional hazard regression model. In patients treated with PP, stage I–IIIA disease at diagnosis, M1a stage and treatment continuation with more than second-line chemotherapy after the first-line treatment were associated with prolonged OS. In patients treated with NPP, metastasis confined to the lung and/or pleura and more than second-line chemotherapy after the first-line treatment were associated with prolonged OS. For all patients, stage I–IIIA disease at diagnosis and lower number of metastases (0–2), M1a metastasis and more Several Platinum Doublet Combinations in EGFR Wild-Type NSCLC
All patients
Table 5. Treatment after failure of first-line chemotherapy
Characteristics/regimen
PP
NPP
Total
Patients, n First-line treatment only ≥Second-line treatment ≤Second line ≤Third line ≥Fourth line Not known Second-line treatment TKI Chemotherapy
71 (43.0) 19 (26.8) 49 (69.0) 17 (23.9) 12 (16.9) 20 (28.2) 3 (4.2) 49 (40.5) 27 (55.1) 22 (44.9)
94 (57.0) 165 19 (20.2) 38 (23.0) 72 (76.6) 121 (73.3) 29 (30.9) 46 (27.9) 19 (20.2) 31 (18.8) 24 (25.5) 44 (26.7) 3 (3.2) 6 (3.6) 72 (59.5)* 121 20 (27.8) 47 (38.8) 52 (72.2) 74 (61.2)
Figures in parentheses are percentages. * p = 0.002.
than second-line treatment after the first-line chemotherapy were associated with prolonged OS (table 4). Relationship between Chemotherapeutic Regimens and Treatment after Failure of the First-Line Chemotherapy Because treatment after failure of the first-line chemotherapy is closely connected with OS, we investigated treatment after first-line chemotherapy in detail. Of the 71 patients in the PP group, 49 (69.0%) had more than second-line chemotherapy and 72 (76.6%) of the 94 patients in the NPP group had more than second-line chemotherapy. In the PP and NPP groups, 28.2 and 25.5% of the patients received more than fourth-line chemotherapy, respectively. Among the 121 patients who received second-line chemotherapy, 47 (38.8%) received TKI and 74 (61.2%) received conventional chemotherapy. The difference was observed in the proportion of patients who were treated with TKI between the PP and NPP groups (p = 0.002). In the PP group, 27 (55.1%) patients received Chemotherapy 2015–16;61:41–50 DOI: 10.1159/000440941
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Multivariate analysis
Discussion
Although more than half of the patients with NSCLC do not have EGFR mutation, little is known about the best treatment for patients with wild-type EGFR NSCLC in clinical practice. These data indicate that the use of several platinum doublets as the first-line treatment show no significant differences in terms of response rate and survival in patients with wild-type EGFR nonsquamous NSCLC. Particularly, pemetrexed plus cisplatin did not show better results than the NPP combination in patients with wild-type EGFR nonsquamous NSCLC. Since the report of the JMDB study and some other studies [11–15], oncologists tend to choose pemetrexed plus cisplatin as the first-line treatment for nonsquamous cell type carcinoma. In addition, the superior survival of patients treated with pemetrexed continuation in the PARAMOUNT study, which analyzed the efficacy of the use of continuation of maintenance with pemetrexed after response to pemetrexed plus cisplatin in the first-line treatment, also empowered the selection of pemetrexed plus cisplatin [16]. However, these studies did not check EGFR mutation status in the tumor tissue of patients included and were conducted with patients regardless of EGFR mutation status; thus, we cannot assume the superiority of PP in case of patients with wild-type EGFR NSCLC. We cannot find the exact number of patients with wild-type or mutant EGFR NSCLC in each study, but we can suspect the proportion of mutant EGFR NSCLC through the percentage of female or never-smokers because EGFR mutations have been found more frequently in female neversmokers [17]. In the JMDB study by Scagliotti et al. [11], which included mostly white people (78% of all patients), 34.5% of the patients were female and 17.2% never-smokers. In the Grønberg study, which was performed in Norwegian patients, 28.7% of the patients were female and 7.5% never-smokers [15]. In the East Asian subgroup analysis of the JMDB study, females and never-smokers represented 38.1 and 50% of the patients, respectively, and 44.5 and 55.4% of the patients in a similar study conducted in Chinese patients with nonsquamous cell carcinoma [13]. Studies conducted in Asian patients included a higher proportion of never-smokers. Moreover, EGFR 48
Chemotherapy 2015–16;61:41–50 DOI: 10.1159/000440941
mutations are more frequently found in Asian patients [17]. Thus, we can suspect that the number of patients with EGFR mutations could be higher in studies performed in Asia than in studies conducted in Western countries. According to the report of Jiang et al. [18], the pemetrexed-cisplatin combination showed a better overall response in lung adenocarcinoma patients with EGFR mutations compared to those with wild-type EGFR. Actually, the OS of patients with nonsquamous NSCLC treated with pemetrexed plus cisplatin was much longer than that of Asian patients treated with gemcitabine plus cisplatin, and a larger gap was observed in terms of hazard ratio (HR) when compared to Western studies [12]. OS was 21.2 months and its HR was 0.7 for patients treated with pemetrexed plus cisplatin in the East Asian subgroup analysis of the JMDB study [12]. However, OS of patients treated with pemetrexed plus cisplatin was only 11.8 months and its HR was 0.81 in the JMDB study [11]. On the contrary, we can suspect that the efficacy of PP would be inferior in patients with wild-type EGFR NSCLC. No difference in survival was observed between the pemetrexed plus carboplatin group and the gemcitabine plus carboplatin group in the study of Grønberg, which was conducted in Norwegian patients, a population expected to have a much larger proportion of patients with wild-type EGFR NSCLC [15]. Thus, we cannot demonstrate the superiority of PP in the case of wild-type EGFR nonsquamous cell lung cancer through our results and that of previous studies. In addition, the choice of the second-line chemotherapeutic agent could affect the survival results. Although there are conflicting opinions, recent systemic reviews and meta-analyses reported that EGFR TKI showed inferior efficacy in patients with wild-type EGFR NSCLC, and they insisted that chemotherapy should be the standard treatment in the second-line therapy for these patients [19, 20]. In our study, a higher percentage of patients in the PP group was treated with EGFR TKI as the secondline treatment than in the NPP group. This could be another explanation for the lack of a difference in the survival of patients between the PP and the NPP group found in our study. Based on our results, no difference in OS and PFS was observed among patients treated with several platinum combinations as well as between the PP and the NPP group. A higher number of patients in the PP group received maintenance treatment than in the NPP group. However, the survival results were independent of the proportion of patients who received maintenance treatment after response to the first-line platinum doublet. BeKang/Min/Hur/Lee/Shim/Kang/Oh/Seo/ Kim
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TKI, whereas 20 (27.8%) patients in the NPP group received TKI as second-line treatment (table 5). However, OS was not different between TKI treatment and conventional chemotherapy (p = 0.74, data not shown).
cause continuation of maintenance with pemetrexed is now allowed in Korea, studies in a larger cohort with a follow-up duration are needed for more detailed data. In this study, the subgroup analysis showed no significant difference between the two treatment regimens. Additionally, similar results were observed when analyzing prognostic factors. Patients who had M1a metastasis and patients who were treated with more than second-line chemotherapy after the first-line treatment were associated with prolonged survival in the PP group as well as in the NPP group. A clear explanation of the relationship between metastatic sites and prognosis is not available. However, patients with metastases of the respiratory system showed better survival in a population-based analysis on metastatic sites and survival [21]. On the contrary, patients with liver or bone metastases featured poor survival in this report [21]. Intrathoracic metastasis, which is classified as M1a, would be a favorable prognostic factor in patients with wild-type EGFR nonsquamous NSCLC irrespective of the first-line chemotherapeutic regimen. Limitations of this study include the fact that this is a retrospective analysis and the absence of toxicity evaluation according to each chemotherapeutic regimen. PP has been shown to present fewer patients with grade 3 or 4 of hematologic toxicity [13, 15, 22], and a longer survival without toxicity was reported for patients treated with pemetrexed plus cisplatin compared to patients treated with gemcitabine plus cisplatin [13]. In our study, the median number of treatment cycles for each treatment regi-
men was not significantly different and no patient stopped chemotherapy due to drug-related toxicity. A more detailed analysis, including toxicity evaluation, would be needed since similar efficacies are observed in this study. An intensive investigation of toxicity and prognostic or predictive markers for each chemotherapeutic regimen could be helpful to determine the best choice for personalized treatment.
Conclusion
This study is the first study to compare the efficacy of several platinum combination regimens as first-line treatment in patients with wild-type EGFR nonsquamous NSCLC. We can conclude that platinum doublets, such as pemetrexed, gemcitabine or taxane plus platinum combinations, have comparable efficacies. Therefore, these platinum doublets could be selected considering the toxicities of each regimen for wild-type EGFR nonsquamous NSCLC. Our results could be a practical guide for the selection of first-line platinum doublets for patients with wild-type EGFR nonsquamous NSCLC in this EGFR TKI era.
Disclosure Statement The authors have no conflict of interest.
1 Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-Small Cell Lung Cancer Collaborative Group. BMJ 1995;311:899–909. 2 Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361:947–957. 3 Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K, Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S, Shimizu E, Saito H, Toyooka S, Nakagawa K, Fukuoka M; West Japan Oncology Group: Gefitinib versus cisplatin plus docetaxel in pa-
Several Platinum Doublet Combinations in EGFR Wild-Type NSCLC
tients 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; 11:121–128. 4 Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T; North-East Japan Study Group: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362: 2380–2388. 5 Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, GarciaGomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A,
Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Munoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, RodriguezAbreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish Lung Cancer Group in collaboration with Groupe Francais de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica: Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13: 239–246.
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49
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References
50
11 Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D: Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008;26:3543–3551. 12 Yang CH, Simms L, Park K, Lee JS, Scagliotti G, Orlando M: Efficacy and safety of cisplatin/ pemetrexed versus cisplatin/gemcitabine as first-line treatment in East Asian patients with advanced non-small cell lung cancer: results of an exploratory subgroup analysis of a phase III trial. J Thorac Oncol 2010; 5: 688– 695. 13 Wu YL, Lu S, Cheng Y, Zhou C, Wang M, Qin S, Lu Y, Zhang Y, Zhu Y, Song X, Wang X, Barraclough H, Zhang X, Chi H, Orlando M: Efficacy and safety of pemetrexed/cisplatin versus gemcitabine/cisplatin as first-line treatment in Chinese patients with advanced nonsquamous non-small cell lung cancer. Lung Cancer 2014;85:401–407. 14 Treat J, Scagliotti GV, Peng G, Monberg MJ, Obasaju CK, Socinski MA: Comparison of pemetrexed plus cisplatin with other first-line doublets in advanced non-small cell lung cancer (NSCLC): a combined analysis of three phase 3 trials. Lung Cancer 2012;76:222–227. 15 Gronberg BH, Bremnes RM, Flotten O, Amundsen T, Brunsvig PF, Hjelde HH, Kaasa S, von Plessen C, Stornes F, Tollali T, Wammer F, Aasebo U, Sundstrom S: Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced nonsmall-cell lung cancer. J Clin Oncol 2009; 27: 3217–3224.
Chemotherapy 2015–16;61:41–50 DOI: 10.1159/000440941
16 Gridelli C, Paz-Ares L: The PARAMOUNT study and the re-challenge chemotherapy issue in advanced non-small cell lung cancer. Eur J Cancer 2013;49:2271–2272. 17 Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS: Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 2011; 29: 2866– 2874. 18 Jiang X, Yang B, Lu J, Zhan Z, Li K, Ren X: Pemetrexed-based chemotherapy in advanced lung adenocarcinoma patients with different EGFR genotypes. Tumor Biol 2015; 36:861–869. 19 Laurie SA, Goss GD: Role of epidermal growth factor receptor inhibitors in epidermal growth factor receptor wild-type nonsmall-cell lung cancer. J Clin Oncol 2013; 31: 1061–1069. 20 Lee JK, Hahn S, Kim DW, Suh KJ, Keam B, Kim TM, Lee SH, Heo DS: Epidermal growth factor receptor tyrosine kinase inhibitors vs conventional chemotherapy in non-small cell lung cancer harboring wild-type epidermal growth factor receptor: a meta-analysis. JAMA 2014;311:1430–1437. 21 Riihimaki M, Hemminki A, Fallah M, Thomsen H, Sundquist K, Sundquist J, Hemminki K: Metastatic sites and survival in lung cancer. Lung Cancer 2014;86:78–84. 22 Zhang X, Lu J, Xu J, Li H, Wang J, Qin Y, Ma P, Wei L, He J: Pemetrexed plus platinum or gemcitabine plus platinum for advanced nonsmall cell lung cancer: final survival analysis from a multicentre randomized phase II trial in the East Asia region and a meta-analysis. Respirology 2013;18:131–139.
Kang/Min/Hur/Lee/Shim/Kang/Oh/Seo/ Kim
Downloaded by: Siriraj Medical Library, Mahidol University 198.143.39.97 - 3/27/2016 4:21:51 PM
6 Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabarbara P, Seymour L; National Cancer Institute of Canada Clinical Trials Group: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–132. 7 Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, Thongprasert S, Tan EH, Pemberton K, Archer V, Carroll K: Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (IRESSA Survival Evaluation in Lung Cancer). Lancet 2005; 366: 1527– 1537. 8 Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, Majem M, Lopez-Vivanco G, Isla D, Provencio M, Insa A, Massuti B, Gonzalez-Larriba JL, Paz-Ares L, Bover I, GarciaCampelo R, Moreno MA, Catot S, Rolfo C, Reguart N, Palmero R, Sanchez JM, Bastus R, Mayo C, Bertran-Alamillo J, Molina MA, Sanchez JJ, Taron M; Spanish Lung Cancer Group: Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361:958–967. 9 Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT, Heeroma K, Itoh Y, Cornelio G, Yang PC: A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014;9:154–162. 10 Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92–98.
Received: February 27, 2015 Accepted: September 7, 2015 Published online: November 1, 2015
Comparison of the Efficacy between Pemetrexed plus Platinum and Non-Pemetrexed plus Platinum as First-Line Treatment in Patients with Wild-Type Epidermal Growth Factor Receptor Nonsquamous Non-Small Cell Lung Cancer: A Retrospective Analysis Eun Joo Kang Kyung Hoon Min Gyu Young Hur Sung Yong Lee Jae Jeong Shim Kyung Ho Kang Sang Cheul Oh Jae Hong Seo Jun Suk Kim Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
Abstract Background: Despite the development of molecular research and targeted therapy, patients with wild-type epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) still receive platinum doublet chemotherapy as the standard first-line treatment. We investigated the efficacy of first-line regimens in patients with wild-type EGFR nonsquamous NSCLC. Methods: We retrospectively analyzed the efficacy of various platinum doublet regimens as first-line treatments. Between 2007 and 2013, a total of 165 patients with wild-type EGFR nonsquamous NSCLC were included in this study. Results: Seventy-one (43.0%) patients were treated with pemetrexed plus platinum (PP) and 94 (57.0%) with non-pemetrexed plus platinum (NPP). The overall response rate was not different between the PP- and NPP-treated groups (26.8 vs. 28.7%, respectively; p = 0.78). The median progression-free survival (PFS) and overall survival (OS) also
© 2015 S. Karger AG, Basel 0009–3157/15/0611–0041$39.50/0 E-Mail [email protected] www.karger.com/che
showed no differences between the two treatment groups (p = 0.12 for PFS, p = 0.42 for OS). The median PFS and OS for the PP group were 4.6 months (95% CI, 3.8–5.4) and 18.7 months (95% CI, 11.7–25.8), respectively, and for the NPP group, they were 4.2 months (95% CI, 3.4–5.0) and 12.2 months (95% CI, 10.3–14.1), respectively. In the subgroup analysis, most subgroups showed no significant difference in PFS and OS between the two treatment groups. Conclusion: Our data showed that the efficacy of various platinum doublet regimens was similar in patients with wild-type EGFR nonsquamous NSCLC. © 2015 S. Karger AG, Basel
Introduction
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. The use of chemotherapy has led to the prolonged survival of patients with advanced, metastatic NSCLC. A two-drug combination, also called ‘platinum doublet’, which includes platinum (e.g. cisplatin or carboplatin) and a non-platinum Sung Yong Lee, MD, PhD Department of Internal Medicine, Korea University Guro Hospital 148, Gurodong-ro, Guro-gu Seoul 152-703 (Republic of Korea) E-Mail dragonett @ naver.com
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Key Words Epidermal growth factor receptor · First-line chemotherapy · Non-small cell lung carcinoma · Wild type
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pemetrexed plus platinum (PP) for patients with wildtype EGFR nonsquamous NSCLC. Notably, we attempted to determine whether PP shows superior results in patients with wild-type EGFR nonsquamous NSCLC. Patients and Methods Patients Patients with wild-type EGFR nonsquamous NSCLC who received platinum doublet chemotherapy as the first-line treatment at the Korea University Guro Hospital between January 2007 and December 2013 were included in this retrospective study. All patients had to meet the following criteria: histologically confirmed nonsquamous NSCLC with distant metastases or recurrent disease after surgical resection, wild-type EGFR confirmed by direct sequencing or peptide nucleic acid (PNA) clamping method using the PNA ClampTM EGFR mutation detection kit (Panagene, Inc., Daejeon, Korea), platinum doublet chemotherapy as first-line treatment and no concurrent active malignancy other than NSCLC. Patients who received a single chemotherapeutic agent or platinum doublet combining targeted therapies with cetuximab or bevacizumab and patients who were enrolled in clinical trials as well as patients who received platinum doublet chemotherapy with concurrent chemoradiotherapy were excluded. Data were collected from the electronic medical records. This study was approved by the Institutional Review Boards of the Korea University Guro Hospital. Data Collection For each patient, the following data were collected and analyzed: age, sex, tumor histology, stage at diagnosis, site(s) of metastases and the number of organs in which a metastasis was found during the first-line chemotherapy, and performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) at the beginning of the first-line chemotherapy. In addition, we analyzed the following data: type of chemotherapy regimen, start and end date of chemotherapy, and response and best response to the first-line chemotherapy according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) guidelines. Patient responses were assessed at 2- to 3-month intervals with enhanced computed tomography. Magnetic resonance imaging, fluorodeoxyglucose positron emission tomography and bone scans were performed based on the physician’s decision. Chemotherapy Regimens Various platinum doublet regimens were used and classified into the following categories: (i) PP (all regimens combining pemetrexed and cisplatin or carboplatin); (ii) taxane + platinum (all regimens combining docetaxel or paclitaxel plus cisplatin or carboplatin); (iii) gemcitabine + platinum (all regimens combining gemcitabine plus cisplatin or carboplatin), and (iv) other agents + platinum (all regimens combining vinorelbine, etoposide or irinotecan plus cisplatin or carboplatin). Statistical Analyses All patients who received at least one cycle of first-line chemotherapy were included in the analysis of efficacy. Rates were compared using the χ2 test. The Kaplan-Meier method was used to estimate overall (OS) and progression-free survival (PFS). PFS was
Kang/Min/Hur/Lee/Shim/Kang/Oh/Seo/ Kim
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drug (e.g. pemetrexed, gemcitabine, taxane or vinorelbine) has been used as the standard first-line treatment in these patients for many years [1]. However, due to the vast development in molecular research and targeted therapy, the NSCLC treatment paradigm has changed. Notably, the use of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), such as erlotinib or gefitinib, resulted in improved response rates and prolonged survival in patients with EGFR mutation-positive NSCLC [2–5]. Therefore, EGFR TKI is approved as the first-line treatment for patients with EGFR mutationpositive NSCLC, and previous studies also demonstrated the favorable efficacy of TKI as second-line treatment in patients with NSCLC irrespective of the EGFR mutation status [6, 7]. Because EGFR mutations have been reported in 10–50% of lung adenocarcinoma cases [8, 9], more than half of the patients with adenocarcinoma and most patients with squamous cell carcinoma should be treated with platinum doublet chemotherapy as first-line treatment. While drug development for EGFR mutation-positive NSCLC progressed tremendously, only little progress has been made for the treatment of patients with wild-type EGFR NSCLC. Except for some trials that were performed only with patients with EGFR mutation-positive NSCLC for the efficacy of EGFR TKI, most clinical studies in NSCLC patients have not addressed the EGFR mutation status. Until now, no study has been conducted to compare the efficacy of various platinum doublet regimens in the treatment of patients with wild-type EGFR NSCLC. A randomized study that compared four platinum doublet regimens, paclitaxel plus cisplatin, gemcitabine plus cisplatin, docetaxel plus cisplatin or paclitaxel plus carboplatin, showed similar advantages over other regimens [10]. However, treatment response and survival were somewhat different according to the tumor histology in a phase III study comparing gemcitabine plus cisplatin with pemetrexed plus cisplatin in patients with NSCLC. Gemcitabine plus cisplatin showed superior results in squamous cell carcinomas, but pemetrexed plus cisplatin showed superior results in adenocarcinomas [11]. Since this study, several studies also reported superior survival results with the use of pemetrexed plus cisplatin in nonsquamous NSCLC. Thus, pemetrexed plus cisplatin is the preferred treatment for nonsquamous NSCLC [12, 13]. However, these results are also from studies conducted in patients with NSCLC regardless of EGFR mutation status. Thus, we performed this study to compare the efficacy of various platinum doublet regimens, including
Table 1. Patient characteristics
Characteristics
Total
PP
NPP
p value
Patients, n Age, years Range Sex Male Female Histology Adenocarcinoma Large cell carcinoma Other Smoking history Never-smoker Current/ex-smoker Stage at diagnosis Stage I–IIIA Stage IIIB–IV ECOG PS 0 1–2 Response CR + PR SD + PD Maintenance treatment Continuation Switch None After first-line treatment First line only ≥Second line Not known Metastatic organs 0–2 ≥3 Brain metastasis Yes No
165 (100.0) 66 29 – 85
71 (43.0) 63 31 – 85
94 (57.0) 68 29 – 81
0.44
118 (71.5) 47 (28.5)
44 (62.0) 27 (38.0)
74 (78.7) 20 (21.3)
151 (91.5) 5 (3.0) 9 (5.5)
66 (93.0) 3 (4.2) 2 (2.8)
85 (90.4) 2 (2.2) 7 (7.4)
62 (37.6) 103 (62.4)
30 (42.3) 41 (57.7)
32 (34) 62 (66)
20 (12.1) 145 (87.9)
11 (15.5) 60 (84.5)
9 (9.6) 85 (90.4)
54 (32.7) 111 (67.3)
29 (40.8) 42 (59.2)
25 (26.6) 69 (73.4)
46 (27.9) 119 (72.1)
19 (26.8) 52 (73.2)
27 (28.7) 67 (71.3)
12 (7.3) 3 (1.8) 150 (90.9)
12 (16.9) 0 59 (83.1)
0 3 (3.2) 91 (96.8)
38 (23.0) 121 (73.3) 6 (3.6)
19 (69.0) 49 (26.8) 3 (4.2)
19 (76.6) 72 (20.2) 3 (3.2)
132 (80) 33 (20)
59 (83.1) 12 (16.9)
73 (77.7) 21 (22.3)
28 (17) 137 (83)
15 (21.1) 56 (78.9)
13 (13.8) 81 (86.2)
0.02 0.33
0.28 0.18 0.05 0.78
0.00 0.55
0.39 0.22
Figures in parentheses are percentages. CR = Complete response; PR = partial response; SD = stable disease; PD = progressive disease.
Patient Characteristics Between January 2007 and December 2013, a total of 534 patients with NSCLC received chemotherapy at our institution, and 165 patients with wild-type EGFR nonsquamous NSCLC who received platinum doublet chemotherapy as the palliative first-line treatment were included in this analysis. The patient characteristics are listed in table 1. Median age was 66 years (range: 29–85). There were 118 males (71.5%) and 47 females (28.5%). Of
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Results
measured from the initiation of the first-line chemotherapy until the first occurrence of progressive disease, death from any cause or the last follow-up if none of the preceding events had occurred. OS was determined by the interval between the 1st day of first-line treatment and death or the last day of the follow-up. The difference between the curves was analyzed using the log-rank test. After univariate analyses using the Kaplan-Meier method, variables significantly associated with poor survival (variables with p < 0.05) were selected, and a Cox proportional hazard regression was conducted for multivariate analyses by the ‘ENTER’ method. The Statistical Package for the Social Sciences for Windows (version 20.0; SPSS Inc., Chicago, Ill., USA) was used for all statistical analysis. A value of p < 0.05 was considered statistically significant.
the 165 patients, 151 (91.5%) were diagnosed with adenocarcinoma, 5 (3.0%) with large-cell carcinoma, and 9 (5.5%) were diagnosed with another histology (4 with sarcomatoid carcinoma, 2 with undifferentiated carcinoma, 2 with adenosquamous cell carcinoma and 1 with pleomorphic carcinoma). Wild-type EGFR was detected using the PNA clamping method in 84 (50.9%) patients and by direct sequencing in 81 (49.1%) patients. At initial diagnosis, 145 (87.9%) patients were diagnosed with stage IIIB or IV disease and treated with chemotherapy as firstline treatment; 20 (12.1%) patients were diagnosed with stage I–IIIA at initial diagnosis and received chemotherapy due to recurrence after curative surgery. Sixty-two (37.6%) patients were never-smokers, 27 (16.4%) were ex-smokers, and 76 (46.1%) were current smokers. One
Table 2. First-line chemotherapeutic regimens
Regimens
n
Pemetrexed + platinum Pemetrexed + cisplatin Non-pemetrexed + platinum Gemcitabine + platinum Gemcitabine + cisplatin Gemcitabine + carboplatin Taxane + platinum Docetaxel + carboplatin Docetaxel + cisplatin Paclitaxel + carboplatin Paclitaxel + cisplatin Other agents + platinum Vinorelbine + cisplatin Etoposide + carboplatin Etoposide + cisplatin Irinotecan + carboplatin Total
%
71
43.0
17 35
10.3 21.2
1 11 18 7
0.6 6.7 10.9 4.2
2 1 1 1
1.2 0.6 0.6 0.6
165
100
hundred and twenty-one (73.3%) patients received at least second-line chemotherapy after failure of the firstline treatment. Thirty-one (18.8%) patients received third-line chemotherapy and 44 (26.7%) received more than fourth-line chemotherapy. Among the 165 patients, 71 (43%) were treated with PP, and all patients in this group were treated with cisplatin. Ninety-four (57.0%) patients were treated with non-pemetrexed plus platinum (NPP); the regimens are listed in table 2. In the NPP group, 52 (31.5%) patients were treated with gemcitabine plus platinum and 37 (22.4%) patients were treated with taxane plus platinum. Patients treated with PP were relatively young, and the proportion of female patients in this group was higher than that in the NPP group (p = 0.018). The median number of treatment cycles was 5 (range: 1–8) in the PP group and 4 (range: 1–10) in the NPP group. In Korea, some maintenance regimens are permitted and partially covered by health insurance since 2012; only 15 (9.1%) patients received treatment continuation or switched to maintenance treatment. Among the 71 patients in the PP group, 12 (16.9%) received continuation of pemetrexed maintenance after 4 cycles of pemetrexed plus cisplatin treatment. In the NPP group, 3 (3.2%) patients were switched to maintenance (2 used erlotinib and 1 used pemetrexed) treatment and none received continuation maintenance. Except for sex and maintenance treatment, there was no significant difference in the clinical characteristics of the patients between the two treatment groups. Efficacy of Platinum Doublet Regimens Of the 165 patients, the best responses were complete remission in 3 patients (1.9%) and partial remission in 39 patients (25.2%). The overall response rate (ORR), including complete and partial remissions, was 26.8% in the PP group and 28.7% in the NPP group; there was no statistical difference in ORR between the two treatment
Table 3. Efficacy analysis
CR
PR
SD
Pemetrexed + platinum Gemcitabine + platinum Taxane + platinum Other agents + platinum
1 (1.5) 0 2 (5.9) 0
18 (26.9) 13 (26.0) 8 (23.5) 0
40 (59.7) 30 (60.0) 20 (58.8) 4 (100.0)
Total
3 (1.9)
39 (39.0)
94 (60.6)
PD
NE
Total
8 (11.9) 7 (14.0) 4 (11.8) 0
4 2 3 1
71 52 37 5
19 (12.3)
10
165
44
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Kang/Min/Hur/Lee/Shim/Kang/Oh/Seo/ Kim
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Figures in parentheses are percentages. CR = Complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = not evaluable.
groups (p = 0.78). ORR of the gemcitabine plus platinum group was 26.0% and ORR of the taxane plus platinum subgroup was 29.4%. The efficacy analysis of the platinum combinations is presented in table 3. No difference was also observed in median PFS and OS between the PP and the NPP group (p = 0.12 for PFS and p = 0.42 for OS). The median PFS and OS for all pa-
1.0
1.0
Pemetrexed + platinum Gemcitabine + platinum Taxane + platinum Other agents + platinum
0.8
OS p = 0.82
0.6
Pemetrexed + platinum
0.4
Non-pemetrexed + platinum
0.8 Cumulative survival
Cumulative survival
tients who received first-line platinum doublet were 4.3 months [95% confidence interval (CI), 4.0–4.6] and 14.3 months (95% CI, 9.7–18.9), respectively. The median PFS and OS of the PP group were 4.6 months (95% CI, 3.8–5.4) and 18.7 months (95% CI, 11.7–25.8), respectively, and those of the NPP group were 4.2 months (95% CI, 3.4–5.0) and 12.2 months (95% CI, 10.3–14.1), re-
OS p = 0.42 0.6
0.4
0.2
0.2
0
0 0
12
24
a
48
60
72
84
96
Time (months)
1.0
0
0.4
36
48
60
72
84
96
Time (months)
Pemetrexed + platinum Non-pemetrexed + platinum 0.8
0.2
PFS p = 0.12
0.6
0.4
0.2
0
0
10
20 Time (months)
30
40
0
12
d
24
36
Time (months)
Fig. 1. OS (a, b) and PFS (c, d) according to the chemotherapeutic regimens. a, c Various platinum doublet regimens. b, d PP and NPP groups.
Several Platinum Doublet Combinations in EGFR Wild-Type NSCLC
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0
c
24
1.0
Cumulative survival
PFS p = 0.07
0.6
12
b
Pemetrexed + platinum Gemcitabine + platinum Taxane + platinum Other agents + platinum
0.8 Cumulative survival
36
HR (95% CI) Age >70 years Age 70 years Male Female Current/ex-smoker Never-smoker ECOG PS 0 ECOG PS 1–2 Stage at diagnosis: I–IIIA Stage at diagnosis: IIIB–IV Number of metastases: 3 Number of metastases: 0–2 Bone metastasis only Others Lung and/or pleural metastases only Other Brain metastasis No brain metastasis Second-line treament: TKI Second-line treatment: chemotherapy
0.84 (0.52–1.35) 1.04 (0.54–2.01) 0.89 (0.57–1.40) 1.21 (0.55–2.64) 0.90 (0.48–1.69) 0.88 (0.54–1.42) 3.38 (0.65–17.5) 1.00 (0.68–1.49) 0.87 (0.28–1.15) 1.11 (0.70–1.74) 0.87 (0.60–1.35) 1.13 (0.52–2.44) 1.32 (0.26–6.60) 0.83 (0.56–1.22) 0.69 (0.35–1.32) 0.89 (0.54–1.45) 1.14 (0.46–2.69) 0.80 (0.52–1.22) 0.76 (0.36–1.61) 0.88 (0.45–1.73) 0.5
a
50
5
Favors PP
Favors NPP HR (95% CI) 0.76 (0.51–1.13) 0.78 (0.44–1.38) 0.85 (0.58–1.24) 0.67 (0.36–1.24) 0.76 (0.50–1.14) 0.79 (0.46–1.35) 1.33 (0.95–1.88) 0.77 (0.28–2.22) 0.68 (0.40–1.18) 0.83 (0.55–1.23) 0.80 (0.56–1.14) 0.68 (0.31–1.50) 0.46 (0.12–1.84) 0.81 (0.58–1.13) 0.99 (0.61–1.60) 0.60 (0.38–0.96) 0.84 (0.37–1.88) 0.75 (0.53–1.06) 0.86 (0.47–1.56) 0.81 (0.49–1.35)
Age >70 years Age 70 years Male Female Current/ex-smoker Never-smoker ECOG PS 0 ECOG PS 1–2 Stage at diagnosis: I–IIIA Stage at diagnosis: IIIB–IV Number of metastases: 3 Number of metastases: 0–2 Bone metastasis only Other Lung and/or pleural metastases only Other Brain metastasis No brain metastasis Second-line treament: TKI Second-line treatment: chemotherapy 0
b
0.5 Favors PP
1.0
1.5
2.0
2.5
Favors NPP
spectively. In detail, the median PFS and OS of the taxane plus platinum subgroup were 4.2 months (95% CI, 2.4– 5.9) and 11.4 months (95% CI, 5.5–17.3), respectively. The median PFS and OS of the gemcitabine plus platinum subgroup were 3.7 months (95% CI, 2.4–5.0) and 46
Chemotherapy 2015–16;61:41–50 DOI: 10.1159/000440941
12.6 months (95% CI, 9.5–15.7), respectively. There was no statistical difference in median PFS and median OS according to the treatment regimens (p = 0.07 for PFS and p = 0.82 for OS). The survival curves for PFS and OS are shown in figure 1. Kang/Min/Hur/Lee/Shim/Kang/Oh/Seo/ Kim
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Fig. 2. a Subgroup analysis: OS (a) and PFS (b).
Table 4. Multivariate analysis for prognostic factors
Sex (male vs. female) Smoking history (current/ex- vs. never-smoker) ECOG PS (0 – 1 vs. 2) Stage at diagnosis (stage IIIB–IV vs. I–IIIA) Number of metastases (≥3 vs. 0 – 2) Metastatic organ (M1b vs. M1a) Treatment after first line (≥second-line vs. first-line treatment only)
PP
NPP
HR
95% CI
p value
HR
95% CI
p value
HR
95% CI
p value
– – 0.83 9.00 1.70 3.07
– – 0.40 to 1.75 2.00 to 40.37 0.76 to 3.81 1.40 to 6.72
– – 0.63 0.00 0.20 0.01
1.63 – – – 1.45 1.72
0.89 to 2.97 – – – 0.80 to 2.63 1.01 to 2.93
0.12 – – – 0.23 0.05
1.25 1.10 – 2.49 1.60 1.86
0.70 to 2.26 0.64 to 1.84 – 1.25 to 4.94 0.99 to 2.57 1.21 to 2.84
0.45 0.75 – 0.01 0.05 0.00
4.34
2.03 to 9.30
0.00
3.62
2.06 to 6.36
0.00
3.29
2.15 to 5.01
0.00
Subgroup Analysis for OS and PFS In order to find differences in PFS or OS according to the treatment groups, we conducted subgroup analysis between the PP and the NPP group using Cox regression analysis. As shown in figure 2, for PFS, patients who had metastases, excluding the lung and pleura at the time of first-line chemotherapy, showed superior results when they were treated with PP (p = 0.03). No statistical significance was found and no statistically significant results were observed for PFS and OS for most other subgroups. Clinical Parameters Related to Treatment Outcomes Univariate analysis showed that the OS for patients treated with PP was significantly associated with the following factors: stage at diagnosis (stage I–IIIA vs. stage IIIB–IV), ECOG PS (0 vs. 1–2), number of organs with metastases (0–2 vs. ≥3), metastatic organs (M1a vs. M1b) and treatment after failure of first-line chemotherapy (≥second-line chemotherapy vs. first-line treatment only). For patients who were treated with NPP, univariate analysis showed that OS was significantly associated with the following factors: gender (male vs. female), number of organs with metastases (0–2 vs. ≥3), metastatic organs (M1a vs. M1b) and treatment after failure of first-line chemotherapy (≥second-line chemotherapy vs. first-line treatment only). We then conducted multivariate analysis for each treatment group using a Cox proportional hazard regression model. In patients treated with PP, stage I–IIIA disease at diagnosis, M1a stage and treatment continuation with more than second-line chemotherapy after the first-line treatment were associated with prolonged OS. In patients treated with NPP, metastasis confined to the lung and/or pleura and more than second-line chemotherapy after the first-line treatment were associated with prolonged OS. For all patients, stage I–IIIA disease at diagnosis and lower number of metastases (0–2), M1a metastasis and more Several Platinum Doublet Combinations in EGFR Wild-Type NSCLC
All patients
Table 5. Treatment after failure of first-line chemotherapy
Characteristics/regimen
PP
NPP
Total
Patients, n First-line treatment only ≥Second-line treatment ≤Second line ≤Third line ≥Fourth line Not known Second-line treatment TKI Chemotherapy
71 (43.0) 19 (26.8) 49 (69.0) 17 (23.9) 12 (16.9) 20 (28.2) 3 (4.2) 49 (40.5) 27 (55.1) 22 (44.9)
94 (57.0) 165 19 (20.2) 38 (23.0) 72 (76.6) 121 (73.3) 29 (30.9) 46 (27.9) 19 (20.2) 31 (18.8) 24 (25.5) 44 (26.7) 3 (3.2) 6 (3.6) 72 (59.5)* 121 20 (27.8) 47 (38.8) 52 (72.2) 74 (61.2)
Figures in parentheses are percentages. * p = 0.002.
than second-line treatment after the first-line chemotherapy were associated with prolonged OS (table 4). Relationship between Chemotherapeutic Regimens and Treatment after Failure of the First-Line Chemotherapy Because treatment after failure of the first-line chemotherapy is closely connected with OS, we investigated treatment after first-line chemotherapy in detail. Of the 71 patients in the PP group, 49 (69.0%) had more than second-line chemotherapy and 72 (76.6%) of the 94 patients in the NPP group had more than second-line chemotherapy. In the PP and NPP groups, 28.2 and 25.5% of the patients received more than fourth-line chemotherapy, respectively. Among the 121 patients who received second-line chemotherapy, 47 (38.8%) received TKI and 74 (61.2%) received conventional chemotherapy. The difference was observed in the proportion of patients who were treated with TKI between the PP and NPP groups (p = 0.002). In the PP group, 27 (55.1%) patients received Chemotherapy 2015–16;61:41–50 DOI: 10.1159/000440941
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Multivariate analysis
Discussion
Although more than half of the patients with NSCLC do not have EGFR mutation, little is known about the best treatment for patients with wild-type EGFR NSCLC in clinical practice. These data indicate that the use of several platinum doublets as the first-line treatment show no significant differences in terms of response rate and survival in patients with wild-type EGFR nonsquamous NSCLC. Particularly, pemetrexed plus cisplatin did not show better results than the NPP combination in patients with wild-type EGFR nonsquamous NSCLC. Since the report of the JMDB study and some other studies [11–15], oncologists tend to choose pemetrexed plus cisplatin as the first-line treatment for nonsquamous cell type carcinoma. In addition, the superior survival of patients treated with pemetrexed continuation in the PARAMOUNT study, which analyzed the efficacy of the use of continuation of maintenance with pemetrexed after response to pemetrexed plus cisplatin in the first-line treatment, also empowered the selection of pemetrexed plus cisplatin [16]. However, these studies did not check EGFR mutation status in the tumor tissue of patients included and were conducted with patients regardless of EGFR mutation status; thus, we cannot assume the superiority of PP in case of patients with wild-type EGFR NSCLC. We cannot find the exact number of patients with wild-type or mutant EGFR NSCLC in each study, but we can suspect the proportion of mutant EGFR NSCLC through the percentage of female or never-smokers because EGFR mutations have been found more frequently in female neversmokers [17]. In the JMDB study by Scagliotti et al. [11], which included mostly white people (78% of all patients), 34.5% of the patients were female and 17.2% never-smokers. In the Grønberg study, which was performed in Norwegian patients, 28.7% of the patients were female and 7.5% never-smokers [15]. In the East Asian subgroup analysis of the JMDB study, females and never-smokers represented 38.1 and 50% of the patients, respectively, and 44.5 and 55.4% of the patients in a similar study conducted in Chinese patients with nonsquamous cell carcinoma [13]. Studies conducted in Asian patients included a higher proportion of never-smokers. Moreover, EGFR 48
Chemotherapy 2015–16;61:41–50 DOI: 10.1159/000440941
mutations are more frequently found in Asian patients [17]. Thus, we can suspect that the number of patients with EGFR mutations could be higher in studies performed in Asia than in studies conducted in Western countries. According to the report of Jiang et al. [18], the pemetrexed-cisplatin combination showed a better overall response in lung adenocarcinoma patients with EGFR mutations compared to those with wild-type EGFR. Actually, the OS of patients with nonsquamous NSCLC treated with pemetrexed plus cisplatin was much longer than that of Asian patients treated with gemcitabine plus cisplatin, and a larger gap was observed in terms of hazard ratio (HR) when compared to Western studies [12]. OS was 21.2 months and its HR was 0.7 for patients treated with pemetrexed plus cisplatin in the East Asian subgroup analysis of the JMDB study [12]. However, OS of patients treated with pemetrexed plus cisplatin was only 11.8 months and its HR was 0.81 in the JMDB study [11]. On the contrary, we can suspect that the efficacy of PP would be inferior in patients with wild-type EGFR NSCLC. No difference in survival was observed between the pemetrexed plus carboplatin group and the gemcitabine plus carboplatin group in the study of Grønberg, which was conducted in Norwegian patients, a population expected to have a much larger proportion of patients with wild-type EGFR NSCLC [15]. Thus, we cannot demonstrate the superiority of PP in the case of wild-type EGFR nonsquamous cell lung cancer through our results and that of previous studies. In addition, the choice of the second-line chemotherapeutic agent could affect the survival results. Although there are conflicting opinions, recent systemic reviews and meta-analyses reported that EGFR TKI showed inferior efficacy in patients with wild-type EGFR NSCLC, and they insisted that chemotherapy should be the standard treatment in the second-line therapy for these patients [19, 20]. In our study, a higher percentage of patients in the PP group was treated with EGFR TKI as the secondline treatment than in the NPP group. This could be another explanation for the lack of a difference in the survival of patients between the PP and the NPP group found in our study. Based on our results, no difference in OS and PFS was observed among patients treated with several platinum combinations as well as between the PP and the NPP group. A higher number of patients in the PP group received maintenance treatment than in the NPP group. However, the survival results were independent of the proportion of patients who received maintenance treatment after response to the first-line platinum doublet. BeKang/Min/Hur/Lee/Shim/Kang/Oh/Seo/ Kim
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TKI, whereas 20 (27.8%) patients in the NPP group received TKI as second-line treatment (table 5). However, OS was not different between TKI treatment and conventional chemotherapy (p = 0.74, data not shown).
cause continuation of maintenance with pemetrexed is now allowed in Korea, studies in a larger cohort with a follow-up duration are needed for more detailed data. In this study, the subgroup analysis showed no significant difference between the two treatment regimens. Additionally, similar results were observed when analyzing prognostic factors. Patients who had M1a metastasis and patients who were treated with more than second-line chemotherapy after the first-line treatment were associated with prolonged survival in the PP group as well as in the NPP group. A clear explanation of the relationship between metastatic sites and prognosis is not available. However, patients with metastases of the respiratory system showed better survival in a population-based analysis on metastatic sites and survival [21]. On the contrary, patients with liver or bone metastases featured poor survival in this report [21]. Intrathoracic metastasis, which is classified as M1a, would be a favorable prognostic factor in patients with wild-type EGFR nonsquamous NSCLC irrespective of the first-line chemotherapeutic regimen. Limitations of this study include the fact that this is a retrospective analysis and the absence of toxicity evaluation according to each chemotherapeutic regimen. PP has been shown to present fewer patients with grade 3 or 4 of hematologic toxicity [13, 15, 22], and a longer survival without toxicity was reported for patients treated with pemetrexed plus cisplatin compared to patients treated with gemcitabine plus cisplatin [13]. In our study, the median number of treatment cycles for each treatment regi-
men was not significantly different and no patient stopped chemotherapy due to drug-related toxicity. A more detailed analysis, including toxicity evaluation, would be needed since similar efficacies are observed in this study. An intensive investigation of toxicity and prognostic or predictive markers for each chemotherapeutic regimen could be helpful to determine the best choice for personalized treatment.
Conclusion
This study is the first study to compare the efficacy of several platinum combination regimens as first-line treatment in patients with wild-type EGFR nonsquamous NSCLC. We can conclude that platinum doublets, such as pemetrexed, gemcitabine or taxane plus platinum combinations, have comparable efficacies. Therefore, these platinum doublets could be selected considering the toxicities of each regimen for wild-type EGFR nonsquamous NSCLC. Our results could be a practical guide for the selection of first-line platinum doublets for patients with wild-type EGFR nonsquamous NSCLC in this EGFR TKI era.
Disclosure Statement The authors have no conflict of interest.
1 Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-Small Cell Lung Cancer Collaborative Group. BMJ 1995;311:899–909. 2 Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361:947–957. 3 Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K, Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S, Shimizu E, Saito H, Toyooka S, Nakagawa K, Fukuoka M; West Japan Oncology Group: Gefitinib versus cisplatin plus docetaxel in pa-
Several Platinum Doublet Combinations in EGFR Wild-Type NSCLC
tients 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; 11:121–128. 4 Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T; North-East Japan Study Group: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362: 2380–2388. 5 Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, GarciaGomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A,
Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Munoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, RodriguezAbreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish Lung Cancer Group in collaboration with Groupe Francais de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica: Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13: 239–246.
Chemotherapy 2015–16;61:41–50 DOI: 10.1159/000440941
49
Downloaded by: Siriraj Medical Library, Mahidol University 198.143.39.97 - 3/27/2016 4:21:51 PM
References
50
11 Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D: Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008;26:3543–3551. 12 Yang CH, Simms L, Park K, Lee JS, Scagliotti G, Orlando M: Efficacy and safety of cisplatin/ pemetrexed versus cisplatin/gemcitabine as first-line treatment in East Asian patients with advanced non-small cell lung cancer: results of an exploratory subgroup analysis of a phase III trial. J Thorac Oncol 2010; 5: 688– 695. 13 Wu YL, Lu S, Cheng Y, Zhou C, Wang M, Qin S, Lu Y, Zhang Y, Zhu Y, Song X, Wang X, Barraclough H, Zhang X, Chi H, Orlando M: Efficacy and safety of pemetrexed/cisplatin versus gemcitabine/cisplatin as first-line treatment in Chinese patients with advanced nonsquamous non-small cell lung cancer. Lung Cancer 2014;85:401–407. 14 Treat J, Scagliotti GV, Peng G, Monberg MJ, Obasaju CK, Socinski MA: Comparison of pemetrexed plus cisplatin with other first-line doublets in advanced non-small cell lung cancer (NSCLC): a combined analysis of three phase 3 trials. Lung Cancer 2012;76:222–227. 15 Gronberg BH, Bremnes RM, Flotten O, Amundsen T, Brunsvig PF, Hjelde HH, Kaasa S, von Plessen C, Stornes F, Tollali T, Wammer F, Aasebo U, Sundstrom S: Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced nonsmall-cell lung cancer. J Clin Oncol 2009; 27: 3217–3224.
Chemotherapy 2015–16;61:41–50 DOI: 10.1159/000440941
16 Gridelli C, Paz-Ares L: The PARAMOUNT study and the re-challenge chemotherapy issue in advanced non-small cell lung cancer. Eur J Cancer 2013;49:2271–2272. 17 Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS: Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 2011; 29: 2866– 2874. 18 Jiang X, Yang B, Lu J, Zhan Z, Li K, Ren X: Pemetrexed-based chemotherapy in advanced lung adenocarcinoma patients with different EGFR genotypes. Tumor Biol 2015; 36:861–869. 19 Laurie SA, Goss GD: Role of epidermal growth factor receptor inhibitors in epidermal growth factor receptor wild-type nonsmall-cell lung cancer. J Clin Oncol 2013; 31: 1061–1069. 20 Lee JK, Hahn S, Kim DW, Suh KJ, Keam B, Kim TM, Lee SH, Heo DS: Epidermal growth factor receptor tyrosine kinase inhibitors vs conventional chemotherapy in non-small cell lung cancer harboring wild-type epidermal growth factor receptor: a meta-analysis. JAMA 2014;311:1430–1437. 21 Riihimaki M, Hemminki A, Fallah M, Thomsen H, Sundquist K, Sundquist J, Hemminki K: Metastatic sites and survival in lung cancer. Lung Cancer 2014;86:78–84. 22 Zhang X, Lu J, Xu J, Li H, Wang J, Qin Y, Ma P, Wei L, He J: Pemetrexed plus platinum or gemcitabine plus platinum for advanced nonsmall cell lung cancer: final survival analysis from a multicentre randomized phase II trial in the East Asia region and a meta-analysis. Respirology 2013;18:131–139.
Kang/Min/Hur/Lee/Shim/Kang/Oh/Seo/ Kim
Downloaded by: Siriraj Medical Library, Mahidol University 198.143.39.97 - 3/27/2016 4:21:51 PM
6 Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabarbara P, Seymour L; National Cancer Institute of Canada Clinical Trials Group: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–132. 7 Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, Thongprasert S, Tan EH, Pemberton K, Archer V, Carroll K: Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (IRESSA Survival Evaluation in Lung Cancer). Lancet 2005; 366: 1527– 1537. 8 Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, Majem M, Lopez-Vivanco G, Isla D, Provencio M, Insa A, Massuti B, Gonzalez-Larriba JL, Paz-Ares L, Bover I, GarciaCampelo R, Moreno MA, Catot S, Rolfo C, Reguart N, Palmero R, Sanchez JM, Bastus R, Mayo C, Bertran-Alamillo J, Molina MA, Sanchez JJ, Taron M; Spanish Lung Cancer Group: Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361:958–967. 9 Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT, Heeroma K, Itoh Y, Cornelio G, Yang PC: A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014;9:154–162. 10 Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92–98.
