Lung Cancer 84 (2014) 51–55
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
A retrospective comparison of adjuvant chemotherapeutic regimens for non-small cell lung cancer (NSCLC): Paclitaxel plus carboplatin versus vinorelbine plus cisplatin Won Jin Chang, Jong-Mu Sun ∗ , Ji Yean Lee, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 16 September 2013 Received in revised form 18 January 2014 Accepted 20 January 2014 Keywords: Adjuvant chemotherapy Vinorelbine Cisplatin Non-small cell lung cancer Paclitaxel Carboplatin
a b s t r a c t Background: Adjuvant chemotherapy with vinorelbine plus cisplatin (NP) has been demonstrated to increase overall survival in patients with stage II or IIIA non-small cell lung cancer (NSCLC). Although paclitaxel plus carboplatin (PC) failed to demonstrate efficacy in patients with stage IB NSCLC, an exploratory analysis suggested that patients with large tumors can benefit from adjuvant PC therapy. Methods: Clinical outcomes of patients who received adjuvant NP or PC regimens after complete resection for their NSCLC were retrospectively compared. Results: Of the 438 patients with completely resected NSCLC, 207 received PC and 231 patients received NP. The median relapse-free survival (RFS) was not significantly different, with 63.6 months for the PC group and 54.8 months for the NP group (P = .68). Overall survival also did not differ significantly between the two groups. The five-year overall survival rates were 73% (95% confidence interval (CI), 66–80%) in PC group and 71% (95% CI, 64–78%) in NP group (P = .71). In the subgroup analysis, RFS was comparable between the two groups across all variables. Analysis of the adverse events indicated that sensory neuropathy, alopecia, and myalgia are more frequent in the PC, while anemia, neutropenia, fatigue, anorexia, and vomiting are more common in the NP. Conclusion: Although the adverse event profiles were different, the efficacy was comparable between the PC and NP regimens as adjuvant chemotherapy for NSCLC. While there is lack of prospective data, our retrospective data suggest that PC regimen can be considered as adjuvant chemotherapy for resected NSCLC. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Non-small-cell lung cancer (NSCLC) accounts more than 80% of all lung tumors and surgical resection is performed with curative intent in early-stage NSCLC. However, 30–70% of patients with surgically resected NSCLC develop recurrence, and early metastatic spread limits long-term overall survival (OS) [1]. Based on evidence from several large prospective studies and meta-analyses, adjuvant platinum-based chemotherapy is the standard treatment modality for completely resected stage II or III NSCLC [2–7]. However, the most appropriate regimen for adjuvant chemotherapy has not been determined. The combination regimen of
∗ Corresponding author at: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Republic of Korea. Tel.: +82 2 3410 1795; fax: +82 2 3410 1754. E-mail addresses: [email protected], [email protected] (J.-M. Sun). 0169-5002/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2014.01.017
vinorelbine plus cisplatin (NP) demonstrated efficacy in terms of disease-free survival (DFS) and OS in two independent studies: the JBR10 and ANITA studies, which respectively included NSCLC patients with tumor stage IB/II and IB/II/IIIA based on the sixth edition of the American Joint Committee on Cancer (AJCC) staging manual, showed that patients who received adjuvant NP lived longer than those without adjuvant chemotherapy [3,4]. In subgroup analyses, however, there was no difference in the survival rate between the groups with and without adjuvant NP chemotherapy in patients with stage IB disease. The CALGB 9633 trial, which included only tumor stage IB NSCLC based on the AJCC sixth edition, addressed the role of adjuvant paclitaxel and carboplatin (PC) regimen [3,4]. Although the preliminary results indicated that this PC regimen improved OS and DFS, leading to the early cessation of the enrollment by the recommendation of the Data and Safety Monitoring Board [5], a mature analysis failed to demonstrate the efficacy of this regimen for patients with stage IB disease [8]. Interestingly, however, the exploratory analysis showed that patients with large tumors (≥4 cm in diameter) got benefit from adjuvant
52
W.J. Chang et al. / Lung Cancer 84 (2014) 51–55
PC therapy in terms of DFS [8]. These data suggested that patients with large tumors or malignant lymph nodes, whose tumor stages could be defined as II or higher based on the revised AJCC seventh edition, would benefit from adjuvant PC regimen. In addition to the efficacy, toxicity profiles are important factors to be considered in the selection of the adjuvant chemotherapeutic regimen. Although its efficacy was demonstrated, the toxicity of the NP regimen has raised some concerns. Grade 3/4 hematologic toxicity and incomplete treatment delivery have been reported frequently in the NP treatment group in adjuvant trials [2,4,9]. Thus, an assessment of appropriate alternatives to the NP regimen that are tolerated better and have an efficacy comparable to that of the NP regimen is both timely and necessary. Previous randomized phase III trials showed that PC is equally efficacious as NP, with better tolerability, in the treatment of advanced NSCLC [10,11]. Given that the CALGB 9633 trial was an underpowered study due to the early cessation of enrollment and the strict eligibility criteria, which included only stage IB disease, adjuvant PC regimen could be an alternative adjuvant therapy for NSCLC. In this study, we compared the clinical outcomes of patients on one of these two regimens, PC and NP, as adjuvant chemotherapy for NSCLC.
Table 1 Patients characteristics.
2. Patients and methods
Abbreviations: PC, paclitaxel, carboplatin; NP, vinorelbine, cisplatin. Based on the American Joint Committee on Cancer seventh edition.
Age (years), median Gender Male Female Smoking status Never smoker Ex-smoker Current smoker Histology Adenocarcinoma Squamous cell carcinoma Large cell neuroendocrine carcinoma Others Pathological stage Ib IIa IIb IIIa Surgical procedure Lobectomy Pneumonectomy
PC (n = 207, %)
NP (n = 231, %)
63 (35–80)
59 (30–76)
156 (75.4) 51 (24.6)
161 (69.7) 70 (30.3)
62 (30.0) 84 (40.6) 61 (29.5)
77 (33.3) 72 (31.2) 82 (35.5)
112 (54.1) 84 (40.6) 5 (2.4)
143 (61.9) 77 (33.3) 6 (2.6)
P value .05 for all variables). Non-hematological toxic effects including sensory neuropathy (43% vs. 11%), alopecia (18% vs. 4%), and myalgia (34% vs. 5%) were more frequent in the PC group, while the incidence of fatigue (11% vs. 18%), anorexia (18% vs. 41%), nausea (16% vs.57%), and vomiting (9% vs. 19%) was higher in the NP group. In the NP group, PICCs were inserted in 142 (61.5%) patients, and grade 1/2
4. Discussion The present study showed that the efficacy of adjuvant PC regimen was similar to that of NP in terms of RFS and OS. Any retrospective study is likely to be associated with selection bias, which complicates the comparison of two treatment modalities. To our knowledge, however, there is no report or ongoing prospective
54
W.J. Chang et al. / Lung Cancer 84 (2014) 51–55
Fig. 2. Subgroup analysis of relapse-free survival.
study to compare these two regimens in the adjuvant setting in NSCLC. Our institute has established a protocol for adjuvant chemotherapy for NSCLC, and all patients with stage IB to IIIA NSCLC have been treated with either the PC or NP regimen according to the protocol. The selection of the regimen, PC or NP, was based on the physicians’ discretion or preference. Accordingly, the baseline clinical characteristics were well-balanced between two groups analyzed in this study, indicating that our study population was not considerably biased, despite the retrospective nature of the study. Furthermore, among recurrent 185 patients, epidermal growth factor receptor (EGFR) mutation test was done in 102 patients (PC, n = 52; NP, n = 50) and the status of activating EGFR (deletion in exon 19 and L858R mutation) was not different between PC and NP group. (PC: deletion in exon 19, n = 9; L858R
mutation, n = 6 versus NP: deletion in exon 19, n = 13; L858R mutation, n = 7). While previous phase III trials demonstrated the efficacy of adjuvant NP, the efficacy of adjuvant PC has not been demonstrated in a prospective trial [3,4]. However, the exploratory analyses [3,4,8], which demonstrated no significant efficacy of NP in stage IB disease, while indicating a significant survival benefit of PC among stage IB NSCLC patients with large tumors. Based on a survey performed in one hospital in the US, half (393/770) of the NSCLC patients received a carboplatin-based regimen, including 33% (254/770) who received PC as adjuvant chemotherapy for NSCLC, even though the final data set for the CALGB 9633 trial was published in 2006 [13]. These universal usage rates for adjuvant PC may have originated from the physicians’ belief that survival gain can be achieved
Table 2 Toxicities related to adjuvant chemotherapy. All grade
Hematologic toxicity Anemia Thrombocytopenia Neutropenia Non-hematologic toxicity Fatigue Anorexia Nausea Vomiting Diarrhea Constipation Neuropathy, sensory Alopecia Myalgia Infection ALT elevation Hyperbilirubinemia Creatinine increase
Grade 3/4
PC, n (%) N = 207
NP, n (%) N = 231
P value
PC, n (%) N = 207
NP, n (%) N = 231
P value
145 (70.0) 28 (13.5) 46 (22.2)
201 (87.0) 2 (0.9) 164 (71.0)
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
A retrospective comparison of adjuvant chemotherapeutic regimens for non-small cell lung cancer (NSCLC): Paclitaxel plus carboplatin versus vinorelbine plus cisplatin Won Jin Chang, Jong-Mu Sun ∗ , Ji Yean Lee, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 16 September 2013 Received in revised form 18 January 2014 Accepted 20 January 2014 Keywords: Adjuvant chemotherapy Vinorelbine Cisplatin Non-small cell lung cancer Paclitaxel Carboplatin
a b s t r a c t Background: Adjuvant chemotherapy with vinorelbine plus cisplatin (NP) has been demonstrated to increase overall survival in patients with stage II or IIIA non-small cell lung cancer (NSCLC). Although paclitaxel plus carboplatin (PC) failed to demonstrate efficacy in patients with stage IB NSCLC, an exploratory analysis suggested that patients with large tumors can benefit from adjuvant PC therapy. Methods: Clinical outcomes of patients who received adjuvant NP or PC regimens after complete resection for their NSCLC were retrospectively compared. Results: Of the 438 patients with completely resected NSCLC, 207 received PC and 231 patients received NP. The median relapse-free survival (RFS) was not significantly different, with 63.6 months for the PC group and 54.8 months for the NP group (P = .68). Overall survival also did not differ significantly between the two groups. The five-year overall survival rates were 73% (95% confidence interval (CI), 66–80%) in PC group and 71% (95% CI, 64–78%) in NP group (P = .71). In the subgroup analysis, RFS was comparable between the two groups across all variables. Analysis of the adverse events indicated that sensory neuropathy, alopecia, and myalgia are more frequent in the PC, while anemia, neutropenia, fatigue, anorexia, and vomiting are more common in the NP. Conclusion: Although the adverse event profiles were different, the efficacy was comparable between the PC and NP regimens as adjuvant chemotherapy for NSCLC. While there is lack of prospective data, our retrospective data suggest that PC regimen can be considered as adjuvant chemotherapy for resected NSCLC. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Non-small-cell lung cancer (NSCLC) accounts more than 80% of all lung tumors and surgical resection is performed with curative intent in early-stage NSCLC. However, 30–70% of patients with surgically resected NSCLC develop recurrence, and early metastatic spread limits long-term overall survival (OS) [1]. Based on evidence from several large prospective studies and meta-analyses, adjuvant platinum-based chemotherapy is the standard treatment modality for completely resected stage II or III NSCLC [2–7]. However, the most appropriate regimen for adjuvant chemotherapy has not been determined. The combination regimen of
∗ Corresponding author at: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Republic of Korea. Tel.: +82 2 3410 1795; fax: +82 2 3410 1754. E-mail addresses: [email protected], [email protected] (J.-M. Sun). 0169-5002/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2014.01.017
vinorelbine plus cisplatin (NP) demonstrated efficacy in terms of disease-free survival (DFS) and OS in two independent studies: the JBR10 and ANITA studies, which respectively included NSCLC patients with tumor stage IB/II and IB/II/IIIA based on the sixth edition of the American Joint Committee on Cancer (AJCC) staging manual, showed that patients who received adjuvant NP lived longer than those without adjuvant chemotherapy [3,4]. In subgroup analyses, however, there was no difference in the survival rate between the groups with and without adjuvant NP chemotherapy in patients with stage IB disease. The CALGB 9633 trial, which included only tumor stage IB NSCLC based on the AJCC sixth edition, addressed the role of adjuvant paclitaxel and carboplatin (PC) regimen [3,4]. Although the preliminary results indicated that this PC regimen improved OS and DFS, leading to the early cessation of the enrollment by the recommendation of the Data and Safety Monitoring Board [5], a mature analysis failed to demonstrate the efficacy of this regimen for patients with stage IB disease [8]. Interestingly, however, the exploratory analysis showed that patients with large tumors (≥4 cm in diameter) got benefit from adjuvant
52
W.J. Chang et al. / Lung Cancer 84 (2014) 51–55
PC therapy in terms of DFS [8]. These data suggested that patients with large tumors or malignant lymph nodes, whose tumor stages could be defined as II or higher based on the revised AJCC seventh edition, would benefit from adjuvant PC regimen. In addition to the efficacy, toxicity profiles are important factors to be considered in the selection of the adjuvant chemotherapeutic regimen. Although its efficacy was demonstrated, the toxicity of the NP regimen has raised some concerns. Grade 3/4 hematologic toxicity and incomplete treatment delivery have been reported frequently in the NP treatment group in adjuvant trials [2,4,9]. Thus, an assessment of appropriate alternatives to the NP regimen that are tolerated better and have an efficacy comparable to that of the NP regimen is both timely and necessary. Previous randomized phase III trials showed that PC is equally efficacious as NP, with better tolerability, in the treatment of advanced NSCLC [10,11]. Given that the CALGB 9633 trial was an underpowered study due to the early cessation of enrollment and the strict eligibility criteria, which included only stage IB disease, adjuvant PC regimen could be an alternative adjuvant therapy for NSCLC. In this study, we compared the clinical outcomes of patients on one of these two regimens, PC and NP, as adjuvant chemotherapy for NSCLC.
Table 1 Patients characteristics.
2. Patients and methods
Abbreviations: PC, paclitaxel, carboplatin; NP, vinorelbine, cisplatin. Based on the American Joint Committee on Cancer seventh edition.
Age (years), median Gender Male Female Smoking status Never smoker Ex-smoker Current smoker Histology Adenocarcinoma Squamous cell carcinoma Large cell neuroendocrine carcinoma Others Pathological stage Ib IIa IIb IIIa Surgical procedure Lobectomy Pneumonectomy
PC (n = 207, %)
NP (n = 231, %)
63 (35–80)
59 (30–76)
156 (75.4) 51 (24.6)
161 (69.7) 70 (30.3)
62 (30.0) 84 (40.6) 61 (29.5)
77 (33.3) 72 (31.2) 82 (35.5)
112 (54.1) 84 (40.6) 5 (2.4)
143 (61.9) 77 (33.3) 6 (2.6)
P value .05 for all variables). Non-hematological toxic effects including sensory neuropathy (43% vs. 11%), alopecia (18% vs. 4%), and myalgia (34% vs. 5%) were more frequent in the PC group, while the incidence of fatigue (11% vs. 18%), anorexia (18% vs. 41%), nausea (16% vs.57%), and vomiting (9% vs. 19%) was higher in the NP group. In the NP group, PICCs were inserted in 142 (61.5%) patients, and grade 1/2
4. Discussion The present study showed that the efficacy of adjuvant PC regimen was similar to that of NP in terms of RFS and OS. Any retrospective study is likely to be associated with selection bias, which complicates the comparison of two treatment modalities. To our knowledge, however, there is no report or ongoing prospective
54
W.J. Chang et al. / Lung Cancer 84 (2014) 51–55
Fig. 2. Subgroup analysis of relapse-free survival.
study to compare these two regimens in the adjuvant setting in NSCLC. Our institute has established a protocol for adjuvant chemotherapy for NSCLC, and all patients with stage IB to IIIA NSCLC have been treated with either the PC or NP regimen according to the protocol. The selection of the regimen, PC or NP, was based on the physicians’ discretion or preference. Accordingly, the baseline clinical characteristics were well-balanced between two groups analyzed in this study, indicating that our study population was not considerably biased, despite the retrospective nature of the study. Furthermore, among recurrent 185 patients, epidermal growth factor receptor (EGFR) mutation test was done in 102 patients (PC, n = 52; NP, n = 50) and the status of activating EGFR (deletion in exon 19 and L858R mutation) was not different between PC and NP group. (PC: deletion in exon 19, n = 9; L858R
mutation, n = 6 versus NP: deletion in exon 19, n = 13; L858R mutation, n = 7). While previous phase III trials demonstrated the efficacy of adjuvant NP, the efficacy of adjuvant PC has not been demonstrated in a prospective trial [3,4]. However, the exploratory analyses [3,4,8], which demonstrated no significant efficacy of NP in stage IB disease, while indicating a significant survival benefit of PC among stage IB NSCLC patients with large tumors. Based on a survey performed in one hospital in the US, half (393/770) of the NSCLC patients received a carboplatin-based regimen, including 33% (254/770) who received PC as adjuvant chemotherapy for NSCLC, even though the final data set for the CALGB 9633 trial was published in 2006 [13]. These universal usage rates for adjuvant PC may have originated from the physicians’ belief that survival gain can be achieved
Table 2 Toxicities related to adjuvant chemotherapy. All grade
Hematologic toxicity Anemia Thrombocytopenia Neutropenia Non-hematologic toxicity Fatigue Anorexia Nausea Vomiting Diarrhea Constipation Neuropathy, sensory Alopecia Myalgia Infection ALT elevation Hyperbilirubinemia Creatinine increase
Grade 3/4
PC, n (%) N = 207
NP, n (%) N = 231
P value
PC, n (%) N = 207
NP, n (%) N = 231
P value
145 (70.0) 28 (13.5) 46 (22.2)
201 (87.0) 2 (0.9) 164 (71.0)
