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Impact of high-dose chemotherapy with autologous hematopoietic stem cell transplantation on small-cell lung cancer
Lung Cancer 65 (2009) 126–127
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Letter to the Editor Impact of high-dose chemotherapy with autologous hematopoietic stem cell transplantation on small-cell lung cancer Small-cell lung cancer (SCLC) is a distinct clinical and histological entity within the range of lung cancers. Combination chemotherapy remains the cornerstone of treatment for both limited-stage and extensive-stage small-cell lung cancer. With the assistance of autologous hematopoietic stem cell transplantation (ASCT), myeloablative chemotherapy has been applied to treat relapse or resistant SCLC since 1972. ASCT is essentially a method of overcoming the marrow toxicity of high-dose therapy by the infusion of stem cells that repopulate the marrow. However, the effects of high-dose chemotherapy (HDT) with ASCT on small-cell lung caner had been evaluated in some randomized controlled trials (RCTs), which were somewhat conflicting. A recent meta-analysis by Jiang et al. [1] suggested that HDT was not superior to conventional chemotherapy in treating SCLC. This study has a problem about hazard ratio (HR) calculations. HR was the preferred summary statistic for reporting time-toevent data. Therefore, the value of HR and its 95% confidence interval (CI) was different at different time to evaluate overall survival (OS). For instance, the HR at 2 and 4 years of Buchholz et al. [2] study is 0.57 (95% CI, 0.30–1.10) and 0.48 (95% CI, 0.29–0.79), respectively. While, in Lorigan et al. study [3], only 2year survival rate could be extracted to make the meta-analysis for evaluation the impact of HDT on SCLC, and the HR at 1 and 2 years is 0.94 (95% CI, 0.71–1.24) and 1.11 (95% CI, 0.68–1.81), respectively. Actually, we found that Santini et al. study [4] was excluded from the OS analysis [5] for evaluation the impact of HDT on aggressive non-Hodgkin lymphoma, although the survival rate at 6 years could be extracted in Santini et al. study [4] to calculate the HR, which only evaluated the OS at 6 years. Accordingly, the HRs and their 95% CI were re-calculated in this letter. Available data was extracted from the original paper to calculate HR and its 95% CI using the method described by Parmar et al. [6]. The HR of overall survival (OS) at 2 years of Leyvarz et al. [7], Lorigan et al. [3], Buchholz et al. [2] and Humblet et al. [8] study was 0.87 (95% CI, 0.58–1.32; P = 0.507), 1.11 (95% CI, 0.68–1.81; P = 0.676), 0.57 (95% CI, 0.30–1.10; P = 0.090) and 0.54 (95% CI, 0.31–1.10; P = 0.056), respectively. The meta-analysis was performed using STATA 10.0 software. The Mantel–Haenszel method and fixed effects model were used for pooling data. The pooled HR was 0.82 (95% CI, 0.62–1.04; P = 0.099) (Fig. 1). There was no statistical significant heterogeneity among the trials (P = 0.313), indicating that the four studies were not too different to be pooled. High-dose chemotherapy with ASCT as initial therapy for SCLC patients is difficult, because they are very likely to have impaired physical performance status and cardiovascular dysfunction due to smoking history, resulting in high mortality rates which limit the applicability of this treatment. The largest limitation of this metaanalysis is the low sample size of RCTs included, which influenced 0169-5002/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2009.03.009
Fig. 1. Forest plot of the hazard ratios of overall survival between high-dose chemotherapy plus autologous hematopoietic stem cell transplantation (HDT) and control chemotherapy.
the outcome of sensitivity analysis and resulted in instable results. Thus, the result (HR 0.71, 95% CI 0.52–0.96, P = 0.028) changed after the Lorigan et al. [3] trial was excluded (a low quality RCT according to Jiang et al.’s quality assessment). A second limitation was the lack of sufficient OS information available from Woll et al. [9]. In conclusion, this meta-analysis included only 591 patients, with possible type II error, resulting the wider 95% CI for OS (0.62–1.04). However, these issues might be addressed by combining individual patient data from the completed trials, and large-scale, high-quality RCTs are still required to clarify the effect of HDT in SCLC. Conflict of interest None. References [1] Jiang J, Shi HZ, Deng JM, Liang QL, Qin SM, Wu C. Efficacy of intensified chemotherapy with hematopoietic progenitors in small-cell lung cancer: a metaanalysis of the published literature. Lung Cancer in press; doi:10.1016/j.lungcan. 2008.11.011. [2] Buchholz E, Manegold C, Pilz L, Thatcher N, Drings P. Standard versus dose-intensified chemotherapy with sequential reinfusion of hematopoietic progenitor cells in small cell lung cancer patients with favorable prognosis. J Thorac Oncol 2007;2:51–8. [3] Lorigan P, Woll PJ, O’Brien ME, Ashcroft LF, Sampson MR, Thatcher N. Randomized phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer. J Natl Cancer Inst 2005;97:666–74. [4] Santini G, Olivieri A, Majolino I, Congiu M, Majolino I, Chisesi T, et al. VACOP-B vs. VACOP-B high-dose sequential therapy (HDS) for aggressive non-
Letter to the Editor / Lung Cancer 65 (2009) 126–127
[5]
[6]
[7]
[8]
[9]
Hodgkin’s lymphoma (NHL). Final analysis of the NHLCSG. ASCO meeting 2003 [abstract]. Greb A, Bohlius J, Trelle S, Schiefer D, De Souza CA, Gisselbrecht C, et al. Highdose chemotherapy with autologous stem cell support in first-line treatment of aggressive non-Hodgkin lymphoma—results of a comprehensive meta-analysis. Cancer Treat Rev 2007;33:338–46. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 1998;17:2815–34. Leyvraz S, Pampallona S, Martinelli G, Ploner F, Perey L, Aversa S, et al. A threefold dose intensity treatment with ifosfamide, carboplatin, and etoposide for patients with small cell lung cancer: a randomized trial. J Natl Cancer Inst 2008;100:533–41. Humblet Y, Symann M, Bosly A, Delaunois L, Francis C, Machiels J, et al. Late intensification chemotherapy with autologous bone marrow transplantation in selected small-cell carcinoma of the lung: a randomized study. J Clin Oncol 1987;5:1864–73. Woll PJ, Thatcher N, Lomax L, Hodgetts J, Lee SM, Burt PA, et al. Use of hematopoietic progenitors in whole blood to support dose-dense chemotherapy: a randomized phase II trial in small-cell lung cancer patients. J Clin Oncol 2001;19:712–9.
127
Jing Wang a,c , Ping Zhan b , Jian Ouyang a,∗ , Bing Chen a , Rongfu Zhou a , Yonggong Yang a a Department of Hematology, The Affiliated DrumTower Hospital of Nanjing University Medical School, Nanjing 210008, PR China b Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing 210029, PR China c Department of Oncology, The Second Hospital of Nanjing, Nanjing 210002, PR China ∗ Corresponding
author. Tel.: +86 25 83105211; fax: +86 25 83105211. E-mail address: [email protected] (J. Ouyang) 23 February 2009
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Letter to the Editor Impact of high-dose chemotherapy with autologous hematopoietic stem cell transplantation on small-cell lung cancer Small-cell lung cancer (SCLC) is a distinct clinical and histological entity within the range of lung cancers. Combination chemotherapy remains the cornerstone of treatment for both limited-stage and extensive-stage small-cell lung cancer. With the assistance of autologous hematopoietic stem cell transplantation (ASCT), myeloablative chemotherapy has been applied to treat relapse or resistant SCLC since 1972. ASCT is essentially a method of overcoming the marrow toxicity of high-dose therapy by the infusion of stem cells that repopulate the marrow. However, the effects of high-dose chemotherapy (HDT) with ASCT on small-cell lung caner had been evaluated in some randomized controlled trials (RCTs), which were somewhat conflicting. A recent meta-analysis by Jiang et al. [1] suggested that HDT was not superior to conventional chemotherapy in treating SCLC. This study has a problem about hazard ratio (HR) calculations. HR was the preferred summary statistic for reporting time-toevent data. Therefore, the value of HR and its 95% confidence interval (CI) was different at different time to evaluate overall survival (OS). For instance, the HR at 2 and 4 years of Buchholz et al. [2] study is 0.57 (95% CI, 0.30–1.10) and 0.48 (95% CI, 0.29–0.79), respectively. While, in Lorigan et al. study [3], only 2year survival rate could be extracted to make the meta-analysis for evaluation the impact of HDT on SCLC, and the HR at 1 and 2 years is 0.94 (95% CI, 0.71–1.24) and 1.11 (95% CI, 0.68–1.81), respectively. Actually, we found that Santini et al. study [4] was excluded from the OS analysis [5] for evaluation the impact of HDT on aggressive non-Hodgkin lymphoma, although the survival rate at 6 years could be extracted in Santini et al. study [4] to calculate the HR, which only evaluated the OS at 6 years. Accordingly, the HRs and their 95% CI were re-calculated in this letter. Available data was extracted from the original paper to calculate HR and its 95% CI using the method described by Parmar et al. [6]. The HR of overall survival (OS) at 2 years of Leyvarz et al. [7], Lorigan et al. [3], Buchholz et al. [2] and Humblet et al. [8] study was 0.87 (95% CI, 0.58–1.32; P = 0.507), 1.11 (95% CI, 0.68–1.81; P = 0.676), 0.57 (95% CI, 0.30–1.10; P = 0.090) and 0.54 (95% CI, 0.31–1.10; P = 0.056), respectively. The meta-analysis was performed using STATA 10.0 software. The Mantel–Haenszel method and fixed effects model were used for pooling data. The pooled HR was 0.82 (95% CI, 0.62–1.04; P = 0.099) (Fig. 1). There was no statistical significant heterogeneity among the trials (P = 0.313), indicating that the four studies were not too different to be pooled. High-dose chemotherapy with ASCT as initial therapy for SCLC patients is difficult, because they are very likely to have impaired physical performance status and cardiovascular dysfunction due to smoking history, resulting in high mortality rates which limit the applicability of this treatment. The largest limitation of this metaanalysis is the low sample size of RCTs included, which influenced 0169-5002/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2009.03.009
Fig. 1. Forest plot of the hazard ratios of overall survival between high-dose chemotherapy plus autologous hematopoietic stem cell transplantation (HDT) and control chemotherapy.
the outcome of sensitivity analysis and resulted in instable results. Thus, the result (HR 0.71, 95% CI 0.52–0.96, P = 0.028) changed after the Lorigan et al. [3] trial was excluded (a low quality RCT according to Jiang et al.’s quality assessment). A second limitation was the lack of sufficient OS information available from Woll et al. [9]. In conclusion, this meta-analysis included only 591 patients, with possible type II error, resulting the wider 95% CI for OS (0.62–1.04). However, these issues might be addressed by combining individual patient data from the completed trials, and large-scale, high-quality RCTs are still required to clarify the effect of HDT in SCLC. Conflict of interest None. References [1] Jiang J, Shi HZ, Deng JM, Liang QL, Qin SM, Wu C. Efficacy of intensified chemotherapy with hematopoietic progenitors in small-cell lung cancer: a metaanalysis of the published literature. Lung Cancer in press; doi:10.1016/j.lungcan. 2008.11.011. [2] Buchholz E, Manegold C, Pilz L, Thatcher N, Drings P. Standard versus dose-intensified chemotherapy with sequential reinfusion of hematopoietic progenitor cells in small cell lung cancer patients with favorable prognosis. J Thorac Oncol 2007;2:51–8. [3] Lorigan P, Woll PJ, O’Brien ME, Ashcroft LF, Sampson MR, Thatcher N. Randomized phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer. J Natl Cancer Inst 2005;97:666–74. [4] Santini G, Olivieri A, Majolino I, Congiu M, Majolino I, Chisesi T, et al. VACOP-B vs. VACOP-B high-dose sequential therapy (HDS) for aggressive non-
Letter to the Editor / Lung Cancer 65 (2009) 126–127
[5]
[6]
[7]
[8]
[9]
Hodgkin’s lymphoma (NHL). Final analysis of the NHLCSG. ASCO meeting 2003 [abstract]. Greb A, Bohlius J, Trelle S, Schiefer D, De Souza CA, Gisselbrecht C, et al. Highdose chemotherapy with autologous stem cell support in first-line treatment of aggressive non-Hodgkin lymphoma—results of a comprehensive meta-analysis. Cancer Treat Rev 2007;33:338–46. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 1998;17:2815–34. Leyvraz S, Pampallona S, Martinelli G, Ploner F, Perey L, Aversa S, et al. A threefold dose intensity treatment with ifosfamide, carboplatin, and etoposide for patients with small cell lung cancer: a randomized trial. J Natl Cancer Inst 2008;100:533–41. Humblet Y, Symann M, Bosly A, Delaunois L, Francis C, Machiels J, et al. Late intensification chemotherapy with autologous bone marrow transplantation in selected small-cell carcinoma of the lung: a randomized study. J Clin Oncol 1987;5:1864–73. Woll PJ, Thatcher N, Lomax L, Hodgetts J, Lee SM, Burt PA, et al. Use of hematopoietic progenitors in whole blood to support dose-dense chemotherapy: a randomized phase II trial in small-cell lung cancer patients. J Clin Oncol 2001;19:712–9.
127
Jing Wang a,c , Ping Zhan b , Jian Ouyang a,∗ , Bing Chen a , Rongfu Zhou a , Yonggong Yang a a Department of Hematology, The Affiliated DrumTower Hospital of Nanjing University Medical School, Nanjing 210008, PR China b Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing 210029, PR China c Department of Oncology, The Second Hospital of Nanjing, Nanjing 210002, PR China ∗ Corresponding
author. Tel.: +86 25 83105211; fax: +86 25 83105211. E-mail address: [email protected] (J. Ouyang) 23 February 2009