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Third generation triplet cytotoxic chemotherapy in advanced non-small cell lung cancer: A systematic overview
Lung Cancer 64 (2009) 194–198
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Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Third generation triplet cytotoxic chemotherapy in advanced non-small cell lung cancer: A systematic overview Hatem A. Azim Jr a , Inas Elattar b , Fausto R. Loberiza Jr c , Hamdy Azim d , Tony Mok e , Apar Kishor Ganti c,f,∗ a
Department of Medical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt Department of Biostatistics and Epidemiology, National Cancer Institute, Cairo University, Cairo, Egypt Department of Internal Medicine, Section of Oncology-Hematology, 987680 University of Nebraska Medical Center, Omaha, NE 68198-7680, USA d Department of Clinical Oncology, Cairo University Hospital, Cairo, Egypt e Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong f Department of Internal Medicine, Omaha VA Medical Center, Omaha, NE, USA b c
a r t i c l e
i n f o
Article history: Received 13 February 2008 Received in revised form 5 August 2008 Accepted 13 August 2008 Keywords: Advanced non-small cell lung cancer Cytotoxic chemotherapy Triplet therapy Doublet therapy Outcomes Response rates Overall survival
a b s t r a c t Background: Previous meta-analysis on three drugs combination for treatment of advanced non-small cell lung cancer (NSCLC) did not demonstrate an improvement in survival, however many of the trials included in this meta-analysis used older and less effective cytotoxic drugs. We conducted this analysis to compare the relative efficacy of third generation triplet therapy with that of standard double therapy in the treatment of advanced NSCLC. Methods: A MEDLINE search was performed using the search terms “lung cancer” and “randomized trials”. Trials not utilizing a third generation cytotoxic chemotherapeutic agent (paclitaxel, docetaxel, vinorelbine, gemcitabine) were excluded. Pooled odds ratios (OR) for the objective response and toxicity rates were calculated using the Mantel-Haenszel estimate. Pooled median ratios for median survival were calculated using the weighted sum of the log-ratio of median ratios of individual study. Results: We analyzed six randomized comparative trials involving 1932 patients. Patients receiving triplet therapy had a significantly higher response rate (OR: 1.33; 95% CI, 1.50–2.23; P < 0.001). Incidence of grade III/IV hematological toxicity was higher with triplet therapy. Non-hematological toxicities, with the exception of neuropathy, were similar. Median survival of triplet therapy was not significantly different from doublet (MR: 1.10; 95% CI: 0.91–1.35; P = 0.059). Conclusions: Triplet therapy with third generation cytotoxic drugs is associated with higher tumor response rate at the expense of increased toxicity. Although triplet therapy had a better overall survival compared to doublet therapy, this did not reach statistical significance. © 2008 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer is the most common malignant neoplasm causing cancer-related death in developed countries [1]. Non-small cell lung cancer (NSCLC) accounts for over 80% of patients with lung cancer and nearly two-thirds present with an advanced stage disease (stage IIIB/IV). Platinum-based chemotherapy for advanced stage NSCLC results in small but statistically significant improvement in outcomes, as compared with best supportive care [2,3].
∗ Corresponding author at: Department of Internal Medicine, Section of Oncology-Hematology, 987680 University of Nebraska Medical Center, Omaha, NE 68198-7680, USA. Tel.: +1 402 559 8121; fax: +1 402 559 6520. E-mail address: [email protected] (A.K. Ganti). 0169-5002/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2008.08.011
Development of third generation cytotoxic agents such as taxanes, gemcitabine and vinorelbine, has further improved survival rates as compared to older regimens [4–6]. Randomized trials have confirmed similar efficacy between platinum-based doublets [6–9] and hence current guidelines recommend the use of a platinum-based doublet in the treatment of good performance status patients with advanced NSCLC [10]. Non-platinum doublets are not different in efficacy and toxicity, but are more costly [11]. Addition of a third agent to platinum-based doublet may be an option to improve outcomes in lung cancer, given the multitude of active agents now available for clinical use. This strategy has been shown to be associated with superior outcomes in other malignancies including gastric [11], head and neck [12,13] and uterine cancer [11]. This led to the conduct of multiple trials comparing
H.A. Azim Jr et al. / Lung Cancer 64 (2009) 194–198
a two drug regimen with a three drug regimen in patients with advanced NSCLC. A previous meta-analysis evaluating the role of adding an agent to doublet therapy showed no survival benefit of triplet chemotherapy over the doublet with significant increase in toxicity [14]. One possible explanation is the type of agents studied in the clinical trials evaluated. Of the 34 trials included in this meta-analysis, 28 used first or second generation agents that are less commonly used in current clinical practice and thus the magnitude of benefit of third generation agents could be diluted. Hence we conducted a systemic overview on published phase III randomized controlled trials comparing combinations of third generation cytotoxic chemotherapeutic agents (gemcitabine, vinorelbine, paclitaxel, docetaxel) and platinum agent (cisplatin or carboplatin) with standard doublet. Study endpoints included tumor response rate, overall survival and toxicity. 2. Methods 2.1. Search strategy Trials comparing doublets to triplets in the management of advanced NSCLC were searched for separately by two of the authors (H.A.A. Jr, A.K.G.). A MEDLINE search was performed using the search terms “lung cancer”, “advanced disease”, “chemotherapy” and “randomized trials”. Abstracted data and data not published in English were excluded. Phase II trials were excluded since these are typically not designed to detect a survival difference. 2.2. Inclusion criteria In order to be eligible for inclusion in this analysis trials had to be prospective, randomized comparative phase III studies that utilized platinum agents (cisplatin or carboplatin) and third generation cytotoxic agents (vinorelbine, paclitaxel, gemcitabine and docetaxel) for treatment-naïve patients with pathologically proven advanced NSCLC. All trials utilized a doublet that comprised of platinum and/or third generation cytotoxic drugs as control.
195
ratio [16]. P-values ≤0.05 were considered significant. Statistical System Analysis (SAS) version 8.02 was used for data management and analysis. 3. Results 3.1. Characteristics of the trials Six trials published between 2000 till June 2007 met the inclusion criteria [17–22]. Details of these trials are summarized in Table 1. None of trials were double-blinded. Our analysis included 2117 patients randomly assigned to either doublet therapy (930 patients) or triplet therapy (1187 patients). In the study by Alberola et al. [19], one of the three study arms was sequential doublet utilizing ifosfamide thus this arm was excluded from our analysis. One study only reported the results of an interim analysis [23] without further updates and hence the results of the interim analysis were used. Sample sizes of the individual trials were evaluated on the funnel plot, and all were away from zero except one indicating an adequate sample size (Fig. 1). Post-study second line treatment was reported in all except one trial [19]. Three trials [19] reported no difference in post study treatment, while in two trials [19], more patients on the doublet control arm received salvage therapy (36% vs. 24% and 42% vs. 29% respectively). 3.2. Response rates Response rates were assessed in all the included trials using standard WHO criteria [24]. Tumor response assessment was made after two cycles in two trials [19,20], after three cycles in two trials [21,22], while two trials [17,18] that had different cycle-duration on the different arms, assessed response at a similar time (after either two or three cycles) from onset of therapy. Objective response rates of 1783 patients from six trials were summarized in Table 2. Patients receiving triplet therapy had a significantly higher response rate (OR: 1.33; 95% CI, 1.50–2.23; P < 0.001) (Fig. 2). All except one trial [18] demonstrated significantly better response rate with triplet therapy than doublet therapy.
2.3. Quantitative data synthesis We calculated odds ratio (OR) to assess objective response rate and toxic events. We constructed 2 × 2 tables from abstracted data for response and toxicity. OR for the subjects who received triplet combination relative to those who received doublet combination were calculated from the tables. For OR calculations, we excluded ineligible subjects from each evaluation. For analysis of the survival data, pooled median ratios for median survival were calculated using the weighted sum of the log-ratio of median ratios of individual study. 2.4. Data analysis Data on response rates, overall survival and toxicity from the trials were analyzed. Pooled odds ratios were calculated using the Mantel-Haenszel estimate. Combined median survival estimates within any trial were obtained by using a weighted average of median survival weighted by the sample size of each treatment arm. Weights used to calculate pooled median survival and P-value for survival were based on sample size. Pooled survival comparisons were made by combining either the P-values or the median survival estimates across all the studies [15]. In order to detect a publication bias, we used linear regression approach to measure funnel plot asymmetry on the natural logarithm scale of the odds
3.3. Overall survival Survival outcomes of 1921 patients from six trials are shown on Table 3. Patients who received triplet chemotherapy had a median survival of 42.8 weeks versus 37.4 weeks for doublet chemotherapy; however this difference did not reach statistical significance (MR: 1.10; 95% CI: 0.91–1.35; P = 0.059). A look at the individual trials suggests that while two of the six [18,21] demonstrated a significant survival advantage with triplet therapy, two other trials [17,22] had a trend favoring triplet therapy, though not statistically significant. 3.4. Toxicity Methods on reporting toxicities were not consistent among the six trials. The most frequently reported toxicities are summarized in Table 4. Combined analysis of toxicity was done comparing doublet therapy with triplet therapy in these trials. Patients who were randomized to receive triplet chemotherapy had significantly more grade III/IV toxicity in terms of myelosuppression, neurological toxicity and diarrhea. However the incidence of oral mucositis, renal dysfunction, nausea and vomiting were not significantly different between the two groups.
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Table 1 Trials comparing doublet to triplet therapy in patients with advanced NSCLC Author
Therapy
n 2
2
Cisplatin 50 mg/m + gemcitabine 1000 mg/m + vinorelbine 25 mg/m on days 1, 8 repeated every 3 weeks Cisplatin 100 mg/m2 on day 1 + gemcitabine 1000 mg/m2 on days 1, 8, 15 repeated every 4 weeks Cisplatin 120 mg/m2 on day 1, 29 and then every 6 weeks + vinorelbine 30 mg/m2 weekly for 10 weeks
Comella et al. [17]
Cisplatin 50 mg/m2 + gemcitabine 1000 mg/m2 + paclitaxel 125 mg/m2 on days 1, 8 repeated every 3 weeks for 5 cycles Cisplatin 50 mg/m2 + gemcitabine 1000 mg/m2 + vinorelbine 25 mg/m2 on days 1, 8 repeated every 3 weeks for 5 cycles Cisplatin 100 mg/m2 on day 1 + gemcitabine 1000 mg/m2 on days 1, 8, 15 repeated every 4 weeks for 5 cycles
Comella et al. [18]
Cisplatin 100 mg/m2 on day 1 + gemcitabine 1000 mg/m2 on day 1, 8 + vinorelbine 25 mg/m2 on day 1, 8 every 21 days Cisplatin 100 mg/m2 on day 1 + gemcitabine 1250 mg/m2 on day 1, 8 repeated every 21 days Gemcitabine 1000 mg/m2 on day 1, 8 + vinorelbine 30 mg/m2 on day 1, 8 for three cycles followed by vinorelbine 30 mg/m2 on day 1, 8 + ifosfamide 3000 mg/m2 on day 1
Alberola et al. [19]
Gemcitabine 1000 mg/m2 + vinorelbine 25 mg/m2 on days 1, 8 + cisplatin 75 mg/m2 on day 2 repeated every 3 weeks Gemcitabine 1000 mg/m2 + vinorelbine 25 mg/m2 on days 1, 8 repeated every 3 weeks
Laack et al. [20]
2
Paccagnella et al. [21]
Comella et al. [22]
2
2
Carboplatin AUC 6 + paclitaxel 200 mg/m on day 1 + gemcitabine 1000 mg/m on days 1 and 8 repeated every 3 weeks for at least 6 cycles Carboplatin AUC 6 + paclitaxel 200 mg/m2 on day 1 repeated every 3 weeks for at least 6 cycles Gemcitabine 1000 mg/m2 + vinorelbine 25 mg/m2 on days 1, 8 repeated every 3 weeks Gemcitabine 1000 mg/m2 + paclitaxel 125 mg/m2 on days 1, 8 repeated every 3 weeks Gemcitabine 1000 mg/m2 + vinorelbine 25 mg/m2 + cisplatin 50 mg/m2 on days 1, 8 repeated every 3 weeks Gemcitabine 1000 mg/m2 + paclitaxel 125 mg/m2 + cisplatin 50 mg/m2 on days 1, 8 repeated every 3 weeks
Fig. 1. Adequacy of sample sizes of the trials.
4. Discussion This current analysis evaluated agents considered as standard by the current ASCO guidelines [25] and may therefore be clinically useful in helping decide what treatment should patients be offered. We found that patients receiving triplet chemotherapy had significantly higher response rates at the expense of increased toxicity. Although the overall survival favored the triplet arm, this difference did not translate into statistical significant improvement in survival. Since second line treatment may influence survival, the unbalanced post study treatment in two of the six trials might have had an impact on the survival analysis of our study [19].
60 60 60
114 117 112
188 182 187
144 143 163 156
110 107 109 107
As expected we found that patients who received triplet therapy had a higher response rate compared to those who received doublet therapy (OR: 1.33; 95% CI, 1.50–2.23; P < 0.001). This was not surprising, since all the trials except one [19] showed improved response rates with the addition of a third cytotoxic agent. The effects on overall survival were more variable. Four trials [17,18,21,22] showed a numerical survival advantage with triplet therapy but only two trials [18,21] reached statistical significance. Interestingly most of the trials used a combination of cisplatin, gemcitabine and vinorelbine as the triplet and the possibility of antagonism between gemcitabine and vinorelbine must be considered. Pre-clinical studies have provided mixed answers to this question. Herbst et al. demonstrated an additive effect between vinorelbine and gemcitabine, not antagonism [26]. In contrast, De Luca et al. demonstrated that if vinorelbine was administered prior to gemcitabine there was antagonism seen in all NSCLC cell lines studied, while treatment with gemcitabine followed by vinorelbine resulted in moderate synergism in one cell line (A549), and in antagonism in two cell lines (H838 and H1355) [27]. Of the studies included in this meta-analysis, only one [20] specified that gemcitabine be given prior to vinorelbine, but despite this there was no benefit to the three drug regimen in this study. We also found that the addition of a third cytotoxic agent significantly increased the incidence of toxicity; both hematological and non-hematological (Table 4). Not all studies mentioned the incidence of febrile neutropenia, which is a more clinically relevant toxicity as compared to neutropenia. Only four trials [18,19,21,22] reported such incidence; there were no differences in any of the trials, except one [19]. The need for blood and platelet transfusions was not reported in all studies, but there was no difference in the need for blood products in one study [22], while another study demonstrated an increased incidence of transfusions and growth
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Fig. 2. Response rates. Table 2 Response rates Author
Regimens
Triplets
Comella et al. [17] Comella et al. [18] Alberola et al. [19] Laack et al. [20] Paccagnella et al. [21] Comella et al. [22]
PGV, PV, PG PG, PGT, PGV GP, GPV, GV-VIa GV, GVP TC, TCG PGV, PGT, GV, GT
Doublets
n
RR (%)
n
RR (%)
60 231 188 106 158 216
46.7 46.3 40.9 28.3 43.7 47
120 112 182 108 150 217
27.5 27.7 42.3 12.9 20.0 34.6
Overall OR P-value Test of heterogeneity
Odds ratio
95% CI
2.31 2.25 0.95 2.65 3.10 1.73
1.21–4.40 1.38–3.67 0.63–1.43 1.31–5.35 1.86–5.16 1.17–2.54
1.33
1.50–2.23 <0.001 0.058
n, number; RR, response rate; CI, confidence interval; OR, odds ratio. P, cisplatin; G, gemcitabine; T, paclitaxel; V, vinorelbine; C, carboplatin; I, ifosfamide. a GV-VI not included in the analysis.
Table 3 Overall survival Author
Regimens
Comella et al. [17] Comella et al. [18] Alberola et al. [19] Laack et al. [20] Paccagnella et al. [21] Comella et al. [22]
PGV, PV, PG PG, PGT, PGV GP, GPV, GV-VIa GV, GVP TC, TCG PGV, PGT, GV, GT
Regimens
Median survival (weeks)
TR (997)
DB (924)
TR (42.8)
DB (37.4)
60 231 188 144 158 216
120 112 182 143 150 217
51.0 51.0 32.8 32.4 43.2 46.8
38.5 38.0 37.2 35.9 33.2 42.0
MR
P-value
1.32 1.34 0.88 0.90 1.30 1.11
NS <0.05 NS 0.730 0.032 0.379
Combined P-value Pooled MR
0.059 1.10 (95% CI: 0.91–1.35)
TR, triplet; DB, doublet; MR, median ratio; CI, confidence interval. P, cisplatin; G, gemcitabine; T, paclitaxel; V, vinorelbine; C, carboplatin; I, ifosfamide. a GV-VI not included in the analysis.
factor usage in the triplet arm [21]. There were no differences in the incidences of renal toxicities or mucositis between the two groups. Treatment delays due to toxicity were more common in the triplet arm in two studies [20,21].
One of the major issues with the available data on therapy for advanced NSCLC is the absence of quality of life (QOL) analyses. Only one study [20] conducted a formal QOL analysis and demonstrated no difference in the QOL scores between the two groups. In a
Table 4 Analysis of grade III/IV toxicities Toxicity
Neutropenia Thrombocytopenia Anemia Nausea, vomiting Oral mucositis Diarrhea Renal Neurological
Triplet
Doublet
Odds ratio
n
% Affected
n
% Affected
954 974 975 977 758 787 978 977
49.8 25.9 13.4 14.2 2.6 3.8 3.2 10.3
886 894 895 906 688 724 906 906
31.7 14.3 9.2 16.0 3.8 1.7 2.8 5.0
2.29 2.00 1.56 0.91 0.60 2.34 1.12 2.06
95% CI
1.88–2.79 1.58–2.53 1.16–2.11 0.69–1.19 0.32–1.1 1.17–4.68 0.64–1.95 1.40–3.03
P-value
<0.001 <0.001 <0.001 0.468 0.104 0.013 0.698 <0.001
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randomized phase II study comparing vinorelbine and gemcitabine either with or without cisplatin, Chen et al. found a significant decrease in most items of the Lung Cancer Symptom Scale (LCSS) on both arms as compared to the pre-treatment scores, but found no differences when the two arms were compared to each other [28]. As the primary role of chemotherapy in patients with advanced NSCLC is palliative, the influence on patients’ quality of life (QOL) is an important issue in determining the true value of new therapy. Recently, the addition of the anti-VEGF antibody bevacizumab, to a combination of carboplatin and paclitaxel demonstrated an improvement in overall survival in certain sub-groups of patients with advanced NSCLC, although there was a significant increase in adverse effects and cost of therapy [29]. The results of this study however cannot be applied to all patients with advanced NSCLC, as this trial excluded patients with predominantly squamous cell carcinoma histology, hemoptysis, central nervous system metastases and patients who were on therapeutic anticoagulation. These patients form a substantial population of patients with advanced NSCLC and other alternatives are needed to improve their survival. Our study has a few drawbacks that should be considered while interpreting the results. The data used for analysis was not individual patient data, which in general gives an independent patient data-based meta-analysis [30], but rather, abstracted data. A major issue affecting the validity of any meta-analysis is publication bias. Although we detected no evidence of publication bias using standard graphical and statistical methods, it would be impossible to exclude this possibility altogether. Furthermore, our study is limited by the number and quality of randomized trials being available. Three of the six studies were conducted by the same group [17,18,22] that adopted similar regimens with only slight variation in the choice of control arm. In conclusion, although triplet therapy was associated with higher response rates at the expense of increased toxicity and there is no evidence for improvement in overall survival. Based on the results of this analysis, we would discourage further study of triplet cytotoxic chemotherapy regimens in the treatment of advanced NSCLC. Conflict of interest None of the authors has any conflict of interest that could influence this work.
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Third generation triplet cytotoxic chemotherapy in advanced non-small cell lung cancer: A systematic overview Hatem A. Azim Jr a , Inas Elattar b , Fausto R. Loberiza Jr c , Hamdy Azim d , Tony Mok e , Apar Kishor Ganti c,f,∗ a
Department of Medical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt Department of Biostatistics and Epidemiology, National Cancer Institute, Cairo University, Cairo, Egypt Department of Internal Medicine, Section of Oncology-Hematology, 987680 University of Nebraska Medical Center, Omaha, NE 68198-7680, USA d Department of Clinical Oncology, Cairo University Hospital, Cairo, Egypt e Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong f Department of Internal Medicine, Omaha VA Medical Center, Omaha, NE, USA b c
a r t i c l e
i n f o
Article history: Received 13 February 2008 Received in revised form 5 August 2008 Accepted 13 August 2008 Keywords: Advanced non-small cell lung cancer Cytotoxic chemotherapy Triplet therapy Doublet therapy Outcomes Response rates Overall survival
a b s t r a c t Background: Previous meta-analysis on three drugs combination for treatment of advanced non-small cell lung cancer (NSCLC) did not demonstrate an improvement in survival, however many of the trials included in this meta-analysis used older and less effective cytotoxic drugs. We conducted this analysis to compare the relative efficacy of third generation triplet therapy with that of standard double therapy in the treatment of advanced NSCLC. Methods: A MEDLINE search was performed using the search terms “lung cancer” and “randomized trials”. Trials not utilizing a third generation cytotoxic chemotherapeutic agent (paclitaxel, docetaxel, vinorelbine, gemcitabine) were excluded. Pooled odds ratios (OR) for the objective response and toxicity rates were calculated using the Mantel-Haenszel estimate. Pooled median ratios for median survival were calculated using the weighted sum of the log-ratio of median ratios of individual study. Results: We analyzed six randomized comparative trials involving 1932 patients. Patients receiving triplet therapy had a significantly higher response rate (OR: 1.33; 95% CI, 1.50–2.23; P < 0.001). Incidence of grade III/IV hematological toxicity was higher with triplet therapy. Non-hematological toxicities, with the exception of neuropathy, were similar. Median survival of triplet therapy was not significantly different from doublet (MR: 1.10; 95% CI: 0.91–1.35; P = 0.059). Conclusions: Triplet therapy with third generation cytotoxic drugs is associated with higher tumor response rate at the expense of increased toxicity. Although triplet therapy had a better overall survival compared to doublet therapy, this did not reach statistical significance. © 2008 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer is the most common malignant neoplasm causing cancer-related death in developed countries [1]. Non-small cell lung cancer (NSCLC) accounts for over 80% of patients with lung cancer and nearly two-thirds present with an advanced stage disease (stage IIIB/IV). Platinum-based chemotherapy for advanced stage NSCLC results in small but statistically significant improvement in outcomes, as compared with best supportive care [2,3].
∗ Corresponding author at: Department of Internal Medicine, Section of Oncology-Hematology, 987680 University of Nebraska Medical Center, Omaha, NE 68198-7680, USA. Tel.: +1 402 559 8121; fax: +1 402 559 6520. E-mail address: [email protected] (A.K. Ganti). 0169-5002/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2008.08.011
Development of third generation cytotoxic agents such as taxanes, gemcitabine and vinorelbine, has further improved survival rates as compared to older regimens [4–6]. Randomized trials have confirmed similar efficacy between platinum-based doublets [6–9] and hence current guidelines recommend the use of a platinum-based doublet in the treatment of good performance status patients with advanced NSCLC [10]. Non-platinum doublets are not different in efficacy and toxicity, but are more costly [11]. Addition of a third agent to platinum-based doublet may be an option to improve outcomes in lung cancer, given the multitude of active agents now available for clinical use. This strategy has been shown to be associated with superior outcomes in other malignancies including gastric [11], head and neck [12,13] and uterine cancer [11]. This led to the conduct of multiple trials comparing
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a two drug regimen with a three drug regimen in patients with advanced NSCLC. A previous meta-analysis evaluating the role of adding an agent to doublet therapy showed no survival benefit of triplet chemotherapy over the doublet with significant increase in toxicity [14]. One possible explanation is the type of agents studied in the clinical trials evaluated. Of the 34 trials included in this meta-analysis, 28 used first or second generation agents that are less commonly used in current clinical practice and thus the magnitude of benefit of third generation agents could be diluted. Hence we conducted a systemic overview on published phase III randomized controlled trials comparing combinations of third generation cytotoxic chemotherapeutic agents (gemcitabine, vinorelbine, paclitaxel, docetaxel) and platinum agent (cisplatin or carboplatin) with standard doublet. Study endpoints included tumor response rate, overall survival and toxicity. 2. Methods 2.1. Search strategy Trials comparing doublets to triplets in the management of advanced NSCLC were searched for separately by two of the authors (H.A.A. Jr, A.K.G.). A MEDLINE search was performed using the search terms “lung cancer”, “advanced disease”, “chemotherapy” and “randomized trials”. Abstracted data and data not published in English were excluded. Phase II trials were excluded since these are typically not designed to detect a survival difference. 2.2. Inclusion criteria In order to be eligible for inclusion in this analysis trials had to be prospective, randomized comparative phase III studies that utilized platinum agents (cisplatin or carboplatin) and third generation cytotoxic agents (vinorelbine, paclitaxel, gemcitabine and docetaxel) for treatment-naïve patients with pathologically proven advanced NSCLC. All trials utilized a doublet that comprised of platinum and/or third generation cytotoxic drugs as control.
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ratio [16]. P-values ≤0.05 were considered significant. Statistical System Analysis (SAS) version 8.02 was used for data management and analysis. 3. Results 3.1. Characteristics of the trials Six trials published between 2000 till June 2007 met the inclusion criteria [17–22]. Details of these trials are summarized in Table 1. None of trials were double-blinded. Our analysis included 2117 patients randomly assigned to either doublet therapy (930 patients) or triplet therapy (1187 patients). In the study by Alberola et al. [19], one of the three study arms was sequential doublet utilizing ifosfamide thus this arm was excluded from our analysis. One study only reported the results of an interim analysis [23] without further updates and hence the results of the interim analysis were used. Sample sizes of the individual trials were evaluated on the funnel plot, and all were away from zero except one indicating an adequate sample size (Fig. 1). Post-study second line treatment was reported in all except one trial [19]. Three trials [19] reported no difference in post study treatment, while in two trials [19], more patients on the doublet control arm received salvage therapy (36% vs. 24% and 42% vs. 29% respectively). 3.2. Response rates Response rates were assessed in all the included trials using standard WHO criteria [24]. Tumor response assessment was made after two cycles in two trials [19,20], after three cycles in two trials [21,22], while two trials [17,18] that had different cycle-duration on the different arms, assessed response at a similar time (after either two or three cycles) from onset of therapy. Objective response rates of 1783 patients from six trials were summarized in Table 2. Patients receiving triplet therapy had a significantly higher response rate (OR: 1.33; 95% CI, 1.50–2.23; P < 0.001) (Fig. 2). All except one trial [18] demonstrated significantly better response rate with triplet therapy than doublet therapy.
2.3. Quantitative data synthesis We calculated odds ratio (OR) to assess objective response rate and toxic events. We constructed 2 × 2 tables from abstracted data for response and toxicity. OR for the subjects who received triplet combination relative to those who received doublet combination were calculated from the tables. For OR calculations, we excluded ineligible subjects from each evaluation. For analysis of the survival data, pooled median ratios for median survival were calculated using the weighted sum of the log-ratio of median ratios of individual study. 2.4. Data analysis Data on response rates, overall survival and toxicity from the trials were analyzed. Pooled odds ratios were calculated using the Mantel-Haenszel estimate. Combined median survival estimates within any trial were obtained by using a weighted average of median survival weighted by the sample size of each treatment arm. Weights used to calculate pooled median survival and P-value for survival were based on sample size. Pooled survival comparisons were made by combining either the P-values or the median survival estimates across all the studies [15]. In order to detect a publication bias, we used linear regression approach to measure funnel plot asymmetry on the natural logarithm scale of the odds
3.3. Overall survival Survival outcomes of 1921 patients from six trials are shown on Table 3. Patients who received triplet chemotherapy had a median survival of 42.8 weeks versus 37.4 weeks for doublet chemotherapy; however this difference did not reach statistical significance (MR: 1.10; 95% CI: 0.91–1.35; P = 0.059). A look at the individual trials suggests that while two of the six [18,21] demonstrated a significant survival advantage with triplet therapy, two other trials [17,22] had a trend favoring triplet therapy, though not statistically significant. 3.4. Toxicity Methods on reporting toxicities were not consistent among the six trials. The most frequently reported toxicities are summarized in Table 4. Combined analysis of toxicity was done comparing doublet therapy with triplet therapy in these trials. Patients who were randomized to receive triplet chemotherapy had significantly more grade III/IV toxicity in terms of myelosuppression, neurological toxicity and diarrhea. However the incidence of oral mucositis, renal dysfunction, nausea and vomiting were not significantly different between the two groups.
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Table 1 Trials comparing doublet to triplet therapy in patients with advanced NSCLC Author
Therapy
n 2
2
Cisplatin 50 mg/m + gemcitabine 1000 mg/m + vinorelbine 25 mg/m on days 1, 8 repeated every 3 weeks Cisplatin 100 mg/m2 on day 1 + gemcitabine 1000 mg/m2 on days 1, 8, 15 repeated every 4 weeks Cisplatin 120 mg/m2 on day 1, 29 and then every 6 weeks + vinorelbine 30 mg/m2 weekly for 10 weeks
Comella et al. [17]
Cisplatin 50 mg/m2 + gemcitabine 1000 mg/m2 + paclitaxel 125 mg/m2 on days 1, 8 repeated every 3 weeks for 5 cycles Cisplatin 50 mg/m2 + gemcitabine 1000 mg/m2 + vinorelbine 25 mg/m2 on days 1, 8 repeated every 3 weeks for 5 cycles Cisplatin 100 mg/m2 on day 1 + gemcitabine 1000 mg/m2 on days 1, 8, 15 repeated every 4 weeks for 5 cycles
Comella et al. [18]
Cisplatin 100 mg/m2 on day 1 + gemcitabine 1000 mg/m2 on day 1, 8 + vinorelbine 25 mg/m2 on day 1, 8 every 21 days Cisplatin 100 mg/m2 on day 1 + gemcitabine 1250 mg/m2 on day 1, 8 repeated every 21 days Gemcitabine 1000 mg/m2 on day 1, 8 + vinorelbine 30 mg/m2 on day 1, 8 for three cycles followed by vinorelbine 30 mg/m2 on day 1, 8 + ifosfamide 3000 mg/m2 on day 1
Alberola et al. [19]
Gemcitabine 1000 mg/m2 + vinorelbine 25 mg/m2 on days 1, 8 + cisplatin 75 mg/m2 on day 2 repeated every 3 weeks Gemcitabine 1000 mg/m2 + vinorelbine 25 mg/m2 on days 1, 8 repeated every 3 weeks
Laack et al. [20]
2
Paccagnella et al. [21]
Comella et al. [22]
2
2
Carboplatin AUC 6 + paclitaxel 200 mg/m on day 1 + gemcitabine 1000 mg/m on days 1 and 8 repeated every 3 weeks for at least 6 cycles Carboplatin AUC 6 + paclitaxel 200 mg/m2 on day 1 repeated every 3 weeks for at least 6 cycles Gemcitabine 1000 mg/m2 + vinorelbine 25 mg/m2 on days 1, 8 repeated every 3 weeks Gemcitabine 1000 mg/m2 + paclitaxel 125 mg/m2 on days 1, 8 repeated every 3 weeks Gemcitabine 1000 mg/m2 + vinorelbine 25 mg/m2 + cisplatin 50 mg/m2 on days 1, 8 repeated every 3 weeks Gemcitabine 1000 mg/m2 + paclitaxel 125 mg/m2 + cisplatin 50 mg/m2 on days 1, 8 repeated every 3 weeks
Fig. 1. Adequacy of sample sizes of the trials.
4. Discussion This current analysis evaluated agents considered as standard by the current ASCO guidelines [25] and may therefore be clinically useful in helping decide what treatment should patients be offered. We found that patients receiving triplet chemotherapy had significantly higher response rates at the expense of increased toxicity. Although the overall survival favored the triplet arm, this difference did not translate into statistical significant improvement in survival. Since second line treatment may influence survival, the unbalanced post study treatment in two of the six trials might have had an impact on the survival analysis of our study [19].
60 60 60
114 117 112
188 182 187
144 143 163 156
110 107 109 107
As expected we found that patients who received triplet therapy had a higher response rate compared to those who received doublet therapy (OR: 1.33; 95% CI, 1.50–2.23; P < 0.001). This was not surprising, since all the trials except one [19] showed improved response rates with the addition of a third cytotoxic agent. The effects on overall survival were more variable. Four trials [17,18,21,22] showed a numerical survival advantage with triplet therapy but only two trials [18,21] reached statistical significance. Interestingly most of the trials used a combination of cisplatin, gemcitabine and vinorelbine as the triplet and the possibility of antagonism between gemcitabine and vinorelbine must be considered. Pre-clinical studies have provided mixed answers to this question. Herbst et al. demonstrated an additive effect between vinorelbine and gemcitabine, not antagonism [26]. In contrast, De Luca et al. demonstrated that if vinorelbine was administered prior to gemcitabine there was antagonism seen in all NSCLC cell lines studied, while treatment with gemcitabine followed by vinorelbine resulted in moderate synergism in one cell line (A549), and in antagonism in two cell lines (H838 and H1355) [27]. Of the studies included in this meta-analysis, only one [20] specified that gemcitabine be given prior to vinorelbine, but despite this there was no benefit to the three drug regimen in this study. We also found that the addition of a third cytotoxic agent significantly increased the incidence of toxicity; both hematological and non-hematological (Table 4). Not all studies mentioned the incidence of febrile neutropenia, which is a more clinically relevant toxicity as compared to neutropenia. Only four trials [18,19,21,22] reported such incidence; there were no differences in any of the trials, except one [19]. The need for blood and platelet transfusions was not reported in all studies, but there was no difference in the need for blood products in one study [22], while another study demonstrated an increased incidence of transfusions and growth
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Fig. 2. Response rates. Table 2 Response rates Author
Regimens
Triplets
Comella et al. [17] Comella et al. [18] Alberola et al. [19] Laack et al. [20] Paccagnella et al. [21] Comella et al. [22]
PGV, PV, PG PG, PGT, PGV GP, GPV, GV-VIa GV, GVP TC, TCG PGV, PGT, GV, GT
Doublets
n
RR (%)
n
RR (%)
60 231 188 106 158 216
46.7 46.3 40.9 28.3 43.7 47
120 112 182 108 150 217
27.5 27.7 42.3 12.9 20.0 34.6
Overall OR P-value Test of heterogeneity
Odds ratio
95% CI
2.31 2.25 0.95 2.65 3.10 1.73
1.21–4.40 1.38–3.67 0.63–1.43 1.31–5.35 1.86–5.16 1.17–2.54
1.33
1.50–2.23 <0.001 0.058
n, number; RR, response rate; CI, confidence interval; OR, odds ratio. P, cisplatin; G, gemcitabine; T, paclitaxel; V, vinorelbine; C, carboplatin; I, ifosfamide. a GV-VI not included in the analysis.
Table 3 Overall survival Author
Regimens
Comella et al. [17] Comella et al. [18] Alberola et al. [19] Laack et al. [20] Paccagnella et al. [21] Comella et al. [22]
PGV, PV, PG PG, PGT, PGV GP, GPV, GV-VIa GV, GVP TC, TCG PGV, PGT, GV, GT
Regimens
Median survival (weeks)
TR (997)
DB (924)
TR (42.8)
DB (37.4)
60 231 188 144 158 216
120 112 182 143 150 217
51.0 51.0 32.8 32.4 43.2 46.8
38.5 38.0 37.2 35.9 33.2 42.0
MR
P-value
1.32 1.34 0.88 0.90 1.30 1.11
NS <0.05 NS 0.730 0.032 0.379
Combined P-value Pooled MR
0.059 1.10 (95% CI: 0.91–1.35)
TR, triplet; DB, doublet; MR, median ratio; CI, confidence interval. P, cisplatin; G, gemcitabine; T, paclitaxel; V, vinorelbine; C, carboplatin; I, ifosfamide. a GV-VI not included in the analysis.
factor usage in the triplet arm [21]. There were no differences in the incidences of renal toxicities or mucositis between the two groups. Treatment delays due to toxicity were more common in the triplet arm in two studies [20,21].
One of the major issues with the available data on therapy for advanced NSCLC is the absence of quality of life (QOL) analyses. Only one study [20] conducted a formal QOL analysis and demonstrated no difference in the QOL scores between the two groups. In a
Table 4 Analysis of grade III/IV toxicities Toxicity
Neutropenia Thrombocytopenia Anemia Nausea, vomiting Oral mucositis Diarrhea Renal Neurological
Triplet
Doublet
Odds ratio
n
% Affected
n
% Affected
954 974 975 977 758 787 978 977
49.8 25.9 13.4 14.2 2.6 3.8 3.2 10.3
886 894 895 906 688 724 906 906
31.7 14.3 9.2 16.0 3.8 1.7 2.8 5.0
2.29 2.00 1.56 0.91 0.60 2.34 1.12 2.06
95% CI
1.88–2.79 1.58–2.53 1.16–2.11 0.69–1.19 0.32–1.1 1.17–4.68 0.64–1.95 1.40–3.03
P-value
<0.001 <0.001 <0.001 0.468 0.104 0.013 0.698 <0.001
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randomized phase II study comparing vinorelbine and gemcitabine either with or without cisplatin, Chen et al. found a significant decrease in most items of the Lung Cancer Symptom Scale (LCSS) on both arms as compared to the pre-treatment scores, but found no differences when the two arms were compared to each other [28]. As the primary role of chemotherapy in patients with advanced NSCLC is palliative, the influence on patients’ quality of life (QOL) is an important issue in determining the true value of new therapy. Recently, the addition of the anti-VEGF antibody bevacizumab, to a combination of carboplatin and paclitaxel demonstrated an improvement in overall survival in certain sub-groups of patients with advanced NSCLC, although there was a significant increase in adverse effects and cost of therapy [29]. The results of this study however cannot be applied to all patients with advanced NSCLC, as this trial excluded patients with predominantly squamous cell carcinoma histology, hemoptysis, central nervous system metastases and patients who were on therapeutic anticoagulation. These patients form a substantial population of patients with advanced NSCLC and other alternatives are needed to improve their survival. Our study has a few drawbacks that should be considered while interpreting the results. The data used for analysis was not individual patient data, which in general gives an independent patient data-based meta-analysis [30], but rather, abstracted data. A major issue affecting the validity of any meta-analysis is publication bias. Although we detected no evidence of publication bias using standard graphical and statistical methods, it would be impossible to exclude this possibility altogether. Furthermore, our study is limited by the number and quality of randomized trials being available. Three of the six studies were conducted by the same group [17,18,22] that adopted similar regimens with only slight variation in the choice of control arm. In conclusion, although triplet therapy was associated with higher response rates at the expense of increased toxicity and there is no evidence for improvement in overall survival. Based on the results of this analysis, we would discourage further study of triplet cytotoxic chemotherapy regimens in the treatment of advanced NSCLC. Conflict of interest None of the authors has any conflict of interest that could influence this work.
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