SYSTEMATIC REVIEW
Doublets versus single-agent therapy as first-line therapy for elderly patients with advanced non-small cell lung cancer? A systematic review of randomised controlled trials C.-A. Xu, Z.-Y. Chang, X.-J. Wang, H.-Y. Qi
Department of Medical Oncology, The Fourth Affiliated Hospital, China Medical University, Shenyang, China Correspondence to: Professor Chong-An Xu, Department of Medical Oncology, the Fourth Affiliated Hospital, China Medical University, #4 Chongshan East Road, Shenyang 110032, China. Tel.: 86 24 62042986 Fax: 86 24 62571119 Email: [email protected] Disclosure None.
SUMMARY
Review criteria
Introduction: Although the standard treatment for advanced non-small cell lung cancer (NSCLC) patients is platinum-based doublet chemotherapy, single-agent therapy is still preferred in elderly patients. Comparison of the efficacy of various combinations of doublets with single-agent chemotherapy is somehow contradictory. This study conducted a systematic review to evaluate the efficacy and tolerability of the third-generation agent-based doublets vs. single-agent chemotherapy in elderly NSCLC patients. Methods: Electronic (PubMed, EMBASE and Cochrane Library database) and manual searches were conducted to collect data from published, randomised, phase 2 and 3 trials which compared doublets with a thirdgeneration single-agent chemotherapy in elderly patients. Pooled relative risks (RRs) were calculated for the incidences of overall response rate (ORR), 1-year survival rate (1-y SR), and grade 3/4 toxicities. Results: Seven eligible trials (2219 patients) were selected from 1170 studies that were initially identified. A significant difference in ORR favouring doublets over single agents was observed [RR, 1.59; 95% confidence interval (95% CI), 1.36–1.86; p < 0.0001] with a slightly, but not significantly improved 1-y SR (RR, 1.19; 95% CI, 0.98–1.45, p = 0.007). Subgroup analysis suggested that platinum (RR, 1.94; 95% CI, 1.47– 2.55, p < 0.0001) or non-platinum- (RR, 1.45; 95% CI, 1.20–1.75, p < 0.0001) based doublets could improve ORR, and the grade 3/4 thrombocytopaenia (RR, 6.64; 95% CI, 1.78–24.86, p = 0.005) and anaemia (RR, 2.86; 95% CI, 1.62– 5.05, p < 0.0001) were preferred to occur in platinum-based doublets. Conclusions: Doublets appear to be more effective and tolerable than single-agent therapy for treating elderly advanced NSCLC patients, and therefore could be considered as a treatment option for elderly populations with good physical status.
Introduction The risk of people suffering from cancer improves in cooperation with significantly increased life expectancy (1). Among the patients with diagnosed lung cancer, more than 50% of the patients with advanced lung cancer are aged over 65, whereas the number of those who are aged over 70 are 30–40% (2,3). Therefore, the treatment of the elderly patients has become a hot topic. Non-small cell lung cancer (NSCLC) accounts for 80–85% of all the lung cancer. Unfortunately, it is usually diagnosed at an advanced stage, and only systemic palliative chemotherapy or
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We included all randomised controlled, phase 2 and 3 trials which were published in English language and compared doublets with a thirdgeneration single-agent chemotherapy in elderly advanced NSCLC patients after searching electronic database (PubMed, EMBASE and Cochrane Library) and relevant books and reference lists from their inception to February 2012.
Message for the clinic Single-agent, but not doublet therapy is currently preferred only for elderly NSCLC patients with good physical status. The results of our systematic review provided evidence of using the third-generation agent-based doublets as a treatment option for elderly advanced NSCLC patients.
molecular targeted therapy can be chosen. It has been verified that platinum-based doublet regimen is superior to the single-agent or three drug combinations by most large sample, multicentre, random controlled clinical trials. However, the prospective large-scale random control study dictated to elderly patients is very few because of constraints of the inclusion and protocol exclusion criteria (4,5). Therefore, the platinum-based doublet regimen is used as the standard first-line chemotherapy only for the non-elderly patients with lung cancer (6,7). Treatment options for the elderly patients with advanced lung cancer are still a controversial issue.
ª 2013 John Wiley & Sons Ltd Int J Clin Pract, November 2013, 67, 11, 1118–1127. doi: 10.1111/ijcp.12167
Doublets versus single-agent therapy as first-line therapy
The present clinical trials have clearly shown that elderly patients with advanced NSCLC who receive the third-generation agent (vinorelbine, gemcitabine, paclitaxel and docetaxel) provided better survival compared to the best supportive care (8–11). However, whether the survival benefit prefers to the doublets rather than single-agent is still unclear. In two published meta-analysis, they had shown that doublets had a higher overall response rate in comparison to single-agent, however, doublets had not provided survival benefit to the elderly patients (12,13). But in meta-analysis which included retrospect subgroup analysis, doublets, especially the platinum-based regimen, had better survival benefit compared with single-agent (14,15). To confirm whether doublets or single agent is more superior in the treatment of elderly patients with advanced NSCLC, the method of the Cochrane systematic review was used in this study to compare the difference between the efficacy and safety of the doublets and single-agent treatment.
Methods Eligibility criteria The trials included in the study must meet the following criteria: the research was limited to phase 2 and 3 randomised controlled trials, and published in the English language. Patients with the pathologically proved diagnosis of stage IIIB/IV NSCLC and with ECOG-performance status 0–2 were enrolled in this study. Age of the newly diagnosed patients without receiving any radiotherapy or chemotherapy treatment, or received no radiotherapy before and during the period of chemotherapy should be more than 65. The reason for excluding was listed in excluded trails.
Identification of trials A thorough bibliographic electronic search of PubMed, EMBASE and the Cochrane Library databases was conducted. All of the randomised controlled trails (up to Feb 2012), including full article and abstract, were collected using the following searching terms: ‘randomized’, ‘phaseII and III’, ‘NSCLC’, ‘cancer’, ‘elderly’ (MeSH), ‘non-small-cell lung/drug therapy’ (MeSH) and ‘antineoplastic combined chemotherapy protocols’ (MeSH). The search was limited to trials that were randomised, controlled and published in the English language. The results were supplemented with manual searches of American Society of Clinical Oncology (ASCO) meeting proceedings, references of selected articles and published reviews. When an abstract from a meeting and a full article referred to the same trial, only the full article
ª 2013 John Wiley & Sons Ltd Int J Clin Pract, November 2013, 67, 11, 1118–1127
was evaluated. When two or more articles reported the same data, the most recently updated data were included.
Definition of outcomes Efficacy was assessed using 1-year survival rate (1-y SR) as the primary outcome and ORR (objective response rate) as the secondary outcome. The 1-y SR is defined as the percentage of patients who remain alive 1 year after randomisation, and the ORR is the percentage of patients who have a complete or partial tumour response according to World Health Organization criteria or Response Evaluation Criteria in Solid Tumors. Regarding toxicity, we considered both haematologic (anaemia, neutropaenia, thrombocytopaenia) and non-haematologic (nausea/vomiting and neurotoxicity) grade 3 and 4 side effects of treatment.
Data extraction Two independent reviewers extracted data by filling in an appropriate form. Mismatches between reviewers were resolved through an independent review by a third investigator. The following data were collected from the identified trials: first author name, journal and year of publication, age of patients, drugs used and administration doses, number of patients, 1-y SR, ORR and percentage of patients who experienced grade 3 and 4 toxicities.
Statistical analysis Analysis was based on the number of patients allocated to treatment (intention to treat). The relative risk (RR), its standard error and 95% confidence interval were calculated by STATA 11.0 (Stata Corporation, College Station, TX) for each outcome and each trial. Relative risk was used because the primary outcome was frequent. The doublets were considered an investigational treatment, and the single agent was used as a control treatment. When a trial compared > 2 different chemotherapy regimens, the investigational or control arm was counted twice or more in the analysis, so that the number of comparisons was greater than the number of included trials. The outcomes were represented by dichotomous variables: The 1-year SR was calculated by applying an intentto-treat analysis; ORR and grade 3 and 4 toxicity analyses were performed by considering the number of patients evaluable for response and toxicity, respectively. For meta-analysis, Cochran Q test and I2 statistic were used to evaluate the heterogeneity of included studies first. The fixed effect model (weight and bottom variance) was used when there is no heterogeneity (p > 0.1 and I2 < 50%) between selected studies, otherwise, the random effect model should
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be used. The results of meta-analysis was described by forest plot, and if RR value is over than 1, it is indicated that doublet chemotherapy could gain more benefit compared with single-agent, while toxicity occurs more often in doublets in comparison with single-agent. Bilateral p-value of 0.05 or less was considered statistical significant.
Results Description of studies Procedure and reason for exclusion were shown in Figure 1. A total of 11 RCTs met the eligibility criteria (16–26). Four trails were excluded from metaanalysis, among which, two trails (16,17) which source from ASCO were considered ineligible because no data on 1-year SR were available on request from the authors, one trail was published twice (18), and one trail (19) was published in Chinese. All data were extracted from the remaining seven trials (20–26), including one phase II RCT (24) and six phase III RCT (20–23,25,26). After the selection procedure, seven trials that included 2219 patients were analysed. Among them, 997 patients received third-generation-based doublet regimen and 1222 patients received single-agent chemotherapy. The lower age limit was 65 years old (23) in only one of the seven trials that were included and 70 years old in the remaining six trials. Because two trials (21,22) had > 2 eligible arms, the number of comparisons was 11 (2715 patients). Drug name, doses, usage, schedules, number of patients in each arm, age of patients in each trial and outcomes (OS, 1-y SR and ORR) for all seven trials are reported in Table 1.
Responses Among all included trails, 11 comparisons provided overall response rate (ORR). There was no heterogeneity among these studies (p = 0.311, I2 = 13.9%), therefore the fixed effect model was used. In the pooled analysis, doublets were associated with significantly increased ORR (RR, 1.59; 95% CI, 1.36–1.86, p < 0.0001) in comparison with that of the singleagent treatment. At the same time, subgroup analysis had also shown that, either platinum- or non-platinum-based doublets significantly increased ORR in comparison to single-agent treatment (Figure 2).
Survival analysis Data of 1 year survival rate were available in all the included trials. As there was obvious between-study heterogeneity (p = 0.001, I2 = 66.5%), the random effect model was used to calculate RR of survival (Figure 3). In the pooled analysis, doublets were not associated with statistical significance in the SR compared with that of the single-agent treatment (RR, 1.19; 95% CI, 0.98–1.45, p = 0.007) (Figure 4). Subgroup analysis had shown that the SR of platinum- and non-platinum-based doublets treatment was similar to that of the single-agent treatment (Figure 5, Table 2).
Toxicity We can only collect 3/4 toxicity and make an analysis on these data. The incidence of grade 3/4 anaemia, neutropaenia and thrombocytopaenia were reported in all trials (20–26). The incidence of grade 3/4 nausea/vomiting and neurotoxicity were reported in seven trials (20–26), and grade 3/4 febrile neutropaenia were reported only in four trials (21,23,25,26). Although incidence of toxicity had increased, only grade 3/4 thrombocytopaenia showed statistical significance (RR, 1.98; 95% CI, 1.08–3.05, p = 0.028) (Table 2). Subgroup analysis had shown that, the incidence of toxicity in non-platinum doublets treatment was similar to that of the single-agent treatment (Table 3), whereas grade 3/4 thrombocytopaenia (RR = 6.64, 95% CI 1.78–24.86, p = 0.005) and grade 3/4 anaemia (RR = 2.86, 95% CI 1.62– 5.05, p < 0.001) were more likely to occur in platinum-based doublets treatment (Table 4).
Discussion
Figure 1 Flow chart of articles identified, included and
excluded
The age-related reduction in the functional reserve of many organs and/or comorbidities may contraindicate the chemotherapy, especially the doublet regimens (including platinum-based doublet chemotherapy) for elderly patients because of concern
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Control Treatment
21
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Control Treatment
25
26
Control Treatment
24
Control
Treatment
Control
Control Treatment
Control Treatment
Control Treatment
Control Treatment
Control Treatment
23
22
Treatment
20
Control Treatment
Arm
Reference
13 44 41 44 45 21 19 21 22 15 19 15 22 65 57 16 16 61 62 0 0
70 70 70 70 70 70 70 70 70 70 70 70 70 > 65 > 65 70 70 70 70 70 70
226 131 126
31 225
171 34
63 174
68 65
63 65
68 68
233 68
233 232
60 232
16
70
60
Gemcitabine at 1200 mg/m2 on days 1 and 8 every 3 weeks Vinorelbine at 30 mg/m2 on days 1 and 8 every 3 weeks Vinorelbine at 30 mg/m2 on days 1 and 8 every 3 weeks Gemcitabine at 1000 mg/m2 on days 1 and 8 every 3 weeks Vinorelbine at 25 mg/m2 on days 1 and 8 every 3 weeks Gemcitabine at 1200 mg/m2 on days 1 and 8 every 3 weeks Gemcitabine at 1000 mg/m2 on days 1 and 8 every 3 weeks Vinorelbine at 25 mg/m2 on days 1 and 8 every 3 weeks Vinorelbine at 30 mg/m2 on days 1 and 8 every 3 weeks Gemcitabine at 1000?1200 mg/m2 on days 1 and 8 every 3 weeks Vinorelbine at 25?30 mg/m2 on days 1 and 8 every 3 weeks Gemcitabine at 1200?1400?1600 mg/m2 on days 1 and 8 and 15 every 4 weeks Gemcitabine at 1000?1200 mg/m2 on days 1 and 8 every 3 weeks Vinorelbine at 25?30 mg/m2 on days 1 and 8 every 3 weeks Paclitaxel at 100?120?140 mg/m2 on days 1, 8 and 15 every 4 weeks Gemcitabine at 1000?1200 mg/m2 on days 1 and 8 every 3 weeks Paclitaxei at 80?100 mg/m2 on days 1 and 8 every 3 weeks Gemcitabine at 1200?1400?1600 mg/m2 on days 1, 8 and 15 every 4 weeks Gemcitabine at 1000?1200 mg/m2 on days 1 and 8 every 3 weeks Paclitaxel at 80?100 mg/m2 on days 1 and 8 every 3 weeks Paclitaxel at 100?120?140 mg/m2 on days 1, 8 and 15 every 4 weeks Docetaxel at 30 mg/m2 on days 1, 8 and 15 every 4 weeks Gemcitabine at 800 mg/m2 on days 1 and 8 and 15 every 4 weeks Docetaxel at 36 mg/m2 on days 1, 8 and 15 every 4 weeks Vinorelbine at 22.5 mg/m2 on days 1 and 8 every 3 weeks Cisplatin at 50 mg/m2 on days 1 every 3 weeks Vinorelbine at 25 mg/m2 on days 1 and 8 every 3 weeks Paclitaxel at 90 mg/m2 on day 1, 8 and 15 every 4 weeks Carboplatin at 6 AUC on day 1 every 4 weeks Gemcitabine at 1150 mg/m2 on days 1 and 8 every 3 weeks & Vinorelbine at 25 mg/m2 on days 1 and 8 every 3 weeks Docetaxel at 20 mg/m2 on days 1, 8 and 15 every 3 weeks Cisplatin at 25 mg/m2 on days 1, 8 and 15 every 3 weeks Docetaxel at 60 mg/m2 on days 1 every 3 weeks
PS:2 n
Age, years
No. of patients
Treatment schedule and dose
Table 1 Baseline characteristics of randomised clinical trials included into systematic review
14.8
13.3
6.2
12 10.3
5.1 11.3
5.1 5.5
5.1 9.2
6.4 9.2
5.1 9.7
36 9.7
28 30
18 30
29
OS, week
58.2
54.5
25.4
50.9 44.5
24 47.2
25 26
29 44
25 44
29 32
38 32
28 30
13 30
30
1-y, SR,%
24.6
34.4
10.2
16.1 27.1
17 (130) 32.4
13 25 (126)
18 32
13 32
18 23
18 23
16 21
15 21
ORR, %
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Figure 2 Comparison of the overall response rate between doublet arms and single-agent arms of all identified, assessable trials. G, gemcitabine; V, vinorelbine; T, Taxol(paclitaxel); D, docetaxel; P, cisplatin; C, carboplatin; OR, odds ratio; 95% CI indicates, 95% confidence interval
Figure 3 Subgroup analysis of comparison of the overall response rate between doublet arms and single-agent arms of all identified, assessable trials. G, gemcitabine V, vinorelbine; T, Taxol(paclitaxel); D, docetaxel; P, cisplatin; C, carboplatin; OR, odds ratio; 95%CI indicates, 95% confidence interval
regarding patients’ tolerability. Unfortunately, the proportions of patients receiving the first-line chemotherapy are still low (27) mainly because of the concerns on the treatment-related and drug-related toxic side effects (5). Although the age is considered to be an absolute or relative contraindication factor in many cancers, the physiological age and the actual age vary widely because elderly are a group of heter-
ogeneous population. Therefore, whether cancer patients should receive chemotherapy could not be determined simply based on their age (28,29). Studies have shown that the age is not the factor of poor prognosis for advanced cancer (30–32), whereas the impact of physiological status, daily living capacity and other factors is more important on survival (25,31). Several studies have helped to identify which
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Figure 4 Comparison of the 1-year survival rate between doublet arms and single-agent arms of all identified, assessable trials. G, gemcitabine V, vinorelbine; T, Taxol(paclitaxel); D, docetaxel; P, cisplatin; C, carboplatin; OR, odds ratio; 95%CI indicates, 95% confidence interval
Figure 5 Subgroup of comparison of the 1-year survival rate between doublet arms and single-agent arms of all identified, assessable trials. G, gemcitabine V, vinorelbine; T, Taxol(paclitaxel); D, docetaxel; P, cisplatin; C, carboplatin; OR, odds ratio; 95% CI indicates, 95% confidence interval
groups of elderly patients are more likely to benefit from the standard treatment for cancer (33–36). However, their clinical application are still quite limited. Thus, the study on predicting the risk/benefit ratio of elderly patients is very important. Evidences for the tolerance and efficacy of the treatment of elderly patients with advanced NSCLC are mainly from two different publications; one is
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prospective clinical trials specially designed for elderly patients, and the other is retrospective subgroup analysis of elderly patients in clinical trials without age limit. In several retrospective subgroup analyses of the large-scale randomised trials that were dictated to elderly patients without age limit, it showed that the platinum-based doublets demonstrated similar tumour response rate, overall survival
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Table 2 Comparison of toxicity between doublet arms and single-agent arms in trials
No. of patients Toxicity
No. of trials
Doublet arms
Single-agent arms
RR
95% CI
p-value
Anaemia Neutropaenia Thrombocytopaenia Nausea & vomiting Neurotoxicity Febrile neutropaenia
7 7 7 7 6 4
1318 1318 1318 1320 1131 1010
1316 1316 1316 1315 1122 1006
1.55 1.17 1.98 1.06 1.73 1.1
0.90–2.69 0.59–2.33 1.08–3.65 0.66–1.70 0.78–3.83 0.27–4.41
0.114 0.65 0.028 0.812 0.175 0.893
Table 3 Comparison of toxicity between non-platinum-based doublet arms and single-agent arms in trials
No. of patients Toxicity
No. of trials
Doublet arms
Single-agent arms
RR
95% CI
p-value
Anaemia Neutropaenia Thrombocytopaenia Nausea & vomiting Neurotoxicity Febrile neutropaenia
4 4 4 4 3 2
932 932 932 932 874 636
926 926 926 926 866 628
1.12 1.24 1.66 0.99 1.11 0.35
0.57–2.18 0.82–1.86 0.88–3.14 0.60–1.66 0.44–2.79 0.00–94.77
< 0.001 0.067 0.116 0.98 0.825 0.711
Table 4 Comparison of toxicity between platinum-based doublet arms and single-agent arms in trials
No. of patients Toxicity
No. of trials
Doublet arms
Single-agent arms
RR
95% CI
p-value
Anaemia Neutropaenia Thrombocytopaenia Nausea & vomiting Neurotoxicity Febrile neutropaenia
3 3 3 3 3 2
386 386 386 388 257 374
390 390 390 389 256 378
2.86 1.11 6.64 1.22 7.06 0.82
1.62–5.05 0.59–2.33 1.78–24.86 0.05–28.32 0.88–56.94 0.46–1.48
< 0.001 < 0.001 0.005 0.902 0.066 0.518
rate and toxicity in elderly and younger patients (37– 43), and did not significantly affect the life quality of the patients (38). Although these data provide the evidences to support the feasibility of application of the doublets regimen for elderly patients, even when those enrolled in these clinical trials have better tolerance for the chemotherapy and may not be representative of the whole elderly population, it is still not enough to conclude the platinum-based doublets as the first-line chemotherapy. The RCT specifically dictated to the elderly patients is therefore urgently needed. Looking at the data from seven previously published clinical trials specially designed for elderly patients with advanced NSCLC, it is still disputable whether doublets treatment has a greater survival benefit than single-agent treatment (three trials
showed single-agent is superior to doublets (21–23), four trials showed the opposite(20,24–26), which may be because of an insufficient sample size (20,24), too many groups (22), insufficient randomisation (20,23,24) and the different drug. To obtain better overall statistical fits and less bias because of lack of patients and insufficient randomisation, current meta-analysis was therefore carried out to reevaluate whether doublets could provide better results than single agents in the treatment of elderly patients with advanced NSCLC. Our meta-analysis indicated a significantly increased response rate (p < 0.0001) with doublets regimens over single-agent chemotherapy and a clear but not significant increasing trend in 1-y SR. Subgroup analysis revealed that either platinum- or nonplatinum-based doublets had a higher increase in
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ORR over that of single-agent treatment, but 1-y SR were similar to that of single-agent treatment. Our results were similar to that of the study by Russo et al. (12), although their study was focussed on the gemcitabine-based doublets regimen, while our study contained doublets regimen with other types of third-generation drugs. The meta-analysis by Des Guetz et al. (14) revealed that elderly patients who received doublets had a higher 1-y SR compared with single-agent (HR, 0.92; 95% CI, 0.87–0.99). However, this meta-analysis contained three retrospective subgroup analysis data, and this result should be deliberated. That is, subgroup analysis could be interfered by selective bias, and its randomness is not enough. Moreover, the included population was not elderly patients and the dose of chemotherapy agent the elderly patients received was a standard dose. Our study only selected RCTs specially designed for elderly patients, and the dose of doublets that elderly patients received had downregulated on different degrees. We could get significant results on survival in case of no difference on dose of drugs. Although the administration dose of the doublets was reduced, the analysis still showed that 3/4 grade thrombocytopaenia was significantly associated with doublet regimens, although it was only in the platinum-based doublets regimen. Non-platinum-based doublets regimen had a higher, but not statistically significant incidence of toxicity. Moreover, the incidence of 3/4 grade anaemia in platinum-based doublets regimen was superior to that of the single-agent regimen, which suggested that the toxicity of doublet chemotherapy is tolerable for the elderly patients and safety can be administrable. Quality of the studies is subject to some restrictions. First, the heterogeneity in data regarding age and elderly assessment among the reviewed studies resulted in the selection bias of the available elderly. In two of the selected studies, younger patients with poor performance status were included together with elderly patients (22,23), leading to a heterogeneous study population. This selection bias should not particularly affect our findings because of the small percentage of younger patients who had a poor performance among those enrolled in these studies (32,44). Second, this meta-analysis was simply based on published data, but not the individual patient data, without assessment by open external procedure, which may result in an over-estimation of treatment effects. On the other hand, to reduce heterogeneity, strict eligibility criteria were established in this study. However, difference in selection, trial design, dose and different combination of drug all can produce heterogeneity. Furthermore, because of the selection bias of the published research results, for example,
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heterogeneity may not be easily represented as numbers of trials reporting the side effect are very few; therefore, we must be careful to explain the assessment. Our study suggests that elderly patients with advanced NSCLC should be given active treatment, rather than the negative best supportive care. Because elderly patients are a heterogeneous group of populations. Even they have the same physiological age, their constitution may not be the same. Therefore, the part of elderly patients will benefit from standard chemotherapy regimens as young patients, and elderly patients with complications and/or the presence of organ dysfunction need to adjust or change the treatment options (45). Therefore, a more individualised treatment plan is preferred, and determination of whether elderly patients could or could not receive chemotherapy, either doublet or single-agent regimen, without serious selection are not appropriate. It must be taken into account the heterogeneity of elderly patients and their physiological characteristic prior to application, and fully consider the toxicity, pharmacokinetics, organ function, complication and patients’ wish to make a comprehensive assessment of risk/benefit ratio associated with the doublet chemotherapy. As our study showed that doublets regimen had a higher ORR over that of single-agent regimen, 1-y SR also tended to increase in doublets regimen and a huge account of retrospective subgroup analysis have shown that elderly patients should receive the same regimen as young patients. In summary, doublet chemotherapy could be taken into account as the first-line chemotherapy of elderly patients with advanced NSCLC. To gain more convincing evidences for the clinical purpose, multicentre, largescale prospective randomised clinical trial comparing doublets and single agent dictated to the elderly patients with advanced NSCLC is necessary. And single-agent chemotherapy with third-generation drug could be used as one of the first-line treatment in non-selected elderly patients with advanced NSCLC. This was because, compared with best supportive care, single-agent chemotherapy could provide benefit for elderly patients, whereas 1-y SR of single-agent was similar to that of doublets.
Author contributions Chong-An Xu: Conception/design, interpretation and final approval of the manuscript. Zi-You Chang: literature research and data analysis. Xiao-Jie Wang and Zi-You Chang: Data collection and statistical analysis. Hai-Yan Qi and Chong-An Xu: manuscript preparation.
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Acknowledgements We thank Dr. Qin Li from Laboratory center, the Fourth Affiliated Hospital of China medical University for his language editing of this manuscript,
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which remarkably improved the quality of this article. This work was supported by the grant from National Natural Science Foundation of China (Project No.: 81001028).
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randomised, phase 3 trial. Lancet 2011; 378: 1079– 88. Abe T, Yokoyama A, Takeda K, et al. Randomized phase III trial comparing weekly docetaxel (D)-cisplatin (P) combination with triweekly D alone in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): an intergroup trial of JCOG0803/WJOG4307L. J Clin Oncol (Meeting Abstract) 2011; 29: 7509. Davidoff AJ, Tang M, Seal B, et al. Chemotherapy and survival benefit in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol 2010; 28: 2191–7. Azzoli CG, Baker S Jr, Temin S, et al. American Society of Clinical Oncology clinical practice guideline update on chemotherapy for stage IV non-small cell lung cancer. J Clin Oncol 2009; 27: 6251–66. Balducci L. Management of cancer in the elderly. Oncology (Williston Park) 2006; 144: 146. Albain KS, Crowley JJ, LeBlanc M, et al. Survival determinants in extensive-stage nonsmall cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol 1991; 9: 1618–26. Stanley KE. Prognostic factors for survival in patients with inoperable lung cancer. J Natl Cancer Inst 1980; 65: 25–32. Ansari RH, Socinski MA, Edelman MJ, et al. A retrospective analysis of outcomes by age in a threearm phase III trial of gemcitabine in combination with carboplatin or paclitaxel vs. paclitaxel plus carboplatin for advanced non-small cell lung cancer. Crit Rev Oncol Hematol 2011; 78: 162–71. Wedding U, K€ odding D, Pientka L, et al. Physicians’judgement and comprehensive geriatric assessment(CGA)select different patients as fit for chemotherapy. Crit Rev Oncol Hematol 2007; 64: 1–9. Repetto L, Fratino L, Audisio RA, et al. Comprehensive geriatric assessment adds information to Eastern Cooperative Oncology Group performance status in elderly cancer patients: an Italian Group for Geriatric Oncology Study. J Clin Oncol 2002; 20: 494–502. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001; 56: M146–56. Rodin MB, Mohile SG. A practical approach to geriatric assessment in oncology. J Clin Oncol 2007; 25: 1936–44. Belani CP, Fossella F. Elderly subgroup analysis of a randomized phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for first-line treatment of advanced non small cell lung carcinoma (TAX 326). Cancer 2005; 104: 2766–74. Langer CJ, Manola J, Bernardo P, et al. Cisplatinbased therapy for elderly patients with advanced non-small-cell lung cancer: the cancer: implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst 2002; 94: 173–81.
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Doublets versus single-agent therapy as first-line therapy
39 Lilenbaum RC, Herndon JE, List MA, et al. Singleagent versus combination chemotherapy in advanced non-small cell lung cancer: the cancer and leukemia group B (study 9730). J Clin Oncol 2005; 23: 190–6. 40 Kelly K, Giarritta S, Akerley W, et al. Should older patient (pts) receive combination chemotherapy for advanced stage non-small cell lung cancer (NSCLC)? An analysis of Southwest Oncology Trials 9509 and 9308. Proc Am Soc Clin Oncol 2001; 1313: 20. 41 Rocha Lima CM, Herndon JE 2nd, Kosty M, et al. Therapy choices among older patients with lung
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carcinoma: an evaluation of two trials of the Cancer and Leukemia Group B. Cancer 2002; 94: 181–7. 42 Langer CJ, Vangel J, Schiller DP, et al. Age-specific subanalysis of ECOG 1594: fit elderly patients (70– 80 yrs) with NSCLC do as well as younger patients (
Doublets versus single-agent therapy as first-line therapy for elderly patients with advanced non-small cell lung cancer? A systematic review of randomised controlled trials C.-A. Xu, Z.-Y. Chang, X.-J. Wang, H.-Y. Qi
Department of Medical Oncology, The Fourth Affiliated Hospital, China Medical University, Shenyang, China Correspondence to: Professor Chong-An Xu, Department of Medical Oncology, the Fourth Affiliated Hospital, China Medical University, #4 Chongshan East Road, Shenyang 110032, China. Tel.: 86 24 62042986 Fax: 86 24 62571119 Email: [email protected] Disclosure None.
SUMMARY
Review criteria
Introduction: Although the standard treatment for advanced non-small cell lung cancer (NSCLC) patients is platinum-based doublet chemotherapy, single-agent therapy is still preferred in elderly patients. Comparison of the efficacy of various combinations of doublets with single-agent chemotherapy is somehow contradictory. This study conducted a systematic review to evaluate the efficacy and tolerability of the third-generation agent-based doublets vs. single-agent chemotherapy in elderly NSCLC patients. Methods: Electronic (PubMed, EMBASE and Cochrane Library database) and manual searches were conducted to collect data from published, randomised, phase 2 and 3 trials which compared doublets with a thirdgeneration single-agent chemotherapy in elderly patients. Pooled relative risks (RRs) were calculated for the incidences of overall response rate (ORR), 1-year survival rate (1-y SR), and grade 3/4 toxicities. Results: Seven eligible trials (2219 patients) were selected from 1170 studies that were initially identified. A significant difference in ORR favouring doublets over single agents was observed [RR, 1.59; 95% confidence interval (95% CI), 1.36–1.86; p < 0.0001] with a slightly, but not significantly improved 1-y SR (RR, 1.19; 95% CI, 0.98–1.45, p = 0.007). Subgroup analysis suggested that platinum (RR, 1.94; 95% CI, 1.47– 2.55, p < 0.0001) or non-platinum- (RR, 1.45; 95% CI, 1.20–1.75, p < 0.0001) based doublets could improve ORR, and the grade 3/4 thrombocytopaenia (RR, 6.64; 95% CI, 1.78–24.86, p = 0.005) and anaemia (RR, 2.86; 95% CI, 1.62– 5.05, p < 0.0001) were preferred to occur in platinum-based doublets. Conclusions: Doublets appear to be more effective and tolerable than single-agent therapy for treating elderly advanced NSCLC patients, and therefore could be considered as a treatment option for elderly populations with good physical status.
Introduction The risk of people suffering from cancer improves in cooperation with significantly increased life expectancy (1). Among the patients with diagnosed lung cancer, more than 50% of the patients with advanced lung cancer are aged over 65, whereas the number of those who are aged over 70 are 30–40% (2,3). Therefore, the treatment of the elderly patients has become a hot topic. Non-small cell lung cancer (NSCLC) accounts for 80–85% of all the lung cancer. Unfortunately, it is usually diagnosed at an advanced stage, and only systemic palliative chemotherapy or
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We included all randomised controlled, phase 2 and 3 trials which were published in English language and compared doublets with a thirdgeneration single-agent chemotherapy in elderly advanced NSCLC patients after searching electronic database (PubMed, EMBASE and Cochrane Library) and relevant books and reference lists from their inception to February 2012.
Message for the clinic Single-agent, but not doublet therapy is currently preferred only for elderly NSCLC patients with good physical status. The results of our systematic review provided evidence of using the third-generation agent-based doublets as a treatment option for elderly advanced NSCLC patients.
molecular targeted therapy can be chosen. It has been verified that platinum-based doublet regimen is superior to the single-agent or three drug combinations by most large sample, multicentre, random controlled clinical trials. However, the prospective large-scale random control study dictated to elderly patients is very few because of constraints of the inclusion and protocol exclusion criteria (4,5). Therefore, the platinum-based doublet regimen is used as the standard first-line chemotherapy only for the non-elderly patients with lung cancer (6,7). Treatment options for the elderly patients with advanced lung cancer are still a controversial issue.
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Doublets versus single-agent therapy as first-line therapy
The present clinical trials have clearly shown that elderly patients with advanced NSCLC who receive the third-generation agent (vinorelbine, gemcitabine, paclitaxel and docetaxel) provided better survival compared to the best supportive care (8–11). However, whether the survival benefit prefers to the doublets rather than single-agent is still unclear. In two published meta-analysis, they had shown that doublets had a higher overall response rate in comparison to single-agent, however, doublets had not provided survival benefit to the elderly patients (12,13). But in meta-analysis which included retrospect subgroup analysis, doublets, especially the platinum-based regimen, had better survival benefit compared with single-agent (14,15). To confirm whether doublets or single agent is more superior in the treatment of elderly patients with advanced NSCLC, the method of the Cochrane systematic review was used in this study to compare the difference between the efficacy and safety of the doublets and single-agent treatment.
Methods Eligibility criteria The trials included in the study must meet the following criteria: the research was limited to phase 2 and 3 randomised controlled trials, and published in the English language. Patients with the pathologically proved diagnosis of stage IIIB/IV NSCLC and with ECOG-performance status 0–2 were enrolled in this study. Age of the newly diagnosed patients without receiving any radiotherapy or chemotherapy treatment, or received no radiotherapy before and during the period of chemotherapy should be more than 65. The reason for excluding was listed in excluded trails.
Identification of trials A thorough bibliographic electronic search of PubMed, EMBASE and the Cochrane Library databases was conducted. All of the randomised controlled trails (up to Feb 2012), including full article and abstract, were collected using the following searching terms: ‘randomized’, ‘phaseII and III’, ‘NSCLC’, ‘cancer’, ‘elderly’ (MeSH), ‘non-small-cell lung/drug therapy’ (MeSH) and ‘antineoplastic combined chemotherapy protocols’ (MeSH). The search was limited to trials that were randomised, controlled and published in the English language. The results were supplemented with manual searches of American Society of Clinical Oncology (ASCO) meeting proceedings, references of selected articles and published reviews. When an abstract from a meeting and a full article referred to the same trial, only the full article
ª 2013 John Wiley & Sons Ltd Int J Clin Pract, November 2013, 67, 11, 1118–1127
was evaluated. When two or more articles reported the same data, the most recently updated data were included.
Definition of outcomes Efficacy was assessed using 1-year survival rate (1-y SR) as the primary outcome and ORR (objective response rate) as the secondary outcome. The 1-y SR is defined as the percentage of patients who remain alive 1 year after randomisation, and the ORR is the percentage of patients who have a complete or partial tumour response according to World Health Organization criteria or Response Evaluation Criteria in Solid Tumors. Regarding toxicity, we considered both haematologic (anaemia, neutropaenia, thrombocytopaenia) and non-haematologic (nausea/vomiting and neurotoxicity) grade 3 and 4 side effects of treatment.
Data extraction Two independent reviewers extracted data by filling in an appropriate form. Mismatches between reviewers were resolved through an independent review by a third investigator. The following data were collected from the identified trials: first author name, journal and year of publication, age of patients, drugs used and administration doses, number of patients, 1-y SR, ORR and percentage of patients who experienced grade 3 and 4 toxicities.
Statistical analysis Analysis was based on the number of patients allocated to treatment (intention to treat). The relative risk (RR), its standard error and 95% confidence interval were calculated by STATA 11.0 (Stata Corporation, College Station, TX) for each outcome and each trial. Relative risk was used because the primary outcome was frequent. The doublets were considered an investigational treatment, and the single agent was used as a control treatment. When a trial compared > 2 different chemotherapy regimens, the investigational or control arm was counted twice or more in the analysis, so that the number of comparisons was greater than the number of included trials. The outcomes were represented by dichotomous variables: The 1-year SR was calculated by applying an intentto-treat analysis; ORR and grade 3 and 4 toxicity analyses were performed by considering the number of patients evaluable for response and toxicity, respectively. For meta-analysis, Cochran Q test and I2 statistic were used to evaluate the heterogeneity of included studies first. The fixed effect model (weight and bottom variance) was used when there is no heterogeneity (p > 0.1 and I2 < 50%) between selected studies, otherwise, the random effect model should
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be used. The results of meta-analysis was described by forest plot, and if RR value is over than 1, it is indicated that doublet chemotherapy could gain more benefit compared with single-agent, while toxicity occurs more often in doublets in comparison with single-agent. Bilateral p-value of 0.05 or less was considered statistical significant.
Results Description of studies Procedure and reason for exclusion were shown in Figure 1. A total of 11 RCTs met the eligibility criteria (16–26). Four trails were excluded from metaanalysis, among which, two trails (16,17) which source from ASCO were considered ineligible because no data on 1-year SR were available on request from the authors, one trail was published twice (18), and one trail (19) was published in Chinese. All data were extracted from the remaining seven trials (20–26), including one phase II RCT (24) and six phase III RCT (20–23,25,26). After the selection procedure, seven trials that included 2219 patients were analysed. Among them, 997 patients received third-generation-based doublet regimen and 1222 patients received single-agent chemotherapy. The lower age limit was 65 years old (23) in only one of the seven trials that were included and 70 years old in the remaining six trials. Because two trials (21,22) had > 2 eligible arms, the number of comparisons was 11 (2715 patients). Drug name, doses, usage, schedules, number of patients in each arm, age of patients in each trial and outcomes (OS, 1-y SR and ORR) for all seven trials are reported in Table 1.
Responses Among all included trails, 11 comparisons provided overall response rate (ORR). There was no heterogeneity among these studies (p = 0.311, I2 = 13.9%), therefore the fixed effect model was used. In the pooled analysis, doublets were associated with significantly increased ORR (RR, 1.59; 95% CI, 1.36–1.86, p < 0.0001) in comparison with that of the singleagent treatment. At the same time, subgroup analysis had also shown that, either platinum- or non-platinum-based doublets significantly increased ORR in comparison to single-agent treatment (Figure 2).
Survival analysis Data of 1 year survival rate were available in all the included trials. As there was obvious between-study heterogeneity (p = 0.001, I2 = 66.5%), the random effect model was used to calculate RR of survival (Figure 3). In the pooled analysis, doublets were not associated with statistical significance in the SR compared with that of the single-agent treatment (RR, 1.19; 95% CI, 0.98–1.45, p = 0.007) (Figure 4). Subgroup analysis had shown that the SR of platinum- and non-platinum-based doublets treatment was similar to that of the single-agent treatment (Figure 5, Table 2).
Toxicity We can only collect 3/4 toxicity and make an analysis on these data. The incidence of grade 3/4 anaemia, neutropaenia and thrombocytopaenia were reported in all trials (20–26). The incidence of grade 3/4 nausea/vomiting and neurotoxicity were reported in seven trials (20–26), and grade 3/4 febrile neutropaenia were reported only in four trials (21,23,25,26). Although incidence of toxicity had increased, only grade 3/4 thrombocytopaenia showed statistical significance (RR, 1.98; 95% CI, 1.08–3.05, p = 0.028) (Table 2). Subgroup analysis had shown that, the incidence of toxicity in non-platinum doublets treatment was similar to that of the single-agent treatment (Table 3), whereas grade 3/4 thrombocytopaenia (RR = 6.64, 95% CI 1.78–24.86, p = 0.005) and grade 3/4 anaemia (RR = 2.86, 95% CI 1.62– 5.05, p < 0.001) were more likely to occur in platinum-based doublets treatment (Table 4).
Discussion
Figure 1 Flow chart of articles identified, included and
excluded
The age-related reduction in the functional reserve of many organs and/or comorbidities may contraindicate the chemotherapy, especially the doublet regimens (including platinum-based doublet chemotherapy) for elderly patients because of concern
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Control Treatment
21
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Control Treatment
25
26
Control Treatment
24
Control
Treatment
Control
Control Treatment
Control Treatment
Control Treatment
Control Treatment
Control Treatment
23
22
Treatment
20
Control Treatment
Arm
Reference
13 44 41 44 45 21 19 21 22 15 19 15 22 65 57 16 16 61 62 0 0
70 70 70 70 70 70 70 70 70 70 70 70 70 > 65 > 65 70 70 70 70 70 70
226 131 126
31 225
171 34
63 174
68 65
63 65
68 68
233 68
233 232
60 232
16
70
60
Gemcitabine at 1200 mg/m2 on days 1 and 8 every 3 weeks Vinorelbine at 30 mg/m2 on days 1 and 8 every 3 weeks Vinorelbine at 30 mg/m2 on days 1 and 8 every 3 weeks Gemcitabine at 1000 mg/m2 on days 1 and 8 every 3 weeks Vinorelbine at 25 mg/m2 on days 1 and 8 every 3 weeks Gemcitabine at 1200 mg/m2 on days 1 and 8 every 3 weeks Gemcitabine at 1000 mg/m2 on days 1 and 8 every 3 weeks Vinorelbine at 25 mg/m2 on days 1 and 8 every 3 weeks Vinorelbine at 30 mg/m2 on days 1 and 8 every 3 weeks Gemcitabine at 1000?1200 mg/m2 on days 1 and 8 every 3 weeks Vinorelbine at 25?30 mg/m2 on days 1 and 8 every 3 weeks Gemcitabine at 1200?1400?1600 mg/m2 on days 1 and 8 and 15 every 4 weeks Gemcitabine at 1000?1200 mg/m2 on days 1 and 8 every 3 weeks Vinorelbine at 25?30 mg/m2 on days 1 and 8 every 3 weeks Paclitaxel at 100?120?140 mg/m2 on days 1, 8 and 15 every 4 weeks Gemcitabine at 1000?1200 mg/m2 on days 1 and 8 every 3 weeks Paclitaxei at 80?100 mg/m2 on days 1 and 8 every 3 weeks Gemcitabine at 1200?1400?1600 mg/m2 on days 1, 8 and 15 every 4 weeks Gemcitabine at 1000?1200 mg/m2 on days 1 and 8 every 3 weeks Paclitaxel at 80?100 mg/m2 on days 1 and 8 every 3 weeks Paclitaxel at 100?120?140 mg/m2 on days 1, 8 and 15 every 4 weeks Docetaxel at 30 mg/m2 on days 1, 8 and 15 every 4 weeks Gemcitabine at 800 mg/m2 on days 1 and 8 and 15 every 4 weeks Docetaxel at 36 mg/m2 on days 1, 8 and 15 every 4 weeks Vinorelbine at 22.5 mg/m2 on days 1 and 8 every 3 weeks Cisplatin at 50 mg/m2 on days 1 every 3 weeks Vinorelbine at 25 mg/m2 on days 1 and 8 every 3 weeks Paclitaxel at 90 mg/m2 on day 1, 8 and 15 every 4 weeks Carboplatin at 6 AUC on day 1 every 4 weeks Gemcitabine at 1150 mg/m2 on days 1 and 8 every 3 weeks & Vinorelbine at 25 mg/m2 on days 1 and 8 every 3 weeks Docetaxel at 20 mg/m2 on days 1, 8 and 15 every 3 weeks Cisplatin at 25 mg/m2 on days 1, 8 and 15 every 3 weeks Docetaxel at 60 mg/m2 on days 1 every 3 weeks
PS:2 n
Age, years
No. of patients
Treatment schedule and dose
Table 1 Baseline characteristics of randomised clinical trials included into systematic review
14.8
13.3
6.2
12 10.3
5.1 11.3
5.1 5.5
5.1 9.2
6.4 9.2
5.1 9.7
36 9.7
28 30
18 30
29
OS, week
58.2
54.5
25.4
50.9 44.5
24 47.2
25 26
29 44
25 44
29 32
38 32
28 30
13 30
30
1-y, SR,%
24.6
34.4
10.2
16.1 27.1
17 (130) 32.4
13 25 (126)
18 32
13 32
18 23
18 23
16 21
15 21
ORR, %
Doublets versus single-agent therapy as first-line therapy 1121
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Doublets versus single-agent therapy as first-line therapy
Figure 2 Comparison of the overall response rate between doublet arms and single-agent arms of all identified, assessable trials. G, gemcitabine; V, vinorelbine; T, Taxol(paclitaxel); D, docetaxel; P, cisplatin; C, carboplatin; OR, odds ratio; 95% CI indicates, 95% confidence interval
Figure 3 Subgroup analysis of comparison of the overall response rate between doublet arms and single-agent arms of all identified, assessable trials. G, gemcitabine V, vinorelbine; T, Taxol(paclitaxel); D, docetaxel; P, cisplatin; C, carboplatin; OR, odds ratio; 95%CI indicates, 95% confidence interval
regarding patients’ tolerability. Unfortunately, the proportions of patients receiving the first-line chemotherapy are still low (27) mainly because of the concerns on the treatment-related and drug-related toxic side effects (5). Although the age is considered to be an absolute or relative contraindication factor in many cancers, the physiological age and the actual age vary widely because elderly are a group of heter-
ogeneous population. Therefore, whether cancer patients should receive chemotherapy could not be determined simply based on their age (28,29). Studies have shown that the age is not the factor of poor prognosis for advanced cancer (30–32), whereas the impact of physiological status, daily living capacity and other factors is more important on survival (25,31). Several studies have helped to identify which
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Doublets versus single-agent therapy as first-line therapy
Figure 4 Comparison of the 1-year survival rate between doublet arms and single-agent arms of all identified, assessable trials. G, gemcitabine V, vinorelbine; T, Taxol(paclitaxel); D, docetaxel; P, cisplatin; C, carboplatin; OR, odds ratio; 95%CI indicates, 95% confidence interval
Figure 5 Subgroup of comparison of the 1-year survival rate between doublet arms and single-agent arms of all identified, assessable trials. G, gemcitabine V, vinorelbine; T, Taxol(paclitaxel); D, docetaxel; P, cisplatin; C, carboplatin; OR, odds ratio; 95% CI indicates, 95% confidence interval
groups of elderly patients are more likely to benefit from the standard treatment for cancer (33–36). However, their clinical application are still quite limited. Thus, the study on predicting the risk/benefit ratio of elderly patients is very important. Evidences for the tolerance and efficacy of the treatment of elderly patients with advanced NSCLC are mainly from two different publications; one is
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prospective clinical trials specially designed for elderly patients, and the other is retrospective subgroup analysis of elderly patients in clinical trials without age limit. In several retrospective subgroup analyses of the large-scale randomised trials that were dictated to elderly patients without age limit, it showed that the platinum-based doublets demonstrated similar tumour response rate, overall survival
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Table 2 Comparison of toxicity between doublet arms and single-agent arms in trials
No. of patients Toxicity
No. of trials
Doublet arms
Single-agent arms
RR
95% CI
p-value
Anaemia Neutropaenia Thrombocytopaenia Nausea & vomiting Neurotoxicity Febrile neutropaenia
7 7 7 7 6 4
1318 1318 1318 1320 1131 1010
1316 1316 1316 1315 1122 1006
1.55 1.17 1.98 1.06 1.73 1.1
0.90–2.69 0.59–2.33 1.08–3.65 0.66–1.70 0.78–3.83 0.27–4.41
0.114 0.65 0.028 0.812 0.175 0.893
Table 3 Comparison of toxicity between non-platinum-based doublet arms and single-agent arms in trials
No. of patients Toxicity
No. of trials
Doublet arms
Single-agent arms
RR
95% CI
p-value
Anaemia Neutropaenia Thrombocytopaenia Nausea & vomiting Neurotoxicity Febrile neutropaenia
4 4 4 4 3 2
932 932 932 932 874 636
926 926 926 926 866 628
1.12 1.24 1.66 0.99 1.11 0.35
0.57–2.18 0.82–1.86 0.88–3.14 0.60–1.66 0.44–2.79 0.00–94.77
< 0.001 0.067 0.116 0.98 0.825 0.711
Table 4 Comparison of toxicity between platinum-based doublet arms and single-agent arms in trials
No. of patients Toxicity
No. of trials
Doublet arms
Single-agent arms
RR
95% CI
p-value
Anaemia Neutropaenia Thrombocytopaenia Nausea & vomiting Neurotoxicity Febrile neutropaenia
3 3 3 3 3 2
386 386 386 388 257 374
390 390 390 389 256 378
2.86 1.11 6.64 1.22 7.06 0.82
1.62–5.05 0.59–2.33 1.78–24.86 0.05–28.32 0.88–56.94 0.46–1.48
< 0.001 < 0.001 0.005 0.902 0.066 0.518
rate and toxicity in elderly and younger patients (37– 43), and did not significantly affect the life quality of the patients (38). Although these data provide the evidences to support the feasibility of application of the doublets regimen for elderly patients, even when those enrolled in these clinical trials have better tolerance for the chemotherapy and may not be representative of the whole elderly population, it is still not enough to conclude the platinum-based doublets as the first-line chemotherapy. The RCT specifically dictated to the elderly patients is therefore urgently needed. Looking at the data from seven previously published clinical trials specially designed for elderly patients with advanced NSCLC, it is still disputable whether doublets treatment has a greater survival benefit than single-agent treatment (three trials
showed single-agent is superior to doublets (21–23), four trials showed the opposite(20,24–26), which may be because of an insufficient sample size (20,24), too many groups (22), insufficient randomisation (20,23,24) and the different drug. To obtain better overall statistical fits and less bias because of lack of patients and insufficient randomisation, current meta-analysis was therefore carried out to reevaluate whether doublets could provide better results than single agents in the treatment of elderly patients with advanced NSCLC. Our meta-analysis indicated a significantly increased response rate (p < 0.0001) with doublets regimens over single-agent chemotherapy and a clear but not significant increasing trend in 1-y SR. Subgroup analysis revealed that either platinum- or nonplatinum-based doublets had a higher increase in
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Doublets versus single-agent therapy as first-line therapy
ORR over that of single-agent treatment, but 1-y SR were similar to that of single-agent treatment. Our results were similar to that of the study by Russo et al. (12), although their study was focussed on the gemcitabine-based doublets regimen, while our study contained doublets regimen with other types of third-generation drugs. The meta-analysis by Des Guetz et al. (14) revealed that elderly patients who received doublets had a higher 1-y SR compared with single-agent (HR, 0.92; 95% CI, 0.87–0.99). However, this meta-analysis contained three retrospective subgroup analysis data, and this result should be deliberated. That is, subgroup analysis could be interfered by selective bias, and its randomness is not enough. Moreover, the included population was not elderly patients and the dose of chemotherapy agent the elderly patients received was a standard dose. Our study only selected RCTs specially designed for elderly patients, and the dose of doublets that elderly patients received had downregulated on different degrees. We could get significant results on survival in case of no difference on dose of drugs. Although the administration dose of the doublets was reduced, the analysis still showed that 3/4 grade thrombocytopaenia was significantly associated with doublet regimens, although it was only in the platinum-based doublets regimen. Non-platinum-based doublets regimen had a higher, but not statistically significant incidence of toxicity. Moreover, the incidence of 3/4 grade anaemia in platinum-based doublets regimen was superior to that of the single-agent regimen, which suggested that the toxicity of doublet chemotherapy is tolerable for the elderly patients and safety can be administrable. Quality of the studies is subject to some restrictions. First, the heterogeneity in data regarding age and elderly assessment among the reviewed studies resulted in the selection bias of the available elderly. In two of the selected studies, younger patients with poor performance status were included together with elderly patients (22,23), leading to a heterogeneous study population. This selection bias should not particularly affect our findings because of the small percentage of younger patients who had a poor performance among those enrolled in these studies (32,44). Second, this meta-analysis was simply based on published data, but not the individual patient data, without assessment by open external procedure, which may result in an over-estimation of treatment effects. On the other hand, to reduce heterogeneity, strict eligibility criteria were established in this study. However, difference in selection, trial design, dose and different combination of drug all can produce heterogeneity. Furthermore, because of the selection bias of the published research results, for example,
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heterogeneity may not be easily represented as numbers of trials reporting the side effect are very few; therefore, we must be careful to explain the assessment. Our study suggests that elderly patients with advanced NSCLC should be given active treatment, rather than the negative best supportive care. Because elderly patients are a heterogeneous group of populations. Even they have the same physiological age, their constitution may not be the same. Therefore, the part of elderly patients will benefit from standard chemotherapy regimens as young patients, and elderly patients with complications and/or the presence of organ dysfunction need to adjust or change the treatment options (45). Therefore, a more individualised treatment plan is preferred, and determination of whether elderly patients could or could not receive chemotherapy, either doublet or single-agent regimen, without serious selection are not appropriate. It must be taken into account the heterogeneity of elderly patients and their physiological characteristic prior to application, and fully consider the toxicity, pharmacokinetics, organ function, complication and patients’ wish to make a comprehensive assessment of risk/benefit ratio associated with the doublet chemotherapy. As our study showed that doublets regimen had a higher ORR over that of single-agent regimen, 1-y SR also tended to increase in doublets regimen and a huge account of retrospective subgroup analysis have shown that elderly patients should receive the same regimen as young patients. In summary, doublet chemotherapy could be taken into account as the first-line chemotherapy of elderly patients with advanced NSCLC. To gain more convincing evidences for the clinical purpose, multicentre, largescale prospective randomised clinical trial comparing doublets and single agent dictated to the elderly patients with advanced NSCLC is necessary. And single-agent chemotherapy with third-generation drug could be used as one of the first-line treatment in non-selected elderly patients with advanced NSCLC. This was because, compared with best supportive care, single-agent chemotherapy could provide benefit for elderly patients, whereas 1-y SR of single-agent was similar to that of doublets.
Author contributions Chong-An Xu: Conception/design, interpretation and final approval of the manuscript. Zi-You Chang: literature research and data analysis. Xiao-Jie Wang and Zi-You Chang: Data collection and statistical analysis. Hai-Yan Qi and Chong-An Xu: manuscript preparation.
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Acknowledgements We thank Dr. Qin Li from Laboratory center, the Fourth Affiliated Hospital of China medical University for his language editing of this manuscript,
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