Comparison of the efficacy and safety of single-agent and doublet chemotherapy in advanced non-small cell lung cancer in the elderly: A meta-analysis

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1 Critical Reviews in Oncology/Hematology 84 (2012) Comparison of the efficacy and safety of single-agent and doublet chemotherapy in advanced non-small cell lung cancer in the elderly: A meta-analysis Gaetan Des Guetz a,, Bernard Uzzan b, Patrick Nicolas b, Dominique Valeyre c, Georges Sebbane d, Jean-François Morere a a Department of Oncology, AP-HP, Avicenne Hospital, Paris-XIII University, 125 route de Stalingrad, Bobigny, France b Department of Pharmacology, AP-HP, Avicenne Hospital, 125 route de Stalingrad, Paris-XIII University, Bobigny, France c Department of Pneumology, AP-HP, Avicenne Hospital, 125 route de Stalingrad, Paris-XIII University, Bobigny, France d Department of Geriatrics, AP-HP, Avicenne Hospital, 125 route de Stalingrad, Paris-XIII University, Bobigny, France Accepted 28 March 2012 Contents 1. Introduction Patients and methods Publication selection Statistical analysis Results Discussion Reviewers References Biography Abstract Background: In patients with advanced non-small cell lung cancer (NSCLC) aged more than 70 years, the benefit-to-risk ratio of doublet chemotherapy vs single-agent is not established. Methods: We performed a meta-analysis (MA), with a PubMed query using keywords simultaneously (Randomized controlled trial, Aged, Anti-neoplastic combined chemotherapy protocols/therapeutic use, Carcinoma, Non-small cell lung/drug therapy). Abstracts from ASCO, WCLC, and ESMO proceedings were reviewed. Articles were also obtained by cross-checking references. Third-generation agents (gemcitabine, vinorelbine, paclitaxel, docetaxel) in combination with or without platinum were included. The efficacy outcomes were Overall Response Rate (ORR) and 1-Year Overall Survival (OS). We used EasyMA software and a random-effect model in case of heterogeneity. Results: This MA comprised 10 studies including 2605 patients (mean age 74; 1866 men and 620 women; 654 stage IIIB and 1677 stage IV; 839 squamous cell cancers, 968 adenocarcinomas, 521 other pathological types). One-year OS (including the last trial by Abe) did not significantly improve for doublets compared with single-agents (HR 0.92; 95% Confidence Interval or CI: ) whereas it improved significantly before inclusion of this last study, when the study by Quoix et al., the most favorable to doublets, was included. However, doublet chemotherapy significantly improved ORR after inclusion of Abe study (HR 1.51; ; p < 0.001). OS was not significantly improved, neither by doublets including platinum (HR 0.90, ), nor by those without platinum (HR 0.94, ). ORR, but not OS, was improved by doublets including a taxane (docetaxel and paclitaxel) (HR 1.72; ) except for paclitaxel with a significant OS and ORR benefit. All-grade neutropenia thrombocytopenia and anemia were significantly more frequent with doublets than with single-agents (HR 1.26, ; 1.75, and 1.33, respectively). Grade 3/4 thrombocytopenia and anemia but not neutropenia were significantly more frequent with doublets (HRs 2.13, and 1.84, respectively). Corresponding author. Tel.: ; fax: address: gdesguetz@gmail.com (G. Des Guetz) /$ see front matter 2012 Elsevier Ireland Ltd. All rights reserved.

2 G. Des Guetz et al. / Critical Reviews in Oncology/Hematology 84 (2012) Conclusion: Compared with single-agents, doublets significantly improved ORR but not OS. They induced significantly more frequent thrombocytopenia and anemia. The benefit-to-risk ratio of doublets in advanced NSCLC might be more favorable than that of single agents, based on ORR but not OS Elsevier Ireland Ltd. All rights reserved. Keywords: Advanced non-small cell lung cancer; Elderly; Chemotherapy; Platinum derivates; Taxanes; Gemcitabine; Meta-analysis 1. Introduction Approximately two-thirds of patients diagnosed with nonsmall cell lung cancer (NSCLC) are 65-year old or older [1]. However, the treatment of elderly patients raises many issues. Standard treatments in oncology are usually based on the results of phase III, randomized controlled trials, but the participation of elderly patients in clinical trials has been consistently lower than expected [2]. Although this may be because of restricted eligibility criteria, it also indicates a residual bias against treating elderly patients with advanced NSCLC. Indeed, Ramsey et al. reviewed the Surveillance, Epidemiology, and End Results Medicare data from 1994 to 1999 and found a lower rate of chemotherapy use among the elderly, which was associated with a lower survival rate [3]. There are many challenges involved in the care of an elderly population with advanced cancer. Many of these patients have pre-existing co-morbid conditions, which, independently of cancer-related symptoms, may adversely affect organ function and functional status [4]. Therefore, clinical data obtained in a younger population cannot be automatically extrapolated to the great majority of non-selected elderly patients with cancer, more specifically NSCLC. In advanced NSCLC, third-generation first line therapy with a single agent such as vinorelbine, gemcitabine, or a taxane (paclitaxel or docetaxel) has been tested and compared with doublets including the same drug used as a single agent. Doublet chemotherapy is now considered as standard therapy for advanced non-operable NSCLCs. However, due to their frailty, many elderly patients are not eligible for aggressive treatments based on combined therapies. Therefore, some authors view single-agent chemotherapy as a standard for this population but the choice between single agents and doublets, the latter being presumably more effective but more toxic, remains controversial. Studies dealing with NSCLC have compared doublets including a platinum derivate (cis-platin or carboplatin) and a taxane (paclitaxel-docetaxel) or doublets without platinum derivate (taxane-gemcitabine) with single agents such as gemcitabine [5]. There is currently no consensus on the choice between single-agent and doublet chemotherapy for treating NSCLC elderly patients (more than 65 years old in the USA or more than 70 years old in Europe). Very recently, guidelines have been issued concerning chemotherapy of stage IV NSCLC [6]: they confirm the absence of general agreement on the choice of chemotherapy in elderly patients with advanced NSCLCs. Frailty of these elderly patients should be balanced with the potential benefit obtained from doublet chemotherapy and its risks (increased toxicity when compared with single agents). The goal of the present meta-analysis (MA) was to combine and analyze simultaneously all randomized phase III studies comparing different modalities of treatment of elderly patients with advanced NSCLC. This could allow a more precise assessment of efficacy and toxicity of these treatments for elderly patients thanks to the increased statistical power related to the high number of patients included. This MA aimed to compare efficacy (1-Year Overall Survival or OS and Overall Response Rate or ORR) and safety of doublet vs single-agent chemotherapy among elderly patients aged 70 years or more. It also aimed to assess the comparative efficacy and side effects of regimens including platinum derivates or not. 2. Patients and methods 2.1. Publication selection We performed our MA according to a predefined written protocol. To be eligible, studies had to deal with elderly patients (70 years or older) treated for metastatic or advanced NSCLC (stage IV and IIIB) with combined therapy (doublets) or single-agent chemotherapy. We only included phase III randomized controlled trials comparing these two treatment modalities, either wholly or partly dedicated to elderly patients. These studies often compared efficacy (1-year OS, ORR) and toxicity (clinical and biological side-effects) of these treatments. Publications were identified by an electronic search using online PubMed, updated on January 2012, with the following keywords used simultaneously: Randomized controlled trial, Aged, Anti-neoplastic combined chemotherapy protocols/therapeutic use, Carcinoma, Non-small cell lung/drug therapy. An EMBASE query did not bring additional references. We did not find a systematic review on this topic in the Cochrane database of Systematic Reviews. Abstracts from the annual proceedings of American Society of Clinical Oncology (ASCO) ( ), World Congress of Lung Cancer (WCLC) (2009) and the 2nd European Lung Cancer Conference (2010) were reviewed. Articles were also obtained from cross-checking all references of publications. As scheduled in a written protocol, each article was carefully read by two reviewers (GDG putting the emphasis on oncological aspects, and BU putting the emphasis on

3 342 G. Des Guetz et al. / Critical Reviews in Oncology/Hematology 84 (2012) methodological aspects). The reviewers had to fill in separately a pre-defined form. Disagreements were resolved by consensus between both reviewers Statistical analysis For each study, the Hazard Ratio (HR) was estimated by a method depending on the data provided by the publication. The simplest method consisted of the direct collection of HRs with their 95% Confidence Intervals (CIs) when mentioned in the original publication. If not available, we looked at the total numbers of events (deaths, response rates) and at the numbers of patients at risk in each group to calculate the HR. When data were only available as graphical survival plots, the calculations were made only if the number of steps on the curves equalled the number of events given in the publication, assuming that the rate of censored patients was constant during the study follow-up. By convention, in each study, we chose as reference the single-agent chemotherapy and HRs lower than 1 meant that survival was better among patients with the combined treatment or that side effects were less frequent with doublets. To analyze ORR, we decided to pool complete responses with partial responses and to compare these pooled data with the pooling of stable diseases and progressions. p values lower than 0.05 were considered as statistically significant. We calculated a HR estimate and its 95% CI by using a fixed-effect model (Mantel Haenszel) in case of absence of heterogeneity between studies and a random-effect model when heterogeneity was present. The statistical calculations used EasyMA.Net ( a software available online (Department of Clinical Pharmacology, Cardiology hospital, Lyon, France). PN performed the statistical analysis. 3. Results Our PubMed query performed on January 2012 found 750 references. Of these, careful reading of titles and abstracts only retrieved 9 studies fulfilling our inclusion criteria [7 15]. We excluded 741 studies. Inclusion of one of these studies [7] was not possible although we obtained additional data from the authors since it was a phase II study. The study by Chen et al. [8] was also a phase II study and was thus excluded. From these excluded studies, two [16,17] compared a single-agent chemotherapy with a doublet, but in non-chemo-naive patients. Two other studies were cohorts without randomization [18,19]. Two other excluded studies compared 2 or more doublets [20,21]. We also found an abstract from the last WCLC meeting [22] selected and one phase II from the last ESMO lung conference [23] excluded. Four papers from ASCO proceedings also corresponded to our inclusion criteria [24 27] but we needed additional data to include two of these trials [24,25]. Although we wrote to these authors, we could not obtain additional information (Fig. 1). Many papers were reviews or articles out of the scope of our MA. We included the 2 articles by Hainsworth et al. [12] and Comella et al. [13], although all patients were not more than 70 years old. The study by Hainsworth et al. [12] included 345 patients, of whom only 34 were less than 65 years old. Similarly, there were only 112 patients with PS2. The study by Comella et al. [13] included 264 patients, of whom 220 were more than 70 years old. Therefore, we deemed that the inclusion in our MA of both studies was justified. Ten studies from Frasci in 2001 to Quoix in 2010 and Abe in 2011 were finally included (see Table 1). These 10 studies included 14 sub-studies since the study by Gridelli et al. [13] had 3 arms (gemcitabine vs vinorelbine vs gemcitabine plus vinorelbine) and the study by Comella et al. [12] had 4 arms (gemcitabine, paclitaxel, gemcitabine plus paclitaxel and gemcitabine plus vinorelbine). All but 5 [10 13,22] were specifically dedicated to elderly patients. Two studies also included PS 2 patients [12,22]. Combination therapies in the 2 [10,11] other studies corresponding to elderly subgroup analyses of large randomized phase III studies were based on carboplatin. Overall, in 4 studies, combination therapy was based on carboplatin [10,11,15,22] and in one study [27], it was based on cis-platinum. Six studies [9,10,12 15] used a combination including gemcitabine. Seven studies [11 13,15,22,26,27] used a combination including a taxane derivate (docetaxel in 3 studies, paclitaxel in 4 studies). The main characteristics of studies and patients are presented in Table 1. The 10 eligible studies included 2605 patients. Their mean age was 74 years. There were 1866 men and 620 women (119 missing data). There were 654 stage IIIB and 1677 stage IV (274 missing data). Pathological examination found 839 squamous cell cancers, 968 adenocarcinomas, 521 other pathological types (277 missing data). [The proportions of stage IIIB patients who had pleural effusion and therefore were not candidates to curative radiation were usually not provided.] One-year OS did not significantly improve with doublets compared with single-agents (HR 0.92; 95% Confidence Interval or CI: ; p = 0.16; random effect model) after inclusion of the two last studies (2011) by Abe [27] et al. (less favorable) and Quoix et al. [15] (the most favorable to doublets) (Fig. 2). However, ORR was significantly superior with doublets compared with single agents both when including the last study by Abe et al. (HR 1.51; ; p < 0.001; random effect model) or when excluding it (HR for ORR 1.52; 95% CI: ; p < 0.001; random effect model) (Fig. 3). The study by Quoix et al. [15] largely contributed to the superiority of doublet therapies compared with single agent therapies. It also contributed to heterogeneity in 1-year OS, since the statistical heterogeneity was suppressed after exclusion of this study and the one by Abe et al. [27]. In this sensitivity analysis, the comparison between doublets and

4 Table 1 Main characteristics of the 13 studies included in the meta-analysis. Number Male/female Abe /83 Quoix /118 Karampeazis /12 Kang /21 Hainsworth /132 Sederholm From Phase 3 >70 yo PS 0 1 = 85% Lilenbaum /49 Comella /28 Patients PS % Median age Charlson score Stage IIIB/IV Pathological type SCC, AC Treatment (dose/mg/m 2 ) schedule Objective response (%) 1-Year Overall Survival (%) >70 yo 76 ND 85/191 SCC 72 Docetaxel 60 mg/m 2 D1 D8 31/116 (27) 77/134 (58) PS 0 1 = 100% D15/22D vs AC 176 Docetaxel 20 mg/m 2 + Cis platin 25 mg/m 2 D1 D8 D15/28D 45/117 (38) 74/138 (54) >70 yo : /363 SCC 151 Vinorelbine 30 mg/m 2 D1 23/211 (11) 61/226 (26) PS 0 1 = 73% >2: 102 AC 229 Gemcitabine 1150 mg/m 2 D1 Paclitaxel 90 mg/m 2 D1 D8 61/210 (29) 101/225 (45) D15 + Carboplatin AUC6 D1/28D >70 yo 76 (70 92) CIRS-G gr 3/4, 0: 29/65 SCC34 Gemcitabine 1200 mg/m 2 D1 5/45 (11) 23/45 (51) PS 0 1 = 83% 35 >1: 21 AC 35 Gemcitabine 13/49 (26) 32/49 (65) 900 mg/m 2 + Docetaxel 30 mg/m 2 D1 D8/21D >70 yo or PS2 72 ND 14/69 SCC 16 Docetaxel 75 mg/m 2 D1/21D vs 11/42 (26) 16/42 (38) AC 43 Docetaxel 35 mg/m 2 D1 8/41 (19) 11/41 (27) D8 + Carboplatin AUC 2.5 D1 D8/21D >65 yo or PS2 74 (45 91) ND 87/258 SCC 67 Docetaxel 36 mg/m 2 D1 D8 22/130 (13) 43/171 (25) D15/28D vs AC 132 Docetaxel 32/132 (18) 43/174 (25) 30 mg/m 2 + Gemcitabine 800 mg/m 2 D1 D8 D15/28D ND ND ND ND Gemcitabine 1250 mg/m 2 D1 D8 ND 23/57 (44) D 15/28D vs Gemcitabine 25/61 (41) 1250 mg/m 2 + Carboplatin D1 D8 D15 (AUC 5)/28D From Phase 3 >70 yo PS 0 1 = 82% >70 yo PS 0 1 = 65% ND ND ND ND Paclitaxel 225 mg/m 2 D1 vs 16/78 (20) 24/78 (31) Paclitaxel 35 mg/m 2 + Carboplatin AUC 2.5 D1 D8/21D 28/77 (36) 27/77 (35) : 161 >2: 16 93/171 SCC 127 Gemcitabine 1200 mg/m 2 D1 D8 D15/28D vs AC 71 Paclitaxel 100 mg/m 2 D1 D8 D15/28D vs Gemcitabine 1000 mg/m 2 + Vinorelbine 25 mg/m 2 D1 Gemcitabine 1000 mg/m 2 + Paclitaxel 80 mg/m 2 D1 D8/21 D 11/68 (16) 17/68 (25) 7/63 (11) 13/63 (21) 13/68 (19) 18/68 (26) 18/65 (28) 25/65 (38) G. Des Guetz et al. / Critical Reviews in Oncology/Hematology 84 (2012)

5 344 G. Des Guetz et al. / Critical Reviews in Oncology/Hematology 84 (2012) Table 1 (Continued) 1-Year Overall Survival (%) Objective response (%) Treatment (dose/mg/m 2 ) schedule Patients PS % Median age Charlson score Stage IIIB/IV Pathological type SCC, AC Number Male/female 42/233 (18) 89/233 (38) 209/489 SCC 315 Vinorelbine 30 mg/m 2 D : 305 >2: 315 >70 yo PS 0 1 = 80% Gridelli /117 37/233 (16) 65/233 (28) 49/232 (21) 70/232 (30) AC 235 Gemcitabine 1200 mg/m 2 D1 Gemcitabine 1200 mg/m 2 + Vinorelbine 30 mg/m 2 D1 D8/21D 9/60 (15) 8/60 (13) SCC 57 Vinorelbine 30 mg/m 2 D1 74 (70 83) 1 2: 69 >2: 22 >70 yo PS 0 1 = 73% Frasci /60 13/60 (22) 18/60 (30) AC 47 Gemcitabine 1200 mg/m 2 + Vinorelbine 30 mg/m 2 D1 D8/21D SCC: squamous cell carcinoma; AC: adenocarcinoma. single agents of 1-year OS did not reach statistical significance whereas ORR remained statistically significant in favor of doublets. Compared with single agent chemotherapy, doublets including a platinum derivate did not improve one-year OS (HR 0.90; ; random effect model). This was also the case for doublets not including platinum (HR 0.94; ; random effect model). Similarly, ORR for doublets including platinum did not differ from that of single-drug therapy (HR 1.61, 95% CI: ; random effect model) (Figs. 2 and 3). Conversely, doublet chemotherapy without a platinum salt significantly improved ORR compared with single-drug chemotherapy (HR 1.36, 95% CI: ; p = 0.003; fixed effect model). In the 8 studies assessing a taxane, doublets did not improve OS (HR 0.89; ; random effect model) but significantly improved ORR (HR 1.72; ; random effect model). More specifically, docetaxel (5 studies) did not improve OS (HR 1.03; ; fixed effect model) but improved ORR (HR 1.40; ; fixed effect model), whereas paclitaxel (3 studies) improved both OS (HR 0.76; ; random effect model) and ORR (HR 2.32; ; fixed effect model). All grade nausea/vomiting was similar for doublets and single agents (HR 1.16, , random effect model), whereas neutropenia, thrombocytopenia and anemia were significantly more frequent for doublets compared with single agents (HRs 1.26, , fixed effect model; 1.75, CI random effect model; 1.33, CI fixed effect model respectively; all p inferior to 0.001) (Fig. 4). HRs for diarrhea and stomatitis were close to 1. All grade toxicity was similar for doublets including platinum derivates compared with doublets without platinum. Concerning grade 3/4 toxicity, two out of three biological side effects were significantly more frequent for doublets: grade 3/4 thrombocytopenia (2.13; , random effect model; p = 0.05) and anemia (1.84; , fixed effect model; p < 0.001), but not grade 3/4 neutropenia (1.27; , random effect model). Some side effects (alopecia, peripheral neuropathy, febrile neutropenia) could not be analyzed precisely due to their low incidence. 4. Discussion This MA of all 10 published randomized studies including abstracts of proceedings from ASCO and WCLC concluded to a slight additional benefit of doublets compared to singleagent chemotherapy in advanced NSCLCs in the elderly, at the expense of an increased hematological toxicity. Compared with single-agent chemotherapy, doublets induced a significantly increased Overall Response Rate (HR 1.51, ) but did not modify 1-Year Overall Survival (HR 0.92, ). For 1-year OS, only 3 studies [9,13,15] showed a statistically significant superiority of doublets over

6 G. Des Guetz et al. / Critical Reviews in Oncology/Hematology 84 (2012) articles from Pub Med 741 articles, out of the scope of the MA. 9 articles analysed (Quoix EA et al l; Zwitter M ett al ; Chen Y-M et al ; Frasci G et al ; Sederholm C et al ; Lilenbaum RC et al ; Hainsworth JD et al ; Comella P et al ; Gridelli C et al) 4 abstracts from ASCO proceedings (Tsukada H et al ; Georgoulias V et al ; Karampeazis et al, abe et al) 1 abstract from WCLCL 2009 proceedings (Kang BW et al) 2 phase II excluded (Zwitter M et al ; Chen Y-M et al) 2 abstracts without available HR (Tsukada H et al ; Georgoulias V et al) 10 Studies OS analysed 7 articles and 3 abstracts ( Frasci G et al ; Sederholm C et al ; Lilenbaum RC et al ; Hainsworth JD et al ; Comella P et al ; Gridelli C et al ; Quoix EA et al; Karampeazis A et al ; Kang BW et al ; Abe et al) Fig. 1. Flow-chart of the meta-analysis. single-agents. For ORR also, 3 studies [11,13,15] showed similarly a statistically significant superiority of doublets, but the most recent study by Abe et al. [27] was also very close to statistical significance. Most studies did not assess the 2- year OS due to insufficient numbers of surviving patients. As expected, the biological side-effects (neutropenia, thrombocytopenia and anemia) were significantly more frequent with doublets. Our MA has several limitations. As all MAs relying on published data, it retrospectively analyzed the included studies and was not performed on an individual patient basis. Included studies were usually randomized trials assessing patients with rather good performance status, who might not be representative of the overall population of elderly patients. The studies did not assess co-morbidities, which could limit the generalization of the conclusions of this MA. In the included studies, there was usually no comprehensive geriatric assessment, which, though cumbersome to complete, is very useful to the definition of high-risk groups, as shown in studies specifically dedicated to the assessment of benefit of precise geriatric evaluation [28,29]. Also, the conclusions of our MA were rather robust since doublets did not significantly improve OS after exclusion of the study by Abe et al. [27], a fortiori when the study by Quoix et al. [15], the most favorable to doublets, was also excluded (sensitivity analyses). As expected, conclusions concerning ORR were more robust. In our MA, Overall Response Rate observed with doublets improved more than Overall Survival. This finding might be explained by the frailty of elderly patients and by the higher toxicity of doublet chemotherapy which might antagonize the potential benefit of doublets on survival. It should be noted that the numbers and causes of deaths were rarely mentioned in the studies, which somewhat obscured their findings. It is not known whether these deaths were related to cancer progression or to toxicity of the chemotherapy. Febrile

7 346 G. Des Guetz et al. / Critical Reviews in Oncology/Hematology 84 (2012) With platinum salt Lilenbaum, 2005 Sederholm, 2005 Kang, 2009 Quoix, 2010 Abe, [0.75 ; 1.17] 0.74 [0.51 ; 1.08] 1.18 [0.87 ; 1.60] 0.64 [0.52 ; 0.79] 1.18 [0.83 ; 1.69] Without platinum salt Comella (PvsGP), 2001 Comella (GvsGV), 2001 Gridelli (GvsGV), 2003 Gridelli (VvsGV), 2003 Frasci, 2004 Hainsworth, 2007 Karampeazis, 2010, 0.74 [0.56 ; 0.98] 0.95 [0.74 ; 1.21] 1.06 [0.87 ; 1.30] 1.17 [0.95 ; 1.44] 0.81 [0.67 ; 0.98] 1.01 [0.89 ; 1.14] 0.71 [0.44 ; 1.15] Overall survival with Platinum salt Overall survival without Platinum salt Overall survival (random model) 0.90 [0.70 ; 1.16] 0.94 [0.84 ; 1.07] 0.92 [0.82 ; 1.03] Favours doublet Favours single-agent Fig. 2. Forest plot of studies including or not a platinum salt and assessing overall survival. By convention, a Hazard Ratio < 1 corresponds to a higher survival for doublet chemotherapy compared with single agent. neutropenia, which could induce severe infections, was not systematically mentioned, and thus could not be assessed precisely in our MA, whereas it might have caused some deaths. The use of growth factors (G-CSF, EPO) was not assessed whereas they could have decreased the morbidity related to cancer and thus influenced the prognosis. The studies had many sources of heterogeneity: various definitions of elderly, various PS scores, various proportions of squamous cell cancers and adenocarcinomas, different treatment regimens, etc. Most studies included in our MA were specifically dedicated to the elderly [9,13 15,26,27]. The Multicentre Italian Lung Cancer in the Elderly Study (MILES) [14] was the largest trial in elderly patients with advanced NSCLC. Nearly 700 patients were randomly assigned to single-agent vinorelbine, single-agent gemcitabine, or the combination of both. Selected toxicities were slightly more frequent in the combination group, but treatments were generally well tolerated. Response rates were similar between single agents and their combination. Progression-free survival and Overall Survival did not significantly differ between all arms, which led the authors to recommend single-agent therapy. Two large phase III studies included in our MA [10,11] were not specifically devoted to geriatric patients and compared carboplatin-based combinations with single-agent therapy. Elderly patients included in both of these studies were probably more highly selected when compared with those in other studies. The study by Lilenbaum et al. included 155 elderly patients (27% of the study population) [11]. There was no significant difference in response or survival between the elderly and the younger patients. Toxicity was also similar between the two groups, except for a higher incidence of leucopenia in the elderly. The non-significant trend toward improved survival in the combination arm observed in the general study population persisted in the elderly subset. The Swedish trial of carboplatin plus gemcitabine compared with gemcitabine alone included 121 patients aged 70 years or older (37% of the study population) [10]. In the overall population, there was a significant improvement in survival favoring the combination arm (median OS, 10 months vs 8.6 months; 1-year OS, 40% vs 32%, respectively). A similar difference was observed in the elderly subset (median, 11 months vs 9.4 months), not reaching statistical significance. Despite a higher incidence of hematological toxicities, there were virtually no episodes of grade 3/4 infection. Exclusion of these 2 studies (Sederholm et al. and Lilenbaum et al.) did not modify the results (significantly increased ORR, unchanged OS).

8 G. Des Guetz et al. / Critical Reviews in Oncology/Hematology 84 (2012) With platinum salt Lilenbaum, 2005 Kang, 2009 Quoix, 2010 Abe, 2011 Without platinum salt Comella (PvsGP), 2001 Comella (GvsGV), 2001 Grid elli (G vsgv), 2003 Gridelli (VvsGV), 2003 Frasci, 2004 Hainsworth, 2007 Karampeazis, [1.05 ; 2.99] 0.71 [0.32 ; 1.56] 2.79 [1.82 ; 4.27] 1.44 [0.99 ; 2.10] 2.30 [1.05 ; 5.04] 1.27 [0.62 ; 2.60] [ ; 1.96] 1.17 [0.81 ; 1.69] 1.07 [0.52 ; 2.19] 1.50 [0.92 ; 2.44] 2.39 [0.92 ; 6.19] Overall response with Platinum salt Overall response without Platinum salt Overall response (random model) 1.61 [1.00 ; 2.57] 1.36 [1.11 ; 1.67] 1.51 [1.22 ; 1.86] Favours single-agent Favours doublet Fig. 3. Forest plot of studies including or not a platinum salt and assessing response rate. By convention, a Hazard Ratio < 1 corresponds to higher response for doublet chemotherapy compared with single agent. The recent study by Quoix et al. [15] compared two therapeutic regimens, a single agent or a modern doublet therapy, specifically among elderly patients. Results clearly favored doublet therapy, the toxicity of which appeared easy to manage. This study was coupled with a specific geriatric assessment. The results of the latest study by Abe et al. [27] were rather puzzling since they favored single-agent therapy (although not statistically significantly). It should be stressed that these authors used a dose of single-agent docetaxel triple to the dose of docetaxel used in association with platinum salt (60 mg/m 2 vs 20 mg/m 2 ), representing an additional variability factor. Platinum-based doublets represent the gold standard of chemotherapy of NSCLC. Our MA does not firmly confirm the superiority of platinum-based doublets among elderly patients. The great majority of studies [10,11,15,22] used carboplatin, which seems preferable since it is devoid of renal toxicity. The results of our MA are consistent with those of a previous MA comparing single-agents with gemcitabine-based doublets for advanced NSCLC in the elderly [30]. This former MA concluded to a statistically significant improvement in Overall Response Rate with doublets whereas the trend for an improved 1-year survival was not significant. There was no difference concerning grade 3 or 4 toxicities among elderly patients or patients who could not receive high-doses of cisplatinum-based chemotherapy. This previous MA included only 4 studies [9,12 14] instead of 10 studies in our MA, representing 6 additional papers [10,11,15,22,26,27], and made an excessive stratification of some studies which led the authors to use several times the data corresponding to the same defined sub-group, a conduct that should be avoided in MAs [30]. In our MA, doublets improved Overall Response Rate, compared with single-agent chemotherapy, but they did not improve 1-year OS. All-grade neutropenia, thrombocytopenia and anemia and grade 3/4 thrombocytopenia and anemia were significantly more frequent with doublets. The benefitto-risk ratio of doublets in advanced NSCLC might be more favorable than that of single agents, at least for doublets including platinum derivates and in elderly patients with good performance status. Doublets not including platinum derivates showed an increased toxicity without improving survival and should therefore be avoided in elderly patients with good performance status. Whether our findings should be generalized to a population of unselected elderly patients is still debatable, because of the potentially higher risk of doublet-induced toxicity. In the elderly patients with NSCLC, future studies should be able to better answer to the following dilemma: to improve OS using doublet chemotherapy at

9 348 G. Des Guetz et al. / Critical Reviews in Oncology/Hematology 84 (2012) Neutropenia, w Neutropenia, w/o Overall (fixed model) Febrile neutropenia, w Febrile neutropenia, w/o Overall (fixed model) [1.15 ; 1.39] 0.41 [0.15 ; 1.09] Thrombocytopenia, w Thrombocytopenia, w/o Overall (random model) [1.11 ; 2.77] Anemia, w Anemia, w/o Overall (fixed model) 1.33[1.17 ; 1.52] Nausea/vomiting, w Nausea/vomiting, w/o Overall (fixed effect) 1.16 [0.92 ; 1.47] Diarrhea, w Diarrhea, w/o Overall (fixed model) 1.12 [0.86 ; 1.46] Mucitis, w Mucitis, w/o Overall (fixed model) 1.19 [0.89 ; 1.60] Neuropathy, w Neuropathy, w/o Overall (random model) 1.13 [0.59 ; 2.16] Alopecia, w Alopecia, w/o Overall (random model) 1.19 [0.83 ; 1.71] Favours doublet Favours single-agent Fig. 4. Forest plot of studies including or not a platinum salt and assessing toxicities. By convention, a Hazard Ratio > 1 corresponds to a higher frequency of side effect among patients receiving doublet chemotherapy compared with single agent. the expense of a higher toxicity or to limit chemotherapy to a single agent. Additional elderly-specific studies should be needed to determine the best chemotherapy regimen including or not targeted therapies [31] for advanced NSCLC in the elderly. Reviewers Athanasios Pallis, M.D., Ph.D., University General Hospital of Heraklion, Dpt of Medical Oncology, Heraklion, Greece. Cesare Gridelli, M.D., S G Moscati Hospital-Avellino, Division of Medical Oncology, Via Circumvallazione, Avellino, Italy. References [1] Ries LAG, Melbert D, Krapcho M, et al. SEER cancer statistics review /; [2] Hutchins LF, Unger JM, Crowley JJ, et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. New England Journal of Medicine 1999;341: [3] Ramsey SD, Howlader N, Etzioni RD, et al. Chemotherapy use, outcomes, and costs for older persons with advanced non-small-cell lung cancer: evidence from surveillance, epidemiology and end resultsmedicare. Journal of Clinical Oncology 2004;22: [4] Yancik R, Ganz PA, Varricchio CG, et al. Perspectives on comorbidity and cancer in older patients: approaches to expand the knowledge base. Journal of Clinical Oncology 2001;19: [5] Klastersky J, Awada A. Milestones in the use of chemotherapy for the management of non-small cell lung cancer (NSCLC). Critical Reviews in Oncology/Hematology 2012;81:49 57.

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An open multicenter phase II trial of docetaxel,gemcitabine in Charlson score and performance status (PS) selected elderly patients with stage IIIB pleura/iv non-small-cell lung cancer (NSCLC): the GFPC 02-02a study. Critical Reviews in Oncology/Hematology 2007;64: [29] Extermann M, Hurria A. Comprehensive geriatric assessment for older patients with cancer. Journal of Clinical Oncology 2007;25: [30] Russo A, Rizzo S, Fulfaro F, et al. Gemcitabine-based doublets versus single-agent therapy for elderly patients with advanced nonsmall cell lung cancer. Cancer 2009;115: [31] Wozniak A. Challenges in the current antiangiogenic treatment paradigm for patients with non-small cell lung cancer. Critical Reviews in Oncology/Hematology 2012;82: Biography Gaetan Des Guetz is a medical oncologist (Department of Oncology, Avicenne university hospital Assistance Publique Hopitaux de Paris). He was graduate in 1998 (MD) and then Assistant Professor of Oncology, Paris VI University ( ) and Senior Medical Oncologist (Curie Institute, Department of Oncology) for 3 years. He has expertise in the field of sarcomas and mainly of GI oncology (PhD in 2007: prognostic factors in colorectal cancer). Since 2005, he has published 8 meta-analyses in GI oncology in peer reviews and had a collaborative work with Cochrane colorectal cancer Group. He is also involved in translational clinical research. His main focus is now geriatric oncology, as he is in charge of an oncology unit specialized in Geriatrics.