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Journal of Clinical Oncology, Vol 26, No 21 (July 20), 2008: pp. 3573-3581 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.2727 Pooled Analysis of the Effect of Age on Adjuvant Cisplatin-Based Chemotherapy for Completely Resected Non–Small-Cell Lung Cancer
From the Department of Medical Oncology, Princess Margaret Hospital, Toronto; National Cancer Institute of Canada Trials Group, Queen‘s University, Kingston, Ontario; University of Alberta, Edmonton, Alberta, Canada; Meta-Analysis Unit; Department of Medicine, Institut Gustave-Roussy, Villejuif; Medical Oncology, Centre René Gauducheau, Nantes, France; Clinical and Biological Sciences, University of Turin, Torino, Italy; and the Department of Thoracic Medicine, University College Hospital, London, United Kingdom Corresponding author: Martin Früh, MD, Department of Medical Oncology, Kantonsspital St Gallen, 9007 St Gallen, Switzerland; e-mail: martin.frueh{at}kssg.ch
Purpose This pooled analysis was undertaken to assess the efficacy and toxicity of adjuvant cisplatin-based chemotherapy in elderly patients with non–small-cell lung cancer (NSCLC).
Methods We used individual patient data from 4,584 patients enrolled onto five trials of cisplatin-based chemotherapy who form the basis for the Lung Adjuvant Cisplatin Analysis (LACE) pooled analysis. Patient and treatment characteristics, overall and event-free survival, cause-specific mortality, chemotherapy toxicity and delivery were compared among three age groups: 3,269 young (71%; < 65), 901 midcategory (20%; 65 to 69), and 414 elderly patients (9%;
Results The hazard ratio (HR) of death for the young patients was 0.86 (95% CI, 0.78 to 0.94), 1.01 for the midcategory (95% CI, 0.85 to 1.21), and 0.90 for elderly patients (95% CI, 0.70 to 1.16; test for trend: P = .29). The HR for event-free survival was 0.82 for young (95% CI, 0.75 to 0.90), 0.90 for the midcategory (95% CI, 0.76 to 1.06), and 0.87 for elderly patients (95% CI, 0.68 to 1.11; test for trend: P = .42). More elderly patients died from non–lung cancer–related causes (12% young, 19% midcategory, 22% elderly; P < .0001). No differences in severe toxicity rates were observed. Elderly patients received significantly lower first and total cisplatin doses, and fewer chemotherapy cycles ( Conclusion Adjuvant cisplatin-based chemotherapy should not be withheld from elderly patients with NSCLC purely on the basis of age.
Non–small-cell lung cancer (NSCLC) is the leading cause of cancer death for men and women in most industrialized countries.1 The median age at presentation is approximately 69 years.2 In the United States, death from lung cancer is increasing in the elderly (age > 70 years) yet decreasing in individuals younger than 50 years of age.3 With the aging of western society, 20% of the population will be older than 65 by the year 2030.4 Thus, the management of elderly patients with cancer is expected to gain increasing importance. Surgery is the primary treatment modality for patients with early stage NSCLC. A substantial percentage of these patients, however, eventually relapse with a two- to three-fold higher proportion of distant failures over local recurrences.5 Consequently, 5-year survival rates after surgery are disappointingly low, ranging from 60% to 70% in stage I, 40% to 50% in stage II, and only 25% to 30% in patients with stage IIIA tumors.6 The 1995 meta-analysis performed by the Non-Small Cell Lung Cancer Collaborative Group suggested an absolute survival advantage at 5 years of 5% with cisplatin-based chemotherapy (hazard ratio [HR], 0.87; 95% CI, 0.74 to 1.02; P = .08).7 Most of the early trials were small and underpowered, and so in the 1990s, larger adjuvant trials were performed, of which three demonstrated significant survival benefits from cisplatin-based chemotherapy.8-10 Absolute 5-year survival differences ranged from 4% to 15% (HRs from 0.69 to 0.86). The Lung Adjuvant Cisplatin Evaluation (LACE) analysis, which included the five largest cisplatin-based adjuvant trials conducted in the late 1990s, demonstrated an absolute overall survival benefit of 5.4% at 5 years and a significant overall reduction in the risk of death (HR, 0.89, 95% CI, 0.82 to 0.95; P < .005).11 Based on these results, postoperative chemotherapy is now widely accepted for patients with NSCLC. Elderly patients are often excluded from clinical trials.12 Therefore, only limited information about platinum-based chemotherapy is available for these patients, most of which is derived from retrospective subset analyses of trials designed for patients of all ages with advanced NSCLC. Several of these studies concluded that platinum-based chemotherapy was well tolerated and treatment outcome was similar for the highly selected elderly patients enrolled in the studies.13-15 Only one study has examined the impact of age on the outcome and toxicity of adjuvant chemotherapy in NSCLC.16 Pepe et al16 showed a significant benefit from chemotherapy in the 155 elderly patients (> 65 years) enrolled onto the North American Intergroup trial National Cancer Institute of Canada Clinical Trials Group study JBR.10 (JBR.10). In view of this and since the remaining mean life expectancy of a 70-year-old is an estimated 15 years4 it seems particularly important not to deny adjuvant chemotherapy to elderly patients. We have performed a pooled analysis of five recently published cisplatin-based adjuvant trials in order to evaluate the influence of age on survival, lung cancer, and non–lung cancer mortality, chemotherapy delivery, and toxicity in patients with resected NSCLC. We report here the results of these analyses.
Inclusion Criteria Age-specific analyses were performed using the LACE database consisting of 4,584 patients from five cisplatin-based adjuvant chemotherapy trials.11 The study populations and chemotherapy regimens for each trial are summarized in Table 1.8-10,17,18 The following criteria had to be met for a trial to be eligible for the LACE analysis: histologically proven, completely resected NSCLC, use of unpredictable randomization, comparison of cisplatin-based chemotherapy versus none, trial completion after the 1995 meta-analysis, and sample size more than 300 patients. Trials evaluating chemotherapy other than cisplatin-based regimens, and those that used concurrent radiation were excluded. Full details and results of the LACE study have been presented previously.11
Statistical Analyses Individual patient data were collected for all randomly assigned patients from the principal investigators. For these analyses, patients were divided into three age groups: younger than 65 (young), 65 to 69 (midcategory), and 70+ (elderly), based on age at the time of random assignment. The primary study end point was overall survival (OS). Secondary end points included event-free survival (EFS), lung cancer, and non–lung cancer mortality, toxicity, and chemotherapy delivery. EFS was defined as locoregional recurrence, distant recurrence, and death from any cause in the absence of recurrence. Non–lung cancer mortality was defined as death of known cause without recurrence and not considered as a lung cancer death. Lung cancer mortality was computed by subtraction and included death of any cause with prior recurrence, death from lung cancer, and death from unknown cause. Analyses comparing the chemotherapy and control arms used an intention to treat analysis. Patients in the chemotherapy arm who received at least one dose of chemotherapy were used to calculate dose delivery and rates of toxicity. In JBR.10, cisplatin was administered on days 1 and 8 and so each administration was counted as 0.5 of a dose in the analysis. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria or WHO criteria depending on which was used in each individual trial.
The age-by-treatment variation for survival and mortality were studied using interaction tests and tests for trend. Both standard log-rank tests stratified by trial19 and Cox models stratified by trial and adjusted for age, sex, stage, performance status (PS), drug administered (vinorelbine-containing regimen, other doublet chemotherapy regimens or three-drug regimens), histology, type of surgery, planned radiotherapy, and total dose of cisplatin given ( To eliminate the potential bias of an incorrect determination of the cause of death after recurrence, the log-rank analysis of non–lung cancer mortality covered only the period before recurrence as proposed by Peto et al.20 An unbiased log-rank analysis of lung cancer mortality was obtained indirectly by subtracting the log-rank statistic for non–lung cancer mortality from the log-rank statistic for all mortality. Chemotherapy compliance by age group, total dose, first dose, and total number of cycles of cisplatin were compared using the Kruskall-Wallis test. Discrete and categoric variables were compared using Fisher's exact test. All CIs were computed based on normal approximations unless otherwise specified.
Statistical analyses used the SAS version 8.2 (SAS Institute, Cary, NC). All comparisons between treatment arms used a two-sided test at an
Baseline Characteristics Baseline prognostic factors for each age group are presented in Table 2. Among 4,584 patients, 3,269 were young (71%), 901 fell into the midcategory (20%), and 414 were elderly (9%). There were 1,718 patients with stage I disease (38%), 1,616 (35%) and 1,247 (27%) with stage II and III, respectively. No significant difference according to age category was observed for stage. However, there were small, but due to large patient numbers, statistically significant differences in several baseline characteristics: young patients were more likely to be female (21% young, 14% midcategory, 19% elderly, P < .0001), to present with better PS (PS 0 in 40% of young patients, 32% and 37% in midcategory and elderly, respectively, P = .0004), to have undergone pneumonectomy (32% v 26% v 18%, P < .0001) and to have adenocarcinoma (42% v 35% v 32%; P < .0001). Similarly, more young and midcategory patients were scheduled to receive radiation therapy (33% young, 33% midcategory, 19% elderly, P < .0001) and more young and midcategory patients actually received postoperative radiation therapy (24% v 24% v 14%, P < .0001). Fewer midcategory patients received vinorelbine-containing chemotherapy regimens (42% v 36% v 45%), and more midcategory patients were treated with triplets (28% v 35% v 24%, P < .0001).
OS, EFS, and Cause-Specific Survival The pooled analyses of all age groups showed a significant beneficial effect of treatment on OS (HR, 0.89; 95% CI, 0.82 to 0.96; P = .005) and EFS (HR, 0.84; 95% CI, 0.78 to 0.91; P < .001).11 Online only Figure A1 shows a Forest plot of HRs of the control group as compared with the cisplatin-based chemotherapy group for OS and EFS by trial and by age group. The overall HR of death was 0.86 (95% CI, 0.78 to 0.94) for young patients, 1.01 for the midcategory (95% CI, 0.85 to 1.21), and 0.90 for elderly patients (95% CI, 0.70 to 1.16; Figs 1A, 1B, and 1C). No statistically significant interaction (P = .26) or test for trend (P = .29) between age and treatment effect for OS was observed. Similarly there were no significant differences for EFS (Figs 1D, 1E, and 1F) among the age groups with HRs of 0.82 (95% CI, 0.75 to 0.90) for the young, 0.90 for the midcategory (95% CI, 0.76 to 1.06), and 0.87 for the elderly (95% CI, 0.68 to 1.11; test for trend P = .42).
Table 3 summarizes cause of death by age. The proportion of deaths from non–lung cancer–related causes increased significantly with age (12% young, 19% midcategory and 22% elderly, P < .0001). No significant interaction between age and lung cancer or non–lung cancer deaths was observed (interaction P = .76 for lung cancer deaths and 0.23 for non–lung cancer deaths).
Treatment-Related Toxicity and Chemotherapy Delivery Toxicities occurring in the British study (Big Lung Trial [BLT]) were not available for analysis. Grade 4 and higher overall toxicity rates were comparable occurring in 34% to 41%, as were treatment related deaths, which were observed in 0.7% of the young, 1.4% of the midcategory, and 1.9% of the elderly (P = .24). Similarly there were no significant differences among the age groups with respect to infection rates, hematologic, renal, gastrointestinal, and neurologic toxicity (Table 4).
The planned dose of cisplatin per cycle was 100 mg/m2 for Adjuvant Lung Project Italy (ALPI), Adjuvant Navelbine International Trialist Association (ANITA), and JBR.10, 80, 100 or 120 mg/m2 for International Adjuvant Lung Cancer Trial (IALT), and 50 or 80 mg/m2 for BLT. Overall, 82% of chemotherapy patients were allocated to 100 mg/m2; 4% were assigned to receive 120 mg/m2, 9% to 80 mg/m2, and 5% to 50 mg/m2 of cisplatin per cycle. Due to heterogeneity in treatment schedules among the trials there were differences in the total chemotherapy doses planned among the age groups as more young patients were assigned to receive a total dose of cisplatin 300 mg/m2 or higher (94% v 84% of elderly; P < .0001; Table 5). A greater proportion of younger patients had a planned first cisplatin dose of 100 mg/m2 or above (87% v 76% of elderly, P < .0001). There was no significant difference in the planned number of chemotherapy cycles among the age groups (P = .18).
Elderly patients received a significantly lower first dose of cisplatin (Table 5) with only 53% receiving higher than 95 mg/m2 versus 71% of younger patients (P < .0001). Moreover, only 42% of the elderly received a total cisplatin dose  275 mg/m2 compared with 64% of young patients (P < .0001). Only 58% of the elderly were able to receive more than two of three or four planned chemotherapy cycles compared with 77% of the young. When comparing the received number of chemotherapy cycles, as well as the total dose of cisplatin received, according to the three age groups using the Kruskal-Wallis test, elderly patients received significantly fewer cycles (P < .0001) and a significantly lower total cisplatin dose (P < .0001).
Adjuvant cisplatin-based chemotherapy has been shown to improve survival in patients with stage IB-IIIA NSCLC.8-10 However, the median age in these studies of approximately 60 years does not reflect the lung cancer patient population seen in clinical practice where the median age is an estimated 69 years.2 Furthermore, more than one third of newly diagnosed patients with lung cancer are older than 70 years,21,22 and this number is expected to increase within the next 25 years due to aging of the population. In the absence of prospective, randomized, clinical trials exclusively involving elderly patients, the optimal postoperative treatment for this group of patients remains uncertain. To our knowledge, our evaluation of the effect of age on survival, treatment toxicity, and delivery in 4,584 patients from five recent trials of adjuvant cisplatin-based chemotherapy represents the largest study addressing this question reported to date. Our analysis demonstrated that elderly patients, who met the eligibility criteria for trial enrollment, had a survival benefit from chemotherapy that was similar to that of their younger counterparts. These findings are consistent with those of the elderly analysis of JBR.10, which did not find any significant difference in survival benefit for patients older than 65 years of age.16 Interestingly, this survival benefit was seen in the elderly despite the significantly lower total cisplatin dose they received. Fewer than 60% of the elderly completed more than half of the planned chemotherapy cycles. A similar age-dependent tendency to omit cisplatin doses was also described in an analysis of elderly patients with small-cell lung cancer.15 We could not analyze to what degree multiple dose reductions contributed to the significantly lower total amount of cisplatin received by the elderly patients. However, when we analyzed the first cisplatin dose, a lower initial dose frequently was given to the elderly patients (P < .0001). This may be explained by the higher proportion of older patients in the BLT trial, the trial with the lowest planned dose. However, none of the trials specifically recommended an initial dose reduction for older patients. Elderly patients had a poorer PS compared with the younger patients (P = .0004), and this also may have contributed to the decreased compliance with both the protocol starting dose of chemotherapy and the completion of four cycles. Although there was no significant interaction between age and treatment effect, the hazard ratio for overall survival in the 65- to 69-year-old subgroup was 1.01. There are several possible explanations for this finding: patients in the midcategory were more likely to be males (P < .0001), less likely to have PS of 0 (P = .0004), less likely to have been treated with vinorelbine (P < .0001), and were more likely to have received older mitomycin-containing triplets (P < .0001). The latter failed to show a survival benefit in the ALPI trial17and were associated with an excess of early deaths in the preoperative setting.23 When analyzing cause-specific mortality, there was no significant interaction among the age groups. Midcategory patients receiving chemotherapy, however, had a higher rate of non–lung cancer deaths compared with the control group that was not due to an increased chemotherapy-related death rate. The explanation for this is not clear and this result may be a random finding occurring in a subgroup with only 93 deaths. We did not observe significant differences in overall or specific toxicity rates, nor in treatment-related death rates among the age groups. This may have been due to the risk-avoidance measure of dose reduction taken by many study physicians. Alternatively, elderly patients may have been less willing to tolerate even grade 1 or 2 toxicities, leading to more frequent dose reduction and omission. Chemotherapy has been reported to be more toxic in the elderly mainly because of increased susceptibility to myelosuppression, neurotoxicity, and mucositis.24-26Many clinicians avoid cisplatin in the elderly, although, clinical experience does not support the concept of increased renal toxicity in elderly patients despite older age being associated with nephron loss and decreased creatinine clearance.24,27 Our analyses support this as we did not see increased nephrotoxicity of any degree in the elderly. Once again, this may have been due to risk-avoiding dose reduction for these patients. Hamada et al28 in their meta-analysis of adjuvant tegafur and uracil in 2,003 Japanese patients did not find a significant difference in treatment effect in patients 70 years or older who represented one fifth of their population. In the update of the NSCLC meta-analysis29,30 that included a heterogeneous patient population and numerous different chemotherapy regimens, no interaction between age and chemotherapy effect was reported. There is evidence from previous analyses15,16 that very elderly patients (older than 75 years) do not tolerate cisplatin-based chemotherapy. Caution should be exercised when extrapolating our data to patients older than 75, as their proportion varied considerably across the different trials. They were excluded from IALT and ANITA, and represented fewer than 10% of patients in the other trials. As there were only 61 patients (1.3%) in this age category, we did not analyze them separately. This issue should be explored in future trials. Only 9% of all patients in this pooled analysis were elderly, reflecting yet again the well-recognized under-representation of patients older than 70 in clinical trials.12 An analysis of the Surveillance, Epidemiology and End Results 8,000+ patient database demonstrated decreasing resection rates with increasing age for various reasons.31 However, in 86% of the patients ages 65 to 74, an adequate surgical resection was performed, emphasizing the importance of surgical consultation for all elderly patients with early-stage potentially resectable NSCLC. Because the proportion of patients who were 70 or older was relatively small (9%), we acknowledge that the power of our analyses may be limited. Moreover there was considerable heterogeneity among trials with respect to chemotherapy regimens, use of radiation therapy, and prognostic factors of the patients within the three age groups. However, the Cox model taking these covariates into account led to similar results. It is important to emphasize, however, that the elderly patients recruited for clinical trials are likely to suffer from fewer comorbidities and may have a better performance status than the elderly population at large, thus making it difficult to generalize these results to the wider population. However, in the absence of prospective randomized clinical trials, this pooled analysis of more than 400 patients older than 70 years of age, represents the largest patient number examined to date to address in detail the influence of age on postoperative cisplatin-based chemotherapy in NSCLC. In summary, we have shown that despite receiving less chemotherapy, selected elderly patients have the potential to derive benefit from adjuvant cisplatin-based chemotherapy without a significant increase in toxicity. Therefore, adjuvant chemotherapy should not be withheld from these patients purely on the basis of age. Further investigation of new, potentially less toxic adjuvant chemotherapy regimens, which may be offered to a broader group of elderly patients, should be encouraged.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Thierry Le Chevalier, GlaxoSmithKline (U) Consultant or Advisory Role: None Stock Ownership: Thierry Le Chevalier, GlaxoSmithKline Honoraria: Giorgio V. Scagliotti, Elli Lilly & Co, Sanofi-aventis, AstraZeneca, Bayer, Roche; Frances A. Shepherd, Pierre Fabre Research Funding: Martin Früh, Sanofi Aventis Canada, Walter Honegger Foundation Switzerland, Krebsliga St. Gallen-Appenzell Switzerland; Jean-Pierre Pignon, Sanofi-aventis; Lesley Seymour, GlaxoSmithKline; Stephen Spiro, Pierre Fabre Oncology Expert Testimony: None Other Remuneration: None
Conception and design: Martin Früh, Estelle Rolland, Jean-Pierre Pignon, Frances A. Shepherd Provision of study materials or patients: Estelle Rolland, Jean-Pierre Pignon, Lesley Seymour, Timothy Winton, Thierry Le Chevalier, Giorgio V. Scagliotti, Jean Yves Douillard, Stephen Spiro, Frances A. Shepherd Collection and assembly of data: Martin Früh, Estelle Rolland, Jean-Pierre Pignon, Hélène Tribodet, Frances A. Shepherd Data analysis and interpretation: Martin Früh, Estelle Rolland, Jean-Pierre Pignon, Keyue Ding, Frances A. Shepherd Manuscript writing: Martin Früh, Estelle Rolland, Jean-Pierre Pignon, Frances A. Shepherd Final approval of manuscript: Martin Früh, Estelle Rolland, Jean-Pierre Pignon, Lesley Seymour, Keyue Ding, Hélène Tribodet, Timothy Winton, Thierry Le Chevalier, Giorgio V. Scagliotti, Jean Yves Douillard, Stephen Spiro, Frances A. Shepherd
We thank Richard Stephens for statistical support.
Supported in part by Programme Hospitalier de Recherche Clinique, Ligue Nationale Contre le Cancer; Sanofi-Aventis; a research fellowship to M. Früh from Sanofi-Aventis, Canada, Walter Honegger Foundation, and Krebsliga St Gallen-Appenzell. F.A.S. holds the Scott Taylor Chair in Lung Cancer Research. Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 P < .0001). 
or > 300 mg/m2) were used. As the two methods led to similar results, only the results of the first method are reported. Time-to-event variables (OS, EFS, and cause-specific survivals) were analyzed using survival curves stratified by trial produced according to Peto's method.
level of 5% unless otherwise specified. 
