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Age and Comorbidity As Independent Prognostic Factors in the Treatment of Non–Small-Cell Lung Cancer: A Review of National Cancer Institute of Canada Clinical Trials Group Trials

Timothy R. Asmis, Keyue Ding, Lesley Seymour, Frances A. Shepherd, Natasha B. Leighl, Tim L. Winton, Marlo Whitehead, Johanna N. Spaans, Barbara C. Graham, Glenwood D. Goss

From the National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada

Corresponding author: Glenwood Goss, MD, Medical Oncology, The Ottawa Hospital Regional Cancer Centre, The University of Ottawa, 503 Smyth Rd, Ottawa, Ontario, Canada, K1H 1C4; e-mail: ggoss{at}ottawahospital.on.ca

	ABSTRACT

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Purpose This study analyzed patients enrolled in two large, prospectively randomized trials of systemic chemotherapy (adjuvant/palliative setting) for non–small-cell lung Cancer (NSCLC). The main objective was to determine if age and/or the burden of chronic medical conditions (comorbidity) are independent predictors of survival, treatment delivery, and toxicity.

Patients and Methods Baseline comorbid conditions were scored using the Charlson comorbidity index (CCI), a validated measure of patient comorbidity that is weighted according to the influence of comorbidity on overall mortality. The CCI score (CCIS) was correlated with demographic data,(ie, age, sex, race), performance status (PS), histology, cancer stage, patient weight, hemoglobin, alkaline phosphatase, lactate dehydrogenase, outcomes of chemotherapy delivery (ie, type, total dose, and dose intensity), survival, and response.

Results A total of 1,255 patients were included in this analysis. The median age was 61 years (range, 34 to 89 years); 34% of patients were elderly (at least 65 years of age); and 31% had comorbid conditions at randomization. Twenty-five percent of patients had a CCIS of 1, whereas 6% had a CCIS of 2 or greater. Elderly patients were more likely to have a CCIS equal to or greater than 1 compared with younger patients (42% v 26%; P < .0001), as were male patients (35% v 21%; P < .0001) and patients with squamous histology (36% v 29%; P = .001). Although age did not influence overall survival, the CCIS appeared prognostic (CCIS 1 v 0; hazard ratio 1.28; 95%CI, 1.09 to 1.5; P = .003).

Conclusion In these large, randomized trials, the presence of comorbid conditions (CCIS 1), rather than age more than 65 years, was associated with poorer survival.

	INTRODUCTION

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The incidence of non–small-cell lung cancer (NSCLC) increases with age; 60% occur in patients aged 60 years and older, and 30% to 40% occur in patients aged 70 years and older.^1,2 The median age of individuals diagnosed with NSCLC in developed countries is 68 years.³ Eighty-five percent of patients either present with or eventually will develop advanced or recurrent NSCLC. In large meta-analyses, the use of chemotherapy in addition to best supportive care (BSC) has been shown to improve overall survival (OS) compared with BSC alone.^4,5 Survival benefits from chemotherapy have also been demonstrated in trials designed specifically for elderly patients^6,7. Despite this, elderly patients are often denied therapy, prematurely discontinued from therapy, and excluded from clinical trials because of perceptions that elderly patients are unable to tolerate aggressive chemotherapy and are more likely to suffer increased toxicity with a resultant poor quality of life.⁸ However, many studies demonstrate that the elderly patient with a good performance status (PS) can tolerate chemotherapy that has similar toxicity and benefits as nonelderly patients.^9-12

Although the definition of elderly is the subject of some debate, two benchmarks are often used—peopled either 65 years and older¹³ or 70 years and older.^9,14 The age of 70 years has been described as the lower boundary of senescence, because the incidence of age-related organ dysfunction and the development of comorbid conditions increase sharply between ages 70 and 75 years.¹⁵ The clinical significance of the relationship between age and comorbid conditions is complex in patients with cancer.¹⁶ Although chronologic age is associated with certain age-related conditions,¹⁷ chronologic age may not be as clinically relevant as physiologic age, which also takes into account the burden of chronic disease (comorbidity).¹⁸

The measurement of comorbidity is challenging. Several scales for determining the burden of illness in a particular patient have been explored for use in an oncology setting.¹⁹ The Charlson comorbidity index (CCI) was developed based on a longitudinal study of 559 patients who were admitted to a medical service during a 1-month period, and it has been validated for predicting major complications of surgery in patients with resectable, stages IA to IIIB NSCLC.²⁰ The sum of the weighted scores of all the comorbid conditions is used to develop a CCI score (CCIS).²¹

We report here the results of a pooled analysis of two large, prospectively randomized trials of systemic chemotherapy conducted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) that examined the relationship between age and comorbidity—specifically, whether age and/or comorbidity are predictive of chemotherapy-related toxicity and whether age and/or comorbidity are independent predictors of outcome.

	PATIENTS AND METHODS

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Patients
BR 18 was a randomized, phase II/III study of 774 patients with advanced NSCLC²² that compared paclitaxel and carboplatin plus placebo (n = 386) with the same regimen plus BMS-275291 (n = 388), an oral matrix metalloproteinase inhibitor (MMPI). Patients were to receive a maximum of eight cycles of chemotherapy but could continue oral MMPI or placebo thereafter until progression or unacceptable toxicity. JBR 10 was a study in which 482 patients with completely resected, stage IB or II NSCLC were randomly assigned to adjuvant vinorelbine and cisplatin chemotherapy (n = 242) or to observation alone (n = 240).²³ Four cycles of vinorelbine/cisplatin were planned.

CCIS, Toxicity, and Objective Response
Baseline medical conditions and medications were scored using the CCI²¹ (Table A1). Laboratory parameters and adverse events were graded using the National Cancer Institute Common Toxicity Criteria Expanded Common Toxicity Criteria (in JBR 10) and version 2.0 of the National Cancer Institute Common Toxicity Criteria toxicity scale (in BR 18). All adverse events, irrespective of causality, were included in the analyses. Objective response (in BR 18 only) was evaluated using the Response Evaluation Criteria In Solid Tumors guidelines.

Statistical Considerations
OS was defined as the time from randomization to death or was censored at the last known alive date. Progression-free survival (PFS) was defined as the time from randomization to the time of documented disease progression or death, whichever came first. Disease-specific survival (DSS) was defined as the date from randomization to the time of death for those who died of lung cancer or of complications of its treatment, and it was censored at the date of death for those who died of other causes or at the date of the last known follow-up, for patients alive at the time of analysis. Exploratory analyses were performed to characterize the relationship between age and CCIS with baseline characteristics and outcomes, including age, sex, race/ethnicity, performance status (PS), histology, stage, hemoglobin, alkaline phosphatase, time from diagnosis to random assignment, and chemotherapy (type, total dose, survival, and tumor response).

The following factors were assessed in both univariate and multivariant analyses for their influence on survival (OS, PFS, and DFS): age (< 65 years v 65 years), CCIS (0 v 1 v 2+), sex, race/ethnicity (white v others), PS (0 v 1 v 2+), hemoglobin ( 120 v < 120 g/dL), alkaline phosphatase (normal v increased), and time from diagnosis to random assignment (< 6 v 6 months). The Cochran-Mantel-Haenszel ² test was used to assess associations between categorical variables; Kaplan-Meier curves were used to estimate the distributions of time to event outcomes; and the Cox regression model stratified by assigned treatment and by disease stage was used to correlate age, CCIS groups, and other baseline factors with the time to event outcomes (OS, PFS, and DSS). The logistic regression model was used to study the effects of age and CCIS on response and toxicity while adjusting for other important prognostic factors. Statistical analyses were carried out using SAS version 8.1 (SAS Institute, Cary, NC). All reported P values are two-sided unless otherwise specified.

	RESULTS

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A total of 1,255 patients were included in this analysis; 481 (38%) were enrolled onto JBR 10, and 774 (62%) were enrolled onto BR 18. One patient was excluded from the analysis because of missing baseline data. The median age was 61 years (range, 34 to 89 years), and 34% were 65 years or older. Elderly patients were more likely than nonelderly to have a PS of 1 (P = .007), squamous histology (34% v 26%; P = .005), time from diagnosis to random assignment of more than 6 months (13% v 5%; P < .0001), and comorbid conditions (42% v 26%; P < .0001; Table 1). As listed in Table 1, 31% of patients had comorbid conditions in addition to NSCLC; 310 had a CCIS of 1; and 81 had CCIS of 2. A greater CCIS was associated with male sex (35% v 21%; P < .0001), a worse PS (P = .003), nonadenocarcinoma histology (P = .001), and a time from diagnosis to random assignment of more than 6 months (P = .004). Comparison between covariates was performed, and there was no evidence of interaction.

Survival
In univariate analyses, age was not prognostic (hazard ratio [HR], 1.03; P = .72; Fig 1), but a CCIS 1 was associated with shorter survival (overall P = .01 [CCIS = 1 v CCIS 2]; CCIS = 1: HR, 1.28; 95% CI, 1.09 to 1.5; P = .003 [CCIS = 1 v CCIS = 0]; CCIS 2: HR, 1.09; 95% CI, 0.83 to 1.44; P = .52 [CCIS 2 v CCIS = 0]; Fig 2). Other poor prognostic factors included PS, male sex, increased alkaline phosphatase, and anemia (Table 5). In multivariate Cox regression models that were stratified by assigned treatment and disease stage, age was not prognostic, but a CCIS of 1 was associated significantly with shorter survival (P = .03; Table 5). Neither age nor comorbidity was significantly associated with PFS in univariate or in multivariate analyses.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Overall survival by age. HR, hazard ratio.

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall survival by Charlson comorbidity index (CCI) score. HR, hazard ratio.

	DISCUSSION

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Although NSCLC is largely a disease of the elderly, significant disparities exist in the delivery of chemotherapy^24,25 and in clinical trial participation²⁶ for elderly patients, partly because of fears of unacceptable toxicity related to comorbid conditions.²⁴ The impacts of age and comorbid conditions on efficacy and toxicity outcomes of standard chemotherapy regimens are important considerations in clinical practice and in clinical trial design.

In this retrospective analysis of more than 1,200 patients, we confirmed a relationship between age and comorbidity. Both age and comorbidity were associated with more severe toxicity and with lower chemotherapy dose intensity. This effect was more pronounced for age in the metastatic trial (BR 18), which suggests that patients in the adjuvant trial (JBR 10) may have been carefully selected. To be eligible for JBR 10, patients needed to be surgical candidates, which likely precluded patients with a serious comorbidity, such as cardiac disease. Comorbidity, but not age, was prognostic and was associated with poorer OS. This prognostic effect seemed more pronounced for a CCIS of 1, but this observation may be confounded by the selected clinical trial population that contained few patients with a CCIS greater than 1. Interestingly, efficacy outcomes were similar in the elderly compared with younger patients, despite lower apparent chemotherapy dose intensity and higher toxicity, which suggests the lack of a clear dose-response effect of chemotherapy used for NSCLC.²⁷ Alternatively, elderly patients may have less aggressive disease or may have age-related decreases in drug clearance that provide a higher-than-anticipated exposure.²⁸

Our analysis resulted in several observations that are hypothesis-generating and warrant further research. Male sex was associated with a higher CCIS, but adenocarcinomas were associated with a lower CCIS. These results are similar to those reported by Colinet et al,²⁹ who used a simplified comorbidity score, although age was prognostic in their study, whereas in ours it was not. Poorer outcomes in males is a common observation in NSCLC clinical trials,³⁰ and our study suggests that this may be accounted for in part by increased comorbidity. The role that sex-dependent hormone pathways might play is as yet not fully understood.³¹ The observed relationship among age, CCIS, and histological subtype may be related to tobacco use, as squamous carcinoma is most closely associated with dose and duration of exposure to tobacco. Younger patients may have a shorter exposure to tobacco and may have exposure to a changing tobacco content of cigarettes, so they may be less likely to have comorbidity and more likely to have adenocarcinoma.³²

Our study was limited in several respects, because this was a retrospective analysis and because both studies excluded patients with poor PS or with significant comorbid conditions, although PS and the CCIS may not be directly correlated.³³ Our study population also had a relatively young median age and therefore may not be representative of the larger NSCLC population. Furthermore, the CCI was not designed specifically for patients with neoplastic disease, and scales designed specifically for cancer patients may be more applicable. Various authors have reviewed comorbidity scales that have been validated in the elderly,^19,34 but further work is necessary to develop a validated, oncology-specific comorbidity scale.

In conclusion, although elderly patients who met the entry criteria for these trials received less chemotherapy, they appeared to derive the same benefit as younger patients in terms of OS. Based on our findings and on those of others,^9-12 elderly patients should not be denied access to clinical trials nor to effective therapies on the basis of age alone. In contrast, the presence of comorbid disease was prognostic in this retrospective study and may be a more relevant selection or exclusion criterion for treatment than chronologic age. Further prospective studies should be conducted to examine the relationship among age, comorbidity, and treatment outcomes such as efficacy and toxicity to better tailor therapy for individual patients.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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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: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Natasha B. Leighl, GlaxoSmithKline Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Timothy R. Asmis, Keyue Ding, Lesley Seymour, Frances A. Shepherd, Natasha B. Leighl, Glenwood D. Goss

Administrative support: Lesley Seymour, Marlo Whitehead

Provision of study materials or patients: Lesley Seymour, Frances A. Shepherd, Natasha B. Leighl, Tim L. Winton

Collection and assembly of data: Timothy R. Asmis, Natasha B. Leighl, Marlo Whitehead, Barbara C. Graham

Data analysis and interpretation: Timothy R. Asmis, Keyue Ding, Lesley Seymour, Frances A. Shepherd, Johanna N. Spaans, Barbara C. Graham, Glenwood D. Goss

Manuscript writing: Timothy R. Asmis, Lesley Seymour, Frances A. Shepherd, Johanna Spaans, Glenwood D. Goss

Final approval of manuscript: Timothy R. Asmis, Keyue Ding, Lesley Seymour, Frances A. Shepherd, Natasha B. Leighl, Tim L. Winton, Marlo Whitehead, Johanna N. Spaans, Barbara C. Graham, Glenwood D. Goss

	Appendix

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	ACKNOWLEDGMENTS

 
The following institutions participated in the study: The Eastern Cooperatative Oncology Group, the Southwest Oncology Group, and the Cancer and Leukemia Group B participated in JBR10.

	NOTES

 
Supported by the Canadian Cancer Society Grant No. 4493, and supported in part by Grant Nos. CA161003 from Bristol Myers Squibb (BR18), CA04326 from the National Cancer Institute (JBR10), 12150 from the National Cancer Institute of Canada, and CA31946 from the Cancer and Leukemia Group B.

Presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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Submitted May 30, 2007; accepted August 21, 2007.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Asmis, T. R. Articles by Goss, G. D. Search for Related Content PubMed Articles by Asmis, T. R. Articles by Goss, G. D. Social Bookmarking                            What's this?