ARTICLE

Outcomes Among African-American/Non-African-American Patients With Advanced Non-Small-Cell Lung Carcinoma: Report From the Cancer and Leukemia Group B

A. William Blackstock, James E. Herndon, II, Electra D. Paskett, Michael C. Perry, Stephen L. Graziano, Joseph J. Muscato, Michael P. Kosty, Wallace L. Akerley, Jimmie Holland, Stewart Fleishman, Mark R. Green

Affiliations of authors: A. W. Blackstock, Wake Forest University School of Medicine, Winston-Salem, NC, and University of North Carolina at Chapel Hill, Chapel Hill, NC; J. E. Herndon II, Cancer and Leukemia Group B Statistical Center, Duke University, Durham, NC; E. D. Paskett, Wake Forest University School of Medicine; M. C. Perry, University of Missouri/Ellis Fischel Cancer Center, Columbia; S. L. Graziano, SUNY Upstate Medical University, Syracuse, NY; J. J. Muscato, Missouri Cancer Associates, Columbia; M. P. Kosty, Scripps Clinic, La Jolla, CA; W. L. Akerley, Women and Infants Hospital of Rhode Island, Providence; J. Holland, Memorial Sloan-Kettering Cancer Center, New York, NY; S. Fleishman, Institute of Oncology, Long Island Jewish Medical Center, New Hyde Park, NY; M. R. Green, Medical University of South Carolina, Charleston.

Correspondence to: A. William Blackstock, M.D., Department of Radiation Oncology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157 (e-mail: ablackst{at}wfubmc.edu).


    ABSTRACT
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: Among patients diagnosed with advanced non-small-cell lung carcinoma (NSCLC), African-Americans have lower survival rates than non-African-Americans. Whether this difference is due to innate characteristics of the disease in the two ethnicities or to disparities in health care is not known. We investigated whether the disparity in survival would persist when patients were treated with similar systemic therapies (i.e., in phase II and phase III Cancer and Leukemia Group B [CALGB] trials). Methods: We assessed 504 consecutive patients (458 non-African-American and 46 African-American) receiving systemic chemotherapy in CALGB studies for advanced NSCLC during the period from 1989 through 1998. Clinical and demographic characteristics, treatment received, and survival data were obtained from the CALGB database. Cox's proportional hazards model was used to assess the effect of race/ethnicity on survival after adjustment for other known prognostic factors. All statistical tests were two-sided. Results: The unadjusted 1-year survival rate was 22% (95% confidence interval [CI] = 13% to 38%) for African-American patients and 30% (95% CI = 26% to 35%) for non-African-American patients, a statistically significant difference (8%; 95% CI on the difference = 5% to 12%; P = .03). Multivariable adjustment for the effect of treatment arm, histology, and metastatic site at presentation did not alter the worse outcome for African-American patients. However, the effect of race/ethnicity disappeared after adjustment for performance status and weight loss. African-American patients were more likely than non-African-Americans to present with a poor performance status (83% versus 60%) and substantial weight loss (41% versus 27%) and to be unmarried (59% versus 28%), disabled (31% versus 15%), unemployed (17% versus 7%), and Medicaid recipients (30% versus 8%). Conclusions: The relationship that we observed between poor performance, weight loss, and socioeconomic status suggests that social circumstances lead to African-Americans presenting with poorer prognostic features.



    INTRODUCTION
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Lung cancer is the leading cause of cancer-related death in the United States and North America (1,2). Non-small-cell lung cancer (NSCLC) is the most common histologic cell type and often presents in an advanced stage. The prognosis for metastatic NSCLC is extremely poor, but several trials have shown that systemic chemotherapy can palliate cancer-related symptoms and modestly improve survival for patients with this disease (3–6). Although the incidence of advanced-stage disease has increased in most race/ethnic groups, the rate of increase has been greatest for African-American patients (7). Moreover, relative 2- and 5-year survival rates for patients with local- and/or regional-stage disease are lower in African-Americans than in non-African-Americans, and these differences in survival rates have become more prominent in recent years (8). National health surveillance statistics and other studies (9–13) examined race/ethnicity in relation to NSCLC prognosis and found that, during the past several decades non-African-Americans have more favorable survival rates than African-Americans.

The prognosis for patients with advanced NSCLC is related to several factors, including pretreatment stage, sex, weight loss, and overall performance status (14–19). In addition, it has been proposed that NSCLC in African-American patients is a biologically more aggressive disease because of a number of genetic factors (20). Race/ethnicity, in and of itself, however, may not be important in determining the prognosis for patients diagnosed with lung cancer. It is possible that the poor outcome observed for African-American patients may be reduced or eliminated by adjusting for comorbid conditions and socioeconomic factors associated with race/ethnicity.

In this study, we examined survival after treatment of advanced NSCLC among African-American and non-African-American patients participating in phase II or phase III Cancer and Leukemia Group B (CALGB) clinical trials. The cooperative group trial design defines the extent of disease at the time of study entry and provides for uniform therapy, thereby controlling for two major confounding factors affecting prognosis and allowing investigation of other determinants of prognosis. The mandate of the National Institutes of Health (NIH) Revitalization Act of 1993 required that all NIH-sponsored clinical trials include minorities and women in sufficient numbers to allow valid subset analysis to ascertain differences in the effect of treatments among women and minority participants (21). Our analysis in this study is an attempt to fulfill the intent of the mandate in a rational and ethically sound manner.


    PATIENTS AND METHODS
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Patient Selection

During the period from 1989 through 1998, the CALGB conducted five consecutive phase II/III clinical trials evaluating systemic chemotherapy as an initial treatment for 529 patients with advanced NSCLC. In this study, we retrospectively evaluated the database from these five trials. A majority of patients outlined in these CALGB trials completed an extensive demographic questionnaire, which provided information on level of education, total yearly income, medical coverage, and marital/employment status.

The five CALGB protocols were protocols 8931, 8932, 9132, 9532, and 9731. During the period from July 1989 through February 1991, 291 patients with American Joint Committee on Cancer stage IIIB or IV NSCLC were accrued to protocol 8931, a randomized placebo-controlled phase III trial that assessed the impact of adding hydrazine sulfate to the standard chemotherapy regimen of cisplatin and vinblastine (22). During the period from February 1989 through June 1990, 40 patients were accrued to protocol 8932, a phase II study that evaluated the efficacy of cisplatin and intravenous etoposide for the treatment of metastatic or recurrent NSCLC (23). During the period from July 1991 through March 1992, 101 patients with stage IIIB or IV NSCLC were accrued to protocol 9132, a randomized phase II study that determined the efficacy of ifosfamide, mesna, cisplatin, and granulocyte colony-stimulating factor (G-CSF) or etoposide, cisplatin, and G-CSF (24). During the period from July 1995 through July 1996, 83 patients were accrued to protocol 9532, a randomized phase II study that evaluated the efficacy of paclitaxel and ifosfamide versus vinorelbine and ifosfamide for patients with stage IV or recurrent NSCLC (25). During the period from July 1997 through April 1998, 39 patients were accrued to CALGB protocol 9731, a phase II study that evaluated the efficacy and toxicity of weekly paclitaxel for patients with chemotherapy-naive, stage IIIB or stage IV NSCLC (26).

All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1 and adequate renal and hepatic functions. No patient received systemic chemotherapy before entry into the study. Additional details of the design of the studies and primary findings can be found elsewhere (22–26).

For inclusion in this analysis, we selected all protocol-eligible patients with follow-up information whose race was reported (442 Caucasian, five Hispanic, three Asian, one Native American, one Asian Indian, two Filipino, 46 African-American, and four not otherwise specified). Patients who were not considered eligible in the original analyses (22–26) and registered patients who withdrew from the study before receiving the protocol treatment are not included in this study. The current analysis did not differentiate between the two treatment arms in CALGB protocol 8931 because the primary analyses of that study showed almost superimposable survival curves (22). Although 529 eligible patients are included in this article, data were missing for 25 patients. Thus, the multivariate survival analyses use data from 504 patients, of which 458 were non-African-American and 46 were African-American patients.

To address the impact of potential socioeconomic factors on treatment outcome, an additional analysis was performed on patients from CALGB protocols 8931, 9532, and 9731. Information was available from 300 non-African-Americans and 30 African-American patients regarding marital status, employment, educational level, insurance, and income for patients treated on these three trials. Information was not available for patients treated on CALGB protocols 8932 and 9132.

Study Endpoints and Statistical Methods

Frequency distributions of selected clinical variables (Table 1Go) were compared between African-Americans and non-African-Americans by chi-square and Fisher's exact tests. The Cox proportional hazards model was used to compute relative risk ratios for African-Americans versus non-African-Americans and to simultaneously assess and control for the confounding influence of other prognostic covariables (27,28). P values from these analyses are two-sided. After adjustment for known prognostic factors and other potential confounders, a variable describing race/ ethnicity (African-American versus non-African-American) was added to the model to determine whether its inclusion strengthened the model. For a subset of patients with socioeconomic data, chi-square tests were used to determine the relationship between socioeconomic measurements and race/ethnicity. Survival times were estimated with the use of Kaplan–Meier curves and were compared by a two-sided log-rank test using the SAS 6.09 and S-plus statistical package (SAS Institute, Inc., Cary, NC) (29,30).


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Table 1. Clinical variables for all patients enrolled in Cancer and Leukemia Group B trials for treatment of advanced non-small-cell lung cancer
 

    RESULTS
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Among the 504 patients included in this analysis, 46 were African-American. Table 1Go reflects the distribution of characteristics by race/ethnicity for all patients. The proportion of non-African-Americans who were 60 years of age or older was statistically significantly greater than that of African-Americans (P = .04). African-Americans were more often male (76%) than non-African-Americans (69%).

We determined the survival estimates for all patients across all protocols by the Kaplan–Meier method (29,30). Although the relative proportion of non-African-Americans and African-Americans differed by trial, the relative prognosis for the two race/ethnic groups did not differ. Without adjustment for other prognostic covariables, the survival pattern for non-African-Americans and African-Americans was statistically significantly different (P = .03). The 1-year survival rate was 30% (95% CI = 26% to 35%) for non-African-Americans and 22% (95% CI = 13% to 38%) for African-Americans (Fig. 1Go). The median survival for non-African-Americans and African-Americans was 7.9 and 7.7 months, respectively.



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Fig. 1. Survival estimates among patients from all advanced non-small-cell lung cancer (NSCLC) trials combined (non-African-Americans = 458; African-Americans = 46). The number of deaths is noted through the entire period of follow-up in all trials. Among non-African-Americans, at 6 months, there were 281 patients at risk (95% confidence interval [CI] = 0.57 to 0.66); at 18 months, there were 75 patients at risk (95% CI = 0.14 to 0.21). Among African-Americans, at 6 months, there were 27 patients at risk (95% CI = 0.46 to 0.75); at 18 months, there were two patients at risk (95% CI = 0.01 to 0.17).

 
We next investigated factors in addition to race/ethnicity that may be associated with survival (Table 2Go). Patients with a performance status of 1 (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework or office work) were at a 40% higher risk of dying (risk ratio [RR] = 1.40; 95% CI = 1.15 to 1.71) than patients with a performance status of 0 (P<.001). Patients with squamous cell lung cancer had a statistically significantly shorter life span than patients with other histologies, and patients with a pretreatment weight loss of greater than or equal to 5% had a statistically significantly higher risk of dying than patients without weight loss (P = .024). Race was incorporated into the clinical multivariate model presented in Table 2Go. After adjustment for known clinical factors (Table 2Go), the effect of race on survival was not statistically significant. That is, race did not have an independent prognostic effect on survival. Only in a multivariable model that did not adjust for weight loss and poor performance status did the effect of race become statistically significant, with a relative risk of 1.45 (95% CI = 1.05 to 1.95).


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Table 2. Clinical predictors of survival among patients enrolled in Cancer and Leukemia Group B trials for treatment of advanced non-small-cell lung cancer*
 
Race/ethnicity was then incorporated into the clinical multivariate model. After adjustment for known clinical factors, race/ethnicity did not statistically significantly affect the survival of patients with NSCLC (Table 2Go). In fact, race/ethnicity did not have an independent prognostic effect on survival (RR = 1.14; 95% CI = 0.82 to 1.5). Only in a multivariable model that did not adjust for weight loss and poor performance status did the effect of race/ethnicity become statistically significant (RR = 1.45; 95% CI = 1.05 to 1.95).

A statistically significant relationship was observed between race/ethnicity and several clinical factors included in the multivariate model. Although not statistically significant (P = .06), the percentage of patients presenting with weight loss of greater than or equal to 5% was greater among African-American patients than among non-African-American patients (RR = 1.28; 95% CI = 1.03 to 1.59). The percentage of patients with a performance status of 1 was also statistically significantly greater among the African-American patients (83%) than among the non-African-American patients (60%) (P = .002).

Table 3Go summarizes the relationship between race/ethnicity and socioeconomic measurements within the subgroup of patients for whom the information was available. A comparison of marital status found that 58% of African-Americans were unmarried versus 27% of non-African-American patients. More African-American patients were disabled or unemployed (31% and 17%, respectively) than non-African-American patients (15% and 7%, respectively). African-American patients were more likely than non-African-American patients to receive Medicaid (P = .001) and less likely to have private group health insurance (P = .037) and had a substantially lower median income when compared with non-African-American patients (Table 3Go).


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Table 3. Relationship between socioeconomic characteristics and race/ethnicity of patients enrolled in Cancer and Leukemia Group B trials for treatment of advanced non-small-cell lung cancer
 

    DISCUSSION
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
NSCLC remains the leading cause of cancer-related death in the United States. Across all stages of the disease, survival for African-American patients continues to lag behind that reported for non-African-American patients (31–33). A number of potential explanations for this observation have been proposed, including later stage at diagnosis, differences in treatment, and differences in the biologic aggressiveness of the disease. Although these factors may be important, perhaps the most relevant factor for African-American patients may be access to routine cancer care. Indeed, on the basis of data from the Black/White Cancer Survival Study Group (34), it has been hypothesized that less access to routine cancer care results in a worse patient condition (i.e., greater weight loss and poorer performance status) at diagnosis. Using the CALGB clinical trial database, we investigated this hypothesis. The CALGB lung cancer database offers several advantages over other data sources. First, stage of disease is comparable because of the constraints of the protocol entry criteria. Second, treatment and follow-up care are conducted according to a uniform standard. Third, detailed information on prognostic covariates, such as performance status and weight loss, is collected. However, one ongoing limitation of the CALGB data and data obtained by other national cooperative groups is the small number of participants from many racial groups, including African-Americans.

In this cohort of 504 patients treated with chemotherapy for advanced NSCLC, the 46 African-Americans and 458 non-African-Americans had similar clinical stages of disease at the time of protocol entry. However, the percentage of patients with a performance status of 1 and/or with greater than or equal to 5% weight loss was higher among African-Americans than among non-African-Americans (83% African-Americans versus 60% non-African-Americans with a performance status of 1; 41% African-Americans versus 27% non-African-Americans with >=5% weight loss). These parameters, which may be perhaps indicators of delayed access to cancer care, are known predictors for poor outcome in patients with NSCLC. The 1-year survival rate observed in the African-American patient cohort was 22%, which was marginally better than that achieved for patients receiving the best supportive care in other trials in advanced NSCLC (35). In our analysis, the 1-year survival rate for non-African-American patients was 30%, a statistically significantly higher survival rate than that for African-Americans. Being African-American did not, however, predict for worse survival above and beyond the clinical factors of diminished performance status or pretreatment weight loss. The 1-year survival rate for patients with a performance status of 1 across both African-American and non-African-American cohorts was comparable, supporting our postulate that equal treatment of racially diverse patients with equivalent pretreatment prognostic features results in equal outcome.

Perhaps the most important observation in our analysis is the relationship among poor performance status, low socioeconomic status, and the overall outcome observed in African-American patients. Table 3Go shows that African-American patients were more likely to be unmarried, to be uninsured or rely upon Medicaid, and, in general, to have a lower income. All of these factors have been shown to predict a poor clinical outcome irrespective of race/ethnicity in a variety of diseases (36–39). In our study population, African-American patients were also more likely at study entry to have a lower performance status, as a result of either their malignancy or other pre-existing comorbidities. Cancer patients with even moderately impaired ambulation or pain at diagnosis have reduced survival and greatly increased toxicity from chemotherapy when compared with patients who have a better performance status (40–43). It is then reasonable to conclude that the survival of African-American patients with advanced NSCLC is not related to race/ethnicity or to inherent differences in the biology of their cancers; it is related to the clinical features at presentation that reflect an increase in the overall tumor burden (i.e., performance status and weight loss) at the time treatment is initiated.

From our analysis, we suggest that for low-income patients, social circumstances lead to a lack of resources and knowledge, poor living conditions, and a lack of access to care services that influence treatment efficacy or toxicity. Because equal treatment yields equal outcome among patients with the same stage of disease regardless of race/ethnicity, continued efforts are needed to encourage disease awareness, promote early detection, and increase minority participation in clinical trials. Ultimately, potential interventions need to be introduced that will decrease the mortality for all patients diagnosed with advanced NSCLC.


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Appendix table 1. Institutions that participated in the study, principal investigator, and grant number*
 

    NOTES
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
See "Appendix" section for the institutions that participated in the study, principal investigators, and grant numbers.

The research for these Cancer and Leukemia Group B studies (protocols 8931, 8932, 9132, 9532, and 9731) was supported, in part, by Public Health Service grant CA31946 from the National Cancer Institute (NCI), National Institutes of Health, Department of Health and Human Services, to the Cancer and Leukemia Group B (Richard L. Schilsky, M.D., Chairman), and GlaxoSmithKline (Research Triangle Park, NC). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCI.

We thank Carrie E. Blackstock, Ph.D. (University of North Carolina, Chapel Hill), for her editorial support.


    REFERENCES
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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Manuscript received May 3, 2001; revised December 14, 2001; accepted December 18, 2001.


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