Affiliations of authors: P. A. Bunn, Jr., University of Colorado Cancer Center, Denver, CO; R. Lilenbaum, Mt. Sinai Cancer Center, Miami Beach, FL.
Correspondence to: Paul A. Bunn, Jr., M.D., Grohne/Stapp Professor and Director, University of Colorado Cancer Center, Denver, CO 80262.
In this issue of the Journal, Gridelli et al. (1) present the results of a randomized three-arm trial that compared a two-drug combination of vinorelbine plus gemcitabine to either agent alone in elderly (aged 70 years or older) patients with advanced non-small-cell lung cancer (NSCLC). The authors report that there were no efficacy differences between either of the single agents and the two-drug combination. Surprisingly, the rates of grade 34 neutropenia were highest in patients treated with single-agent vinorelbine. Other toxicity rates were higher in patients treated with the two-drug combination arm than in patients treated with either of the single agents. This study raises two important questions: Should elderly patients with advanced NSCLC be offered therapy and if so, then which therapy?
The median age of newly diagnosed lung cancer patients in developed countries is approximately 68 years, and as many as 40% of patients may be older than 70 years at diagnosis. There are approximately 170 000 new cases of lung cancer in the United States each year (2), with approximately one-third of these patients presenting with stage IV disease. This means that, each year in the United States alone, there are as many as 23 000 new cases of advanced NSCLC in patients who are older than 70 years. The median age of patients in most of the large therapeutic studies is 6062 years (35), suggesting that there is a selection bias against elderly patients. In addition, practice surveys indicate that most elderly patients are not offered treatment with chemotherapeutic agents. For example, the Medicare survey conducted by Earle et al. (6) indicated that only 22% of elderly (aged older than 65 years) Medicare patients with NSCLC received chemotherapy. A Surveillance, Epidemiology, and End Results (SEER)1 program survey reported that 32% of elderly patients received chemotherapy (7).
The question of whether elderly patients should receive chemotherapy can be addressed by examining a meta-analysis of randomized trials of patients of all ages, by analysis of population surveys, by randomized trials restricted to elderly patients, and by subset analyses of randomized trials comparing different chemotherapy combinations. All four types of analyses provide evidence to support the notion that elderly patients with NSCLC should be offered systemic chemotherapy.
META-ANALYSES
The Non-Small Cell Lung Cancer Collaborative Clinical Trials Cooperative Group performed an extensive meta-analysis of randomized trials comparing cisplatin-based chemotherapy with best supportive care (8). For all patients, the hazard ratio was 0.73 in favor of chemotherapy. Subgroup analysis was unable to identify groups of patients less likely to benefit on the basis of age, sex, histology, or stage. For elderly patients (>65 years) with stage IV disease, the hazard ratio was 0.87, although the number of elderly patients was small.
The Cancer Research Campaign (CRC) unit for cancer studies in the United Kingdom used data from phase III trials comparing mitomycin C, ifosfamide, and cisplatin with best supportive care to analyze the effect of stage, sex, age, histology, and performance status on outcome (9). All subgroups defined by age consistently benefited from chemotherapy.
POPULATION SURVEYS
Earle et al. (6) analyzed 6232 elderly (aged 65 years or older) patients with NSCLC from the SEER registry of the National Cancer Institute. Median survival was 30 weeks for patients receiving chemotherapy and 23 weeks for patients receiving supportive care. One-year survival was 24% for patients receiving chemotherapy but only 17% for those patients receiving supportive care. In a Cox proportional hazards model, chemotherapy administration was associated with a hazard ratio of 0.81 (95% confidence interval = 0.76 to 0.85). This reduction in the hazard ratio of death was similar to the 0.87 hazard ratio reported in the meta-analysis of randomized trials described above (8).
RANDOMIZED TRIALS IN ELDERLY PATIENTS
The first large randomized trial that restricted enrollment to elderly patients with advanced NSCLC was conducted by the Elderly Lung Cancer Vinorelbine Study Group (ELVIS) (10). This trial compared single-agent vinorelbine with best supportive care in NSCLC patients who were aged 70 years or older, were ineligible for radiotherapy, had stage IV or IIIB, and had a performance status of 02. There was a statistically significant survival advantage for patients receiving vinorelbine, with a median survival of 28 weeks compared with 21 weeks for patients receiving the best supportive care (P = .03). The relative hazard of death for patients receiving vinorelbine was 0.65. The 1-year survival rate also favored patients receiving vinorelbine (32% versus 14%) (11). Importantly, this trial also showed an improved quality of life for patients receiving vinorelbine (10,11).
COOPERATIVE GROUP ANALYSES
Several cooperative groups analyzed the results of their randomized trials comparing various chemotherapy combinations to determine whether age influenced outcome. The Cancer and Leukemia Group B (CALGB) analyzed two large randomized trials (12). Patients (N = 515) were divided into four cohorts on the basis of age (aged <50, 5059, 6069, and 70 years). No statistically significant differences were seen in response, survival, or continuation of treatment based on age cohort. Statistically significantly increased leukocyte toxicity was seen in older cohorts without a concomitant increase in severe or worse infections. The Eastern Cooperative Oncology Group (ECOG) compared the results of patients treated on a randomized trial that compared etoposide plus cisplatin with paclitaxel plus cisplatin (3). There were no statistically significant differences in survival outcome based on age. The 1- and 2-year survival rates were 29% and 12% for older patients (i.e., those aged
70 years) versus 38% and 14% for younger patients. The Southwest Oncology Group (SWOG) analyzed the effect of age on their study comparing vinorelbine plus cisplatin with paclitaxel plus carboplatin (4,13). There were no statistically significant differences in survival between subjects aged 70 years or older and those who were younger. In each of these trials, there were some increased toxicity rates among the elderly patients, but none of the studies indicated that these toxicity rates were unacceptably high or should influence choice of therapy.
If we thus conclude that chemotherapy regimens can be administered safely to elderly patients and can improve both survival and quality of life, which chemotherapy combinations should be recommended? Table 1 summarizes the results of three randomized trials that address this issue (1,5,14). The results of these trials are conflicting. The results of the Multicenter Italian Lung Cancer in the Elderly Study (MILES) trial (1), published in this issue of the Journal, showed no advantage for the two-drug combination of vinorelbine plus gemcitabine compared with either agent alone. The MILES results contrast with those of a smaller Italian randomized study (14) that compared vinorelbine plus gemcitabine with vinorelbine alone. Frasci et al. (14) demonstrated a statistically significant survival advantage for patients receiving the two-drug combination. The doses of chemotherapy in the two-drug vinorelbine/gemcitabine combination were higher in the study of Frasci et al. (14) than in the study by Gridelli et al. (1). This translated to a higher, but acceptable, rate of grade 34 neutropenia (Table 1
). Interestingly, the rate of grade 34 neutropenia in the study by Gridelli et al. (1) was higher in patients in the single-agent vinorelbine arm than in patients in the two-drug combination arm. The survival experiences of patients in the two-drug combination arms of both trials were similar, but patients in the single-agent vinorelbine arm fared much better in the study by Gridelli et al. (1) than in the study by Frasci et al. (14).
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Taken together, these results indicate that elderly patients with advanced NSCLC can benefit from both single-agent therapy and from some combinations and that both single agents and some combinations can be delivered safely. The issue of whether some combinations (e.g., paclitaxel plus carboplatin) are preferred over single agents cannot be definitely determined from the studies to date. It is hoped that less toxic targeted therapies given sequentially or in combination will provide further advances in the future.
NOTES
1 Editors note: SEER is a set of geographically defined, population-based, central cancer registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Registry data are submitted electronically without personal identifiers to the NCI on a biannual basis, and the NCI makes the data available to the public for scientific research.
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