Minimize Toxicity or Preserve Efficacy? A Delicate Trade-Off in the Management of Older Patients With Lung Cancer

Lung cancer is a disease of older patients in large part because of the long latency between tobacco carcinogen exposure and the development of lung cancer. Non–tobacco-related lung cancer mortality also increases with age. The majority of the patients with lung cancer in the United States are diagnosed in the seventh decade of life, and approximately 14% of elderly patients with lung cancer are in fact 80 years of age or older. Therefore, optimal management for this large population of patients is critically important and continues to evolve. The definition of‘elderly patients varies widely across trials and is without consensus. Nonetheless, patients older than 65 years of age are less likely to be included in paradigm-defining studies in lung cancer. Particularly in the real world setting, older patients frequently go untreated even when free of comorbid illnesses. The Elderly Lung Vinorelbine Italian Study (ELVIS) established the efficacy of singleagent systemic chemotherapy in elderly patients defined as those older than 70 years for the treatment of advanced non–small-cell lung cancer (NSCLC). This study was the first to show that age by itself does not preclude clinical benefit from systemic chemotherapy. With the recognition in fit younger patients that platinum-based two-drug combination regimens confer superior survival benefit over single-agent chemotherapy, a series of studies have been conducted to assess the benefit of combination therapy in elderly patients. These studies have proceeded in two parallel fashions either through elderly-specific clinical trials or as subset analysis of outcomes in elderly patients enrolled in age nonspecific studies. The randomized phase III study by Abe et al accompanying this editorial extends our understanding of the potential clinical benefit and limitation of combination chemotherapy in elderly ( 70 years) patients with NSCLC. The study compared the combination of cisplatin/docetaxel to docetaxel alone in elderly patients with NSCLC. Cisplatin/docetaxel combination was administered on a weekly schedule (days 1, 8, and 15 of a 4-week schedule), while docetaxel was administered on day 1 of a 3-week schedule. A total of 364 patients were required to demonstrate a 30% improvement in survival for the combination regimen over monotherapy. A prespecified interim analysis conducted after 50% of the target enrollment showed an estimated hazard ratio (HR) of 1.56 (95% CI, 0.98 to 2.49) in favor of the docetaxel-only arm. The study was therefore terminated after enrolling 220 patients based on the estimated probability of less than 1% that a superior outcome could be observed with combination therapy, even if full accrual goal was met. What lesson can we learn from this study and how should the results influence current management of elderly patients with lung cancer? First, it is important to accurately interpret the findings of this study, which is that the combination of cisplatin/docetaxel administered on a weekly schedule is not superior to single-agent docetaxel given every 3 weeks in patients with lung cancer older than 70 years of age. The study does not negate the well-founded recognition that patient age does not preclude clinical benefit of systemic anticancer therapy and that elderly patients with lung cancer should be offered systemic therapy if they are fit enough to tolerate the treatment. Furthermore, there is robust evidence from a well-conducted, prospective, randomized, elderly-specific study of platinum-based chemotherapy that demonstrated superior efficacy for combination chemotherapy over single-agent therapy. The IFCT (Intergroupe Francophone de Cancerologie Thoracique) 0501 study compared the combination of carboplatin and weekly paclitaxel against monotherapy with gemcitabine or vinorelbine in elderly patients with NSCLC defined by age of 70 to 89 years. The study enrolled 451 patients with a median age of 77 years. The median overall survival was 10.3 months in patients treated with combination chemotherapy versus 6.2 months in the single-agent group (HR, 0.64; 95% CI, 0.52 to 0.78; P .001). The improved efficacy was accomplished at the expense of a higher toxicity with the combination regimen. In addition, retrospective analyses of individual patient datasets from large randomized clinical trials have also supported the use of platinum-based combinations for elderly patients with lung cancer, including the combination of docetaxel and cisplatin. These analyses have demonstrated comparable advantages for older patients with the use of combination regimen as in younger patients. If these prior studies showed a consistent pattern of benefit in elderly patients, how do we explain the negative result of the comparative study of cisplatin/docetaxel versus docetaxel reported by Abe et al? Is the only interpretation of the study data that the combination regimen is not superior to single-agent chemotherapy in elderly patients or can we find other plausible and well-founded alternative explanations? Since the result of a clinical trial is only an estimate of the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 6 FEBRUARY 2