Limited-Stage Small-Cell Lung Cancer: An Age Limit for Combined Modality Therapy?

Limited-stage small-cell lung cancer (LSCLC) stands out as a disease entity for which the role of radiotherapy has been extensively studied and defined through prospective phase III trials in North America, Europe, and Asia. Meta-analyses in the 1990s confirmed a survival benefit with the addition of thoracic radiotherapy to chemotherapy, and the landmark Intergroup 0096 phase III trial demonstrated that altering the way thoracic radiotherapy was administered (twice daily) could affect overall survival. Additional randomized studies have assessed thoracic radiotherapy timing and sequencing, as reflected in current National Comprehensive Cancer Network guidelines that recommend concurrent thoracic radiotherapy starting with either the first or second cycle of chemotherapy. Likewise, substantial evidence supports a role for prophylactic cranial radiotherapy (PCI) in patients with responsive chest disease. Despite the multitude of clinical trials performed, relatively little prospective data are available to guide therapy for elderly patients, because they have been under-represented in these studies. Given the dearth of robust data for the elderly, and given a median age of patients with SCLC that approaches 70 years, the review by Corso et al, the article that accompanies this editorial, provides a meaningful look into the management of the disease in elderly patients. Their National Cancer Data Base analysis included more than 8,000 patients age 70 years or older who were treated in the modern era; although the results are disheartening, they are not completely unexpected. Perhaps most telling is that greater than 40% of patients did not receive thoracic radiotherapy and were treated with chemotherapy alone, presumably in an effort to avoid potential toxicities. As such, thoracic radiotherapy was less likely to be given with increasing age, higher stage, and the presence of medical comorbidities. Women were less likely to receive thoracic radiotherapy, for unclear reasons. Of note, treatment with chemoradiotherapy had the strongest association with survival on multivariable analysis. The benefit of chemoradiotherapy remained significant even when the analysis was revised to try to account for selection bias, including propensity score matching and a subset analysis that restricted the chemotherapy cohort to patients for whom radiation was explicitly recommended but not delivered. Likewise, the survival advantage with chemoradiotherapy retained significance in populations that traditionally were less likely to benefit from intensive therapy, such as in patients older than age 80 years and in patients with multiple medical comorbidities. The traditional belief that age alone is a determinant of benefit from aggressive therapy is not necessarily borne out from experience with prospective trials. For example, Radiation Therapy Oncology Group (RTOG) study 9410 was key in defining the superiority of concurrent chemoradiotherapy over sequential therapy for locally advanced non–small-cell lung cancer, yet a subset analysis showed that fit elderly patients derived the greatest benefit from concurrent therapy (median overall survival, 22.4 months with concurrent v 10.5 months with sequential therapy). Evidence is also available from prospective LSCLC trials, including Intergroup 0096, in which similar response rates and event-free survival rates were observed in patients younger and older than 70 years of age. Although 5-year overall survival favored younger patients, 16% of patients age 70 or older were still alive 5 years after therapy. Reviews of trials conducted by the National Cancer Institute of Canada, North Central Cancer Treatment Group, and Cancer and Leukemia Group B suggest that elderly patients tolerate treatment reasonably well and are not necessarily more likely to need treatment interruptions during thoracic radiotherapy, although severe treatment-related myelosuppression and fatalities may be more commonly observed in the older population. These data support chemoradiotherapy for the select group of elderly fit enough to qualify for prospective trials (generally Eastern Cooperative Oncology Group performance status [PS] of 0 to 2 and minimal weight loss before diagnosis), though closer monitoring for treatment-related effects appears indicated. Although the results from Corso et al are provocative, a major limitation is that the National Cancer Data Base lacks information on PS, on PCI, and on details of chemotherapy itself, all of which may affect outcomes. Because it is not clear why patients did not receive thoracic radiotherapy, the finding that patients treated with chemoradiotherapy do better than patients treated with chemotherapy alone may be substantially biased by including patients who are unable to tolerate initial chemotherapy or who have early disease progression and, therefore, never become candidates for thoracic radiotherapy. Despite these limitations, such retrospective analyses do provide important information regarding treatment in the real-world setting. The decision-making process in the elderly patient with LSCLC should address two questions: First, should the patient not be offered chemoradiotherapy for any reason? Second, does the patient understand the goals of treatment? It is noteworthy that a significant proportion of patients, particularly among the elderly, do not understand the goals of cancer treatment therapy. In the prevailing paradigm, the treating team may use clinical judgment to formulate a treatment plan. However, this may lead to prohibitive toxicity in those unable to JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 36 DECEMBER 2

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