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Originally published as JCO Early Release 10.1200/JCO.2003.04.002 on July 21 2003 © 2003 American Society for Clinical Oncology
Aggressive Treatment for the Fit Elderly With Non–Small-Cell Lung Cancer? Yes!Massachusetts General Hospital Cancer Center, Dana-Farber/Partners Cancer Care, Harvard Medical School, Boston, MA WHAT IS the optimal treatment for a 76-year-old person with locally advanced non–small-cell lung cancer (NSCLC)? Do elderly patients tolerate aggressive therapy? Is their outcome comparable with that of younger patients? Do we need to do elder-specific trials in NSCLC? These are some of the key questions as we struggle to define the best care for an increasingly large population of patients. Lung cancer is primarily a disease of those older than 65 years. The median age of patients newly diagnosed with lung cancer is 70 years, and one third are older than 75 years.1 The good news is that the age-adjusted incidence rates for lung cancer continue to decline in the United States. The bad news is that the absolute number of patients is increasing, primarily due to the aging of the population. As this trend continues, the magnitude of the lung cancer epidemic in the elderly will increase.2 Nearly a third of elderly patients have locally advanced NSCLC at the time of diagnosis. The cure rates for patients with stage III disease are low even in patients with the best prognosis. Although it is widely believed that multimodality therapy offers the best hope of achieving cure in stage III NSCLC,3–5 there has been hesitation in treating older patients with chemoradiotherapy, particularly using a concurrent schedule. We know that elderly patients are more vulnerable to the toxicity of combined chemoradiation. Yet, when asked, older patients value the potential survival benefit of this approach as much as younger patients.6 A 75-year-old person wants to be a 76-year-old person as strongly as a 55-year-old person wants to be a 56-year-old person. In this issue of the Journal of Clinical Oncology, Schild et al7 examine the timely question of whether elderly patients with locally advanced NSCLC benefit from combined-modality treatment. They retrospectively examined age as a predictor of both survival and toxicity in North Central Cancer Treatment Group (NCCTG) 94-24-52, a phase III randomized trial of concurrent chemoradiotherapy in 234 patients with locally advanced NSCLC. Like much of the data regarding the treatment of special populations with lung cancer, this was not an elder-specific trial, but rather an analysis of patients older than 70 years (n = 63) who participated in a larger Radiation Therapy Oncology Group (RTOG) study. All of the patients who entered were believed by their treating physician to be capable of tolerating an aggressive approach. In essence, we are looking at a population of patients that can be called the "fit elderly." NCCTG 94-24-52 randomized patients to receive either daily x2 radiation therapy (RT) (60 Gy in 40 twice-daily fractions with a treatment break) or once daily RT (60 Gy in 30 fractions), both given concurrently with etoposide at 100 mg/m2 and cisplatin at 30 mg/m2 for days 1 to 3 and 28 to 30 during RT. There was no age limit for study enrollment, but all patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and be free of significant cardiac, pulmonary, renal or hematologic comorbidities. The results for all patients in the parent study showed no difference between the once daily RT and daily x2 RT groups in terms of overall survival, time to progression, local failure rates, and treatment-related toxicity.8 The Schild et al retrospective analysis pooled study participants from both treatment groups and compared those younger than 70 years (younger patients) with those older than 70 years (elderly patients). The age of 70 years is a clinically relevant distinction and has been used by several investigators in similarly designed studies. Elderly patients represented 26% of the study population, were equally distributed between both treatment groups, and completed prescribed therapy at a rate similar to that of younger patients. In terms of efficacy of treatment, Schild et al found that the 2-year and 5-year freedom from progression and survival rates did not differ between elderly and younger patients, with 5-year overall survival rates of 18% and 13% in elderly and younger patients, respectively (P = .37). However, toxicities of grade 4 or higher were significantly more common in the elderly patients (81%) compared with the younger patients (62%; P = .007). This difference was largely attributable to hematologic toxicity, as 78% of elderly patients experienced grade 4 hematologic toxicity, compared with only 56% of younger patients. From this important analysis, we can conclude that "fit elderly" patients can tolerate and benefit from combined-modality treatment. These results are consistent with several published subgroup analyses from other phase III randomized trials. Rocha Lima et al9 analyzed older patients from a randomized Cancer and Leukemia Group B (CALGB) trial of induction chemotherapy followed by either RT alone or concurrent chemoradiotherapy for locally advanced NSCLC. The analysis of the CALGB trial showed that patients older than 70 years (n = 54) completed treatment to the same extent as younger patients and attained similar response and survival rates, but suffered from increased toxicity, especially nephrotoxicity. Langer et al10 presented data at the 2002 American Society of Clinical Oncology (ASCO) meeting regarding 595 patients on the RTOG 94-10 study, a randomized trial of concurrent versus sequential chemoradiotherapy for locally advanced NSCLC. Subgroup analysis of patients older than 70 years (n = 104) showed that elderly patients benefit from concurrent, as compared with sequential chemoradiation in a similar magnitude as younger patients, but that they suffer from increased toxicity, especially severe esophagitis. The Schild et al analysis adds power to the argument that aggressive multimodality treatment of the "fit elderly" is warranted. This finding is in agreement with the recent pooled analysis performed by Sargent et al,11 supporting the benefit of adjuvant therapy of colorectal cancer in the elderly. Contradictory reports suggesting that elderly patients may not benefit from combined-modality treatment are more difficult to interpret. The RTOG meta-analysis by Werner-Wasik, of 2,000 patients with locally advanced NSCLC (of whom approximately 470 patients underwent chemoradiation), showed that patients who were younger than 70 years enjoyed a survival advantage.12 Movsas et al13 used a quality-adjusted survival analysis to examine six prospective RTOG trials, including 979 patients with inoperable stage II to IIIB lung cancer treated with a variety of treatments: RT alone, and sequential and concurrent chemoradiotherapy. All of the patients in this analysis had also been included in the previously mentioned RTOG meta-analysis by Werner-Wasik.12 They found that elderly patients (>71 years) had the best quality-adjusted survival with RT alone, in contrast with younger patients, who benefited from more aggressive combined-modality approaches. These meta-analyses are somewhat difficult to interpret because the compilation of patients treated on separate protocols implies a comparison between patients with a variety of entry criteria used to define eligibility and different treatment regimens administered, including single-modality RT in many of these studies. The suggestion in the meta-analyses that elderly patients do not benefit from aggressive combined-modality treatment has not been substantiated by subgroup analyses of single, large, prospective randomized trials such as that presented by Schild et al in this issue of the Journal of Clinical Oncology. What about the additional toxicity? The analysis of Schild et al demonstrates increased hematologic toxicity; that of Rocha-Lima et al, increased nephrotoxicity; and the analysis of Langer et al, increased esophagitis. The increased toxicity, however, did not have an adverse impact on survival. The toll of combined chemoradiotherapy is extensive, even in younger patients, and needs to be accurately presented to patients of all ages in a realistic discussion of risks and benefits. If "fit elderly" patients can tolerate aggressive multimodality therapy, does this mean that all older patients should be treated this way? The answer is no. As stated previously, the older patients that comprise the subgroups in the analysis of Schild et al are different from the patients that come into our clinics. We recognize that performance status is the single best predictor of outcome in lung cancer. Patients who have advanced age combined with an impaired performance status do not tolerate the toxicity of aggressive chemoradiotherapy and should not be treated in this fashion. However, performance status alone may not be sufficient to select older patients for aggressive treatment. More sophisticated tools to assess comorbidity in elderly patients may yield more precise estimates of prognosis than performance status alone, and are areas of ongoing research. Do we need elder-specific studies in lung cancer? We would answer yes! It is well established that the elderly are underrepresented in clinical trials. The Southwest Oncology Group (SWOG) analysis of more than 16,000 clinical trial participants found that only 39% of the lung cancer subjects enrolled in SWOG trials between 1993 and 1996 were older than 65 years, whereas 66% of the lung cancer population in the United States is older than 65 years.14 The time has come for separate studies that enroll patients who are older than 70 years. The questions asked in these studies would still focus on efficacy of treatment, but would allow a greater evaluation of toxicity in a patient population that is more likely to suffer adverse events. It is disappointing that there has not been a trial of combined-modality treatment for locally advanced NSCLC that solely studies elderly patients. The most important reason to perform elder-specific studies is the consistent observation of increased toxicity in this population. Physicians need to know what the expected degree of toxicity will be of a given treatment in patients older than 70 years. Basing our clinical practices on the small number of patients who are older than 70 years and who make their way onto the larger cooperative group studies may not accurately reflect the costs of our treatments. Outside of the clinical trials setting, elderly patients (that is, more than 75 years old) with cancer may be less likely to receive appropriate treatment, and this can contribute to higher mortality rates than those of younger patients.15,16 However, elderly patients are as likely to desire aggressive chemotherapy for both curative and palliative purposes as their younger counterparts.6 Given that the study of Schild et al confirms that older patients suffer increased toxicity from aggressive treatment, we need to design and conduct elder-specific trials to assure that we are not subjecting patients to extreme toxicity. Only by performing elder-specific studies will we be able to treat patients who are more representative of the population of patients older than 70 years, and not just the "fit elderly." The recently published MILES17 study from Italy is a good example of a well-done trial of chemotherapy for older patients with stage IV disease. The time has come to perform similar trials using combined-modality treatment in stage III NSCLC. In summary, NSCLC is a significant problem in the elderly population, and its impact will grow over the next few decades. Locally advanced NSCLC is a difficult disease to treat, due to high rates of toxicity associated with potentially curative combined-modality therapy. Historically, there has been reticence to treat elderly patients as aggressively as their younger counterparts. With this article in the Journal of Clinical Oncology, Schild et al make an important contribution toward expanding the evidence in support of aggressive treatment for the "fit elderly." It is still difficult for the clinical oncologist to know how best to apply these data to the wider population of elderly NSCLC patients seen in the clinic. There is a unique opportunity to study newer treatments that may be less toxic, including three-dimensional conformal RT, intensity-modulated RT, utilization of non–platinum-containing chemotherapy regimens, and novel targeted therapies. Future use of tools to more preciselyassess functional status in the elderly will hopefully play a role in evaluating these novel approaches in elder-specific trials. REFERENCES 1. Edwards BK, Howe HL, Ries LAG, et al: Annual report to the nation on the status of cancer, 1973–1999, featuring implications of age and aging on the U.S. cancer burden. Cancer 94:2766–2792, 2002[CrossRef][Medline] 2. Yancik R: Cancer burden in the aged. Cancer 80:1273–1283, 1997[CrossRef][Medline]
3. Sause W, Kolesar P, Taylor S: Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer. Chest 117:358–364, 2000
4. Furuse K, Fukuoka M, Kawahara M: Phase III study of concurrent versus sequential thoracic RT in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 17:2692–2699, 1999
5. Dillman RO, Herndon J, Seagren SL, et al: Improved survival in stage III non-small-cell lung cancer: Seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 88:1210–1215, 1996
6. Yellen SB, Cella DF, Leslie WT: Age and clinical decision making in oncology patients. J Natl Cancer Inst 86:1766–1770, 1994
7. Schild SE, Stella PJ, Geyer SM, et al: The outcome of combined modality therapy for stage III non-small cell lung cancer (NSCLC) in the elderly. J Clin Oncol 21:3201–3206, 2003 8. Schild SE, Stella PJ, Geyer SM, et al: Phase III trial comparing chemotherapy plus once-daily or twice-daily radiotherapy in stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 54:370–378, 2002[CrossRef][Medline] 9. Rocha Lima CMS, Herndon JE, Kosty M, et al: Therapy choices among older patients with lung carcinoma: An evaluation of two trials of the cancer and leukemia group B. Cancer 94:181–187, 2002[CrossRef][Medline] 10. Langer CJ, Hsu C, Curran WJ, et al: Elderly patients (pts) with locally advanced non-small cell lung cancer (LA-NSCLC) benefit from combined modality therapy: Secondary analysis of radiation therapy oncology group (RTOG) 94-10. Presented at the Annual Meeting of the Am Soc Clin Oncol, Orlando, FL, May 18–21, 2002
11. Sargent D, Goldberg R, Jacobson S, et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 345:1091–1097, 2001 12. Werner-Wasik M, Scott C, Cox JD: Recursive partitioning analysis of 1999 radiation therapy oncology group (RTOG) patients with locally-advanced non-small-cell lung cancer (LA-NSCLC): Identification of five groups with different survival. Int J Radiat Oncol Biol Phys 48:1475–1482, 2000[CrossRef][Medline] 13. Movsas B, Scott C, Sause W: The benefit of treatment intensification is age and histology-dependent in patients with locally advanced non-small cell lung cancer (NSCLC): A quality-adjusted survival analysis of radiation therapy oncology group (RTOG) chemoradiation studies. Int J Radiat Oncol Biol Phys 45:1143–1149, 1999[CrossRef][Medline]
14. Hutchins LF, Unger JM, Crowley JJ, et al: Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 341:2061–2067, 1999 15. Goodwin JS, Hunt WC, Samet JM: Determinants of cancer therapy in elderly patients. Cancer 72:594–601, 1993[CrossRef][Medline]
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17. Gridelli C, Perrone F, Gallo C, et al: Chemotherapy for elderly patients with advanced non-small-cell lung cancer: The Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 95:362–372, 2003 (comment)
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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