clinical investigations The Experience of an Academic Multidisciplinary Program

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1 clinical investigations Lung Cancer in Patients < 50 Years of Age* The Experience of an Academic Multidisciplinary Program Shirish M. Gadgeel, MD; Sakkaraiappan Ramalingam, MD; Glenn Cummings, PhD; Michael J. Kraut, MD; Antoinette J. Wozniak, MD; Laurie E. Gaspar, MD; and Gregory P. Kalemkerian, MD Objective: To determine if the clinicopathologic features and survival of lung cancer patients < 50 years of age differ from those of older patients. Design: Retrospective review of patients with primary bronchogenic carcinoma diagnosed at a single, multidisciplinary cancer center. Setting: A National Cancer Institute-designated comprehensive cancer center in urban Detroit, MI. Patients: All patients with primary bronchogenic carcinoma evaluated in the Multidisciplinary Lung Cancer Clinic at the Barbara Ann Karmanos Cancer Institute between 1990 and Results: Of 1,012 patients with lung cancer, 126 (12.5%) were < 50 years old at diagnosis, with a median age of 44 years. The median age of the 886 patients > 50 years of age was 65 years. The gender (p 0.08) and racial (p 0.12) characteristics of the younger and older patient groups were not significantly different. More than 90% of patients in both groups were smokers. The incidence of adenocarcinoma was significantly higher in younger patients (48.4% vs 36.0%, p < 0.001), and early-stage disease was less frequently diagnosed in younger patients (4.8% vs 19.7%, p < 0.001). Younger patients were more likely than older patients to undergo treatment, including surgery and combined-modality therapy (p < 0.001). Median survival was 13 months in younger and 9 months in older patients, while overall survival was similar in younger and older patients (p 0.13). Conclusions: Although younger patients with lung cancer present with more advanced-stage disease, their overall survival is similar to that of older patients, suggesting that lung cancer is not an inherently more aggressive disease in patients < 50 years of age. (CHEST 1999; 115: ) Key words: age; epidemiology; lung cancer; prognosis; young Abbreviations: SEER Surveillance, Epidemiology, and End Results *From the Departments of Internal Medicine (Drs. Gadgeel, Ramalingam, Cummings, Kraut, Wozniak, and Kalemkerian) and Radiation Oncology (Dr. Gaspar), Wayne State University and the Barbara Ann Karmanos Cancer Institute, Detroit, MI. Manuscript received July 6, 1998; revision accepted December 1, Correspondence to: Gregory P. Kalemkerian, MD, University of Michigan Medical Center, 7216 CCGC, 1500 E Medical Center Dr, Ann Arbor, MI Lung cancer is the leading cause of cancerrelated mortality in both men and women in the United States, with 160,000 deaths predicted in Although most cases of lung cancer occur in the sixth through eighth decades of life, 5 to 10% are diagnosed in patients 50 years of age. 2 Several studies have suggested that younger patients with lung cancer have a more aggressive disease course and a worse prognosis than older patients. 3 6 However, other investigators have reported that the prognosis of lung cancer in younger and older patient cohorts is similar Most prior studies have been limited by small patient samples at academic medical 1232 Clinical Investigations

2 centers, and many have relied solely on data from clinical patient subsets, such as those undergoing surgical resection. To overcome these limitations, we recently published an analysis of young patients with lung cancer utilizing a communitybased Surveillance, Epidemiology, and End Results (SEER) registry. 12 We now report the findings of a similar analysis conducted using data from the largest cancer center in the metropolitan Detroit SEER catchment area in order to identify particular clinicopathologic differences between younger and older lung cancer patients that may be specific to an academic cancer center. Materials and Methods The computerized databases of the Multidisciplinary Lung Cancer Clinic at the Barbara Ann Karmanos Cancer Institute, which include data on patients seen in the affiliated medical, radiation, and surgical oncology practices, were reviewed to identify eligible patients presenting from January 1990 to December These databases contain data on demographics, histology, staging, and treatment. Survival data were obtained through cross-referencing with the metropolitan Detroit SEER registry. Eligibility criteria included histologic or cytologic diagnosis consistent with primary bronchogenic small cell, large cell, squamous cell, or adenocarcinoma. This review identified 126 patients 50 years of age at diagnosis (younger group) and 886 patients 50 years of age at diagnosis (older group). The medical charts of all younger patients were reviewed to obtain more detailed clinical data. By definition, cancer-directed surgery excluded diagnostic, staging, and palliative procedures. Comparisons between age groups in frequency of demographic variables, stage, tumor histology, and treatment received were tested using Fisher s Exact Test and 2 methods. All p values were two tailed. Survival was calculated using the method of Kaplan and Meier 13 and compared by log-rank testing. A computer program (SAS; Cary, NC) was used for all statistical analyses. Results Demographic Characteristics Over the 4-year study period, 1,012 lung cancer patients were entered into the Multidisciplinary Lung Cancer Clinic databases. Of these, 126 (12.5%) were 50 years of age at diagnosis. Within this group of younger patients, 99 (78.6%) were 40 to 49 years of age, 26 (20.6%) were 30 to 39 years, and only 1 (0.8%) was 30 years of age. The median ages of the younger and older patient groups were 44 and 65 years, respectively (Table 1). The differences in the proportional incidences of gender (p 0.08) and racial (p 0.12) categories between the younger and older patient groups were not statistically significant (Table 1). Data regarding the habitual use of tobacco were available on all younger patients and 97% of older patients. Tobacco use was common in the entire cohort, with 90% of patients in both groups Table 1 Demographic Characteristics Age at Diagnosis, yr 50 (%) 50 (%) p Value* No. of patients 126 (12.5) 886 (87.5) Median age, yr (range) 44 (21 49) 65 (50 88) Gender 0.08 Male 83 (65.9) 512 (57.8) Female 43 (34.1) 374 (42.2) Race 0.12 White 63 (50.0) 527 (59.5) Black 62 (49.2) 350 (39.5) Other 1 (0.8) 9 (1.0) Tobacco use 0.36 Never smoker 10 (7.9) 50 (5.8) Smoker 116 (92.1) 808 (94.2) *p value based on the difference in the proportional incidence distribution between younger and older patient populations for each parameter. reporting a history of cigarette smoking (Table 1). In the younger group, median cumulative cigarette consumption among smokers was 30 pack-years (range, 3 to 100 pack-years). The occupations of younger patients with lung cancer were diverse, with the largest subgroup consisting of 16 (12.7%) factory workers. Only one younger patient reported a history of asbestos exposure. Occupational and exposure histories were not available on older patients. Pathologic Characteristics Although adenocarcinoma was the most common histologic subtype diagnosed in both age groups, the distribution of histologic subtypes in younger patients differed significantly from that in older patients (p 0.001) (Table 2). The incidence of large cell carcinoma and adenocarcinoma was greater in younger patients, while squamous cell and small cell carcinoma were more frequently diagnosed in older Table 2 Pathologic Characteristics Age at Diagnosis, yr 50 (%) 50 (%) p Value* Histology Adenocarcinoma 61 (48.4) 319 (36.0) Squamous cell 23 (18.3) 273 (30.8) Large cell 30 (23.8) 145 (16.4) Small cell 12 (9.5) 149 (16.8) Stage I II 6 (4.8) 166 (19.7) III 65 (51.6) 289 (34.4) IV 55 (43.6) 386 (45.9) *p value based on the difference in the proportional incidence distribution between younger and older patient populations for each parameter. CHEST / 115 / 5/ MAY,

3 patients. Information on tumor stage was available for 100% of younger and 95% of older patients. Stage distribution was significantly different between the age groups (p 0.001), with only 4.8% of younger patients presenting with stage I or II disease compared with 19.7% of older patients (Table 2). The most common site of metastatic involvement among the 55 younger patients with stage IV disease at presentation was the brain (60%), followed by bone (49%), liver (15%), and adrenal gland (15%). Treatment and Survival Data regarding treatment received were available on all younger patients and 82% of older patients. The use of combined-modality therapy was significantly more common in younger patients (p 0.001), while older patients were more likely to receive single-modality therapy or no specific anticancer treatment (p 0.001) (Table 3). Although older patients underwent more cancer-directed surgery as single-modality therapy, the overall use of cancer-directed surgery was significantly greater in younger patients, usually as part of combined-modality treatment (25.4% vs 15.0%, p 0.001). Similarly, younger patients were more likely than older patients to receive any chemotherapy (61.1% vs 51.0%, p 0.001) or radiotherapy (84.1% vs 41.0%, p 0.001) as part of their overall treatment regimen. Survival data were available for all 126 younger patients and 94% of older patients. Median survival in the younger and older groups was 13 and 9 months, respectively, and the 1-, 2-, and 5-year survival rates were 52.4%, 27.4%, and 11.8% in younger patients and 41.2%, 23.3%, and 10.1% in older patients (Table 4). However, the apparent trend in overall survival in favor of the younger patient group was not statistically significant (p 0.13) (Fig 1). As of last follow-up, 15.9% of younger and 11.0% of older patients were alive with median survivor follow-up times of 48 months (range, 16 to 72 months) and 55 months (range, 3 to 92 months), respectively. Survival was also analyzed Table 4 Survival of Younger and Older Lung Cancer Patients by Stage and Histology Median Survival, mo 5-yr Survival, % p Value* Overall survival yr (n 126) yr (n 836) Stage I II yr (n 6) yr (n 153) Stage III yr (n 65) yr (n 276) Stage IV yr (n 55) yr (n 364) Non-small cell yr (n 114) yr (n 694) Small cell yr (n 12) yr (n 142) *Based on log-rank analysis of survival distribution. by stage of disease in all younger patients and 90% of older patients (Table 4). Although median and 5-year survival appeared greater in younger patients with stage I to II and stage III disease, this difference was significant only for stage III disease due to the small number of younger patients with stage I to II disease. The prognosis of patients with stage IV disease was equally poor in both age groups. Analysis of survival by histologic subtype in all younger patients and 94% of older patients revealed that although the overall survival of patients with nonsmall cell lung cancer appeared to be marginally Table 3 Therapy Age at Diagnosis, % Treatment 50 yr (n 126) 50 yr (n 726) p Value Single modality Surgery* Chemotherapy Radiotherapy Combined modality None *Defined as cancer-directed surgery, excluding diagnostic, staging, and palliative procedures. Figure 1. Overall survival of lung cancer patients whose conditions were diagnosed at 50 years of age (n 126; dotted line) compared with patients whose conditions were diagnosed at 50 years of age (n 836; solid line) Clinical Investigations

4 better than that of patients with small cell lung cancer, patient age did not significantly affect survival within either histologic subtype (Table 4). Discussion In the present study, 12.5% of patients seen at a single, academic cancer center were 50 years of age at diagnosis, a figure that is consistent with the percentage of younger patients in previous reports. 8,12,14 One difficulty in comparing the results of prior studies on young lung cancer patients is the variability of the age cutoff used to define young. For the present study, 50 years of age was selected to ensure adequate numbers of younger patients to allow for meaningful statistical analyses and because the incidence of lung cancer increases rapidly after this point. Most previous studies have reported a higher female to male ratio in younger lung cancer patients, suggesting that women may be more susceptible to lung carcinogens. 6,9,14 In support of this hypothesis, a population-based registry study found that women developed lung cancer at an earlier age while smoking fewer cigarettes. 15 In addition, Zang and Wynder 16 recently reported that women had a 1.5- fold higher relative risk of lung cancer, even when controlling for body size and exposure to cigarette smoke. In the present study, the proportional incidence of female subjects was lower in the younger patient group, with male to female ratios of 1.9:1 and 1.4:1 in the younger and older groups, respectively. This finding contrasts with those of our metropolitan Detroit SEER analysis in which the male to female ratios in younger and older patients were 1.5:1 and 2.2:1, respectively. 12 These differences may be due to the local demographic composition of the population directly served by our center, or it may reflect varying inclinations for specific demographic subpopulations to seek out referrals to university medical centers. Nearly all reports, including the present one, have found tobacco use to be equally high among lung cancer patients of all ages, 3,5,6,8,10,11 and the clear dose-response relationship between cumulative cigarette consumption and lung cancer risk may explain the relatively low incidence in patients 50 years of age. An interaction between cigarette smoking and occupational carcinogen exposure has been postulated to be a potential cause of lung cancer in young adults. 17 In the present study, 12.7% of younger patients were factory workers, but only one reported exposure to a known lung carcinogen. In the past decade, adenocarcinoma has surpassed squamous cell carcinoma as the most common histologic subtype of lung cancer in the United States. Most studies have found adenocarcinoma to be the most common subtype of lung cancer in younger patients, even those reported prior to the recent histologic shift. 3 6,12,14,18,19 This finding, along with the increased relative incidence of adenocarcinoma in nonsmokers, 20,21 suggests that the development of adenocarcinoma may require less cumulative genetic injury than other histologic subtypes. Several previous reports have concluded that younger patients present with more advanced-stage lung cancer than older patients, 3 5,18,22 and it has been suggested that a delay in diagnosis, perhaps due to a lower degree of suspicion in younger patients, could account for this finding. In the present study, 5% of younger patients presented with local-stage disease, and data on 63 younger patients revealed that the median duration of symptoms prior to the diagnosis of lung cancer was 7 months, with 35% of patients reporting symptoms for 1 year. Our recent analysis of the metropolitan Detroit SEER registry identified local-stage disease in 19% and 25% of younger and older patients, respectively. 12 Although the lower incidence of early-stage disease in the present study may reflect differences in stage classification between our databases and the SEER registry, it also may suggest that patients with potentially curable, early-stage disease are less likely to seek care at an academic medical center. Younger patients with lung cancer were more likely than older patients to receive anticancer treatment, including combined-modality therapy. In addition, despite presenting with more advanced-stage disease, younger patients were more likely to undergo cancer-directed surgery. Previous studies from academic centers, 4,6,11,19,23 as well as our review of the SEER registry, 12 have reported similar findings, suggesting that such age-based treatment trends are widespread. Although the present study is limited by the lack of comorbidity data, it is likely that at least some of the age-specific differences in treatment and survival are due to the poorer overall health and performance status of older patients. 24 It is also possible that the trend toward better survival in the younger patient group may have been due to the use of more aggressive treatment, particularly in patients with locally advanced disease. The survival data in the present study are comparable to those reported in our community-based SEER analysis. 12 In that report, overall survival was significantly better in younger patients, with 2- and 5-year survival rates of 26% and 16% in younger patients and 23% and 13% in older patients, respectively. 12 Nearly all of this difference was attributable to patients with early-stage disease. Several previous studies have reported lower survival rates among CHEST / 115 / 5/ MAY,

5 younger patients when compared with older patients with lung cancer, leading to the widely held belief that the disease is more aggressive in young patients. However, the results of our studies and those of a recent analysis of 90,000 lung cancer patients that reported similar overall survival in all age groups 25 should dispel the notion that lung cancer is more aggressive in younger patients. The facts remain that the overall survival of patients with lung cancer is poor regardless of their age, and that treatment needs to be based on sound clinical judgment and realistic expectations. Unfortunately, the recent increase in tobacco use among US teenagers virtually ensures that lung cancer in the young will continue to be a significant medical and societal problem for the foreseeable future. 26 It is important for all primary care providers to consider the possibility of lung cancer in symptomatic smokers, regardless of age, so as to increase the detection rate of earlystage, potentially curable disease. ACKNOWLEDGMENTS: We are grateful to Dr. Mary Varterasian for critical review of the manuscript; to Dave Maier, Don Ragan, and Gordon Brown for database support; and to the Charlotte A. Woody Lung Cancer Research Fund and Drs. Manuel Valdivieso and Zwi Steiger for continued support. References 1 Landis SH, Murray T, Bolden S, et al. Cancer statistics, CA Cancer J Clin 1998; 48: Schottenfeld D. Epidemiology of lung cancer. In: Pass HI, Mitchell JB, Johnson DH, et al, eds. Lung cancer: principles and practice. Philadelphia, PA: Lippincott-Raven, 1996; Neuman HW, Ellis FH, McDonald JR. Bronchogenic carcinoma in persons under 40 years of age. N Engl J Med 1956; 254: Bourke W, Milstein D, Giura R, et al. Lung cancer in young adults. Chest 1992; 102: Antkowiak JG, Regal A, Hiroshi T. Bronchogenic carcinoma in patients under age 40. Ann Thorac Surg 1989; 47: DeCaro L, Benfield JR. Lung cancer in young persons. J Thorac Cardiovasc Surg 1982; 83: Kyriakos M, Webber B. Cancer of the lung in young men. J Thorac Cardiovasc Surg 1974; 67: Roviaro GC, Varoli F, Zannini P, et al. Lung cancer in the young. Chest 1985; 87: Ganz PA, Vernon SE, Preston D, et al. Lung cancer in younger patients. West J Med 1980; 133: Icard P, Regnard JF, denapoli S, et al. Primary lung cancer in young patients: a study of 82 surgically treated patients. Ann Thorac Surg 1992; 54: Capewell S, Wathen CG, Sankaran R, et al. Lung cancer in young patients. Respir Med 1992; 86: Ramalingam S, Pawlish K, Gadgeel S, et al. Lung cancer in young patients: analysis of a SEER database. J Clin Oncol 1998; 16: Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: McDuffie HH, Klaassen DJ, Dosman JA. Characteristics of patients with primary lung cancer diagnosed at age of 50 years or younger. Chest 1989; 96: McDuffie HH, Klaassen DJ, Dosman JA. Female-male differences in patients with primary lung cancer. Cancer 1987; 57: Zang EA, Wynder EL. Differences in lung cancer risk between men and women: examination of the evidence. J Natl Cancer Inst 1996; 88: Ives JC, Buffler PA, Greenberg SD. Environmental associations and histopathologic patterns of carcinoma of the lung: the challenge and dilemma in epidemiologic studies. Am Rev Respir Dis 1983; 128: Anderson AE, Buechner HA, Yager I, et al. Bronchogenic carcinoma in young men. Am J Med 1954; 16: Larrieu AJ, Jamieson WR, Nelems JM, et al. Carcinoma of the lung in patients under 40 years of age. Am J Surg 1985; 149: Lubin JH, Blot WJ. Assessment of lung cancer risk factors by histologic category. J Natl Cancer Inst 1984; 73: Vena JE, Byers TE, Cookfair D, et al. Occupation and lung cancer risk: an analysis by histologic subtypes. Cancer 1985; 56: Green LS, Fortoul TI, Ponciano G, et al. Bronchogenic cancer in patients under 40 years old: the experience of a Latin American country. Chest 1993; 104: McKneally MF. Lung cancer in young patients. Ann Thorac Surg 1983; 36: Smith TJ, Penberthy L, Desch CE, et al. Differences in initial treatment patterns and outcomes of lung cancer in the elderly. Lung Cancer 1995; 13: Fry WA, Menck HR, Winchester DP. The National Cancer Database report on lung cancer. Cancer 1996; 77: Trends in teenage smoking. J Natl Cancer Inst 1997; 89: Clinical Investigations