1. The impact of smoking on cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803 Nadine A. Jackson, Charles S. Fuchs, Donna Niedzwiecki, Donna Hollis, Leonard B. Saltz, Robert J. Mayer, Jeffrey A. Meyerhardt Dana-Farber Cancer Institute, Boston, MA; CALGB Statistical Center, Durham, NC; Memorial Sloan-Kettering Cancer Center, New York, NY REVISED ABSTRACT Background: Although tobacco use is linked to the development of colon cancer, little is known about its impact in colon cancer survivors. Methods: We prospectively collected data on prior and current cigarette smoking on 965 patients with stage III colon cancer enrolled in a phase III adjuvant chemotherapy trial (bolus 5-FU/leucovorin +/- irinotecan). Patients (pts) reported tobacco use in self- report questionnaires during (Q1) & 6 months after completion of adjuvant therapy (Q2). Smoking status was defined as never, current, or past. Lifetime pack years (pyr) were defined as # of packs of cigarettes over pt’s lifetime. Since there was no difference in efficacy between the two treatments, data for all patients were combined. Cox proportional hazards were computed for disease-free survival (DFS, our primary endpoint) and overall survival (OS). DFS and OS were measured from completion of Q1 to event of interest, excluding events within the 1st 90 days to avoid biases of change in behavior due to impending event. Results: Data on smoking history were captured on 1084 patients of 1,264 in the phase III trial (479 [44%] past smokers; 108 [10%] current smokers; 497 [46%] never smokers). In analyses adjusted for age, gender, BMI at diagnosis, N and T stage, grade of differentiation, and presence of bowel obstruction at dx, past smokers had hazard ratio (HR) for DFS of 1.19 (95% CI, 0.84-1.69; p=0.4) and current smokers had HR for DFS of 1.11 (95% CI, 0.88-1.39; p=0.4), compared to never smokers. Consistent with prior analyses, we defined pyr categories as 0, 0-10, 10-20, 20 or more. In unadjusted analyses, HR for DFS were 1.06 (95% CI, 0.75-1.50), 1.26 (95% CI, 0.96-1.66) and 1.34 (95% CI, 1.02-1.75) for lifetime pyr 0-10, 10- 20 and 20+, respectively, compared to never smoking (p trend 0.03). In adjusted analyses, HR for 20+ pyr was 1.22 (95% CI, 0.92-1.61) compared to never smoking (p trend 0.16). HRs for OS were similar as DFS for smoking status and lifetime pyr. Conclusion: Lifetime total of tobacco usage may influence outcomes in patients with stage III colon cancer. Further research with larger datasets is warranted. CONCLUSIONS In a cohort of patients with stage III colon cancer treated with surgery and adjuvant chemotherapy surviving without cancer recurrence or death 3 months after the completion of a self- report questionnaire, higher levels of pack-yrs smoked prior to age 30 was associated with increased risk of colon cancer recurrence or death. Compared to nonsmokers, higher levels of smoking intensity (pack-yrs) was associated with a non-statistically significant trend in dose-response to the risk of colon cancer recurrence or death. These data suggest that a prolonged induction period may be associated with an increased risk of colon cancer recurrence and death. Further prospective analyses are warranted to further substantiate the impact of smoking in colon cancer recurrence. CALGB 89803 was supported, in part, by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (Richard L. Schilsky, M.D., Chairman) and to the CALGB Statistical Center (Stephen George, PhD, CA33601) as well as support from Pharmacia & Upjohn Company, now Pfizer Oncology. Epidemiologic and scientific research indicates that duration and intensity of tobacco use has a significant influence on the risk of developing adenomas and colon cancer. Earlier studies noted an association of longer induction period of tobacco use (prior to age 30) and incidence of premalignant colorectal adenomas. The influence of smoking on colon cancer recurrences is unknown. RESULTS BACKGROUND METHODS Table 2: Survival Probability by Smoking Status CALGB 89803 is a multicenter, randomized phase III adjuvant therapy trial randomizing 1,264 pts with resected stage III adenocarcinoma of the colon to bolus 5-FU/leucovorin +/- irinotecan. A detailed description of the statistical plan for the initial study has been published (Saltz JCO 2007 3456). Since there was no difference in efficacy between the two treatments in the initial trial, data for all patients were combined. Information on tobacco use was obtained by self-report on questionnaires administered during (Q1) and 6 months following (Q2) therapy. Tobacco use was defined by smoking status, intensity and duration. Smoking status was defined as never, current, or past at time of Q1. Smoking intensity was defined as lifetime pack years by calculating the number of packs of cigarettes over the patient’s lifetime until Q1. Smoking intensity was further stratified by pack years smoked before and after age 30. For this companion study, disease-free survival (DFS) was the primary endpoint. Overall survival (OS) and recurrence-free survival (RFS) were secondary endpoints. Q1 = questionnaire 1 (midway through adjuvant therapy) Q2 = questionnaire 2 (6 months after completion of adjuvant therapy) Tables 3 : Survival Probability by Smoking Intensity SMOKING ANALYSIS COHORT Table 1: Baseline Characteristics by Smoking Status Tables 4 : Survival Probability by Smoking Intensity before Age 30 Abbreviations: FU, fluorouracil; LV, leucovorin; CPT-11, irinotecan; CEA, carcinoembryonic antigen; ECOG PS, Eastern Cooperative Oncology Group performance status; BMI, body mass index  p <.05; *  2 test; †Wilcoxon score ‡Missing information on smoking status = 180 Missing information on smoking intensity = 210 Smoking StatusNeverCurrentPast Disease-free survival Number of cases / at risk149/49741/108163/479 HR (95% CI), unadjusted1.001.30 (0.93-1.84)1.19 (0.96-1.49) HR (95% CI), adjusted†1.001.11 (0.88-1.39)1.19 (0.84-1.69) Overall survival Number of cases / at risk98/49735/108112/479 HR (95% CI), unadjusted1.001.20 (0.93-1.56)1.65 (1.12-2.42) HR (95% CI), adjusted†1.001.48 (1.00-2.20)1.09 (0.83-1.43) Recurrence-free survival Number of cases / at risk142/49734/108151/479 HR (95% CI), unadjusted1.001.11 (0.76-1.61)1.15 (0.92-1.44) HR (95% CI), adjusted†1.001.02 (0.69-1.50)1.10 (0.86-1.39) HR = hazard ratio; CI = confidence interval † Adjusted for age, gender, number of. positive lymph nodes, extent of invasion through bowel wall, tumor differentiation, body mass index, presentation with bowel obstruction at diagnosis Overall Smoking Intensity0 pack-yr0-10 pack-yr10-20 pack-yr20+ pack-yrP trend Disease-free survival Number of cases / at risk130/46734/12371/21058/203 HR (95% CI), unadjusted1.001.06 (0.75-1.50)1.26 (0.96-1.66)1.34 (1.02-1.75)0.03 HR (95% CI), adjusted†1.000.99 (0.70-1.41)1.17 (0.89-1.55)1.22 (0.92-1.61)0.16 Overall survival Number of cases / at risk98/46728/12353/21058/203 HR (95% CI), unadjusted1.001.08 (0.72-1.65)1.29 (0.93-1.78)1.44 (1.05-1.97)0.03 HR (95% CI), adjusted†1.001.02 (0.67-1.55)1.19 (0.86-1.65)1.23 (0.88-1.71)0.22 Recurrence-free survival Number of cases / at risk142/46735/12373/21070/203 HR (95% CI), unadjusted1.001.03 (0.72-1.48)1.22 (0.92-1.62)1.19 (0.89-1.58)0.23 HR (95% CI), adjusted†1.000.98 (0.68-1.41)1.15 (0.86-1.53)1.12 (0.83-1.52)0.41 Quartiles computed via SAS v.9 † Adjusted for age, gender, number of. positive lymph nodes, extent of invasion through bowel wall, tumor differentiation, body mass index, presentation with bowel obstruction at diagnosis 0 pack-yr0-4 pack-yr4-12 pack-yr12+ pack-yrP trend Disease-free survival Number of cases / at risk143/54150/17652/18049/162 HR (95% CI), unadjusted1.001.10 (0.82-1.48)1.17 (0.87-1.57)1.49 (1.13-1.97) 0.005 HR (95% CI), adjusted†1.001.06 (0.79-1.43)1.12 (0.81-1.54)1.40 (1.00-1.97)0.05 HR (95% CI), adjusted‡1.001.06 (0.78-1.43)1.10 (0.81-1.49)1.37 (1.02-1.84)0.04 Overall survival Number of cases / at risk110/54138/17644/18045/162 HR (95% CI), unadjusted1.001.07 (0.75-1.52)1.24 (0.88-1.75)1.40 (1.00-1.96) 0.04 HR (95% CI), adjusted†1.001.02 (0.71-1.46)1.09 (0.75-1.59)1.20 (0.80-1.81)0.37 HR (95% CI), adjusted‡1.001.03 (0.72-1.47)1.13 (0.80-1.60)1.27 (0.89-1.80)0.17 Recurrence-free survival Number of cases / at risk154/54152/17655/18060/162 HR (95% CI), unadjusted1.001.07 (0.78-1.45)1.16 (0.85-1.57)1.32 (0.98-1.78) 0.06 HR (95% CI), adjusted†1.001.05 (0.77-1.43)1.17 (0.84-1.63)1.38 (0.96-1.98)0.08 HR (95% CI), adjusted‡1.001.04 (0.76-1.42)1.12 (0.82-1.52)1.29 (0.94-1.76)0.11 Quartiles computed via SAS v.9 † Adjusted for age, gender, number of. positive lymph nodes, extent of invasion through bowel wall, tumor differentiation, body mass index, presentation with bowel obstruction at diagnosis ‡ Adjusted as above as well as smoking intensity after age 30 (in analyses of pre-age 30) or before age 30 (in analyses of post-age 30)