1. Impact of age and comorbidities on treatment effect, tolerance and toxicity in metastatic colorectal cancer (mCRC) patients (pts) treated on CALGB 80203 JA Meyerhardt 1, N Jackson McCleary 1, D Niedzwiecki 2, D Hollis 2, A Venook 3, RJ Mayer 1, R Goldberg 4 1. Dana-Farber Cancer Institute, Boston, MA; 2. CALGB Statistical Center, Durham, NC; 3. University of California San Francisco Medical Center, San Francisco, CA; 4. University of North Carolina, Chapel Hill, NC REVISED ABSTRACT Background: Little is known regarding the interaction of comorbid conditions (CC) & age when treating pts for mCRC. We sought to determine the impact of CC and age (<70 & ≥70 yrs) on survival & toxicity in these pts. Methods: We utilized a cohort of 238 pts with mCRC enrolled in CALGB 80203, a curtailed, multicenter 2x2 phase III trial of fluorouracil/leucovorin + oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) ± cetuximab. Endpoints were overall survival (OS; time to death), progression-free survival (PFS; time to recurrence or death), and grade 3/4 toxicity. 219 pts (92%) completed a self-administered questionnaire on diet and lifestyle that included a modified Charlson’s comorbidity survey. Those who completed the questionnaire were included in the comorbidity analyses; the entire cohort was included in the age analyses. Cox models were adjusted for treatment arm, gender, & prior rx. Results: In CALGB 80203, 77% were 70. Thirty-eight percent of pts had at least one CC (36% < 70 yrs; 46% ≥ 70 yrs). At least one grade 3/4 toxicity was experienced by 87% of pts ≥70 v 66% <70 (p=0.002), primarily hematologic (56% v 31%, p=0.003). Amongst 238 pts, 94% and 84% experienced a PFS event & OS event, respectively. No pts are censored prior to 3 yrs. Median follow-up was 23 mos. The adjusted hazard ratio (HR) for ≥70 v <70 of PFS was 1.0 (0.7-1.4) and of OS was 1.1 (0.8- 1.6). Similarly, there were no significant differences in HR for PFS and OS by number of CC. Table 2 demonstrates no evidence of interaction between CC and age. Conclusions: While the early closure of CALGB 80203 presents sample size limitations for subset analyses, we did not observe an impact on PFS or OS by age &/or CC. Older pts did experience more toxicity from therapy. Further studies with larger datasets are warranted. CONCLUSIONS In a cohort of patients with mCRC self-reporting comorbid conditions, we did not observe an impact of age or number of comorbid conditions on progression-free or overall survival. Possible limitations of this study include accuracy of self- reported comorbidity data and early closure of the parent study limiting sample size. Further prospective studies investigating the impact of the number, type and severity of comorbid conditions by age with larger datasets are warranted. CALGB 80203 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 Bristol-Meyers Squibb. This companion study was partially funded by an unrestricted grant to the CALGB Foundation from Sanofi-Aventis. Dr. Jackson McCleary was supported by an ASCO/Hartford Foundation Young Investigators Award 2008-09. Gastrointestinal cancers are primarily diseases of persons in their sixth, seventh, and eighth decade of life with incidence and mortality increasing with advancing age. Although the 5-year relative survival (66%) with this cancer is identical for persons under the age of 65 and for persons 65 to 74 years, it declines to 60% for individuals 75 years or older. There is a paucity of information concerning the factors that modify treatment effect, tolerance and toxicity of elderly patients with gastrointestinal malignancies. Comorbid conditions are thought to modify treatment response, tolerance and toxicity, distinct from performance status and has a negative impact of comorbidity on cancer survival independent of functional status. Little has been shown depicting normative data for comorbid conditions in older individuals receiving treatment in the adjuvant or metastatic setting for colorectal cancer, particularly in a non-research, standard treatment setting versus a clinical trial. RESULTS BACKGROUND METHODS The Cancer and Leukemia Group B (CALGB) clinical trial 80203 is a multicenter, 2 x 2 randomized clinical trial evaluating the treatment efficacy of irinotecan, 5-florouracil/leucovorin (FOLFIRI) versus oxaliplatin, 5-florouracil/leucovorin (FOLFOX) with and without cetuximab in individuals with untreated metastatic colorectal cancer. The study opened in December 2003 and closed in January 2005. Of the 238 patients accrued, 54 (23%) are 70 years and older. This trial was later modified to CALGB 80405 to include randomization to bevacizumab. CALGB 80203 included a self-completed questionnaire that featured a modified Charlson’s survey; thus, it uniquely addresses the question of comorbidity in the context of a biologic agent, cetuximab, in combination with chemotherapy. Available data include patient demographics, ECOG performance status, disease stage, treatment arm, treatment response, comorbid conditions, and treatment-related toxicity. Endpoints were overall survival (OS; time to death), progression-free survival (PFS; time to recurrence or death), and grade 3/4 toxicity. Cox models were adjusted for treatment (rx) arm, gender, & prior rx. Table 1: Baseline characteristics by age Table 4- Grade 3 or higher toxicity by age and number of comorbid conditionsTable 2 - Survival (unadjusted and adjusted) by # comorbid conditions and age *Adjusted for treatment arm, gender, prior adjuvant therapy Table 3 – Kaplan Meier survival estimates for comorbidity and age The objective of this study is to elucidate treatment outcomes in regards to treatment response, survival, tolerance and toxicity in older colorectal cancer patients as modified by the presence of comorbid conditions. OBJE CTIVES  Comparing those with <2 comorbid conditions to those with 2 or more within age groups *Comparing those with grade 3 or higher toxicity to those without across age groups £P-value not applicable †P-value calculated by Chi-square test or Fisher exact test given small n within each cell, whichever is appropriate *Missing N=19 – analysis of comorbidity (age <70: 171 (78%), 70+: 48 (22%) limited to those who completed the questionnaire.