1. Improving colon cancer prognosis using Index of Metastasis: A SEER analysis George J. Chang, Chung-Yuan Hu, Miguel A. Rodriguez-Bigas, John M. Skibber The University of Texas, M.D. Anderson Cancer Center Houston, Texas Abstract 4019

2. Disclosure Slide

3. Background Colon cancer affects approximately 107,000 new patients each year and is the second leading cause of cancer death among men and women. Survival and staging in localized colon cancer is related to the number of lymph nodes containing metastasis. Related to the total number of lymph nodes evaluated. Fewer than one-half of cases of resected colon cancer have had an adequate LN evaluation based on a benchmark of 12 or more lymph nodes.

4. Limitations of AJCC 6 th Edition American Joint Committee on Cancer (AJCC) TNM staging does not account for the cases with only few lymph nodes. Survival within an AJCC/TNM stage can range widely due to the heterogeneous nature of the sub-stage cohort and variations in surgical and pathologic quality.

5. Objective To evaluate the predictive value of the Index of Metastasis (IM) for survival among Stage III colon cancer patients and to define the boundaries of this relationship.

6. Methods—Data Source and Patient Characteristics Surveillance Epidemiology and End Results (SEER 17) Program of the NCI Patients diagnosed 1988 to 2005, histologically confirmed invasive colon cancer. AJCC 6th edition stage III EXCLUSIONS Age 90 years; >1 primary tumor; missing data regarding lymph nodes.

7. Methods—Statistical Analysis Patients were stratified by the total number of LN (totLN) evaluated and by IM quartile within each T stage category (T1-2, T3, or T4). Stratified Kaplan-Meier analysis was performed to compare cancer specific survival (CSS). Log-rank cut-point analysis was performed to determine degree of sensitivity of AJCC sub-staging and IM staging to the total number of lymph nodes evaluated. Data were analyzed using STATA Intercooled v.10.0 (rel. 2007, College Station, TX).

8. Results CHARACTERISTICN(%) Age (median yrs and IQR)70(59-78) Sex Male Female 21,150(47.1) 23,840(52.9) Tumor Stage IIIA IIIB IIIC 3,873(8.6) 26,158(58.1) 14,959(33.3) Tumor Grade Well Differentiated Mod. Differentiated Poorly Differentiated Undifferentiated Unknown 2,330(5.2) 28,554(63.5) 12,076(26.8) 519(1.1) 1,511(3.4) CHARACTERISTICN(%) Tumor Grade Low High Unknown 30,884(68.7) 12,595(28.0) 1,511(3.3) Ethnicity White (incl. Hispanic) Black Asian (incl. Pac Island) Unknown or others 36,217(80.5) 4,698(10.5) 3,968(8.8) 107(0.2) Median positive LN (IQR)2(1-4) Median total LN (IQR)12(8-18) Median Index of Metastasis (IQR).22(.11-.45) Total N= 44,990

9. Distribution of cases by TN stage and IM quartile T1-2 (N=4,513) IMT3 (N=31,575) IMT4 (N=8,877) IM IM Q11,1348,4422268 IM Q21,1350.0917,6990.11122510.133 IM Q31,2210.1677,6540.22221460.286 IM Q41,0230.3337,7800.42922120.563 N13,87321,0595099 N264010,5163778 IM Quartile distribution specific to each T stage group

10. Survival by AJCC Stage varies widely within each stage group and is affected by the total number LN examined GROUP 5-yr Cancer-Related Survival (%) Stratified by totLN quartile and N stage T1-2 (N=4,513)T3 (31,575)T4 (N=8,877) <7All * >15<9All>18<9All>18 N182.985.089.361.468.376.741.750.260.7 N282.171.969.641.647.552.024.529.035.2 Median Total LN examined and IQR = 9 (6, 15) for T1-2, 12 (8, 18) for T3, and 12(8, 18) for T4 tumors. * Total LN examined quartile 1 (0-25 th percentile) specific to each T stage group (1-2, 3, or 4). † Entire cohort of patient within T stage group. ‡ Total LN examined quartile 4 (75 th -100 th percentile) specific to each T stage group (1-2, 3, or 4).

11. Cancer-specific survival by total number LN examined quartile 73.3 56.1 48.7 39.0

12. T-stage stratified IM accurately predicts survival GROUP 5-yr Cancer-Related Survival (%) Stratified by Total Number LN Evaluated (totLN) and IM quartile T1-2 (N=4,513)T3 (31,575)T4 (N=8,877) totLN <7 * All † totLN >15‡ totLN <9 All totLN >18 totLN <9 All totLN >18 IM Q1--87.790.0--76.077.458.060.062.0 IM Q284.785.182.069.068.567.044.346.446.1 IM Q384.583.882.261.858.254.441.836.633.0 IM Q480.977.559.646.642.629.926.121.713.2 Median Total LN examined and IQR = 9 (6, 15) for T1-2, 12 (8, 18) for T3, and 12(8, 18) for T4 tumors * Total LN examined quartile 1 (0-25 th percentile) specific to each T stage group (1-2, 3, or 4). † Entire cohort of patient within T stage group. ‡ Total LN examined quartile 4 (75 th -100 th percentile) specific to each T stage group (1-2, 3, or 4).

13. CSS among T3 patients by IM quartile 5 yr AJCC6 IIIB AJCC6 IIIC 25% of patients N156% of patients N1

14. Cut point analysis shows AJCC stage is highly sensitive to totLN IIIB IIIC IM Q4 for T3

15. Summary of results 5-year CSS for each AJCC stage group was dependent upon the total number of LN examined. Range of 5-year CSS within a single TN stage group varies based on the total number of LN examined. AJCC staging incorrectly predicts prognosis when few LN are evaluated

16. Summary of results Cut point analysis demonstrated survival prognosis by AJCC stage is very sensitive to the total number of LN examined. IM reliably predicts CSS and is not sensitive to the total number of LN examined.

17. Conclusions AJCC 6 th ed. staging poorly predicts prognosis in an individual patient due in part to variability in the total number of LN examined at resection. When stratified by T stage, index of metastasis more accurately predicts survival and except at the highest IM levels, is not influenced by the number of LN examined.