MJ O’Connell for the ACCENT Collaborative Group Survival Following Recurrence in Patients with Adjuvant Colon Cancer: Findings from the ACCENT Dataset MJ O’Connell for the ACCENT Collaborative Group

Goal of This Study Utilize the collaborative ACCENT database to examine four possible prognostic factors in patients with tumor recurrence following treatment for stage II or III colon cancer

Trials Included Total: 17 trials; 17,381 pts 3517 QUASAR 867 GIVIO 905 GERCOR 718 NSABP C02 3547 INT 0089 773 NSABP C01 1078 SWOG 9415 259 FFCD 878 N914653 359 NCIC 915 N894651 239 Siena 2176 NSABP C05 408 N874651 2151 NSABP C04 926 INT 0035 1081 NSABP C03 247 N784852 N Trial Active Control No Treatment Control Total: 17 trials; 17,381 pts

Prognostic Factors Examined Time from randomization on surgical adjuvant protocol to tumor recurrence (<1, 1-2, 2-3, 3-4, >4 years) Initial stage of colon cancer (II, III) 5FU-based adjuvant therapy vs surgery alone Era patient entered onto surgical adjuvant protocol (1978-1985, 1986-1992, 1993-1999)

Methods Analyses were restricted to only those patients who recurred after initial therapy Univariate analyses performed using Kaplan-Meier methods and log-rank testing Cox proportional hazards models, stratified by study, used for multivariate analyses Interaction tests between each factor and the baseline variables of age, gender, tumor site, and initial stage performed using a likelihood ratio test Analysis of prognostic value of initial treatment was limited to patients randomized to 5FU-based treatment versus surgery alone

Results Median follow-up of patients still alive: 8 years from randomization, 30.5 months from tumor recurrence 5,722 of 17,381 patients (32.9%) experienced tumor recurrence Overall median survival following recurrence was 13.1 months No data regarding tumor characteristics or treatment at time of recurrence is available

Selected Patient Characteristics Percent Stage II 20% III 80% Treatment Surgery alone 16% Surgery plus chemotherapy 84%

Time from Recurrence to Death by Year of Recurrence 100 Year 0- 1 (N=1846) Year 1-2 (N=1854) Year 2-3 (N=924) Year 3-4 (N=516) Year 4+ (N=582) Total (N=5722) 80 60 % Alive 40 Log Rank P-Value = <0.0001 20 1 2 3 4 5 6 7 8 Time (Years)

Time from Recurrence to Death by Year of Recurrence for Stage II Patients 100 Year 0-1 (N=311) Year 1-2 (N=351) Year 2-3 (N=198) Year 3-4 (N=118) Year 4+ (N=175) Total (N=1153) 80 60 % Alive 40 Log Rank P-Value = 0.1368 20 1 2 3 4 5 6 7 8 Time (Year)

Time from Recurrence to Death by Year of Recurrence for Stage III Patients 100 Year 0-1 (N=1533) Year 1-2 (N=1499) Year 2-3 (N=724) Year 3-4 (N=394) Year 4+ (N=400) Total (N=4550) 80 60 % Alive 40 Log Rank P-Value = <0.0001 20 1 2 3 4 5 6 7 8 Time (Year)

Time from Recurrence to Death by Stage 100 Stage II (N=1153) Stage III (N=4550) Total (N=5703) 80 60 % Alive Log Rank P-Value = <0.0001 40 20 1 2 3 4 5 6 7 8 Time (Years)

Time from Recurrence to Death by Era 100 1978-1985 (N=628) 1986-1992 (N=3904) 80 1993-1999 (N=1190) Total (N=5722) 60 % Alive 40 Log Rank P-Value = <0.0001 20 1 2 3 4 5 6 7 8 Time (Years)

Time from Recurrence to Death by Adjuvant Treatment vs. Surgery Alone 100 Surgery Alone (N=916) Adjuvant Treatment (N=754) Total (N=1670) 80 60 % Alive 40 Log Rank P-Value = 0.0005 20 1 2 3 4 5 6 7 8 Time (Years)

Forest Plot of Multivariate Model Hazard Ratios CM923700-14

Forest Plot of Multivariate Model Hazard Ratios by Stage Time to Recurrence Era Initial Trt Time to Recurrence Era Initial Trt Hazard Ratio CM923700-15

Conclusions Time from initial surgery and stage of the primary colon cancer were important prognostic variables in patients with recurrent colon cancer Patients who have recurrent tumor following 5FU-based adjuvant therapy had worse prognosis than those without adjuvant chemotherapy Survival following recurrence improved from 1978-1999

Clinical Research Implications These prognostic factors should be taken into consideration in the design and analysis of treatment protocols for recurrent colon cancer Differences in clinical behavior of stage II and stage III colon cancer were identified The importance of contemporary (rather than historical) controls to evaluate treatment benefit was confirmed The recent availability of new effective agents to treat metastatic colon cancer is likely to prolong survival duration following recurrence

ACCENT: Future plans Update ACCENT based on newer trials Oxaliplatin: MOSAIC, C-07 Irinotecan: PETACC-3; C89803 Capecitabine: X-ACT Validate existing model; extend based on new data Develop interactive calculator to define optimal clinical trial endpoint, based on user defined inputs (e.g. mechanism of action, stage mix, post-recurrence survival) DFS vs OS; best time point

ACCENT Collaborative Group G Yothers, M O’Connell, N Wolmark, S Wieand– NSABP J Benedetti, C Blanke – SWOG R Labianca – Ospedali Riuniti (Italy) D Haller, P Catalano, A Benson – ECOG C O’Callaghan – NCIC JF Seitz – University of the Mediterranean (France) G Francini – University of Siena (Italy) A de Gramont, T Andre – GERCOR R Goldberg – CALGB M Buyse – IDDI (Belgium) R Gray, D Kerr – Oxford D Sargent, A Grothey, E Green, S Alberts - NCCTG