Meta-analysis of three trials investigating 5-FU and irinotecan. Folprecht, Rougier, Saltz, van Cutsem, Douillard, Sastre, Mitry, Hecker, Schubert, Köhne: Irinotecan in first line therapy of elderly and non-elderly patients... Irinotecan in first line therapy of elderly and non-elderly patients with metastatic colorectal cancer: Meta-analysis of three trials investigating 5-FU and irinotecan. Gunnar Folprecht1, Philippe Rougier2, Leonard Saltz3, Eric van Cutsem4, Jean-Yves Douillard5, Javier Sastre6, Emmanuel Mitry2, Hartmut Hecker7, Ute Schubert8, Claus-Henning Köhne8 1University hospital Dresden, Germany; 2Hopital Ambroise Paré, Boulogne, France; 3Memorial Sloan Kettering Cancer Center, New York; 4University Hospital Gasthuisberg, Leuven, Belgium; 5Centre R Gauducheau, St. Herblain, France; 6Hospital Clinico San Carlos, Madrid, Spain; 7Medical School Hannover, Germany; 8Klinikum Oldenburg, Germany ASCO 2006, abstract 3578

5-FU/FA ± irinotecan in elderly patients < 70 years ≥ 70 years 1259 pts from 3 randomized trials Progression free survival 5-FU 5-FU + Irinotecan HR 0.72 (0.62-0.82) p<0.0001 Overall survival 5-FU 5-FU + Irinotecan HR 0.82 (0.72-0.94) p=0.004

Elderly vs. younger pts. with 5-FU/irinotecan 1259 pts from 3 randomized trials Progression free survival < 70 y. ≥ 70 y. HR 1.11 (0.93-1.32) p=0.24 Overall survival < 70 y. ≥ 70 y. HR 0.99 (0.83-1.17) p=0.87

Administration of 5-FU/ irinotecan in elderly patients < 70 years ≥ 70 years Overall survival 1259 pts from 3 randomized trials 5-FU Bolus + Irinotecan 5-FU Infus. Folprecht et al, ASCO 2006

Background Irinotecan has been shown to improve response rates and progression free survival in three randomized studies. Data regarding efficacy and toxicity with irinotecan in elderly patients are lacking. With 5-FU- therapy, pooled analyses describe a similar treatment benefit in elderly as in younger patients in palliative (Folprecht. Ann Oncol 2004) and in adjuvant treatment (Sargent. NEJM 2001). Although no increased toxicity was described in a analysis from the Royal Marsden hospital with palliative treatment of elderly patients, slightly higher rates of stomatitis (Popescu. JCO 1999) or leucocytopenia (Sargent. NEJM 2001) are reported in adjuvant 5-FU containing therapy. Folprecht et al, ASCO 2006

Methods We performed a metaanalysis using source data of three randomized trials investigating 5-FU/FA/irinotecan vs. 5-FU/FA (Saltz 2000, Douillard 2000, Köhne 2005 [EORTC 40986]) to explore the efficacy and toxicity in elderly (≥70 years) and non-elderly (< 70 years) patients. The data from the 5-FU/FA and Irinotecan/5-FU/FA arms were included, only. All patients who did not receive therapy were excluded. Differences in proportional values were investigated using the chi square test or Fisher’s exact test, where appropriated. For progression free survival or overall survival, Kaplan-Meier plots and log rank tests were used. A multivariate analysis including treatment (5-FU/FA vs. 5-FU/FA/irinotecan) and age (< 70 y. vs. ≥ 70y.) was performed. Folprecht et al, ASCO 2006

Patients’ characteristics (I) Patients: age groups   Study group treatment <70 years ≥70 years 70...74 y. 75...79 y. ≥80 y. Saltz et al * IFL 170 55 35 15 5 NEJM 2000 Mayo 49 29 16 4 Douillard et al Iri/AIO 40 14 12 2 Lancet 2000 AIO 8 7 1 FOLFIRI 124 21 LV5FU2 121 22 19 3 EORTC (Köhne et al) 173 41 JCO 2005 177 39 9 Pts. with 5-FU/Irinotecan 507 131 97 Pts. with 5-FU monotherapy 503 118 84 total 1010 249 181 58 10 * pts receiving irinotecan monotherapy or no treatment were excluded Folprecht et al, ASCO 2006

Patients’ characteristics (II) <70 years ≥70 years p   5-FU/Irinotecan 5-FU mono N=507 N=503 N=131 N=118 Gender male 328 (64,7%) 277 (55,1%) 87 (66,4%) 75 (63,6%) 0,007 female 179 (35,3%) 226 (44,9%) 44 (33,6%) 43 (36,4%) PS 245 (48,3%) 259 (51,5%) 65 (49,6%) 50 (42,4%) 0,30 1 222 (43,8%) 201 (40,0%) (38,2%) 59 (50,0%) 2 40 (7,9%) (8,5%) 16 (12,2%) 9 (7,6%) No tumor sites 280 (55,2%) 273 (54,3%) 79 (60,3%) 76 (64,4%) 0,17 >1 225 (44,4%) 230 (45,7%) 52 (39,7%) 42 (35,6%) unknown (0,4%) (0,0%) adjuvant yes 102 (20,1%) 90 (17,9%) 27 (20,6%) 23 (19,5%) 0,84 treatment no 286 (56,4%) 293 (58,3%) 72 (61,0%) 119 (23,5%) 120 (23,9%) 25 (19,1%) primary tumor site rectum 183 (36,1%) 178 (35,4%) (30,5%) 32 (27,1%) 0,19 colon 321 (63,3%) 325 (64,6%) 91 (69,5%) 85 (72,0%) unknown or both 3 (0,6%) (0,8%) Folprecht et al, ASCO 2006

Results: Toxicity (I) <70 years ≥70 years 5-FU/Irinotecan 5-FU mono   <70 years ≥70 years 5-FU/Irinotecan 5-FU mono Comp. ≥70 y. vs. < 70 y. Leucopenia Grade ≥3 100 (22,6%) 49 (11,5%) 35 (29,2%) 13 (12,9%) all patients p=0.12 Grade <3 342 (77,4%) 377 (88,5%) 85 (70,8%) 88 (87,1%) p=0.14 p<0.001 p=0.003 p=0.70 Neutro- 161 (35,0%) 125 (27,2%) 48 (39,3%) 41 (37,3%) p=0.03 penia 299 (65,0%) 335 (72,8%) 74 (60,7%) 69 (62,7%) p=0.37 p=0.01 p=0.81 Thrombo- 5 (1,4%) 2 (2,4%) 1 (1,3%) p=0.72 343 (98,6%) 81 (97,6%) 75 (98,7%) p=0.62 p=1.00 Infection (1,2%) (1,1%) (2,8%) p=0.60 171 (98,8%) 175 (98,9%) 40 (97,2%) Stomatitis 6 (3,1%) (5,7%) 4 (8,7%) (8,3%) p=0.10 185 (96,9%) 217 (94,3%) 42 (91,3%) 55 (91,7%) p=0.11 p=0.25 p=0.55 For each age group and treatment group, significance was calculated with the Chi-square test or Fisher's exact test Folprecht et al, ASCO 2006

Results: toxicity (II) Folprecht, Rougier, Saltz, van Cutsem, Douillard, Sastre, Mitry, Hecker, Schubert, Köhne: Irinotecan in first line therapy of elderly and non-elderly patients... Results: toxicity (II)   <70 years ≥70 years 5-FU/Irinotecan 5-FU mono Comp. ≥70 y. vs. < 70 y. Diarrhea Grade ≥3 91 (27,8%) 59 (19,8%) 31 (34,1%) 18 (22,8%) all patients p=0.20 Grade <3 236 (72,2%) 239 (80,2%) 60 (65,9%) 61 (77,2%) p=0.25 p=0.02 p=0.11 p=0.56 Nausea 37 (12,1%) 26 (8,9%) 15 (17,4%) 6 (8,2%) p=0.34 269 (87,9%) 265 (91,1%) 71 (82,6%) 67 (91,8%) p=0.21 p=0.09 p=0.85 Vomiting 27 (9,8%) (6,9%) 10 (13,5%) 2 (3,5%) p=0.78 249 (90,2%) 242 (93,1%) 64 (86,5%) 55 (96,5%) p=0.39 p=0.23 p=0.05 p=0.40 Hand-foot- (1,2%) 3 (1,7%) (0,0%) 1 (2,6%) p=1.00 syndrome 171 (98,8%) 174 (98,3%) 41 (100,0%) 38 (97,4%) p=0.48 Cerebro- 4 (2,3%) 5 (2,8%) (7,7%) p=0.72 vascular 169 (97,7%) 172 (97,2%) 36 (92,3%) p=0.59 p=0.75 p=0.37 Thrombosis 9 (4,9%) 8 (4,2%) (4,3%) (4,5%) 176 (95,1%) 182 (95,8%) 44 (95,7%) 42 (95,5%) p=0.80 For each age group and treatment group, significance was calculated with the Chi-square test or Fisher's exact test. Folprecht et al, ASCO 2006, abstract 3578 Folprecht et al, ASCO 2006 ASCO 2006, abstract 3578

Efficacy <70 years ≥70 years 5-FU/Irinotecan 5-FU mono   <70 years ≥70 years 5-FU/Irinotecan 5-FU mono Comp. ≥70 y. vs. < 70 y. Response N=507 N=503 N=131 N=117 CR 16 (3,2%) 10 (2,0%) 4 (3,1%) 2 (1,7%) PR 199 (39,3%) 109 (21,7%) 57 (43,5%) 35 (29,9%) OR 215 (42,4%) 119 (23,7%) 61 (46,6%) 37 (31,6%) p=0.39 95% CI (38,2-46,7%) (20,2-27,6%) (38,2-55,1%) (23,9-40,5%) p=0.07 SD 153 (30,2%) 225 (44,7%) 34 (26,0%) 59 (50,4%) PD/other 139 (27,4%) 159 36 (27,5%) 21 (17,9%) Comp. OR p<0.0001 p=0.016 Time to progression N=373 N=365 N=107 N=91 median 7,53 4,83 8,05 6,31 p=0.58 (6.84-8.22) (4.12-5.55) (7.04-9.07) (5.04-7.59) p=0.18 p=0.063 Overall survival N=497 N=499 N=130 N=115 17,33 14,4 18,02 15,45 p=0.59 (15.71-18.94) (12.70-16.10) (14.51-21.52) (12.79-18.11) p=0.78 p=0.0042 p=0.45 Folprecht et al, ASCO 2006

Progression free survival 5-FU/FA 5-FU/FA 5-FU/FA 5-FU/FA + Irinotecan 5-FU/FA + Irinotecan 5-FU/FA + Irinotecan < 70 y. ≥ 70 y. HR 1.11 (0.93-1.32) p=0.24 < 70 years < 70 years < 70 years ≥ 70 years ≥ 70 years ≥ 70 years 5-FU 5-FU + Irinotecan HR 0.72 (0.62-0.82) p<0.0001

Overall survival 5-FU/FA 5-FU/FA + Irinotecan < 70 y. ≥ 70 y. HR 0.99 (0.83-1.17) p=0.87 < 70 years ≥ 70 years 5-FU 5-FU + Irinotecan HR 0.82 (0.72-0.94) p=0.004

Conclusions Elderly patients have similar response rates, progression free and overall survival with irinotecan/5-FU/FA as younger patients do. No significant differences were found between the efficacy in younger and elderly patients The response rates are significantly improved with irinotecan in elderly patients. Although progression free and overall survival significantly differ in younger patients between the irinotecan- and non-irinotecan arms, no formal significant differences were observed in elderly patients. At least with progression free survival, this is probably due to the lower number of events. A trend to an unfavourable overall survival during the first treatment weeks was observed with elderly versus younger patients in the irinotecan- arm. Regarding the subgroups, this trend could only be observed in the bolus 5-FU groups, but not with infusional 5-FU (Fig 3). This trend might be explained by the early mortality with the IFL- regimen (Rothenberg. JCO 2001). However, comparing toxicity in elderly and non-elderly patients, there was found a slightly higher rate of neutropenia in elderly patients, only - receiving 5-FU/FA but not receiving irinotecan/5-FU/FA. All other toxicities did not differ significantly. Folprecht et al, ASCO 2006, abstract 3578