1. Phase III trial of chemotherapy with or without irinotecan in the front-line treatment of metastatic colorectal cancer in elderly patients. FFCD 2001-02 trial. Results of a planned interim analysis. E Mitry, JM Phelip, F Bonnetain, S Lavau Denes, X Adhoute, M Gasmi, JL Jouve, F Khemissa, T Lecomte, T Aparicio

2. Introduction (1) CRC is a disease of elderly –Median age at diagnosis: 73 years (SEER) A Public Health problem –US population ≥65 y. : x2 in 2030 –Suboptimal management –No improvement in survival

3. Introduction (2) Palliative CT in elderly –Standard regimens not prospectively validated –Subgroup analyses, phase II trials suggest feasibility in fit elderly Which optimal regimen in 1 st line ? –Tolerance/Efficacy –Combination with IRI/OXA or 5FU only ?

4. Study design R1 mCRC ≥ 75 years Stratification criteria Center Charlson index (0 vs 1-2 vs 3+) Karnofsky index (100 vs 90-80 vs 70-60) Previous adjuvant CT Sex Age (< 80 vs.  80 yrs) Alkaline phosphatases (≤ 2N vs. > 2N) LV5FU2 R2 0 IRINOTECAN LV5FU2s

5. Study design LV5FU2s FOLFIRI LV5FU2-IRI LV5FU2 5FU arm IRI arm LV 200 mg/m² D1+2 5FU 400 mg/m² IV bolus D1+2 5FU 600 mg/m² 22h infusion D1+2 LV 400 mg/m² D1 5FU 400 mg/m² IV bolus D1 5FU 2400 mg/m² 46h infusion D1-2 LV5FU2s Irinotecan IV 90mn D1 LV5FU2 Irinotecan IV 90mn D1 Irinotecan - 150 mg/m² for C1 and C2 - 180 mg/m² ≥ C3 if toxicity ≤ grade 2 (except. alopecia)

6. Main inclusion criteria Histologically confirmed unresectable mCRC Age ≥75 years Karnofsky index ≥60 Estimated life expectancy > 6 months ≥ 1 bi-dimensionally measurable lesion (RECIST) No previous CT for metastatic disease Adjuvant therapy allowed if stopped at least months before randomization Adequate organ and bone marrow function Creatinin clearance ≥ 45 ml/mn (Cockroft) Signed informed consent

7. Study endpoints Primary endpoint –Progression-free survival 5FU arm vs IRI arm as assessed by blinded independent review events : progression or death

8. Study endpoints Secondary endpoints –Objective response rate (independently reviewed) –Overall survival (events: deaths all causes) –Quality of life (Spitzer scale) –Geriatric assessment (IADL, Mini Mental State Examination, Geriatric Depression Scale) –Safety –Comparison of simplified vs. non simplified regimen

9. Statistical considerations Assumption for sample size calculation –240 progressions or deaths (282 pts) –increase of median PFS from 5.5 to 8 months in the IRI arm, HR 0.70 –bilateral 5% type I error, 80% power Planned interim analysis –After inclusion of 140 pts with ≥ 8 weeks of follow-up –Tolerance and response (investigators) –Only descriptive, no statistical comparisons –IDMC

10. Population 06/2003 – 12/2007 : –209 pts included Interim analysis 08/2007 –166 pts included –142 pts with ≥ 8 weeks of follow-up

11. Baseline characteristics (1) 5FUIRI n7567 Median age years [range] 79 [74-90]80 [75-91] Age group (%) <80 yrs5251 ≥80 yrs4849 Gender (%) Male/Female53/4751/49 Karnofsky index (%) 100/80-90/60-70/missing19/51/29/110/61/25/3 Charlson index (%) 0/1-2/3+/missing48/43/7/363/33/3/1

12. Baseline characteristics (2) 5FU IRI Alkaline Phosphatases (%) ≤ 2N / > 2N88/1285/15 Adjuvant CT (%) 176 Metastatic sites (%) Liver7784 Lung3946 Distant lymph nodes2724 Peritoneum1518

13. Administration All pts received at least one cycle (%) 5FUIRI Bolus 5FU8167 Continuous 5FU8087 Irinotecan-87 Pts with ≥75% of the planned CT dose during cycles 1 to 4

14. Deaths 81 deaths –5FU: 43 (57% of pts) –IRI: 38 (57% of pts) Causes of death –Progression 5FU: 37/43 (86%) IRI: 33/38 (87%) –2 toxic deaths 60d mortality rate: 12.7%

15. Toxicity (1) (%) All gradesGrade 3-4 5FUIRI5FUIRI Any93981648 Anemia476013 Neutropenia1366128 Febrile neutropenia1919 Maximal toxicities by patient observed during cycles 1 to 4

16. Toxicity (2) (%) All gradesGrade 3-4 5FUIRI5FUIRI Nausea374806 Vomiting193006 Diarrhea3963016 Thromboembolic event1313 Asthenia324836 Mucositis172100 Myocardial infarction1010 Maximal toxicities by patient observed during cycles 1 to 4

17. Tumoral response As estimated by investigators RECIST criteria Best observed response after 1 st or 2 nd evaluation (%) 5FUIRI CR11 PR1730 SD5157 PD259 NE53 6988

18. Conclusion Preliminary and descriptive A phase III trial specific to elderly patients with mCRC is feasible Results suggest that patients aged of 75+ years can be treated with standard CT regimens with manageable toxicity

20. Introduction (3) « The major challenge in caring for older adults with cancer rests with the lack of data from prospective clinical trials » « incorporation of a geriatric assessment in oncology clinical trials » JCO December 1 2007, editorial from Arti Hurria

21. Serious adverse events –During treatment or < 30 days after the end of treatment –Results in death –Is immediatly life threatening –Requires hospitalisation or prologation of existing hospitalisation –Results in persistent or significant disability or incapacity

22. Serious adverse events 68 SAE among 54 pts All5FUIRI SAE 542825 Death 1486 Not related752 Unlikely related202 Possibly related220 Related21 *1° ND101 * Febrile neutropenia, ° severe diarrhea