1. Who can benefit from chemotherapy holidays after first-line therapy for advanced colorectal cancer ? N. Perez-Staub, B. Chibaudel, A. Figer, A. Cervantes, G. Lledo, P. Artru, F. Maindrault-Goebel, C. Louvet, C. Tournigand, A. de Gramont ASCO 2008. Abstract n° 35468

2. Abstract Background : Chemotherapy free-intervals (CFI) in patients with advanced colorectal cancer who benefit from improved therapy are frequently done. However, early CFI after 6 cycles of first-line FOLFOX could negatively affect overall survival (Optimox 2 study, ASCO 2007, abs 4013). The ongoing study was performed to determine the best time to stop therapy, the predictive factors for a prolonged CFI and the impact of CFI on survival. Methods : All patients who had a 3-months CFI in the two Optimox studies (N = 822) were studied according to the time to CFI. Patients who had R0 or R1 metastases resection after 3 months of CFI were censored at time of surgery, patients who had surgery before 3 months of CFI or with progressive disease at time of CFI were excluded. Additionally, patients were individually matched with patients who did not stop chemotherapy (CT), had a PFS at least 3 months longer than time to CFI, similar tumor response and baseline features (PS, LDH, ALP). Results : 184 patients were eligible. Median OS were 24.6 months in 90 patients who stopped CT at, or, before 6 months and 39.8 months when CT was stopped after 6 months (N=94). Median duration of CFI was 5.9 months. Median OS were 22.8 months for patients with CFI duration ≤ 6 months (N=87) and 43.9 months for CFI > 6 months (N=97). There was no correlation between duration of CT and CFI duration. OS of all patients who had a ≥ 3-month CFI and of the matched patients were 30.8 and 21.2 months, respectively. Conclusions : These results demonstrate that a significant number of patients can benefit from chemotherapy holidays. Baseline characteristics do not allow to select these patients and additional studies are needed to solve this important issue.

3. Why is this study important ? –Chemotherapy-free interval (CFI) is frequently done –But early CFI decided at baseline may have a negative impact on Overall Survival (OS), as shown in the OPTIMOX2 study (1) 1 Maindrault-Goebel F. et al. ASCO 2007, abstract 4013 2 Tournigand C. et al. J Clin Oncol 2006 24:394-400 Objectives & Methods Which questions remain unanswered about CFI ? –What is the optimal chemotherapy duration before CFI ? –Is there a correlation between duration of CFI and duration of chemotherapy ? –Does survival depend on the duration of CFI ? –Can we identify patients who will benefit from CFI ?

4. How to answer these questions ? –Survival analysis of the patients who had >3 months CFI in the OPTIMOX 1 and 2 studies (1,2), looking at overall survival according to time to CFI and duration of CFI –Case-control study, matching on baseline prognostic factors, tumor response, PFS ≥ time to CFI+3 mths, patients with CFI and control patients continuing on therapy, looking at predictive survival factors. –Analysis of these factors in the CFI population Objectives & Methods

5. How many patients can enjoy chemotherapy holidays > 3 months? 19%42%

6. Patients Characteristics :  3 months 3 – 9 months > 9 months % % % CFI > 3 months : n = 184 Time to CFI

7. What is the optimal chemotherapy duration before > 3 months chemotherapy holidays? Optimal chemotherapy duration before CFI: ≥ 6 months

8. What is the duration of chemotherapy holidays ? Does the duration of CFI depend on the duration of chemo? Median duration of CFI is almost 6 months NO: prolonged chemotherapy does not improve the duration of CFI

9. Does survival depend on the duration of CFI ? R0-R1 resection after 3 months CFI N = 13 (13.4%) N = 10 (11.5%) YES: A prolonged CFI predicts a prolonged survival Does survival after CFI depend on the duration of CFI ? Survival after CFI is prolonged in patients who had a long CFI

10. Which patients can benefit of prolonged survival after >3 months CFI ? CFI NoCFI

11. What is the survival in matched patients with the same baseline prognostic? All patients, no pause vs. pause Median PFS 9.9 vs 12.9 months 2-Year Survival 40% vs 66% Surgery excluded, no pause vs. pause Median PFS 9.9 vs 12.2 months 2-Year Survival 39% vs 61% Baseline prognostic factors, response to chemotherapy and time to CFI or PFS ≥ time to CFI+3 months do not predict survival

12. What predictive factors in the matched patients ? Univariate analysis : at 2 or 3 months of therapy, CEA (p<0.0001), ALP (p<0.03) Multivariate analysis: CEA (p=0.002) and ALP (p=0.024) What predictive factors in the CFI patients ? Normal CEA within 3 months of therapy P=0.015

13. Conclusion  A significant number of patients can benefit from chemotherapy holidays. Baseline characteristics do not allow to select these patients  Median duration of CFI is almost 6 months  Optimal duration of chemotherapy before CFI is 6 months. There is no correlation between chemotherapy duration and CFI duration  A prolonged CFI (> 6 months) predicts a prolonged survival  A normal CEA level during chemotherapy was the single identified predictive factor of prolonged survival in patients who had a >3 months CFI  Additional studies will be done to identify other factors which may help to offer CFI to patients with advanced colorectal cancer.