1. Impact of the Type and Modalities of Preoperative Chemotherapy on the Outcome of Liver Resection for Colorectal Metastases R. Adam, E. Barroso, C. Laurent, G. Nuzzo, C. Hubert, G. Mentha, J. Ijzermans, L. Capussotti, S. Lopezben, D. Mirza, G. Kaiser, E. Oussoultzoglou, T. Gruenberger, G. J. Poston, O. Skipenko, and The LiverMetSurvey Centers

2. Impact of the type and modalities of preoperative chemotherapy on the outcome of liver resection for colorectal metastases R. Adam, E. Barroso, C. Laurent, G. Nuzzo, C. Hubert, G. Mentha, J. Ijzermans, L. Capussotti, S. Lopez-Ben, D. Mirza, G. Kaiser, E. Housseau, T. Gruenberger, G. J. Poston, O. Skipenko, The LiverMetSurvey Centers

3. LiverMetsurvey Background Prognostic factors of survival have been extensively reported after resection of colorectal liver metastases. However, a specific analysis of patients submitted to preoperative chemotherapy (PCT), with the real impact of type and modalities of treatment on patient outcome is lacking.

4. LiverMetsurvey Aim of the study To evaluate impact of the type and modalities of PCT on the long-term outcome of resected patients for colorectal liver metastases in a large multicenter cohort, LiverMetsurvey.

5. LiverMetsurvey Number of patients

6. LiverMetsurvey Study design LiverMetsurvey Jan 1995 – June 2010 8912 Patients – 151 Centers in 39 Countries No Preop Chemotherapy 4468 Preop Chemotherapy 4444 49.9% Study population

7. LiverMetsurvey Patients and Methods LiverMetSurvey is an international, internet-based prospective registry designed to assess the efficacy of multimodality treatment options for colorectal liver metastases (CLM). 4444 patients (49.9%) received chemotherapy before liver resection. The distribution of potential prognostic factors including age, sex, primary tumor site, timing of metastasis diagnosis, tumor number, diameter of the largest metastasis, bilaterality, initial resectability, and type and duration of chemotherapy were compared to overall (OS) and disease-free (DFS) survivals using univariate and multivariate analyses.

8. LiverMetsurvey Overall Survival : Global Population Without Preop. chemo With Preop. chemo No of exposed pts Preop. chemo 65% 58%47% 39%

9. LiverMetsurvey Overall Survival : Initially resectable patients No of exposed pts Preop. chemo Without Preop. chemo With Preop. chemo 65% 62% 47% 44%

10. LiverMetsurvey Overall Survival : Initially non resectable patients No of exposed pts Preop. chemo Without Preop. chemo With Preop. chemo 54% 50% 33%

11. LiverMetsurvey Patients and Tumour Characteristics (1) Characteristics Male Age (yrs,mean±sd) Tumor localization Left including sigmoid Rectum Right Transverse Multiple localizations Metast. primary lymph nodes No meta. at diagnosis 1-3 4-7 >7 Meta. at diagnosis ≥ 30mm No chemo preop 62.3% 64 ± 11 42.3% 32.1% 18.7% 3.5% 3.4% 60.7% 88.9% 8.9% 2.2% 56.6% Chemo preop 62.1% 61 ± 11 46.3% 30.7% 16.9% 3.2% 3.0% 66.6% 67.5% 23.8% 8.7% 59.5% P NS < 0.0001 0.005 < 0.0001 0.01

12. LiverMetsurvey Patients and Tumour Characteristics (2) Characteristics Synchronous Initial resectability Bilateral localization Abnormal prehep CEA level (>5) Concomitant extrahepatic disease Major hepatectomy R2 resection Combined techniques Post-op chemotherapy Center volume (mean±sd) (Max done in a year) No chemo preop 38.4% 95.0% 23.8% 67.0% 8.6% 46.2% 6.7% 14.1% 47.4% 45.1 ± 33.1 Chemo preop 68.7% 62.8% 49.0% 58.1% 12.8% 63.6% 12.9% 28.2% 57.9% 57.8 ± 38.4 P < 0.0001

13. LiverMetsurvey Patients with preoperative chemotherapy No of exposed pts Overall Survival Disease Free Survival (Non palliative pts) 90% 62% 58% 30%

14. LiverMetsurvey - Overall survival Patients with preoperative chemotherapy Multivariate Analysis Risk factors Metastatic primary lymph nodes Abnormal CEA levels (>5) Concomitant extrahepatic disease Metastases >3 Tumoral progression Type of chemotherapy More than 1 line of Chemo. R2 resection P 0.005 < 0.0001 0.006 0.04 NS 0.0002 < 0.0001 RR 1.29 1.46 1.66 1.29 1.31 - 1.45 1.65 CI 95% [1.1-1.5] [1.2-1.7] [1.4-2.0] [1.1-1.5] [1.0-1.7] - [1.2-1.8] [1.3-2.1]

15. LiverMetsurvey - Overall survival Patients with preoperative chemotherapy No of exposed pts Metastatic primary lymph nodes No metastatic primary lymph nodes Metastatic primary lymph nodes 67% 54% 47% 35%

16. LiverMetsurvey - Overall survival Patients with preoperative chemotherapy No of exposed pts Concomitant extrahep. metastases No concomitant extrahep. metastases Concomitant extrahep. metastases 60% 42% 18%

17. No of exposed pts Prehep. CEA ≥ 5 Prehep. CEA < 5 ng/ml Prehep. CEA ≥ 5 ng/ml LiverMetsurvey - Overall survival Patients with preoperative chemotherapy 67% 52% 49% 31%

18. No of exposed pts Pre-op last line result No preop. Progression Preop. Progression LiverMetsurvey - Overall survival Patients with preoperative chemotherapy 59% 42% 41% 23%

19. No of exposed pts No Metastases at diagnosis > 3 Metastases 1-3 Metastases LiverMetsurvey - Overall survival Patients with preoperative chemotherapy 63% 51% 46% 31%

20. No of exposed pts Liver curative Palliative resection Curative resection LiverMetsurvey - Overall survival Patients with preoperative chemotherapy 62% 36% 43% 20%

21. No of exposed pts No lines preop > 1 line chemotherapy Only 1 line chemotherapy LiverMetsurvey - Overall survival Patients with preoperative chemotherapy 59% 51% 42% 27%

22. LiverMetsurvey - Overall survival Patients with preoperative chemotherapy No of exposed pts Preop. Chemo. type Irino-based Oxali-based Oxali-Irino-based 61% 57% 41% 34%

23. No of exposed pts Preop. Targeted therapy No preop. Targeted therapy Preop. Targeted therapy LiverMetsurvey - Overall survival Patients with Oxaliplatin-based preop. chemo. 62% 58% 48% 41%

24. No of exposed pts Preop. Targeted therapy No preop. Targeted therapy Preop. Targeted therapy LiverMetsurvey - Overall survival Patients with Irinotecan-based preop. chemo. 58% 56% 54% 40%

25. No of exposed pts Preop. Targeted therapy No preop. Targeted therapy Preop. Targeted therapy LiverMetsurvey - Overall survival Patients with Oxali-Irino-based preop. chemo. 70% 56% 42% 34%

26. No of exposed pts Preop. Targeted therapy LiverMetsurvey - Overall survival Patients with preoperative chemotherapy No preop. Targeted therapy Preop. Targeted therapy 59% 58% 48% 39%

27. No of exposed pts Preop. Targeted therapy Bevacizumab Cetuximab/Panitumumab Without Preop. Targeted therapy LiverMetsurvey - Overall survival Patients with preoperative chemotherapy 59% 57% 50% 39%

28. Risk factors Metastatic primary lymph nodes Abnormal CEA levels (>5) Metastases >3 Tumoral progression Type of chemotherapy Major hepatectomy More than 6 cycles P 0.0008 0.005 0.0001 0.05 NS 0.04 0.004 RR 1.32 1.25 1.4 1.3 - 1.2 1.25 CI 95% [1.1-1.6] [1.1-1.5] [1.2-1.7] [1.0-1.7] - [1.0-1.4] [1.1-1.5] LiverMetsurvey – Disease free survival Patients with preoperative chemotherapy Multivariate Analysis

29. LiverMetsurvey – Disease free survival Patients with preoperative chemotherapy No of exposed pts No cycles preop > 6 cycles 1-6 cycles 33% 25% 26% 17%

30. LiverMetsurvey Conclusion Preoperative Chemotherapy is used in half patients overall, 63% of whom with initially resectable CLM. The type of Chemotherapy does not influence the outcome provided that resection is achieved. However, the shorter is the Chemotherapy and the more limited is the number of lines, the best is the survival after surgery.

31. LiverMetsurvey - Overall survival Patients with preoperative chemotherapy No of exposed pts Initially resectable Not initially resectable Initially resectable 62% 54% 44% 33%