1. Clara Natoli, MD Professor of Medical Oncology University G. D ' Annunzio Chieti - Pescara Clara Natoli, MD Professor of Medical Oncology University G. D ' Annunzio Chieti - Pescara

3. Cancer Res. 1958 May;18(4):478-84. 15 mg x 70Kg = 1050 mg totali

4. Continuous Administration of Fluorinated Pyrimidines Sullivan, R. D., Young, C. W., Miller, E., Glatstein, N., Clarkson, B., and Burchenal, J. H. The Clinical Effects of the Continuous Administration of Fluorinated Pyrimidines (5- Fluorouracil and 5-Fluoro-2'-deoxyuridine). Cancer Chemotherapy Rept., 8: 77-83, 1960.

6. an intraluminal 5 FU or intraluminal control (Saline) group receiving intraluminal 5 FU (30mg/kg) received intravenous 5 FU (10mg/kg) on each of the two first postoperative days and 5 subsequent postoperative courses of oral 5FU (90 mg/kg in each 18 day course) over a one year period. no significant benefit from this intensive adjuvant course of 5 FU thus far. Patients were randomly assigned to an intraluminal 5 FU or intraluminal control (Saline) group and were so treated at the time of surgical resection if findings at operation indicated that all gross neoplastic disease could be resected. Those patients receiving intraluminal 5 FU (30mg/kg) received intravenous 5 FU (10mg/kg) on each of the two first postoperative days and 5 subsequent postoperative courses of oral 5FU (90 mg/kg in each 18 day course) over a one year period. By December 31, 1973 (6 years) 156 patients undergoing "curative" resection were entered into the study. Survival curves and "disease free" curves for comparison of the group receiving adjuvant 5 FU therapy with the control or "No Treat” group reveal no significant benefit from this intensive adjuvant course of 5 FU thus far.

8. Kaplan Meier curves Kaplan E, Meier P: Non-parametric estimation from incomplete observation. J Am Stat Assoc 53:457- 481, 1958

10. The European license for first-line treatment with oxaliplatin/FU/LV was granted in 1999. However, the Oncologic Drugs Advisory Committee and the FDA did not approve the first-line indication of oxaliplatin for advanced CRC in March of 2000 because of the lack of an overall survival advantage. Furthermore, use of infused FU/LV regimens in the control arms of the European studies was difficult to compare with the standard bolus method of FU/LV administration used in the United States.  Clinton impeachment trial  The war in Kosovo

11. At the same Oncologic Drugs Advisory Committee meeting, approval was granted for the use of irinotecan in combination with FU/LV (by bolus or infusion) as first-line treatment of metastatic disease based on two randomized trials, one European and one North American, that showed survival advantages to the combination compared with FU/LV. By then, irinotecan/FU/LV had already been approved in Europe. As a result, in Europe, clinicians could choose to use either oxaliplatin or irinotecan in combination with FU/LV as first-line treatment, and many patients were offered the alternative agent on treatment failure. In the United States, irinotecan/bolus FU/LV (IFL) became the new standard first-line treatment, but oxaliplatin remained unavailable.

14. Eur J Cancer. 2001 Mar;37(5):597-604.

16. On February 26, 2004, the FDA approved bevacizumab in combination IFL as a first line treatment for patients with metastatic colorectal cancer Bevacizumab was approved by the EMEA in January 12, 2005 for use in metastatic CRC. On June 20, 2006, the FDA granted approval for a labeling extension for bevacizumab in combination with i.v. 5-FU-based chemotherapy, for the second-line treatment of metastatic carcinoma of the colon or rectum. AIFA 04.1 Indicazioni terapeutiche Avastin (bevacizumab) in combinazione con chemioterapia a base di fluoropirimidine è indicato per il trattamento di pazienti con carcinoma metastatico del colon e del retto.

17. On January 9, 2004, the FDA approved oxaliplatin, for use in combination with infusional 5-fluorouracil and leucovorin for the initial treatment of advanced colorectal cancer. Oxaliplatin previously received accelerated approval on August 9, 2002, for use in combination with infusional 5-FU/LV for the treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed during or within six months of completion of first line therapy with the combination of bolus 5-FU/LV and irinotecan.

19. 30 metastatic colorectal cancer patients treated by cetuximab

22. Baseline markers “Dynamic” markers Baseline & “Dynamic” markers Predictive markers of benefit from anti-VEGF agents Plasma VEGF levels Plasma levels of Angiogenesis-related factors Hypertension VEGF genetics Bevacizumab for advanced colorectal cancer NEJM 2004 VEGF expression MVD analysis 2005 KRAS BRAF p53 200620072008 DC- NMR (imaging ) Circulating endothelial cells (CEC) Circulating Endothelial Progenitors (CEP) 2009-2010 ?

23. ©2011 by American Society of Clinical Oncology JCO 2011;29:17-24

24. Therapeutic Targeting of the Hallmarks of Cancer