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Current Opinion in the Colorectal Cancer Treatment

Dott. Carlo Garufi Oncologia Medica C Istituto Regina Elena – Roma garufi@ifo.it. Current Opinion in the Colorectal Cancer Treatment. Treatment Strategies in ACC in2007. III. II. I. Adjuvant CHT. IFL+BEVA. CETU +IRI. FOLFOX. FOLFIRI+BEVA. CETU +IRI. FOLFOX. FU/FA+ BEVA. FOLFOX.

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Current Opinion in the Colorectal Cancer Treatment

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  1. Dott. Carlo Garufi Oncologia Medica C Istituto Regina Elena – Roma garufi@ifo.it Current Opinion in the Colorectal Cancer Treatment

  2. Treatment Strategies in ACC in2007 III II I Adjuvant CHT IFL+BEVA CETU+IRI FOLFOX FOLFIRI+BEVA CETU+IRI FOLFOX FU/FA+BEVA FOLFOX FOLFIRI CETU+IRI 5FU/FA Capecitabine or FOLFOX CAPE+BEVA FOLFOX CETU+IRI FOLFIRI FU/FA CAPE CETU+IRI FOLFOX IRI O FOLFIRI FOLFOX CETU + IRI FOLFOX+BEVA FOLFOX CETU+IRI FOLFIRI CETU + IRI FOLFOX

  3. Cancro colon-retto avanzato:tutti i trattamenti sono uguali? FOLFOX = FOLFIRI CAPOX = CAPIRI Tournigand 2004, Colucci 2005, Grothey 2004 FOLFOX > IFL Goldberg 2004 The use of all available drugs is strongly suggested Grothey 2004

  4. Statistical Considerations

  5. Cancro colon-retto avanzato: ruolo del bevacizumab BEVA+ IFL >IFL in Prima Linea Hurwitz H 2004 BEVA + FOLFOX4 >FOLFOX4 in II linea Giantonio BJ 2005 ma ……

  6. The addition of Bevacizumab to IFL increases PFS and OS

  7. Saltz L ASCO 2007

  8. Saltz L ASCO 2007

  9. Aggiunta di BEVA alle doppiettein prima linea • Bevacizumab aumenta OS se usato con IFL • Non aumenta OS se usato con XELOX o FOLFOX4

  10. Canro colorettale e Cetuximab Cetuximab is the most active drug in pretreated patients Lentz 2005 Cetuximab + FOLFOX4 is a very active regimen (Resp Rate >60%) Colucci 2006, Tabernero 2004

  11. CRYSTAL Trial: Study Design Cetuximab + FOLFIRI Cetuximab IV 400 mg/m2 on day 1, then 250 mg/m2 weekly+ irinotecan (180 mg/m2) + 5-FU (400 mg/m2 bolus + 2400 mg/m2 as 46-hr continuous infusion) + FA every 2 weeks EGFR-expressing metastatic CRC R FOLFIRI irinotecan (180 mg/m2) + 5-FU 400 mg/m2 bolus + 2400 mg/m2 as 46-hr continuous infusion) + FA every 2 weeks Stratification factors: • Regions • ECOG PS Populations • Randomized patients n=1217 • Safety population n=1202 • ITT population: n=1198 Van Custen et al, ASCO 2007

  12. CRYSTAL Trial: Study Endpoint • Primary endpoint: • Progression-free survival time (as assessed by blinded independent review) • Secondary endpoints: • Overall response rate (independently reviewed) • Disease control rate (CR+PR+SD) • Overall survival time • Quality of life (EORTC QLQ C30) • Safety

  13. CRYSTAL Trial: Primary End-Point PFS

  14. CRYSTAL trial:Independent Assessment of Response p-value* = 0.0038 *Cochran-Mantel-Haenszel (CMH) test ** DCR: disease control rate

  15. CRYSTAL Trial: Conclusions • The CRYSTAL trial met its primary objective of demonstrating that the addition of cetuximab to FOLFIRI in the first-line treatment of EGFR-detectable mCRC significantly increased PFS • There was a 15% risk reduction for progression in patients treated with cetuximab plus FOLFIRI compared to FOLFIRI • The addition of cetuximab to FOLFIRI was associated with: • Higher response rates (p=0.0038) • Threefold higher R0 resection rates for initially unresectable disease (p=0.0034) • Skin reactions showed a strong correlation with efficacy

  16. Differences in Treatment Strategies Between US and Europe A. Grothey WCGC 2007

  17. Unsolved Questions • Is there a clear advantage in survival with the use of polichemotherapy rather then monochemotherapy as first line treatment? (Seymour 2007, Punt 2007) • What is the role of the stop and go strategy? (GISCAD 2006, ) • What is the role of triplet in patients with liver metastases? (Falcone A. 2006, Garufi C 2007) • Is colorectal cancer a unique clinical disease?

  18. Lancet 2007

  19. FOCUS TRIAL

  20. CAIRO TRIAL

  21. CAIRO TRIAL

  22. Which strategy as first line treatment? • Perhaps the answer is to define a “Minimal Therapy” or an “Intense Therapy” • Introduction of the concept of “Continuum Treatment” (Hoff ASCO 2007)

  23. (Hoff ASCO 2007)

  24. (Hoff ASCO 2007)

  25. (Hoff ASCO 2007)

  26. Unsolved Questions • Is there a clear advantage in survival with the use of polichemotherapy rather then monochemotherapy as first line treatment? (Maughan T. 2003) • What is the role of the stop and go strategy? (GISCAD ASCO2006, OPTIMOX2 ASCO 2007) • What is the role of triplet in patients with liver metastases? (Falcone A. 2006, Garufi C) • Is colorectal cancer a unique clinical disease?

  27. Rationale • Chemotherapy-free intervals have been previously • studied in patients receiving 5-FU based therapy • Hejna et al. (Br J Cancer 1998) • Maughan et al. (Lancet 2003) • New combination therapies have improved survival • but there is still the risk of cumulative toxicities like • Oxaliplatin sensory neuropathy • Clinical rationale: quality of life preservation, • costs reduction and social impact improvement

  28. Continuos vs Intermittent Therapy ? MRC Trial “Our findings provided no clear evidence of benefit in continuing therapy indefinitly until disease progression” Maugan et al., Lancet 2003

  29. GISCAD Trial: Design (ASCO 2006) FOLFIRI N=336 R Evaluation 4 mos Primary end point: OS Non inferiority : 15< Median OS (months)< 11

  30. Greem ASCO 2007 Discussant

  31. STOP and GO STRATEGY • At this time there are no clear advantage from a stop and go strategy. It seems that continuing treatment until progression, if not hampered by severe toxicity, is still a valid option

  32. We should consider Stage IV different groups of colorectal cancer patients • Clinical History (PS, comorbidity, age) • Interdisciplinary Teams (surgery and/or RT) • Different median survival (<12 e >24 mesi) • Necessity to identify new prognostic factors

  33. We need new trials for old and new Prognostic Factors • Gender(Giacchetti S. et al JCO 2006) • Hb(Tampellini M. et al Br J Cancer 2006) • LDH (Koehne et al ASCO 2006) • Resectability(Poston G et al JCO 2006) • GenicPolimorphysm (Toffoli G et al JCO 2006)

  34. Clinical determinants of survival in patients with 5-fluorouracil- based treatment for metastatic colorectal cancer: results of a multivariate analysis of 3825 patients C.-H. Kohne, D. Cunningham, F. Di Costanzo, B. Glimelius, et al Ann. Onc.,  2002; 13(2): 308 - 317.

  35. Diferent Stage IV Disease in Different Patients • Disseminated Disease • Local Recurrences • Peritoneal Carcinosis • Non-measurable Disease • Lung Metastases • Liver Metastases • Resected • Resectable • Non-resectable

  36. Diferent Stage IV Disease in Different Patients • Disseminated Disease • Local Recurrences • Peritoneal Carcinosis • Non-measurable Disease • Lung Metastases • Liver Metastases • Resected • Resectable • Non-resectable

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