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THERAPEVTIC PUZZLE IN SYSTEMIC TREATMENT OF COLO-RECTAL CANCER

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THERAPEVTIC PUZZLE IN SYSTEMIC TREATMENT OF COLO-RECTAL CANCER

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    1. THERAPEVTIC PUZZLE IN SYSTEMIC TREATMENT OF COLO-RECTAL CANCER Rado Janša University Clinical centre Ljubljana, Slovenia DPT of gastroenterology

    2. Epidemiology of colorectal cancer (CRC)

    3. CRC: an evolution of treatment options and complexity Common cancer – advanced disease Introduction of new chemotherapeutic agents Introduction of new biologicals Improved surgical/imaging techniques Continuum of care approach Improved understanding of tumour biology

    4. COMBINATION !!!

    5. OPTIONS FOR TREATMENT OF CRC OPERATION RADIOTHERAPHY ADJUVANT THERAPHY NEOADJUVANT THERAPHY SYSTEMIC TREATMENT OF PROGRESSIVE DISEASE

    6. What is New in the Systemic Treatment of Colorectal Cancer?

    7. Major Advances New chemotherapy Irinotecan Oxaliplatin Capecitabine Antibodies VEGF antibodies (bevacizumab) EGFR antibodies (cetuximab, panitumumab)

    8. Advances in the Treatment of Metastatic Colorectal Cancer

    9. Adjuvant Chemotherapy Stage III colon cancer (T1-4, N1-2, M0) Increase 5-y survival rate for 15% XELODA 5y survival 81% 5-FU/LV 5y survival 78% FOLFOX 4 (2006) 5y survival 84% Stage II T3,4, N0, M0 5-y survival rate 70-80% Treatment in clinical trials Perforation of GIT, ileus, large tumor, T4, vascular and perinevral invasion, CEA very high befor operation

    10. X-ACT Capecitabin (Xeloda)- standard adjuvant treatment of CRC

    11. Xeloda = 5-FULV

    13. ADJUVANT THREATMENT OF RECTAL CANCER Tumor – 12 cm upper of anus Stage II and stage III Standard theraphy = a combination of radiation and chemotheraphy Preoperative or postoperative radiotherapy (5 weeks, TD 45-50-54) + Capecitabine

    14. METASTATIC COLORECTAL CANCER

    15. What are the key issues in the management of CRC liver metastases? Agree on resectability Which metastases, considered initially not resectable, can become resectable after response to chemotherapy? Which chemotherapy regimen? Chemotherapy Preoperative? Postoperative? Perioperative?

    16. Colon cancer metastases: Treatment profile

    17. Secondary resection of CRC liver metastases

    18. Neoadjuvant chemotherapy for resectable liver metastases Rationale Eliminate micrometastatic disease and allow eradication of dormant cancer cells Increase rate of complete resection and of less extended liver resections, upon tumor shrinkage1 Response to neoadjuvant therapy is an important prognostic factor2,3 Can serve as a test for chemoresponsiveness

    19. Neoadjuvant chemotherapy for resectable liver metastases Potential disadvantages May induce hepatic damage and affect postoperative outcome Disappearance of liver metastases on imaging with neoadjuvant therapy can complicate the next therapeutic steps Progression during perioperative chemotherapy

    20. Liver damage

    21. Vascular lesions: Oxaliplatin (Rubbia-Brandt et al, 2004) Steatosis: 5FU, irinotecan? (Parikh et al, 2003) Steatohepatitis: irinotecan (Vauthey et al, 2006) Liver damage induced by chemotherapy

    22. NEOADJUVANT CHEMOTHERAPY TARGET AGENTS COMBINATION

    23. TARGET THERAPY

    24. VEGF is a key mediator of angiogenesis IGF = insulin-like growth factor; PDGF = platelet-derived growth factor; EGF = epidermal growth factor; IL = interleukin; bFGF = basic fibroblast growth factor; VEGF = vascular endothelial growth factor; TGF = transforming growth factor; HER2 = human epidermal growth factor-2 Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev 1997;18:4–25. Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2002;2:727–39. IGF = insulin-like growth factor; PDGF = platelet-derived growth factor; EGF = epidermal growth factor; IL = interleukin; bFGF = basic fibroblast growth factor; VEGF = vascular endothelial growth factor; TGF = transforming growth factor; HER2 = human epidermal growth factor-2 Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev 1997;18:4–25. Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2002;2:727–39.

    25. Avastin prevents angiogenesis through a novel mechanism of action Avastin prevents the binding of VEGF to its receptors recognises all major isoforms of human VEGF

    26. Avastin adds strong benefit to all regimens: OS

    27. BRiTE*: Continuation of Avastin post-first progression significantly increases OS (time from initiation of first-line treatment to death)

    28. Avastin has a well-established safety profile in phase III trials and clinical practice

    29. CETUKSIMAB block EGFR receptor Antitumor activity

    30. KRAS analysis: Objective and methodology To retrospectively investigate the impact of the KRAS mutation status of tumors on PFS and RR in the first-line treatment of mCRC with FOLFIRI ± ERBITUX Efficacy analyses repeated on KRAS evaluable population Genomic DNA isolated from archived tumor material Paraffin-embedded, formalin-fixed tissue KRAS mutation status of codons 12/13 determined using quantitative PCR-based assay

    31. Relating KRAS status to efficacy Secondary endpoint: Response

    32. ERBITUX + CT in KRAS wild-type: Consistent results

    33. Avastin demonstrates OS benefit regardless of KRAS mutation status

    34. KRAS testing

    35. SURGICAL THERAPY OF METASTATIC CRC

    36. SUBSTRATS on CYP system (kompetition) ANTICANCER AGENTS:kapecitabin, ciklofosfamid, docetaxel, erlotinib, gefitinib, imatinib, doxorubicin, hexamethylmelanine, dacarbazine, irinotekan, fulvestrant, exemestane(aromazin), anastrozole(arimidex) NSAR, PARACETAMOL ETANOL PPI: omeprazol ANTIEPILEPTIKI STATINI, ANTIKOAGULANTI, BLOKATORJI Ca KANALCKOV ANTIBIOTIKI

    37. INHIBITION on CYP system: - amiodaron - antifungics - omeprazol - cimetidin - eritromicin - klaritromicin - ciprofloksacin - inhiitors of HIV - verapamil - disulfiram - grapefruit

    38. Chemotherapy: What we know Downsizing with systemic chemotherapy provides response rates of 40–60% and allows ~10% of non-resectable patients to become resectable 5-year survival rates similar to that of patients with primarily resectable metastases Chemotherapy is associated with hepatic toxicity

    39. Biomarkers The KRAS biomarker is predictive for efficacy and will allow for tailored therapy, improving outcomes for patients with mCRC CRYSTAL – OPUS - BRITE Multidisciplinary team Greater emphasis on a multidisciplinary approach is required to achieve optimal results

    40. CONCLUSIONS

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