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Mario Scartozzi Clinica di Oncologia Medica Ancona

Mario Scartozzi Clinica di Oncologia Medica Ancona. HIGHLIGHTS IN COLORECTAL CANCER MANAGEMENT TREATMENT OF METASTATIC DISEASE. Bittoni, Giampieri et al, CROH 2012. Colon Cancer: what we already know.

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Mario Scartozzi Clinica di Oncologia Medica Ancona

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  1. Mario Scartozzi Clinica di Oncologia Medica Ancona HIGHLIGHTS IN COLORECTAL CANCER MANAGEMENT TREATMENT OF METASTATIC DISEASE

  2. Bittoni, Giampieri et al, CROH 2012

  3. Colon Cancer: what we already know • Chemotherapy has determined a relevant improvement in survival in the last 15 years: from 6 to 18 months • Probably FOLFOX = FOLFIRI and XELOX=FOLFOX(XELIRI has PHYLOSOPHICAL problems with toxicity) • Concept of all three drugs • Some patients with stage IV disease can be cured by an interdisciplinary approach

  4. Colon Cancer: what we already know • Chemotherapy has determined a relevant improvement in survival in the last 15 years: from 6 to 18 months • Probably FOLFOX = FOLFIRI and XELOX=FOLFOX(XELIRI has PHYLOSOPHICAL problems with toxicity) • Concept of all three drugs • Some patients with stage IV disease can be cured by an interdisciplinary approach

  5. Not all liver metastases are created equal

  6. Bittoni, Giampieri et al, CROH 2012

  7. Multimodality Management of CRC Liver Metastases • Neoadjuvant chemotherapy • Resectable liver metastases: • Facilitate surgery • Obtain predictive and prognostic information • Early systemic therapy for poor-prognosis pts • Conversion chemotherapy • Unresectable liver metastases: • Allow R0 resection via downsizing • Postoperative (adjuvant) chemotherapy • Hepatic arterial infusion (HAI) • Systemic treatment

  8. Colon Cancer: NOT all liver metastases are created equal BIOLOGICALLY CHALLANGING PFS/OS

  9. Colon Cancer: MULTIMODALITY management • Neoadjuvant chemotherapy • Resectable liver metastases: • Facilitate surgery • Obtain predictive and prognostic information • Early systemic therapy for poor-prognosis pts • Conversion chemotherapy • Unresectable liver metastases: • Allow R0 resection via downsizing • Postoperative (adjuvant) chemotherapy

  10. Colon Cancer: MULTIMODALITY management • Neoadjuvant chemotherapy • Resectable liver metastases: • Facilitate surgery • Obtain predictive and prognostic information • Early systemic therapy for poor-prognosis pts • Conversion chemotherapy • Unresectable liver metastases: • Allow R0 resection via downsizing • Postoperative (adjuvant) chemotherapy

  11. Colon Cancer: EORTC 40983 (the EPOC trial) • 364 patients randomized • Potentially resectable (≤ 4 liver metastases) • Goal: Improve PFS • Interim objective: Evaluate tumor response to perioperative CT • Perioperative CT (n = 182) • 159 (87.3%) underwent surgery • 151 (83.0%) resected • Surgery (n=182) • 170 (93.4%) underwent surgery • 152 (83.0%) resected FOLFOX4 for 6 cycles (12 wks) (n = 182) Surgery FOLFOX4 for 6 cycles (12 wks) R Surgery (n = 182) Nordlinger B, et al. Lancet 2008

  12. Efficacy Results MOSAIC: 3-yr DFS for stage III: +7.2% Adapted from Nordlinger B, et al. Lancet 2008;371(9617):1007-16.

  13. 2012 Nordlinger et al

  14. Biologicals: How Do They Fit Into This Strategy? Biologicals Chemotherapy Surgery

  15. Colon Cancer: PFS in BEVACIZUMAB trials Wagner et al. Cochrane Review ‘09

  16. Colon Cancer: PFS in anti-EGFR trials Loupakis, Bria E et al. Cancer 2011

  17. BEVACIZUMAB: PFS on TREATMENT! Saltz, et al. ASCO GI 2007

  18. Colon Cancer: NOT all liver metastases are created equal TECHNICALLY CHALLANGING RR/R0/OS

  19. Colon Cancer: MULTIMODALITY management • Neoadjuvant chemotherapy • Resectable liver metastases: • Facilitate surgery • Obtain predictive and prognostic information • Early systemic therapy for poor-prognosis pts • Conversion chemotherapy • Unresectable liver metastases: • Allow R0 resection via downsizing • Postoperative (adjuvant) chemotherapy

  20. Colon Cancer: MULTIMODALITY management • Neoadjuvant chemotherapy • Resectable liver metastases: • Facilitate surgery • Obtain predictive and prognostic information • Early systemic therapy for poor-prognosis pts • Conversion chemotherapy • Unresectable liver metastases: • Allow R0 resection via downsizing • Postoperative (adjuvant) chemotherapy

  21. What Do We Expect from Ideal Conversion Chemo? • High (anatomical) response rate • RR = goal of therapy in stage IV CRC only for • Conversion therapy • Patients with significant tumor-related symptoms • Good toxicity profile • No hepatotoxicity • No interference with surgery • No interference with liver regeneration

  22. Conversion Therapy: Liver Toxicities • 5-FU: hepatic steatosis, associated with increased postoperative morbidity - yellow liver • Irinotecan: non-alcoholic steatohepatitis (especially in obese patients), can affect hepatic reserve and increase morbidity and mortality after hepatectomy - orange liver • Oxaliplatin: hepatic sinusoidal obstruction syndrome, does not appear to be associated with increased risk of perioperative death - blue liver • Both response rate and toxicity should be considered when selecting preoperative CT in patients with colorectal liver metastases REMEMBER: AS SOON AS…. Adapted from Zorzi D, et al. Br J Surg 2007;94:274-86.

  23. Colon Cancer: Rate of Liver Resections/RR Rate of liver resection following CT Data from studies/retrospective analyses with “selected pts”, only liver MTS (r=0.96) (p=0.002) Selected pts (liver mets) △ Data from studies/retrospective analyses with “non selected pts” (r=0.74) (p<0.001), solid line ▲ Not selected pts: only phase III trials (r=0,67) (p=0.024), dashed line Not selected pts Folprecht et al. Ann Oncol ‘05

  24. FOLFIRI vs FOLFOXIRI: RESULTS Falcone A, JCO ‘07 & Masi JNCI’10

  25. Cetuximab: CELIM & RR & R0 resection (LLD) Folprecht et al. Lancet Oncology 2010

  26. Cetuximab: CELIM & RR & R0 resection (LLD) Folprecht et al. Lancet Oncology 2010

  27. Colon Cancer: Rate of Liver Resections/RR Rate of liver resection following CT Data from studies/retrospective analyses with “selected pts”, only liver MTS (r=0.96) (p=0.002) K-RAS wt △ Data from studies/retrospective analyses with “non selected pts” (r=0.74) (p<0.001), solid line ▲ Not selected pts: only phase III trials (r=0,67) (p=0.024), dashed line Not selected pts Folprecht et al. Ann Oncol ‘05

  28. Colon Cancer: Rate of Liver Resections/RR Rate of liver resection following CT Data from studies/retrospective analyses with “selected pts”, only liver MTS (r=0.96) (p=0.002) Selected pts (liver mets) K-RAS wt △ Data from studies/retrospective analyses with “non selected pts” (r=0.74) (p<0.001), solid line K-RAS mt ▲ Not selected pts: only phase III trials (r=0,67) (p=0.024), dashed line Not selected pts Folprecht et al. Ann Oncol ‘05

  29. Cetuximab: CELIM & RR & R0 resection (LLD) Folprecht et al. Lancet Oncology 2010

  30. Colon Cancer: Rate of Liver Resections/RR Rate of liver resection following CT Data from studies/retrospective analyses with “selected pts”, only liver MTS (r=0.96) (p=0.002) Selected pts (liver mets) K-RAS wt △ Data from studies/retrospective analyses with “non selected pts” (r=0.74) (p<0.001), solid line K-RAS mt ▲ Not selected pts: only phase III trials (r=0,67) (p=0.024), dashed line Not selected pts Folprecht et al. Ann Oncol ‘05

  31. Response Rate in anti-EGFR trials Loupakis F, Bria E et al. Cancer 2011

  32. Response Rate in BEVACIZUMAB trials Wagner et al. Cochrane Review ‘09

  33. CT Morphology vs RECIST A - Pretreatment B - Posttreatment D - Posttreatment C - Pretreatment

  34. CT Morphology vs RECIST to Determine Response on BEV • 234 pts with CRC liver mets treated with chemo + BEV • 50 pts underwent hepatic resection • Three blinded radiologists evaluated response of liver mets according to • Standard RECIST criteria • Novel CT morphology criteria Adapted from Chun YS, et al. JAMA 2009;302(21):2338-44.

  35. Response Evaluation: Morphology vs. RECIST Patients with unresectable tumor Morphologicresponse criteria RECIST 1.0 1.0 0.8 0.8 0.6 0.6 Proportion surviving Proportion surviving 0.4 0.4 0.2 0.2 Log-rank p=0.009 Log-rank p=0.45 0.0 0.0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 Months Months Adapted from Chun YS, et al. JAMA 2009;302(21):2338-44.

  36. Colon Cancer: NEVER (NEVER!) resectable Bad, Bad luck….. PFS/OS/QoL

  37. Phase III randomized trials: gains in activity and efficacy in 1st line therapy

  38. Overall Survival in BEVACIZUMAB trials Wagner et al. Cochrane Review ‘09

  39. Overall Survival in anti-EGFRs trials Loupakis, Bria E et al. Cancer 2011

  40. Phase III randomized trials: gains in activity and efficacy in 2nd line therapy

  41. Amado JCO 2008

  42. Amado JCO 2008

  43. PFS/DFS for EGFR inhibitors improves across lines of therapy in KRAS wild-type patients 1.2 1.0 0.8 0.6 Hazard ratio 0.4 NORDIC VII2 0.2 Study 1817 CRYSTAL5 Amado8 PRIME4 N01471 CO.179 COIN3 EPIC6 0 Adjuvant First line Second line Salvage (single agent) 1. Alberts, et al. JAMA 2012; 2. Tveit, et al. JCO 2012; 3. Maughan, et al. Lancet 2011 4. Douillard, et al. ASCO 2011; 5. Van Cutsem, et al. JCO 2011; 6. Langer, et al. ESMO 2008 7. Sobrero, et al. ASCO GI 2012; 8. Amado, et al. JCO 2008; 9. Karapetis, et al. NEJM 2008 Slide Courtesyof A Grothey

  44. 2012 Arnold D, et Al

  45. 2012 Arnold D, et Al

  46. 2012 Arnold D, et Al

  47. 2012 Arnold D, et Al

  48. AFLIBERCEPT

  49. 2012 Allegra C, et Al

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