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Management of Liver Metastases of CRC origin

Management of Liver Metastases of CRC origin. Mohamed Abdulla (M.D.) Professor of Clinical Oncology Kasr El-Aini School of Medicine Cairo University 12/2008. Hepatic Metastases From Colorectal Carcinoma. CRC annual US incidence [1] ~ 150,000 patients. Hepatic metastases (~ 50%) [2]

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Management of Liver Metastases of CRC origin

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  1. Management of Liver Metastases of CRC origin Mohamed Abdulla (M.D.) Professor of Clinical Oncology Kasr El-Aini School of Medicine Cairo University 12/2008

  2. Hepatic Metastases From Colorectal Carcinoma CRC annual US incidence[1] ~ 150,000 patients Hepatic metastases (~ 50%)[2] 75,000 patients Hepatic resection, with expanded indications[3] 10,000-15,000 patients Mets confined to liver (~ 30%) 22,500 patients Historical hepatic resection,rate (10% to 25%)[2] 2250-5625 patients • Jemal A, et al. CA Cancer J Clin. 2007;57:43-66. 2. Leonard GD, et al. J Clin Oncol. 2005;23:2038-2048. 3. Pawlik TM, et al. J Gastrointest Surg. 2007;11:1057-1077.

  3. Nonresectable 75% to 80% Hepatic Metastases From Colorectal Carcinoma Liver Metastases Location Resectable20% to 25% Number Size Downsizing Survival Benefit 30% to 50% at 5 years 15% at 10 years Resectable10% to 20% Leonard GD, et al. J Clin Oncol. 2005;23:2038-2048.

  4. Hepatic Resection: A Cure for mCRC? Pawlik TM, et al. J Gastrointest Surg. 2007;11:1057-1077.

  5. Resection of CRLM: 5-Year Survival,Selected Reports (≥ 100 Pts) Over Time *Patients included from multiple institutions (vs single-institution series).

  6. Survival After Hepatic Resection Has Improved Over Time • Lower operative mortality • ~ 1% with experienced hepatobiliary surgeons • Improved patient selection • CT, MRI, PET, PET/CT • Improved surgical techniques • Intraoperative US, portal vein embolism, radiofrequency ablation • Increased rates of repeat hepatectomy after recurrence • More frequent and better perioperative chemotherapy • Irinotecan, oxaliplatin, biologics

  7. Historical Contraindications For Resection of Liver Limited mCRC: Abdalla EK, et al. Ann Surg Oncol. 2006;13:1271-1280. Pawlik TM, et al. J Gastrointest Surg. 2007;11:1057-1077.

  8. Expanded Indications: New Criteria Defining Resectability *1-cm margins not required. †Portal vein embolization may be used to preoperatively increase the size of the future liver remnant by inducing hypertrophy. Abdalla EK, et al. Ann Surg Oncol. 2006;13:1271-1280. Pawlik TM, et al. J Gastrointest Surg. 2007;11:1057-1077.

  9. Neoadjuvant Cytotoxic Chemotherapy • Is there an “optimal” cytotoxic regimen? • FOLFOX • FOLFIRI • FOLFOXIRI

  10. EORTC 40983: FOLFOX4 in mCRC With Resectable Liver Metastases Phase III study: patients with CRC and resectable liver metastases; WHO/ECOG performance score 0-2 (N = 364) FOLFOX4 for 6 cycles (12 wks) (n = 182) Surgery FOLFOX4 for 6 cycles (12 wks) Surgery (n = 182) Nordlinger B, et al. ASCO 2007. Abstract LBA5.

  11. EORTC 40983: PFS in Resected Patients PFS at 3 Years 100 80 HR: 0.73; 95% CI: 0.55-0.97; P = .025 60 Patients (%) 42.4 40 33.2 20 0 Surgery Only Peri-Op CT Nordlinger B, et al. ASCO 2007. Abstract LBA5.

  12. Summary: Initially Resectable • Little clinical trial data to guide treatment decisions • EORTC 40983: benefit less than expected • Current EORTC 40051 trial assessing addition of targeted agents • Cetuximab plus bevacizumab vs cetuximab alone when administered preoperatively and perioperatively

  13. Resection of Initially Unresectable Liver Metastases After Systemic Chemo Lévi F, et al. Cancer. 1992;69:893-900. Fowler WC, et al. J Surg Oncol.1992;51:122-125. Bismuth H, et al. Annals of Surgery. 1996;224:509-522. Giacchetti S, et al. Ann Oncol. 1999;10:663-669. Adam R, et al. Ann Surg Oncol. 2001;8:347-353. Wein A, et al. Ann Oncol. 2001;12:1721-1727. Rivoire M, et al. Cancer. 2002;95:2283-2292.

  14. Outcome Based on Initial Response to Chemotherapy 131 patients with colorectal metastases received preoperative Cth. Partial response (n = 58) 95 100 Stabilization (n = 39) 92 Progression (n = 34) 80 63 60 55 P < .0001 OS (%) 44 37 40 30 20 12 8 88 0 1 Year 3 Years 5 Years Adam R, et al. Ann Surg. 2004;240:1052-1064.

  15. Neoadjuvant Oxaliplatin Before Surgery Paul Brousse hospital study: 2047 patients with colorectal liver metastases treated from April 1988 to December 2003 14% of 1512 patients treated with chemotherapy achieved a response, permitting resection Chemotherapy (N = 1512) Resection (N = 740) 205 (28%) Initially unresectable 205 (14%) 1307 (86%) 535 (72%) Initially resectable Adam R et al. Ann Surg Oncol. 2001;4:347-353. (Updated at ASCO GI Cancer Symposium 2007)

  16. Survival After Primary or SecondaryResection of Liver Metastases 100 Resectable (n = 425) 80 Initially nonresectable (n = 95) 54% 60 Proportion Surviving 34% 40 50% 27% 34% 20 29% 19% 0 0 1 2 3 4 5 6 7 8 9 10 Survival Time (Years) Adam R, et al. Chemotherapy and surgery: new perspectives on the treatment of unresectable liver metastases, Annals of Oncology, 2003, Vol. 14, supplement 2, pp.ii13-ii16, by permission of Oxford University Press. Adam R. Ann Oncol. 2003;14(suppl 2):ii13-iii16.

  17. NCCTG Study 97-46-51: FOLFOX4 in Unresectable Colon Cancer Prospective, multi-institutional study Patients with unresectable liver-only metastases received FOLFOX4* (N = 42) Clinical response to chemotherapy (n = 25) No response to chemotherapy† (n = 17) Surgery not possible (n = 8) Surgery (n = 17) *FOLFOX4: biweekly oxaliplatin 85 mg/m2 followed sequentially by leucovorin 200 mg/m2, bolus FU 400 mg/m2 and continuous FU infusion 600 mg/m2 over 22 hours on Day 1. Alberts SR, et al. J Clin Oncol. 2005;23:9243-9249.

  18. NCCTG Study 97-46-51: Response and OS Alberts SR, et al. J Clin Oncol. 2005;23:9243-9249.

  19. FOLFIRI for Unresectable Liver Metastases 1. Barone C, et al. Br J Cancer. 2007;97:1035-1039. 2. Falcone A, et al. J Clin Oncol. 2007;25:1670-1676.

  20. Summary of Cytotoxic Regimens Alberts SR, et al. J Clin Oncol. 2005;23:9243-9249. Barone C, et al. Br J Cancer. 2007;97:1035-1039. De La Cámara R, et al. ASCO 2004. Abstract 3593. Falcone A, et al. J Clin Oncol. 2007;25:1670-1676. Abad A, et al. ASCO 2005. Abstract 3618. Ho WM, et al. Med Oncol. 2005;22:303-312.

  21. Role of Biologic, Targeted Therapy

  22. Role of Targeted Therapy: EGFR Inhibitors • First-line therapy with FOLFOX + cetuximab for metastatic colorectal cancer • Response rate: 72% • 10 of 43 (23%) patients underwent potentially curative resection Tabernero J, et al. J Clin Oncol. 2007;25:5225-5232. Folprecht, et al. Ann Oncol. 2006;17:450-456. Cervantes, et al. ECCO 2005. Abstract 642. Peeters, et al. ECCO 2005. Abstract 664.

  23. N014A: Resection of Unresectable CRC Limited to Liver FOLFOX6 + Cetuximab CR/PR resectable  OR  CT x 2 PR, unresectable  Rx to prog/tolerability Prog  off study, Rx per MD Evaluation • Endpoints: resectability, response rate, survival • Initial assessment: surgical response rate 25% Clinical Trials.gov. Available at: http://clinicaltrials.gov/ct2/show/NCT00056030. Accessed January 10, 2008.

  24. CRYSTAL Trial: Surgery With Curative Intent • In cetuximab arm, significantly more patients undergoing surgery with curative intent had successful resection *P = .0034 Van Cutsem, et al. ASCO 2007. Abstract 4000.

  25. Summary: Current Experience With Cetuximab • Compared with chemotherapy alone • Consistently increased RR in all trials • Evidence of improved resectability • Initially unresectable metastatic colorectal cancer • First-line and refractory • Nonselected and selected (liver-limited) patients

  26. Role of Bevacizumab • Phase II trial: XELOX + bevacizumab • 54 patients with potentially resectable liver metastases • 6 cycles of neoadjuvant therapy (1 week on, 1 week off) • Clinical response: 74% • pCR: 11% • No long-term follow-up reported Gruenberger B, et al. ASCO 2007. Abstract 4060.

  27. Downstaging of Unresectable mCRC:Randomized Studies *P =.0034 for cetuximab + FOLFIRI vs FOLFIRI alone, all patients. Van Cutsem E, et al. ASCO 2007. Abstract 4000. Bokemeyer C, et al. ASCO 2007. Abstract 4035. Cassidy J, et al. ASCO 2007. Abstract 4030. Hecht JR, et al. World GI Congress 2007.

  28. Liver Toxicity of Neoadjuvant Therapy

  29. A Combined Study of Liver Toxicity of Neoadjuvant Therapy • Patients from M. D. Anderson Cancer Center and Istituto per la Ricera e la Cura del Cancro Candiolo (Torino, Italy) who underwent hepatic surgery for colorectal metastases with curative intent between (June 1992 - June 1999) • Primary endpoint: toxicity No chemotherapy n = 158 5-FU/LV n = 63 Patients aged 18-86 years divided on basis of preoperative chemotherapy regimen* (N = 406) 5-FU/LV + Irinotecan n = 94 5-FU/LV + Oxaliplatin n = 79 Other Therapy n = 12 *Primary colon carcinoma: 76.3%; node-positive disease: 60.3% Vauthey JN, et al. J Clin Oncol 2006;24:2065-2072.

  30. Liver Toxicity of Neoadjuvant Therapy *P = .0001 compared with no treatment arm. Patients with steatohepatitis had an increased 90-day mortality compared with patients who did not develop steatohepatitis (P = .001) Vauthey JN, et al. J Clin Oncol. 2006;24:2065-2072.

  31. Complications Following Neoadjuvant Bevacizumab Retrospective study of preoperative bevacizumab therapy and postoperative complications in patients with colorectal cancer who underwent hepatic surgery for liver metastases (N = 1186) • No increase in hepatobiliary, wound, or other postoperative complications • Optimal timing of surgery in patients receiving bevacizumab not known Patient Selection?? Kesmodel S, et al. ASCO 2007. Abstract 234.

  32. Treatment-Associated Liver Toxicity • Irinotecan: steatohepatitis (80%) • Oxaliplatin: sinusoidal/vascular injury • Bevacizumab • Impaired liver regeneration • Wound healing complications • Need to wait 6-8 weeks before surgical resection • Cetuximab: no acute or chronic effects to date • Morbidity increased with prolonged use

  33. Does a Clinical CR or Pathologic CR Lead to Survival Benefit? • Clinical series from MSKCC[1] • 435 patients treated with neoadjuvant therapy • 39 (9%) of patients had 117 lesions disappear on CT scan • 43 pathological CR in lesions • Durable CR in 26 patients (> 40 months) • 791 consecutive patients receiving neoadjuvant therapy[2] • Pathological CR: 4% (31 patients) • “Strongly impacted” OS 1. Taylor RA, et al. ASCO 2007. Abstract 4058. 2. Wicherts, DA et al. ASCO 2007. Abstract 4063.

  34. Issues to Consider • Increased duration of therapy raises risk of hepatic toxicity • Duration of therapy must be balanced with limiting liver toxicity • CR may inhibit ability to resect and/or ablate

  35. Summary • Neoadjuvant chemotherapy appears to enhance long-term outcomes • Multiagent chemotherapy regimens provide similar clinical benefit with resection rates in the 20% to 30+% range • pCR appears to be 5% to 10% with current regimens • Role of targeted therapy appears promising • Cetuximab may offer advantages in clinical efficacy and safety over bevacizumab • Active area of clinical investigation • Multidisciplinary team approach required

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