Current Colorectal Cancer Reports

, Volume 9, Issue 1, pp 68–73

Colon Cancer Liver Metastasis: Addition of Antiangiogenesis or EGFR Inhibitors to Chemotherapy

Personalized Medicine in Colorectal Cancer (CMS Rocha-Lima, Section Editor)
  • 109 Downloads

Abstract

For patients with unresectable colorectal liver metastases (CRLM), selection of adequate drug combinations, with or without biological agents, for immediate use is crucial for success of conversion to resectable CRLM with potentially curative results. This paper addresses the use of biological agents directed against the two main targets in colorectal cancer—vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). Addition of the anti-angiogenic monoclonal antibody (MAb) bevacizumab to chemotherapy may increase resection of CRLM for patients with KRAS mutated or for unselected patients. Caution must be exercised with wound healing complications when surgery is performed after bevacizumab use. Patients with KRAS wild-type should be considered for combination therapy with EGFR inhibitors, because this strategy has led to promising results with improved R0 resection.

Keywords

Colorectal liver metastases Chemotherapy EGFR VEGF Cetuximab Panitumumab Bevacizumab Aflibercept Resectability Response 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10–29.PubMedCrossRefGoogle Scholar
  2. 2.
    Manfredi S, et al. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg. 2006;244(2):254–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Kohne CH, et al. Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986. J Clin Oncol. 2005;23(22):4856–65.PubMedCrossRefGoogle Scholar
  4. 4.
    Engebraaten O, et al. Effects of EGF, bFGF, NGF and PDGF(bb) on cell proliferative, migratory and invasive capacities of human brain-tumour biopsies in vitro. Int J Cancer. 1993;53(2):209–14.PubMedCrossRefGoogle Scholar
  5. 5.
    Jonker DJ, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357(20):2040–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Van Cutsem E, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy–refractory metastatic colorectal cancer. J Clin Oncol. 2007;25(13):1658–64.PubMedCrossRefGoogle Scholar
  7. 7.
    Wang J, et al. A Q-TWiST analysis comparing panitumumab plus best supportive care (BSC) with BSC alone in patients with wild-type KRAS metastatic colorectal cancer. Br J Cancer. 2011;104(12):1848–53.PubMedCrossRefGoogle Scholar
  8. 8.
    Choti MA, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg. 2002;235(6):759–66.PubMedCrossRefGoogle Scholar
  9. 9.
    Pawlik TM, et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg. 2005;241(5):715–22. discussion 722–4.PubMedCrossRefGoogle Scholar
  10. 10.
    Benoist S, et al. Complete response of colorectal liver metastases after chemotherapy: does it mean cure? J Clin Oncol. 2006;24(24):3939–45.PubMedCrossRefGoogle Scholar
  11. 11.
    McLoughlin JM, Jensen EH, Malafa M. Resection of colorectal liver metastases: current perspectives. Cancer Control. 2006;13(1):32–41.PubMedGoogle Scholar
  12. 12.
    Heinrich S and Lang H. Liver metastases from colorectal cancer: technique of liver resection. J Surg Oncol. 2012.Google Scholar
  13. 13.
    • Berri RN, Abdalla EK. Curable metastatic colorectal cancer: recommended paradigms. Curr Oncol Rep. 2009;11(3):200–8. This paper summarizes the current multidiscliplinary approach to treatment of CLMs, detailing the new models for resectability. PubMedCrossRefGoogle Scholar
  14. 14.
    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Carmeliet P, Collen D. Molecular basis of angiogenesis. Role of VEGF and VE-cadherin. Ann N Y Acad Sci. 2000;902:249–62. discussion 262–4.PubMedCrossRefGoogle Scholar
  16. 16.
    Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407(6801):249–57.PubMedCrossRefGoogle Scholar
  17. 17.
    •• Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov. 2011;10(6):417–27. An important overview of angiogenesis showing there is still an open debate about its mechanisms in cancer and how anti-angiogenic therapy works. A complementary paper showing theory changes and debate over the last decade is Ref. [16] by the same authors. PubMedCrossRefGoogle Scholar
  18. 18.
    •• Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. A pioneering publication on biological steps for cancer development.PubMedCrossRefGoogle Scholar
  19. 19.
    Hurwitz H, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42.PubMedCrossRefGoogle Scholar
  20. 20.
    Okines A, et al. Surgery with curative-intent in patients treated with first-line chemotherapy plus bevacizumab for metastatic colorectal cancer First BEAT and the randomised phase-III NO16966 trial. Br J Cancer. 2009;101(7):1033–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Wong R, et al. A multicentre study of capecitabine, oxaliplatin plus bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection. Ann Oncol. 2011;22(9):2042–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Nordlinger B, et al. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Francaise de Chirurgie. Cancer. 1996;77(7):1254–62.PubMedCrossRefGoogle Scholar
  23. 23.
    Giacchetti S, et al. Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol. 1999;10(6):663–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Fong Y, et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230(3):309–18. discussion 318–21.PubMedCrossRefGoogle Scholar
  25. 25.
    Falcone A, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007;25(13):1670–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Masi G, et al. Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. Lancet Oncol. 2010;11(9):845–52.PubMedCrossRefGoogle Scholar
  27. 27.
    Saltz LB, et al. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol. 2007;25(29):4557–61.PubMedCrossRefGoogle Scholar
  28. 28.
    Hecht JR, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009;27(5):672–80.PubMedCrossRefGoogle Scholar
  29. 29.
    Tol J, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360(6):563–72.PubMedCrossRefGoogle Scholar
  30. 30.
    Van Cutsem E, et al. Addition of Aflibercept to Fluorouracil, Leucovorin, and Irinotecan Improves Survival in a Phase III Randomized Trial in Patients with Metastatic Colorectal Cancer Previously Treated With an Oxaliplatin-Based Regimen. J Clin Oncol. 2012.Google Scholar
  31. 31.
    Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer. 2008;8(8):579–91.PubMedCrossRefGoogle Scholar
  32. 32.
    Gordon MS, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol. 2001;19(3):843–50.PubMedGoogle Scholar
  33. 33.
    Gruenberger B, et al. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol. 2008;26(11):1830–5.PubMedCrossRefGoogle Scholar
  34. 34.
    Kesmodel SB, et al. Preoperative bevacizumab does not significantly increase postoperative complication rates in patients undergoing hepatic surgery for colorectal cancer liver metastases. J Clin Oncol. 2008;26(32):5254–60.PubMedCrossRefGoogle Scholar
  35. 35.
    Cacheux W, et al. Reversible tumor growth acceleration following bevacizumab interruption in metastatic colorectal cancer patients scheduled for surgery. Ann Oncol. 2008;19(9):1659–61.PubMedCrossRefGoogle Scholar
  36. 36.
    Nordlinger B, et al. Combination of surgery and chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel. Ann Oncol. 2009;20(6):985–92.PubMedCrossRefGoogle Scholar
  37. 37.
    Normanno N, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene. 2006;366(1):2–16.PubMedCrossRefGoogle Scholar
  38. 38.
    Winder T, Lenz HJ. Vascular endothelial growth factor and epidermal growth factor signaling pathways as therapeutic targets for colorectal cancer. Gastroenterology. 2010;138(6):2163–76.PubMedCrossRefGoogle Scholar
  39. 39.
    Baselga J. Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist. 2002;7 Suppl 4:2–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol. 2003;21(14):2787–99.PubMedCrossRefGoogle Scholar
  41. 41.
    •• Van Cutsem E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360(14):1408–17. This is the first RCT that showed benefit of a EGFR inhibitor, cetuximab, in initial therapy for metastatic CRC and also presented KRAS status as an important predictive biomarker of this new class of biologic agents. PubMedCrossRefGoogle Scholar
  42. 42.
    Bokemeyer C, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011;22(7):1535–46.PubMedCrossRefGoogle Scholar
  43. 43.
    Bokemeyer C, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27(5):663–71.PubMedCrossRefGoogle Scholar
  44. 44.
    •• Bokemeyer C, et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012;48(10):1466–75. An individual patient data combined analysis that confirmed the importance of patient selection based on KRAS wild-type status and also presented information about BRAF status as predictive biomarker. PubMedCrossRefGoogle Scholar
  45. 45.
    Claus-Henning Kohne CB, Folprecht G, Sartorius U, Schlichting M, Rougier PR, Van Cutsem E. Chemotherapy plus cetuximab in patients with liver-limited or non-liver-limited KRAS wild-type colorectal metastases: a pooled analysis of the CRYSTAL and OPUS studies. J Clin Oncol. 2012;30(suppl;abstr 3562).Google Scholar
  46. 46.
    Folprecht G, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol. 2010;11(1):38–47.PubMedCrossRefGoogle Scholar
  47. 47.
    Garufi C, et al. Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial. Br J Cancer. 2010;103(10):1542–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Douillard JY, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010;28(31):4697–705.PubMedCrossRefGoogle Scholar
  49. 49.
    Petrelli F, Barni S. Resectability and outcome with anti-EGFR agents in patients with KRAS wild-type colorectal liver-limited metastases: a meta-analysis. Int J Colorectal Dis. 2012;27(8):997–1004.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Centro Avançado de Oncologia Hospital Sao Jose, Sao PauloSao PauloBrazil
  2. 2.Johns Hopkins Singapore International Medical CentreJohns Hopkins University School of MedicineSingaporeSingapore

Personalised recommendations