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Systemic Therapy for Patients with Colorectal Cancer: State of the Art

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Multidisciplinary Treatment of Colorectal Cancer

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Abstract

Recent modalities and strategies have increased the complexity of treatment choice in patients with colorectal cancer (CRC), and therefore all cases should be assessed at a multidisciplinary conference.

Adjuvant chemotherapy for 6 months increases the chance of cure by absolutely 5 % in stage II and 10–15 % in stage III. Targeted therapy is not recommended in the adjuvant setting.

Treatment options in patients with non-resectable CRC are based on the extent of disease (resectable/potential resectable/non-resectable) and symptoms. Surgery first or chemotherapy first in patients with synchronous metastasis is one of several yet unsolved questions which should be discussed at a MDT in each case taking into account patients symptoms and performance.

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References

  1. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.

    PubMed  Google Scholar 

  2. Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med. 2005;352:476–87.

    CAS  PubMed  Google Scholar 

  3. Longley DB, Harkin DP, Johnston PG. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3:330.

    CAS  PubMed  Google Scholar 

  4. Sobrero AF, Aschele C, Bertino JR. Fluorouracil in colorectal cancer–a tale of two drugs: implications for biochemical modulation. J Clin Oncol. 1997;15:368–81.

    CAS  PubMed  Google Scholar 

  5. Ragnhammar P, Hafstrom L, Nygren P, et al. A systematic overview of chemotherapy effects in colorectal cancer. Acta Oncol. 2001;40:282–308.

    CAS  PubMed  Google Scholar 

  6. Glimelius B, Jakobsen A, Graf W, et al. Bolus injection (2–4 min) versus short-term (10–20 min) infusion of 5-fluorouracil in patients with advanced colorectal cancer: a prospective randomised trial. Nordic Gastrointestinal Tumour Adjuvant Therapy Group. Eur J Cancer. 1998;34:674–8.

    CAS  PubMed  Google Scholar 

  7. Fischel JL, Etienne MC, Formento P, et al. Search for the optimal schedule for the oxaliplatin/5-fluorouracil association modulated or not by folinic acid: preclinical data. Clin Cancer Res. 1998;4:2529–35.

    CAS  PubMed  Google Scholar 

  8. Lokich J, Anderson N. Dose intensity for bolus versus infusion chemotherapy administration: review of the literature for 27 anti-neoplastic agents. Ann Oncol. 1997;8:15–25.

    CAS  PubMed  Google Scholar 

  9. Meta-analysis Group in Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol. 1998;16:301–8.

    Google Scholar 

  10. Rustum YM, Trave F, Zakrzewski SF, et al. Biochemical and pharmacologic basis for potentiation of 5-fluorouracil action by leucovorin. NCI Monogr 1987;5:165–70.

    Google Scholar 

  11. Advanced Colorectal Cancer Meta-Analysis Project. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J Clin Oncol. 1992;10:896–903.

    Google Scholar 

  12. The Meta-Analysis Group. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis. J Clin Oncol. 2004;22:3766–75.

    Google Scholar 

  13. Choong YS, Lee SP, Alley PA. Comparison of the pyrimidine nucleoside phosphorylase activity in human tumours and normal tissues. Exp Pathol. 1988;33:23–5.

    CAS  PubMed  Google Scholar 

  14. Miwa M, Ura M, Nishida M, et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer. 1998;34:1274–81.

    CAS  PubMed  Google Scholar 

  15. Schüller J, Cassidy J, Dumont E, et al. Preferential activation of capecitabine in tumour following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol. 2000;45:291–7.

    PubMed  Google Scholar 

  16. Van Cutsem E, Findlay M, Osterwalder B, et al. Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: results of a randomized phase II study. J Clin Oncol. 2000;18:1337–45.

    PubMed  Google Scholar 

  17. Hoff PM, Ansari R, Batist G, et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001;19:2282–92.

    CAS  PubMed  Google Scholar 

  18. Van Cutsem E, Twelves C, Cassidy J, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001;19:4097–106.

    PubMed  Google Scholar 

  19. Carmichael J, Popiela T, Radstone D, et al. Randomized comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2002;20:3617–27.

    CAS  PubMed  Google Scholar 

  20. Douillard JY, Hoff PM, Skillings JR, et al. Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2002;20:3605–16.

    CAS  PubMed  Google Scholar 

  21. Liu G, Franssen E, Fitch MI, et al. Patient preference for oral versus intravenous palliative chemotherapy. J Clin Oncol. 1997;15:110–5.

    CAS  PubMed  Google Scholar 

  22. Borner M, Schöffski P, de Wit R, et al. Patient preferences and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: a randomised crossover trial in advanced colorectal cancer. Eur J Cancer. 2002;38:349–58.

    CAS  PubMed  Google Scholar 

  23. Pfeiffer P, Mortensen JP, Bjerregaard B, et al. Patient preference for oral or intravenous chemotherapy: a randomised cross-over trial comparing capecitabine and Nordic fluorouracil/leucovorin in patients with colorectal cancer. Eur J Cancer. 2006;42:2738–43.

    CAS  PubMed  Google Scholar 

  24. Twelves C, Gollins S, Grieve R, Samuel L. A randomised cross-over trial comparing patient preference for oral capecitabine and 5-fluorouracil/leucovorin regimens in patients with advanced colorectal cancer. Ann Oncol. 2006;17:239–45.

    CAS  PubMed  Google Scholar 

  25. Jerremalm E, Wallin I, Ehrsson H. New insights into the biotransformation and pharmacokinetics of oxaliplatin. J Pharm Sci. 2009;98:3879–85.

    CAS  PubMed  Google Scholar 

  26. Woynarowski JM, Faivre S, Herzig MCS, et al. Oxaliplatin-induced damage of cellular DNA. Mol Pharmacol. 2000;58:920–7.

    CAS  PubMed  Google Scholar 

  27. Raymond E, Lawrence R, Izbicka E, et al. Activity of oxaliplatin against human tumour colony-forming units. Clin Cancer Res. 1998;4:1021–9.

    CAS  PubMed  Google Scholar 

  28. Rothenberg ML, Oza AM, Bigelow RH, et al. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol. 2003;21:2059–69.

    CAS  PubMed  Google Scholar 

  29. Gamelin E, Gamelin L, Bossi L, et al. Clinical aspects and molecular basis of oxaliplatin neurotoxicity: current management and development of preventive measures. Semin Oncol. 2002;29:21–33.

    CAS  PubMed  Google Scholar 

  30. Grothey A. Clinical management of oxaliplatin-associated neurotoxicity. Clin Colorectal Cancer. 2005;5 Suppl 1:S38–46.

    CAS  PubMed  Google Scholar 

  31. Chollet P, Bensmaine MA, Brienza S, et al. Single agent activity of oxaliplatin in heavily pretreated advanced epithelial ovarian cancer. Ann Oncol. 1996;7:1065–70.

    CAS  PubMed  Google Scholar 

  32. Pfeiffer P, Hahn P, Jensen HA. Short time infusion of oxaliplatin (Eloxatin®) in combination with capecitabine (Xeloda®) in patients with advanced colorectal cancer. Acta Oncol. 2003;42:832–6.

    CAS  PubMed  Google Scholar 

  33. Pfeiffer P, Sørbye H, Ehrsson H, et al. Short-time infusion of oxaliplatin in combination with capecitabine (XELOX30) as second line therapy in patients with advanced colorectal cancer after failure to irinotecan and 5-fluorouracil. Ann Oncol. 2006;17:252–8.

    CAS  PubMed  Google Scholar 

  34. Dupont J, Jensen HA, Jensen BV, et al. Phase I study of short-time oxaliplatin, capecitabine and epirubicin (EXE) as first line therapy in patients with non-resectable gastric cancer. Acta Oncol. 2007;46:330–5.

    CAS  PubMed  Google Scholar 

  35. Schonnemann KR, Jensen HA, Yilmaz M, et al. Phase II study of short-time oxaliplatin, capecitabine and epirubicin (EXE) as first-line therapy in patients with non-resectable gastric cancer. Br J Cancer. 2008;99:858–61.

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Qvortrup C, Yilmaz M, Ogreid D, Berglund A, Balteskard L, Ploen J, Fokstuen T, Starkhammar H, Sørbye H, Tveit K, Pfeiffer P. Chronomodulated capecitabine in combination with short-time oxaliplatin: A Nordic phase II study of second-line therapy in patients with metastatic colorectal cancer after failure to irinotecan and 5-flourouracil. Ann Oncol. 2008;19:1154–9.

    CAS  PubMed  Google Scholar 

  37. Qvortrup C, Jensen BV, Fokstuen T, Nielsen SE, Keldsen N, Glimelius B, Bjerregaard B, Mejer J, Larsen FO, Pfeiffer P. A randomized study comparing short-time infusion of oxaliplatin in combination with capecitabine XELOX30 and chronomodulated XELOX30 as first-line therapy in patients with advanced colorectal cancer. Ann Oncol. 2010;21:87–91.

    CAS  PubMed  Google Scholar 

  38. Kaneda N, Nagata H, Furuta T, et al. Metabolism and pharmacokinetics of the camptothecin analogue CPT-11 in the mouse. Cancer Res. 1990;50:1715–20.

    CAS  PubMed  Google Scholar 

  39. Kawato Y, Furuta T, Aonuma M, et al. Antitumour activity of a camptothecin derivative, CPT-11, against human tumour xenografts in nude mice. Cancer Chemother Pharmacol. 1991;28:192–8.

    CAS  PubMed  Google Scholar 

  40. Hsiang YH, Hertzberg R, Hecht S, et al. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem. 1985;260:14873–8.

    CAS  PubMed  Google Scholar 

  41. Iyer L, Hall D, Das S, et al. Phenotype-genotype correlation of in vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism. Clin Pharmacol Ther. 1999;65:576–82.

    CAS  PubMed  Google Scholar 

  42. Kweekel D, Guchelaar HJ, Gelderblom H. Clinical and pharmacogenetic factors associated with irinotecan toxicity. Cancer Treat Rev. 2008;34:656–69.

    CAS  PubMed  Google Scholar 

  43. Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil as adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990;322:352–8.

    CAS  PubMed  Google Scholar 

  44. Sargent D, Sobrero A, Grothey A, et al. Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol. 2009;27:872–7.

    PubMed Central  PubMed  Google Scholar 

  45. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;352:2696–704.

    CAS  PubMed  Google Scholar 

  46. Lembersky BC, Wieand HS, Petrelli NJ, et al. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol. 2006;24:2059–64.

    Google Scholar 

  47. Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343–51.

    CAS  PubMed  Google Scholar 

  48. Andre T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009;27:3109–16.

    CAS  PubMed  Google Scholar 

  49. Kuebler JP, Wieand HS, O’Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007;25:2198–204.

    CAS  PubMed  Google Scholar 

  50. Haller D, Tabernero J, Maroun J et al. First efficacy findings from a randomized phase III trial of capecitabine + oxaliplatin vs bolus 5-FU/LV for stage III colon cancer (NO16968/XELOXA study). ECCO 2009. Abstr 5LBA.

    Google Scholar 

  51. Gill S, Loprinzi CL, Sargent DJ, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: Who benefits and by how much? J Clin Oncol. 2004;22:1797–806.

    Google Scholar 

  52. Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ. QUASAR Collaborative Group: Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet 2007; 370: 2020–9.

    Google Scholar 

  53. QUASAR Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007;370:2020–9.

    Google Scholar 

  54. Gunderson LL, Jessup JM, Sargent DJ, et al. Revised TN categorization for colon cancer based on national survival outcomes data. J Clin Oncol. 2010;28:264–71.

    PubMed Central  PubMed  Google Scholar 

  55. Labianca R, Nordlinger B, Beretta GD. Primary colon cancer: ESMO Clinical Practice Guidelines for diagnosis, adjuvant treatment and follow-up. Ann Oncol. 2010;21 Suppl 5:v70–7.

    PubMed  Google Scholar 

  56. NCCN Clinical Practice Guidelines in Oncology (NCCN GuidelinesTM). Colon cancer, version 1.2011, NCCN.org.

    Google Scholar 

  57. Sargent DJ, Marsoni S, Monges G, et al. J Clin Oncol. 2010;28:3219–26.

    Google Scholar 

  58. Zaanan A, Cuilliere-Dartigues P, Guilloux A, et al. Impact of p53 expression and microsatellite instability on stage III colon cancer disease-free survival in patients treated by 5-fluorouracil and leucovorin with or without oxaliplatin. Ann Oncol. 2010;21:772–80.

    CAS  PubMed  Google Scholar 

  59. Van Cutsem E, Labianca R, Bodoky G, et al. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol. 2009;27:3117–25.

    PubMed  Google Scholar 

  60. Ychou M, Raoul JL, Douillard JY, et al. A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802). Ann Oncol. 2009;20:674–80.

    CAS  PubMed  Google Scholar 

  61. Saltz LB, Niedzwiecki D, Hollis D, et al. Irinotecan fluorouracil plus leucovorin is Not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol. 2007;25:3456–61.

    CAS  PubMed  Google Scholar 

  62. Wolmark N, Yothers G, O’Connell MJ, et al. A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon: results of NSABP protocol C-08. ASCO 2009; LBA4.

    Google Scholar 

  63. Goldberg RM, Sargent DJ, Thibodeau SN, et al. Adjuvant mFOLFOX6 plus or minus cetuximab (Cmab) in patients (pts) with KRAS mutant (m) resected stage III colon cancer (CC): NCCTG Intergroup Phase III Trial N0147. ASCO 2010; abstract 3508.

    Google Scholar 

  64. Alberts SR, Sargent DJ, Smyrk TC, et al. Adjuvant mFOLFOX6 with or without cetuxiumab (Cmab) in KRAS wild-type (WT) patients (pts) with resected stage III colon cancer (CC): results from NCCTG Intergroup Phase III Trial N0147. ASCO 2010; abstract CRA 3507.

    Google Scholar 

  65. Poston GJ, Figueras J, Giuliante F, et al. Urgent need for a New staging system in advanced colorectal cancer. J Clin Oncol. 2008;26:4828–33.

    PubMed  Google Scholar 

  66. Glimelius B, Hoffman K, Graf W, et al. Quality of life during chemotherapy in patients with symptomatic advanced colorectal cancer. The Nordic Gastrointestinal Tumour Adjuvant Therapy Group. Cancer. 1994;73:556–62.

    CAS  PubMed  Google Scholar 

  67. Scheithauer W, Rosen H, Kornek GV, et al. Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ. 1993;306:752–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Cunningham D, Pyrhonen S, James RD, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998;352:1413–8.

    CAS  PubMed  Google Scholar 

  69. Rougier P, Van Cutsem E, Bajetta E, et al. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet. 1998;352:1407–12.

    CAS  PubMed  Google Scholar 

  70. Kim GP, Sargent DJ, Mahoney MR, et al. Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil: N9841. J Clin Oncol. 2009;27:2848–54.

    CAS  PubMed Central  PubMed  Google Scholar 

  71. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000;18:2938–47.

    PubMed  Google Scholar 

  72. Giacchetti S, Perpoint B, Zidani R, et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2000;18:136–47.

    CAS  PubMed  Google Scholar 

  73. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000;355:1041–7.

    CAS  PubMed  Google Scholar 

  74. Kohne CH, Van Cutsem E, Wils J, 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;23:4856–65.

    PubMed  Google Scholar 

  75. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000;343:905–14.

    CAS  PubMed  Google Scholar 

  76. Lim DH, Park YS, Park BB, et al. Mitomycin-C and capecitabine as third-line chemotherapy in patients with advanced colorectal cancer: a phase II study. Cancer Chemother Pharmacol. 2005;56:10–4.

    CAS  PubMed  Google Scholar 

  77. Rosati G, Rossi A, Germano D, et al. Raltitrexed and mitomycin-C as third-line chemotherapy for colorectal cancer after combination regimens including 5-fluorouracil, irinotecan and oxaliplatin: a phase II study. Anticancer Res. 2003;23:2981–5.

    CAS  PubMed  Google Scholar 

  78. Glimelius B, Sorbye H, Balteskard L, et al. A randomized phase III multicenter trial comparing irinotecan in combination with the Nordic bolus 5-FU and folinic acid schedule or the bolus/infused de Gramont schedule (Lv5FU2) in patients with metastatic colorectal cancer. Ann Oncol. 2008;19:909–14.

    CAS  PubMed  Google Scholar 

  79. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22:23–30.

    CAS  PubMed  Google Scholar 

  80. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22:229–37.

    CAS  PubMed  Google Scholar 

  81. Grothey A, Sargent D, Goldberg RM, et al. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol. 2004;22:1209–14.

    CAS  PubMed  Google Scholar 

  82. Koopman M, Antonini NF, Douma J, et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. The Lancet. 2007;370:135–42.

    CAS  Google Scholar 

  83. Seymour MT, Maughan TS, Ledermann JA, et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007;370:143–52.

    CAS  PubMed  Google Scholar 

  84. Scheithauer W, Kornek GV, Raderer M, et al. Randomized multicenter phase II trial of two different schedules of capecitabine plus oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2003;21:1307–12.

    CAS  PubMed  Google Scholar 

  85. Cassidy J, Clarke S, Diaz-Rubio E, et al. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008;26:2006–12.

    CAS  PubMed  Google Scholar 

  86. Diaz-Rubio E, Tabernero J, Gomez-Espana A, et al. Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish cooperative group for the treatment of digestive tumours trial. J Clin Oncol. 2007;25:4224–30.

    CAS  PubMed  Google Scholar 

  87. Ducreux M, Bennouna J, Hebbar M, et al. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer. Int J Cancer 2011;128:682–90.

    Google Scholar 

  88. Porschen R, Arkenau HT, Kubicka S, et al. Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol. 2007;25:4217–23.

    CAS  PubMed  Google Scholar 

  89. Arkenau HT, Arnold D, Cassidy J, et al. Efficacy of oxaliplatin plus capecitabine or infusional fluorouracil/leucovorin in patients with metastatic colorectal cancer: a pooled analysis of randomized trials. J Clin Oncol. 2008;26:5910–7.

    CAS  PubMed  Google Scholar 

  90. Rothenberg ML, Cox JV, Butts C, et al. Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study. Ann Oncol. 2008;19:1720–6.

    CAS  PubMed  Google Scholar 

  91. Labianca R, Floriani I, Cortesi E, et al. Alternating versus continuous “FOLFIRI” in advanced colorectal cancer (ACC): a randomized “GISCAD” trial. ASCO 2006; abstract 3505.

    Google Scholar 

  92. Maughan TS, James RS, Kerr DJ, et al. Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: a multicentre randomised trial. Lancet. 2003;361:457–64.

    CAS  PubMed  Google Scholar 

  93. Tournigand C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer: a GERCOR study. J Clin Oncol. 2006;24:394–400.

    CAS  PubMed  Google Scholar 

  94. Chibaudel B, Maindrault-Goebel F, Lledo G, et al. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 study. J Clin Oncol. 2009;27:5727–33.

    CAS  PubMed  Google Scholar 

  95. Hochster HS. Stop and go: yes or no? J Clin Oncol. 2009;27:5677–9.

    PubMed  Google Scholar 

  96. Perez-Staub N, Chibaudel B, Figer A, et al. Who can benefit from chemotherapy holidays after first-line therapy for advanced colorectal cancer? A GERCOR study. ASCO 2008; abstract 4037.

    Google Scholar 

  97. Adams R, Wilson RH, Seymour MT, et al. Intermittent versus continuous oxaliplatin-fluoropyrimidine (Ox-Fp) chemotherapy (CT) in first-line treatment of patients (pts) with advanced colorectal cancer (aCRC): predictive factors (PF), quality of life (QL), and final efficacy results from the MRC COIN trial. ASCO 2010; abstract 3525.

    Google Scholar 

  98. Maughan T, Adams R, Wilson R, et al. Chemotherapy-free intervals for patients with metastatic colorectal cancer remain an option. J Clin Oncol. 2010;28:e275–6.

    PubMed  Google Scholar 

  99. Tabernero J, Aranda E, Gomez A, et al. Phase III study of first-line XELOX plus bevacizumab (BEV) for 6 cycles followed by XELOX plus BEV or single-agent (s/a) BEV as maintenance therapy in patients (pts) with metastatic colorectal cancer (mCRC): The MACRO Trial (Spanish Cooperative Group for the Treatment of Digestive Tumours [TTD]). ASCO 2010; abstract 3501.

    Google Scholar 

  100. Pfeiffer P, Qvortrup C, Bjerregaard JK. Current status of treatment of metastatic colorectal cancer with special reference to cetuximab and elderly patients. Onco Targets and Therapy. 2009;2:17–27.

    CAS  Google Scholar 

  101. Sargent DJ, Goldberg RM, Jacobson SD, et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med. 2001;345:1091–7.

    CAS  PubMed  Google Scholar 

  102. Goldberg RM, Tabah-Fisch I, Bleiberg H, et al. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol. 2006;24:4085–91.

    CAS  PubMed  Google Scholar 

  103. Folprecht G, Seymour MT, Saltz L, et al. Irinotecan/fluorouracil combination in first-line therapy of older and younger patients with metastatic colorectal cancer: combined analysis of 2,691 patients in randomized controlled trials. J Clin Oncol. 2008;26:1443–51.

    CAS  PubMed  Google Scholar 

  104. Sanoff HK, Bleiberg H, Goldberg RM. Managing older patients with colorectal cancer. J Clin Oncol. 2007;25:1891–7.

    PubMed  Google Scholar 

  105. McKibbin T, Frei CR, Greene RE, Kwan P, Simon J, Koeller JM. Disparities in the use of chemotherapy and monoclonal antibody therapy for elderly advanced colorectal cancer patients in the community oncology setting. Oncologist. 2008;13:876–85.

    CAS  PubMed  Google Scholar 

  106. Tournigand C, Andre T, Bachet J, et al. FOLFOX4 as adjuvant therapy in elderly patients (pts) with colon cancer (CC): subgroup analysis of the MOSAIC trial. ASCO 2010; abstract 3522.

    Google Scholar 

  107. Haller DG, Cassidy J, Tabernero J, et al. Efficacy findings from a randomized phase III trial of capecitabine plus oxaliplatin versus bolus 5-FU/LV for stage III colon cancer (NO16968): impact of age on disease-free survival (DFS). ASCO 2010; abstract 3521.

    Google Scholar 

  108. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.

    CAS  PubMed  Google Scholar 

  109. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (5-fluorouracil)/leucovorin (LV) with 5-fluorouracil/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21:60–5.

    CAS  PubMed  Google Scholar 

  110. Kabbinavar F, Shulz J, McCleod M, et al. Addition of bevacizumab to bolus fluorouracil/leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005;23:3697–705.

    CAS  PubMed  Google Scholar 

  111. Tebbutt NC, Wilson K, Gebski VJ, et al. Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian gastrointestinal trials group randomized phase III MAX study. J Clin Oncol. 2010;28:3191–8.

    CAS  PubMed  Google Scholar 

  112. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–9.

    CAS  PubMed  Google Scholar 

  113. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group study E3200. J Clin Oncol. 2007;25:1539–44.

    CAS  PubMed  Google Scholar 

  114. Pfeiffer P, Qvortrup C, Eriksen JG. Current role of antibody therapy in patients with metastatic colorectal cancer. Oncogene. 2007;26:3661–78.

    CAS  PubMed  Google Scholar 

  115. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337–45.

    CAS  PubMed  Google Scholar 

  116. Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357:2040–8.

    CAS  PubMed  Google Scholar 

  117. Van Cutsem E, Peeters M, Siena S, 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;25:1658–64.

    PubMed  Google Scholar 

  118. Nielsen DL, Pfeiffer P, Jensen BV. Re-treatment with cetuximab in patients with severe hypersensitivity reactions to cetuximab. Two case reports. Acta Oncol. 2006;45(8):1137–8.

    PubMed  Google Scholar 

  119. Nielsen DL, Pfeiffer P, Jensen BV. Six cases of treatment with panitumumab in patients with severe hypersensitivity reactions to cetuximab. Ann Oncol. 2009;20:798.

    CAS  PubMed  Google Scholar 

  120. Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:2311–9.

    CAS  PubMed  Google Scholar 

  121. Peeters M, Price TJ, Cervates A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28:4706–13.

    Google Scholar 

  122. Tabernero J, Pfeiffer P, Cervantes A. Two-weekly administration of cetuximab in the treatment of metastatic colorectal cancer: an effective, more convenient alternative to weekly administration? Oncologist. 2008;13:113–9.

    CAS  PubMed  Google Scholar 

  123. Pfeiffer P, Nielsen D, Bjerregaard J, Qvortrup C, Yilmaz M, Jensen BV. Biweekly cetuximab and irinotecan as third line therapy in patients with advanced colorectal cancer after failure to irinotecan, oxaliplatin and 5-fluorouracil. Ann Oncol. 2008;2008(19):1141–5.

    Google Scholar 

  124. Jensen BV, Schou JV, Johannesen HH, et al. Cetuximab every second week with irinotecan in patients with metastatic colorectal cancer refractory to 5-FU, oxaliplatin, and irinotecan: KRAS mutation status and efficacy. ASCO 2010; abstract 3573.

    Google Scholar 

  125. Macarulla T, Ramos FJ, Elez E, Capdevila J, Peralta S, Tabernero J. Update on novel strategies to optimize cetuximab therapy in patients with metastatic colorectal cancer. Clin Colorectal Cancer. 2008;7:300–8.

    CAS  PubMed  Google Scholar 

  126. Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–17.

    PubMed  Google Scholar 

  127. Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663–71.

    CAS  PubMed  Google Scholar 

  128. Douillard JY, Siena S, Cassidy J, Tabernero J, 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;28:4697–705.

    CAS  PubMed  Google Scholar 

  129. Maughan T, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based combination chemotherapy (CT) in patients with KRAS wild-type advanced colorectal cancer (ACRC): a randomised superiority trial (MRC COIN). ECCO 2009; abstract 6 LBA.

    Google Scholar 

  130. Lenz HJ, Chu E, Grothey A. KRAS mutation in metastatic colorectal cancer and its impact on the use of EGFR inhibitors. Clin Adv Hematol Oncol. 2008;6:1–13.

    PubMed  Google Scholar 

  131. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626–34.

    CAS  PubMed  Google Scholar 

  132. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–65.

    CAS  PubMed  Google Scholar 

  133. Di Fiore F, Van Cutsem E, Laurent-Puig P, et al. Role of KRAS mutation in predicting response, progression-free survival, and overall survival in irinotecan-refractory patients treated with cetuximab plus irinotecan for a metastatic colorectal cancer: analysis of 281 individual data from published series. ASCO 2008; 4035.

    Google Scholar 

  134. Van Cutsem E, Lang I, Folprecht G, et al. Cetuximab plus FOLFIRI in the treatment of metastatic colorectal cancer (mCRC): the influence of KRAS and BRAF biomarkers on outcome: updated data from the CRYSTAL trial. ASCO GI 2010; abstract 281.

    Google Scholar 

  135. Saltz LB, Lenz HJ, Kindler HL, 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;25:4557–61.

    CAS  PubMed  Google Scholar 

  136. Hecht JR, Mitchell E, Chidiac T, 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;27:672–80.

    CAS  PubMed  Google Scholar 

  137. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360:563–72.

    CAS  PubMed  Google Scholar 

  138. Pfeiffer P, Rasmussen F. A multidisciplinary approach to the treatment of colorectal liver metastases is mandatory. Acta Radiol. 2009;50:707–8.

    PubMed  Google Scholar 

  139. Adam R, Haller DG, Poston G. Toward optimized front-line therapeutic strategies in patients with metastatic colorectal cancer–an expert review from the International Congress on Anti-Cancer Treatment (ICACT) 2009. Ann Oncol. 2010;21:1579–84.

    CAS  PubMed  Google Scholar 

  140. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371:1007–16.

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Sorbye H, Mauer M, Gruenberger T, et al. Predictive factors for the effect of perioperative FOLFOX for resectable liver metastasis in colorectal cancer patients (EORTC phase III study 40983). ASCO 2010; abstract 3544.

    Google Scholar 

  142. Mitry E, Fields A, Bleiberg H, et al. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of Two randomized trials. J Clin Oncol. 2008;26:4906–11.

    CAS  PubMed  Google Scholar 

  143. Folprecht G, Grothey A, Alberts S, et al. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol. 2005;16:1311–9.

    CAS  PubMed  Google Scholar 

  144. Mulier S, Ni Y, Jamart J, Michel L, Marchal G, Ruers T. Radiofrequency ablation versus resection for respectable colorectal liver metastases: time for a randomized trial? Ann Surg Oncol. 2008;15:144–57.

    PubMed  Google Scholar 

  145. Curley SA. Radiofrequency ablation versus resection for resectable colorectal liver metastases: time for a randomized trial? Ann Surg Oncol. 2008;15:11–3.

    PubMed Central  PubMed  Google Scholar 

  146. Robinson PJA. The effects of cancer chemotherapy on liver imaging. Eur J Radiol. 2009;19:1752–62.

    Google Scholar 

  147. Poultsides GA, Servais EL, Saltz LB, et al. Outcome of primary tumour in patients with synchronous stage IV colorectal cancer receiving combination chemotherapy without surgery as initial treatment. J Clin Oncol. 2009;27:3379–84.

    PubMed Central  PubMed  Google Scholar 

  148. Kopetz S, Chang GJ, Overman MJ, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol. 2009;27:3677–83.

    PubMed Central  PubMed  Google Scholar 

  149. Dy GK, Hobday TJ, Nelson G, et al. Long-term survivors of metastatic colorectal cancer treated with systemic chemotherapy alone: a North Central Cancer Treatment Group review of 3811 patients, N0144. Clin Colorectal Cancer. 2009;8:88–93.

    PubMed Central  Google Scholar 

  150. Sanoff HK, Sargent DJ, Campbell ME, et al. Five-year data and prognostic factor analysis of oxaliplatin and irinotecan combinations for advanced colorectal cancer: N9741. J Clin Oncol. 2008;26:5721–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  151. Sorbye H, Pfeiffer P, Cavalli-Bjorkman N, et al. Clinical trial enrollment, patient characteristics, and survival differences in prospectively registered metastatic colorectal cancer patients. Cancer. 2009;115:4679–87.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Oncology, Odense University Hospital, Sdr. Boulevard 29, DK – 5000, Odense, Denmark

    Per Pfeiffer MD, PhD & Camilla Qvortrup

  2. Department of Medical Oncology, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona, Spain

    Josep Tabernero

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  1. Per Pfeiffer MD, PhD
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  2. Camilla Qvortrup
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Correspondence to Per Pfeiffer MD, PhD .

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  1. Institute of Regional Health Science, University of Southern Denmark, Odense, Denmark

    Gunnar Baatrup

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Pfeiffer, P., Qvortrup, C., Tabernero, J. (2015). Systemic Therapy for Patients with Colorectal Cancer: State of the Art. In: Baatrup, G. (eds) Multidisciplinary Treatment of Colorectal Cancer. Springer, Cham. https://doi.org/10.1007/978-3-319-06142-9_13

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