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转移性结直肠癌的全身化疗：已完成的临床试验

Authors
Jeffrey W Clark, MD
Axel Grothey, MD
Section Editor
Richard M Goldberg, MD
Deputy Editor
Diane MF Savarese, MD
Translators
李达, 副主任医师

引言

大多数转移性结肠或直肠癌患者不能被治愈，但有肝脏和/或肺部孤立性病变的患者亚组可能可以手术治愈。对于其他转移性结直肠癌患者(metastatic colorectal cancer, mCRC)，治疗是姑息性的，通常采用全身化疗。 (参见“潜在可切除的结直肠癌肝转移的处理”和“肺转移灶的外科切除：各种组织学的结局”和“肺转移瘤手术切除的益处、指征、术前评估及手术技巧”)

在过去几十年，5-氟尿嘧啶(fluorouracil, 5-FU)曾是唯一的有效药物。自2000年以来，随着以下药物的批准，这种状况有了重大的改变，它们包括：伊立替康；奥沙利铂；3种人源化单克隆抗体(monoclonal antibody, MoAb)，这3种MoAb分别为，以血管内皮生长因子(vascular endothelial growth factor, VEGF)为靶点的贝伐珠单抗，以及以表皮生长因子受体(epidermal growth factor receptor, ERGF)为靶点的西妥昔单抗和帕尼单抗；静脉用阿柏西普，是一种重组融合蛋白，由人VEGF受体1和2的VEGF结合部分与人免疫球蛋白G1的Fc段融合而成；瑞格非尼，是一种对如下激酶具有口服活性的抑制剂：血管生成性酪氨酸激酶(包括VEGF受体1、2和3)，以及参与正常细胞功能和病理过程的数种其他膜结合和细胞内激酶；曲氟尿苷-替吡嘧啶(TAS-102)，是一种口服细胞毒性药物，包含核苷类似物曲氟尿苷(一种抑制胸苷酸合成酶的细胞毒性抗代谢物，在肿瘤细胞内修饰后，被并入DNA，造成链断裂)和替吡嘧啶(一种强效胸苷磷酸化酶抑制剂，可以抑制曲氟尿苷代谢，还有抗血管生成性质)。尚不确定这些药物的组合及应用顺序的最佳方案。

本专题将总结评价不可切除mCRC全身化疗的临床试验数据。治疗的一般原则和特异性治疗的推荐，包括使用生物标记物来选择治疗和治疗方案的概述，以及全身疗法在以降低可能可切除结直肠癌(colorectal cancer, CRC)肝转移瘤分期为目的患者中的使用，均参见其他专题。 (参见“转移性结直肠癌的全身化疗：一般原则”和“不可切除的转移性结直肠癌的全身化疗：治疗推荐”和“小肠癌和大肠癌的治疗方案”和“潜在可切除的结直肠癌肝转移的处理”，关于‘肝转移切除术后的治疗’一节)

氟尿嘧啶

氟尿嘧啶类(如5-FU)用于治疗mCRC已有40余年的历史。其细胞毒性的主要机制被认为是通过抑制胸苷酸合酶(thymidylate synthase, TS)损害的DNA合成。RNA合成抑制可能进一步促成快速给药方案的细胞毒性[1]。

氟尿嘧啶可被快速代谢为非活性化合物。患者间关键代谢酶二氢嘧啶脱氢酶(dihydropyrimidine dehydrogenase, DPD)的活性差异可能是毒性反应差异的原因[2]。缺乏DPD的个体会发生严重副作用，可能会致命。 (参见“化疗药物的肠道毒性”)

                                                                  

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References
Top
  1. 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.
  2. van Kuilenburg AB, Muller EW, Haasjes J, et al. Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil: frequency of the common IVS14+1G>A mutation causing DPD deficiency. Clin Cancer Res 2001; 7:1149.
  3. O'Dwyer PJ, Manola J, Valone FH, et al. Fluorouracil modulation in colorectal cancer: lack of improvement with N -phosphonoacetyl- l -aspartic acid or oral leucovorin or interferon, but enhanced therapeutic index with weekly 24-hour infusion schedule--an Eastern Cooperative Oncology Group/Cancer and Leukemia Group B Study. J Clin Oncol 2001; 19:2413.
  4. Meta-analysis Group In Cancer, Piedbois P, Rougier P, et al. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998; 16:301.
  5. Meta-Analysis Group In Cancer, Lévy E, Piedbois P, et al. Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors. J Clin Oncol 1998; 16:3537.
  6. Mini E, Trave F, Rustum YM, Bertino JR. Enhancement of the antitumor effects of 5-fluorouracil by folinic acid. Pharmacol Ther 1990; 47:1.
  7. Thirion P, Michiels S, Pignon JP, et al. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis. J Clin Oncol 2004; 22:3766.
  8. Buyse M, Thirion P, Carlson RW, et al. Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer. Lancet 2000; 356:373.
  9. Kovoor PA, Karim SM, Marshall JL. Is levoleucovorin an alternative to racemic leucovorin? A literature review. Clin Colorectal Cancer 2009; 8:200.
  10. Poon MA, O'Connell MJ, Moertel CG, et al. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 1989; 7:1407.
  11. Jäger E, Heike M, Bernhard H, et al. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1. J Clin Oncol 1996; 14:2274.
  12. Petrelli N, Herrera L, Rustum Y, et al. A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol 1987; 5:1559.
  13. Buroker TR, O'Connell MJ, Wieand HS, et al. Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol 1994; 12:14.
  14. Wang WS, Lin JK, Chiou TJ, et al. Randomized trial comparing weekly bolus 5-fluorouracil plus leucovorin versus monthly 5-day 5-fluorouracil plus leucovorin in metastatic colorectal cancer. Hepatogastroenterology 2000; 47:1599.
  15. Saltz LB. Another study of how to give fluorouracil? J Clin Oncol 2003; 21:3711.
  16. de Gramont A, Bosset JF, Milan C, et al. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol 1997; 15:808.
  17. Lévi F, Zidani R, Misset JL. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Lancet 1997; 350:681.
  18. Lincoln DW 2nd, Hrushesky WJ, Wood PA. Circadian organization of thymidylate synthase activity in normal tissues: a possible basis for 5-fluorouracil chronotherapeutic advantage. Int J Cancer 2000; 88:479.
  19. Curé H, Chevalier V, Adenis A, et al. Phase II trial of chronomodulated infusion of high-dose fluorouracil and l-folinic acid in previously untreated patients with metastatic colorectal cancer. J Clin Oncol 2002; 20:1175.
  20. Kopec JA, Yothers G, Ganz PA, et al. Quality of life in operable colon cancer patients receiving oral compared with intravenous chemotherapy: results from National Surgical Adjuvant Breast and Bowel Project Trial C-06. J Clin Oncol 2007; 25:424.
  21. Borner MM, Schoffski P, de Wit R, et al. Patient preference 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.
  22. Schüller J, Cassidy J, Dumont E, et al. Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 2000; 45:291.
  23. 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.
  24. 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.
  25. Hoff PM, Pazdur R, Lassere Y, et al. Phase II study of capecitabine in patients with fluorouracil-resistant metastatic colorectal carcinoma. J Clin Oncol 2004; 22:2078.
  26. Lee JJ, Kim TM, Yu SJ, et al. Single-agent capecitabine in patients with metastatic colorectal cancer refractory to 5-fluorouracil/leucovorin chemotherapy. Jpn J Clin Oncol 2004; 34:400.
  27. Cassidy J, Twelves C, Van Cutsem E, et al. First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Ann Oncol 2002; 13:566.
  28. Feliu J, Escudero P, Llosa F, et al. Capecitabine as first-line treatment for patients older than 70 years with metastatic colorectal cancer: an oncopaz cooperative group study. J Clin Oncol 2005; 23:3104.
  29. Hennig IM, Naik JD, Brown S, et al. Severe sequence-specific toxicity when capecitabine is given after Fluorouracil and leucovorin. J Clin Oncol 2008; 26:3411.
  30. Sulkes A, Benner SE, Canetta RM. Uracil-ftorafur: an oral fluoropyrimidine active in colorectal cancer. J Clin Oncol 1998; 16:3461.
  31. 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.
  32. 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.
  33. Jackman AL, Taylor GA, Gibson W, et al. ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in vitro and in vivo: a new agent for clinical study. Cancer Res 1991; 51:5579.
  34. Maughan TS, James RD, Kerr DJ, et al. Comparison of survival, palliation, and quality of life with three chemotherapy regimens in metastatic colorectal cancer: a multicentre randomised trial. Lancet 2002; 359:1555.
  35. Cunningham D, Zalcberg JR, Rath U, et al. Final results of a randomised trial comparing 'Tomudex' (raltitrexed) with 5-fluorouracil plus leucovorin in advanced colorectal cancer. "Tomudex" Colorectal Cancer Study Group. Ann Oncol 1996; 7:961.
  36. Cocconi G, Cunningham D, Van Cutsem E, et al. Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. Tomudex Colorectal Cancer Study Group. J Clin Oncol 1998; 16:2943.
  37. Cortinovis D, Bajetta E, Di Bartolomeo M, et al. Raltitrexed plus oxaliplatin in the treatment of metastatic colorectal cancer. Tumori 2004; 90:186.
  38. Comella P, Casaretti R, Crucitta E, et al. Oxaliplatin plus raltitrexed and leucovorin-modulated 5-fluorouracil i.v. bolus: a salvage regimen for colorectal cancer patients. Br J Cancer 2002; 86:1871.
  39. Laudani A, Gebbia V, Leonardi V, et al. Activity and toxicity of oxaliplatin plus raltitrexed in 5-fluorouracil refractory metastatic colorectal adeno-carcinoma. Anticancer Res 2004; 24:1139.
  40. Aparicio J, Vicent JM, Maestu I, et al. Multicenter phase II trial evaluating a three-weekly schedule of irinotecan plus raltitrexed in patients with 5-fluorouracil-refractory advanced colorectal cancer. Ann Oncol 2003; 14:1121.
  41. Weingart SN, Brown E, Bach PB, et al. NCCN Task Force Report: Oral chemotherapy. J Natl Compr Canc Netw 2008; 6 Suppl 3:S1.
  42. 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.
  43. Rougier P, Bugat R, Douillard JY, et al. Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 1997; 15:251.
  44. Cunningham D, Pyrhönen 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.
  45. 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.
  46. Michael M, Hedley D, Oza A, et al. The palliative benefit of irinotecan in 5-fluorouracil-refractory colorectal cancer: its prospective evaluation by a Multicenter Canadian Trial. Clin Colorectal Cancer 2002; 2:93.
  47. Fuchs CS, Moore MR, Harker G, et al. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol 2003; 21:807.
  48. 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.
  49. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000; 343:905.
  50. Köhne 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.
  51. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol 2007; 25:4779.
  52. Delaunoit T, Goldberg RM, Sargent DJ, et al. Mortality associated with daily bolus 5-fluorouracil/leucovorin administered in combination with either irinotecan or oxaliplatin: results from Intergroup Trial N9741. Cancer 2004; 101:2170.
  53. Rothenberg ML, Meropol NJ, Poplin EA, et al. Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol 2001; 19:3801.
  54. Van Cutsem E, Douillard JY, Köhne CH. Toxicity of irinotecan in patients with colorectal cancer. N Engl J Med 2001; 345:1351.
  55. 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.
  56. Falcone A, Di Paolo A, Masi G, et al. Sequence effect of irinotecan and fluorouracil treatment on pharmacokinetics and toxicity in chemotherapy-naive metastatic colorectal cancer patients. J Clin Oncol 2001; 19:3456.
  57. Ratain MJ. Irinotecan dosing: does the CPT in CPT-11 stand for "Can't Predict Toxicity"? J Clin Oncol 2002; 20:7.
  58. Mathijssen RH, Verweij J, de Jonge MJ, et al. Impact of body-size measures on irinotecan clearance: alternative dosing recommendations. J Clin Oncol 2002; 20:81.
  59. Felici A, Verweij J, Sparreboom A. Dosing strategies for anticancer drugs: the good, the bad and body-surface area. Eur J Cancer 2002; 38:1677.
  60. Miya T, Goya T, Fujii H, et al. Factors affecting the pharmacokinetics of CPT-11: the body mass index, age and sex are independent predictors of pharmacokinetic parameters of CPT-11. Invest New Drugs 2001; 19:61.
  61. Raymond E, Boige V, Faivre S, et al. Dosage adjustment and pharmacokinetic profile of irinotecan in cancer patients with hepatic dysfunction. J Clin Oncol 2002; 20:4303.
  62. Mathijssen RH, Marsh S, Karlsson MO, et al. Irinotecan pathway genotype analysis to predict pharmacokinetics. Clin Cancer Res 2003; 9:3246.
  63. Michael M, Thompson M, Hicks RJ, et al. Relationship of hepatic functional imaging to irinotecan pharmacokinetics and genetic parameters of drug elimination. J Clin Oncol 2006; 24:4228.
  64. Innocenti F, Kroetz DL, Schuetz E, et al. Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics. J Clin Oncol 2009; 27:2604.
  65. Souglakos J, Ziras N, Kakolyris S, et al. Randomised phase-II trial of CAPIRI (capecitabine, irinotecan) plus bevacizumab vs FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) plus bevacizumab as first-line treatment of patients with unresectable/metastatic colorectal cancer (mCRC). Br J Cancer 2012; 106:453.
  66. Pectasides D, Papaxoinis G, Kalogeras KT, et al. XELIRI-bevacizumab versus FOLFIRI-bevacizumab as first-line treatment in patients with metastatic colorectal cancer: a Hellenic Cooperative Oncology Group phase III trial with collateral biomarker analysis. BMC Cancer 2012; 12:271.
  67. Skof E, Rebersek M, Hlebanja Z, Ocvirk J. Capecitabine plus Irinotecan (XELIRI regimen) compared to 5-FU/LV plus Irinotecan (FOLFIRI regimen) as neoadjuvant treatment for patients with unresectable liver-only metastases of metastatic colorectal cancer: a randomised prospective phase II trial. BMC Cancer 2009; 9:120.
  68. Ducreux M, Adenis A, Pignon JP, et al. Efficacy and safety of bevacizumab-based combination regimens in patients with previously untreated metastatic colorectal cancer: final results from a randomised phase II study of bevacizumab plus 5-fluorouracil, leucovorin plus irinotecan versus bevacizumab plus capecitabine plus irinotecan (FNCLCC ACCORD 13/0503 study). Eur J Cancer 2013; 49:1236.
  69. Köhne CH, De Greve J, Hartmann JT, et al. Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer. EORTC study 40015. Ann Oncol 2008; 19:920.
  70. Guo Y, Shi M, Shen X, et al. Capecitabine plus irinotecan versus 5-FU/leucovorin plus irinotecan in the treatment of colorectal cancer: a meta-analysis. Clin Colorectal Cancer 2014; 13:110.
  71. Haller DG, Cassidy J, Clarke S, et al. Tolerability of fluoropyrimidines appears to differ by region (abstract). J Clin Oncol 2006; 24:149s.
  72. 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. Lancet 2007; 370:135.
  73. Mayer RJ. Should capecitabine replace infusional fluorouracil and leucovorin when combined with oxaliplatin in metastatic colorectal cancer? J Clin Oncol 2007; 25:4165.
  74. Yasui H, Muro K, Shimada Y, et al. A phase 3 non-inferiority study of 5-FU/l-leucovorin/irinotecan (FOLFIRI) versus irinotecan/S-1 (IRIS) as second-line chemotherapy for metastatic colorectal cancer: updated results of the FIRIS study. J Cancer Res Clin Oncol 2015; 141:153.
  75. Tournigand C, André 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.
  76. Recchia F, Saggio G, Nuzzo A, et al. Multicentre phase II study of bifractionated CPT-11 with bimonthly leucovorin and 5-fluorouracil in patients with metastatic colorectal cancer pretreated with FOLFOX. Br J Cancer 2004; 91:1442.
  77. Bidard FC, Tournigand C, André T, et al. Efficacy of FOLFIRI-3 (irinotecan D1,D3 combined with LV5-FU) or other irinotecan-based regimens in oxaliplatin-pretreated metastatic colorectal cancer in the GERCOR OPTIMOX1 study. Ann Oncol 2009; 20:1042.
  78. Grothey A, Sargent D, Goldberg RM, Schmoll HJ. 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.
  79. Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med 2005; 352:476.
  80. deBraud F, Munzone E, Nolè F, et al. Synergistic activity of oxaliplatin and 5-fluorouracil in patients with metastatic colorectal cancer with progressive disease while on or after 5-fluorouracil. Am J Clin Oncol 1998; 21:279.
  81. Armand JP, Boige V, Raymond E, et al. Oxaliplatin in colorectal cancer: an overview. Semin Oncol 2000; 27:96.
  82. Bécouarn Y, Ychou M, Ducreux M, et al. Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers. J Clin Oncol 1998; 16:2739.
  83. 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.
  84. 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.
  85. Grothey A, Deschler B, Kroening H, et al. Phase III study of bolus 5-fluorouracil (5-FU)/folinic acid (FA) (Mayo) vs weekly high-dose 24h 5-FU infusion/FA + oxaliplatin in advanced colorectal cancer (abstract). Proc Am Soc Clin Oncol 2002; 21:129a.
  86. 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.
  87. Colucci G, Gebbia V, Paoletti G, et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol 2005; 23:4866.
  88. Ducreux M, Malka D, Mendiboure J, et al. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial. Lancet Oncol 2011; 12:1032.
  89. Ashley AC, Sargent DJ, Alberts SR, et al. Updated efficacy and toxicity analysis of irinotecan and oxaliplatin (IROX) : intergroup trial N9741 in first-line treatment of metastatic colorectal cancer. Cancer 2007; 110:670.
  90. Yamakazi K, Nagase M, Tamagawa H, et al. A randomized phase III trial of mFOLFOX6 plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment for metastatic colorectal cancer: West Japan Oncology Group study 4407G (WJOG4407G) (abstract). J Clin Oncol 32: 5s, 2014 (suppl; abstr 3534). Abstract available online at http://meetinglibrary.asco.org/content/128765-144 (Accessed on June 12, 2014).
  91. Sørbye H, Glimelius B, Berglund A, et al. Multicenter phase II study of Nordic fluorouracil and folinic acid bolus schedule combined with oxaliplatin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2004; 22:31.
  92. Feliu J, Salud A, Escudero P, et al. XELOX (capecitabine plus oxaliplatin) as first-line treatment for elderly patients over 70 years of age with advanced colorectal cancer. Br J Cancer 2006; 94:969.
  93. Cassidy J, Tabernero J, Twelves C, et al. XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 2004; 22:2084.
  94. 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.
  95. Zeuli M, Nardoni C, Pino MS, et al. Phase II study of capecitabine and oxaliplatin as first-line treatment in advanced colorectal cancer. Ann Oncol 2003; 14:1378.
  96. Shields AF, Zalupski MM, Marshall JL, Meropol NJ. Treatment of advanced colorectal carcinoma with oxaliplatin and capecitabine: a phase II trial. Cancer 2004; 100:531.
  97. Hochster HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol 2008; 26:3523.
  98. Comella P, Natale D, Farris A, et al. Capecitabine plus oxaliplatin for the first-line treatment of elderly patients with metastatic colorectal carcinoma: final results of the Southern Italy Cooperative Oncology Group Trial 0108. Cancer 2005; 104:282.
  99. 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.
  100. Díaz-Rubio E, Tabernero J, Gómez-España 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 Tumors Trial. J Clin Oncol 2007; 25:4224.
  101. Cassidy J, Clarke S, Díaz-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.
  102. 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.
  103. 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.
  104. Hong YS, Park YS, Lim HY, et al. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol 2012; 13:1125.
  105. Yamada Y, Takahari D, Matsumoto H, et al. Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol 2013; 14:1278.
  106. Rothenberg ML, Oza AM, Burger B, et al. Final results of a phase III trial of 5-FU/Leucovorin versus oxaliplatin versus the combination in patients with metastatic colorectal cancer following irinotecan, 5-FU and leucovorin (abstract). Proc Am Soc Clin Oncol 2003; 22:252a.
  107. Kemeny N, Garay CA, Gurtler J, et al. Randomized multicenter phase II trial of bolus plus infusional fluorouracil/leucovorin compared with fluorouracil/leucovorin plus oxaliplatin as third-line treatment of patients with advanced colorectal cancer. J Clin Oncol 2004; 22:4753.
  108. 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.
  109. Hochster H, Chachoua A, Speyer J, et al. Oxaliplatin with weekly bolus fluorouracil and low-dose leucovorin as first-line therapy for patients with colorectal cancer. J Clin Oncol 2003; 21:2703.
  110. Maindrault-Goebel F, de Gramont A, Louvet C, et al. Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer. Oncology Multidisciplinary Research Group (GERCOR). Ann Oncol 2000; 11:1477.
  111. Bécouarn Y, Gamelin E, Coudert B, et al. Randomized multicenter phase II study comparing a combination of fluorouracil and folinic acid and alternating irinotecan and oxaliplatin with oxaliplatin and irinotecan in fluorouracil-pretreated metastatic colorectal cancer patients. J Clin Oncol 2001; 19:4195.
  112. Stathopoulos GP, Rigatos SK, Stathopoulos JG, et al. Efficacy and tolerability of oxaliplatin plus irinotecan 5-fluouracil and leucovorin regimen in advanced stage colorectal cancer patients pretreated with irinotecan 5-fluouracil and leucovorin. Am J Clin Oncol 2005; 28:565.
  113. Souglakos J, Androulakis N, Syrigos K, et al. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer 2006; 94:798.
  114. Goetz MP, Erlichman C, Windebank AJ, et al. Phase I and pharmacokinetic study of two different schedules of oxaliplatin, irinotecan, Fluorouracil, and leucovorin in patients with solid tumors. J Clin Oncol 2003; 21:3761.
  115. Schalhorn A, Ludwig F, Quietzsch D, et al. Phase III Trial of Irinotecan Plus Oxalipatin (IROX) Versus Irinotecan Plus 5-FU/Folinic Acid (FOLFIRI) as First-Line Treatment of Metastatic Colorectal Cancer (CRC): The FIRE-Trial (abstract). J Clin Oncol 2005; 23:250s.
  116. Falcone A, Ricci S, Brunetti I, 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; 25:1670.
  117. Hoff PM, Wolff RA, Xiong H, et al. Phase II trial of combined irinotecan and oxaliplatin given every 3 weeks to patients with metastatic colorectal cancer. Cancer 2006; 106:2241.
  118. 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.
  119. Masi G, Vasile E, Loupakis F, et al. Randomized trial of two induction chemotherapy regimens in metastatic colorectal cancer: an updated analysis. J Natl Cancer Inst 2011; 103:21.
  120. Fischer von Weikersthal L, Schalhorn A, Stauch M, et al. Phase III trial of irinotecan plus infusional 5-fluorouracil/folinic acid versus irinotecan plus oxaliplatin as first-line treatment of advanced colorectal cancer. Eur J Cancer 2011; 47:206.
  121. Masi G, Loupakis F, Pollina L, et al. Long-term outcome of initially unresectable metastatic colorectal cancer patients treated with 5-fluorouracil/leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) followed by radical surgery of metastases. Ann Surg 2009; 249:420.
  122. Loupakis F, Cremolini C, Masi G, et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 2014; 371:1609.
  123. Falcone A, Cremolini C, Masi G, et al. FOLFOXIRI/Bevacizumab versus FOLFIRI/bevacizumab as first-line treatment in unresectable metastatic colorectal cancer patients: Results of the phase III TRIBE trial by GONO group (abstract). J Clin Oncol 2013; 31:(suppl; abstr 3505). http://meetinglibrary.asco.org/content/115186-132 (Accessed on June 13, 2013).
  124. Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol 2015; 16:1306.
  125. Hurwitz HI, Tebbutt NC, Kabbinavar F, et al. Efficacy and safety of bevacizumab in metastatic colorectal cancer: pooled analysis from seven randomized controlled trials. Oncologist 2013; 18:1004.
  126. 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.
  127. Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol 2008; 26:689.
  128. Stathopoulos GP, Batziou C, Trafalis D, et al. Treatment of colorectal cancer with and without bevacizumab: a phase III study. Oncology 2010; 78:376.
  129. Passardi A, Nanni O, Tassinari D, et al. Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann Oncol 2015; 26:1201.
  130. 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.
  131. Saltz LB, Clarke S, Díaz-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.
  132. Vincenzi B, Santini D, Russo A, et al. Bevacizumab in association with de Gramont 5-fluorouracil/folinic acid in patients with oxaliplatin-, irinotecan-, and cetuximab-refractory colorectal cancer: a single-center phase 2 trial. Cancer 2009; 115:4849.
  133. Kabbinavar FF, Schulz J, McCleod M, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 2005; 23:3697.
  134. Hurwitz HI, Fehrenbacher L, Hainsworth JD, et al. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol 2005; 23:3502.
  135. Kabbinavar FF, Hambleton J, Mass RD, et al. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol 2005; 23:3706.
  136. Chen HX, Mooney M, Boron M, et al. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301. J Clin Oncol 2006; 24:3354.
  137. 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.
  138. Grothey A, Sugrue MM, Purdie DM, et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol 2008; 26:5326.
  139. Bekaii-Saab TS, Grothey A, Bendell JC, et al. Effectiveness and safety of second-line (2L) irinotecan- and oxaliplatin-based regimens after first-line (1L) bevacizumab (BV)-containing treatment (tx) for metastatic colorectal cancer (mCRC): Results from the ARIES observational cohort study (abstract). J clin oncol 2012; 30 (suppl 4): abstract 535. Abstract available online at http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=115&abstractID=88734 (Accessed on March 06, 2012).
  140. Cartwright TH, Yim YM, Yu E, et al. Survival outcomes of bevacizumab beyond progression in metastatic colorectal cancer patients treated in US community oncology. Clin Colorectal Cancer 2012; 11:238.
  141. Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol 2013; 14:29.
  142. Masi G, Salvatore L, Boni L, et al. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: final results of the randomized BEBYP trial. Ann Oncol 2015; 26:724.
  143. Ranpura V, Hapani S, Wu S. Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis. JAMA 2011; 305:487.
  144. Yeh J, Frieze D, Martins R, Carr L. Clinical utility of routine proteinuria evaluation in treatment decisions of patients receiving bevacizumab for metastatic solid tumors. Ann Pharmacother 2010; 44:1010.
  145. Maitland ML, Bakris GL, Black HR, et al. Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. J Natl Cancer Inst 2010; 102:596.
  146. Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A 2002; 99:11393.
  147. Van Cutsem E, Tabernero J, Lakomy R, 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; 30:3499.
  148. Tabernero J, Van Cutsem E, Lakomý R, et al. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer 2014; 50:320.
  149. Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 2015; 16:499.
  150. http://www.cancer.gov/cancertopics/treatment/drugs/fda-ramucirumab#crc (Accessed on May 01, 2015).
  151. Goldstein DA, El-Rayes BF. Considering Efficacy and Cost, Where Does Ramucirumab Fit in the Management of Metastatic Colorectal Cancer? Oncologist 2015; 20:981.
  152. Kawamoto K, Onodera H, Kan S, et al. Possible paracrine mechanism of insulin-like growth factor-2 in the development of liver metastases from colorectal carcinoma. Cancer 1999; 85:18.
  153. Messa C, Russo F, Caruso MG, Di Leo A. EGF, TGF-alpha, and EGF-R in human colorectal adenocarcinoma. Acta Oncol 1998; 37:285.
  154. el-Hariry I, Pignatelli M, Lemoine N. Fibroblast growth factor 1 and fibroblast growth factor 2 immunoreactivity in gastrointestinal tumours. J Pathol 1997; 181:39.
  155. Allegra CJ, Rumble RB, Hamilton SR, et al. Extended RAS Gene Mutation Testing in Metastatic Colorectal Carcinoma to Predict Response to Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Therapy: American Society of Clinical Oncology Provisional Clinical Opinion Update 2015. J Clin Oncol 2016; 34:179.
  156. Jonker DJ, O'Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007; 357:2040.
  157. 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.
  158. Au HJ, Karapetis CS, O'Callaghan CJ, et al. Health-related quality of life in patients with advanced colorectal cancer treated with cetuximab: overall and KRAS-specific results of the NCIC CTG and AGITG CO.17 Trial. J Clin Oncol 2009; 27:1822.
  159. Saltz L, Rubin M, Hochster H, et al. Cetuximab (IMC-225) plus irinotecan is active in CPT-11-refractory colorectal cancer that expresses epidermal growth factor receptor (abstract). Proc Am Soc Clin Oncol 2001; 20:3a.
  160. 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.
  161. 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; 351:337.
  162. Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009; 360:1408.
  163. Van Cutsem E, Köhne CH, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011; 29:2011.
  164. Souglakos J, Kalykaki A, Vamvakas L, et al. Phase II trial of capecitabine and oxaliplatin (CAPOX) plus cetuximab in patients with metastatic colorectal cancer who progressed after oxaliplatin-based chemotherapy. Ann Oncol 2007; 18:305.
  165. 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.
  166. Tabernero J, Van Cutsem E, Díaz-Rubio E, et al. Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and oxaliplatin in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2007; 25:5225.
  167. Venook A, Niedzwicki D, Hollis D, et al. Phase III study of irinotecan/5FU/LV (FOLFIRI) or oxaliplatin/5FU/LV (FOLFOX) ± cetuximab for patients with untreated metastatic adenocarcinoma of the colon or rectum (MCRC): CALGB 80203 preliminary results (abstract). J Clin Oncol 2006; 24:148s.
  168. Folprecht G, Gruenberger T, Bechstein WO, 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; 11:38.
  169. Bokemeyer C, Bondarenko I, Hartmann JT, 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; 22:1535.
  170. Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 2011; 377:2103.
  171. Tveit KM, Guren T, Glimelius B, et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol 2012; 30:1755.
  172. Price TJ, Peeters M, Kim TW, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol 2014; 15:569.
  173. Primrose J, Falk S, Finch-Jones M, et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial. Lancet Oncol 2014; 15:601.
  174. Jennis A, Polikoff J, Mitchell E, et al. Erbitux (Cetuximab) plus FOLFOX for colorectal cancer (EXPLORE): Preliminary efficacy analysis of a randomized phase III trial (abstract). J Clin Oncol 2005; 23:264s.
  175. 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.
  176. Van Cutsem E, Siena S, Humblet Y, et al. An open-label, single-arm study assessing safety and efficacy of panitumumab in patients with metastatic colorectal cancer refractory to standard chemotherapy. Ann Oncol 2008; 19:92.
  177. 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.
  178. Hecht JR, Patnaik A, Berlin J, et al. Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer. Cancer 2007; 110:980.
  179. Price T, Peeters M, Kim TW, et al. ASPECCT: A randomized, multicenter, open-label, phase 3 study of panitumumab versus cetuximab for previously treated wild-type KRAS metastatic colorectal cancer (abstract). Data presented at the 2013 European Cancer Congress, Amsterdam the Netherlands, September 29, 2013 (abstract LBA18). http://eccamsterdam2013.ecco-org.eu/Scientific-Programme/Searchable-Programme.aspx#anchorScpr (Accessed on November 21, 2013).
  180. Douillard JY, Siena S, Cassidy 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.
  181. Berlin J, Posey J, Tchekmedyian S, et al. Panitumumab with irinotecan/leucovorin/5-fluorouracil for first-line treatment of metastatic colorectal cancer. Clin Colorectal Cancer 2007; 6:427.
  182. Köhne CH, Hofheinz R, Mineur L, et al. First-line panitumumab plus irinotecan/5-fluorouracil/leucovorin treatment in patients with metastatic colorectal cancer. J Cancer Res Clin Oncol 2012; 138:65.
  183. Cohn AL, Shumaker GC, Khandelwal P, et al. An open-label, single-arm, phase 2 trial of panitumumab plus FOLFIRI as second-line therapy in patients with metastatic colorectal cancer. Clin Colorectal Cancer 2011; 10:171.
  184. André T, Blons H, Mabro M, et al. Panitumumab combined with irinotecan for patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy: a GERCOR efficacy, tolerance, and translational molecular study. Ann Oncol 2013; 24:412.
  185. Seymour MT, Brown SR, Middleton G, et al. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol 2013; 14:749.
  186. Peeters M, Price TJ, Cervantes A, et al. Final results from a randomized phase 3 study of FOLFIRI {+/-} panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol 2014; 25:107.
  187. Douillard JY, Siena S, Cassidy J, et al. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol 2014; 25:1346.
  188. Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013; 369:1023.
  189. O'Neil BH, Allen R, Spigel DR, et al. High incidence of cetuximab-related infusion reactions in Tennessee and North Carolina and the association with atopic history. J Clin Oncol 2007; 25:3644.
  190. Wilke H, Glynne-Jones R, Thaler J, et al. Cetuximab plus irinotecan in heavily pretreated metastatic colorectal cancer progressing on irinotecan: MABEL Study. J Clin Oncol 2008; 26:5335.
  191. Van Cutsem E, Humblet Y, Gelderblom H, et al. Cetuximab dose-escalation study in patients with metastatic colorectal cancer aith no or slight skin reactions on cetuximab standard dose treatment (EVEREST): pharmacokinetics and efficacy data of a randomized study (abstract). Data presented at the 4th annual ASCO Gastrointestinal Cancers Symposium, Orlando, FL, January 20, 2007.
  192. Peeters M, Siena S, Van Cutsem E, et al. Association of progression-free survival, overall survival, and patient-reported outcomes by skin toxicity and KRAS status in patients receiving panitumumab monotherapy. Cancer 2009; 115:1544.
  193. Berlin J, Van Cutsem E, Peeters M, et al. Predictive value of skin toxicity severity for response to panitumumab in patients with metastatic colorectal cancer (mCRC): pooled analysis of five clinical trials (abstract). J Clin Oncol 2007; 25:196s.
  194. Van Cutsem E, Tejpar S, Vanbeckevoort D, et al. Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study. J Clin Oncol 2012; 30:2861.
  195. Ensslin CJ, Rosen AC, Wu S, Lacouture ME. Pruritus in patients treated with targeted cancer therapies: systematic review and meta-analysis. J Am Acad Dermatol 2013; 69:708.
  196. Schrag D, Chung KY, Flombaum C, Saltz L. Cetuximab therapy and symptomatic hypomagnesemia. J Natl Cancer Inst 2005; 97:1221.
  197. Tejpar S, Piessevaux H, Claes K, et al. Magnesium wasting associated with epidermal-growth-factor receptor-targeting antibodies in colorectal cancer: a prospective study. Lancet Oncol 2007; 8:387.
  198. Stintzing S, Fischhaber D, Mook C, et al. Clinical relevance and utility of cetuximab-related changes in magnesium and calcium serum levels. Anticancer Drugs 2013; 24:969.
  199. Cao Y, Liu L, Liao C, et al. Meta-analysis of incidence and risk of hypokalemia with cetuximab-based therapy for advanced cancer. Cancer Chemother Pharmacol 2010; 66:37.
  200. Petrelli F, Cabiddu M, Borgonovo K, Barni S. Risk of venous and arterial thromboembolic events associated with anti-EGFR agents: a meta-analysis of randomized clinical trials. Ann Oncol 2012; 23:1672.
  201. Townsley CA, Major P, Siu LL, et al. Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer. Br J Cancer 2006; 94:1136.
  202. Rothenberg ML, LaFleur B, Levy DE, et al. Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma. J Clin Oncol 2005; 23:9265.
  203. Meyerhardt JA, Zhu AX, Enzinger PC, et al. Phase II study of capecitabine, oxaliplatin, and erlotinib in previously treated patients with metastastic colorectal cancer. J Clin Oncol 2006; 24:1892.
  204. Kuo T, Cho CD, Halsey J, et al. Phase II study of gefitinib, fluorouracil, leucovorin, and oxaliplatin therapy in previously treated patients with metastatic colorectal cancer. J Clin Oncol 2005; 23:5613.
  205. Zampino MG, Magni E, Massacesi C, et al. First clinical experience of orally active epidermal growth factor receptor inhibitor combined with simplified FOLFOX6 as first-line treatment for metastatic colorectal cancer. Cancer 2007; 110:752.
  206. Weickhardt AJ, Price TJ, Chong G, et al. Dual targeting of the epidermal growth factor receptor using the combination of cetuximab and erlotinib: preclinical evaluation and results of the phase II DUX study in chemotherapy-refractory, advanced colorectal cancer. J Clin Oncol 2012; 30:1505.
  207. Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 2014; 15:1065.
  208. Heinemann V, et al. Analysis of KRAS/NRAS and BRAF mutations in FIRE-3: A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients (abstract). Data presented at the 13th annual European Cancer Congress (ECC) , Amsterdam, the Netherlands, September 28, 2013. http://eccamsterdam2013.ecco-org.eu/Scientific-Programme/Searchable-Programme.aspx#anchorScpr (Accessed on November 21, 2013).
  209. Schwartzberg LS, Rivera F, Karthaus M, et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 2014; 32:2240.
  210. Venook AP, Niedzwiecki D, Lenz H-J, et al. CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC) (abstract). J Clin Oncol 32: 5s, 2014 (suppl; abstr LBA3). Abstract avialable online at http://meetinglibrary.asco.org/content/126013-144 (Accessed on June 12, 2014).
  211. Lenz H, Niedzwiecki D, Innocenti F, et al. CALGB/SWOG 80405: PHASE III trial of irinotecan/5-FU/Leucovorin (FOLFIRI) or oxalipolatin/5-FU/leucovorin (mFOLFOX) with bevacizumab or cetuximab for patients with expanded ras analysis untreated metastatic adenocarcinoma of the colon or rectum (abstract 501O). Data presented at the 2014 ESMO congress, September 27-30, Madrid, Spain. Abstract available online atSpain, https://www.webges.com/cslide/library/esmo/browse/search/rBc#9faw03oW (Accessed on December 04, 2014).
  212. 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.
  213. Segal NH, Reidy-Lagunes D, Capanu M, et al. Phase II study of bevacizumab in combination with cetuximab plus irinotecan in irinotecan-refractory colorectal cancer patients who have progressed on a bavacizumab containing regimen (the BOND 2.5 study) (Abstract # 4087). J Clin Oncol 2009; 27:189s.
  214. 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.
  215. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009; 360:563.
  216. Heskamp S, Boerman OC, Molkenboer-Kuenen JD, et al. Bevacizumab reduces tumor targeting of antiepidermal growth factor and anti-insulin-like growth factor 1 receptor antibodies. Int J Cancer 2013; 133:307.
  217. 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.
  218. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381:303.
  219. Li J, Qin S, Xu R, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2015; 16:619.
  220. Lenz HJ, Stintzing S, Loupakis F. TAS-102, a novel antitumor agent: a review of the mechanism of action. Cancer Treat Rev 2015; 41:777.
  221. Yoshino T, Mizunuma N, Yamazaki K, et al. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol 2012; 13:993.
  222. Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 2015; 372:1909.
  223. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm463650.htm.
  224. Oh DY, Venook AP, Fong L. On the Verge: Immunotherapy for Colorectal Carcinoma. J Natl Compr Canc Netw 2015; 13:970.
  225. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015; 372:2509.
  226. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch repair deficiency (abstract). J Clin Oncol 33, 2015 (suppl; abstr LBA100). Abstract available online at http://meetinglibrary.asco.org/content/143531-156 (Accessed on August 17, 2015).
  227. J Natl Compr Canc Netw 2015; 13:970.
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