Skip to main content

Metastatic Colorectal Cancer

  • Chapter
  • First Online:
Textbook of Gastrointestinal Oncology

Abstract

Although the mainstay of treatment for metastatic colorectal cancer (mCRC) is chemotherapy, as has been the case for decades, the comprehensive management of mCRC actually requires a multimodality approach that involves care of the patient as a whole, not just their disease. Input from medical oncologists, surgeons, interventional radiologists, radiation oncologists, nurses, social workers, and supportive family and friends is essential, combined with nutritional and psychological support and palliative care.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Global Burden of Disease Cancer C, Fitzmaurice C, Dicker D, Pain A, Hamavid H, Moradi-Lakeh M, et al. The global burden of cancer 2013. JAMA Oncol. 2015;1(4):505–27.

    Article  Google Scholar 

  2. 2018. ACSCFFAACS. Available from: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2018.html. 2018.

  3. Cancer of the colon and rectum – seer stat fact sheets [database on the Internet] 2015. Available from: http://seer.cancer.gov/statfacts/html/colorect.html.

  4. Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2012, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/archive/csr/1975_2012/, based on November 2014 SEER data submission, posted to the SEER web site, April 2015.

  5. Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, 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(13):1306–15.

    Article  CAS  PubMed  Google Scholar 

  6. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360(14):1408–17.

    Article  PubMed  Google Scholar 

  7. Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, 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(31):4706–13.

    Article  CAS  PubMed  Google Scholar 

  8. Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, 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(10):1065–75.

    Article  CAS  PubMed  Google Scholar 

  9. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, phase iii trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (folfox4) versus folfox4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the prime study. J Clin Oncol. 2010;28(31):4697–705.

    Article  CAS  PubMed  Google Scholar 

  10. Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, 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(21):2240–7.

    Article  CAS  PubMed  Google Scholar 

  11. Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, 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(21):3523–9.

    Article  CAS  PubMed  Google Scholar 

  12. Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, et al. Phase iii trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (folfoxiri) compared with infusional fluorouracil, leucovorin, and irinotecan (folfiri) as first-line treatment for metastatic colorectal cancer: the gruppo oncologico nord ovest. J Clin Oncol. 2007;25(13):1670–6.

    Article  CAS  PubMed  Google Scholar 

  13. Cassidy J, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, 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(12):2006–12.

    Article  CAS  PubMed  Google Scholar 

  14. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000;18(16):2938–47.

    Article  PubMed  Google Scholar 

  15. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-folfox4 treatment and ras mutations in colorectal cancer. N Engl J Med. 2013;369(11):1023–34.

    Article  CAS  PubMed  Google Scholar 

  16. Fuchs CS, Marshall J, Mitchell E, Wierzbicki R, Ganju V, Jeffery M, 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(30):4779–86.

    Article  CAS  PubMed  Google Scholar 

  17. Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, 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(15):2011–9.

    Article  CAS  PubMed  Google Scholar 

  18. Hecht JR, Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, et al. A randomized phase iiib trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009;27(5):672–80.

    Article  CAS  PubMed  Google Scholar 

  19. Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360(6):563–72.

    Article  CAS  PubMed  Google Scholar 

  20. Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757–65.

    Article  CAS  PubMed  Google Scholar 

  21. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, et al. Wild-type kras is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(10):1626–34.

    Article  CAS  PubMed  Google Scholar 

  22. Atreya CE, Corcoran RB, Kopetz S. Expanded ras: refining the patient population. J Clin Oncol. 2015;33(7):682–5.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, 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(7):1346–55.

    Article  CAS  PubMed  Google Scholar 

  24. Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, et al. Wild-type braf is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26(35):5705–12.

    Article  CAS  PubMed  Google Scholar 

  25. Kim G, McKee AE, Ning YM, Hazarika M, Theoret M, Johnson JR, Xu QC, Tang S, Sridhara R, Jiang X, He K, Roscoe D, McGuinn WD, Helms WS, Russell AM, Miksinski SP, Zirkelbach JF, Earp J, Liu Q, Ibrahim A, Justice R, Pazdur R. FDA approval summary: vemurafenib for treatment of unresectable or metastatic melanoma with the BRAFV600E mutation. Clin Cancer Res. 2014;20(19):4994–5000.

    Article  CAS  PubMed  Google Scholar 

  26. Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, et al. Vemurafenib in multiple nonmelanoma cancers with braf v600 mutations. N Engl J Med. 2015;373(8):726–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to pd-1 blockade. Science. 2017;357(6349):409–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (checkmate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18(9):1182–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bertotti A, Papp E, Jones S, Adleff V, Anagnostou V, Lupo B, et al. The genomic landscape of response to egfr blockade in colorectal cancer. Nature. 2015;526(7572):263–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. National Comprehensive Cancer Network. Nccn guidelines version 1.2016 colon cancer. 2015 [November 15, 2015]; Available from: http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf.

  31. Brule SY, Jonker DJ, Karapetis CS, O’Callaghan CJ, Moore MJ, Wong R, et al. Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in ncic co.17. Eur J Cancer. 2015;51(11):1405–14.

    Article  CAS  PubMed  Google Scholar 

  32. Schrag D, Weng S, Brooks G, Meyerhardt JA, Venook AP. The relationship between primary tumor sidedness and prognosis in colorectal cancer. J Clin Oncol. 2016;34(15_suppl):3505.

    Article  Google Scholar 

  33. Tejpar S, Stintzing S, Ciardiello F, Tabernero J, Van Cutsem E, Beier F, et al. Prognostic and predictive relevance of primary tumor location in patients with ras wild-type metastatic colorectal cancer: retrospective analyses of the crystal and fire-3 trials. JAMA Oncol. 2016.

    Google Scholar 

  34. Venook AP, Niedzwiecki D, Innocenti F, Fruth B, Greene C, O’Neil BH, Shaw JE, Atkins JN, Horvath LE, Polite BN, Meyerhardt JA, O’Reilly EM, Goldberg RM, Hochster HS, Blanke CD, Schilsky RL, Mayer RJ, Bertagnolli MM, Lenz H-J. Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance). J Clin Oncol. 2016;34(15_suppl):3504.

    Article  Google Scholar 

  35. Salem ME, Lenz H-J, Xiu J, Hwang JJ, Philip PA, Shields AF, et al. Colorectal cancer: impact of primary tumor location on genetic alterations. J Clin Oncol. 2017;35(15_suppl):3578.

    Article  Google Scholar 

  36. Andre T, Bensmaine MA, Louvet C, Francois E, Lucas V, Desseigne F, et al. Multicenter phase ii study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol. 1999;17(11):3560–8.

    Article  CAS  PubMed  Google Scholar 

  37. Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, et al. A ‘modified de gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002;87(4):393–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27(5):663–71.

    Article  CAS  PubMed  Google Scholar 

  39. Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al. Folfiri followed by folfox6 or the reverse sequence in advanced colorectal cancer: a randomized gercor study. J Clin Oncol. 2004;22(2):229–37.

    Article  CAS  PubMed  Google Scholar 

  40. Reidy DL, Chung KY, Timoney JP, Park VJ, Hollywood E, Sklarin NT, et al. Bevacizumab 5 mg/kg can be infused safely over 10 minutes. J Clin Oncol. 2007;25(19):2691–5.

    Article  CAS  PubMed  Google Scholar 

  41. Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, et al. Randomized controlled trial of cetuximab plus chemotherapy for patients with kras wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013;31(16):1931–8.

    Article  CAS  PubMed  Google Scholar 

  42. Tabernero J, Ciardiello F, Rivera F, Rodriguez-Braun E, Ramos FJ, Martinelli E, et al. Cetuximab administered once every second week to patients with metastatic colorectal cancer: a two-part pharmacokinetic/pharmacodynamic phase i dose-escalation study. Ann Oncol. 2010;21(7):1537–45.

    Article  CAS  PubMed  Google Scholar 

  43. Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, Shimma N, Umeda I, Ishitsuka H. 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(8):1274–81.

    Article  CAS  PubMed  Google Scholar 

  44. Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage iii colon cancer. J Clin Oncol. 2011;29(11):1465–71.

    Article  CAS  PubMed  Google Scholar 

  45. Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan study group. N Engl J Med. 2000;343(13):905–14.

    Article  CAS  PubMed  Google Scholar 

  46. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42.

    Article  CAS  PubMed  Google Scholar 

  47. Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, 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(1):107–16.

    Article  CAS  PubMed  Google Scholar 

  48. Patt YZ, Lee FC, Liebmann JE, Diamandidis D, Eckhardt SG, Javle M, et al. Capecitabine plus 3-weekly irinotecan (xeliri regimen) as first-line chemotherapy for metastatic colorectal cancer: phase ii trial results. Am J Clin Oncol. 2007;30(4):350–7.

    Article  CAS  PubMed  Google Scholar 

  49. 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(4):689–90.

    Article  PubMed  Google Scholar 

  50. Venook AP, Niedzwiecki D, Lenz H, Innocenti F, Mahoney MR, O’Neil BH, 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). J Clin Oncol. 2014;32(5s):abstr LBA3.

    Article  Google Scholar 

  51. Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, et al. Initial therapy with folfoxiri and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014;371(17):1609–18.

    Article  CAS  PubMed  Google Scholar 

  52. Minagawa M, Yamamoto J, Miwa S, Sakamoto Y, Kokudo N, Kosuge T, et al. Selection criteria for simultaneous resection in patients with synchronous liver metastasis. Arch Surg. 2006;141(10):1006–12; discussion 1013.

    Article  PubMed  Google Scholar 

  53. Fong Y, Cohen AM, Fortner JG, Enker WE, Turnbull AD, Coit DG, et al. Liver resection for colorectal metastases. J Clin Oncol. 1997;15(3):938–46.

    Article  CAS  PubMed  Google Scholar 

  54. Reddy SK, Pawlik TM, Zorzi D, Gleisner AL, Ribero D, Assumpcao L, Barbas AS, Abdalla EK, Choti MA, Vauthey J-N, Ludwig KA, Mantyh CR, Morse MA, Clary BM. Simultaneous resections of colorectal cancer and synchronous liver metastases: a multi-institutional analysis. Ann Surg Oncol. 2007;14(12):3481–91.

    Article  PubMed  Google Scholar 

  55. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. Perioperative folfox4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (eortc 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14(12):1208–15.

    Article  CAS  PubMed  Google Scholar 

  56. Suzuki H, Kiyoshima M, Kitahara M, Asato Y, Amemiya R. Long-term outcomes after surgical resection of pulmonary metastases from colorectal cancer. Ann Thorac Surg. 2015;99(2):435–40.

    Article  PubMed  Google Scholar 

  57. Folprecht G, Gruenberger T, Bechstein W, Raab HR, Weitz J, Lordick F, et al. Survival of patients with initially unresectable colorectal liver metastases treated with folfox/cetuximab or folfiri/cetuximab in a multidisciplinary concept (celim study). Ann Oncol. 2014;25(5):1018–25.

    Article  CAS  PubMed  Google Scholar 

  58. Folprecht G, Gruenberger T, Bechstein WO, Raab HR, Lordick F, Hartmann JT, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the celim randomised phase 2 trial. Lancet Oncol. 2010;11(1):38–47.

    Article  CAS  PubMed  Google Scholar 

  59. Gruenberger T, Bridgewater J, Chau I, Garcia Alfonso P, Rivoire M, Mudan S, et al. Bevacizumab plus mfolfox-6 or folfoxiri in patients with initially unresectable liver metastases from colorectal cancer: the olivia multinational randomised phase ii trial. Ann Oncol. 2015;26(4):702–8.

    Article  CAS  PubMed  Google Scholar 

  60. Huiskens J, van Gulik TM, van Lienden KP, Engelbrecht MR, Meijer GA, van Grieken NC, et al. Treatment strategies in colorectal cancer patients with initially unresectable liver-only metastases, a study protocol of the randomised phase 3 cairo5 study of the dutch colorectal cancer group (dccg). BMC Cancer. 2015;15:365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Portier G, Elias D, Bouche O, Rougier P, Bosset JF, Saric J, et al. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: Ffcd achbth aurc 9002 trial. J Clin Oncol. 2006;24(31):4976–82.

    Article  CAS  PubMed  Google Scholar 

  62. Ychou M, Hohenberger W, Thezenas S, Navarro M, Maurel J, Bokemeyer C, et al. A randomized phase iii study comparing adjuvant 5-fluorouracil/folinic acid with folfiri in patients following complete resection of liver metastases from colorectal cancer. Ann Oncol. 2009;20(12):1964–70.

    Article  CAS  PubMed  Google Scholar 

  63. Kemeny N, Huang Y, Cohen AM, Shi W, Conti JA, Brennan MF, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med. 1999;341(27):2039–48.

    Article  CAS  PubMed  Google Scholar 

  64. Sirtex. Sir-spheres microspheres package insert. http://www.sirtex.com/media/29845/ssl-us-10.pdf2014 [cited 2015 November 29].

  65. van Hazel GA, Heinemann V, Sharma NK, Findlay MP, Ricke J, Peeters M, et al. Sirflox: randomized phase iii trial comparing first-line mfolfox6 (plus or minus bevacizumab) versus mfolfox6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. J Clin Oncol. 2016;34(15):1723–31.

    Article  CAS  PubMed  Google Scholar 

  66. Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, et al. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (foxfire, sirflox, and foxfire-global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 2017;18(9):1159–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hubbard JM, Grothey A. When less is more: maintenance therapy in colorectal cancer. Lancet (London, England). 2015;385(9980):1808–10.

    Article  Google Scholar 

  68. Kasi PM, Grothey A. Chemotherapy maintenance. Cancer J (Sudbury, Mass). 2016;22(3):199–204.

    Article  Google Scholar 

  69. Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, 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(3):394–400.

    Article  CAS  PubMed  Google Scholar 

  70. Chibaudel B, Maindrault-Goebel F, Lledo G, Mineur L, Andre T, Bennamoun M, et al. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The gercor optimox2 study. J Clin Oncol. 2009;27(34):5727–33.

    Article  CAS  PubMed  Google Scholar 

  71. Labianca R, Sobrero A, Isa L, Cortesi E, Barni S, Nicolella D, Aglietta M, Lonardi S, Corsi D, Turci D, Beretta GD, Fornarini G, Dapretto E, Floriani I, Zaniboni A, Italian Group for the Study of Gastrointestinal Cancer-GISCAD. Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomised ‘GISCAD’ trial. Ann Oncol. 2011;22(5):1236–42. https://doi.org/10.1093/annonc/mdq580. Epub 2010 Nov 15. PubMed PMID: 21078826.

    Article  CAS  PubMed  Google Scholar 

  72. Diaz-Rubio E, Pietrantonio F, de Braud F. Continuing single-agent bevacizumab as maintenance therapy after induction xelox (or folfox) plus bevacizumab in first-line treatment of metastatic colorectal cancer. Oncologist. 2012;17(11):1426–8.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Koeberle D, Betticher DC, von Moos R, Dietrich D, Brauchli P, Baertschi D, et al. Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase iii non-inferiority trial (sakk 41/06). Ann Oncol. 2015;26(4):709–14.

    Article  CAS  PubMed  Google Scholar 

  74. Simkens LH, van Tinteren H, May A, ten Tije AJ, Creemers GJ, Loosveld OJ, et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (cairo3): a phase 3 randomised controlled trial of the dutch colorectal cancer group. Lancet (London, England). 2015;385(9980):1843–52.

    Article  CAS  Google Scholar 

  75. Hegewisch-Becker S, Graeven U, Lerchenmuller CA, Killing B, Depenbusch R, Steffens CC, et al. Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (aio 0207): a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol. 2015;16(13):1355–69.

    Article  CAS  PubMed  Google Scholar 

  76. Tournigand C, Chibaudel B, Samson B, Scheithauer W, Vernerey D, Mesange P, et al. Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (gercor dream; optimox3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2015;16(15):1493–505.

    Article  CAS  PubMed  Google Scholar 

  77. Alfonso PG, Benavides M, Ruiz AS, Guillen-Ponce C, Safont MJ, Alcaide J, et al. 499ophase ii study of first-line mfolfox plus cetuximab (c) for 8 cycles followed by mfolfox plus c or single agent (s/a) c as maintenance therapy in patients (p) with metastatic colorectal cancer (mcrc): the macro-2 trial (spanish cooperative group for the treatment of digestive tumors [ttd]). Ann Oncol. 2014;25(suppl 4):iv168.

    Article  Google Scholar 

  78. Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, 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(15):1755–62.

    Article  CAS  PubMed  Google Scholar 

  79. Pfeiffer P, Sorbye H, Qvortrup C, Karlberg M, Kersten C, Vistisen K, et al. Maintenance therapy with cetuximab every second week in the first-line treatment of metastatic colorectal cancer: the nordic-7.5 study by the nordic colorectal cancer biomodulation group. Clin Colorectal Cancer. 2015;14(3):170–6.

    Article  PubMed  Google Scholar 

  80. Wasan H, Meade AM, Adams R, Wilson R, Pugh C, Fisher D, et al. Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with <em>kras</em> wild-type advanced colorectal cancer (coin-b): a randomised phase 2 trial. Lancet Oncol. 2014;15(6):631–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Chibaudel B, Tournigand C, Bonnetain F, Maindrault-Goebel F, Lledo G, Andre T, et al. Platinum-sensitivity in metastatic colorectal cancer: towards a definition. Eur J Cancer. 2013;49(18):3813–20.

    Article  CAS  PubMed  Google Scholar 

  82. de Gramont A. Re-challenge and the concept of lines of therapy in metastatic colorectal cancer. Eur J Cancer. 2011;47(Suppl 3):S76–84.

    Article  PubMed  Google Scholar 

  83. Townsley CA, Major P, Siu LL, Dancey J, Chen E, Pond GR, et al. Phase ii study of erlotinib (osi-774) in patients with metastatic colorectal cancer. Br J Cancer. 2006;94(8):1136–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Mesange P, Poindessous V, Sabbah M, Escargueil AE, de Gramont A, Larsen AK. Intrinsic bevacizumab resistance is associated with prolonged activation of autocrine vegf signaling and hypoxia tolerance in colorectal cancer cells and can be overcome by nintedanib, a small molecule angiokinase inhibitor. Oncotarget. 2014;5(13):4709–21.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ml18147): a randomised phase 3 trial. Lancet Oncol. 2013;14(1):29–37.

    Article  CAS  PubMed  Google Scholar 

  86. Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausova J, Macarulla T, 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(28):3499–506.

    Article  CAS  PubMed  Google Scholar 

  87. Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, 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(5):499–508.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  89. Saltz LB, Lenz HJ, Kindler HL, Hochster HS, Wadler S, Hoff PM, et al. Randomized phase ii trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the bond-2 study. J Clin Oncol. 2007;25(29):4557–61.

    Article  CAS  PubMed  Google Scholar 

  90. Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357(20):2040–8.

    Article  CAS  PubMed  Google Scholar 

  91. Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, 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(14):2311–9.

    Article  CAS  PubMed  Google Scholar 

  92. Middleton G, Brown S, Lowe C, Maughan T, Gwyther S, Oliver A, et al. A randomised phase iii trial of the pharmacokinetic biomodulation of irinotecan using oral ciclosporin in advanced colorectal cancer: results of the panitumumab, irinotecan & ciclosporin in colorectal cancer therapy trial (piccolo). Eur J Cancer. 2013;49(16):3507–16.

    Article  CAS  PubMed  Google Scholar 

  93. Seymour MT, Brown SR, Middleton G, Maughan T, Richman S, Gwyther S, 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(8):749–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ferrell BR, Temel JS, Temin S, Alesi ER, Balboni TA, Basch EM, Firn JI, Paice JA, Peppercorn JM, Phillips T, Stovall EL, Zimmermann C, Smith TJ. Integration of palliative care into standard oncology care: american society of clinical oncology clinical practice guideline update. J Clin Oncol. 2017;35(1):96–112.

    Article  PubMed  Google Scholar 

  95. Bottomley A. The cancer patient and quality of life. Oncologist. 2002;7(2):120–5.

    Article  PubMed  Google Scholar 

  96. Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, et al. Open-label phase iii trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25(13):1658–64.

    Article  CAS  PubMed  Google Scholar 

  97. Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, 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(6):569–79.

    Article  CAS  PubMed  Google Scholar 

  98. Kim JH. Chemotherapy for colorectal cancer in the elderly. World J Gastroenterol. 2015;21(17):5158–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Foubert F, Matysiak-Budnik T, Touchefeu Y. Options for metastatic colorectal cancer beyond the second line of treatment. Dig Liver Dis. 2014;46(2):105–12.

    Article  PubMed  Google Scholar 

  100. Abou-Elkacem L, Arns S, Brix G, Gremse F, Zopf D, Kiessling F, et al. Regorafenib inhibits growth, angiogenesis, and metastasis in a highly aggressive, orthotopic colon cancer model. Mol Cancer Ther. 2013;12(7):1322–31.

    Article  CAS  PubMed  Google Scholar 

  101. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (correct): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet (London, England). 2013;381(9863):303–12.

    Article  CAS  Google Scholar 

  102. Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, Xu J, Bai Y, Chi Y, Wang L, Yeh KH, Bi F, Cheng Y, Le AT LJK, Liu T, Ma D, Kappeler C, Kalmus J, Kim TW, CONCUR Investigators. 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(6):619–29. https://doi.org/10.1016/S1470-2045(15)70156-7. Epub 2015 May 13. PubMed PMID: 25981818.

    Article  CAS  PubMed  Google Scholar 

  103. Goldstein DA, Ahmad BB, Chen Q, Ayer T, Howard DH, Lipscomb J, et al. Cost-effectiveness analysis of regorafenib for metastatic colorectal cancer. J Clin Oncol. 2015;33(32):3727–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Heidelberger C, Parsons DG, Remy DC. Syntheses of 5-trifluoromethyluracil and 5-trifluoromethyl-2′-deoxyuridine. J Med Chem. 1964;7:1–5.

    Article  CAS  PubMed  Google Scholar 

  105. Peters GJ. Therapeutic potential of tas-102 in the treatment of gastrointestinal malignancies. Ther Adv Med Oncol. 2015;7(6):340–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lenz HJ, Stintzing S, Loupakis F. Tas-102, a novel antitumor agent: a review of the mechanism of action. Cancer Treat Rev. 2015;41(9):777–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Rahman L, Voeller D, Rahman M, Lipkowitz S, Allegra C, Barrett JC, et al. Thymidylate synthase as an oncogene: a novel role for an essential DNA synthesis enzyme. Cancer Cell. 2004;5(4):341–51.

    Article  CAS  PubMed  Google Scholar 

  108. Temmink OH, Emura T, de Bruin M, Fukushima M, Peters GJ. Therapeutic potential of the dual-targeted tas-102 formulation in the treatment of gastrointestinal malignancies. Cancer Sci. 2007;98(6):779–89.

    Article  CAS  PubMed  Google Scholar 

  109. Fukushima M, Suzuki N, Emura T, Yano S, Kazuno H, Tada Y, et al. Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2′-deoxyribonucleosides. Biochem Pharmacol. 2000;59(10):1227–36.

    Article  CAS  PubMed  Google Scholar 

  110. Bendell JC, Rosen LS, Mayer RJ, Goldman JW, Infante JR, Benedetti F, et al. Phase 1 study of oral tas-102 in patients with refractory metastatic colorectal cancer. Cancer Chemother Pharmacol. 2015;76(5):925–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Yoshino T, Mizunuma N, Yamazaki K, Nishina T, Komatsu Y, Baba H, et al. Tas-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2012;13(10):993–1001.

    Article  CAS  PubMed  Google Scholar 

  112. Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, et al. Randomized trial of tas-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372(20):1909–19.

    Article  PubMed  Google Scholar 

  113. Singh PP, Sharma PK, Krishnan G, Lockhart AC. Immune checkpoints and immunotherapy for colorectal cancer. Gastroenterol Rep (Oxf). 2015;3(4):289–97.

    Google Scholar 

  114. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20. https://doi.org/10.1056/NEJMoa1500596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. McCain J. The mapk (erk) pathway: Investigational combinations for the treatment of braf-mutated metastatic melanoma. P T. 2013;38(2):96–108.

    PubMed  PubMed Central  Google Scholar 

  116. Kopetz S, Desai J, Chan E, Hecht JR, O’Dwyer PJ, Maru D, et al. Phase ii pilot study of vemurafenib in patients with metastatic braf-mutated colorectal cancer. J Clin Oncol. 2015;33(34):4032–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Mesteri I, Bayer G, Meyer J, Capper D, Schoppmann SF, von Deimling A, et al. Improved molecular classification of serrated lesions of the colon by immunohistochemical detection of braf v600e. Mod Pathol. 2014;27(1):135–44.

    Article  CAS  PubMed  Google Scholar 

  118. Tran B, Kopetz S, Tie J, Gibbs P, Jiang ZQ, Lieu CH, et al. Impact of braf mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011;117(20):4623–32.

    Article  CAS  PubMed  Google Scholar 

  119. Pietrantonio F, Petrelli F, Coinu A, Di Bartolomeo M, Borgonovo K, Maggi C, et al. Predictive role of braf mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer. 2015;51(5):587–94.

    Article  CAS  PubMed  Google Scholar 

  120. Corcoran RB, Dias-Santagata D, Bergethon K, Iafrate AJ, Settleman J, Engelman JA. Braf gene amplification can promote acquired resistance to mek inhibitors in cancer cells harboring the braf v600e mutation. Sci Signal. 2010;3(149):ra84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kopetz S, McDonough SL, Morris VK, Lenz H-J, Magliocco AM, Atreya CE, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in braf-mutant metastatic colorectal cancer (swog 1406). J Clin Oncol. 2017;35(4_suppl):520.

    Article  Google Scholar 

  122. Leto SM, Trusolino L. Primary and acquired resistance to egfr-targeted therapies in colorectal cancer: impact on future treatment strategies. J Mol Med (Berlin, Germany). 2014;92(7):709–22.

    Article  CAS  Google Scholar 

  123. Iqbal N, Iqbal N. Human epidermal growth factor receptor 2 (her2) in cancers: overexpression and therapeutic implications. Mol Biol Int. 2014;2014:852748.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Moja L, Tagliabue L, Balduzzi S, Parmelli E, Pistotti V, Guarneri V, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. 2012;4:CD006243.

    Google Scholar 

  125. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of her2-positive advanced gastric or gastro-oesophageal junction cancer (toga): a phase 3, open-label, randomised controlled trial. Lancet (London, England). 2010;376(9742):687–97.

    Article  CAS  Google Scholar 

  126. Seo AN, Kwak Y, Kim DW, Kang SB, Choe G, Kim WH, et al. Her2 status in colorectal cancer: its clinical significance and the relationship between her2 gene amplification and expression. PLoS One. 2014;9(5):e98528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Siena S, Sartore-Bianchi A, Trusolino L, Martino C, Bencardino K, Lonardi S, et al. Therapeutic dual inhibition of her2 pathway for metastatic colorectal cancer (mcrc): the heracles trial. ASCO Meet Abstr. 2015;33(3_suppl):565.

    Google Scholar 

  128. Sartore-Bianchi A, Marsoni S, Trusolino L, Martino C, Lonardi S, Leone F, et al. D26pertuzumab and trastuzumab-emtansine in her2 positive metastatic colorectal cancer: the heracles b trial. Ann Oncol. 2016;27(suppl_4):iv47.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to John L. Marshall .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Salem, M.E. et al. (2019). Metastatic Colorectal Cancer. In: Yalcin, S., Philip, P. (eds) Textbook of Gastrointestinal Oncology. Springer, Cham. https://doi.org/10.1007/978-3-030-18890-0_8

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-18890-0_8

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-18888-7

  • Online ISBN: 978-3-030-18890-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics