Skip to main content

Colorectal Cancer: Metastatic Disease

  • Chapter
  • First Online:
Practical Medical Oncology Textbook

Abstract

Most patients diagnosed with metastatic colorectal cancer (mCRC) develop metastases during the disease course after resection of the primary locoregional cancer. To date, the liver represents the most common site of metastatic involvement. Although several different biological and clinical hallmarks exist between the colon and rectum (different embryological origin, anatomy, and molecular biology), mCRC requires similar staging procedures and systemic treatment strategies (first and subsequent lines) in terms of a multimodal approach treatment as a part of a “continuum of care.” Patients affected by oligometastatic disease should undergo an upfront evaluation by a multidisciplinary team for assessing a potentially curative approach with improved long-term survival rates. So far, the standard of care for treatment of unresectable mCRC has been built on the backbone of 5-fluorouracil (5-FU)-based chemotherapy, including first-line combination treatment with either oxaliplatin or irinotecan (FOLFOX and FOLFIRI, respectively), plus a monoclonal antibody (bevacizumab versus cetuximab or panitumumab). In the era of personalized medicine, genotyping of tumor tissue (either primary tumor or metastasis) for RAS and BRAF testing in all patients with mCRC has been associated with significant prognostic and predictive implications, thus strongly recommended. Primary tumor location appeared to impact both prognosis and prediction of responsiveness to targeted therapy in advanced disease.

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

Access this chapter

eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
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

Similar content being viewed by others

References

  1. De Greef K, Rolfo C, Russo A, et al. Multisciplinary management of patients with liver metastasis from colorectal cancer. World J Gastroenterol. 2016;22:7215–25.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Li FY, Lai MD. Colorectal cancer, one entity or three. J Zhejiang Univ Sci B. 2009;10:219–29.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Baguley E, Hughes GR. Antiendothelial cell antibodies. J Rheumatol. 1989;16:716–7.

    CAS  PubMed  Google Scholar 

  4. Sakai K, Nakagawa M, Hosoda S, Nakano K, Koyanagi H. Changes in the treatment procedures for mitral stenosis. Jpn Circ J. 1992;56 Suppl 5:1369–72.

    CAS  PubMed  Google Scholar 

  5. Bufill JA. Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med. 1990;113:779–88.

    Article  CAS  PubMed  Google Scholar 

  6. Distler P, Holt PR. Are right- and left-sided colon neoplasms distinct tumors? Dig Dis. 1997;15:302–11.

    Article  CAS  PubMed  Google Scholar 

  7. Dejea CM, Wick EC, Hechenbleikner EM, et al. Microbiota organization is a distinct feature of proximal colorectal cancers. Proc Natl Acad Sci U S A. 2014;111:18321–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023–34.

    Article  CAS  PubMed  Google Scholar 

  9. 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;15:1065–75.

    Article  CAS  PubMed  Google Scholar 

  10. Russo A, Incorvaia L, Del Re M, et al. The molecular profiling of solid tumors by liquid biopsy: a position paper of the AIOM-SIAPEC-IAP-SIBioC-SIC-SIF italian scientific societies. ESMO Open. 2021;6(3):100164. https://doi.org/10.1016/j.esmoop.2021.100164.

  11. Tsai MS, Su YH, Ho MC, et al. Clinicopathological features and prognosis in resectable synchronous and metachronous colorectal liver metastasis. Ann Surg Oncol. 2007;14:786–94.

    Article  PubMed  Google Scholar 

  12. Floriani I, Torri V, Rulli E, et al. Performance of imaging modalities in diagnosis of liver metastases from colorectal cancer: a systematic review and meta-analysis. J Magn Reson Imaging. 2010;31:19–31.

    Article  PubMed  Google Scholar 

  13. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230:309–18; discussion 18–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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;15:601–11.

    Article  CAS  PubMed  Google Scholar 

  15. 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;11:38–47.

    Article  CAS  PubMed  Google Scholar 

  16. Bruera G, Ricevuto E. Intensive chemotherapy of metastatic colorectal cancer: weighing between safety and clinical efficacy: evaluation of Masi G, Loupakis F, Salvatore L, et al. Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. Lancet Oncol 2010;11:845–52. Expert Opin Biol Ther. 2011;11:821–4.

    Article  CAS  PubMed  Google Scholar 

  17. Carrato A, Abad A, Massuti B, et al. First-line panitumumab plus FOLFOX4 or FOLFIRI in colorectal cancer with multiple or unresectable liver metastases: a randomised, phase II trial (PLANET-TTD). Eur J Cancer. 2017;81:191–202.

    Article  CAS  PubMed  Google Scholar 

  18. 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;25:1346–55.

    Article  CAS  PubMed  Google Scholar 

  19. Stintzing S, Modest DP, Rossius L, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol. 2016;17:1426–34.

    Article  CAS  PubMed  Google Scholar 

  20. Piessevaux H, Buyse M, Schlichting M, et al. Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol. 2013;31:3764–75.

    Article  CAS  PubMed  Google Scholar 

  21. Bhutiani N, Akinwande O, Martin RC. Efficacy and toxicity of hepatic intra-arterial drug-eluting (Irinotecan) bead (DEBIRI) therapy in irinotecan-refractory unresectable colorectal liver metastases. World J Surg. 2016;40:1178–90.

    Article  PubMed  Google Scholar 

  22. Scorsetti M, Arcangeli S, Tozzi A, et al. Is stereotactic body radiation therapy an attractive option for unresectable liver metastases? A preliminary report from a phase 2 trial. Int J Radiat Oncol Biol Phys. 2013;86:336–42.

    Article  PubMed  Google Scholar 

  23. Rusthoven KE, Kavanagh BD, Cardenes H, et al. Multi-institutional phase I/II trial of stereotactic body radiation therapy for liver metastases. J Clin Oncol. 2009;27:1572–8.

    Article  PubMed  Google Scholar 

  24. Petre EN, Jia X, Thornton RH, et al. Treatment of pulmonary colorectal metastases by radiofrequency ablation. Clin Colorectal Cancer. 2013;12:37–44.

    Article  PubMed  Google Scholar 

  25. Benson AB, Geschwind J-F, Mulcahy MF, et al. Radioembolisation for liver metastases: results from a prospective 151 patient multi-institutional phase II study. Eur J Cancer. 2013;49:3122–30.

    Article  PubMed  Google Scholar 

  26. Garlipp B, Gibbs P, Van Hazel GA, et al. REsect: blinded assessment of amenability to potentially curative treatment of previously unresectable colorectal cancer liver metastases (CRC LM) after chemotherapy ± RadioEmbolization (SIRT) in the randomized SIRFLOX trial. J Clin Oncol. 2017;35:3532.

    Article  Google Scholar 

  27. Hendlisz A, Van den Eynde M, Peeters M, et al. Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. J Clin Oncol. 2010;28:3687–94.

    Article  CAS  PubMed  Google Scholar 

  28. Elias D, Mariani A, Cloutier AS, et al. Modified selection criteria for complete cytoreductive surgery plus HIPEC based on peritoneal cancer index and small bowel involvement for peritoneal carcinomatosis of colorectal origin. Eur J Surg Oncol. 2014;40:1467–73.

    Article  CAS  PubMed  Google Scholar 

  29. Turaga K, Levine E, Barone R, et al. Consensus guidelines from the American Society of Peritoneal Surface Malignancies on standardizing the delivery of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer patients in the United States. Ann Surg Oncol. 2014;21:1501–5.

    Article  CAS  PubMed  Google Scholar 

  30. Cremolini C, Schirripa M, Antoniotti C, et al. First-line chemotherapy for mCRC—a review and evidence-based algorithm. Nat Rev Clin Oncol. 2015;12:607–19.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  32. 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;25:4779–86.

    Article  CAS  PubMed  Google Scholar 

  33. Van Cutsem E, Hoff PM, Harper P, et al. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer. 2004;90:1190–7.

    Article  PubMed  PubMed Central  Google Scholar 

  34. 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;26:2006–12.

    Article  CAS  PubMed  Google Scholar 

  35. 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;25:1670–6.

    Article  CAS  PubMed  Google Scholar 

  36. Van Cutsem E, Köhne C-H, 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;29:2011–9.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  38. Douillard J-Y, 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;28:4697–705.

    Article  CAS  PubMed  Google Scholar 

  39. Pietrantonio F, Petrelli F, Coinu A, et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer. 2015;51:587–94.

    Article  CAS  PubMed  Google Scholar 

  40. Shahjehan F, Kamatham S, Chandrasekharan C, Kasi PM. Binimetinib, encorafenib and cetuximab (BEACON trial) combination therapy for patients with BRAF V600E-mutant metastatic colorectal cancer. Drugs Today. 2019;55:683.

    Article  CAS  Google Scholar 

  41. Petrelli F, Borgonovo K, Barni S. The predictive role of skin rash with cetuximab and panitumumab in colorectal cancer patients: a systematic review and meta-analysis of published trials. Target Oncol. 2013;8:173–81.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  43. Kabbinavar F, Irl C, Zurlo A, Hurwitz H. Bevacizumab improves the overall and progression-free survival of patients with metastatic colorectal cancer treated with 5-fluorouracil-based regimens irrespective of baseline risk. Oncology. 2008;75:215–23.

    Article  CAS  PubMed  Google Scholar 

  44. Cunningham D, Lang I, Marcuello E, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol. 2013;14:1077–85.

    Article  CAS  PubMed  Google Scholar 

  45. 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;26:2013–9.

    Article  CAS  PubMed  Google Scholar 

  46. Loupakis F, Cremolini C, Masi G, et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014;371:1609–18.

    Article  PubMed  Google Scholar 

  47. Holch JW, Ricard I, Stintzing S, Modest DP, Heinemann V. The relevance of primary tumour location in patients with metastatic colorectal cancer: a meta-analysis of first-line clinical trials. Eur J Cancer. 2017;70:87–98.

    Article  PubMed  Google Scholar 

  48. Arnold D, Lueza B, Douillard JY, et al. Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Ann Oncol. 2017;28:1713–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Holch JW, Ricard I, Stintzing S, et al. Relevance of baseline carcinoembryonic antigen for first-line treatment against metastatic colorectal cancer with FOLFIRI plus cetuximab or bevacizumab (FIRE-3 trial). Eur J Cancer. 2019;106:115–25.

    Article  CAS  PubMed  Google Scholar 

  50. Simkens LH, van Tinteren H, May A, 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. 2015;385:1843–52.

    Article  CAS  PubMed  Google Scholar 

  51. Hegewisch-Becker S, Graeven U, Lerchenmüller CA, 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;16:1355–69.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  53. Peeters M, Oliner KS, Price TJ, et al. Analysis of KRAS/NRAS mutations in a phase III study of panitumumab with FOLFIRI compared with FOLFIRI alone as second-line treatment for metastatic colorectal cancer. Clin Cancer Res. 2015;21:5469–79.

    Article  CAS  PubMed  Google Scholar 

  54. Cascinu S, Rosati G, Nasti G, et al. Treatment sequence with either irinotecan/cetuximab followed by FOLFOX-4 or the reverse strategy in metastatic colorectal cancer patients progressing after first-line FOLFIRI/bevacizumab: an Italian Group for the Study of Gastrointestinal Cancer phase III, randomised trial comparing two sequences of therapy in colorectal metastatic patients. Eur J Cancer. 2017;83:106–15.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  56. 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;26:724–30.

    Article  CAS  PubMed  Google Scholar 

  57. 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;50:320–31.

    Article  CAS  PubMed  Google Scholar 

  58. Galvano A, Taverna S, Badalamenti G, et al. Detection of RAS mutations in circulating tumor DNA: a new weapon in an old war against colorectal cancer. A systematic review of literature and meta-analysis. Ther Adv Med Oncol. 2019;11:1758835919874653. Published 2019 Sep 10. https://doi.org/10.1177/1758835919874653.

  59. 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;16:499–508.

    Article  CAS  PubMed  Google Scholar 

  60. 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;351:337–45.

    Article  CAS  PubMed  Google Scholar 

  61. Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372:1909–19.

    Article  PubMed  Google Scholar 

  62. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with Nivolumab plus Ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal Cancer. J Clin Oncol. 2018;36:773–9.

    Article  CAS  PubMed  Google Scholar 

  64. PD-1 Inhibitor Bests Chemo for Colorectal Cancer. Cancer Discov. 2020 Jul;10(7):OF2. https://doi.org/10.1158/2159-8290.CD-NB2020-051. Epub 2020 Jun 1. PMID: 32482631.

  65. Russo A, Incorvaia L, Malapelle U, et al. The tumor-agnostic treatment for patients with solid tumors: a position paper on behalf of the AIOM-SIAPEC/IAP-SIBIOC-SIF italian scientific societies [published online ahead of print, 2021 Aug 6]. Crit Rev Oncol Hematol. 2021;103436. https://doi.org/10.1016/j.critrevonc.2021.103436.

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Galvano, A. et al. (2021). Colorectal Cancer: Metastatic Disease. In: Russo, A., Peeters, M., Incorvaia, L., Rolfo, C. (eds) Practical Medical Oncology Textbook. UNIPA Springer Series. Springer, Cham. https://doi.org/10.1007/978-3-030-56051-5_38

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-56051-5_38

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-56050-8

  • Online ISBN: 978-3-030-56051-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics