Skip to main content

Chemotherapy, Still an Option in the Twenty-First Century in Metastatic Colorectal Cancer?

Abstract

Substantial improvements have been made in the systemic treatment of colorectal cancer over the last two decades. Median overall survival (OS) of patients with metastatic colorectal cancer (mCRC) has been constantly increased and the most recent first-line studies exceeded the 30-month median overall survival. The standard first-line regimen for mCRC is a combination of chemotherapy plus a biological agent either targeting the main angiogenic growth factor vascular endothelial growth factor (VEGF) via Bevacizumab or by antibodies targeting the epidermal growth factor receptor (EGRF) via Panitumumab or Cetuximab. Recent improvements have been shown in the efficacy of the biological agent by stratifying these agents according to the primary tumor location. In this context EGFR-inhibitors showed improved OS when used first-line in tumors derived from the left-sided colon or rectum, while tumor sidedness was not predictive for anti-VEGF-antibodies. Furthermore, the biological activity of anti-EGFR antibodies is restricted to tumors with a rat sarcoma virus (RAS)-wild-type genotype but not RAS-mutated tumors. The RAS-mutation status is not predictive for VEGF-inhibitors. Recent developments in the molecular characterisation of tumor cells led to the development of specific so called targeted therapies in colorectal cancer.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

  1. 1.

    Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013;49:1374–403.

    Article  CAS  Google Scholar 

  2. 2.

    Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.

    Article  CAS  Google Scholar 

  3. 3.

    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;22:229–37.

    Article  CAS  Google Scholar 

  4. 4.

    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;23:4866–75.

    Article  CAS  Google Scholar 

  5. 5.

    Petrelli F, Cabiddu M, Barni S, et al. 5-Fluorouracil or capecitabine in the treatment of advanced colorectal cancer: a pooled-analysis of randomized trials. Med Oncol. 2012;29:1020–9.

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    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 

  7. 7.

    Venook AP, Niedzwiecki D, Lenz HJ, et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA. 2017;317:2392–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    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 

  9. 9.

    Saltz LB, Clarke S, Dıaz-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  Google Scholar 

  10. 10.

    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;30:3499–506.

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with secondline 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 

  12. 12.

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

    Article  Google Scholar 

  13. 13.

    Van Cutsem E, Kohne CH, Lang 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  CAS  PubMed  Google Scholar 

  14. 14.

    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;28:4697–705.

    Article  CAS  Google Scholar 

  15. 15.

    Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17:738–46.

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Meric-Bernstam F, Hurwitz H, Raghav KPS, et al. Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2019;20:518–30.

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Modest DP, Stintzing S, von Weikersthal FL, et al. Exploring the effect of primary tumor sidedness on therapeutic efficacy across treatment lines in patients with metastatic colorectal cancer: analysis of the FIRE-3 (AIOKRK0306). Oncotarget. 2017;8:105749–60.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1°) 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(suppl):3504.

    Article  Google Scholar 

  19. 19.

    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  Google Scholar 

  20. 20.

    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;14:29–37.

    Article  CAS  Google Scholar 

  21. 21.

    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 openlabel, randomised phase 3 trial. Lancet Oncol. 2013;14:1077–85.

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    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  CAS  Google Scholar 

  23. 23.

    Misale S, Di Nicolantonio F, Sartore-Bianchi A, et al. Resistance to anti-EGFR therapy in colorectal cancer: from heterogeneity to convergent evolution. Cancer Discov. 2014;4:1269–80.

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Therkildsen C, Bergmann TK, Henrichsen-Schnack T, et al. The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: a systematic review and meta-analysis. Acta Oncol. 2014;53:852–64.

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    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  Google Scholar 

  26. 26.

    Van Cutsem E, Lenz HJ, Köhne CH, et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015;33:692–700.

    Article  CAS  Google Scholar 

  27. 27.

    Lacouture ME, Mitchell EP, Piperdi B, et al. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28:1351–7.

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Meguid RA, Slidell MB, Wolfgang CL, et al. Is there a difference in survival betweenright-versus left-sided colon cancers? Ann Surg Oncol. 2008;15:2388–94.

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Heinemann V, Modest DP, von Weikersthal FL, et al. Gender and tumor location as predictors for efficacy: influence on endpoints in first-line treatment with FOLFIRI in combination with cetuximab or bevacizumab in the AIO KRK 0306 (FIRE3) trial. J Clin Oncol. 2014;32(suppl_5):3600.

    Article  Google Scholar 

  30. 30.

    Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1°) 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;34:3504.

    Article  Google Scholar 

  31. 31.

    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;26:2006–612.

    Article  CAS  PubMed  Google Scholar 

  32. 32.

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

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    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 

  34. 34.

    Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebocontrolled, phase 3 trial. Lancet. 2013;381:303–12.

    Article  CAS  Google Scholar 

  35. 35.

    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 colrectal cancer (CONCUR): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16:619–29.

    Article  CAS  Google Scholar 

  36. 36.

    Bekaii-Saab TS, Ou FS, Anderson DM, et al. Regorafenib dose optimization study (ReDOS): randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC) An ACCRU Network study. J Clin Oncol. 2018;36:611.

    Article  Google Scholar 

  37. 37.

    Wasan HS, Gibbs P, Sharma NK, 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;18:1159–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Meijerink MR, Puik RS, vam Tilborg AAJM, et al. Radiofrequency and microwave ablation compared to systemic chemotherapy and to partial hepatectomy in the treatment of colorectal liver metastases: a systematic review and meta-analysis. Cardiovasc Intervent Radiol. 2018;41:1189–204.

    Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Sugarbaker PH. Improving oncologic outcomes for colorectal cancer at high risk for local-regional recurrence with novel surgical techniques. Expert Rev Gastroenterol Hepatol. 2016;10:205–13.

    Article  CAS  PubMed  Google Scholar 

  40. 40.

    Sinicrope FA, Mahoney MR, Smyrk TC, et al. Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy. J Clin Oncol. 2013;31:3664–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Tran B, Kopetz S, Tie J, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011;117:4623–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Kopetz S, Desai J, Chan E, et al. Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer. J Clin Oncol. 2015;33:4032–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Corcoran RB, Ebi H, Turke A, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012;2:227–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Kopetz S, McDonough SL, Lenz H-J, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406). J Clin Oncol. 2017;35(Suppl 4):520.

    Article  Google Scholar 

  45. 45.

    Corcoran RB, André T, Yoshino T, et al. Efficacy and circulating tumor DNA (ctDNA) analysis of the BRAF inhibitor dabrafenib (D), MEK inhibitor trametinib (T), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E–mutated (BRAFm) metastatic colorectal cancer (mCRC). Ann Oncol 2016;27(suppl 6):vi556.

  46. 46.

    Ryan B, Corcoran RB, André T, et al. Combined BRAF, EGFR, and MEK Inhibition in patients with BRAFV600E-Mutant Colorectal Cancer. Cancer Disc. 2018;8:428–43.

    Article  CAS  Google Scholar 

  47. 47.

    Van Cutsem E, Cuyle P-J, Huijberts S, et al. BEACON CRC study safety lead-in (SLI) in patients with BRAFV600E metastatic colorectal cancer (mCRC): efficacy and tumor markers. J Clin Oncol 2018;36(suppl 4):627.

  48. 48.

    Soreide K, Janssen EA, Soiland H, et al. Microsatellite instability in colorectal cancer. Br J Surg. 2006;93:395–406.

    Article  CAS  PubMed  Google Scholar 

  49. 49.

    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 

  50. 50.

    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 

  51. 51.

    Lenz HJ, van Cutsem E, Limon ML, et al. Durable clinical benefit with nivolumab (NIVO) plus lowdose ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). Ann Oncol. 2018;29(Suppl 8):714.

    Google Scholar 

  52. 52.

    Chalabi M, Fanchi MF, van den Berg JG, et al. Neoadjuvant ipilimumab plus nivolumab in early stage colon cancer. Ann Oncol. 2018;29(Suppl 8):731.

    Google Scholar 

  53. 53.

    Bendell J, Ciardiello F, Tabernero J, et al. Efficacy and safety results from IMblaze370, a randomised Phase III study comparing atezolizumab + cobimetinib and atezolizumab monotherapy vs regorafenib in chemotherapy-refractory metastatic colorectal cancer. Ann Oncol. 2018;29(Suppl_5):v122.

    Article  Google Scholar 

  54. 54.

    Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27:1386–1422.

    Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Wolfgang Eisterer.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Eisterer, W., Prager, G. Chemotherapy, Still an Option in the Twenty-First Century in Metastatic Colorectal Cancer?. Cardiovasc Intervent Radiol 42, 1213–1220 (2019). https://doi.org/10.1007/s00270-019-02278-7

Download citation

Keywords

  • Metastatic colorectal cancer
  • Chemotherapy
  • Immune therapy
  • Targeted therapy
  • Oligometastatic disease