Colorectal cancer

Role of biological agents in first-line treatment of metastatic colorectal cancer

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Clinical practice guidelines for the prevention, early detection and management of colorectal cancer > Role of biological agents in first-line treatment of metastatic colorectal cancer



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Dr Louise Nott BMedSci MBBS.Hons FRACP, Dr Muhammad Khattak, Professor Timothy Price MBBS, DHlthSc (Medicine), FRACP, Dr Amanda Townsend, Cancer Council Australia Colorectal Cancer Guidelines Working Party. Guidelines:Colorectal cancer/Biological agents first-line treatment of metastatic CRC . In: Clinical practice guidelines for the prevention, early detection and management of colorectal cancer. Sydney: Cancer Council Australia. [Version URL: https://wiki.cancer.org.au/australiawiki/index.php?oldid=173115, cited 2023 Dec 11]. Available from: https://wiki.cancer.org.au/australia/Guidelines:Colorectal_cancer.


Last modified:
7 November 2017 23:43:22





Background[edit source]

Biological agents are generally indicated for the first-line treatment of patients with metastatic colorectal cancer unless contraindicated due to, for example, reduced organ function, poor performance status or cardiovascular insufficiency.

Biological agents reimbursed for use in the treatment of patients with metastatic colorectal cancer in Australia include:

  • Anti-VEGF therapy: bevacizumab – a humanised monoclonal antibody that targets vascular endothelial growth factor-A (VEGF-A), a member of a family of VEGF receptor-activating ligands.
  • Anti EGFR therapy: cetuximab and panitumumab – monoclonal antibodies that target epidermal growth factor receptor (EGFR).

Overview of evidence (non-systematic literature review)[edit source]

No systematic reviews were undertaken for this topic. Practice points were based on selected reviews, primary studies, and other clinical practice guidelines (see Guideline development process).

Anti-VEGF therapy – bevacizumab[edit source]

In a pivotal early randomised controlled trial (RCT), the addition of bevacizumab to the bolus irinotecan, leucovorin (folinic acid), and fluorouracil (IFL) regimen significantly improved response rates (45% versus 35%), increased time to tumour progression (11 versus 6 months), and prolonged overall survival (20 versus 16 months).[1]

Since then, benefit for adding bevacizumab to a variety of fluoropyrimidine, irinotecan, and oxaliplatin-containing regimens used for first-line therapy has been confirmed, although the magnitude of both the overall and progression-free survival benefits are relatively modest.[2] To date, there are still only limited data on the benefit of adding bevacizumab to an oxaliplatin-based regimen[3] although this has been a standard first-line treatment in many patients, and no RCT comparing FOLFIRI versus FOLFIRI plus bevacizumab has been published.

XELOX [CAPOX] can also be combined with bevacizumab. The evidence supporting this and FOLFOX4 combined with bevacizumab in the first line comes from the randomised phase III, NO16966 trial by Saltz et al[3]. Patients were randomly assigned in a 2 X 2 factorial design to FOLFOX 4 or XELOX followed by bevacizumab or placebo. After a median follow-up of 27.6 months, PFS was significantly increased with bevacizumab compared with placebo when combined with oxaliplatin-based chemotherapy (HR=0.83; p=0.0023), the median PFS duration being 9.4 months with bevacizumab plus chemotherapy versus 8.0 months with placebo plus chemotherapy.[3]

However, the overall survival differences did not reach statistical significance, and response rate was not improved by the addition of bevacizumab. The lack of continuation of either bevacizumab or flluoropyrimidine until disease progression may have blunted the contribution of bevacizumab, thereby diminishing its impact on OS and PFS.[3]

An open-label, phase 3 trial (the TRIBE study) reported that the combination of leucovorin calcium (folinic acid), 5FU, oxaliplatin and irinotecan hydrochloride (FOLFOXIRI) in combination with bevacizumab enhanced response rate and progression-free survival, compared with FOLFIRI plus bevacizumab[4] and reported a median overall survival of 29.8 months. The use of FOLFOXIRI–bevacizumab treatment is limited to select patients with excellent performance status and minimal comorbidities. The contribution bevacizumab makes to the triplet regimen is uncertain.

Bevacizumab can be associated with a number of potentially serious side effects, including proteinuria, hypertension, bleeding, bowel perforation, impaired wound healing, arterial (but not venous) thromboembolic events (such as transient ischemic attack, stroke, angina, myocardial infarction), and reversible posterior multifocal leukoencephalopathy.[5]

For patients with RAS and BRAF wild-type tumours, an important question is whether a bevacizumab-containing regimen provides superior outcomes as compared with an initial regimen that contains an anti-EGFR agent. Emerging data suggest that first-line cetuximab-containing regimens may provide superior outcomes for patients with RAS/BRAF wild-type metastatic colorectal cancer with a primary tumour site in the left colon (see Left-sided versus right-sided tumours).[6]

Currently there is no validated predictive biomarker for bevacizumab.

See eviQ protocols:


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Anti-EGFR therapy[edit source]

The EGFR antibodies cetuximab and panitumumab are active in various combinations, either alone or with cytotoxic chemotherapy agents.

The activity of EGFR antibodies is limited to patients with RAS wild-type tumours. Thus, knowledge of the RAS mutational status of the patient is a prerequisite to treatment with EGFR antibodies.

Unlike cetuximab (a chimeric monoclonal antibody produced in a murine culture), panitumumab is a fully human monoclonal antibody, and has a lower incidence of infusion reactions. The available evidence suggests that antitumor efficacy is similar to that of cetuximab, and that the two drugs might be interchangeable.[7][8]

The addition of cetuximab to FOLFIRI has been shown to improve response rate, median progression-free survival rate and overall survival rate in first-line use, compared with FOLFIRI alone in metastatic colorectal cancer patients with RAS wild-type tumours.[9][10][11] Both cetuximab and panitumumab also increase the activity of the cytotoxic doublet FOLFOX in metastatic colorectal cancer patients with RAS wild-type tumours.[12][13][14][15][16][17] In contrast, benefits have not been shown for the addition of EGFR antibodies to oxaliplatin-based regimens where non-infusional fluoropyrimidines were used, such as bolus administration, the combination of 5-flourouracil (5FU), calcium leucovorin (folinic acid) and oxaliplatin (FLOX), capecitabine, or capecitabine plus oxaliplatin (CAPOX).[16][18] Capecitabine-based therapy should not be used in combination with EGFR antibody therapies.[16]

Combinations of cetuximab or panitumumab plus an irinotecan or oxaliplatin-based cytotoxic regimen that contains infusional 5FU (i.e, FOLFIRI and FOLFOX) are safe and effective. These are a reasonable first-line option for patients with RAS and BRAF wild-type tumours, especially for patients with a primary tumour on the left side.

See eviQ protocols for cetuximab:

See eviQ protocols for panitumumab:


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Biological agents targeting EGFR or VEGF in combination with chemotherapy are recommended in the first-line treatment of most patients unless contraindicated.


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EGFR antibodies should:

  • be used in patients with RAS wild-type tumours
  • be used in combination with FOLFIRI or FOLFOX
  • not be combined with capecitabine-based and bolus 5FU-based regimen.


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Patients with left sided colorectal cancer should be considered for initial doublet chemotherapy and anti-EGFR therapy where appropriate. Alternate options remain appropriate based on patient preference and comorbidity.See left vs. right section


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EGFR antibodies may be less efficacious in patients with BRAF mutations.


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VEGF antibody (bevacizumab):

  • should be used in combination with cytotoxic doublets including FOLFOX, XELOX and FOLFIRI
  • can be used in combination with the triplet cytotoxic regimen FOLFOXIRI in select fit patients where tumour shrinkage is the goal, and potentially in fit patients with a BRAF mutation
  • can be used in combination with fluoropyrimidine monotherapy in less fit patients unlikely to be suitable for a doublet cytotoxic regimen.


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Patients with right sided colorectal cancer should be considered for initial doublet chemotherapy plus or minus anti-VEGF. See left vs. right section

Next section: treatment and continuum of care model
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References[edit source]

  1. ↑ 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 Jun 3;350(23):2335-42 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15175435.
  2. ↑ Hurwitz HI, Tebbutt NC, Kabbinavar F, Giantonio BJ, Guan ZZ, Mitchell L, et al. Efficacy and safety of bevacizumab in metastatic colorectal cancer: pooled analysis from seven randomized controlled trials. Oncologist 2013;18(9):1004-12 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23881988.
  3. ↑ 3.0 3.1 3.2 3.3 Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, 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 Apr 20;26(12):2013-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18421054.
  4. ↑ 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 Oct;16(13):1306-15 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26338525.
  5. ↑ Roche. Avastatin (bevacizumab) TGA-approved product information. Last updated 13 October 2015. [homepage on the internet]; Available from: Available at: www.ebs.tga.gov.au.
  6. ↑ Sandrine Hiret, Christophe Borg, Aurelie Bertaut, Olivier Bouche, Antoine Adenis, Gael Deplanque, Eric Francois, Thierry Conroy, Francois Ghiringhelli, Gaetan Des Guetz, Jean-François Seitz, Pascal Artru, Trevor Stanbury, Marc G. Denis, Jaafar Bennouna. Bevacizumab or cetuximab plus chemotherapy after progression with bevacizumab plus chemotherapy in patients with wtKRAS metastatic colorectal cancer: A randomized phase II study (Prodige 18 –UNICANCER GI). J Clin Oncol; 2016.
  7. ↑ 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 Nov 15;357(20):2040-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18003960.
  8. ↑ 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 May;15(6):569-79 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24739896.
  9. ↑ Van Cutsem E, Köhne 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 Apr 2;360(14):1408-17 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19339720.
  10. ↑ Van Cutsem E, Köhne CH, Láng 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 May 20;29(15):2011-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21502544.
  11. ↑ Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 2015 Mar 1;33(7):692-700 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25605843.
  12. ↑ 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 Feb 10;27(5):663-71 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19114683.
  13. ↑ Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, 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 Jul;22(7):1535-46 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21228335.
  14. ↑ 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 Sep 12;369(11):1023-34 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24024839.
  15. ↑ Bokemeyer C, Köhne CH, Ciardiello F, Lenz HJ, Heinemann V, Klinkhardt U, et al. FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer. Eur J Cancer 2015 Jul;51(10):1243-52 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25937522.
  16. ↑ 16.0 16.1 16.2 Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, 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 Jun 18;377(9783):2103-14 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21641636.
  17. ↑ 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 Jul;25(7):1346-55 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24718886.
  18. ↑ 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 May 20;30(15):1755-62 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22473155.

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Referring to the large bowel, comprising the colon and rectum.

A study in which people are allocated at random (by chance alone) to receive one of several clinical interventions. One of these interventions is the standard of comparison or control.

Systemic chemotherapy using a combination of the drugs Leucovorin (folinic acid), Fluorouracil, and Oxaliplatin.

A recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.

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