Colorectal cancer

Systemic chemotherapy treatment options for first-line treatment

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Clinical practice guidelines for the prevention, early detection and management of colorectal cancer > Systemic chemotherapy treatment options for first-line treatment



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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/Systemic chemotherapy first-line treatment . 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=173120, cited 2023 Dec 11]. Available from: https://wiki.cancer.org.au/australia/Guidelines:Colorectal_cancer.


Last modified:
7 November 2017 23:43:56





Background[edit source]

Chemotherapy combinations commonly used in the treatment of metastatic colorectal cancer include:

First line chemotherapy for metastatic colorectal cancer typically contains a fluoropyrimidine (intravenous 5FU or oral capecitabine) in combination with either oxaliplatin or irinotecan in various schedules.

For information on protocols, see eviQ cancer treatments.

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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).

The cytotoxic chemotherapy backbone[edit source]

Systemic chemotherapy produces clinically meaningful improvements in median survival and progression-free survival. These benefits are most pronounced with regimens containing irinotecan or oxaliplatin in combination with 5FU.

Therapy should be individualised, based upon biomarker studies (see Molecular pathology and biomarkers), previous treatment, disease extent, organ function, and medical comorbidities. For most patients, treatment will be palliative, not curative. The treatment goals may be to prolong overall survival and maintain quality of life for as long as possible. Although specific regimens may be designated as initial therapy, second line therapy after progression, maintenance and beyond, it is important to clarify that these designations represent a continuum of care and that these lines of therapy are blurred rather than distinct.

Combination chemotherapy with a fluoropyrimidine plus either oxaliplatin or irinotecan (FOLFOX or FOLFIRI) achieves higher response rates and improved progression free survival times than a fluoropyrimidine or 5FU/LV alone.[1][2] FOLFOX and FOLFIRI are both acceptable choices for first-line therapy. This recommendation is consistent with consensus-based guidelines by the US National Comprehensive Cancer Network (NCCN)[3] and the European Society for Medical Oncology (ESMO).[4]

5FU chemotherapy can be delivered in a number of different ways. Continuous infusion 5FU is generally less toxic than some bolus and oral regimens. See eviQ protocol Colorectal Metastatic De Gramont (Modified) (Fluorouracil and Leucovorin). Capecitabine, the oral formulation, can be used as an alternative to 5FU/LV alone[5] (XELOX and XELIRI) or as monotherapy in patients with poor performance status or medical comorbidities precluding the use of combination therapy approaches. The combination of capecitabine and irinotecan (XELIRI) has been shown to be inferior and more toxic (higher rates of severe vomiting, diarrhoea and dehydration) than infusional fluorouracil and irinotecan (FOLFIRI).[6][7] The preferred regimen of the eviQ reference committee is FOLFIRI or irinotecan monotherapy.

When determining the choice, duration and specific combination of systemic therapies a patient’s performance status, comorbidities and treatment related toxicities need to be taken into consideration. The major dose-limiting side effect of oxaliplatin is a cumulative, late-onset predominantly sensory neuropathy, which may require drug discontinuation despite ongoing tumour response. It occurs with increasing frequency above cumulative doses of 680 mg/m2.[8] Guidelines for dosing modifications for all common toxicities of agents described in this section are available at eviQ Cancer Treatments online.

The following monoclonal antibodies have been shown to improve the clinical outcome of patients with metastatic colorectal cancer when combined with combination chemotherapy in the first-line setting:[9][10][11][12][13][14][15][16][17][18]

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Patients who are candidates for intensive chemotherapy[edit source]

For patients who are able to tolerate it, we suggest combination chemotherapy with a doublet (FOLFOX, XELOX, or FOLFIRI) rather than a single-agent sequential therapy for initial treatment of metastatic colorectal cancer, particularly for those who have limited liver metastases that might become potentially resectable. This recommendation is consistent with consensus-based guidelines from NCCN)[3] and ESMO.[4]

The three active conventional chemotherapy agents for metastatic colorectal cancer are fluoropyrimidines, irinotecan, and oxaliplatin. The proportion of patients exposed to all three drug classes at some point in the continuum of care correlates with an increased median survival as evidenced from a combined analysis of data from seven phase III clinical studies.[19]Results from a randomised study to evaluate the efficacy of FOLFIRI and FOLFOX regimens as initial therapy and to evaluate the effect of using sequential therapy with the alternate regimen on progression showed no sequence to be superior with respect to progression free survival or overall survival.[20]

The triplet combination chemotherapy regimen FOLFOXIRI with or without bevacizumab can be considered for first-line therapy in selected patients who are able to tolerate intensive therapy and for whom a more aggressive initial approach is chosen due to patient factors such as excellent performance status, younger age, higher tumour load, conversion therapy for initially non-resectable liver metastases, contraindication to cetuximab/panitumumab (e.g. RAS/BRAF mutation). In an Italian study FOLFOXIRI was shown to be superior to FOLFIRI in terms of response rate (the primary end point, 66% versus 41%) the number of patients able to undergo complete secondary surgical cytoreduction of liver metastases, median progression-free survival, and median overall survival (23 versus 17 months).[21][22]

Similar high response rates and improved median overall survival were noted with FOLFOXIRI plus bevacizumab as compared to FOLFIRI plus bevacizumab in the TRIBE trial, but it did not confirm higher rates of secondary surgical resection of liver metastases with an initial three-drug chemotherapy backbone.[23] Furthermore, grade 3 to 4 toxic effects that were more common with FOLFOXIRI included diarrhoea, stomatitis, neutropenia, and peripheral neuropathy. Not all studies have concluded a benefit from triplet cytotoxic therapy versus a standard doublet[24] and the contribution bevacizumab makes to the triplet regimen remains uncertain.

For patients in whom either oxaliplatin or irinotecan need to be withheld because of toxicity, it is reasonable to continue the fluoropyrimidine plus bevacizumab. See Discontinuation of treatment and maintenance therapy.

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Patients who are not candidates for intensive chemotherapy[edit source]

For patients who are not candidates for an intensive first-line oxaliplatin or irinotecan-based combination regimen, we suggest fluoropyrimidine therapy alone.[25] This recommendation is consistent with consensus-based guidelines from the NCCN[3] and ESMO.[4]

Capecitabine monotherapy is an effective first-line regimen when fluoropyrimidines alone are indicated. If intravenous 5FU is used, short-term infusional FU/LV rather than bolus 5FU administration is preferable because of its favourable toxicity profile.

The use of FU/LV or capecitabine plus bevacizumab is also appropriate in patients who are not good candidates for oxaliplatin or irinotecan and who do not have contraindications to antiangiogenesis therapy. In two phase II randomised controlled trials (RCTs) in which previously untreated patients were assigned to bolus FU/LV with or without bevacizumab (5 or 10 mg/kg every two weeks), response rates were approximately two fold higher with bevacizumab, and median survival was extended by 7.7 and 3.7 months for the two doses, respectively.[26][27]

Furthermore, in the multi-centre AVEX trial, 280 patients age 70 or older with previously untreated metastatic colorectal cancer were randomly assigned to capecitabine with or without bevacizumab at standard doses.[28] Combined therapy was associated with significantly longer median progression-free survival (the primary endpoint, 9.1 versus 5.1 months) and a non-significant trend toward longer overall survival (median 21 versus 17 months). However, there were significantly more events leading to treatment discontinuation in the bevacizumab arm (25 versus 15 percent), and higher rates of all-grade haemorrhage (25 versus 7 percent), hypertension (19 versus 5 percent), and venous thromboembolic events (12 versus 5 percent, grade 3 or higher, 8 versus 4 percent). There were six arterial thromboembolic events in the combined therapy group, compared with three with capecitabine monotherapy (4 versus 2 percent). Although rates of grade 5 (fatal) toxicities were not higher with bevacizumab (8.2 versus 11.8 percent with capecitabine alone), they were higher than expected in both groups.[28]

Combination of capecitabine and bevacizumab is therefore an option for elderly patients or those not suitable for more intensive regimens. Caution is warranted when prescribing bevacizumab in combination with chemotherapy for elderly patients with a history of atherosclerotic cardiovascular disease. The risks probably outweigh the benefits in patients with a history of stroke or myocardial infarction within the preceding 6 to 12 months, or a history of thromboembolic disease, and the drug is contraindicated in patients with severe uncontrolled hypertension. See eviQ protocol Colorectal Metastatic Capecitabine with Bevacizumab

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Practice points[edit source]

For patients who are candidates for intensive chemotherapy


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For patients who are able to tolerate it, combination chemotherapy with a doublet (FOLFOX, XELOX [CAPOX], or FOLFIRI) rather than a single agent sequential therapy for initial treatment of metastatic colorectal cancer, is preferred.

When the aim is cytoreduction prior to surgical resection


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Patients with potentially resectable metastatic disease should be discussed at a multidisciplinary meeting, and treatment plans should consider patient comorbidity and suitability for an aggressive treatment strategy


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Monotherapy is not appropriate and combination chemotherapy with a doublet (FOLFOX, XELOX [CAPOX], or FOLRIR) should be used where the aim of therapy is significant cytoreduction. For those with RAS wild-type tumours, an anti-EGFR antibody in conjunction with combination chemotherapy can be considered especially in those with left sided primaries.


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For those with good performance status and without significant comorbidities intensive triplet chemotherapy with FOLFIRINOX can be considered.

For patients who are not candidates for intensive chemotherapy


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Patient comorbidities, ECOG performance status, and location and burden of metastatic disease should be considered in treatment decisions.


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For patients who are medically unfit with poor performance status, a supportive care approach may be appropriate.


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In patients with poor performance status or significant comorbidities palliative treatment with single agent fluoropyrimidine (with or without bevacizumab) may be preferred to doublet chemotherapy. Fluoropyrimidine-based therapy alone (or in combination with bevacizumab) can be considered in patients with low-volume unresectable disease.

Next section: biological agents first-line treatment of metastatic CRC
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References[edit source]

  1. ↑ 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 Aug;18(16):2938-47 Available from: http://www.ncbi.nlm.nih.gov/pubmed/10944126.
  2. ↑ Douillard JY, V-303 Study Group.. Irinotecan and high-dose fluorouracil/leucovorin for metastatic colorectal cancer. Oncology (Williston Park) 2000 Dec;14(12 Suppl 14):51-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/11200150.
  3. ↑ 3.0 3.1 3.2 National Comprehensive Cancer Network. NCCN Guidelines: Colon Cancer. National Comprehensive Cancer Network; 2016.
  4. ↑ 4.0 4.1 4.2 Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016 Aug;27(8):1386-422 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27380959.
  5. ↑ Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour 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 Mar 22;90(6):1190-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15026800.
  6. ↑ 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 Oct 20;25(30):4779-86 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17947725.
  7. ↑ Köhne CH, De Greve J, Hartmann JT, Lang I, Vergauwe P, Becker K, et al. Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer. EORTC study 40015. Ann Oncol 2008 May;19(5):920-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18065406.
  8. ↑ Detailed analysis of oxaliplatin-associated neurotoxicity in Intergroup trial N9741 (abstract) In: Green E SD, Goldberg RM, Grothey A. ASCO Gastrointestinal Cancers Symposium; 2005; Hollywood, Florida.;.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  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. ↑ 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 Nov 1;28(31):4697-705 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20921465.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004 Apr 1;22(7):1209-14 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15051767.
  20. ↑ Tournigand C, André 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 Jan 15;22(2):229-37 Available from: http://www.ncbi.nlm.nih.gov/pubmed/14657227.
  21. ↑ 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 May 1;25(13):1670-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17470860.
  22. ↑ Masi G, Vasile E, Loupakis F, Cupini S, Fornaro L, Baldi G, et al. Randomized trial of two induction chemotherapy regimens in metastatic colorectal cancer: an updated analysis. J Natl Cancer Inst 2011 Jan 5;103(1):21-30 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21123833.
  23. ↑ 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.
  24. ↑ Souglakos J, Androulakis N, Syrigos K, Polyzos A, Ziras N, Athanasiadis A, et al. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer 2006 Mar 27;94(6):798-805 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16508637.
  25. ↑ Goldberg RM, Rothenberg ML, Van Cutsem E, Benson AB 3rd, Blanke CD, Diasio RB, et al. The continuum of care: a paradigm for the management of metastatic colorectal cancer. Oncologist 2007 Jan;12(1):38-50 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17227899.
  26. ↑ Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Hecht JR, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 2005 Jun 1;23(16):3697-705 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15738537.
  27. ↑ Vincenzi B, Santini D, Russo A, Spoto C, Venditti O, Gasparro S, et al. Bevacizumab in association with de Gramont 5-fluorouracil/folinic acid in patients with oxaliplatin-, irinotecan-, and cetuximab-refractory colorectal cancer: a single-center phase 2 trial. Cancer 2009 Oct 15;115(20):4849-56 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19626652.
  28. ↑ 28.0 28.1 Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB, 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 Oct;14(11):1077-85 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24028813.

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

Anti-cancer drugs that are injected into a vein or given by mouth. These drugs travel through the bloodstream to all parts of the body.

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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