Colorectal cancer

Systemic options for second-line treatment

From Cancer Guidelines Wiki

Background[edit source]

‘Second-line therapy’ currently refers to therapy administered from the time the first-line chemotherapy backbone has to be changed. The aim is to offer second-line therapy to as many patients with metastatic colorectal cancer as possible. It is usually proposed for patients with good performance status and adequate organ function and is dependent on the treatment used in the first line setting. Treatment strategies will also depend on predictive biomarkers (e.g. tumour RAS mutation status for EGFR antibody therapy).

Chemotherapy combinations commonly used in the second-line treatment of non-resectable metastatic colorectal cancer include:

  • leucovorin calcium (folinic acid), 5-fluorouracil (5FU) and oxaliplatin (FOLFOX)
  • leucovorin calcium (folinic acid), 5FU and irinotecan hydrochloride (FOLFIRI)
  • capecitabine plus oxaliplatin (XELOX) – also called CAPOX.

Biologic agents used in the second line setting include:

  • Anti-VEGF therapy: bevacizumab
  • Anti EGFR therapy: cetuximab and panitumumab

For information on protocols, see eviQ cancer treatments.

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).

Second-line choice following FOLFOX or FOLFIRI[edit source]

Most patients initially treated with FOLFOX (or XELOX) are offered FOLFIRI, while those initially treated with FOLFIRI are generally offered FOLFOX (or XELOX). The treatment model of FOLFOX followed by FOLFIRI, or FOLFIRI followed by FOLFOX was the evaluated in the GERCOR study[1] which still represents one of the longest median survivals (21 months) for patients with metastatic colorectal cancer reported in the prebiologics era.

Second-line choice following 5FU monotherapy[edit source]

Patients initially progressing on 5FU monotherapy should be offered an irinotecan or oxaliplatin-containing regimen if they have adequate performance status.[2][3][4] As shown in the GERCOR study, treatment with all three cytotoxic agents during the treatment of metastatic colorectal cancer is associated with longer survival times.[5]

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Anti-EGFR therapy[edit source]

Both of the therapeutic monoclonal antibodies that target the epidermal growth factor receptor (EGFR), cetuximab and panitumumab, have well-documented and comparable single-agent activity in patients with previously treated metastatic colorectal cancer that lacks mutations in RAS (and, possibly, BRAF).[6][7] Regimens that combine an anti-EGFR agent with irinotecan alone or a chemotherapy doublet have been shown to increase response rates, progression free survival but not overall survival in the second line setting[8][7][9] and can be considered if not previously used in RAS wild type patients. Alternatively, they can be used as monotherapy in the third line setting with similar relative benefit.[10]

The combination of cetuximab or panitumumab with second-line FOLFIRI after failure of initial FOLFOX is associated with improved response rates and prolonged progression-free survival. The Erbitux Plus Irinotecan in Colorectal cancer (EPIC) trial[10] reported on 1300 patients with EGFR-expressing, but not RAS-selected, metastatic colorectal cancer who had failed initial FOLFOX therapy and were randomly assigned to single-agent irinotecan with or without cetuximab. The addition of cetuximab quadrupled the response rate (16% versus 4%), significantly prolonged progression-free survival (4 versus 2.6 months) and, despite the higher frequency of side effects, was associated with better quality of life.[10] Similar results were reported in a phase III randomised controlled trial (RCT) of panitumumab plus FOLFIRI versus FOLFIRI alone after failure of initial 5FU-containing chemotherapy.[8] In the KRAS wild-type group (n = 597), the addition of panitumumab was associated with a significant improvement in response rate (35% versus 10%) and median progression-free survival (5.9 versus 3.9 months).[8]

Emerging data support the view that anti-EGFR antibodies do not appear to be useful for right-sided tumours in the setting of first-line therapy[11] (see Role of biological agents in with the treatment of metastatic colorectal cancer.)

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Anti-VEGF therapy[edit source]

Therapy targeting vascular endothelial growth factor (VEGF) also has a role in second-line systemic therapy for metastatic colorectal cancer.

If bevacizumab (anti-VEGF monoclonal antibody) was not used as the first-line biological agent, it should be considered in second line. FOLFOX plus bevacizumab was shown to improve overall survival, compared with FOLFOX alone, in a phase III trial[12] and this finding was confirmed by subsequent studies.

For patients treated with a first-line bevacizumab-containing chemotherapy regimen, the use of bevacizumab beyond progression in conjunction with a second-line fluoropyrimidine-based chemotherapy regimen can be considered, based on the available data. However, this approach is not subsidised by the Australian Pharmaceutical Benefits Scheme (PBS) as of May 2017. Data from two RCTs, the phase III TML study[13] and the BEBYP study,[14] showed that continuation of bevacizumab treatment with second-line chemotherapy benefited patients previously treated with bevacizumab. The benefit of continuing bevacizumab beyond progression in the European phase III TML trial was a modest improvement in overall survival (median 11.2 versus 9.8 months) without an increase in bevacizumab-related adverse events.[12] In the BEBYP study there was an improvement in progression free survival by 1.5 months utilising this strategy. This degree of benefit was more modest than prior retrospective analyses of registry data had suggested.

There are only limited data as to whether bevacizumab should be continued into 2nd line therapy in RAS WT patients or whether it is a better strategy to initiate anti-EGFR therapy. Phase II PRODIGE 18 trial[11] preliminary report presented at the ASCO 2016 suggested continuation with bevacizumab was associated with a numerically higher but not statistically significant PFS rate at four months (79 versus 67 percent, p = 0.09) and overall survival (15.9 versus 10.6 months, p = 0.08) compared to cetuximab plus chemotherapy. Data from this small phase 2 study (n=135) should be interpreted with caution and further data are needed to guide practice in this sub-set of patients.[11]

Aflibercept, an anti-angiogenic fusion protein, has shown benefit in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer that is resistant to, or has progressed following, an oxaliplatin-containing regimen. The placebo-controlled VELOUR trial, in which 1226 patients with oxaliplatin-refractory metastatic colorectal cancer were randomly assigned to aflibercept (4 mg/kg IV) or placebo, plus FOLFIRI, every 2 weeks until progression, reported improved median overall survival in patients treated with aflibercept (13.5 versus 12.1 months).[15] Benefit and safety were similar regardless of prior bevacizumab exposure, but side effect profile and discontinuation rates for toxicity were higher than what would be expected with bevacizumab in this trial. This cost of this agent is not reimbursed in Australia by PBSi.

Ramucirumab, a recombinant monoclonal antibody of the IgG1 class that binds to the VEGFR-2, blocking receptor activation, has also shown second line efficacy in metastatic colorectal cancer. In the double-blind phase III RAISE trial[16], 1072 patients with progression after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine were randomly assigned to FOLFIRI with ramucirumab (8 mg/kg IV every two weeks) or placebo until disease progression, unacceptable toxicity, or death. Median survival was modestly but significantly greater with ramucirumab (13.3 versus 11.7 months), as was median progression-free survival.[16] Given the modest benefit and expense the role of this agent remains uncertain. Ramucirumab treatment is not subsidised by PBS.

Emerging data suggest that anti-EGFR antibodies are not useful in first-line therapy for right-sided tumours[11] (see Role of biological agents in with the treatment of metastatic colorectal cancer.) However, whether these results can be extrapolated to later lines of therapy is not clear. Nevertheless, some clinicians would favour the use of continued bevacizumab over an anti-EGFR antibody for right-sided tumours.

i As of May 2017.

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Patients who did not receive bevacizumab as part of first-line therapy should be considered for bevacizumab in second-line therapy, in combination with a second-line cytotoxic regimen.

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Patients who received bevacizumab as part of the first-line regimen and have RAS wild-type (BRAF wild-type) metastatic colorectal cancer should be considered for combination EGFR monoclonal antibodies with FOLFIRI/irinotecan.

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Patients who received a first-line oxaliplatin-containing regimen should be switched to an irinotecan-containing regimen, and vice versa.

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Patients who experience disease progression during first-line 5FU monotherapy should be offered an irinotecan or oxaliplatin-containing regimen if they have adequate performance status.

Next section: systemic options third-line treatment
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References[edit source]

  1. 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:
  2. Haller DG, Rothenberg ML, Wong AO, Koralewski PM, Miller WH Jr, Bodoky G, et al. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single-agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol 2008 Oct 1;26(28):4544-50 Available from:
  3. Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet 2007 Jul 14;370(9582):135-42 Available from:
  4. Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet 2007 Jul 14;370(9582):143-52 Available from:
  5. 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:
  6. 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:
  7. 7.0 7.1 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 May 1;25(13):1658-64 Available from:
  8. 8.0 8.1 8.2 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 Nov 1;28(31):4706-13 Available from:
  9. 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 Jul;14(8):749-59 Available from:
  10. 10.0 10.1 10.2 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 May 10;26(14):2311-9 Available from:
  11. 11.0 11.1 11.2 11.3 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.
  12. 12.0 12.1 Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, 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 Apr 20;25(12):1539-44 Available from:
  13. Bennouna J, Sastre J, Arnold D, Österlund 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 Jan;14(1):29-37 Available from:
  14. Masi G, Salvatore L, Boni L, Loupakis F, Cremolini C, Fornaro 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 Apr;26(4):724-30 Available from:
  15. Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová 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 Oct 1;30(28):3499-506 Available from:
  16. 16.0 16.1 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 May;16(5):499-508 Available from:

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