Colorectal cancer affects hundreds of thousands of individuals in the United States each year. Men have a slightly higher incidence and mortality rate than women. Approximately one-fifth of patients with newly diagnosed colorectal cancer cases present with distant metastasis at the time of diagnosis.
Today, we’re comparing the ESMO, ASCO, and NCCN guidelines, focusing on first-line and second-line systemic therapy recommendations for metastatic colorectal cancer. The NCCN guideline is specifically for colon cancer. There is a separate guideline focusing on rectal cancer that can be viewed, but the colon cancer guideline was selected for today's side-by-side comparison.
Guidelines for Comparison
| Metastatic Colorectal Cancer | Treatment of Metastatic Colorectal Cancer | Colon Cancer | |
|---|---|---|---|
| Authoring Organization | ESMO | ASCO | NCCN |
| Publication Date | April 2026 | October 2022 | April 2026 |
| Links | Summary / Full Text | Summary / Full Text | Full Text |
Guideline Scope
Each of the three guidelines featured today varies in scope. The following represents a brief breakdown of what can be found within each of the three featured guidelines.
The ESMO guideline features recommendations and algorithms for managing metastatic colorectal cancer. With recommendations on diagnosis, pathology, staging, initial assessment, colorectal liver metastasis, systemic therapy, and follow-up, the guideline covers a wide range of topics.
The ASCO guideline focuses on the treatment of metastatic colorectal cancer. It features ten recommendations regarding chemotherapy, EGFR-targeted therapy, cytoreductive surgery, stereotactic body radiation therapy, and more. Of the three guidelines featured today, the ASCO publication is the oldest, being published in October 2022.
The NCCN guideline is divided into key sections: clinical presentations and workup, Treatment for pMMR/MSS Colon Cancer, Surveillance and Recurrence, Treatment for dMMR/MSI-H Colon Cancer, and sections detailing principles of imaging, pathologic and molecular review, surgery and locoregional therapies, systemic therapy for advanced or metastatic disease, and more.
Side-by-Side Comparison of Recommendations
| Item | ESMO | ASCO | NCCN |
|---|---|---|---|
| First-Line Systemic Therapy | For patients with dMMR or MSI-H mCRC, nivolumab–ipilimumab is recommended. Pembrolizumab is recommended if ICI doublet therapy is not possible. For patients with pMMR, MSS, RAS-mutated mCRC, FOLFOXIRI–bevacizumab can be recommended. FOLFOXIRI can only be recommended for patients aged <70 years with ECOG PS 0-2 or aged 71-75 years with ECOG PS 0. For patients with pMMR, MSS, BRAFV600E-mutated mCRC, FOLFOX–encorafenib–cetuximab is recommended. FOLFIRI–encorafenib–cetuximab is recommended, particularly for patients previously treated with oxaliplatin-based adjuvant regimens or with contraindications to oxaliplatin. Oxaliplatin-based doublet–bevacizumab can be recommended if FOLFOX–encorafenib–cetuximab is not available. FOLFOXIRI–bevacizumab can be recommended in selected patients with right-sided tumours if FOLFOX–encorafenib–cetuximab is not available. For patients with pMMR, MSS, RAS-wt, BRAF-wt mCRC with left-sided primaries, FOLFIRI–anti-EGFR or FOLFOX–anti-EGFR are recommended. FOLFOXIRI–bevacizumab or doublet ChT–bevacizumab can also be recommended. mFOLFOXIRI–anti-EGFR may also be considered. For patients with pMMR, MSS, RAS-wt, BRAF-wt mCRC with right-sided primaries, FOLFOXIRI–bevacizumab can be recommended. FOLFIRI–bevacizumab or oxaliplatin-based doublet-bevacizumab can also be recommended. FOLFIRI–anti-EGFR, FOLFOX–anti-EGFR or mFOLFOXIRI–anti-EGFR may also be considered. For patients with pMMR or MSS mCRC who are unfit to receive the ChT regimens listed above, fluoropyrimidine–bevacizumab is recommended. For patients with RAS-wt, BRAF-wt disease with left-sided primaries, 5-FU–LV–anti-EGFR can be recommended and anti-EGFR alone can be considered. | Doublet (FOLFOX or FOLFIRI) backbone chemotherapy should be offered as first-line therapy to patients with initially unresectable MSS or pMMR mCRC. Triplet (FOLFOXIRI) backbone chemotherapy may be offered as first-line therapy to selected patients with initially unresectable MSS or pMMR mCRC. Pembrolizumab should be offered as first-line therapy to patients with MSI-H or dMMR mCRC. Anti-EGFR therapy plus doublet chemotherapy should be offered as first-line therapy to patients with MSS or pMMR left-sided RAS wild-type mCRC. | KRAS WT/NRAS WT/BRAF WT: CAPEOX (capecitabine/Oxaliplatin) ± Bevacizumab CAPEOX + (Cetuximab or Panitumumab) (left-sided tumors only) FOLFIRI (Leucovorin/Flurouracil/Irinotecan) ± Bevacizumab FOLFIRI (Leucovorin/Fluorouracil/Irinotecan) ± Bevacizumab FOLFIRI + (Cetuximab or Panitumumab) (left-sided tumors only) FOLFIRINOX (Leucovorin/Fluorouracil/Irinotecan/Oxaliplatin) ± Bevacizumab FOLFOX (Leucovorin/Fluorouracil/Oxaliplatin) ± Bevacizumab FOLFOX + (Cetuximab or Panitumumab) (left-sided tumors only) (KRAS mutation or NRAS mutation) and BRAF WT: CAPEOX ± Bevacizumab FOLFIRI ± Bevacizumab FOLFIRINOX ± Bevacizumab FOLFOX ± Bevacizumab KRAS WT/NRAS WT/BRAF V600E Mutation: Preferred: FOLFIRI/Encorafenib + (Cetuximab or Panitumumab) FOLFOX/Encorafenib + (Cetuximab or Penitumumab) Other Recommended: CAPEOX ± Bevacizumab CAPEOX/Encorafenib + (Cetuximab or Panitumumab) FOLFIRI ± Bevacizumab FOLFIRINOX ± Bevacizumab FOLFOX ± Bevacizumab |
| Second-Line Systemic Therapy | For patients with dMMR or MSI-H mCRC who have not previously received ICIs, nivolumab–ipilimumab is recommended. Pembrolizumab can also be recommended. For patients with BRAFV600E-mutated mCRC (pMMR or MSS, or dMMR or MSI-H previously treated with ICIs), encorafenib–cetuximab is recommended if not previously used. Regardless of primary tumour location and RAS and BRAF mutational status, FOLFIRI–bevacizumab (for patients with disease progression on a prior oxaliplatin-based regimen; ESMO-MCBS v2.0 score: 3) or oxaliplatin-based doublet–bevacizumab (for patients with disease progression on a prior irinotecan-based regimen; ESMO-MCBS v2.0 score: 1) is recommended. FOLFIRI–aflibercept and FOLFIRI–ramucirumab are also recommended for patients previously treated with oxaliplatin-based regimens. Reintroducing the original induction treatment can be recommended, especially following maintenance with fluoropyrimidine–bevacizumab or treatment breaks. After first-line FOLFOXIRI–bevacizumab, FOLFIRI–bevacizumab (ESMO-MCBS v2.0 score: 3) or oxaliplatin-based doublet–bevacizumab (ESMO-MCBS v2.0 score: 1) is recommended. Reintroduction of FOLFOXIRI–bevacizumab can be recommended for patients with ECOG PS 0, prior RECIST response to FOLFOXIRI–bevacizumab and progression after an oxaliplatin- and irinotecan-free interval of ≥4 months. For patients with left-sided RAS-wt and BRAF-wt tumours who previously received oxaliplatin-based doublet ChT or FOLFOXIRI–bevacizumab and have not been treated with anti-EGFR agents, FOLFIRI–cetuximab (ESMO-MCBS v2.0 score: 4; EMA approved, not FDA approved), FOLFIRI–panitumumab (ESMO-MCBS v2.0 score: 2; EMA approved, not FDA approved) or irinotecan–cetuximab (ESMO-MCBS v2.0 score: 2) may be considered, noting that no OS benefit has been demonstrated. | Encorafenib plus cetuximab should be offered to patients with previously treated BRAF V600E–mutant mCRC that has progressed after at least one previous line of therapy. | KRAS WT/NRAS WT/BRAF WT: Prior Oxaliplatin: FOLFIRI + (Cetuximab or Panitumumab) FOLFIRI ± (Bevacizumab [preferred] or Ziv-afilbercept or Ramucirumab) Irinotecan + (Cetuximab or Panitumumab) Irinotecan ± (Bevacizumab [preferred] or Ziv-aflibercept or Ramucirumab) Prior Irinotecan: CAPEOX ± Bevacizumab CAPEOX + (Cetuximab or Panitumumab) FOLFOX ± Bevacizumab FOLFOX + (Cetuximab or Panitumumab) Irinotecan + (Cetuximab or Panitumumab) (KRAS mutation or NRAS mutation) and BRAF WT: Prior Oxaliplatin: FOLFIRI ± (Bevacizumab [preferred] or Ziv-aflibercept or Ramucirumab) Irinotecan ± (Bevacizumab [preferred] or Ziv-aflibercept or Ramucirumab) Prior Irinotecan: FOLFOX ± Bevacizumab CAPEOX ± Bevacizumab KRAS WT/NRAS WT/BRAF V600E Mutation: Prior Oxaliplatin: FOLFIRI ± (Bevacizumab [preferred] or Ziv-afilbercept or Ramucirumab) Irinotecan ± (Bevacizumab [preferred] or Ziv-afilbercept or Ramucirumab) Prior Irinotecan: CAPEOX ± Bevacizumab FOLFOX ± Bevacizumab |
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