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Colon Cancer

Designed for students and trainees, this section summarizes key clinical trials in colon cancer across adjuvant, metastatic, and immunotherapy settings. Learn the evidence behind today’s treatment strategies with clear, concise takeaways.

Adjuvant chemotherapy in stage II/III colon cancer

Trial

Key contribution

MOSAIC (2004)

Established FOLFOX (oxaliplatin + 5-FU/leucovorin) as standard adjuvant therapy; improved disease-free survival vs 5-FU/LV alone.

NSABP C-07 (2007)

Showed adding oxaliplatin to bolus 5-FU/LV improved DFS, confirming benefit of oxaliplatin.

QUASAR (2007)

Showed adjuvant chemotherapy improves survival even in selected stage II patients; benefit is modest.

IDEA collaboration (2018)

Pooled analysis comparing 3 vs 6 months of adjuvant FOLFOX/CAPOX; found non-inferiority in low-risk stage III with 3 months, but not high-risk.

Trial

Key contribution

CRYSTAL (2009)

Addition of cetuximab to FOLFIRI improved response and PFS in RAS wild-type mCRC.

OPUS (2008)

Similar findings as CRYSTAL, adding cetuximab to FOLFOX.

CALGB/SWOG 80405 (2014)

Head-to-head: cetuximab vs bevacizumab with chemotherapy; similar OS; choice depends on toxicity and other factors.

FIRE-3 (2014)

FOLFIRI + cetuximab vs FOLFIRI + bevacizumab; no OS difference as primary endpoint, but exploratory analysis suggested better OS with cetuximab in RAS WT patients.

NO16966 (2007)

Showed adding bevacizumab to XELOX/FOLFOX improved PFS in first-line mCRC.

Trial

Key contribution

KEYNOTE-177 (2020)

Pembrolizumab vs chemotherapy in untreated MSI-H mCRC; superior PFS and response rate with pembrolizumab.

CheckMate-142 (2017 & 2018)

Nivolumab (alone or with ipilimumab) showed durable responses in previously treated MSI-H mCRC.

Trial

Key contribution

FOCUS (2003)

Helped guide first-line vs sequential use of chemotherapy in mCRC.

TOMOX / Tournigand (2004)

Showed that sequence of FOLFOX and FOLFIRI matters less than both being used at some point.

ASCO Rechallenge & Maintenance studies

Informed strategies like EGFR rechallenge and maintenance with fluoropyrimidine or targeted agents.

  • Trial Name / Acronym
    MOSAIC
  • Publication Details
    Title: Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon Cancer
    Journal: New England Journal of Medicine (NEJM)
    Year: 2004
    DOI: 10.1056/NEJMoa032709
  • Patient Population
    Patients with stage II or III colon cancer after curative resection.
  • Intervention / Control
    Experimental arm: FOLFOX4 (oxaliplatin + leucovorin + 5-FU)
    Control arm: LV5FU2 (leucovorin + 5-FU)
  • Key Findings / Outcomes
  • In stage III patients, 6-year disease-free survival: 58.9% with FOLFOX4 vs 49.6% with LV5FU2.
  • Overall survival: 72.9% vs 68.7%.
  • The benefit was mainly in stage III disease; limited effect in stage II.
  • Impact / Significance
    Established FOLFOX as standard adjuvant chemotherapy for stage III colon cancer
  • Trial Name / Acronym
    NSABP C-07
  • Publication Details
    Title: Oxaliplatin Added to Weekly Fluorouracil and Leucovorin in the Adjuvant Treatment of Stage II and III Colon Cancer
    Journal: Journal of Clinical Oncology (JCO)
    Year: 2007
    DOI: 10.1200/JCO.2006.08.2974
  • Patient Population
    Stage II or III colon cancer after curative surgery.
  • Intervention / Control
    Experimental arm: FLOX (bolus 5-FU/LV + oxaliplatin)
    Control arm: 5-FU/LV alone
  • Key Findings / Outcomes
  • 3-year disease-free survival: 76.1% with FLOX vs 71.8% with 5-FU/LV.
  • Oxaliplatin added significant benefit, consistent with MOSAIC.
  • Impact / Significance
    Confirmed oxaliplatin’s role; further supported oxaliplatin-based adjuvant chemotherapy as standard.
  • Trial Name / Acronym
    QUASAR
  • Publication Details
    Title: Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study
    Journal: The Lancet
    Year: 2007
    DOI: 10.1016/S0140-6736(07)60462-2
  • Patient Population
    Primarily stage II colon cancer patients after resection.
  • Intervention / Control
    Experimental arm: 5-FU/LV adjuvant chemotherapy
    Control arm: Observation
  • Key Findings / Outcomes
  • Reduced risk of death by ~18%.
  • Absolute survival benefit about 3.6%.
  • Impact / Significance
    Showed modest but real benefit of adjuvant chemotherapy even in stage II disease; helped guide individualized treatment.
  • Trial Name / Acronym
    IDEA (International Duration Evaluation of Adjuvant chemotherapy)
  • Publication Details
    Title: Duration of adjuvant chemotherapy for stage III colon cancer
    Journal: New England Journal of Medicine (NEJM)
    Year: 2018
    DOI: 10.1056/NEJMoa1713709
  • Patient Population
    Stage III colon cancer patients treated with FOLFOX or CAPOX.
  • Intervention / Control
    Experimental arm: 3 months adjuvant chemotherapy
    Control arm: 6 months adjuvant chemotherapy
  • Key Findings / Outcomes
  • For low-risk patients (T1-3, N1): 3 months non-inferior to 6 months.
  • For high-risk (T4 or N2): 6 months still better.
  • Impact / Significance
    Changed practice to shorter duration (3 months) in low-risk patients, reducing toxicity without sacrificing efficacy.
  • Trial Name / Acronym
    CRYSTAL
  • Publication Details
    Title: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer
    Journal: New England Journal of Medicine (NEJM)
    Year: 2009
    DOI: 10.1056/NEJMoa0805019
  • Patient Population
    Previously untreated metastatic colorectal cancer; later analysis focused on KRAS wild-type.
  • Intervention / Control
    Experimental arm: FOLFIRI + cetuximab
    Control arm: FOLFIRI alone
  • Key Findings / Outcomes
  • In KRAS WT: median PFS improved (9.9 vs 8.7 months).
  • Response rate also higher (57.3% vs 39.7%).
  • Impact / Significance
    Established EGFR inhibitors as effective in first-line treatment for RAS wild-type mCRC.
  • Trial Name / Acronym
    OPUS
  • Publication Details
    Title: Cetuximab plus FOLFOX-4 in first-line treatment of metastatic colorectal cancer
    Journal: Annals of Oncology
    Year: 2008
    DOI: 10.1093/annonc/mdn415
  • Patient Population
    Untreated metastatic colorectal cancer; later analysis in KRAS WT subgroup.
  • Intervention / Control
    Experimental arm: FOLFOX-4 + cetuximab
    Control arm: FOLFOX-4 alone
  • Key Findings / Outcomes
  • KRAS WT subgroup: response rate 61% vs 37%.
  • Median PFS: 7.7 vs 7.2 months.
  • Impact / Significance
    Reinforced benefit of cetuximab in combination with oxaliplatin-based chemo for RAS WT patients.
  • Trial Name / Acronym
    CALGB/SWOG 80405
  • Publication Details
    Title: Cetuximab versus bevacizumab in combination with chemotherapy for metastatic colorectal cancer
    Journal: Journal of Clinical Oncology (JCO)
    Year: 2017
    DOI: 10.1200/JCO.2017.74.8855
  • Patient Population
    Previously untreated KRAS WT metastatic colorectal cancer.
  • Intervention / Control
    All received either FOLFOX or FOLFIRI; randomized to:
  • Cetuximab + chemo
  • Bevacizumab + chemo
  • Key Findings / Outcomes
  • Median OS: cetuximab 30.0 months vs bevacizumab 29.0 months.
  • No significant difference in OS.
  • Impact / Significance
    Supported both EGFR and VEGF inhibitors as valid first-line options in KRAS WT mCRC.
  • Trial Name / Acronym
    FIRE-3
  • Publication Details
    Title: FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab in first-line treatment of KRAS wild-type metastatic colorectal cancer
    Journal: Lancet Oncology
    Year: 2014
    DOI: 10.1016/S1470-2045(14)70027-2
  • Patient Population
    KRAS exon 2 WT metastatic colorectal cancer.
  • Intervention / Control
    Experimental arm: FOLFIRI + cetuximab
    Control arm: FOLFIRI + bevacizumab
  • Key Findings / Outcomes
  • ORR higher with cetuximab (65% vs 57%).
  • No PFS difference; median OS longer with cetuximab (28.7 vs 25.0 months).
  • Impact / Significance
    Suggested potential OS benefit with cetuximab; important in discussions of first-line biologic choice.
  • Trial Name / Acronym
    NO16966
  • Publication Details
    Title: Bevacizumab plus oxaliplatin-based chemotherapy as first-line treatment for metastatic colorectal cancer
    Journal: New England Journal of Medicine (NEJM)
    Year: 2007
    DOI: 10.1056/NEJMoa0708154
  • Patient Population
    Previously untreated mCRC.
  • Intervention / Control
    XELOX (capecitabine + oxaliplatin) or FOLFOX, with or without bevacizumab.
  • Key Findings / Outcomes
  • Median PFS: 9.4 vs 8.0 months with bevacizumab.
  • OS: 21.3 vs 19.9 months.
  • Impact / Significance
    Confirmed benefit of bevacizumab beyond irinotecan regimens; broadened its use with oxaliplatin-based chemotherapy.
  • Trial Name / Acronym
    KEYNOTE-177
  • Publication Details
    Title: Pembrolizumab versus Chemotherapy for Microsatellite Instability–High Metastatic Colorectal Cancer
    Journal: New England Journal of Medicine (NEJM)
    Year: 2020
    DOI: 10.1056/NEJMoa2017699
  • Patient Population
    Previously untreated MSI-H/dMMR metastatic colorectal cancer.
  • Intervention / Control
    Experimental arm: Pembrolizumab
    Control arm: Standard chemotherapy (choice of mFOLFOX6 or FOLFIRI ± bevacizumab or cetuximab)
  • Key Findings / Outcomes
  • Median PFS: 16.5 months with pembrolizumab vs 8.2 months with chemotherapy.
  • Fewer adverse events with immunotherapy.
  • Impact / Significance
    Established PD-1 inhibitor as first-line standard in MSI-H mCRC.
  • Trial Name / Acronym
    CheckMate-142
  • Publication Details
    Title: Nivolumab plus ipilimumab in patients with DNA mismatch repair–deficient/microsatellite instability–high metastatic colorectal cancer
    Journal: Journal of Clinical Oncology (JCO)
    Year: 2018
    DOI: 10.1200/JCO.2018.78.6784
  • Patient Population
    Previously treated MSI-H/dMMR mCRC.
  • Intervention / Control
    Nivolumab + ipilimumab (single-arm study).
  • Key Findings / Outcomes
  • ORR: 55%.
  • 12-month PFS: 71%.
  • Impact / Significance
    Demonstrated efficacy of dual immune checkpoint blockade in MSI-H mCRC; added an option beyond PD-1 monotherapy.
  • Trial Name / Acronym
    FOCUS
  • Publication Details
    Title: Combination chemotherapy versus sequential single-agent chemotherapy for treatment of advanced colorectal cancer
    Journal: Journal of Clinical Oncology (JCO)
    Year: 2007
    DOI: 10.1200/JCO.2006.09.8468
  • Patient Population
    Previously untreated advanced/metastatic colorectal cancer.
  • Intervention / Control
  • Trial Name / Acronym
    Tournigand et al.
  • Publication Details
    Title: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer
    Journal: Journal of Clinical Oncology (JCO)
    Year: 2004
    DOI: 10.1200/JCO.2004.08.029
  • Patient Population
    Previously untreated mCRC.
  • Intervention / Control
    FOLFIRI followed by FOLFOX6 at progression, or reverse sequence.
  • Key Findings / Outcomes

Table Of Content

  • GOG-111 (1996)

  • ICON3 (2002)

  • GOG-218 (2011)

  • ICON7 (2011)

  • SOLO-1 (2018)
  • PRIMA (2020)
  • PAOLA-1 (2020)

  • Study 19 (2012)

  • NOVA (2016)

  • ARIEL3 (2017)

  • GOG-0213 (2019)
  • ATHENA-MONO (2022)

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