Colon Cancer

Increased risk of CRC:

• Personal history of adenoma, Sessile Serrated polyp (SSP)/ lesion (SSL), CRC, IBD, Cystic fibrosis, childhood cancers

• Positive family history of CRC

  
  

Screening:

• Average risk adults:

  • Age 45–75 years with a life expectancy of ≥10 years

  • Screening between ages 76–85 should be individualized based on comorbidity status, life expectancy, and prior screening history.

Colonoscopy	Every 10 years
Flexible sigmoidoscopy	Every 5-10 years
CT Colonoscopy	Every 5 years
High-sensitivity guaiac test	Annually
Quantitative FIT	Every 3 years
DNA and RNA	Every 3 years

• Increased risk adults:

  • For individuals with ≥1 first-degree relative with CRC at any age, screening should begin with colonoscopy at age 40 OR 10 years before the earliest diagnosis of CRC, whichever is first, with repeat colonoscopy every 5 years.

Work-up:

• All newly diagnosed:

  • CBC, BMP, CEA

  • CAP CT scan

  • Colonoscopy

  • Check MSI/MMR:

    • If Microsatellite Instability-High/deficient Mismatch Repair (MSI-H/dMMR):

      • Failure of the DNA mismatch repair system → unstable microsatellite DNA

      • ~15% of all CRCs  and ~5% of metastatic CRCs

      • Either due to Lynch syndrome or sporadic mutations

      • Improved prognosis in stage II

      • Do not benefit from 5-FU adjuvant therapy alone

      • Methods:

        • Immunohistochemistry (IHC) for MMR proteins (MLH1, PMS2, MSH2, MSH6)

        • Molecular testing: PCR , NGS

      • Respond exceptionally well to immunotherapy

• All metastatic diseases:

  • Check KRAS (45%), NRAS (5%), and BRAF V600E (8%), HER-2 amplification (4%)

  • Consider PET scan if surgically curable M1 in selected areas

    • PET scan is not indicated for stage II/III

• Consider Lynch Syndrome

  • Autosomal dominant hereditary cancer syndrome

  • Caused by mutations in MMR genes (MLH1, PMS2, MSH2, MSH6)

  • Most common genetic cause of colorectal cancer

    • ~3% of all CRC cases and ~10% of cases diagnosed before age 50

    • Germline testing recommended in patients diagnosed <50

  
  

Treatment:

Non-Metastatic Colorectal Cancer:

• Stage I/II (Any T, N0):

  • Surgical resection → Observation

  • Consider adjuvant chemo for Stage IIC (T4b, N0)

    • If >70 years: Only give 5FU, no benefit with addition of oxaliplatin (MOSAIC)

• Stage III (N+):

  • Surgical resection → Adjuvant therapy

  • Adjuvant therapy:

    • Low risk stage III (T1-3, N1):

      • Preferred:

        • FOLFOX + Atezolizumab

        • CAPEOX + Atezolizumab

        • CAPEOX (3 months)

        • FOLFOX (3-6 months)

      • Category 2B:

        • Capecitabine (6 months)

        • 5-FU (6 months)

    • High Risk Stage III (T4 or N2):

      • Preferred:

        • FOLFOX + Atezolizumab

        • CAPEOX + Atezolizumab

        • CAPEOX (3-6 months)

        • FOLFOX (6 months)

      • Category 2B:

        • Capecitabine (6 months)

        • 5-FU (6 months)

• If stage II/III and positive PIK3CA mutation:

  • Add Aspirin 100-162 mg daily for 3 years to the treatment

Metastatic Colorectal Cancer:

• Oligometastatic to liver (if resectable):

  • Preferred:

    • Primary colon surgery + Resection of liver mets

  • Other options:

    • Neoadjuvant chemo for 2-3 months → Surgery

    • Colectomy → Chemo → Resection of liver mets

• Right sided cancers have worse outcomes (~1.5 years). Left sided cancers are more likely to benefit from EGFR inhibitors.

• Check NGS for RAS, BRAF V600E, RET, HER2, MSI, PD-L1

• First line Treatment:

  • FOLFOX or FOLFIRI

    • Consider oxaliplatin for 3-6 months → 5-FU maintenance

    • Consider FOLFIRINOX if rapid tumor shrinkage required

      • Needs good performance status

  • If KRAS/NRAS mutated:

    • Add bevacizumab (or another VEGF-targeted agent) to chemo.

  • If RAS/BRAF wild type + left sided:

    • Add EGFR inhibitors such as Cetuximab or Panitumumab (CALGB 80405, PRIME)

  • If MSI-H:

    • Pembolizumab (Keynote-177)

    • Nivolumab

    • Ipi/Nivo (Checkmate-142)

• Subsequent Lines:

  • If BRAF V600E mutated:

    • Encorafenib + Cetuximab (BEACON)

      • Can monitor BRAF mutations with ctDNA assays

  • If KRAS G12C mutated:

    • Adagrasib + Cetuximab (KRYSTAL)

    • Sotorasib + Panitumumab (CodeBreaK 300)

  • If NTRK-fusion positive:

    • Larotrectinib

    • Entrectinib

  • If HER2 amplified:

    • Enhertu

    • Trastuzumab + Tucatinib

  • TAS-102 (Lonsurf) + Bevacizumab (SUNLIGHT)

    • TAS-102 is an oral combination of Trifluridine (a thymidine-based nucleoside analog) + Tipiracil (a thymidine phosphorylase inhibitor)

  • VEGFR inhibitor

    • Fruquintinib

      • FRESCO-2 Trial → mOS was 7.4 months (fruquintinib) vs 4.8 months (placebo)

    • Regorafenib

      • CORRECT Trial → mOS 6.4 months (regorafenib) vs 5.0 months (placebo)

Surveillance:

• H&P and CEA:

  • q 3–6 M for 2 y, then q 6 M for a total of 5 y

• CAP CT scan:

  • q 6–12 M for up to 5 y

• Colonoscopy:

  • 1 year after surgery

    • If normal:

      • Repeat in 3 years, then q 5 y

    • If advanced adenoma:

      • Repeat in 1 year

Recurrence:

• If serial CEA elevation → Colonoscopy + CAP CT scan

  • If negative:

    • PET scan

    • Reevaluate with CAP CT scan in 3 months

  • If positive:

    • Treatment depends on whether the disease is surgically resectable.