What is the recommended diagnostic work‑up, staging imaging, molecular testing, and stage‑specific treatment (including surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy) for a patient with suspected colorectal cancer?

Colorectal Cancer Diagnosis and Management

Diagnostic Work-Up

All patients with suspected colorectal cancer require colonoscopy with biopsy for histopathological confirmation before initiating any treatment. 1

Essential Initial Evaluation

• Perform digital rectal examination with rigid proctoscopy to measure the exact distance from the anal verge; tumors ≤15 cm are classified as rectal cancer (requiring neoadjuvant therapy consideration), while more proximal lesions are colonic cancer. 2

• Complete colonoscopy is mandatory to exclude synchronous lesions and obtain tissue diagnosis. 1, 2

• Physical examination must assess for hepatomegaly, abdominal masses, supraclavicular lymphadenopathy, ascites, and signs of anemia (pallor, tachycardia). 2

• Laboratory testing includes complete blood count, comprehensive metabolic panel (liver and renal function), and carcinoembryonic antigen (CEA) level. 1

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Staging Imaging

Colon Cancer

• Contrast-enhanced CT of chest, abdomen, and pelvis is the primary staging modality. 1

• Abdominal/pelvic ultrasonography or MRI can supplement CT findings. 1

• FDG-PET scan is NOT recommended for routine initial staging but may be useful when tumor markers are elevated without CT evidence of metastases, or to clarify potentially resectable metastatic disease. 1, 3

Rectal Cancer (≤15 cm from anal verge)

• High-resolution pelvic MRI is mandatory for local staging to determine depth of invasion (T-stage), nodal status, circumferential resection margin (CRM) involvement, and extramural vascular invasion. 2, 3

• Endoscopic ultrasound is valuable for early cT1-T2 lesions but less useful in locally advanced disease. 2, 3

• Chest/abdomen/pelvis CT is still required for distant metastasis staging. 1, 2

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Molecular Testing

Testing for MMR status, KRAS, NRAS (exons 2,3,4), and BRAF mutations is mandatory in all patients at the time of metastatic CRC diagnosis. 1

Essential Biomarkers (Metastatic Disease)

• MMR/MSI status predicts response to immune checkpoint inhibitors and assists in Lynch syndrome genetic counseling. 1

• RAS testing (KRAS/NRAS) is mandatory before anti-EGFR monoclonal antibody therapy (cetuximab, panitumumab). 1

• BRAF V600E mutation provides prognostic information and predicts response to cetuximab-encorafenib combination. 1

• HER2 amplification (IHC or FISH) should be tested in RAS-wild-type patients to identify candidates for HER2-targeted therapy. 1

• NTRK fusion testing is recommended when feasible (incidence <0.5%); if positive, larotrectinib or entrectinib is indicated. 1

• DPD deficiency testing must be performed before initiating fluoropyrimidine-based chemotherapy (5-FU, capecitabine) to prevent severe toxicity. 1

Testing NOT Recommended Outside Trials

• ALK and ROS1 gene fusions, PIK3CA mutations, and HER2 activating mutations should not be routinely tested. 1

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Stage-Specific Treatment

Stage 0 and T1 Low-Risk (Polyp-Contained Cancer)

Local excision alone is sufficient for T1 tumors with favorable features: well/moderately differentiated, no lymphovascular invasion, negative margins ≥1 mm, and no tumor budding. 3, 4

• Formal colectomy with lymph node dissection is mandatory for T1 high-risk features (poor differentiation, lymphovascular invasion, positive/close margins <1 mm, tumor budding, or sessile morphology). 3, 4

Stage I (T1-2, N0, M0)

Wide surgical resection with ≥5 cm margins and removal of ≥12 lymph nodes is the definitive treatment; adjuvant chemotherapy is NOT indicated. 3

Stage II (T3-4, N0, M0)

Surgery alone with ≥5 cm margins and ≥12 lymph node harvest is standard. 3

• Adjuvant chemotherapy is NOT routinely recommended for low-risk stage II disease. 3

• Consider adjuvant chemotherapy for high-risk features: T4 depth, <12 nodes examined, poor differentiation, lymphovascular invasion, obstruction/perforation, or tumor budding. 3

Stage III (Any T, N1-2, M0)

Adjuvant chemotherapy is mandatory for all stage III colon cancer and must be initiated within 12 weeks after surgery. 3

• FOLFOX (oxaliplatin + 5-FU/leucovorin) is the preferred regimen, providing superior disease-free survival compared to 5-FU/leucovorin alone. 3

• Capecitabine monotherapy is an acceptable alternative with comparable efficacy and reduced toxicity. 3

• Surgery requires ≥5 cm margins and harvest of ≥12 lymph nodes. 3

Rectal Cancer: Stage-Specific Approach

Early Favorable (cT1-2, N0)

Total mesorectal excision (TME) surgery alone without neoadjuvant therapy is appropriate. 2

Intermediate Risk (Most cT3 without threatened mesorectal fascia, N+)

Preoperative short-course radiotherapy (25 Gy in 5 fractions) followed by immediate TME surgery is recommended. 2

Locally Advanced (cT3 with threatened CRM, cT4)

Preoperative long-course chemoradiotherapy (50 Gy in 1.8 Gy fractions with concurrent 5-FU) is mandatory, with surgery delayed 6-8 weeks after completion. 2

• Total mesorectal excision with sharp dissection along the mesorectal fascia is the surgical standard for all rectal cancers not amenable to local excision. 2

• Adjuvant chemotherapy should be considered for stage III rectal cancer, though evidence is less robust than for colon cancer. 2

• Postoperative chemoradiotherapy is reserved for positive CRM, tumor perforation, or high local recurrence risk when preoperative radiotherapy was not given. 2

Stage IV (Metastatic Disease)

First-line palliative chemotherapy consists of 5-FU/leucovorin combined with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI). 2

• Resection of liver or lung metastases should be considered as part of curative-intent treatment in selected cases. 2

• Anti-EGFR monoclonal antibodies (cetuximab, panitumumab) are indicated only in RAS-wild-type tumors. 1

• Bevacizumab (anti-VEGF) can be added to chemotherapy backbones. 5

• Immune checkpoint inhibitors (pembrolizumab, nivolumab) are highly effective in dMMR/MSI-high metastatic CRC. 1

• Cetuximab-encorafenib combination is indicated for BRAF V600E-mutated metastatic CRC. 1

• HER2-targeted therapy should be considered in RAS-wild-type, HER2-amplified tumors after progression on standard therapies. 1

• Larotrectinib or entrectinib is recommended for the rare NTRK fusion-positive tumors. 1

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Critical Surgical Principles

Pathologic examination must retrieve ≥12 lymph nodes to ensure accurate staging; fewer nodes constitute a quality failure that risks understaging and inappropriate therapy. 3

• Laparoscopic resection is acceptable for experienced surgeons when the cancer is non-obstructed, non-perforated, and technically feasible. 3

• For rectal cancer, a negative CRM (>1 mm from mesorectal fascia) is essential to minimize local recurrence. 2, 3

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Common Pitfalls and Caveats

• Inadequate lymph node sampling (<12 nodes) is the most frequent staging error, leading to understaging and omission of life-saving adjuvant chemotherapy. 3

• Failure to distinguish colon from rectal cancer (using rigid proctoscopy to measure distance from anal verge) results in inappropriate omission of neoadjuvant therapy for rectal cancer. 2

• Initiating anti-EGFR therapy without RAS testing exposes RAS-mutant patients to ineffective, toxic, and expensive treatment. 1

• Starting fluoropyrimidines without DPD deficiency testing can cause life-threatening toxicity in deficient patients. 1

• Omitting MMR/MSI testing in metastatic disease misses the opportunity for highly effective immunotherapy in dMMR/MSI-high patients. 1