What are the treatment options for colorectal cancer?

Treatment of Colorectal Cancer

Initial Assessment and Molecular Testing

All patients with colorectal cancer must undergo molecular testing for microsatellite instability (MSI-H/dMMR), RAS mutation status, and BRAF V600E mutation status before initiating systemic therapy, as these biomarkers fundamentally alter treatment selection. 1

• Staging must include clinical examination, complete blood count, liver and renal function tests, carcinoembryonic antigen (CEA), and CT scan of abdomen and chest 1
• Performance status is the strongest individual prognostic factor and determines treatment intensity 1
• FDG-PET can identify equivocal lesions before planned resection of metastases 1
• Multidisciplinary team discussion is mandatory for optimal treatment strategy 1

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Stage-Specific Treatment Algorithms

Resectable Disease (Stages I-III)

Surgery with en bloc resection is the primary curative treatment for resectable colon cancer. 2

Stage I-II Colon Cancer

• Surgery alone is standard treatment with >60% 5-year survival 3
• Adjuvant chemotherapy is not routinely indicated for stage II disease unless high-risk features present 1
• For high-risk stage II, consider fluoropyrimidine monotherapy (capecitabine 1,250 mg/m² orally twice daily days 1-14, every 3 weeks for 8 cycles) 1

Stage III Colon Cancer

• Surgery followed by adjuvant chemotherapy is mandatory 1
• Preferred regimen: CAPEOX (capecitabine 1,000 mg/m² orally twice daily days 1-14 + oxaliplatin 130 mg/m² IV day 1, every 3 weeks for 8 cycles) 1
• Alternative: mFOLFOX6 (oxaliplatin 85 mg/m² + leucovorin 400 mg/m² + 5-FU 400 mg/m² bolus + 5-FU 2,400 mg/m² continuous infusion over 46-48 hours, every 2 weeks for 12 cycles) 1
• Adjuvant therapy must start within 8 weeks post-surgery; delays beyond 12 weeks significantly compromise survival 4

Rectal Cancer

• For locally advanced rectal cancer, neoadjuvant chemoradiotherapy or short-course radiation followed by surgery is standard 1
• Pathological response grading using modified Ryan scoring provides prognostic stratification post-neoadjuvant therapy 4
• Ryan Grade 0 (complete pathological response) occurs in 18-26% of patients with 10-year distant metastasis rates of only 10.5% 4
• Clinical complete response assessment using combined MRI, endoscopy, and digital rectal examination identifies candidates for organ preservation strategies 4

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Metastatic Disease Treatment

First-Line Therapy Selection Based on Molecular Profile

MSI-H/dMMR Tumors

Pembrolizumab immunotherapy is the recommended first-line treatment for MSI-H/dMMR metastatic colorectal cancer, superior to chemotherapy. 1

• Pembrolizumab should be prioritized over traditional chemotherapy regardless of other factors 4
• This represents a paradigm shift from chemotherapy-first approaches 1

MSS/pMMR, RAS Wild-Type, Left-Sided Tumors

Chemotherapy plus anti-EGFR therapy (cetuximab or panitumumab) is recommended. 1

• FOLFOX or FOLFIRI backbone with cetuximab or panitumumab 1
• Anti-EGFR therapy provides superior outcomes in left-sided, RAS wild-type disease 1

MSS/pMMR, RAS Wild-Type, Right-Sided Tumors

Chemotherapy plus anti-VEGF therapy (bevacizumab) is recommended. 1

• Bevacizumab 5 mg/kg IV every 2 weeks with FOLFOX or FOLFIRI 5
• Alternative: bevacizumab 7.5 mg/kg IV every 3 weeks 5
• Right-sided tumors respond poorly to anti-EGFR therapy 1

MSS/pMMR, RAS Mutant Tumors

Chemotherapy plus bevacizumab is the standard approach. 1, 5

• Anti-EGFR therapy is contraindicated in RAS-mutant disease 1

Chemotherapy Regimen Selection

Initially Unresectable Disease

Doublet chemotherapy (FOLFOX or FOLFIRI) should be offered; triplet therapy (FOLFOXIRI) may be offered to fit patients. 1

• FOLFOX: Oxaliplatin 85 mg/m² + leucovorin 400 mg/m² + 5-FU 400 mg/m² bolus + 5-FU 2,400 mg/m² continuous infusion, every 2 weeks 1
• FOLFIRI: Irinotecan 180 mg/m² + leucovorin 400 mg/m² + 5-FU 400 mg/m² bolus + 5-FU 2,400 mg/m² continuous infusion, every 2 weeks 1
• FOLFOX and FOLFIRI have similar efficacy but different toxicity profiles: more alopecia and diarrhea with irinotecan, more polyneuropathy with oxaliplatin 1
• Combination chemotherapy provides higher response rates and longer progression-free survival than fluoropyrimidine monotherapy 1

Potentially Resectable After Conversion

High-intensity triplet chemotherapy (FOLFOXIRI) plus bevacizumab achieves the highest response rates for conversion to resectability. 1

• Objective response is the primary goal when metastases are potentially resectable 1
• Patients should be re-evaluated every 2 months for resectability 1
• When bevacizumab is used, the last dose must be administered at least 6 weeks before surgery 1

Sequential Monotherapy Approach

Sequential fluoropyrimidine monotherapy followed by combination therapy at progression is acceptable only in frail patients or those prioritizing quality of life over response rate. 1

• Two randomized studies showed sequential therapy was not inferior for overall survival 1
• However, combination therapy remains preferred when objective response is needed 1
• Approximately 15% of patients are appropriate for initial monotherapy 1

Resectable Metastatic Disease

Liver or Lung Metastases

Perioperative chemotherapy or surgery alone should be offered to patients with resectable liver metastases. 1

• For low-risk patients (Clinical Risk Score 0-2): simultaneous or staged resection of primary and metastases plus postoperative adjuvant chemotherapy 1
• For high-risk patients (Clinical Risk Score 3-5): neoadjuvant chemotherapy followed by resection plus postoperative adjuvant chemotherapy 1
• Perioperative FOLFOX improves progression-free survival in resectable liver metastases 1
• Long-term survival is achievable with complete resection 1

Oligometastatic Disease

Stereotactic body radiation therapy may be recommended following systemic therapy for patients with liver oligometastases not candidates for resection. 1

• Selective internal radiation therapy is not routinely recommended 1
• Local ablative treatments (RFA, microwave ablation) are options for unresectable oligometastatic disease 6

Colorectal Peritoneal Metastases

Cytoreductive surgery plus systemic chemotherapy may be recommended for selected patients; however, hyperthermic intraperitoneal chemotherapy is not recommended. 1

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Later-Line and Targeted Therapies

BRAF V600E-Mutant Disease

Encorafenib plus cetuximab is recommended for previously treated BRAF V600E-mutant metastatic colorectal cancer that has progressed after at least one prior line of therapy. 1

• This combination provides significant survival benefit in this poor-prognosis subgroup 1

Second-Line Therapy

For patients progressing on first-line bevacizumab-containing regimen, switch chemotherapy backbone (FOLFOX to FOLFIRI or vice versa) and continue bevacizumab. 1, 5

• Bevacizumab 5 mg/kg IV every 2 weeks or 7.5 mg/kg IV every 3 weeks with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy 5

Refractory Disease

Regorafenib and trifluridine/tipiracil demonstrate survival benefit in later lines when improving quality of life becomes predominant. 6

• These agents are reserved for patients who have exhausted standard chemotherapy options 6

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Special Populations and Situations

Elderly Patients (≥75 Years)

Elderly patients are frequently understaged and undertreated; fit elderly patients should receive the same aggressive treatment as younger patients based on comprehensive geriatric assessment, not chronological age. 1, 4

• Performance status and comorbidity assessment, not age alone, should guide treatment intensity 1
• Geriatrician involvement is recommended for patients with physical or psychological comorbidities 1

Symptomatic Primary Tumor with Metastatic Disease

Obstruction or Bleeding

For symptomatic primary lesions, surgery for symptom relief followed by systemic therapy is recommended. 1

• Alternative: interventional embolization or endoscopic treatment plus systemic therapy 1
• For bleeding colon mass: argon plasma coagulation, epinephrine injection, or endoscopic clips as first-line 7
• If endoscopic therapy fails: transcatheter arteriography with embolization 7
• Endoscopic stent implantation for obstruction is an option 1

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Critical Pitfalls and Caveats

• Never combine two targeted agents (anti-EGFR plus anti-VEGF)—this approach is not recommended and increases toxicity without benefit 1
• Bevacizumab must be withheld at least 28 days prior to elective surgery and not resumed until at least 28 days post-surgery with adequate wound healing 5
• Anti-EGFR therapy is contraindicated in RAS-mutant tumors and provides minimal benefit in right-sided primary tumors 1
• Adjuvant chemotherapy is not indicated for stage I-II colon cancer outside of high-risk features 1
• Total treatment duration including neoadjuvant and adjuvant phases should not exceed 6 months 4
• MRI has only 64% overall accuracy for response assessment post-neoadjuvant therapy; clinical complete response rates are generally much lower than pathological complete response rates 4