What is the treatment for colorectal cancer?

Treatment of Rectal Cancer

Rectal cancer requires a multidisciplinary treatment approach with surgery as the cornerstone, combined with neoadjuvant chemoradiotherapy for locally advanced disease (T3-4 or node-positive), followed by adjuvant chemotherapy for high-risk patients, with the specific sequence and intensity determined by tumor stage, molecular markers (particularly MSI-H/dMMR status), and resectability of metastatic disease. 1, 2

Stage-Based Treatment Algorithm

Early Stage Disease (Stage I-II)

• Stage I rectal cancer: Surgical resection alone is curative in the majority of patients, with 5-year survival exceeding 60% 1, 3
• Stage II disease: Surgery remains primary treatment, with selective use of adjuvant chemotherapy only in patients with high-risk features including T4 tumors, poorly differentiated histology, vascular/lymphatic/perineural invasion, obstruction, perforation, or <12 lymph nodes examined 1

Locally Advanced Disease (Stage III)

The standard approach is neoadjuvant chemoradiotherapy followed by surgery and adjuvant chemotherapy 1, 2

• Neoadjuvant options: Short-course radiotherapy (5 fractions) or long-course chemoradiotherapy (combining radiation with fluoropyrimidine-based chemotherapy) 1
• Surgical resection: Perform en bloc resection with total mesorectal excision 6-12 weeks after completion of neoadjuvant therapy 1, 2
• Adjuvant chemotherapy: Fluoropyrimidine-based regimens (5-FU/leucovorin or capecitabine) or FOLFOX (5-FU/leucovorin/oxaliplatin) for 6 months total treatment duration including neoadjuvant phase 1, 2

Critical timing: Adjuvant chemotherapy must start within 8 weeks post-surgery; delays beyond 12 weeks significantly compromise survival 2

Assessment Post-Neoadjuvant Therapy

Evaluate treatment response at 8±4 weeks after completing neoadjuvant therapy using multimodal assessment 2

• Clinical complete response (cCR) assessment: Digital rectal examination showing no palpable tumor, flexible sigmoidoscopy showing no residual tumor or only erythematous scar, and MRI demonstrating substantial downsizing with fibrosis only 2
• Pathological response grading: Modified Ryan scoring provides definitive prognostic stratification, with Ryan Grade 0 (complete pathological response) occurring in 18-26% of patients and conferring 10-year disease-free survival of 89.5% 2

Important caveat: MRI has only 64% overall accuracy for response assessment, with tendency to overestimate residual tumor, so clinical complete response rates are generally much lower than pathological complete response rates 2

Organ Preservation Strategy

For patients achieving clinical complete response, organ preservation with intensive surveillance ("watch and wait") is an option 2

• Surveillance protocol: MRI, endoscopy, and digital rectal examination every 3-4 months for first 2 years, then every 6 months for years 3-5 2
• Exclusion criteria: Post-treatment FDG-PET/CT SUVmax >4.3 highly correlates with lack of complete response (negative predictive value 94%) and should exclude patients from organ preservation 2

Metastatic Disease Management

Resectable Metastases

For patients with resectable liver or lung metastases, surgical resection offers potential cure 1

Treatment algorithm based on Clinical Risk Score (CRS):

• Low-risk (CRS 0-2): Primary tumor resection + simultaneous or staged metastasectomy + adjuvant chemotherapy 1
• High-risk (CRS 3-5): Neoadjuvant chemotherapy + primary resection + metastasectomy + adjuvant chemotherapy 1

CRS parameters (1 point each): Positive lymph nodes in primary tumor, synchronous metastases or metachronous within 12 months, >1 liver metastasis, CEA >200 ng/mL, maximum metastasis diameter >5 cm 1

Unresectable Metastatic Disease

First-line systemic therapy aims to prolong survival and maintain quality of life, with potential conversion to resectability in select cases 1

Standard first-line regimens:

• Combination chemotherapy: FOLFOX (5-FU/leucovorin/oxaliplatin 85 mg/m² every 2 weeks) or FOLFIRI (5-FU/leucovorin/irinotecan every 2 weeks) provide superior response rates and survival compared to fluoropyrimidine monotherapy 1
• Bevacizumab addition: 5 mg/kg IV every 2 weeks or 7.5 mg/kg every 3 weeks combined with fluoropyrimidine-based chemotherapy for first- or second-line treatment 4

Toxicity profiles differ: FOLFOX causes more polyneuropathy; FOLFIRI causes more alopecia and diarrhea 1

Sequential monotherapy alternative: For frail or elderly patients, sequential fluoropyrimidine monotherapy followed by combination therapy at progression achieves similar overall survival with reduced upfront toxicity 1

When to use combination therapy upfront: Symptomatic metastases, need for tumor downsizing for potential resection, or good performance status patients seeking maximum response 1

Molecular Marker-Directed Therapy

MSI-H/dMMR Tumors

PD-1 immune checkpoint inhibitors should be prioritized over traditional chemotherapy regardless of stage 1, 2

• These patients can consider immunotherapy for conversion therapy in locally advanced disease or palliative treatment in metastatic disease 1

pMMR/MSS Tumors

Standard chemotherapy regimens apply based on stage and pathological response grading 2

Special Population Considerations

Elderly Patients (≥70-75 years)

Age alone should not preclude aggressive curative treatment in fit patients 1

• Elderly patients are frequently understaged and undertreated, receiving fewer elective operations and less adjuvant therapy than younger counterparts 1
• Modified Ryan grading should guide adjuvant therapy decisions regardless of chronological age in patients with adequate performance status 1, 2
• For frail elderly patients, sequential monotherapy starting with oral fluoropyrimidines (capecitabine) represents a valid option 1

Surveillance After Curative Treatment

Conservative post-treatment surveillance program for patients with no residual disease 1

• History and physical examination: Every 3 months for 2 years, then every 6 months for years 3-5 1
• CEA monitoring: Every 3 months for 2 years, then every 6 months for years 3-5, only if patient is candidate for aggressive curative surgery upon recurrence detection 1
• Colonoscopy: Within 1 year of resection (or 3-6 months postoperatively); repeat annually if neoplastic polyps found, otherwise every 3 years 1
• Imaging: Liver ultrasonography every 6 months for 3 years, then at years 4-5; CT chest/abdomen for higher-risk patients 1

Management of elevated CEA with negative imaging: Repeat scans every 3 months; do NOT perform blind abdominal exploration 1

Common Pitfalls and Caveats

Surgical timing: Never administer bevacizumab within 28 days before elective surgery or until adequate wound healing after major surgery 4

Adjuvant therapy delays: Starting adjuvant chemotherapy beyond 8 weeks post-surgery significantly compromises outcomes; beyond 12 weeks is associated with markedly worse survival 2

MRI interpretation challenges: Difficulty distinguishing tumor from radiation-induced fibrosis may cause discordance between imaging and surgical findings; tumor fragmentation can cause overestimation of response 2

Persistent CRM involvement: Post-treatment MRI showing persistent circumferential resection margin involvement mandates referral to experienced multivisceral resection team rather than attempting standard resection 2

Bevacizumab is NOT indicated for adjuvant treatment of colon cancer 4