Rectal Cancer Management Per Stage

Initial Staging and Assessment

All patients with rectal cancer require comprehensive staging with pelvic MRI (with dedicated rectal sequences), complete colonoscopy, chest/abdominal CT, CEA level, and assessment for microsatellite instability (MSI) and mismatch repair (MMR) status. 1 Pelvic MRI is the most accurate test for defining locoregional staging, detecting extramural vascular invasion (EMVI), determining T substage, distance to the circumferential resection margin (CRM), and predicting risks of metastases 1. At least 12 regional lymph nodes should be examined pathologically 1.

Stage I (T1-T2, N0)

T1 Tumors Without Adverse Features

Local excision (transanal excision or transanal endoscopic microsurgery) is appropriate for cT1N0 tumors without adverse features (no grade 3, no lymphovascular invasion, no perineural invasion, well to moderately differentiated, <3 cm size, <30% circumference, within 8 cm of anal verge). 1
If post-excision pathology reveals adverse features (grade 3-4, positive margins, lymphovascular invasion, or upstaging to T2), proceed to radical resection with total mesorectal excision (TME) 1.

T2 Tumors and T1 with Adverse Features

Radical TME surgery is the standard of care due to 7-14% risk of nodal metastases even in early tumors. 1, 2
For mid-to-upper rectal tumors: low anterior resection 1
For low rectal tumors: abdominoperineal resection or coloanal anastomosis 1
No adjuvant therapy required for pathologic stage I disease 1

Stage II-III (T3-T4 and/or Node-Positive)

Locally Advanced Disease Without High-Risk Features

For upper rectal cancer with ≤5 mm extramural invasion, treatment options are outside the scope of current ASCO guidelines, but generally require less aggressive neoadjuvant therapy. 1

Locally Advanced Disease With High-Risk Features

Total neoadjuvant therapy (TNT) should be offered to patients with low rectal cancer and/or one or more of the following high-risk features: T4, EMVI, tumor deposits, threatened mesorectal fascia or intersphincteric plane, or inability to achieve sphincter-sparing surgery. 1

TNT Regimen Options (in order of preference):

Long-course chemoradiotherapy (45-50 Gy over 5-6 weeks with concurrent fluoropyrimidine) followed by chemotherapy (preferred approach) 1
Neoadjuvant FOLFOX (fluorouracil, leucovorin, oxaliplatin) with selective addition of chemoradiotherapy if tumor response is insufficient 1
Short-course radiotherapy (5×5 Gy) followed immediately by chemotherapy starting 11-18 days later 1

Surgery (TME) should be performed 6-8 weeks after completion of neoadjuvant therapy 1
TME quality assessment with photographic documentation is a strong quality control measure 1

Special Population: MSI-H or dMMR Tumors

Immunotherapy should be offered to patients with MSI-H or dMMR locally advanced rectal cancer. 1 Patients with contraindications to immunotherapy may consider standard options for microsatellite stable (MSS) or proficient MMR (pMMR) tumors, though dMMR tumors are sensitive to chemoradiation and historically fluorouracil-based chemotherapy has been less effective 1.

Postoperative Adjuvant Chemotherapy

Adjuvant chemotherapy is recommended for all patients with pathologic stage II/III rectal cancer after neoadjuvant chemoradiotherapy and surgery if they did not receive neoadjuvant chemotherapy, regardless of surgical pathology results. 1 However, the scientific evidence for benefit is weaker than in colon cancer and likely limited to disease-free survival rather than overall survival 1. The decision should be risk-balanced, considering predicted toxicity and risk of relapse 1.

Clinical Complete Response (cCR) After Neoadjuvant Therapy

Nonoperative management (watch-and-wait) may be discussed as an alternative to TME in patients achieving cCR, particularly those requiring abdominoperineal resection. 1

Definition of cCR:

Digital rectal examination and rectoscopy: no palpable tumor, no residual tumor material, no erythematous ulcer or scar 1
MRI: substantial downsizing with no observable residual tumor or residual fibrosis only (limited signal on diffusion-weighted imaging) 1
Endoscopic biopsy: not mandatory and should not be performed if DRE, rectoscopy, and MRI criteria are fulfilled 1

This approach requires experienced multidisciplinary teams, strict surveillance protocols, and patient understanding that surgical salvage will be performed for tumor regrowth. 1 Surveillance should include digital rectal examination and sigmoidoscopy every 3-6 months for the first 3 years, then every 6-12 months for 2 years 1.

Stage IV (Metastatic Disease)

Resectable Oligometastatic Disease

For patients with resectable oligometastatic disease, initiate short-course radiotherapy (5×5 Gy) followed by combination chemotherapy (FOLFOX or FOLFIRI with or without biologics), then perform surgical resection of both primary and metastatic sites. 3

Surgery for the primary can be safely delayed up to 5-6 months after radiotherapy when synchronous metastases are present 3
Complete a total of 6 months of perioperative chemotherapy (pre- and postoperative combined) 4, 3
In highly selected cases with limited, resectable liver or lung metastases, surgical resection should be considered 4

Unresectable Metastatic Disease

Start with systemic combination chemotherapy (FOLFOX or FOLFIRI) as the cornerstone of treatment. 4, 3

Systemic Therapy Regimens:

First-line: FOLFOX (5-FU/leucovorin/oxaliplatin) or FOLFIRI (5-FU/leucovorin/irinotecan) 4, 5
Add bevacizumab (anti-VEGF) regardless of KRAS mutation status 4, 3
Add cetuximab or panitumumab (anti-EGFR) only for wild-type KRAS tumors 4, 3
Consider checkpoint inhibitors if MSI-H 3
Second-line: Switch chemotherapy backbone (FOLFOX to FOLFIRI or vice versa) for patients maintaining good performance status after first-line progression 3

Management of Symptomatic Primary Tumor:

Palliative radiotherapy for local symptom control (bleeding, pain, obstruction) 4, 3
Endoluminal stenting or surgical diversion for obstruction 4
Preoperative radiotherapy is preferred over postoperative when radiation is indicated, as it is more effective and less toxic 4, 3

Monitoring:

Re-evaluate with imaging (CT or MRI) and CEA after 2-3 cycles of chemotherapy 4, 3

Local Recurrence

If radiotherapy was not previously given, patients should receive preoperative chemoradiotherapy (45-50 Gy in 5-6 weeks with concurrent fluoropyrimidine) or short-course radiotherapy (5×5 Gy) followed by fluoropyrimidine and oxaliplatin-based chemotherapy prior to attempted resection. 1

In patients previously irradiated, re-irradiation to lower doses with concomitant chemotherapy is safe and can be used in selected patients to facilitate curative resection or for palliative symptom control. 1 Salvage surgery should be performed 6-8 weeks after radiotherapy by specialist teams 1. If salvage surgery is not an option, systemic palliative chemotherapy may be used to downstage the tumor, though reports of efficacy are rare 1.

Follow-Up Surveillance

Stage I-III After Curative Treatment:

Clinical visits every 3 months for 3 years, then every 6 months for 2 years, with CEA testing (in patients amenable to resection of recurrence) 1, 6
Complete colonoscopy at initial diagnosis, then every 5 years if no findings 1, 6
CT chest and abdomen every 6-12 months in high-risk disease (confined to patients amenable to resection of hepatic or pulmonary recurrence) 1
For rectal cancer patients after local excision: digital rectal examination and sigmoidoscopy every 3-6 months for 3 years, then every 6-12 months for 2 years 1
Surveillance for multimodal-treated rectal cancers should continue beyond 5 years, as perioperative treatment may delay recurrence 1

Critical Pitfalls to Avoid

Do not use conventional long-course chemoradiotherapy (50 Gy with fluoropyrimidine) as upfront treatment in synchronous metastases, as this delays systemic therapy and reduces dose intensity 3
Ensure KRAS mutation testing is performed before considering EGFR inhibitors, as these are ineffective in KRAS mutant tumors 3
Maintain at least a 6-week interval between the last dose of bevacizumab and elective surgery due to wound healing concerns 3
Neither FDG-PET nor MRI nor CT can accurately determine pathologic complete response, complicating patient selection for nonoperative management 1
Lymph node metastases are still seen in a subset of patients with pathologic complete response 1

What is the management approach for an adult patient with rectal cancer, based on the stage of the disease and assuming no significant comorbidities?

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