Colorectal Cancer Management

Evaluation

Staging of Colorectal Cancer  

Revised Tumors, Nodes and Metastasis (TNM) System


The revised tumors, nodes, and metastasis (TNM) system is proposed by the American Joint Committee on Cancer. TNM staging is based on the depth of tumor invasion on the colorectal lining (T), the number of regional lymph nodes affected (N), and the presence or absence of distant metastasis (M). Colon cancer and rectal cancer share the same staging system since TNM categories show very similar survival outcomes for colon and rectal cancer.

The assessment of primary tumor (T) is as follows:

• TX: Primary tumor cannot be evaluated
• T0: No evidence of primary tumor
• Tis: Carcinoma in situ (intraepithelial penetration of lamina propria)
• T1: Tumor reaches submucosa
• T2: Tumor penetrates muscularis propria
• T3: Tumor reaches muscularis propria
• T4a: Tumor reaches the surface of the peritoneal viscera
• T4b: Tumor invades or adheres to adjacent organs or structures

The assessment of regional lymph nodes (N) is as follows:

• NX: Regional lymph nodes cannot be evaluated
• N0: No regional nodal metastasis
• N1: Metastasis involves 1-3 regional lymph nodes
• N1a: Metastasis involves 1 regional lymph node
• N1b: Metastasis involves 2-3 regional lymph nodes
• N1c: No regional lymph node metastasis but with tumor spread in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues

The assessment of distant metastasis (M) is as follows:

• M0: No distant metastasis
• M1a: Metastasis in one organ or site (eg lung, liver, ovary, nonregional node)
• M1b: Metastasis in >1 organ or site without peritoneal metastasis
• M1c: Metastases to the peritoneum with or without organ metastases

Staging of Colorectal Cancer   

The pathologic staging is the single most important prognostic factor following surgical resection of tumors and are staged as follows:

• Stage 0: Tis N0 M0       
• Stage I: T1-T2 N0 M0
• Stage IIA: T3 N0 M0
• Stage IIB: T4a N0 M0
• Stage IIC: T4b N0 M0
• Stage IIIA:
  • T1-T2 N1/N1c M0
  • T1 N2a M0
• Stage IIIB:
  • T3-T4a N1/N1c M0
  • T2-T3 N2a M0
  • T1-T2 N2b M0
• Stage IIIC:
  • T4a N2a M0
  • T3-T4a N2b M0
  • T4b N1-N2 M0
• Stage IVA: Any T, Any N, M1a
• Stage IVB: Any T, Any N, M1b
• Stage IVC: Any T, Any N, M1c

Staging Evaluation  

CT (with contrast) of the abdomen and pelvis is recommended to estimate the stage of colon cancer. Beyond the rectum, chest CT scan is mandatory for the assessment of distal metastasis in rectal cancer.    

The locoregional extent of colorectal cancer is best evaluated during surgical exploration and by pathologic examination of the specimen. A minimum of 12 lymph nodes needs to be examined to establish the N stage.  In selected cases, a preoperative CT scan will aid in identifying involved neighboring structures. In locoregional colon cancer staging, MRI has no advantage over a CT scan.  

Preoperative locoregional staging of rectal cancer is needed to plan surgery and when considering the need for preoperative adjuvant chemotherapy. For patients with rectal cancer, MRI should be offered to evaluate the risk of local recurrence.  

Endorectal ultrasound may be done in rectal CA if MRI is contraindicated or if MRI shows disease amenable to local excision. The overall accuracy for detecting lymph node metastases is approximately 80%. It is not a very accurate method for staging rectal cancer. One cannot fully visualize large or bulky rectal tumors or areas beyond the immediate primary tumor (eg vascular invasion, tumor deposits).  

Findings from the digital rectal examination should not be used in staging colorectal cancer.  All patients with metastatic colorectal cancer should have tumor tissue genotyped for RAS (KRAS and NRAS) and BRAF mutations. It is performed only in certified laboratories.  

All patients with a V600 BRAF mutation appear to have a poorer prognosis. KRAS/NRAS/BRAF testing may be done on archived specimens, using either the primary tumor or a metastasis.  Fresh biopsies should not be performed solely for the purpose of KRAS/NRAS genotyping.  

Testing for universal mismatch repair (MMR) or MSI is recommended for all newly diagnosed colon and rectal cancer patients. It is only performed in certified laboratories. 

Pharmacological therapy

Neoadjuvant Therapy

Colon Cancer  

Nonmetastatic Colon Cancer  

Consider neoadjuvant therapy for patients with resectable clinical T4b tumors or bulky nodal disease. First-line regimens for advanced or metastatic disease (FOLFOX or CapeOx) are recommended. Checkpoint inhibitor immunotherapy (eg Nivolumab with or without Ipilimumab, Pembrolizumab) may be used for patients with dMMR/MSI-H disease. Neoadjuvant chemoradiotherapy (chemoRT) (5-FU or Capecitabine or 5-FU/LV + radiation therapy [RT]) may be considered in patients with locally unresectable or medically inoperable disease.    

Metastatic Colon Cancer  

Neoadjuvant therapy for 2-3 months with FOLFOX or CapeOx is an option for resectable synchronous liver and/ or lung pMMR/MSS-positive metastases. FOLFIRI or FOLFIRINOX may also be used if FOLFOX and CapeOx are unavailable or contraindicated.  

Neoadjuvant therapy for 2-3 months with FOLFOX or CapeOx is an option for resectable metachronous pMMR/MSS- and dMMR/MSI-H-positive metastases. 5-FU/LV or Capecitabine may also be used.  

Pembrolizumab, Dostarlimab-gxly or Nivolumab with or without Ipilimumab, as preferred options for neoadjuvant therapy of resectable dMMR/MSI-H metastatic CRC.  

Please see Systemic Therapy for further information about Synchronous and Metachronous Metastases.  

Rectal Cancer  

Resectable Nonmetastatic or Locally Unresectable Rectal Cancer  

Neoadjuvant Therapy  

FOLFOX or CapeOx are preferred neoadjuvant treatment options for resectable synchronous and metachronous pMMR/MSS metastases. 5-FU/LV or Capecitabine may also be used.  

Infusional 5-FU with pelvic radiotherapy or Capecitabine with radiotherapy are treatment options for resectable synchronous and metachronous pMMR/MSS metastases with involved circumferential resection margin (CRM).  

Please see Systemic Therapy for further information about Synchronous and Metachronous Metastases.  

Checkpoint inhibitor immunotherapy agents Pembrolizumab, Dostarlimab-gxly or Nivolumab with or without Ipilimumab, are preferred options for neoadjuvant therapy of resectable dMMR/MSI-H metastatic colorectal cancer. They are also used in resectable synchronous liver only and/or lung only dMMR/MSI-H metastases.  

Total Neoadjuvant Therapy (TNT)  

For patients with nonmetastatic, locally unresectable, or medically inoperable rectal cancer. Neoadjuvant therapy precedes chemoradiotherapy and surgery, composed of FOLFOX or CapeOx, infusional 5-FU or oral Capecitabine, or bolus 5-FU/LV. FOLFIRINOX may be considered, and treatment duration of 12-16 weeks is recommended.  

Benefits include improved tolerance and completion rates of chemotherapy, early prevention, or eradication of micrometastases, facilitate resection, increased rates of pathologic complete response, and minimized duration of ileostomy.  

Neoadjuvant Chemoradiotherapy  

Preoperative chemoradiotherapy is recommended for stage II/III rectal cancer. Standard preoperative chemoRT involves either infusional 5-FU or bolus 5-FU/LV or oral Capecitabine Bolus 5-FU/LV/RT may be given as an alternative for patients unable to tolerate Capecitabine or infusional 5-FU. 

Systemic Therapy

The choice of therapeutic agents for colorectal cancer is based on factors such as goals of therapy, type, and timing of prior therapy, efficacy, and toxicity profiles of the drugs.  

Colon Cancer  

Nonmetastatic Colon Cancer  

The choice of adjuvant therapy for resected, nonmetastatic colon cancer depends on the stage of the disease. Stage I and low-risk stage II disease do not require adjuvant therapy.  

The management of stage II disease depends on the presence or absence of high-risk features such as T4 tumors (stage IIB/IIC), lymphovascular invasion, poorly differentiated histology (except those that are MSI-H¹), perineural invasion (PNI), lesions with localized perforation or positive margins, bowel obstruction, inadequately sampled nodes (<12 lymph nodes).  

Low-risk stage II disease can be managed with clinical trials or observed without adjuvant therapy in patients with dMMR/MSI-H colon cancer or considered for Capecitabine or 5-Fluorouracil/Leucovorin (5-FU/LV) in patients with pMMR/MSS colon cancer.  

High-risk stage II disease can be managed with observation without adjuvant therapy or with chemotherapy with the following regimens: Capecitabine or 5-FU/LV or infusional 5-FU/LV/Oxaliplatin (FOLFOX) or Capecitabine/Oxaliplatin (CapeOx).  

The addition of Oxaliplatin to 5-FU/LV did not show additional survival benefits among stage II colon cancer patients and in patients ≥70 years of age.  

Stage III disease is managed with 3-6 months of adjuvant chemotherapy after primary surgical treatment; chemotherapeutic options include:

• FOLFOX (preferred): 3-6 months in low-risk stage III patients and 6 months in high-risk stage III patients
• CapeOx (preferred): 3 months in low-risk stage III patients and 3-6 months in high-risk stage III patients
• Single-agent Capecitabine
• 5-FU/LV in those whom Oxaliplatin is inappropriate

FOLFOX or CapeOx is superior to 5-FU/LV for stage III colon cancer. FOLFOX may be considered in stage II colon cancer with multiple high-risk factors. Capecitabine appears to be equivalent to a bolus of 5-FU/LV combination in patients with stage III colon cancer. CapeOx is superior to 5-FU/LV/Oxaliplatin combination. 5-FU/LV/Oxaliplatin combination is an alternative to FOLFOX. Studies show that grade 3 to 4 diarrhea is higher with 5-FU/LV/Oxaliplatin combination than with FOLFOX.  

¹Microsatellite Instability-High (MSI-H) refers to those with stage II disease colon cancer having highly favorable outcomes and are less likely to benefit from adjuvant therapy with Fluoropyrimidine alone.  

Rectal Cancer  

Systemic therapy for rectal cancer often includes locoregional treatment due to the relatively high risk of recurrence. For patients treated with preoperative chemoradiotherapy, a 5 to 12-week interval is recommended prior to surgical resection to allow recovery from toxicities.  

Resectable Local or Nonmetastatic Rectal Cancer  

Adjuvant Chemotherapy  

Adjuvant chemotherapy is recommended for all stage II/III rectal cancer patients post-neoadjuvant chemoradiotherapy or surgery regardless of pathological results. Studies show that adjuvant chemotherapy should be given as soon as the patient is medically able. The preferred regimen for higher-risk patients is FOLFOX or CapeOx and alternative regimens include 5-FU/LV or Capecitabine. Adjuvant chemotherapy is believed to be important to be given to patients even following a complete response. Postoperative chemoradiotherapy is recommended when stage I rectal cancer is upstaged to stage II or III after a pathologic review of the surgical specimen.  

Adjuvant chemotherapy often uses a “sandwich” approach - chemotherapy is administered before and after the chemoradiotherapy regimen. The recommended “sandwich” regimen consists of the following:

• An optional first round of adjuvant chemotherapy with 5-FU with or without LV or FOLFOX or Capecitabine with or without Oxaliplatin; followed by
• Concurrent Capecitabine/RT (preferred) or 5-FU/RT (preferably, infusional or bolus infusion with LV); followed by
• 5-FU with or without LV or FOLFOX or Capecitabine with or without Oxaliplatin

A total of approximately 6 months of perioperative therapy is recommended. Chemotherapy alone can be given to patients with pathologic evidence of proximal T3, N0, M0 disease with favorable features and clear margins. Those with pathologic stage I disease (T1-T2, N0, M0), following resection, may be managed with observation only.  

Locally Unresectable Rectal Cancer and/or T4 Lesions  

For locally unresectable rectal cancer and/or T4 lesions, the treatment approach can be chemoradiotherapy or total neoadjuvant therapy consisting of 12-16 weeks of chemotherapy followed by chemoradiotherapy. Patients with locally unresectable disease or those medically inoperable may be treated with Capecitabine/RT or infusional 5-FU/RT or bolus 5-FU/LV/RT. A total of approximately 6 months of perioperative therapy is recommended. When resection is contraindicated following primary treatment (combination chemoradiotherapy or chemotherapy), patients should receive a systemic regimen for advanced or metastatic disease.  

Metastatic Colorectal Cancer  

For patients undergoing resection for liver or lung colorectal metastasis, consider approximately 6 months of perioperative chemotherapy to increase the chance of eradicating residual microscopic disease. The decision to initiate chemotherapy prior to or after surgery depends on several factors. Potential advantages of preoperative chemotherapy include earlier treatment of micrometastatic disease, responsiveness to chemotherapy can be determined, and avoidance of local therapy for those with early disease progression.  

Potential risks associated with preoperative chemotherapy include the possible development of liver steatohepatitis (with Irinotecan-based regimen), sinusoidal liver injury (Oxaliplatin-based), and missing out on the “window of opportunity” for resection. The choice of agents depends on therapeutic goals, mutational profile of the tumor, toxicity profiles, type and timing of prior therapy.  

Advanced or Metastatic Colorectal Cancer  

The chemotherapeutic options for advanced or metastatic colorectal cancer include the following, either as single agents or in combination: 5-FU/LV, Bevacizumab, Capecitabine, Cetuximab, Dostarlimab-gxly, Encorafenib, Entrectinib, Ipilimumab, Irinotecan, Lapatinib, Larotrectinib, Oxaliplatin, Panitumumab, Pembrolizumab, Pertuzumab, Nivolumab, Ramucirumab, Regorafenib, Selpercatinib, Trastuzumab, Trifluridine-Tipiracil, Tucatinib, and Ziv-aflibercept.  

As part of the pretreatment work-up, it is recommended for all metastatic colorectal cancer patients to undergo KRAS/NRAS and BRAF gene status testing at diagnosis of stage IV disease for the purpose of planning the treatment continuum. Testing for HER2 amplification is also recommended for patients with metastatic colorectal cancer and it is not required if KRAS/NRAS/BRAF mutation in the tumor is already known. Patients with any known KRAS mutation or NRAS mutation should not be treated with Cetuximab or Panitumumab.  

The addition of a biologic agent (eg Bevacizumab, Cetuximab, Panitumumab) to first-line therapy regimens FOLFIRI and FOLFOX is an option for patients with RAS wild-type tumors. The recommended initial regimens in those appropriate for intensive therapy are as follows:¹

• FOLFOX with or without Bevacizumab
• CapeOx with or without Bevacizumab 
• FOLFOX or FOLFIRI or CapeOx + (Cetuximab or Panitumumab) for KRAS/NRAS/BRAF wild-type2 and left-sided tumors
• FOLFIRI with or without Bevacizumab
• FOLFIRINOX with or without Bevacizumab
• (Nivolumab with or without Ipilimumab) or Pembrolizumab or Dostarlimab-gxly for dMMR/MSI-H; response to treatment should be closely monitored for 10 weeks

The recommended initial regimens for patients who cannot tolerate intense initial therapy are as follows: 

• Infusional 5-FU with or without LV with or without Bevacizumab
• Capecitabine with or without Bevacizumab
• Cetuximab or Panitumumab for KRAS/NRAS/BRAF wild-type² and left-sided tumors
• (Nivolumab with or without Ipilimumab) or Pembrolizumab or Dostarlimab-gxly for dMMR/MSI-H
• Trastuzumab with (Pertuzumab or Lapatinib or Tucatinib) for HER2-amplified and RAS/BRAF wild-type gene tumors

Oxaliplatin should be discontinued from CapeOx or FOLFOX after 3 to 4 months of therapy (or sooner, should ≥grade 2 neurotoxicity develops). 5-FU in combination with Irinotecan or Oxaliplatin should be given through an infusional biweekly regimen.
¹Patients who can tolerate intensive therapy with a high response rate.
²KRAS/NRAS/BRAF wild-type tumors are those negative for KRAS/BRAF mutation.

For patients previously given Oxaliplatin-based regimens without Irinotecan, the recommended subsequent therapy regimens include:

• For patients previously given Oxaliplatin-based regimens without Irinotecan, the recommended subsequent therapy regimens include:
• FOLFIRI or Irinotecan
• FOLFIRI + Bevacizumab¹ or Ziv-aflibercept or Ramucirumab
• Irinotecan + Bevacizumab¹ or Ziv-aflibercept or Ramucirumab
• FOLFIRI + (Cetuximab or Panitumumab) for KRAS/NRAS/BRAF wild-type² and left-sided tumors
• Cetuximab or Panitumumab with or without Irinotecan for KRAS/NRAS/BRAF wild-type² and left-sided tumors 
• Encorafenib + (Cetuximab or Panitumumab) for BRAF V600E mutation; addition of Binimetinib to Encorafenib + Cetuximab may be considered 
• (Nivolumab with or without Ipilimumab) or Pembrolizumab or Dostarlimab-gxly for dMMR/MSI-H without prior immunotherapy
• Trastuzumab + (Pertuzumab or Lapatinib or Tucatinib) or Fam-trastuzumab deruxtecan-nxki for HER2- amplified and RAS/BRAF wild-type gene tumors

For patients previously given Irinotecan-based regimens without Oxaliplatin, the recommended subsequent therapy regimens include:

• FOLFOX with or without Bevacizumab 
• CapeOx with or without Bevacizumab
• FOLFOX or CapeOx + (Cetuximab or Panitumumab) for KRAS/NRAS/BRAF wild-type² tumors and left-sided tumors
• Cetuximab or Panitumumab with or without Irinotecan for KRAS/NRAS/BRAF wild-type² tumors and left-sided tumors
• Encorafenib + (Cetuximab or Panitumumab) for BRAF V600E mutation; addition of Binimetinib to Encorafenib + Cetuximab may be considered
• (Nivolumab with or without Ipilimumab) or Pembrolizumab or Dostarlimab-gxly for dMMR/MSI-H without prior immunotherapy
• Trastuzumab + (Pertuzumab or Lapatinib or Tucatinib) or Fam-trastuzumab deruxtecan-nxki for HER2- amplified and RAS/BRAF wild-type gene tumors

For patients previously given Oxaliplatin and Irinotecan, the recommended subsequent therapy regimens include: 

• Cetuximab or Panitumumab with or without Irinotecan for KRAS/NRAS/BRAF wild-type³ tumors and left-sided tumors
• Encorafenib + (Cetuximab or Panitumumab) for BRAF V600E mutation; addition of Binimetinib to Encorafenib + Cetuximab may be considered
• Regorafenib
• Trifluridine + Tipiracil with or without Bevacizumab
• (Nivolumab with or without Ipilimumab) or Pembrolizumab or Dostarlimab-gxly for dMMR/MSI-H without prior immunotherapy
• Trastuzumab + (Pertuzumab or Lapatinib or Tucatinib) or Fam-trastuzumab deruxtecan-nxki for HER2- amplified and RAS/BRAF wild-type gene tumors

For patients with previous therapy without Irinotecan or Oxaliplatin, the recommended subsequent therapy regimens include:

• FOLFOX or CapeOx with or without Bevacizumab
• FOLFIRI or Irinotecan with or without Bevacizumab² or Ziv-aflibercept or Ramucirumab 
• Irinotecan + Oxaliplatin with or without Bevacizumab
• FOLFIRINOX with or without Bevacizumab
• Encorafenib + (Cetuximab or Panitumumab) for BRAF V600E mutation
• (Nivolumab with or without Ipilimumab) or Pembrolizumab or Dostarlimab-gxly for dMMR/MSI-H without prior immunotherapy
• Trastuzumab + (Pertuzumab or Lapatinib or Tucatinib) or Fam-trastuzumab deruxtecan-nxki for HER2- amplified and RAS/BRAF wild-type gene tumors

¹Preferred agent as recommended by NCCN clinical practice guidelines on colon cancer. Version 2.2023  and NCCN clinical practice guidelines on rectal cancer. Version 4.2023.
²KRAS/NRAS/BRAF wild-type tumors are those negative for KRAS/BRAF mutation.

For patients with previous therapy without Irinotecan or Oxaliplatin given FOLFOX or CapeOx with or without Bevacizumab, the recommended subsequent therapy regimens include:

• Irinotecan
• (Cetuximab or Panitumumab) with or without Irinotecan for KRAS/NRAS/BRAF wild-type¹ tumors
• Encorafenib + (Cetuximab or Panitumumab) for BRAF V600E mutation
• (Nivolumab with or without Ipilimumab) or Pembrolizumab or Dostarlimab-gxly for dMMR/MSI-H without prior immunotherapy
• Trastuzumab + (Pertuzumab or Lapatinib or Tucatinib) or Fam-trastuzumab deruxtecan-nxki for HER2- amplified and RAS/BRAF wild-type gene tumors

Checkpoint inhibitor immunotherapy (eg Nivolumab with or without Ipilimumab, Pembrolizumab, Dostarlimab-gxly) is a treatment option for dMMR/MSI-H-positive patients who have not previously received checkpoint inhibitor immunotherapy. Nivolumab ± Ipilimumab are approved for dMMR/MSI-H-positive patients that have progressed following treatment with 5-FU, Oxaliplatin, and Irinotecan.  

Regorafenib is a treatment option for those who progressed despite using available regimens. Larotrectinib or Entrectinib are treatment options for NTRK gene fusion-positive patients. Selpercatinib is a treatment option for locally advanced or metastatic RET gene fusion-positive CRC tumors that have progressed during or following prior systemic treatment or those who have no satisfactory alternative treatment options. Trifluridine-Tipiracil with or without Bevacizumab is an oral combination drug and an additional option for patients who still progressed on standard therapies. Fruquintinib is an additional option in patients pretreated with fluoropyrimidines, Oxaliplatin, Irinotecan and biologics. Fruquintinib is approved for use in China by the National Medical Products Administration (NMPA) in September 2018 and submitted for review to the United States Food and Drug Administration in May 2023.  

Resectable Synchronous Metastases

A total of approximately 6 months of perioperative therapy is recommended for most patients undergoing liver or lung resection. A total neoadjuvant therapy approach is recommended. The most effective sequencing of chemotherapy remains unclear. The management of resectable synchronous metastases has been shown to improve disease-free survival and progression-free survival. The choice of therapy depends on the patient’s history of chemotherapy, clear or involved circumferential resection margin as per MRI evaluation, and the safety and toxicity profile of the regimens.  

Preoperative Systemic Therapy  

Preoperative chemotherapy is limited to about 2 to 3 months, while carefully monitored by a multidisciplinary team to reduce the possibility of developing hepatotoxicity. The treatment approach differs between colon and rectal cancer with resectable synchronous metastasis. For colon cancer, chemotherapy is given, while for rectal cancer, chemotherapy with or without radiotherapy is given.  

The choice of regimen includes FOLFOX² or CapeOx²; 5-FU/LV or Capecitabine; FOLFIRI for metastatic colon cancer; FOLFIRINOX; or Nivolumab with or without Ipilimumab or Pembrolizumab or Dostarlimab-gxly for dMMR/MSI-H.  

Postoperative Systemic Therapy  

For postoperative systemic therapy, the choice of regimen includes FOLFOX² or CapeOx² or 5-FU/LV or Capecitabine. FOLFIRI and FOLFIRINOX may also be considered following colectomy.  

¹KRAS/NRAS/BRAF wild-type tumors are those negative for KRAS/BRAF mutation.
²Preferred agent as recommended by NCCN clinical practice guidelines on colon cancer. Version 2.2023 and NCCN clinical practice guidelines on rectal cancer. Version 4.2023.  

Unresectable Synchronous Metastatic Colorectal Cancer
 
Patients are given intensive systemic chemotherapy to attempt conversion to resectable status. Patients may be evaluated for resection after 2 months of chemotherapy and every 2 months thereafter while under chemotherapy.  

Preoperative Systemic Therapy  

Preoperative systemic therapy is considered in highly selected cases in an attempt to convert to resectable status by reducing the size of the metastases. The surgery is performed as soon as the patient’s status becomes resectable to limit the development of hepatotoxicity.  

Any active chemotherapeutic regimen for metastases can be used in attempting to convert to resectable status. The choice of regimen includes the following: 

• FOLFOX or CapeOx or FOLFIRI or FOLFIRINOX with or without Bevacizumab
• FOLFOX or FOLFIRI with or without Panitumumab or Cetuximab (for KRAS/NRAS/BRAF wild-type tumors¹ and left-sided tumors only)
• Nivolumab with or without Ipilimumab or Pembrolizumab or Dostarlimab-gxly for dMMR/MSI-H (first-line option if without a history of immunotherapy use and a candidate for immunotherapy)

The addition of monoclonal antibodies against epidermal growth factor receptors (EGFR) and against vascular endothelial growth factor (VEGF) to cytotoxics should be considered in metastatic colorectal cancer patients.  

Bevacizumab, an anti-VEGF antibody, increases the activity of an active cytotoxic regimen. An interval of ≥6 weeks between the last dose of Bevacizumab and elective surgery is currently recommended to avoid potential surgical complications. Bevacizumab improves progression-free survival when combined with Fluoropyrimidine and Oxaliplatin. Studies suggest that Bevacizumab modestly improves response rate to Irinotecan-based regimens. It is usually continued in combination with a cytotoxic agent until toxicity, progression, or until metastases are resectable.  

Cetuximab and Panitumumab, anti-EGFR antibodies, are active as a single agent in metastatic colorectal cancer that is chemorefractory; however, the activity of anti-EGFRs is confined to KRAS/NRAS wild-type¹ tumors.  

Postoperative Systemic Therapy  

Postoperative systemic therapy is considered once the disease becomes resectable post-systemic therapy. A total of 6 months of perioperative therapy is required. The recommended treatment options for adjuvant therapy are systemic treatment regimens for advanced or metastatic disease.  

Metachronous Metastases  

KRAS/NRAS genotyping test should be done to determine whether anti-EGFR agents (Cetuximab, Panitumumab) can be considered for metachronous metastases. Testing for BRAF mutation and HER2 amplification as well as MSI/MMR is also recommended to determine if targeted therapy can be considered. Assessment of the patient’s chemotherapy history is important.  

In patients with resectable disease, the treatment is resection with 6 months of perioperative chemotherapy (pre-operative, postoperative, or both). The choice of regimen is based on the previous therapy. CapeOx or FOLFOX are preferred, although Capecitabine or 5-FU/LV can also be considered. A treatment duration of 2-3 months is recommended. Observation is preferred if Oxaliplatin-based therapy was previously given or when the tumor has grown during neoadjuvant therapy. Systemic therapy combined with biologic agents may be considered.  

(Nivolumab with or without Ipilimumab) or Pembrolizumab or Dostarlimab-gxly may be considered in patients with dMMR/MSI-H resectable metachronous metastases without a history of immunotherapy use.  

The following systemic therapy regimens may be considered in patients with unresectable disease given adjuvant FOLFOX/CapeOx within the past 12 months: 

• (FOLFIRI or Irinotecan) with or without Bevacizumab² or Ziv-aflibercept or Ramucirumab
• (FOLFIRI or Irinotecan) with or without (Cetuximab or Panitumumab) for KRAS/NRAS/BRAF wild-type¹ tumors
• Encorafenib + (Cetuximab or Panitumumab) for BRAF V600E mutation
• Trastuzumab + (Pertuzumab or Lapatinib or Tucatinib) or Fam-trastuzumab deruxtecan-nxki for HER2- amplified and RAS/BRAF wild-type gene tumors

For patients who received adjuvant FOLFOX/CapeOx >1 year before diagnosis of metachronous metastasis, or received 5-FU/LV or Capecitabine, or have no previous history of chemotherapy, general regimens for advanced or metastatic colorectal cancer are recommended.  

¹KRAS/NRAS/BRAF wild-type tumors are those negative for KRAS/BRAF mutation.
²Preferred agent as recommended by NCCN clinical practice guidelines on colon cancer. Version 2.2023 and NCCN clinical practice guidelines on rectal cancer. Version 4.2023.  

Surgery

Surgical Management of Colon Cancer  

Malignant Polyps  

A complete endoscopic polypectomy is preferred should the morphological structure of the polyp allow. Resection is recommended in the presence of the following unfavorable histological features: 

• Grade 3 or 4 differentiation
• Level 4 invasion (invasion of the submucosal bowel wall below the polyp)
• Venous or lymphatic invasion
• Positive margin of resection (presence of tumor within 1 to 2 mm of the transected margin)

In patients with pedunculated or sessile polyps with invasive carcinoma that has been completely resected and with favorable histologic features (clear resection margins, grade 1 or 2 lesions, and no angiolymphatic invasion), observation may be considered without additional surgery or colectomy.  

Colectomy with en bloc removal of lymph nodes is recommended for all polyps which are fragmented, with unfavorable histologic features, and if margins cannot be assessed. Total colonoscopy with follow-up surveillance colonoscopy is indicated in all patients who have resected polyps to rule out other synchronous polyps.  

Localized Disease  

Colectomy with En Bloc Removal of Lymph Nodes  

The goal of surgery is to do wide resection of the involved segment of the bowel including the removal of its lymphatic drainage. To be considered curative, resection needs to be complete. Resection should include a segment of the colon of at least 5 cm on either side of the tumor. Consider more extensive colectomy for those with a strong family history of colon cancer or those <50 years of age.  

The extent of colonic resection is determined by the tumor location, blood supply, and regional lymph node distribution. At least 12 lymph nodes must be resected to clearly define stage II from stage III and to determine and prevent potential lymph node metastases. Suspicious clinically positive lymph nodes outside the area of resection should be biopsied or removed, if possible.  

Obstructive tumors can be treated in 1 or 2 stages. The two-stage procedures include colostomy followed by colonic resection or Hartmann’s procedure followed by colostomy closure and anastomosis (diversion followed by colectomy). The one-stage procedure is done with either subtotal colectomy and ileorectal anastomosis (resection with diversion), or in selected cases, intraoperative colonic lavage followed by segmental resection.  

Laparoscopic colectomy may be considered if the following criteria are met:

• The surgeon must be technically experienced in conducting laparoscopic colorectal surgeries
• The disease must not be locally advanced
• Preoperative marking of lesions must be considered 
• No acute bowel perforation, abdominal adhesions, or obstruction from cancer; and if found to have adhesions during laparoscopy, the procedure should be converted to open surgery

Surgical Management of Rectal Cancer  

The aim is to treat with the lowest possible risk of residual disease in the pelvis. There is a relatively high risk of locoregional recurrence due to the close proximity of the rectum to pelvic structures and organs. Sphincter and genitourinary functions should be preserved.  

Malignant Polyps  

Malignant rectal polyps refer to those which have invaded the muscularis mucosa and submucosa. Completely resected polyps (pedunculated and single specimen sessile) with favorable histologic features and clear margins, observation may be considered without additional surgery.  

Rectal surgery is recommended for all polyps with unfavorable histologic features (grade 3 or 4, with angiolymphatic invasion, positive margin of resection). Transanal excision or transabdominal resection may be done for polyps with fragmented specimens or margins that cannot be assessed. Transabdominal resection may be done in those with unfavorable pathologic features to include lymphadenectomy.  

Localized Resectable Rectal Cancer  

Endoscopic Mucosal Resection (EMR)  

An endoscopic mucosal resection involves an endoscopic snare resection of gastrointestinal tumors >2 cm in diameter located in the mucosal layer.  

Endoscopic Submucosal Dissection (ESD)

An endoscopic submucosal dissection is a procedure that involves en-bloc resection of large submucosal gastrointestinal tumors by using a specialized dissecting knife.  

Transanal Excision  

Transanal excision is appropriate for selected early-stage cancers (T1, N0). It is indicated for <3 cm, well to moderately differentiated tumors within 8 cm of the anal verge and <30% of the bowel circumference, with clear margin (>3 mm), without nodal involvement or evidence of lymphadenopathy on pretreatment imaging, mobile or nonfixed, and without lymphovascular or perineural invasion (PNI). It is also for endoscopically removed polyps with cancer or indeterminate pathology.  

Its disadvantage includes the absence of pathologic staging for nodal metastases. Lymph node micrometastases are common in early rectal cancers and are likely to be missed by endorectal ultrasound.  

Transanal Endoscopic Microsurgery (TEM) or Transanal Minimally Invasive Surgery (TAMIS)  

Transanal endoscopic microsurgery or transanal minimally invasive surgery may be done when the lesion can be adequately identified in the rectum. These procedures may be technically feasible for more proximal lesions.  

Transabdominal Resection  

Transabdominal resection is for those that cannot be managed with local resection. Low anterior resection or abdominoperineal resection or coloanal anastomosis using total mesorectal excision may be done.  

Total mesorectal excision is recommended and involves en bloc removal of the mesorectum, including angiolymphatic structures, mesorectal fascia, and fatty tissues. If possible, biopsy or remove clinically suspicious nodes beyond the field of resection. In the absence of clinically suspicious nodes, extended resection is not necessary. Low anterior resection (LAR) extended 4 to 5 cm below the distal edge of the tumors followed by colorectal anastomosis creation is the procedure of choice for tumors located in the mid to upper rectum.  

It is done 5-12 weeks after 5.5 weeks of full-dose neoadjuvant chemoradiation. It may be done at 3 to 7 days or 4-8 weeks after short-course neoadjuvant chemoradiation.  

A digital rectal examination with or without a rigid or flexible endoscopy is needed to assess the distal margin prior to initiating this procedure; preoperative assessment of anticipated circumferential margins using MRI or prior to initiation of neoadjuvant therapy should be considered.  

Laparoscopic Surgery  

Laparoscopic surgery may be considered if it is conducted by an experienced surgeon, thorough abdominal exploration is included, and is limited to lower-risk tumors. It is associated with higher rates of circumferential resection margin positivity and incomplete total mesorectal excision in some studies.  

T4 Lesions and/or Locally Unresectable or Medically Inoperable Rectal Cancer  

Resection should be considered following preoperative chemoradiotherapy unless with a clear contraindication. If surgery is contraindicated following primary treatment, patients should be given a chemotherapy regimen for advanced or metastatic diseases.  

Surgical Management of Metastatic Colorectal Cancer  

Most treatment recommendations both apply to liver and lung metastases. Complete resection based on anatomic location and extent of disease with maintenance of adequate function is required. Resection must be done with curative intent, either by one operation or a staged approach.  

Hepatic resection is the management of choice for resectable hepatic metastases from colorectal cancer.  Re-resection of hepatic and lung metastases can be considered in select patients. Re-evaluation for resection and ablation should be considered in unresectable patients after 2 months of preoperative chemotherapy and every 2 months thereafter. Evidence supporting resection of extrahepatic metastases remains limited. 

Radiation Therapy

Radiation Therapy

Unresectable Nonmetastatic Colon Cancer  

Neoadjuvant radiation therapy with concurrent fluoropyrimidine-based chemotherapy may be considered for initially unresectable or medically inoperable non-metastatic T4 colon cancer to aid resectability. Intraoperative radiotherapy (IORT) may be considered for patients with T4 tumors, locally unresectable or medically inoperable tumors, or recurrent cancers. The recommended dose is 45-50 Gy in 25-28 fractions; additional 10-20 Gy external beam radiation therapy (EBRT) and/or brachytherapy could be considered if intraoperative radiotherapy is not available.  

Resectable Nonmetastatic Rectal Cancer  

Resectable nonmetastatic rectal cancer is associated with decreased rates of local recurrence for rectal cancer. The administration should include the tumor bed with a 2-5-cm margin, mesorectum, internal iliac nodes, and presacral nodes. External iliac nodes are included in T4 tumors involving anterior structures. Risks include increased hematologic toxicities and radiation-induced injury.  

Preoperative versus Postoperative Radiation Therapy (RT)  

Preoperative radiation therapy (along with chemotherapy) is recommended for those with stage II and III rectal cancer. Short-course radiation therapy may be an option for patients with T3N0 or T1-3N1-2 rectal cancer.  The recommended dose is 45-50 Gy in 25-30 fractions to the pelvis; consider a tumor bed boost of 5.4 Gy in 3 fractions with a 2-cm margin after 45 Gy.  

The advantages of preoperative radiation therapy include an increased rate of sphincter preservation, increased sensitivity to radiation therapy of surgically-naive tissues, avoidance of radiation-induced injury that can arise from post-surgical adhesions, and increased likelihood that an anastomosis with a healthy colon can be done.  

The disadvantage of preoperative radiation therapy is the possibility of overtreating early-stage tumors that do not require radiation therapy.    

Postoperative radiation therapy is recommended when stage I rectal cancer has been upstaged to stage II or III after pathologic review of the surgical specimen. The recommended dose is 5.4-9.0 Gy in 3-5 fractions.  

Intraoperative Radiotherapy (IORT)  

Intraoperative radiotherapy is recommended for patients with T4 tumors or recurrent cancer, or if margins are positive or close. It involves direct exposure of tumors to radiation therapy intraoperatively while normal structures are removed from the field of treatment. It is considered an additional boost to facilitate surgery. If unavailable, brachytherapy and/or 10-20 Gy external beam radiation therapy may be considered soon after resection, prior to adjuvant chemotherapy.  

Metastatic Colorectal Cancer  

Arterial Radioembolization  

While toxicity is relatively low, evidence supporting the use of arterial radioembolization is still lacking. It is an alternative for highly selected patients with predominantly hepatic metastases and with chemotherapy-resistant or refractory disease.  

External Beam Radiation Therapy (EBRT)  

External beam radiation therapy may be considered in highly selected cases where patients have a limited number of liver or lung metastases or in symptomatic patients or in the setting of a clinical trial. It should not replace surgical resection.  

Intensity-modulated radiation therapy (IMRT) should be reserved for special situations (eg reirradiation of previously irradiated patients with recurrent disease) or unique anatomical sites where tissue dose-volume constraints are necessary. Stereotactic body radiation therapy (SBRT) should be considered for patients with oligometastatic disease. Image-guided RT (IGRT) with kilovoltage (kV) imaging or cone-beam CT imaging should be routinely used during treatment with intensity-modulated radiation therapy and stereotactic body radiation therapy. Arterially-directed catheter therapy (ie yttrium-90 microsphere-selective internal radiation) is an option in highly selected patients with chemotherapy-resistant or refractory disease and with predominant hepatic metastases.  

Local Therapy – Metastatic Colorectal Cancer  

Local therapy is an option for select patients with liver-only or liver-dominant metastatic disease which cannot be resected or ablated with clear margins. Studies have demonstrated similar efficacy of hepatic arterial infusion chemotherapy (HAIC) and transcatheter arterial chemoembolization in patients with unresectable colorectal hepatic metastases.  

Hepatic Arterial Infusion Chemotherapy (HAIC)  

Hepatic arterial infusion chemotherapy involves the placement of a hepatic arterial port or implantable pump during liver resection where subsequent infusion of chemotherapy directed to the liver metastases will be given. It is limited by its potential for biliary toxicity and requires technical expertise. It should be considered selectively and in institutions capable of this procedure.  

Transhepatic Arterial Chemoembolization (TACE)  

Transhepatic arterial chemoembolization involves catheterization of the hepatic artery, causing vessel occlusion with local chemotherapy. Its use is still limited to clinical trials.  

Tumor Ablation

Examples: Cryoablation, electro-coagulation (irreversible electroporation), microwave ablation, percutaneous ethanol injection, radiofrequency ablation (RFA)  

Tumor ablation may be considered in those who cannot undergo resection due to comorbidity, location of metastases or an estimate inadequate organ volume post-resection. It is not a substitute for resection in those patients with resectable diseases. 

Prevention

Colorectal Cancer Primary Prevention  

Diet  

Diet is regarded as the most important acquired factor in colorectal cancer. Diets rich in fruits and vegetables may help reduce the risk of colorectal cancer. Calcium salts and calcium-rich foods may have a protective role in colorectal cancer since they decrease colon cell turnover and reduce the cancer-promoting effects of fatty acids and bile acids. Consumption of red meat should be limited to <500 g (18 oz) per week but processed food should be avoided.  

Weight Management  

Maintenance of body mass index (BMI) near the lower limit of the normal range is important to reduce the risk of colorectal cancer.  

Physical Activity  

Adults should aim to have at least 2.5 hours of moderate-intensity exercise (eg brisk walking) a week or 30 minutes at least 5 days a week.  

Alcohol  

Alcohol should be limited to no more than 2 drinks per day (30 g of ethanol or 4 units) for men and 1 drink per day (15 g of ethanol or 2 units) for women.  

Smoking  

Patients should be discouraged from smoking or, for smokers, encouraged to quit smoking.  

Aspirin  

The intake of low-dose Aspirin of at least 5-10 years duration may have a protective effect against colorectal cancer development in patients 45-59 years old.