Colorectal cancer

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

rectal cancer, suitable for surgery

stage 1, low risk (<3 cm; <30% circumference of the bowel; within 8 cm of the anal verge; moderately or well differentiated; no lymphadenopathy on pretreatment imaging; localized; full thickness excision feasible)

1st line – local excision or radical excision

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1st line –

local excision or radical excision

Stage 1 tumors are T1-2, N0, M0.

Local excision of rectal cancer may be appropriate for low-risk cancers that fulfill all the following criteria: <3 cm diameter; within 8 cm of the anal verge; involves <30% of the circumference of the bowel; moderately or well differentiated histology with no adverse features of tumor budding or lymphovascular invasion; no evidence of lymphadenopathy on pretreatment imaging; localized (T1, N0, M0); full thickness excision is feasible.[127]

For a known cancer, a transanal approach should be full thickness.[127]

Standard contraindications to a local excision include: >3 cm diameter; poor differentiation; >pT1, with grade 3 or lymphovascular or perineural invasion; invasion of the anal sphincter complex.[127]

Transanal resection of tumor (TART), transanal endoscopic microsurgery (TEM), or transanal minimally invasive surgery (TAMIS) are some of the local excision techniques that may be used for the excision of early cancers in the rectum.

One systematic review found that TEM may be associated with a shorter operation time and a reduced risk of postoperative complications compared with radical resection of early rectal cancer, but overall survival and oncologic outcomes did not differ.[215] In one meta-analysis, TEM was associated with fewer complications than standard surgery in patients with T1 and T2 rectal cancers, but higher local and overall recurrence; neither technique demonstrated a survival advantage.[216] One subsequent systematic review of mostly retrospective studies found that TEM is oncologically superior to transanal excision.[217]

Endoscopic submucosal dissection (ESD) is a minimally invasive, organ-preserving technique that can provide curative resection for early rectal cancers by removing the complete lesion and can stage the disease accurately.[127] The National Comprehensive Cancer Network guidelines recommend that patients with rectal cancer with no distal metastases (T1, N0) who are not candidates for surgery may undergo ESD, while those who are candidates for surgery may undergo ESD or local excision.[127] However, in practice, as ESD may not be readily available, it is not the preferred first-line treatment for patients who are candidates for surgery.

Retrospective studies have found similar local recurrence, R0 resection rate, and adverse events with ESD and TEM/TAMIS.[218][219][220] Patient preference and operator expertise in ESD should be considered while selecting the appropriate technique.[127]

Definitive surgery or subsequent radiation therapy may be necessary after local resection if the resection margins are positive, if the pathology reveals pT2 stage, or if the tumor is graded as pT1 but has unfavorable histologic features. The standard of care in these situations with best oncologic outcomes remains definitive definitive (low anterior or abdominoperineal resection) surgery.[127]

stage 1, high risk (not fulfilling low-risk criteria)

1st line – radical resection

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1st line –

radical resection

Stage 1 tumors are T1-2, N0, M0.

T1 tumors that are not suitable for local resection and T2 tumors that are in the upper third of the rectum are managed with anterior resection with sphincter preservation and colorectal anastomosis.[127] For tumors not amenable to local excision that are in the middle and lower third of the rectum, excision is achieved by low anterior resection and coloanal anastomosis.[127] A colonic pouch or coloplasty may improve function in some cases. Such a low anastomosis is usually defunctionalized with a temporary ileostomy.[127] Diverting ileostomy should be considered for patients with low rectal anastomosis who have received neoadjuvant radiation and are at an increased risk for anastomotic leak.[221][222]

Abdominoperineal resection (APR) is required if the tumor invades the pelvic floor, sphincter complex, or anal canal. APR entails a permanent colostomy.[127]

Consider – preoperative radiation therapy ± chemotherapy

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Consider –

preoperative radiation therapy ± chemotherapy

Treatment recommended for SOME patients in selected patient group

For patients with early stage cancer (cT1-2N0) who require an abdominoperineal resection because of tumor location, neoadjuvant chemoradiation may be recommended after multidisciplinary discussion to increase the chance of sphincter preservation.[223]

Diverting ileostomy should be considered for patients with low rectal anastomosis who have received neoadjuvant radiation and are at an increased risk for anastomotic leak.[221][222]

stage 2-3

1st line – radical resection

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1st line –

radical resection

Stage 2-3 tumors range from T3-4, N0, M0 to any T, N1-2, M0.

The treatment for patients with clinical stage 2 and 3 rectal cancer is sphincter-preserving low anterior resection or abdominoperineal resection, depending upon location of the tumor in relationship to the anal sphincters, upon completion of a course of preoperative radiation therapy.[127]

Plus – preoperative chemoradiation therapy

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Plus –

preoperative chemoradiation therapy

Treatment recommended for ALL patients in selected patient group

Neoadjuvant treatment in the US includes long-course radiation therapy delivered over 5 weeks with concurrent fluoropyrimidine-based chemotherapy. Preoperative short-course radiation is an accepted alternative used in selected patients with T3 disease.[224] Preoperative radiation improves postoperative function for the patient, as well as tolerance of treatment, and is the standard of care for clinical stage 2 and 3 rectal cancers in the US.[127] For patients with locally advanced cancer, neoadjuvant long-course chemoradiation is preferred over short-course radiation therapy.[152]

The addition of fluoropyrimidine chemotherapy to the preoperative regimen reduces local recurrence, but does not improve survival, and has a negative effect on quality of life dimensions.[225][226][227] Neoadjuvant chemotherapy with FOLFIRINOX (fluorouracil/leucovorin with oxaliplatin and irinotecan) and preoperative chemoradiation therapy significantly improved disease-free survival compared with standard-of-care (e.g., chemoradiation therapy followed by total mesorectal excision and adjuvant chemotherapy) in patients with biopsy-proven, rectal adenocarcinoma staged cT3 or cT4 M0. (3-year disease-free survival 76% vs. 69%, respectively.)[228] The addition of oxaliplatin to neoadjuvant chemoradiation therapy schedules is not currently recommended.[127]

In many countries outside the US, short-course neoadjuvant radiation has become the standard of care for clinical stage 2 and 3 rectal cancers. The complete pathologic response rate is less following short-course radiation, potentially due to a longer period of time between radiation and surgery. Older trials suggest that the long-term outcomes appear similar to those of long-course preoperative radiation.[229][230][231][232] More recent results from the RAPIDO trial indicate higher rates of local recurrence with short-course radiation.[233][234] Further investigation on the optimal radiation therapy schedule is ongoing, with the ACO/ARO/AIO-18.1 randomized phase 3 trial of the German Rectal Cancer Study Group comparing two different total neoadjuvant therapy regimens, with control arm consisting of short-course radiation therapy followed by consolidation chemotherapy and surgery or watchful waiting, and investigational arm with long-course chemoradiation therapy, followed by consolidation systemic therapy and surgery or watchful waiting.[235]

Preoperative short-course radiation is typically used for smaller, nonbulky lesions with lack of extension or encroachment on the fascia propria of the mesorectum. The main advantages of this strategy are that ileostomy can potentially be avoided, treatment times are significantly shortened, and radiation toxicities are reduced.

When short-course preoperative radiation treatment is used, it is recommended to perform surgery <3 days after completion of radiation treatment, or delay surgery 4-8 weeks for those patients felt to benefit from downstaging.[236][237]

For patients with locally advanced lesions (T3-4 and/or lymph node involvement), treatment volumes should include the whole rectum, mesorectum, presacral nodes, obturator nodes, and internal iliac nodes. In patients with invasion of anterior structures such as prostate/seminal vesicles, bladder, cervix, or vagina, inclusion of external iliac nodes should be considered. For cancers with anal canal involvement, inclusion of external iliac and inguinal nodes can be considered, though the data in this setting are limited.[238]

Intensity-modulated radiation therapy and volumetric modulated arc therapy techniques have been associated with lower toxicity as compared to 3D conformal techniques in some studies, but can be subject to more variation due to changes in daily set up, and therefore should be used in conjunction with daily image guidance.[238]

The selection of the optimal patient treatment position is dependent on several factors. A prone set up on a belly board can displace small bowel out of the field, decreasing the overall bowel dose. A supine position is more appropriate for patients with a colostomy, or when inguinal nodes are included in the treatment volumes.[238]

In some centers, preoperative neoadjuvant treatment is given on a selective basis depending on tumor level and distance to resection margins. A rationale for appropriate selection is provided in the UK National Institute for Health and Care Excellence (NICE) clinical guidelines on colorectal cancer.[89]

See local specialist protocols for chemoradiation therapy dosing guidelines.

Primary options

fluorouracil

and

leucovorin

capecitabine

Plus – postoperative chemotherapy

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Plus –

postoperative chemotherapy

Treatment recommended for ALL patients in selected patient group

When preoperative radiation therapy or chemoradiation therapy is given, the benefit of further fluoropyrimidine postoperative adjuvant chemotherapy is unconfirmed and a matter of debate.[239][241] [ ] Practice guidelines can be variable. For initially found T3/T4 or node positive disease, up to 6 months of fluoropyrimidine-based chemotherapy should be considered, regardless of the pathologic findings at resection.[127]

The long-term results of one randomized controlled trial indicate that adjuvant FOLFOX (fluorouracil and leucovorin plus oxaliplatin) improves disease-free survival at 6 years, compared with fluorouracil with leucovorin, in patients with rectal cancer with stage 2 and 3 disease after preoperative chemoradiotherapy.[242] The study suggests that adjuvant FOLFOX may be considered on the basis of the postoperative pathologic stage in those who received preoperative chemoradiation and mesorectal excision.[242]

When preoperative radiation therapy or chemoradiation therapy is not given, adjuvant treatment may be given in the postoperative period if adverse histopathologic features are found and should be delivered as early as possible for patients who required an abdominoperineal resection.[241][243]

Postoperative radiation therapy as a single modality is obsolete.

Options include fluorouracil plus leucovorin, FOLFOX, and capecitabine with or without oxaliplatin. The use of FOLFOX and capecitabine (with or without oxaliplatin) is based on extrapolation of data from colon cancer studies and, as in colon cancer, either oxaliplatin-containing regimen is the preferred option for adjuvant therapy in rectal cancer.

See local specialist protocols for chemotherapy dosing guidelines.

Primary options

fluorouracil

and

leucovorin

oxaliplatin

and

leucovorin

and

fluorouracil

capecitabine

and

oxaliplatin

1st line – total neoadjuvant therapy

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1st line –

total neoadjuvant therapy

Total neoadjuvant therapy (TNT) is the preferred treatment strategy for patients with locally advanced rectal cancer.[127][244] Patients with low rectal cancer and/or patients at a higher risk for local and/or distant metastases may benefit from this therapy.[152]

These patients will receive multiagent chemotherapy and chemoradiation therapy prior to surgery. The recommended timing for chemotherapy is after chemoradiation.[152] TNT improves delivery of planned therapy, increases downstaging, addresses micrometases sooner, requires temporary ileostomy reversal, achieves higher complete response rates (including pathologic and sustained clinical), and may avoid the need for surgery altogether.[127] Long-term follow-up is needed to determine if findings translate to improved survival. TNT may facilitate nonoperative treatment strategies for organ preservation.[245]

stage 4

1st line – surgical resection

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1st line –

surgical resection

Stage 4 tumors are any T, any N, M1a, b, c.

About 15% to 25% of patients with colorectal cancer present with synchronous liver, lung, and peritoneal metastases.[246] Resection of lung or liver metastases with clear tumor margins considerably alters the prognosis. Five-year survival rates following resection of colorectal cancer metastases are in the region of 30% to 40%, compared with almost 0% survival in patients not undergoing surgery.[247][248][249]

The criteria for determining resectability of liver metastases are evolving and are no longer restricted simply to the number, size, margins of resection, and location of hepatic lesions, but are more likely to reflect the likelihood of achieving complete microscopic negative resection (R0) with preservation of at least 30% liver function, and maintaining adequate vascular and biliary drainage.

Potentially resectable liver metastases may be managed by: staged or synchronous resection of liver metastases and primary tumor with postoperative chemotherapy with or without pelvic radiation therapy depending on T and N staging of the tumor (may be more appropriate in a patient with clearly resectable metastatic disease); preoperative chemotherapy alone or chemoradiation therapy followed by staged or synchronous resection of liver metastases and rectal tumor with postoperative adjuvant treatment depending on T and N staging of the rectal tumor (considered in patients with borderline or initially unresectable disease); perioperative hepatic arterial infusion pump chemotherapy (HAI) with perioperative systemic chemotherapy (retrospective data suggest that HAI is associated with improved overall survival after resection of colorectal liver metastases).[127][250][251]

One systematic review and meta-analysis found similar oncologic outcomes between minimally invasive surgery and open techniques; however, minimally invasive hepatectomy had a shorter length of hospital stay, lower blood loss, and a lower complication rate, for both staged and simultaneous resections.[252][253]

Resection of liver metastases should not be performed in the presence of unresectable disease at extrahepatic sites.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) may improve survival outcomes in patients with colorectal cancer with peritoneal metastases.[257][258] The HIPEC technique is restricted to specialized oncologic centers; data from randomized controlled trials are lacking.

Additional treatments directed at the primary tumor may be necessary to control symptoms. These include endoscopic stenting of an obstructing tumor, radiation therapy, laser recanalization, or diverting colostomy.

Consider – locally ablative procedures

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Consider –

locally ablative procedures

Treatment recommended for SOME patients in selected patient group

For patients with oligometastatic liver or lung disease who do not desire surgery, image-guided thermal ablation or stereotactic body radiation therapy can be used in lieu of surgery.[127][254]

Consider – chemotherapy or immunotherapy ± radiation therapy

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Consider –

chemotherapy or immunotherapy ± radiation therapy

Treatment recommended for SOME patients in selected patient group

Neoadjuvant chemotherapy or immunotherapy should be offered to patients with resectable synchronous liver-only and/or lung-only metastases. The preferred chemotherapy regimens are FOLFOX (fluorouracil and leucovorin plus oxaliplatin) or capecitabine and oxaliplatin (CapeOX). Other regimens include fluorouracil plus leucovorin, or capecitabine. Immunotherapy, including pembrolizumab, nivolumab, nivolumab and ipilimumab, or dostarlimab may be considered for patients with mismatch repair deficient or high microsatellite instability cancers. Chemotherapy or immunotherapy may be followed by radiation therapy.[127]

Initial radiation therapy or chemoradiation may be considered for patients with tumor involvement of the resection margin.[127]

Preoperative elevated neutrophil-to-lymphocyte ratio has been associated with poorer prognosis in patients with localized or metastatic colorectal cancer to the liver. It is, therefore, a useful biomarker for identifying patients who would benefit from adjuvant therapies.[259][260][261][262][263][264][265]

Systematic reviews have reported that BRAF mutation is associated with reduced disease-free and overall survival in patients with stage 2/3 colorectal cancer receiving adjuvant chemotherapy after curative resection, and in patients with colorectal cancer with liver metastases.[266][267][285]

Generally, the combination of pre- and postoperative chemotherapy and chemoradiation should total 6 months of therapy, and the sequence in which the therapy is employed is patient dependent.

See local specialist protocols for dosing guidelines.

Primary options

fluorouracil

and

leucovorin

and

oxaliplatin

capecitabine

and

oxaliplatin

fluorouracil

and

leucovorin

capecitabine

pembrolizumab

nivolumab

and

ipilimumab

dostarlimab

rectal cancer, not suitable for surgery

stage 1-4

1st line – chemotherapy

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1st line –

chemotherapy

Stage 1 tumors are T1-2, N0, M0; stage 2-3 tumors are T3-4, N0, M0 to any T, N1-2, M0. Stage 4 tumors are any T, any N, M1.

The backbone of chemotherapy is generally fluorouracil/leucovorin with oxaliplatin (FOLFOX or FLOX) or irinotecan (FOLFIRI).

Capecitabine can be substituted for fluorouracil/leucovorin with equal efficacy when used in combination with oxaliplatin; toxicity precludes the use of capecitabine plus irinotecan.[127][291][295][296]

In pooled analysis, FOLFOXIRI (fluorouracil/leucovorin with oxaliplatin and irinotecan) increased survival by 25% compared with FOLFOX or FOLFIRI.[297] However, FOLFOXIRI also increased toxicity by 25%, and its use is limited to those patients with good performance status.

See local specialist protocols for dosing guidelines.

Primary options

oxaliplatin

and

fluorouracil

and

leucovorin

irinotecan

and

fluorouracil

and

leucovorin

capecitabine

and

oxaliplatin

Secondary options

fluorouracil

and

leucovorin

and

oxaliplatin

and

irinotecan

Consider – vascular endothelial growth factor inhibitor or epidermal growth factor receptor inhibitor

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Consider –

vascular endothelial growth factor inhibitor or epidermal growth factor receptor inhibitor

Treatment recommended for SOME patients in selected patient group

Several targeted therapies (vascular endothelial growth factor [VEGF] inhibitor or epidermal growth factor receptor [EGFR] inhibitor) are indicated in the treatment of metastatic colorectal cancer. These agents are prescribed in combination with chemotherapy.

Bevacizumab, a VEGF-A inhibitor, improves progression-free and/or overall survival when combined with both oxaliplatin- and irinotecan-containing regimens in frontline and subsequent lines of therapy, including when bevacizumab is continued after progression on a bevacizumab-containing regimen.[298][299][300][301][302][303][304][305] However, bevacizumab may increase the risk of bleeding.[300][302][306]

Two other VEGF inhibitors, ziv-aflibercept and ramucirumab, are approved for use in combination with FOLFIRI after progression on an oxaliplatin-containing regimen.[307][308]

In the NRAS and KRAS wild-type patient population with metastatic colorectal cancer, cetuximab or panitumumab (EGFR inhibitors) can be used in combination with oxaliplatin- and irinotecan-containing regimens in frontline or subsequent lines of therapy, and as single agents after progression on at least one line of systemic therapy.[309][310][311][312] [ ] [Evidence A]

The American Society for Clinical Pathology guideline recommends testing for EGFR signaling pathway genes for mutations since they behave as negative predictors of benefit to anti-EGFR therapies in colorectal cancer.[313][314]

Patients can be treated with an oxaliplatin- or an irinotecan-containing regimen, with either bevacizumab or cetuximab, without any significant difference in progression-free or overall survival between regimens.[293] FOLFOXIRI with bevacizumab yields improved progression-free survival, but not overall survival, compared with FOLFIRI and bevacizumab in the frontline setting.[317] However, this combination is associated with significant toxicity and is reserved for only the fittest patients.[317]

Most commonly in the US, frontline therapy for patients with metastatic colorectal cancer is FOLFOX or CapeOX with bevacizumab. The duration of therapy is dependent on tolerability. Intensive first-line therapies are often followed by less intensive maintenance therapy until progression is considered.[130]

Most, but not all, studies support the use of a maintenance strategy (fluorouracil/leucovorin or capecitabine and bevacizumab) after 6-8 cycles of frontline therapy with FOLFOX or CapeOX with bevacizumab, with the re-addition of oxaliplatin at the time of progression.[318][319][320][321] Meta-analyses of randomized controlled trials report that, in patients with metastatic colorectal cancer: bevacizumab-based maintenance therapy and continuous chemotherapy are similarly effective, but the former is associated with less toxicity; bevacizumab-based maintenance therapy significantly improves progression-free survival compared with observation alone; the addition of erlotinib to bevacizumab as maintenance therapy significantly increases overall survival and progression-free survival.[323][324]

See local specialist protocols for dosing guidelines.

Primary options

bevacizumab

Secondary options

ziv-aflibercept

ramucirumab

cetuximab

panitumumab

Consider – stenting

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Consider –

stenting

Treatment recommended for SOME patients in selected patient group

Stenting may be appropriate for some patients with obstructing tumors of the rectum.

1st line – immunotherapy

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1st line –

immunotherapy

The immune checkpoint inhibitors nivolumab (with or without ipilimumab), pembrolizumab, or dostarlimab may be used for patients with unresectable or metastatic MSI-H or dMMR or POLE/ POLD1 rectal cancer who have not previously been treated with an immune checkpoint inhibitor.[127]

Pembrolizumab is approved by the Food and Drug Administration and the European Medicines Agency as first-line treatment for patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer. Compared with chemotherapy, pembrolizumab significantly improves progression-free survival in patients with metastatic MSI-H-dMMR colorectal cancer, and leads to clinically meaningful improvements in health-related quality of life.[335][336][337]

See local specialist protocols for dosing guidelines.

Primary options

pembrolizumab

nivolumab

and

ipilimumab

dostarlimab

Consider – stenting

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Consider –

stenting

Treatment recommended for SOME patients in selected patient group

Stenting may be appropriate for some patients with obstructing tumors of the rectum.

2nd line – alternative chemotherapy/targeted therapy regimen

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2nd line –

alternative chemotherapy/targeted therapy regimen

Stage 1 tumors are T1-2, N0, M0; stage 2-3 tumors are T3-4, N0, M0 to any T, N1-2, M0. Stage 4 tumors are any T, any N, M1.

In patients who are considered to be unsuitable for surgery, it is not possible to determine the precise staging of the tumor. As such, all treatment is appropriately palliative, with the possibility of a stent for obstructing tumors.

Treatment options for these patients in whom disease progresses on initial therapy with a FOLFOX- or CapeOX-based regimen include FOLFIRI with or without bevacizumab, ziv-aflibercept, or ramucirumab in all patients, or, in KRAS and NRAS wild-type patients, cetuximab or panitumumab alone or in combination with FOLFIRI.[353][354] [ ] [ ] Ziv-aflibercept or ramucirumab can be used instead of bevacizumab in combination with an irinotecan-containing regimen if the initial therapy was an oxaliplatin-containing regimen.

FOLFOX or CapeOX with or without bevacizumab can be considered in a patient initially treated with a FOLFIRI-based regimen even if bevacizumab was used in the first line. For patients with wild-type KRAS or NRAS genes, FOLFOX or CapeOX in combination with cetuximab or panitumumab, or single-agent cetuximab or panitumumab can also be considered.[127]

Regorafenib is an oral multikinase inhibitor with anti-vascular endothelial growth factor (VEGF) properties. After progression on all other lines of therapy, regorafenib as a single agent modestly improves survival compared with placebo.[326][327][328]

Trifluridine/tipiracil is an oral combination drug containing trifluridine, a thymidine-based nucleic acid analog that acts as the cytotoxic component of the drug, and tipiracil, a thymidine phosphorylase inhibitor that prevents the rapid breakdown of trifluridine. In one phase 3 randomized, placebo-controlled trial, trifluridine/tipiracil was associated with a 1.6-month improvement in overall survival in patients who had progressed on at least two prior chemotherapy regimens.[329] Trifluridine/tipiracil alone or in combination with bevacizumab is approved in patients with metastatic colorectal cancer who have received a fluoropyrimidine, oxaliplatin, irinotecan, at least one VEGF inhibitor, and an epidermal growth factor receptor inhibitor (if RAS wild type).[330][331] The bevacizumab combination is preferred over trifluridine/tipiracil alone.[127][130]

Fruquintinib, an oral, highly selective and potent small molecule inhibitor of VEGF-1, VEGF-2, and VEGF-3 receptors, is approved for the treatment of previously-treated metastatic colorectal cancer regardless of biomarker status.[332][333][334] Fruquintinib may be an option for the treatment of metastatic colorectal cancer that has progressed through all other available regimens.[127][130] It can be given before or after trifluridine/tipiracil or regorafenib; data regarding the best order of therapies are limited.[127][130]

Pembrolizumab monotherapy is approved for patients with metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) unresectable or metastatic colorectal cancer who have received previous fluoropyrimidine-based combination therapy.[127][130]

Nivolumab, and nivolumab plus ipilimumab, have received accelerated approval from the Food and Drug Administration and approval from the European Medicines Agency to treat patients with unresectable or metastatic solid tumors that have been identified as MSI-H or dMMR.[338] These therapies are approved for colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, and are recommended as subsequent-line treatment options for patients with metastatic MMR deficient colorectal cancer.[127]

Dostarlimab is approved by the Food and Drug Administration (FDA) for dMMR recurrent or advanced solid tumors that have progressed on or following prior treatment and who have no satisfactory alternative treatment options.

ICI-related inflammatory myositis has been identified as a rare but severe adverse effect for patients with cancer receiving ICI treatment.[355]

The most common all-grade adverse events are anemia, fatigue, and dysphagia, and the most common grade 3 or higher adverse events were neutropenia, hypertension, lipase increase, and lymphopenia.[341] Toxicity profiles of PD-1 or PD-L1 inhibitor-based combination therapies have been published.[341]

The BRAF kinase inhibitor encorafenib, in combination with cetuximab or panitumumab, is recommended for patients with BRAF V600E mutation positive unresectable or metastatic colorectal cancer who experience disease progression despite previous treatment.[127][130][342]

Combined therapy with encorafenib, cetuximab, and binimetinib (triplet therapy) significantly increased overall survival compared with control (cetuximab plus the investigators’ choice of irinotecan-based chemotherapy) in one open-label phase 3 trial of 665 patients with BRAF V600E-mutated metastatic colorectal cancer with disease progression after one or two previous regimens (median survival 9.0 months vs. 5.4 months, respectively).[343] One descriptive analysis found no significant difference in survival between triplet therapy and doublet therapy consisting of encorafenib and cetuximab (estimated 6-month survival 71% and 65%, respectively).[343] Anti-EGFR therapy may be considered in patients with BRAF mutations other than V600E.[127][130]

The tropomyosin receptor kinase inhibitors larotrectinib, entrectinib, and repotrectinib are approved and recommended for patients with metastatic colorectal cancer that is neurotrophic tyrosine receptor kinase (NTRK) gene fusion positive when there are no other effective treatment options.[127][130]

KRAS G12C inhibitors (e.g., sotorasib, adagrasib) may be considered with or without EGFR inhibitors for tumors that harbor the KRAS G12C mutation.[127][130][344][345][346] Treatment with sotorasib or adagrasib alone can be considered in patients who are unable to tolerate EGFR inhibitors owing to their toxicity.[127][130] The combination of adagrasib plus cetuximab has received approval from the FDA for the treatment of KRAS G12C-mutated previously treated locally advanced or metastatic colorectal cancer based on the findings of the KRYSTAL-1 trial.[344][347][348]

Fam-trastuzumab deruxtecan monotherapy, or trastuzumab in combination with pertuzumab, lapatinib, or tucatinib may be used as a treatment option for HER2-amplified tumors that are also RAS and BRAF wild type.[127][130][349] The combination of tucatinib plus trastuzumab has received approval from the FDA for the management of RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, based on responses received in the phase 2 MOUNTAINEER trial.[127][130][350]

Selpercatinib, a CNS-active RET kinase inhibitor, has shown promise in the open-label, basket trial LIBRETTO-001 trial comprising patients ages 18 years and older with RET-altered cancers.[351][352] It may be used in patients with unresectable or metastatic RET gene fusion positive mutation colorectal cancer.[127][130]

See local specialist protocols for dosing guidelines.

Primary options

irinotecan

and

leucovorin

and

fluorouracil

irinotecan

and

leucovorin

and

fluorouracil

-- AND --

bevacizumab

ziv-aflibercept

ramucirumab

cetuximab

panitumumab

cetuximab

panitumumab

oxaliplatin

and

leucovorin

and

fluorouracil

oxaliplatin

and

leucovorin

and

fluorouracil

-- AND --

bevacizumab

cetuximab

panitumumab

oxaliplatin

and

capecitabine

oxaliplatin

and

capecitabine

-- AND --

bevacizumab

cetuximab

panitumumab

pembrolizumab

nivolumab

and

ipilimumab

dostarlimab

Secondary options

regorafenib

trifluridine/tipiracil

and

bevacizumab

fruquintinib

encorafenib

-- AND --

cetuximab

panitumumab

larotrectinib

entrectinib

repotrectinib

sotorasib

adagrasib

sotorasib

adagrasib

-- AND --

cetuximab

panitumumab

fam-trastuzumab deruxtecan

trastuzumab

-- AND --

pertuzumab

lapatinib

tucatinib

selpercatinib

Consider – stenting

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Consider –

stenting

Treatment recommended for SOME patients in selected patient group

Stenting may be appropriate for some patients with obstructing tumors of the rectum.

colon cancer, suitable for surgery

stage 1-3

1st line – surgical resection

Back

1st line –

surgical resection

Stage 1 tumors are T1-2, N0, M0; stage 2-3 tumors are T3-4, N0, M0 to any T, N1-2, M0.

For patients without metastases, the primary treatment is colectomy with en bloc removal of the regional lymph nodes.[113][269] The extent of the colectomy depends on resection of the portion of the colon and arterial arcade that contains the regional lymph nodes. Contiguously involved structures should also be resected; adhesions should not be divided because they may contain malignant cells.[113] A minimally invasive surgical approach, using laparoscopic or robotic surgical techniques, is preferred for elective colectomy where expertise is available.[113] One systematic review suggests that robot-assisted right hemicolectomy for right colon cancer results in similar long-term oncologic outcomes as laparoscopic right hemicolectomy.[272] Resection and examination of a minimum of 12 nodes is necessary for accurate staging.[270][271] An obstructing cancer can be managed by resection with temporary diversion or, rarely and in very specific circumstances, interim endoscopic stent insertion followed by resection.

Plus – postoperative chemotherapy

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Plus –

postoperative chemotherapy

Treatment recommended for ALL patients in selected patient group

Patients with stage 3 disease should be offered chemotherapy.[130][273][274][275] However, the role of adjuvant chemotherapy in patients with stage 2 disease is unclear.[273]

Subgroup analyses suggest that patients with potentially high-risk stage 2 disease benefit from adjuvant therapy, albeit to a lesser extent than patients with stage 3 disease.[276]

The National Comprehensive Cancer Network (NCCN) and the American Society for Clinical Oncology (ASCO) recommend that adjuvant chemotherapy be offered to patients with high-risk stage 2 colon cancer, which includes patients (exclusive of high levels of microsatellite instability [MSI-H]) cancers with inadequately sampled nodes (<12 nodes), poorly differentiated/undifferentiated histology, lymphatic/vascular invasion, bowel obstruction, perineural invasion, localized perforation, ≥10 tumor buds, or close, indeterminate, or positive margins.[130][274][277]

Patients with stage 2B colon cancer (tumor penetrating visceral peritoneum) or stage 2C colon cancer (tumor invading surrounding organs) should also be offered adjuvant chemotherapy.[277] Adjuvant chemotherapy is not recommended for patients with stage 1 colon cancer, or stage 2A colon cancer without high-risk features.[130][277]

The addition of oxaliplatin to adjuvant chemotherapy (fluorouracil and leucovorin) improves overall survival at 10 years among patients who underwent resection with curative intent for stage 2 or 3 colon cancer.[278] The combination of fluorouracil and leucovorin plus oxaliplatin (FOLFOX) is recommended as adjuvant therapy for patients with resected high-risk stage 2, or stage 3, nonmetastatic colon cancer.[130] However, one pooled analysis reported no overall survival benefit of adjuvant oxaliplatin in patients with high-risk stage 2 colon cancer, suggesting that oxaliplatin should not be considered standard of care in this patient group.[279]

FOLFOX has not been compared directly with CapeOX (capecitabine and oxaliplatin), but data from a retrospective cohort of consecutively treated patients with stage 3 colon cancer suggest that overall survival does not differ by regimen.[280]

There is controversy as to whether patients ages >70 years with stage 2 disease benefit from the addition of oxaliplatin to chemotherapy.[281] Patients with stage 2 colon cancers that demonstrate MSI-H or defective mismatch repair have an overall good prognosis and may have adverse overall survival if treated with adjuvant chemotherapy.[282] If patients with MSI-H or mismatch repair deficient (dMMR) cancers and high-risk features proceed with adjuvant chemotherapy after shared decision-making, oxaliplatin-containing regimens are recommended.[277]

When adjuvant therapy is given, it should start within 8 weeks of surgery.[283] One meta-analysis showed that a 4-week increase in time to adjuvant chemotherapy is associated with a significant decrease in both disease-free survival and overall survival.[284]

The NCCN and ASCO recommend that adjuvant chemotherapy be offered to patients with stage 3 colon cancer who are at a high risk of recurrence (T4 and/or N2) for a duration of 6 months if using FOLFOX, or 3 to 6 months if using CapeOX. For patients with stage 3 colon cancer who are at a low risk of recurrence (T1, T2, or T3 and N1); either 6 months of adjuvant chemotherapy or a shorter duration of 3 months may be offered on the basis of a potential reduction in adverse events and no significant difference in disease-free survival with the 3-month regimen.[130][274]

Patients with high-risk stage 2A, stage 2B, or stage 2C colon cancer should be offered therapy for 3 to 6 months, after an individualized discussion of the potential benefits and harms of the treatment and its duration.[277]

There is no apparent role for subsequent therapy in the absence of disease recurrence.

See local specialist protocols for dosing guidelines.

Primary options

fluorouracil

and

leucovorin

and

oxaliplatin

capecitabine

and

oxaliplatin

stage 4

1st line – surgical resection after preoperative chemotherapy

Back

1st line –

surgical resection after preoperative chemotherapy

Stage 4 tumors are any T, any N, M1a, b, c.

About 15% to 25% of patients with colorectal cancer present with synchronous liver, lung, and peritoneal metastases.[246] Resection of lung or liver metastases with clear tumor margins considerably alters the prognosis. Five-year survival rates following resection of colorectal cancer metastases are in the region of 30% to 40% compared with almost 0% survival in patients not undergoing surgery.[247][248][249]

The criteria for determining resectability are evolving and are no longer restricted simply to the number, size, margins of resection, and location of hepatic lesions, but are more likely to reflect the likelihood of achieving complete microscopic negative resection (R0) with preservation of at least 30% liver function, and maintaining adequate vascular and biliary drainage.

Resection of liver metastases should not be performed in the presence of unresectable disease at extrahepatic sites.

Consider – locally ablative procedures

Back

Consider –

locally ablative procedures

Treatment recommended for SOME patients in selected patient group

For patients with oligometastatic liver or lung disease who do not desire surgery, image-guided thermal ablation or stereotactic body radiation therapy can be used in lieu of surgery.[130][254]

Plus – preoperative chemotherapy

Back

Plus –

preoperative chemotherapy

Treatment recommended for ALL patients in selected patient group

Preoperative chemotherapy comprises either FOLFOX (oxaliplatin, leucovorin, and fluorouracil), FOLFIRI (irinotecan, leucovorin, and fluorouracil), or CapeOX (oxaliplatin and capecitabine) given with or without bevacizumab.[130]

See local specialist protocols for dosing guidelines.

Primary options

oxaliplatin

and

leucovorin

and

fluorouracil

irinotecan

and

leucovorin

and

fluorouracil

oxaliplatin

and

capecitabine

Consider – vascular endothelial growth factor inhibitor or epidermal growth factor receptor inhibitor

Back

Consider –

vascular endothelial growth factor inhibitor or epidermal growth factor receptor inhibitor

Treatment recommended for SOME patients in selected patient group

Bevacizumab, a VEGF-A inhibitor, improves progression-free and/or overall survival when combined with both oxaliplatin- and irinotecan-containing regimens in frontline and subsequent lines of therapy, including when bevacizumab is continued after progression on a bevacizumab-containing regimen.[298][299][300][301][302][303] However, bevacizumab may increase the risk of bleeding.[300][302][306]

Two other VEGF inhibitors, ziv-aflibercept and ramucirumab, are approved for use in combination with FOLFIRI after progression on an oxaliplatin-containing regimen.[307][308]

Most, but not all, studies support the use of a maintenance strategy (fluorouracil/leucovorin or capecitabine and bevacizumab) after 6 to 8 cycles of frontline therapy with FOLFOX or CapeOX with bevacizumab, with the re-addition of oxaliplatin at the time of progression.[318][319][320][321] Meta-analyses of randomized controlled trials report that, in patients with metastatic colorectal cancer: bevacizumab-based maintenance therapy and continuous chemotherapy are similarly effective, but the former is associated with less toxicity; bevacizumab-based maintenance therapy significantly improves progression-free survival compared with observation alone; the addition of erlotinib to bevacizumab as maintenance therapy significantly increases overall survival and progression-free survival.[323][324]

See local specialist protocols for dosing guidelines.

Primary options

bevacizumab

Secondary options

ziv-aflibercept

ramucirumab

cetuximab

panitumumab

1st line – surgical resection after preoperative immunotherapy

Back

1st line –

surgical resection after preoperative immunotherapy

Stage 4 tumors are any T, any N, M1a, b, c.

About 15% to 25% of patients with colorectal cancer present with synchronous liver, lung, and peritoneal metastases.[246] Resection of lung or liver metastases with clear tumor margins considerably alters the prognosis. Five-year survival rates following resection of colorectal cancer metastases are in the region of 30% to 40% compared with almost 0% survival in patients not undergoing surgery.[247][248][249]

Resection of liver metastases should not be performed in the presence of unresectable disease at extrahepatic sites.

Consider – locally ablative procedures

Back

Consider –

locally ablative procedures

Treatment recommended for SOME patients in selected patient group

For patients with oligometastatic liver or lung disease who do not desire surgery, image-guided thermal ablation or stereotactic body radiation therapy can be used in lieu of surgery.[130][254]

Plus – preoperative immunotherapy

Back

Plus –

preoperative immunotherapy

Treatment recommended for ALL patients in selected patient group

Patients with high microsatellite instability/mismatch repair deficient tumors may receive preoperative pembrolizumab, nivolumab, nivolumab and ipilimumab, or dostarlimab.[130]

See local specialist protocols for dosing guidelines.

Primary options

pembrolizumab

nivolumab

and

pembrolizumab

dostarlimab

1st line – immediate surgical resection

Back

1st line –

immediate surgical resection

Stage 4 tumors are any T, any N, M1.

Immediate surgery, rather than neoadjuvant treatment followed by resection, may be a more appropriate approach in low-risk (medically fit, 4 or fewer lesions, unilobar or bilobar involvement) patients with colon cancer and liver or lung metastases.[356]

Consider – locally ablative procedures

Back

Consider –

locally ablative procedures

Treatment recommended for SOME patients in selected patient group

For patients with oligometastatic liver or lung disease who do not desire surgery, image-guided thermal ablation or stereotactic body radiation therapy can be used in lieu of surgery.[127][254]

Plus – postoperative chemotherapy

Back

Plus –

postoperative chemotherapy

Treatment recommended for ALL patients in selected patient group

Postoperative chemotherapy, which may be fluorouracil, capecitabine, FOLFOX (oxaliplatin, leucovorin, and fluorouracil), FOLFIRI (irinotecan, leucovorin, and fluorouracil), or CapeOX (oxaliplatin and capecitabine), is then administered for 4-6 months postoperatively.

See local specialist protocols for dosing guidelines.

Primary options

leucovorin

and

fluorouracil

capecitabine

oxaliplatin

and

leucovorin

and

fluorouracil

irinotecan

and

leucovorin

and

fluorouracil

oxaliplatin

and

capecitabine

Consider – vascular endothelial growth factor inhibitor or epidermal growth factor receptor inhibitor

Back

Consider –

vascular endothelial growth factor inhibitor or epidermal growth factor receptor inhibitor

Treatment recommended for SOME patients in selected patient group

Bevacizumab, a VEGF-A inhibitor, improves progression-free and/or overall survival when combined with both oxaliplatin- and irinotecan-containing regimens in frontline and subsequent lines of therapy, including when bevacizumab is continued after progression on a bevacizumab-containing regimen.[298][299][300][301][302][303] However, bevacizumab may increase the risk of bleeding.[300][302][306]

Two other VEGF inhibitors, ziv-aflibercept and ramucirumab, are approved for use in combination with FOLFIRI after progression on an oxaliplatin-containing regimen.[307][308]

See local specialist protocols for dosing guidelines.

Primary options

bevacizumab

Secondary options

ziv-aflibercept

ramucirumab

cetuximab

panitumumab

colon cancer, not suitable for surgery

stage 1-4

1st line – chemotherapy

Back

1st line –

chemotherapy

Stage 1 tumors are T1-2, N0, M0; stage 2-3 tumors are T3-4, N0, M0 to any T, N1-2, M0. Stage 4 tumors are any T, any N, M1.

The backbone of chemotherapy is generally fluorouracil/leucovorin with oxaliplatin (FOLFOX or FLOX) or irinotecan (FOLFIRI).

See local specialist protocols for dosing guidelines.

Primary options

oxaliplatin

and

leucovorin

and

fluorouracil

irinotecan

and

leucovorin

and

fluorouracil

capecitabine

and

oxaliplatin

Secondary options

fluorouracil

and

leucovorin

and

oxaliplatin

and

irinotecan

Consider – vascular endothelial growth factor inhibitor or epidermal growth factor receptor inhibitor

Back

Consider –

vascular endothelial growth factor inhibitor or epidermal growth factor receptor inhibitor

Treatment recommended for SOME patients in selected patient group

Two other VEGF inhibitors, ziv-aflibercept and ramucirumab, are approved for use in combination with FOLFIRI after progression on an oxaliplatin-containing regimen.[307][308]

See local specialist protocols for dosing guidelines.

Primary options

bevacizumab

Secondary options

ziv-aflibercept

ramucirumab

cetuximab

panitumumab

Consider – stenting

Back

Consider –

stenting

Treatment recommended for SOME patients in selected patient group

Stenting may be appropriate for some patients with obstructing tumors of the sigmoid colon.

1st line – immunotherapy

Back

1st line –

immunotherapy

The immune checkpoint inhibitors nivolumab (with or without ipilimumab), pembrolizumab, or dostarlimab may be used for patients with unresectable or metastatic MSI-H or dMMR colon cancer who have not previously been treated with an immune checkpoint inhibitor.[130]

Nivolumab, or nivolumab and ipilimumab, are also approved for the first-line treatment of metastatic, MSI-H, or dMMR colorectal cancer.

Dostarlimab is approved by the FDA for dMMR recurrent or advanced solid tumors that have progressed on or following prior treatment and who have no satisfactory alternative treatment options.

See local specialist protocols for dosing guidelines.

Primary options

pembrolizumab

nivolumab

and

ipilimumab

dostarlimab

Consider – stenting

Back

Consider –

stenting

Treatment recommended for SOME patients in selected patient group

Stenting may be appropriate for some patients with obstructing tumors of the sigmoid colon.

2nd line – alternative chemotherapy/targeted therapy regimen

Back

2nd line –

alternative chemotherapy/targeted therapy regimen

Stage 1 tumors are T1-2, N0, M0; stage 2-3 tumors are T3-4, N0, M0 to any T, N1-2, M0. Stage 4 tumors are any T, any N, M1.

Treatment options for these patients if disease progresses on initial therapy with a FOLFOX- or CapeOX-based regimen include FOLFIRI with or without bevacizumab, ziv-aflibercept, or ramucirumab in all patients, or, in the KRAS and NRAS wild-type patient population, cetuximab or panitumumab alone or in combination with FOLFIRI.[353][354][357][358] [ ] [ ] FOLFOX or CapeOX with or without bevacizumab can be considered in a patient initially treated with a FOLFIRI-based regimen even if bevacizumab was used in the first line.

In patients with wild-type KRAS or NRAS genes, FOLFOX or CapeOX in combination with cetuximab or panitumumab, or single-agent cetuximab or panitumumab can also be considered in a patient who was initially treated with a FOLFIRI-based regimen.[130]

Regorafenib is an oral multikinase inhibitor with anti-vascular endothelial growth factor (VEGF) inhibitor properties. After progression on all other lines of therapy, regorafenib as a single agent modestly improves survival compared with placebo.[326][327][328]

The immune checkpoint inhibitors nivolumab (with or without ipilimumab), pembrolizumab, or dostarlimab may be used for patients with unresectable or metastatic MSI-H or dMMR colon cancer who have not previously been treated with an immune checkpoint inhibitor.[130]

Pembrolizumab monotherapy is approved for patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) unresectable or metastatic colorectal cancer who have received previous fluoropyrimidine-based combination therapy.[127][130]

Dostarlimab is approved by the FDA for dMMR recurrent or advanced solid tumors that have progressed on or following prior treatment and who have no satisfactory alternative treatment options.

ICI-related inflammatory myositis has been identified as a rare but severe adverse effect for patients with cancer receiving ICI treatment.[355]

The most common all-grade adverse events are anemia, fatigue, and dysphagia, and the most common grade 3 or higher adverse events were neutropenia, hypertension, lipase increase, and lymphopaenia.[341] Toxicity profiles of PD-1 or PD-L1 inhibitor-based combination therapies have been published.[341]

See local specialist protocols for dosing guidelines.

Primary options

irinotecan

and

leucovorin

and

fluorouracil

irinotecan

and

leucovorin

and

fluorouracil

-- AND --

bevacizumab

ziv-aflibercept

ramucirumab

cetuximab

panitumumab

cetuximab

panitumumab

oxaliplatin

and

leucovorin

and

fluorouracil

oxaliplatin

and

leucovorin

and

fluorouracil

-- AND --

bevacizumab

cetuximab

panitumumab

oxaliplatin

and

capecitabine

oxaliplatin

and

capecitabine

-- AND --

bevacizumab

cetuximab

panitumumab

pembrolizumab

nivolumab

and

ipilimumab

dostarlimab

Secondary options

regorafenib

trifluridine/tipiracil

and

bevacizumab

fruquintinib

encorafenib

-- AND --

cetuximab

panitumumab

larotrectinib

entrectinib

repotrectinib

sotorasib

adagrasib

sotorasib

adagrasib

-- AND --

cetuximab

panitumumab

fam-trastuzumab deruxtecan

trastuzumab

-- AND --

pertuzumab

lapatinib

tucatinib

selpercatinib

Consider – stenting

Back

Consider –

stenting

Treatment recommended for SOME patients in selected patient group

Stenting may be appropriate for some patients with obstructing tumors of the sigmoid colon.

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Colorectal cancer

Treatment algorithm

rectal cancer, suitable for surgery

local excision or radical excision

radical resection

preoperative radiation therapy ± chemotherapy

radical resection

preoperative chemoradiation therapy

Primary options

postoperative chemotherapy

Primary options

total neoadjuvant therapy

surgical resection

locally ablative procedures

chemotherapy or immunotherapy ± radiation therapy

Primary options

rectal cancer, not suitable for surgery

chemotherapy

Primary options

Secondary options

vascular endothelial growth factor inhibitor or epidermal growth factor receptor inhibitor

Primary options

Secondary options

stenting

immunotherapy

Primary options

stenting

alternative chemotherapy/targeted therapy regimen

Primary options

Secondary options

stenting

colon cancer, suitable for surgery

surgical resection

postoperative chemotherapy

Primary options

surgical resection after preoperative chemotherapy

locally ablative procedures

preoperative chemotherapy

Primary options

vascular endothelial growth factor inhibitor or epidermal growth factor receptor inhibitor

Primary options

Secondary options

surgical resection after preoperative immunotherapy

locally ablative procedures

preoperative immunotherapy

Primary options

immediate surgical resection

locally ablative procedures

postoperative chemotherapy

Primary options

vascular endothelial growth factor inhibitor or epidermal growth factor receptor inhibitor

Primary options

Secondary options

colon cancer, not suitable for surgery

chemotherapy

Primary options

Secondary options

vascular endothelial growth factor inhibitor or epidermal growth factor receptor inhibitor

Primary options

Secondary options

stenting

immunotherapy

Primary options

stenting

alternative chemotherapy/targeted therapy regimen

Primary options

Secondary options

stenting