Colorectal cancer

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

Surgical resection for localised colorectal cancer is the mainstay of curative treatment. Surgery should be avoided when the risks are thought to outweigh the potential benefits: for example, when the patient is unfit for major surgery due to underlying comorbidities, or when resection of advanced disease (stage 4) may not alter survival or quality of life. Other than palliative resection (e.g., for obstruction), the aim of surgery is curative based on clear resection margins both macroscopically and histologically.

Evidence suggests that outcomes are better in surgical units that perform high volumes of colorectal cancer surgery.[190]

Prior to surgery, patients who may require a stoma should be seen by a stoma nurse to ensure appropriate stoma marking, adequate time for fitting of the appliance, and education for the patient on stoma care. Multi-modal prehabilitation may improve functional capacity and postoperative recovery and may reduce severe postoperative complications; more trials are warranted.[191][192]

Principles of surgery

Minimally invasive surgical techniques, including laparoscopic or robotic techniques, are increasingly used for colon cancer. In most circumstances, it is preferred to open surgery given appropriate expertise.[115] The benefits of resection performed by an appropriately trained surgeon using minimally invasive surgical techniques include reduced postoperative pain, shorter hospital stay, superior inflammatory profile, and a shorter recovery period compared with open surgery.[193][194] Time to tumour recurrence, long-term quality of life, and survival are similar with both laparoscopic and open surgical techniques.[195][196][197][198][199]

Management of rectal cancer

The surgical treatment of rectal cancer (classified as any cancer whose distal margin is seen at 15 cm or less from the anal verge using a rigid sigmoidoscope) differs from that of colon cancer in its increased technical complexity.[200]

Surgery for rectal cancer varies according to the stage and location of the cancer. Total mesorectal excision is the international standard surgical procedure for rectal cancer.[128]

Minimally invasive surgical techniques used for rectal resection have the same advantages as those used for colon resection, and are associated with similar oncological outcomes compared with open rectal surgery.[201][202][203][204][205] However, one non-inferiority study found that laparoscopic resection may not be appropriate in stage 2 and 3 rectal cancer.[206]

Systematic reviews, which included randomised and observational studies, suggest that robot-assisted surgery for rectal cancer results in similar oncological outcomes as laparoscopic surgery.[207][208][209][210] One network meta-analysis noted an improvement in distal resection margin distance and reduction in hospital stay with robot-assisted total mesorectal excision.[211] Another meta-analysis reported better preservation of urinary and sexual functions with robot-assisted surgery, compared with laparoscopic surgery.[212] One randomised controlled trial (RCT) evidence found that robot-assisted laparoscopic surgery did not significantly reduce the risk of conversion to open laparotomy compared with conventional laparoscopic surgery.[213]

Fast-track surgery

Fast-track surgery combines a variety of techniques (e.g., epidural or regional anaesthesia, minimally invasive techniques, optimal pain control, and aggressive postoperative rehabilitation) to reduce the time required for full recovery. Fast-track surgery, incorporating the principles of the Enhanced Recovery After Surgery (ERAS) programme, has been shown to reduce overall complications and the length of stay after colorectal surgery.[214][215][216] [ ]

Rectal cancer stage 1 (T1 and T2)

Local excision of rectal cancer may be appropriate for low-risk cancers that fulfil all the following criteria.[129]

<3 cm diameter
Within 8 cm of the anal verge
Involves <30% of the circumference of the bowel
Mobile, non-fixed
Margin clear (>3 mm)
Moderately or well-differentiated histology with no adverse features of tumour budding or lymphovascular invasion
No evidence of lymphadenopathy on pre-treatment imaging
Localised (T1, N0, M0)
Full-thickness excision is feasible.

Standard contraindications to a local excision include:[129]

>3 cm diameter

poor differentiation

>pT1, with grade 3 or lymphovascular or perineural invasion

invasion of the anal sphincter complex.

Transanal resection of tumour (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 oncological outcomes did not differ.[217] 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.[218] One subsequent systematic review of mostly retrospective studies found that TEM is oncologically superior to transanal excision.[219]

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.[129] 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.[129] 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.[220][221][222] Patient preference and operator expertise in ESD should be considered while selecting the appropriate technique.[129]

Definitive surgery or subsequent radiotherapy may be necessary after local resection if the resection margins are positive, if the pathology reveals pT2 stage, or if the tumour is graded as pT1 but has unfavourable histological features. The standard of care in these situations, with best oncological outcomes, remains definitive (low anterior or abdominoperineal resection) surgery.[129]

T1 tumours that are not suitable for local resection and T2 tumours that are in the upper third of the rectum are managed with anterior resection with sphincter preservation and colorectal anastomosis.[129] For tumours not amenable to local excision that are in the middle and lower third of the rectum, excision is achieved by low anterior resection (LAR) and colo-anal anastomosis.[129] A colonic pouch, side to end colorectal anastomosis, or coloplasty may improve function in some cases. Such a low anastomosis is usually defunctionalised with a temporary ileostomy. 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.[223][224]

Abdominoperineal resection (APR) is required if the tumour invades the pelvic floor, sphincter complex, or anal canal. APR entails a permanent colostomy.[129] For patients with early stage cancers (cT1-2N0) who require an APR because of tumour location, neoadjuvant chemoradiation may be recommended after multidisciplinary discussion to increase the chance of sphincter preservation.[225]

Rectal cancer stage 2-3

The treatment for patients with clinical stage 2 and 3 rectal cancer in many centres is preoperative radiotherapy with concomitant fluoropyrimidine-based chemoradiotherapy, followed by a sphincter-preserving LAR or APR, depending upon location of the tumour in relationship to the anal sphincters.[129]

Neoadjuvant treatment in the US includes long-course radiotherapy consisting of delivered over 5 weeks with concurrent fluoropyrimidine-based chemotherapy. Preoperative short-course radiation is an accepted alternative used in selected patients with T3 disease.[226] 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.[129] For patients with locally advanced cancer, neoadjuvant long-course chemoradiation is preferred over short-course radiotherapy.[154]

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.[227][228][229] Neoadjuvant chemotherapy with FOLFIRINOX (fluorouracil/folinic acid with oxaliplatin and irinotecan) and preoperative chemoradiotherapy significantly improved disease-free survival compared with standard-of-care (e.g., chemoradiotherapy 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).[230] The addition of oxaliplatin to neoadjuvant chemoradiotherapy schedules is not currently recommended.[129]

Short-course neoadjuvant radiation

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 pathological 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.[231][232][233][234] More recent results from the RAPIDO trial indicate higher rates of local recurrence with short-course radiation.[235][236] Further investigation on the optimal radiotherapy schedule is ongoing, with the ACO/ARO/AIO-18.1 randomised phase 3 trial of the German Rectal Cancer Study Group comparing two different total neoadjuvant therapy regimens, with control arm consisting of short-course radiotherapy followed by consolidation chemotherapy and surgery or watchful waiting, and investigational arm with long-course chemoradiotherapy, followed by consolidation systemic therapy and surgery or watchful waiting.[237]

Preoperative short-course radiation is typically used for smaller, non-bulky 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.[238][239]

Radiation volumes and techniques

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.[240]

Intensity-modulated radiotherapy 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.[240]

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.[240]

Patient selection

In some centres, preoperative neoadjuvant treatment is given on a selective basis depending on tumour level and distance to resection margins. A rationale for appropriate selection is provided in National Institute for Health and Care Excellence clinical guidelines on colorectal cancer.[91]

Postoperative adjuvant therapy

When preoperative radiotherapy or chemoradiotherapy is given, the benefit of further fluoropyrimidine postoperative adjuvant chemotherapy is unconfirmed and a matter of debate.[241][242][243] [ ] Practice guidelines can be variable. However, for initially found T3/T4 or node positive disease, up to 6 months of fluoropyrimidine-based chemotherapy should be considered, regardless of the pathological findings at resection.[129]

The long-term results of one RCT indicate that adjuvant FOLFOX (fluorouracil and folinic acid plus oxaliplatin) improves disease-free survival at 6 years, compared with fluorouracil with folinic acid, in patients with rectal cancer with stage 2 and 3 disease after preoperative chemoradiotherapy.[244] The study suggests that adjuvant FOLFOX may be considered on the basis of the postoperative pathological stage in those who received preoperative chemoradiation and mesorectal excision.[244]

When preoperative radiotherapy or chemoradiotherapy is not given, adjuvant treatment may be given in the postoperative period if adverse histopathological features are found and should be delivered as early as possible for patients who required an abdominoperineal resection.[243][245] Postoperative radiotherapy as a single modality is obsolete.

Total neoadjuvant therapy (TNT)

TNT is the preferred treatment strategy for patients with locally advanced rectal cancer.[129][246] Patients with low rectal cancer and/or patients at a higher risk for local and/or distant metastases may benefit from this therapy.[154] These patients will receive multi-agent chemotherapy and chemoradiotherapy prior to surgery. The recommended timing for chemotherapy is after chemoradiation.[154] TNT improves delivery of planned therapy, increases downstaging, addresses micrometastases sooner, requires temporary ileostomy reversal, achieves higher complete response rates (including pathological and sustained clinical), and may avoid the need for surgery altogether.[129] Long-term follow-up is needed to determine if findings translate to improved survival. TNT may facilitate non-operative treatment strategies for organ preservation.[247]

Rectal cancer stage 4 with resectable metastases

About 15% to 25% of patients with colorectal cancer present with synchronous liver, lung, and peritoneal metastases.[248] Resection of lung or liver metastases with clear tumour 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.[249][250][251]

Resection of liver metastases

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.

Potentially resectable liver metastases may be managed by:[129][139][252][253]

Staged or synchronous resection of liver metastases and primary tumour with postoperative chemotherapy, with or without pelvic radiotherapy (depending on T and N staging of the tumour): may be more appropriate in a patient with clearly resectable metastatic disease
Preoperative chemotherapy alone or chemoradiotherapy followed by staged or synchronous resection of liver metastases and rectal tumour with postoperative adjuvant treatment depending on T and N staging of the rectal tumour: 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.

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

One systematic review and meta-analysis found similar oncological 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.[254][255]

For patients with oligometastatic liver or lung disease who do not desire surgery, image-guided thermal ablation or stereotactic body radiotherapy (SBRT) can be used in lieu of surgery.[129][139][256]

Studies have compared laparoscopic microwave ablation with percutaneous microwave ablation and microwave ablation with radiofrequency ablation in patients with hepatocellular carcinoma and colorectal liver metastases with lesions <5 cm.[257][258] Albeit limited evidence, similar safety and feasibility profiles have been reported for microwave ablation and radiofrequency ablation, and either technique can be considered in appropriately selected patients.[258] Further, similar outcomes have been observed with laparoscopic and percutaneous microwave ablation. While laparoscopic microwave ablation had better local control, percutaneous microwave ablation had lower complication rates.[257][258] Either approach can be used depending on patient-specific factors.[258]

Managing peritoneal metastases

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) may improve survival outcomes in patients with colorectal cancer with peritoneal metastases.[259][260] The HIPEC technique is restricted to specialised oncological centres; data from RCTs are lacking.

Identifying patients with rectal cancer with poor prognosis

Preoperative elevated neutrophil-to-lymphocyte ratio has been associated with poorer prognosis in patients with localised or metastatic colorectal cancer to the liver. It is, therefore, a useful biomarker for identifying patients who would benefit from adjuvant therapies.[261][262][263][264][265][266][267]

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.[268][269] KRAS and BRAF mutated tumours have been associated with inferior progression-free survival and overall survival compared with non-mutated tumours.[270]

Neoadjuvant treatment

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 or capecitabine and oxaliplatin (CapeOX). Other regimens include fluorouracil plus folinic acid, or capecitabine. Immunotherapy, including pembrolizumab, nivolumab, nivolumab and ipilimumab, or dostarlimab is preferred for patients with mismatch repair deficient (dMMR) or high microsatellite instability (MSI-H) cancers. Chemotherapy or immunotherapy may be followed by radiotherapy.[129] Radiotherapy or chemoradiation may be considered for patients with tumour involvement of the resection margin.[129]

Rectal cancer stage 4: symptom control

Additional treatments directed at the primary tumour may be necessary to control symptoms. These include endoscopic stenting of an obstructing tumour, radiotherapy, laser recanalisation, or diverting colostomy.

Colon cancer stage 1-3

For patients without metastases, the primary treatment is colectomy with en bloc removal of the regional lymph nodes.[115][271] The extent of the colectomy depends on resection of the portion of the colon and arterial arcade that contains the regional lymph nodes. Resection and examination of a minimum of 12 nodes is necessary for accurate staging.[272][273] Contiguously involved structures should also be resected; adhesions should not be divided because they may contain malignant cells.[115] A minimally invasive surgical approach, using laparoscopic or robotic surgical techniques, is preferred for elective colectomy where expertise is available.[115] One systematic review suggests that robot-assisted right hemicolectomy for right colon cancer results in similar long-term oncological outcomes as laparoscopic right hemicolectomy.[274] 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.

Patients with stage 3 disease should be offered adjuvant chemotherapy.[139][275][276][277]

The role for adjuvant chemotherapy in patients with stage 2 disease is unclear.[275] 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.[278]

The National Comprehensive Cancer Network (NCCN) and the American Society for Clinical Oncology (ASCO) recommend that adjuvant chemotherapy be offered to:[139][279]

Patients with stage 2B colon cancer (tumour penetrating visceral peritoneum) or stage 2C colon cancer (tumour invading surrounding organs)
Patients with high-risk stage 2A colon cancer, which includes patients (exclusive of MSI-H [high levels of microsatellite instability] cancers with inadequately sampled nodes (<12 nodes), poorly differentiated/undifferentiated histology, lymphatic/vascular invasion, bowel obstruction, perineural invasion, localised perforation, ≥10 tumour buds, or close, indeterminate, or positive margins.

Adjuvant chemotherapy should not be offered routinely to people with stage 2A colon cancer without high-risk features.

The addition of oxaliplatin to adjuvant chemotherapy (fluorouracil and folinic acid) improves overall survival at 10 years among patients who underwent resection with curative intent for stage 2 or 3 colon cancer.[280] FOLFOX is recommended as adjuvant therapy for patients with resected high-risk stage 2, or stage 3, non-metastatic colon cancer.[139] 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.[281]

FOLFOX has not been compared directly with CapeOX, but data from a retrospective cohort of consecutively treated patients with stage 3 colon cancer suggest that overall survival does not differ by regimen.[282]

There is controversy as to whether patients aged >70 years with stage 2 disease benefit from the addition of oxaliplatin to chemotherapy.[283] Patients with stage 2 colon cancers that demonstrate MSI-H or dMMR have an overall good prognosis and may have adverse overall survival if treated with adjuvant chemotherapy.[284] If patients with MSI-H or dMMR cancers and high-risk features proceed with adjuvant chemotherapy after shared decision-making, oxaliplatin-containing regimens are recommended.[279]

When adjuvant therapy is given, it should start within 8 weeks of surgery.[285] 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.[286]

The NCCN and ASCO recommend that adjuvant chemotherapy be offered to:[139][276][279]

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 3-6 months if using CapeOX
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
Patients with high-risk stage 2A, stage 2B, or stage 2C colon cancer for 3-6 months, after an individualised discussion of the potential benefits and harms of the treatment and its duration.

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

Adjuvant chemotherapy is not recommended for patients with stage 1 colon cancer.[139]

Identifying patients with colon cancer with poor prognosis

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.[268][269][287] KRAS and BRAF mutated tumours have been associated with inferior progression-free survival and overall survival compared with non-mutated tumours.[270]

Molecular profiling to identify patients who have stage 2 colorectal cancer with a high risk of recurrence is beginning to be adopted in clinical practice.[288]

One randomised controlled trial has demonstrated promise of neoadjuvant chemotherapy in operable locally advanced colon cancer. The trial concluded that preoperative oxaliplatin plus fluoropyrimidine chemotherapy for 6 weeks produced marked histopathological downstaging, fewer incomplete resections, and better 2-year disease control in patients with operable colon cancer.[289]

Colon cancer stage 4 with resectable metastases

The management of patients with resectable metastases follows similar principles to patients with rectal cancer and resectable metastases, both in the timing of surgery in relation to chemotherapy and the optimum chemotherapy regimens.

Guidelines recommend several possible first-line therapies for patients with stage 4 colon cancer with resectable metastases:[139]

Resection following preoperative chemotherapy with the addition of vascular endothelial growth factor (VEGF) or epidermal growth factor receptor if required (EGFR)
Resection following preoperative immunotherapy with pembrolizumab, nivolumab, nivolumab and ipilimumab, or dostarlimab (for patients with dMMR/MSI-H or POLE/POLD mutation)
Resection followed by postoperative chemotherapy in combination with either VEGF or EGFR.

Unresectable metastatic (stage 4) or medically inoperable colorectal cancer

Treatment is part of a palliative rather than curative approach, with goals of prolonging overall survival and maintaining quality of life.

Systemic therapy is the mainstay of treatment, but liver-directed therapy such as microwave ablation, hepatic artery infusion, transarterial chemoembolisation, or radioembolisation may be utilised.[290][291][292]

Survival estimates for patients with disseminated disease receiving best supportive care are about 6 months. The use of fluorouracil/folinic acid can increase survival to approximately 10-12 months; oxaliplatin plus fluorouracil/folinic acid and irinotecan plus fluorouracil/folinic acid can increase survival to 20-21 months.[293][294] The addition of a biological agent to this backbone prolongs survival to approximately 27-33 months.[295]

Systemic therapy

The majority of patients with unresectable stage 4 colorectal cancer will receive a two-drug chemotherapy backbone and a vascular endothelial growth factor (VEGF) inhibitor or an epidermal growth factor receptor (EGFR) antagonist.[296]

The chemotherapy backbone is generally fluorouracil/folinic acid with oxaliplatin (FOLFOX or FLOX) or irinotecan (FOLFIRI). Capecitabine can be substituted for fluorouracil/folinic acid with equal efficacy when used in combination with oxaliplatin; toxicity precludes the use of capecitabine plus irinotecan.[293][297][298] In pooled analysis, FOLFOXIRI (fluorouracil/folinic acid with oxaliplatin and irinotecan) increased survival by 25% compared with FOLFOX or FOLFIRI.[299] However, FOLFOXIRI also increased toxicity by 25%, and its use is limited to those patients with good performance status.

Vascular endothelial growth factor (VEGF) inhibitors

Bevacizumab, a VEGF-A inhibitor, improves progression-free and/or overall survival when combined with both oxaliplatin- and irinotecan-containing regimens in front-line and subsequent lines of therapy, including when bevacizumab is continued after progression on a bevacizumab-containing regimen.[300][301][302][303][304][305][306][307] However, bevacizumab may increase the risk of bleeding.[129][139][302][304][308]

Two other VEGF inhibitors, aflibercept and ramucirumab, are approved for use in combination with FOLFIRI after progression on an oxaliplatin-containing regimen.[309][310]

Epidermal growth factor receptor (EGFR) antagonists

In the NRAS and KRAS wild-type patient population with metastatic colorectal cancer, cetuximab or panitumumab can be used in combination with oxaliplatin- and irinotecan-containing regimens in front-line or subsequent lines of therapy, and as single agents after progression on at least one line of systemic therapy.[311][312][313][314] [ ] [Evidence A] Except for patients with tumours having KRAS G12C mutation, those with tumours having mutations in exons 2, 3, or 4 of KRAS or NRAS genes should not be treated with cetuximab or panitumumab, either alone or in combination with chemotherapy agents, as no benefit may be seen.[129][139][314] The American Society for Clinical Pathology guideline recommends testing for EGFR signalling pathway genes for mutations since they behave as negative predictors of benefit to anti-EGFR therapies in colorectal cancer.[315][316]

Addition of panitumumab to fluorouracil and folinic acid maintenance therapy significantly improved progression-free survival compared with fluorouracil and folinic acid alone in patients with RAS wild-type metastatic colorectal cancer (following induction therapy with fluorouracil, folinic acid, and oxaliplatin plus panitumumab).[317]

One randomised clinical trial that compared addition of panitumumab versus bevacizumab to first-line chemotherapy reported significant improvement in overall survival in patients with left-sided tumours and in the overall population with panitumumab plus chemotherapy, compared with bevacizumab plus chemotherapy.[318]

Outcomes and patient selection

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.[295] FOLFOXIRI with bevacizumab yields improved progression-free survival, but not overall survival, compared with FOLFIRI and bevacizumab in the front-line setting.[319] However, this combination is associated with significant toxicity and is reserved for only the fittest patients.[319]

Most commonly in the US, front-line 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.[139]

Most, but not all, studies support the use of a maintenance strategy (fluorouracil/folinic acid or capecitabine and bevacizumab) after 6-8 cycles of front-line therapy with FOLFOX or CapeOX with bevacizumab, with the re-addition of oxaliplatin at the time of progression.[320][321][322][323][324] Meta-analyses of RCTs report that, in patients with metastatic colorectal cancer:[325][326]

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.

At the time of progression on an oxaliplatin- and bevacizumab-containing regimen, patients with preserved performance status can be switched to FOLFIRI and bevacizumab. Alternatively, bevacizumab can be substituted for aflibercept or ramucirumab or, if the patient is KRAS and NRAS wild type, to cetuximab or panitumumab.[327] The regimen is continued until progression, either with maintenance or with treatment breaks. At progression, the patient can be considered for an anti-EGFR therapy, if not already received, or agents such as regorafenib or trifluridine/tipiracil.

Patients who have progressed on all other lines of therapy

Regorafenib is an oral multikinase inhibitor with anti-VEGF properties. After progression on all other lines of therapy, regorafenib as a single agent modestly improves survival compared with placebo.[328][329][330] The National Institute for Health and Care Excellence in the UK recommends regorafenib for treating adults with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-based chemotherapy, anti‑VEGF therapy, and anti‑EGFR therapy, or for treating those who found these treatments unsuitable.[331]

Trifluridine/tipiracil is an oral combination drug containing trifluridine, a thymidine-based nucleic acid analogue 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 randomised, 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.[332] 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 EGFR inhibitor (if RAS wild type).[333][334] The bevacizumab combination is preferred over trifluridine/tipiracil alone.[129][139]

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.[335][336][337] Fruquintinib may be an option for the treatment of metastatic colorectal cancer that has progressed through all other available regimens.[129][139] It can be given before or after trifluridine/tipiracil or regorafenib; data regarding the best order of therapies are limited.[129][139]

Unresectable or metastatic MSI-H or dMMR colorectal cancer

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 colorectal cancer who have not previously been treated with an immune checkpoint inhibitor.[129][139]

Pembrolizumab is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as first-line treatment for patients with unresectable or metastatic MSI-H or 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.[338][339][340]

Pembrolizumab monotherapy is also approved for patients with MSI-H or dMMR unresectable or metastatic colorectal cancer who have received previous fluoropyrimidine-based combination therapy.[129][139] The National Institute for Health and Care Excellence (NICE) in the UK recommends pembrolizumab therapy as an option in these patients, only if treatment with nivolumab plus ipilimumab is not feasible.[341]

Nivolumab, and nivolumab plus ipilimumab, have received accelerated approval from the US FDA and approval from the EMA to treat patients with unresectable or metastatic solid tumours that have been identified as MSI-H or dMMR.[342] These therapies may be considered as first-line treatment or as subsequent therapy for colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.[129][139]

Dostarlimab is approved by the FDA for dMMR recurrent or advanced solid tumours that have progressed on or following prior treatment and who have no satisfactory alternative treatment options. One prospective phase 2 study is underway, looking at the effect of dostarlimab, a PD-1-blocking monoclonal antibody, on patients with mismatch-repair deficient (dMMR) locally advanced stage 2 or 3 rectal adenocarcinoma.[343] Preliminary results have been published after 12 patients completed 6 months of treatment and underwent at least 6 months of follow-up. All 12 patients had a complete clinical response, with no evidence of tumour on imaging (magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography), endoscopic visualisation, digital rectal examination, or biopsy. No adverse events of grade 3 or higher were reported during the period of follow-up.[344] This suggests that dMMR locally advanced rectal cancer is highly sensitive to single-agent PD-1 blockade, but longer follow-up is needed to assess the duration of response.

The most common all-grade adverse effects are anaemia, fatigue, and dysphagia. The most common grade 3 or higher adverse effects are neutropenia, hypertension, increased lipase, and lymphopaenia.[345] Toxicity profiles of PD-1 or PD-L1 inhibitor-based combination therapies have been published.[345]

Unresectable or metastatic BRAF V600 mutation colorectal cancer

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.[129][139][346]

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).[347] 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).[347] Anti-EGFR therapy may be considered in patients with BRAF mutations other than V600E.[129][139]

Unresectable or metastatic NTRK gene fusion positive colorectal cancer

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.[129][139]

Unresectable or metastatic KRASG12C-mutated colorectal cancer

KRAS G12C inhibitors (e.g., sotorasib, adagrasib) may be considered with or without EGFR inhibitors for tumours that harbour the KRAS G12C mutation.[129][139][348][349][350] Treatment with sotorasib or adagrasib alone can be considered in patients who are unable to tolerate EGFR inhibitors owing to their toxicity.[129][139] 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.[348][351][352]

Unresectable or metastatic HER2-positive colorectal cancer

Trastuzumab deruxtecan monotherapy, or trastuzumab in combination with pertuzumab, lapatinib, or tucatinib may be used as a treatment option for HER2-amplified tumours that are also RAS and BRAF wild type.[129][139][353] 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.[129][139][354]

Unresectable or metastatic RET gene fusion positive mutation colorectal cancer

Selpercatinib, a CNS-active RET kinase inhibitor, has shown promise in the open-label, basket trial LIBRETTO-001 trial comprising patients aged 18 years and older with RET-altered cancers.[355][356] It may be used in patients with unresectable or metastatic RET gene fusion positive mutation colorectal cancer.[129][139]

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