Surgery forms the mainstay of treatment for colon cancer except in those patients with widespread metastases and limited life expectancy. It restores the normal function of the bowel (either through anastamosis or stoma), relieves obstruction and removes the primary tumour. Adjuvant therapies are used when there is nodal involvement (chemotherapy) or invasion of adjacent structures (radiotherapy).
Surgery
Regardless of the tumour site within the colon, all patients undergo similar preparation to remove as much faeces from the bowel as possible. This is generally not possible in emergency cases.
- Low residue diet for 2 days
- Fluid diet for 1 day
- Active bowel preparation the night prior to surgery
- Parenteral antibiotics prior to surgical incision
- Low molecular weight heparin and other DVT prophylaxis measures
The surgical technique used depends on the site of disease and the underlying vascular supply of the colon (ileocolic, right colic, middle colic from superior mesenteric artery, and the left colic and superior rectal artery from the inferior mesenteric artery).
- Right hemicolectomy removes the terminal ileum, caecum, ascending and proximal half of the transverse colon. It is indicated for tumours arising in the caecum or ascending colon.
- Transverse colectomy removes the transverse colon, hepatic and splenic flexures.
- Left colectomy removes the distal transverse colon, the descending colon and the sigmoid colon.
- Subtotal colectomy removes all parts of the colon except the rectum. It is used when there are synchronous primaries of the right and left sides of the colon.
The two ends of bowel are then stapled or sutured together. In most cases, a temporary loop ileostomy is created to allow the anastamotic site to heal.
Outcomes with Surgery Alone
Surgery remains an excellent treatment for stage I tumours. Patients have 5 year survival of up to 95% without additional therapy. For patients with stage II tumours (T3-4b) control with surgery alone falls significantly (60-80%) and for those with stage IIIA/B disease a similar outcome is seen. Stage IIIC disease has the worst outcomes outside of metastatic disease with survival after surgery alone of 30-40%.
Adjuvant therapies are therefore considered for patients with disease stage greater than I.
Adjuvant Systemic Therapy
It is a long held belief that cancers of the colon tend to recur at distant sites whereas cancers of the rectum recur locally. This has shaped the development of adjuvant therapies, with chemotherapy the main focus of interest for colon cancer.
Stage II disease
Recommendations in stage II disease are controversial. 5-FU studies have shown non-significant results but with trends towards better outcomes with high risk stage II disease (eg high grade, stage T4). The initial FOLFOX study (MOSAIC) demonstrated equivalent survival in patients who received FOLFOX vs 5-FU based regimens. There have been many studies, most with non-significant results. Meta-analysis of these studies show some benefit (eg. 5-year survival 82% vs 80%, not significant). Patients require discussion with a medical oncologist regarding their personal risks, and recommendations may be more definite for patients with higher stage II disease (eg. T4a or T4b) or high grade tumours.
Studies of patients with mismatch repair deficiency has shown that those with intact mismatch repair respond better to 5-fluorouracil based chemotherapy, and patients with MMR deficiency may do worse with systemic therapy. It is important to test tumours for the presence of MMR defects and avoid chemotherapy Stage II patients with this problem.
Stage III disease
In contrast to Stage II disease, patients with lymph node involvement have been repeatedly shown in a large number of randomised controlled trials to derive benefit from adjuvant chemotherapy. Initial studies with 5-fluorouracil and leucovorin followed by the MOSAIC study which incorporated oxaliplatin have led to the current use of the FOLFOX (leucovorin, 5-fluorouracil and oxaliplatin) regimen. This is given every 2 weeks for 12 cycles.
Non-cytotoxic therapies
Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), is used in metastatic disease with improved outcomes. In locally advanced cases, bevacizumab has been demonstrated to cause more toxicity with no improvement in outcomes and is not recommended.
Cetuximab, a monoclonal antibody directed against the ERBB1/EGFR receptor, has been shown to have no impact on outcomes in stage III disease.
Adjuvant Radiotherapy
In contrast to chemotherapy, radiotherapy has not been extensively studied in colon cancer due to the feeling that tumours are unlikely to recur locally. This is very true for tumours of the colon where the colon is located within the peritoneum (eg. caecum, transverse colon and sigmoid colon). These sites allow surgeons to obtain wide margins. For other sites within the colon, surgical resection is more limited and this raises the possibility of local recurrence. This is particularly true when tumours have invaded adjacent structures (eg. T4b tumours) which are far more likely in those anatomic sites where the colon is retroperitoneal.
In a series from Massachusetts patients with T4b tumours, both node negative and positive, there was a significant increase in local control and relapse free survival when radiotherapy was employed. This suggests that radiotherapy is useful in these select situations.
Most would recommend a discussion at least of radiotherapy for patients with T4b tumours or for those with positive margins.
Adjuvant radiotherapy to the liver has not been shown to impact local control or survival from colon cancer. Adjuvant whole-abdominal radiotherapy was also proposed for high risk patients but survival advantages were also not seen. These approaches are only used in trial settings.
Metastatic Disease
Stage IVA disease
For patients with metastasis localised to a single organ, aggressive management is typically indicated. This was initally based on retrospective data that examined the 5-year survival in patients who had liver lesions resected versus those who did not; 5 year survival in the former group was 25% compared to 0% in the latter. Most evidence comes from liver and lung oligometastases.
Resectable Liver Metastases
Patients should be evaluated by a liver surgeon and undergo resection of the primary tumour and liver metastases synchronously if possible. Resectable patients are those with operable primary disease, operable metastatic disease, and no other unresectable tumour in other locations. Patients must also be fit enough to undergo curative resection. If patients fit these criteria, about 30% will be cured despite the presence of metastatic disease.
Inoperable Patients
Patient unable to receive surgery can be offered a variety of non-surgical techniques.
Radiofrequency Ablation
The most widespread option is radiofrequency ablation, which is preferred due to its outpatient nature and visibility on imaging. This is not appropriate for all lesions (eg. near large vessels due to loss of heat, or near other critical structures such as bowel or lung). When compared to surgical excision, which has randomised data showing survival improvements, RFA is significantly lacking in outcomes and remains an option only for surgically unfit patients.
Other Ablative Techniques
Other ablative technques include hyperthermia, cryotherapy,
External Beam Radiotherapy
Stereotactic Radiotherapy remains a potential option in medically inoperable patients, but evidence is limited. Patient should ideally be enrolled onto a clinical trial if possible. Case series suggest good local control for inoperable patients but there is no randomised evidence. Doses range from 50 Gy in 5# to 60 Gy in 3#.
In patients with unresectable disease due to the size of involvement, neoadjuvant chemotherapy with FOLFOX or FOLFIRI can be considered. Restaging after 2 months to determine reduction in size of metastases may allow resection to occur at that time.
Local Drug Therapies
Most hepatic tumours over 0.5 cm draw their blood supply from the hepatic artery. This is in contrast to the hepatocytes which obtain most of their supply through the portal system. Injecting chemotherapy preferentially into the hepatic artery has been viewed as a way to localise the impact of systemic therapies to the metastatic disease within the liver. When performing these techniques, it is important to ensure that the liver tumours will receive the therapy (ie. they receive supply from the hepatic artery) and there is not sufficient on-flow of drug to other organs (eg. lung). This can be assessed with technitium nuclear medicine scans.
Evidence supporting TACE in the liver shows benefit when compared to systemic 5-fluorouracil. This is in contrast to modern systemic therapies (FOLFOX, FOLFOXIRI) and it is not known whether TACE has a role in the setting of these modern therapies. TACE has not been shown to increase overall survival in meta-analysis.
Ytrrium Microspheres
90Y microspheres remain a controversial topic. Instead of chemotherapy coupled with beads, beads can be combined with yttrium-90. The beads become stuck in tumour vessels and deliver a local, high dose of radiation. There have been controlled trials exploring the role of yttrium microspheres, suggesting improved local control when compared to systemic therapy. There is no overall survival benefit seen. Criticisms of the trials include poor reporting of adverse events, small patient numbers and poor responses in the control arms.
The role of 90Y microspheres appears limited to those patients who have unresectable disease with sufficient hepatic reserve that are also not suitable for radiofrequency ablation. Similar to TACE, it is vital to perform pre-treatment imaging with technitium to ensure there is limited dose to the remainder of the body. The benefit versus trans-arterial chemotherapy is not clear. The treatment is also highly costly.
Resectable Lung Metastases
Similar guidelines to liver metastases are used. Radiotherapy has similar indications. Long term survival is possible, particularly if metastases are metachronos (over 1 year between primary and metastasis developing).
Stage IVB disease
Patients may still require surgery to prevent bowel obstruction. Symptomatic patients should always receive surgery unless life expectancy is very short (days-weeks). Asymptomatic patients may not require surgery (NSABP trial showed no adverse events with chemotherapy alone). There is debate as to the role of resection versus end-stoma only, but there is no randomised evidence to guide surgical technique.
Modern chemotherapy is typically FOLFOX or FOLFIRI. Cetuximab and bevacizumab have also shown benefit when used in combination; the evidence is not as strong for first line use. FOLFOXIRI has not been shown to be more effective than FOLFOX or FOLFIRI alone.
An important mutation to test for is k-Ras. Wild-type k-Ras tumours will respond to cetuximab, whereas mutated k-ras tumours will usually resist cetuximab as the mutation is downstream to the receptor. Bevacizumab or cytotoxic agents are preferred in patients with the mutated k-Ras gene.
