Clinical Review: Colorectal cancer

Asymptomatic patients are increasingly being detected by the bowel cancer screening programme.

CRC incidence up 6% in 10 years (SPL)
CRC incidence up 6% in 10 years (SPL)

Section 1  Epidemiology and aetiology

Colorectal cancer (CRC) is the fourth most common cancer in the UK, with more than 41,000 new cases diagnosed annually.

In men, it is the third most common cancer after prostate and lung cancer and in women, it is the third most common cancer after breast and lung cancer. CRC incidence rates have increased by 6% over the past decade.

According to Cancer Research UK, the lifetime risk for men more than doubled between 1975 and 2010. For men, it has risen from 3% (one in 29) to 7% (one in 14) and for women, from 4% (one in 26) to 6% (one in 18).

CRC causes more than 16,000 deaths a year and is the second most common cause of cancer death. Increasing age is strongly associated with CRC risk and 95% of cases arise in people aged 50 and over.

In the UK, between 2009 and 2011, 43% of cases were diagnosed in patients aged 75 and over.1

More than 95% of sporadic CRC develops from benign adenomas in the bowel. One in four adults will develop an adenoma by age 50 and half of all adults by age 70.

An adenoma that is 1cm across has a 1:6 chance of developing into CRC over 10 years.

Other risk factors include family history. If a first-degree relative is diagnosed with CRC over the age of 60, the risk is 1:12; if below 60 or with two first-degree relatives involved, the risk rises to 1:6.

Approximately 5% of CRC cases develop in those with inherited syndromes, such as familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer, also known as Lynch  syndrome.

Lynch syndrome is the most common hereditary syndrome, accounting for 1-4% of all colon cancers, whereas FAP accounts for <1% of cases. FAP is usually caused by mutations in the adenomatous polyposis coli tumour suppressor gene, whereas Lynch syndrome is associated with germline mutations in the mismatch repair genes: MSH2, MLH1, MSH6, PMS1 and PMS2.

The Amsterdam criteria and Bethesda guidelines are commonly used to identify patients at risk of developing Lynch syndrome.2,3

The mismatch repair genes encode for proteins which normally repair bases that are incorrectly added to, or deleted from, microsatellites (segments of nucleotide repeats) during DNA replication.
In the presence of mutated mismatch repair genes, base repair mechanisms are ineffective, leading to microsatellite instability (MSI).

In practice, immunohistochemistry involving antibodies against the proteins corresponding to the mismatch repair genes is used as a surrogate for MSI.

MSI is not unique to patients with Lynch syndrome; about 15% of sporadic colon cancers exhibit MSI as a result of somatic hypermethylation of the MLH1 promoter.

These tumours characteristically harbour somatic BRAF mutations, so testing for the presence of BRAF mutations can help to differentiate between Lynch syndrome and sporadic cases with evidence of MSI.4

The risk of CRC is increased in the presence of other conditions, particularly acromegaly and inflammatory bowel disease, but also obesity and type 2 diabetes. Part of the increased incidence over the past two decades may be explained by the rise in body weight and frequency of associated diabetes, driven by high-calorie foods and lack of exercise.

It is difficult to estimate the exact contribution of different foodstuffs, but high fibre and dietary or supplementary calcium would seem to be protective, whereas moderate to high levels of alcohol and frequent consumption of red meat increase the
risk.1,5-7

Physical activity has been shown to decrease the risk of CRC. A meta-analysis demonstrated a 24% reduction in the risk of colon cancer when comparing the most active with the least active individuals.1,6

Section 2  Making the diagnosis

The most common symptoms of CRC are rectal bleeding associated with a change in bowel habit, most often with an increase in stool frequency, a sensation of incomplete emptying or straining.

Weight loss suggests more advanced disease. Iron deficiency anaemia as a consequence of occult blood loss suggests right-sided colonic tumours. Abdominal bloating with a reduction in stool frequency, increased borborygmi and visible peristalsis may indicate impending obstruction.

On examination, an abdominal mass may be detected, particularly with right-sided tumours. A palpable liver may also indicate metastatic disease. Any patient with rectal bleeding should have a digital rectal examination.

With the advent of the NHS Bowel Cancer Screening Programme (NHSBCSP), patients are increasingly being detected when asymptomatic, with earlier stage disease and a better prognosis.
Faecal occult blood test

The NHSBCSP offers faecal occult blood testing (FOBT) every two years to all people aged 60-69. The age is currently being extended to 74.

FOBT seems to be less sensitive for right-sided colon cancer.

Conventional FOBT uses the guaiac test, which can give false positives with red meat in the diet. The use of three consecutive tests increases the sensitivity to 92%.

Alternative tests include faecal immunochemical testing (FIT) with antibodies to globin, and faecal DNA testing for 23 DNA alterations found in CRC.

A recent study compared a multi-target stool DNA test with a FIT test in patients with an average risk of CRC and found the multi-target stool test detected significantly more cancers than FIT, but was associated with more false positives.8

Flexible sigmoidoscopy
Results from a large population-based study showed that for patients attending screening, flexible sigmoidoscopy reduces the incidence of CRC by 33% (50% for distal cancers) and mortality by 43%.9

CTC versus colonoscopy
In a landmark study, 2,600 patients underwent CT pneumocolon (CTC) and colonoscopy.10 In 17%, a 1cm polyp was identified by CTC, but only one in four of these patients had such a polyp and in addition, 10% of polyps >10mm were missed. Extra colonic findings were identified in 66%, which might necessitate further investigations in 16%.

There could be a potential benefit in detecting asymptomatic ovarian pathology, for example, but this could increase patients’ anxiety because of the need for further imaging. In addition, after CTC, 17% of patients would need to have an additional colonoscopy, requiring a second bowel preparation.
Newer techniques using minimal bowel preparation and faecal tagging may increase the acceptability of CTC.

Colonoscopy
Colonoscopy enables the detection and removal of adenomas. Polypectomy reduces subsequent cancer risk by 53% over 23 years.11 Having had a colonoscopy in the preceding 10 years decreases the incidence of CRC by 77%.12 Having a negative colonoscopy confers great protection.

In the Indianapolis physicians’ study, 17,000 doctors were invited to undergo screening colonoscopy, with higher-risk individuals excluded. After 18 years, the standardised mortality ratio reduced to 0.35.

Having a normal colonoscopy is reassuring; in 2,436 individuals with a negative index colonoscopy at five-year follow-up, no cancers were detected. A total of 201 adenomas (16%) were found, of which 19 had advanced histology (1.3%).13

A more recent study evaluated the association between adenoma detection rate and the risks of subsequent CRC diagnosed six months to 10 years after colonoscopy and cancer-related death. The adenoma detection rate ranged from 7.4-52.5%.

The study found that adenoma detection rate was inversely associated with the risks of interval CRC, advanced stage interval cancer and fatal interval cancer.

The findings may be explained by the enhanced detection of precancerous lesions, although other factors, such as completeness of adenoma resection, may be involved.14

Results from another study investigating long-term mortality after adenoma removal were publishedthis year. They concluded that after a median 7.7 years of follow-up, CRC mortality was lower among patients who had low-risk adenomas removed and moderately higher among those who had high-risk adenomas removed, compared with the general population.15

In low-risk individuals after a negative colonoscopy, most clinicians would advocate a second look in seven to 10 years. However, with the presence of any new symptoms, further colonoscopy is advised.

The most appropriate test depends on local expertise and availability. The more invasive tests confer greater protection, but have a lower patient acceptability rate.

Evidence continues to emerge that screening leads to prevention and early detection.16

Section 3  Managing the condition

For most patients with localised disease, resection will be the treatment of choice, with consideration given to adjuvant chemotherapy.

Definitive surgery includes removal of the affected bowel segment with its mesentery, vascular pedicle and draining lymph nodes.

Dukes’ classification of bowel cancer (Astler-Coller modification)

Dukes A    Tumours invade through the muscularis mucosae into the submucosa but do not reach the muscularis propria

Dukes B1    Tumours invade into the muscularis propria

Dukes B2    Tumours completely penetrate the smooth muscle layer into the serosa

Dukes C     Tumours encompass any degree of invasion but are defined by regional lymph node involvement

Dukes C1    Tumours invade the muscularis propria with fewer than four positive nodes

Dukes C2    Tumours completely penetrate the smooth muscle layer into the serosa with four or more involved nodes

Dukes D    Lesions with distant metastases

Adjuvant chemotherapy
Patients who have had potentially curative resections of CRC with no residual disease (margin negative resection) may require adjuvant chemotherapy, depending on the stage of their disease (see box).

In the past decade, clinical trials have shown significant survival benefit from six months of adjuvant chemotherapy with 5FU or capecitabine and combination chemotherapy with oxaliplatin and fluoropyrimidine (5FU or capecitabine, that is, FOLFOX or CAPOX) after surgical resection of stage III (Dukes C) cancer.17-22

Patients with Dukes B cancer can achieve a modest absolute survival benefit of 3.6% over five years, with no benefit seen in patients over 70,23 and adjuvant chemotherapy in patients with Dukes B cancer must be weighed against potential side-effects, individual risk factors and patient preference.

Evaluation of mismatch repair gene status guides chemotherapy decisions in patients with Dukes B cancer. Deficient status is associated with a better prognosis and these patients do not benefit from fluoro­pyrimidine chemotherapy.24

Advanced age is not a contraindication for adjuvant therapy, although recent evidence suggests patients over 70 derive less benefit from combination chemotherapy than younger counterparts. Ideally, adjuvant chemotherapy should start six to eight weeks after resection.

Adjuvant radiotherapy
Patients with positive margins following resection in whom further surgery is excluded could be considered for adjuvant radiotherapy with or without concurrent chemotherapy.

Rectal tumours
In patients with tumours that have low risk of positive circumferential resection margin, total mesorectal excision surgery is the primary modality, apart from very early stage rectal tumours, which may be amenable to transanal endoscopic microsurgery.25,26 In selected cases, short-course neoadjuvant radiotherapy may be considered to reduce the risk of local recurrence.

Those with low or poor prognosis tumours with a threatened circumferential resection margin may benefit from neoadjuvant long-course chemoradiation that downstages the tumour and may allow for sphincter-preserving surgery.27

This is usually delivered over five to six weeks with concurrent capecitabine, followed by reassessment for rectal surgery. Low rectal tumours may require abdominal perineal resection, which results in a permanent stoma bag.

Patients with rectal cancer who have positive margins postoperatively and did not receive preoperative chemoradiation should be offered postoperative chemoradiation.

Advanced CRC
Approximately 25% of bowel cancer patients present with metastatic disease and almost 50% will develop metastases.28 Treatment for each patient takes account of factors such as performance status, previous therapy, extent of metastatic disease and tumour genetic profile.

Traditionally, multiple lines of chemotherapy using a 5FU backbone or its oral pro-drug capecitabine combined with oxaliplatin or irinotecan are administered with or without targeted novel biologics.29,30

Metastatic CRC patients with only one or limited sites (oligometastatic) of metastatic disease should be considered for systemic chemotherapy followed by consolidative localised treatment, including liver resection, radiofrequency ablation, selective internal radiation therapy spheres or external beam radiotherapy/cyberknife.

Patients who undergo curative resection for solitary liver metastases have a 20-45% five-year overall survival rate.28 Similar survival benefit has been reported in patients suitable for resection of isolated lung metastases.

Recent advances have allowed the incorporation of biological therapies in different lines of treatment in the advanced setting. In the first-line setting, in patients with a good performance status, options include FOLFOX (5FU with oxaliplatin), CAPOX (capecitabine and oxaliplatin) or FOLFIRI (5FU with irinotecan).

Molecular characterisation to assess for the presence of certain mutations is now routine clinical practice, as this dictates the choice of biological therapies that can be administered alongside chemotherapy.

The presence of RAS mutations predicts for lack of response to the anti-EGFR monoclonal antibodies, cetuximab and panitumumab. Therefore only patients with a RAS wild type status have the option of receiving cetuximab or panitumumab in addition to the chemotherapy backbone.

Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor that can be administered in addition to chemotherapy in all patients with metastatic CRC, irrespective of RAS status.

Currently there is no definitive evidence to support the use of cetuximab- over bevacizumab-based regimens in the first-line setting of RAS wild type CRC.

Therefore, the choice of chemotherapy backbone and biological agent is based on the preference of the patient and the treating oncologist. In elderly patients deemed unsuitable for oxaliplatin- or irinotecan-based chemotherapy, a trial conducted in patients aged 70 years or older showed that a combination of capecitabine and bevacizumab is effective and well-tolerated.31

In the second-line metastatic setting, treatment options include combining FOLFIRI with the newer anti-angiogenic agent aflibercept in patients whose disease progressed following oxaliplatin-based chemotherapy,32 or FOLFOX/CAPOX in patients who have already received irinotecan-based chemotherapy. Bevacizumab can be added to the chosen chemotherapy regimen if this was not given first-line.

In RAS wild type patients, cetuximab can be given in the second-line setting in combination with irinotecan-based chemotherapy if this has not been given first-line.

In the third-line setting, cetuximab monotherapy remains an option for patients with RAS wild type if this has not been given before. Regorafenib, an anti-angiogenic tyrosine kinase inhibitor with the advantage of oral administration, has evidence for its use following all other standard therapies, irrespective of RAS status.33

However, regorafenib is currently not accessible for NHS patients in the UK. For patients in England, aflibercept, bevacizumab and cetuximab can be accessed via the cancer drugs fund if certain indications are met. Outside England, reimbursement would be via local policy.

Biological agents tend to be relatively well tolerated, but do have distinct side-effect profiles. For example, anti-angiogenics can be associated with hypertension and proteinuria, whereas anti-EGFR monoclonal antibodies can cause rash and hypomagnesaemia.

Immunotherapy is an area of much research and has shown promise in some other solid malignancies. This is not currently an established treatment option in CRC, but trials are investigating whether there may be a role for immunotherapy in CRC.

Section 4  Prognosis

The five-year survival rate is >90% for resected Dukes A bowel cancer patients.

For patients with Dukes B and C tumours, five-year survival with adjuvant chemotherapy reaches up to 86% and 73% respectively.34

In the past 10 years, there have been advances in the treatment of metastatic CRC.

The overall survival in the era of 5FU was 11-12 months. However, with the advent of novel drugs, the
average median survival time has doubled and when exposed to multiple lines of therapy, patients routinely survive for longer than two years.

All new cases of bowel cancer should be discussed in a multidisciplinary team meeting.

With new advances and improved survival outcomes, the role of primary care physicians is becoming increasingly important with respect to long-term toxicity management, screening of secondary cancers and family members, and the opportunity to impart appropriate lifestyle advice.

Section 5  Case study

A 59-year-old man presented in June 2010 with a three-month history of altered bowel habit and intermittent rectal bleeding. He was diagnosed with a moderately differentiated adenocarcinoma of the upper rectum, following colonoscopy and biopsy of the rectal tumour.

He had staging investigations which included a CT scan of his chest, abdomen and pelvis and an MRI scan of his pelvis. Metastatic disease was excluded and his disease was staged as T3cN1M0 with extra-mural invasion.

He was offered treatment with preoperative chemo-radiation over six weeks, with concurrent oral capecitabine tablets and 54Gy in 30# of radiotherapy. He completed his chemoradiation in September with a good response and considerable shrinkage in his primary tumour.

In November 2011, he proceeded to surgery with an anterior resection. Histology confirmed moderately differentiated adenocarcinoma with 2/21 lymph nodes positive for tumour involvement. His postoperative CT scan showed no evidence of residual disease.

He completed 12 cycles of adjuvant chemotherapy with FOLFOX from January to July 2011. He encountered no significant toxicity, other than mild peripheral neuropathy from the oxaliplatin, which improved following chemotherapy. His stoma was reversed in November 2011.

A routine surveillance CT scan in December 2011 showed increase in the size of a lung nodule from 5mm to 8mm and this was associated with an increase in his carcinoembryonic antigen tumour marker from three to five.

A PET scan was organised, which demonstrated fluorodeoxyglucose uptake in the right lung nodule and an area of uptake within the lateral aspect of the hepatic dome.

The patient was referred for consideration of resection of his solitary lung metastasis and an MRI liver was requested, which was consistent with a solitary liver metastasis within segment VIII.

Following discussion by the multidisciplinary team, as the patient had a good performance status, the recommendation was to proceed with neoadjuvant chemotherapy followed by consideration of surgery or radiofrequency ablation to the liver metastasis.

In February 2012, he had laser metastasectomy via left thoracotomy and the histology was consistent with metastatic disease from his rectal primary.

Between March and May 2012, the peripheral neuropathy from his adjuvant chemotherapy had fully resolved so he was able to receive oxaliplatin again. He completed four cycles of neoadjuvant chemotherapy with capecitabine and oxaliplatin. His MRI liver demonstrated response to treatment (see images).

He underwent surgical resection of the solitary liver metastasis in July 2012. In September 2012 his postoperative CT scan before commencing adjuvant chemotherapy with capecitabine and oxaliplatin revealed a new isolated pulmonary nodule consistent with metastatic disease.

A CT in December 2012 following completion of four cycles of adjuvant chemotherapy showed the lung nodule was stable. As he was of good performance status, the multidisciplinary team recommended referral for surgical excision. He underwent a right thoracotomy and metastasectomy in January 2013 and the histology was consistent with a colorectal primary. He continued to attend the clinic for surveillance.

Since August 2014, his tumour marker has increased to 18 and a CT scan revealed a new right lung nodule and a hypoattenuating lesion in the liver.

Findings on PET scan were consistent with a solitary left lobe liver metastasis and small right middle lobe lung metastasis. In view of the two sites of disease, the multidisciplinary team recommended chemotherapy to gain control over the disease and for surgery or radiofrequency ablation to be considered following this. He has now commenced second-line chemotherapy in the metastatic setting with FOLFIRI and aflibercept.

Section 6  Evidence base

Guideline

  • NICE. Colorectal cancer: the diagnosis and management of colorectal cancer. CG131. London, NICE, November 2011 (update due for release in 2015).

Online resources

  • European Society of Medical Oncology Clinical Practice Guidelines www.esmo.org/
  • Thanks to Dr Anita Wale, research fellow in clinical radiology, The Royal Marsden Hospital, for case study images

Click here to take a test on this article and claim a certificate on MIMS Learning

  • By Dr Shelize Khakoo, Dr Amitesh Roy, Professor Julian Teare, Dr Sheela Rao, Dr Naureen Starling and Professor David Cunningham.
CPD IMPACT: EARN MORE CREDITS

These further action points may allow you to earn more credits
by increasing the time spent and the impact achieved.

  • Audit your patients who have been diagnosed with CRC in the past five years. How did they present and what can be learned?
  • Ask your local bowel surgeon to give a talk about how GPs can improve their diagnostic skills in CRC.
  • Use the National Cancer Action Team (www.ncat.nhs.uk/) tools and information to improve the diagnosis of CRC in primary care.

Save this article and add notes with your free online CPD organiser at gponline.com/cpd

Take clinical tests and claim certificates for CPD at myCME.com/gp



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Dr Shelize Khakoo, Dr Amitesh Roy, Professor Julian Teare, Dr Sheela Rao, Dr Naureen Starling and Professor David Cunningham recommends

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