Clinical Review - Colorectal cancer

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

Colorectal cancer: resection is usually the treatment of choice (Photograph: SPL)
Colorectal cancer: resection is usually the treatment of choice (Photograph: SPL)

Section 1: Epidemiology and aetiology

Colorectal cancer (CRC) is the third most common cancer in the UK following breast and lung cancer. More than 41,000 people are diagnosed each year.

CRC is rising in incidence. According to Cancer Research UK, the lifetime risk for men almost doubled between 1975 and 2008. For men, it has risen from 3.5% (one in 29) to 6.9% (one in 14) and for women, from 3.9% (one in 26) to 5.4% (one in 19).

CRC causes 16,000 deaths a year and is the second most common cause of cancer death. More than 86% of cases arise in people who are aged over 60.

Risk factors include family history. If a first-degree relative is diagnosed 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.

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.

The other 5% of cases develop in those with inherited syndromes such as familial adenomatous polyposis, often developing at a much younger age.

The risk of CRC is increased with the presence of other medical 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 less exercise.

It is difficult to estimate the exact contribution of different foodstuffs, but high fibre would seem to be protective, while frequent consumption of red meat increases the risk.

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, patients are increasingly being detected when asymptomatic, with earlier stage disease and therefore a better prognosis.

Faecal occult blood test
The NHS Bowel Cancer Screening Programme offers faecal occult blood testing (FOBT) to all people aged 60-69. This 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 with antibodies to globin, and faecal DNA testing for 23 differing DNA alterations found in CRC. These tests are being evaluated in population studies.

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%.1

CT pneumocolon versus colonoscopy
In a landmark study, 2,600 patients underwent both CT pneumocolon (CTC) and colonoscopy.2 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.There were extra colonic findings identified in 66%, that may necessitate further investigations in 16%.

This may be a benefit in detecting asymptomatic ovarian pathology, for example, but may increase patients' anxiety because of the need for further imaging. In addition, after CTC, 17% of patients would go on to have a colonoscopy, with 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.3 Having had a colonoscopy in the preceding 10 years decreases the incidence of CRC by 77%.4 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%).5

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

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.

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.

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 below).

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

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 5FU (FOLFOX) after surgical resection of stage III (Dukes C) cancer.6,7

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, and adjuvant chemotherapy in patients with Dukes B cancer must be weighed against potential side-effects.

Advanced age is not a contraindication for adjuvant therapy, although recent evidence suggests that 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 of treatment, apart from very early stage rectal tumours, which may be amenable to transanal endoscopic microsurgery.8,9 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.10 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. 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 combined with oxaliplatin or irinotecan are administered with or without the addition of targeted novel biologics.11 Metastatic colorectal 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.

Recent advances have allowed the incorporation of biological therapies in different lines of treatment in the advanced setting.

Molecular characterisation to assess driver mutations such as KRAS is now routine. KRAS mutations predict for lack of response to the anti-EGFR monoclonal antibody cetuximab. Bevacizumab, a monoclonal antibody targeting tumour angiogenesis, has proven efficacy and is employed with combination chemotherapy in this setting.

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, the five-year survival rate with adjuvant chemotherapy reaches up to 86% and 73% respectively.12

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 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 lifestyle advice.

Section 5: Case study

A 67-year-old patient with rectal bleeding was diagnosed with adenocarcinoma of the ascending colon in 2009 following colonoscopy and biopsy. Other symptoms were intermittent lower abdominal pain and lethargy.

A staging CT scan excluded distant disease and the patient later had a left hemicolectomy. Histopathological diagnosis confirmed resected poorly differentiated adenocarcinoma with 4/16 lymph nodes positive for tumour involvement. Overall staging was Dukes C cancer.

The patient was commenced on adjuvant FOLFOX chemotherapy. This was stopped after five months due to oxaliplatin-related peripheral neuropathy.

On the one-year surveillance CT scan, he was found to have a solitary metastatic liver lesion. His case was discussed by the multidisciplinary team.

Following NICE guidance, he underwent four months of combination chemotherapy (FOLFIRI plus cetuximab). His treatment was complicated by a cetuximab-induced rash, which was managed by topical steroidal cream and oral lymecycline. He achieved a partial response and underwent a hemi-hepatectomy in January 2011 with no postoperative morbidity.He later presented with symptoms of weight loss, lethargy and increased carcinoembryonic antigen.

Disease relapse was confirmed on CT scan showing two new liver lesions and three sub-centimetre nodules in the left lung. Further chemotherapy with FOLFOX and bevacizumab was recommended. The patient had a good performance status and the previous neuropathy was almost resolved.

His most recent imaging after three months of this treatment demonstrated good response (see images below). He continues to tolerate chemotherapy well and will continue treatment for three months, switching to maintenance with 5FU and bevacizumab until disease progression.

Section 6: Evidence base

Guidelines

Online

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

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.
  • Access the National Cancer Action Team website (www.ncat.nhs.uk/) and use its tools and information to improve the diagnosis of CRC in primary care.
  • Contributed by By Dr Amitesh Roy, clinical research fellow, Dr Julian Teare, consultant gastroenterologist, Dr Sheela Rao, consultant medical oncologist, and Professor David Cunningham, consultant medical oncologist, The Royal Marsden NHS Foundation Trust, London.

References
1. Atkin WS, Edwards R, Kralj-Hans I et al. Lancet 2010; 375(9726): 1624-33.

2. Johnson CD, Chen MH, Toledano AY et al. N Engl J Med 2008; 359(12): 1207-17.

3. Zauber AG, Winawer SJ, O'Brien MJ et al. N Engl J Med 2012; 366(8): 687-96.

4. Brenner H, Chang-Claude J, Seiler CM et al. Protection from colorectal cancer after colonoscopy: a population-based, case-control study. Ann Intern Med 2011; 154(1): 22-30.

5. Imperiale TF, Glowinski EA, Lin-Cooper C et al. Five-year risk of colorectal neoplasia after negative screening colonoscopy. N Engl J Med 2008; 359(12): 1218-24.

6. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Lancet 1995; 345(8955): 939-44.

7. Andre T, Boni C, Navarro M et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009; 27(19): 3109-16.

8. Steele RJ. Anterior resection with total mesorectal excision. J R Coll Surg Edinb 1999; 44(1): 40-5.

9. Tsai BM, Finne CO, Nordenstam JF et al. Transanal endoscopic microsurgery resection of rectal tumors: outcomes and recommendations. Dis Colon Rectum 2010; 53(1): 16-23.

10. Sauer R, Becker H, Hohenberger W et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351(17): 1731-40.

11. Chau I, Cunningham D. Treatment in advanced colorectal cancer: what, when and how? Br J Cancer 2009; 100(11): 1704-19.

12. O'Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 2004; 96(19): 1420-5.

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