Prof David Cunningham MD, Prof Wendy Atkin PhD, Prof Heinz-Josef Lenz MD, Prof Henry T Lynch MD, Prof Bruce Minsky MD, Prof Bernard Nordlinger MD, Naureen Starling MRCP
Substantial progress has been made in colorectal cancer in the past decade. Screening, used to identify individuals at an early stage, has improved outcome. There is greater understanding of the genetic basis of inherited colorectal cancer and identification of patients at risk. Optimisation of surgery for patients with localised disease has had a major effect on survival at 5 years and 10 years. For rectal cancer, identification of patients at greatest risk of local failure is important in the selection of patients for preoperative chemoradiation, a strategy proven to improve outcomes in these patients. Stringent postoperative follow-up helps the early identification of potentially radically treatable oligometastatic disease and improves long-term survival. Treatment with adjuvant fluoropyrimidine for colon and rectal cancers further improves survival, more so in stage III than in stage II disease, and oxaliplatin-based combination chemotherapy is now routinely used for stage III disease, although efficacy must be carefully balanced against toxicity. In stage II disease, molecular markers such as microsatellite instability might help select patients for treatment. The integration of targeted treatments with conventional cytotoxic drugs has expanded the treatment of metastatic disease resulting in incremental survival gains. However, biomarker development is essential to aid selection of patients likely to respond to therapy, thereby rationalising treatments and improving outcomes.
Worldwide, every year, more than 1 million individuals will develop colorectal cancer,1 and the disease-specific mortality rate is nearly 33% in the developed world. Here we summarise some of the important developments and advances in molecular carcinogenesis, prognostic and predictive molecular markers, hereditary predispositions, screening, diagnosis, and treatment during the past 5 years.
The classic description of colorectal carcinogenesis is the adenoma-carcinoma sequence and multistep tumourigenesis that is determined by gatekeeper and caretaker molecular pathways, which takes years to decades.2 Colorectal cancer is increasingly classified into specific phenotypes on the basis of molecular profiles (table 1), two of which represent genetic instability classes. Most sporadic cases (about 85%) have chromosomal instability, an allelic imbalance at several chromosomal loci (including 5q, 8p, 17p, and 18q), and chromosome amplification and translocation, which together contribute to tumour aneuploidy.4—7 By contrast, the remaining cases (about 15%) have high-frequency microsatellite instability phenotypes—ie, frameshift mutations and base-pair substitutions that commonly arise in short tandemly repeated nucleotide sequences (microsatellites).8, 9 Microsatellite instability is a measure of the inability of the DNA nucleotide mismatch-repair system to correct errors that often occur during DNA replication, which is controlled by several genes (including MLH1, MSH2, and MSH6), and is characterised by the accumulation of single nucleotide mutations and length alterations in repetitive microsatellite nucleotide sequences that are common throughout the genome.10 These tumours are characterised by proximal location, mucinous histology, poor differentiation, and lymphocytic infiltration. The genetic mechanism that contributes to this phenotype is mutation or loss of function through epigenetic gene silencing of DNA mismatch-repair genes.11, 12 In most sporadic cases, microsatellite instability occurs when the promoter region of the genes in the mismatch-repair system (often MLH1) is silenced by hypermethylation of CpG islands.12 The analysis of methylation of CpG islands as a mechanism of silencing genes in colon tumours has resulted in the identification of the CpG island methylator phenotype, which seems to be complex, and its prognostic significance in patients with colon cancer has not been thoroughly investigated.13, 14
Molecular classification of colorectal carcinoma
Adapted from Noffsinger.3 CIMP=CpG island methylator phenotype. MSS=microsatellite stability. MSI=microsatellite instability. MSI-H=high-level microsatellite instability. MSI-L=low-level microsatellite instability. +++=present. +/−=might or might not be present. −−−=absent.
The serrated pathway, often arising in a serrated precursor lesion (pathological classification is controversial but includes hyperplastic polyp, sessile serrated polyp, and serrated adenoma), usually occurs in the right colon,15 and seems to be governed by progression of different molecular mechanisms to the classic adenoma-carcinoma sequence.3 Clinical management of these precursor lesions is not clear.
Most cases of colorectal cancer arise sporadically. Risk factors include increasing age, male sex, previous colonic polyps, or previous colorectal cancer, and environmental factors (eg, red meat, high-fat diet, inadequate intake of fibre, obesity, sedentary lifestyle, diabetes mellitus, smoking, and high consumption of alcohol).16 Inflammatory bowel disease (ulcerative colitis and Crohn’s disease) accounts for roughly two-thirds of the incidence,17, 18 and the risk increases with duration of illness (2% at 10 years, 18% by 30 years18), and severity and extent of inflammation.19 Although colitis-associated colorectal cancer has many of the same molecular carcinogenic mechanisms as has sporadic cancer, with similar frequencies of chromosomal (about 85%) and microsatellite instability (about 15%), there are important molecular differences.20
Of the hereditary syndromes, the frequencies for inherited syndromes are as follows; the Lynch syndrome, also known as hereditary non-polyposis colorectal cancer, occurs in roughly one in 300 people with colorectal cancer. Familial adenomatous polyposis is much less frequent, and arises in about one in 7000 people affected by colorectal cancer, whereas MYH-associated polyposis occurs in about one in 18 000 individuals with colorectal cancer. All familial cases of colorectal cancer of the syndrome type account for nearly 6% of cases—namely, 3% of those with Lynch syndrome, 2% with familial colorectal cancer non-Lynch syndrome, and about 1% constitute all of the others, including the TACSTD1 deletion of MSH2. At this time, there is no reliable quantitative estimate of the frequency of TACSTD1 deletion of MSH2 in Lynch syndrome.
Genetic epidemiology: Lynch syndrome as model
More than a fifth of patients with colorectal cancer might have a familial component, and about 3% of cases will develop Lynch syndrome,21 which is the most common hereditary syndrome associated with this cancer (panel 1). Less than 1% of cases will have familial adenomatous polyposis or one of the hereditary syndromes of hamartomatous polyposis.24, 25 At least 20% of cases of colorectal cancer are familial (defined by two or more first-degree relatives with this cancer). Although this familial category remains aetiologically elusive, it is estimated to have a two-fold to three-fold greater risk than has the general population. Type X familial colorectal cancer, a new susceptibility category, meets the Amsterdam criteria26 for Lynch syndrome but lacks the molecular genetic features.27, 28 The Amsterdam criteria26 and Bethesda guidelines29 are widely used as clinical screening methods for assessment of risk (panel 2).
Cardinal features of Lynch syndrome (hereditary non-polyposis colorectal cancer)
*Autosomal dominant inheritance pattern of syndrome cancers in the family pedigree.
*Onset of colorectal cancer at a younger average age than in the general population: average age of 45 years in individuals with Lynch syndrome versus 63 years in the general population.
*Proximal (right-sided) colonic cancer predilection: 70—85% of colorectal cancers in people with Lynch syndrome are proximal to the splenic flexure.
*Accelerated carcinogenesis (small adenomas can develop into carcinomas quickly): within 2·3 years in Lynch syndrome versus 8—10 years in the general population.
*High risk of additional colorectal cancers: 25—30% of patients having surgery for a cancer associated with Lynch syndrome will have a second primary colorectal cancer within 10 years of surgical resection if the surgery was less than a subtotal colectomy.
*Increased risk of malignancy at specific extracolonic sites:22, 23 endometrium (40—60% lifetime risk in carriers of mutation); ovary (12—15% lifetime risk in mutation carriers); stomach (increased risk in Oriental families, reason not known); small bowel; hepatobiliary tract; pancreas; upper uroepithelial tract (transitional cell carcinoma of the ureter and renal pelvis); and brain (in Turcot’s syndrome, a variant of Lynch syndrome).
*Sebaceous adenomas, sebaceous carcinomas, and multiple keratoacanthomas in Muir-Torre’s syndrome, a variant of Lynch syndrome.
*Pathology of colorectal cancer is often poorly differentiated, with an excess of mucoid and signet cell features, a Crohn’s-like reaction, and an excess of infiltrating lymphocytes within the tumour.
*Increased survival when compared by stage in non-Lynch-syndrome-associated colorectal cancer.
*The requirement for diagnosis is the identification of a germline mutation in a mismatch repair gene (most commonly MLH1, MSH2, or MSH6) that segregates in the family—ie, members who have the mutation have a much higher rate of syndrome-related cancers than do those who do not have the mutation.
Revised Bethesda guidelines29 and Amsterdam criteria26 for identification of patients at risk of developing Lynch syndrome
Traditionally, one Bethesda criterion or all Amsterdam criteria should be met to potentially identify individuals at risk of Lynch syndrome.
*Colorectal cancer diagnosed in a patient who is younger than 50 years
*Presence of synchronous, metachronous colorectal, or other tumours associated with Lynch syndrome, irrespective of age
*Diagnosis of colorectal cancer with histologically high-level microsatellite instability in a patient younger than 60 years
*Colorectal cancer diagnosed in one or more first-degree relatives with a Lynch syndrome-associated tumour, with one of the cancers diagnosed before age 50 years
*Colorectal cancer diagnosed in two or more first-degree or second-degree relatives with Lynch-syndrome-related tumours irrespective of age
Amsterdam I and II criteria:
*One individual diagnosed with colorectal cancer (or extracolonic Lynch-syndrome-associated tumours) before age 50 years
*Three affected relatives, one a first-degree relative of the other two
*Two successive affected generations
*Familial adenomatous polyposis should be excluded
*Tumours should be verified by pathological examination
The public health implications of hereditary colorectal cancer are substantial because close relatives of an index patient could benefit from genetic counselling and, potentially, from mutation testing. Once a diagnosis is strongly suspected on the basis of family pedigree or molecular confirmation in the index patient, the next question is which family members should be tested.30 Many physicians might not be cognisant of the molecular genetic and phenotypic features of the syndromes associated with hereditary colorectal cancer, or their clinical implications for the patient and family. Referral should be made to a cancer geneticist so that sensitive and appropriate counselling, and appropriate management and surveillance, can be offered.
The genetic basis of Lynch syndrome is germline mutation in one of the genes in the DNA nucleotide mismatch-repair system, most commonly MSH2 and MLH1 (accounting for roughly two-thirds of the known mutations) and less commonly MSH6, PMS1, and PMS2. Several environmental factors or yet-to-be-identified low-penetrant gene mutations might affect the ultimate phenotypic expression of this syndrome. Most cases of familial adenomatous polyposis are caused by germline mutations in the APC tumour suppressor gene. Almost all colorectal tumours associated with Lynch syndrome have microsatellite instability. Immunohistochemistry can be used to identify loss of mismatch-repair proteins, such as MSH2 and MLH1, in tumours positive for microsatellite instability, and thereby direct mutational testing for a specific gene, which cannot be done with tests for microsatellite instability.31 If the tumour is microsatellite stable, the low probability of an informative immunohistochemistry test needs to be weighed against the cost of doing the test.32 Microsatellite instability should not be used as the only basis for selection of patients for mutational testing for Lynch syndrome, because some patients with microsatellite-stable tumours can have mutations.32 This difficulty can be resolved more cost effectively with tests for the BRAF V600E mutation than with those for the genes in the mismatch-repair system, since the presence of this mutation excludes Lynch syndrome.33
The clinical phenotypes in Lynch syndrome might differ according to the mutations. MSH2 is associated with an increased frequency of extracolonic types of cancer and includes Muir-Torre’s syndrome. Expression of MLH1 in colorectal cancer is higher than the expression of MSH2, and lower in extracolonic cancer. MSH6 shows a reduction in expression in colorectal cancer but an increase in endometrial cancer. PMS2 mutations contribute importantly to the development of Lynch syndrome, although penetrance in carriers of monoallelic PMS2 mutations seems to be lower than that for other genes in the DNA nucleotide mismatch-repair system.34 These clinical and molecular genetic changes in Lynch syndrome, and in many other hereditary cancer syndromes, have led to a new era of genetic counselling.
In 500 consecutive patients with colorectal cancer,21 18 (3·6%) had Lynch syndrome and were positive for microsatellite instability, 17 (94%) were correctly predicted with immunohistochemistry for the presence of mismatch repair proteins, eight (44%) were diagnosed when they were younger than 50 years, and 13 (72%) met the revised Bethesda guidelines29 (table 2). The investigators concluded that one in 35 patients with colorectal cancer had Lynch syndrome (a high prevalence for a highly penetrant, lethal autosomal dominant condition), and each of these patients had at least three relatives with this syndrome. These relatives could potentially benefit from increased cancer surveillance and management. Restriction of molecular screening to patients meeting the Bethesda guidelines would not identify 28% of cases of Lynch syndrome. The authors also showed that immunohistochemistry for mismatch-repair proteins was almost as sensitive as microsatellite instability for identification of this syndrome. This finding has important implications for potential large-scale screening because immunohistochemistry is readily available in most pathology laboratories and is useful for directing gene testing, whereas tests for microsatellite instability require specialist molecular diagnostics. This finding supports the argument that all patients with colorectal cancer, irrespective of family history, should be screened for microsatellite instability or mismatch-repair protein deficiency by immunohistochemistry. Similar evidence for molecular genetic screening of all newly diagnosed cases of colorectal cancer was reported by the Evaluation of Genomic Applications in Practice and Prevention Working Group,43 linking such screening with improved health outcomes in relatives of identified individuals. However, currently large-scale molecular screening of all patients is not done.
Selected novel preoperative chemoradiation regimens
pCR=pathological complete response rate. CAPEOX= capecitabine and oxaliplatin. CI 5-FU=continuous infusion of fluorouracil. FOLFOX=fluorouracil and oxaliplatin. FOLFIRI=fluorouracil and irinotecan. R=randomised. BID=twice a day. CAPIRI=capecitabine and irinotecan.
Surveillance for colorectal cancer in individuals with a germline mutation in the DNA nucleotide mismatch-repair system is highly effective and cheaper than a lack of surveillance.44, 45 Because of the early age of onset of this cancer in Lynch syndrome and proximal colon occurrence, full colonoscopy should be started by age 20—25 years in individuals with mutations in the mismatch-repair system, and in those thought to be at risk on the basis of pedigree analysis. Colonoscopy should be done at least every 1—2 years until 40 years of age, and yearly thereafter, because of accelerated colorectal carcinogenesis in Lynch syndrome.46 Similar guidelines apply to familial adenomatous polyposis. Women with a germline mutation for Lynch syndrome should have yearly screening for endometrial cancer (40—60% lifetime risk) beginning at 30—35 years. This screening should include endometrial aspiration and transvaginal ultrasound, although evidence-based data showing survival benefit from such screening is lacking. Prophylactic hysterectomy and salpingo-oophorectomy in women with germline mutations in the mismatch repair system substantially reduce the occurrence of endometrial and ovarian cancer in women with confirmed Lynch syndrome.47 These surgeries can be considered when childbearing is complete. Evidence-based data showing survival advantage for urological, gastric, and small bowel screening are not available.
Screening of colorectal cancer
Survival rates in individuals with colorectal cancer have increased substantially in the past few years, possibly as a result of early diagnosis and improved treatment. Although substantial information about risk factors exists, about 75% of diagnoses are in patients with no apparent risk factors other than older age.48 5-year survival is still less than 60% in most European countries.49 Population screening therefore continues to offer the best prospects for reduction in mortality rates.
The aim of screening for colorectal cancer is to prevent the development of advanced cancers through detection of localised cancers or premalignant adenomas, from which at least 80% of cancers are thought to arise. Several technologies exist. Those that are used to target cancers early reduce mortality rates, but cause a temporary increase in incidence rates as cancers are typically diagnosed at screening 2—3 years earlier than in symptomatic cases. These tests need to be offered at least biennially, which has implications for costs and compliance rates. Tests that are used to detect adenomas can be offered less frequently and because these tests should reduce incidence rates of colorectal cancer, they also reduce the costs of treatment and, thereby, of the screening programme.50, 51 However, since most adenomas do not develop into symptomatic cancers, screening for them can result in overtreatment, which can increase the risk of complications.
The guaiac-based faecal occult blood test is the most extensively studied, but possibly least sensitive, screening method. Several randomised trials and a Cochrane review52 have provided high-quality evidence that this test, if offered every 2 years, has the potential to reduce mortality rates associated with colorectal cancer by 16%. For this home-test kit, two samples are collected from three consecutive stools and sent for processing in an accredited laboratory. Collection of one stool sample by a physician during digital rectal examination is ineffective and is strongly discouraged.53 Investigation by colonoscopy is recommended if a specific number of the test cards are positive; the exact number varies according to local practice.54, 55 Several countries have introduced screening with the faecal occult blood test.55 Costs have been assessed in the European and US contexts, and were well below the commonly used threshold of US$50 000 per life-year gained.50, 56 Immunochemical faecal occult blood tests have several improved features compared with the standard test. They are not subject to interference from animal blood in the diet, only one or two stool samples are needed, and they are more sensitive for detection of colorectal cancer and advanced adenomas, though at the expense of lower specificity.57 Some tests can be automated, and the cutoff for positivity can be adjusted according to available endoscopy resources.58
Flexible sigmoidoscopy, with a 60 cm endoscope, allows examination of the sigmoid colon and rectum where 60% of cancers and adenomas are located. Bowel preparation for this sigmoidoscopy requires only one self-administered enema.59 Results from epidemiological studies suggest that sigmoidoscopy screening reduces incidence and mortality rates of distal colorectal cancer by roughly 60—80%;60, 61 four large trials are in progress.62—65 Screening is recommended every 5 years from 50 years of age in the USA,66 although the protection afforded by one flexible sigmoidoscopy might last for many years.60, 61, 67 The value of a once-in-a-lifetime screen with this method at about 60 years of age is being investigated in UK and Italian trials.62, 63 Small polyps are removed during the sigmoidoscopy screening, and colonoscopy follows only if several or advanced adenomas are found. The results of both trials will be reported this year. Colonoscopy every 10 years is the most common method of screening in the USA despite evidence that it has little efficacy in reducing rates of proximal colon cancer.68, 69 This method is associated with a higher risk of serious complications than are other methods,70 and about 48 h are needed for bowel preparation and recovery from sedation. Population screening with colonoscopy also presents manpower difficulties that have yet to be resolved, although high-quality programmes are available in Germany and Poland.71, 72 CT colonography (virtual colonoscopy) is as sensitive as colonoscopy for the detection of cancers and large adenomas, but includes exposure to radiation, requires full bowel preparation, and colonoscopy is necessary to confirm and remove detected lesions.57, 73 CT colonography also detects extracolonic lesions, which might lead to further invasive tests without any clinical benefit.74 It is thus an expensive option for screening.75
Investigations of DNA-based tests of blood or stool are in progress.76, 77 The sensitivity and specificity of markers need to be optimised, and automated systems need to be developed to reduce costs and ensure reliability. Many other colonic imaging technologies are being investigated78 to improve the acceptability of colonoscopy or increase the detection of flat lesions.
Whatever technology or combination of technologies is used, population screening is costly with the risk of exposing healthy individuals to potential harm. To obtain the maximum benefits and cost effectiveness of any scheme, delivery of screening within a high-quality programme is essential.55
Diagnosis and staging
Colorectal cancer is diagnosed on the basis of the results of colonoscopy or sigmoidoscopy with tumour biopsy. Treatment strategy is guided by adequate staging. The pretreatment workup of a newly diagnosed cancer includes physical examination, a complete colonoscopy to rule out metachronous tumour, and CT of the chest, abdomen, and pelvis to identify metastatic disease.79
CT colonography is valuable for precise localisation of the tumour and can help surgical approaches, especially in patients who are candidates for laparoscopic resection. It might also be used to identify other colonic lesions or polyps that are not detected at colonoscopy, for instance because of an obstructive lesion.80—82 Routine use of PET with the 18-fluoro-2-deoxy-D-glucose (FDG-PET) is not recommended at the time of initial diagnosis.83 In patients with rectal cancer, assessment of local tumour extension is essential for optimum treatment. High-resolution MRI can be used to accurately measure the spread of tumour in the surrounding mesorectum, and to assess the circumferential resection margin between the edge of tumour and the fascia recti (figure).84 Measurement of the depth of invasion in the bowel wall with endorectal ultrasound is particularly useful for early rectal cancers.85Panel 3 shows the advantages and limitations of pelvic MRI and endorectal ultrasound for the assessment of local spread of rectal cancer.
High-resolution MRI of rectal cancer
Red arrow shows T2 (tumour invading muscularis propria) rectal tumour; white arrow shows lymph node in the mesorectum; and yellow dotted line shows the rectal fascia.
Advantages and limitations of MRI and endorectal ultrasound for staging of primary tumours (T) and regional lymph nodes (N) in rectal cancer
*Global staging of rectal tumour
*Circumferential resection margin assessment
*Assessment of extramural venous invasion
*Guide the indication for radiation treatment
*Assessment of pelvic spread of the tumour (iliac nodes)
*Node staging—MRI is more accurate than is endorectal ultrasound, but there are some limitations in correlation between radiological and pathological findings
*Measure of depth of invasion in the bowel wall
*Measurement of T staging
*Early rectal cancer
*User-dependent imaging modality
*Measurement of node staging
*Assessment of circumferential resection margin assessment and extramural venous invasion
In patients with suspected liver metastases from colorectal cancer, extent of disease is determined by ultrasound, CT, and MRI. Although these imaging methods are used to detect metastases, new methods can be useful to define the characteristics of liver metastases. In particular, enhanced hepatic ultrasound86 and enhanced MRI can help to characterise liver nodules.87 FDG-PET can be used to rule out occult extrahepatic spread of the disease that could change the treatment strategy.88, 89 Detection of peritoneal carcinomatosis with imaging remains a challenge, and performance of the different diagnostic methods is inadequate.90 Involvement of the multidisciplinary team from the start helps to provide the best treatment. Once diagnosis is made, staging is described according to the TNM (tumour, node, metastases) system (panel 4).91
TMN classification of colon cancer91
TX=primary tumour cannot be assessed
T0=no evidence of primary tumour
Tis=carcinoma in situ: intraepithelial or invasion of lamina propria
T1=tumour invades submucosa
T2=tumour invades muscularis propria
T3=tumour invades through the muscularis propria into subserosa or into non-peritonealised pericolic or perirectal tissues
T4a=tumour penetrates the surface of the visceral peritoneum
T4b=tumour directly invades or is histologically adherent to other organs or structures
N=regional lymph nodes
NX=regional lymph nodes cannot be assessed
N0=no regional lymph node metastasis
N1a=metastasis in one regional lymph node
N1b=metastasis in two to three regional lymph nodes
N2a=metastasis in four to six regional lymph nodes
N2b=metastasis in seven or more regional lymph nodes
MX=distant metastasis cannot be assessed
M0=no distant metastasis
M1a=distant metastasis to one site
M1b=distant metastasis to more than one site
Surveillance, Epidemiology and End Results Program data for 5-year stage-specific relative survival rates in colon cancers:91, 92
*Stage I (T1, T2, N0): 97·1%
*Stage IIA (T3, N0): 87·5%
*Stage IIB (T4, N0): 71·5%
*Stage IIIA (T1, T2, N1): 87·7%
*Stage IIIB (T1, T2, N2): 75·0%
*Stage IIIB (T3, N1): 68·7%
*Stage IIIC (T3, N2): 47·3%
*Stage IIIC (T4, N1): 50·5%
*Stage IIIC (T4, N2): 27·1%
5-year stage-specific relative survival rates were similar for rectal cancer as compared with colon cancer.
For colon cancer, total resection of the tumour should be done with adequate margins, and lymphadenectomy. Distal margins of 5 cm or more are recommended. At least 12 lymph nodes should be taken and analysed to allow appropriate nodal staging;93—95 analysis of fewer than ten nodes might understage the tumour.12 En-bloc resection of invaded adjacent organs might be needed for T4 tumours to obtain R0 resection (no evidence of microscopic cancer at the margins). Surgical resection of the rectum for invasive rectal cancer should include total excision of the mesorectum (TME) with adequate circumferential and distal margins, and inferior mesenteric lymphadenectomy. TME is associated with a reduced risk of local recurrence whether or not combined with preoperative radiotherapy or chemoradiotherapy.96—98 Sphincter-saving surgery is feasible in most patients with mid and low rectal cancers if the distal margin is 1 cm or more. Intestinal continuity can be restored with colorectal or coloanal anastomosis according to the level of the tumour. For very low tumours, TME can be combined with resection of the internal sphincter of the anus without increasing the rate of local recurrence.99, 100 Abdominoperineal resection is a valuable alternative for very low tumours.101 Functional results after TME are associated with the level of the anastomosis. Risk of faecal incontinence is increased in patients with very low coloanal anastomosis, particularly after preoperative radiation.102, 103
In patients with early rectal cancer, the choice of treatment is complete local excision or TME, and depends on the risk of lymph-node involvement, which is associated with the depth of invasion of the tumour in the rectal wall. Local excision—transanal excision or endoscopic microsurgery for tumours in the upper-third layer of the submucosa (T1Sm1) and some in the middle layer (T1Sm2)—is valuable if excision is completed with adequate margins.104—106
Laparoscopic colectomy is safe for colon cancer, particularly left-sided cancer. The long-term oncological results of this surgery are similar to those of the open approach.107—110 Although laparoscopic colectomy is technically demanding, advantages are reduced pain, length of hospital stay, and duration of ileus.111 Comparison of laparoscopic and open resection (with TME) of rectal cancer112 showed similar 3-year local recurrence rates and survival despite earlier reports of an increased rate of R1 resection (ie, microscopic tumour present at the resection margin) with the laparoscopic approach.108 There was a non-significantly higher risk of sexual complications after laparoscopy than after open TME.113
The liver is the most common site of relapse after surgery for colorectal cancer, and lung recurrence is common. Resection of the liver and lung metastases is the standard of care for potentially resectable oligometastatic disease, and, when feasible, substantially improves 5-year and 10-year survival rates. Improvement of strategies for liver surgery, including preoperative embolisation, two-stage liver resections, and refinements of non-surgical techniques, such as radiofrequency ablation of small lesions, have increased the number of patients undergoing complete local treatment of liver metastases. Important progress has been made in the treatment of this disease with use of multimodality and multidisciplinary methods. Chemotherapy (oxaliplatin-based) given before and after surgery versus surgery alone reduced the risk of cancer relapse after surgery (progression-free survival at 3 years was improved by 7·3% in all patients [p=0·058], and by 9·2% in patients undergoing resection [p=0·025]) in the EORTC 40983 study.114 In patients with unresectable liver metastases, initial or conversion chemotherapy can render metastases resectable if the response to treatment is good. Preoperative chemotherapy for resectable lung metastases could improve outcomes, but there are few supporting data.115 Radiofrequency ablation might also have a role in non-resectable liver-only metastatic disease, and the survival outcomes with local radiofrequency ablation added to systemic palliative chemotherapy are being assessed in the EORTC CLOCC trial.116
Radiation treatment for rectal cancer
The risk of local failure in treatment of rectal cancer is affected by involvement of the circumferential resection margin, lymph-node status, and extramural venous invasion.84 Since a significantly lower incidence of local recurrence and toxicity, and a higher incidence of sphincter preservation were reported with preoperative than with postoperative chemoradiation in the German CAO/ARO/AIO 94 trial,117 the conventional treatment for clinical stage T3 (cT3) or node-positive rectal cancer is preoperative treatment, and is the choice in most countries. Radiation, a local control strategy, is used with conventional fractionation (50·4 Gy in 28 fractions) since short-course radiation (5 Gy×5) cannot be safely used with adequate doses of chemotherapy. Systemic chemotherapy improves survival. In Scandinavia and most northern European countries, treatment depends on preoperative MRI assessment of the circumferential resection margin.118—120 Generally, if this margin is likely to be negative at the time of surgery, patients undergo surgery alone or are given five doses of 5 Gy. If the margin is likely to be positive, patients are given preoperative radiation (5 Gy×5) or chemoradiation. A positive circumferential resection margin is not sufficiently controlled with postoperative treatment.121, 122
Overstaging is a disadvantage of preoperative treatment (18% in the German trial117), thereby patients with pathological stage T1-2N0 disease are at risk of being overtreated. Preoperative treatment is still preferred to surgery first since even after preoperative chemoradiation 22% of patients still have node-positive disease.123 These patients would then need postoperative chemoradiation, which has inferior outcome and higher toxicity than preoperative chemoradiation.
There are no prospective randomised data for local recurrence based on distance from the anal verge, only subset analysis from randomised trials that were not stratified by distance. With univariate analysis, high tumours (10—11 cm) had a lower incidence of local recurrence than did mid and lower tumours.122, 124 By contrast, there was no significant difference between mid and upper tumours in the German trial.125 On the basis of the conflicting data and the fact that the incidence of positive nodes after preoperative chemoradiation is the same from 0—12 cm from the anal verge,123 treatment decisions should not be based on distance if it is shorter than 12 cm.
Chemoradiation and short-course radiotherapy have been the main preoperative strategies assessed in randomised studies. Short-course preoperative radiation in patients with rectal cancer resulted in a survival advantage for the total treatment group in a Swedish trial.124 Despite TME, the local recurrence rate with node-positive disease was 21% in the Dutch CKVO 95-04 trial.126 Therefore patients with node-positive tumours need adjuvant radiation. The challenge is accurate identification of positive nodes to allow proper selection of patients for preoperative treatment. In the randomised study by Bujko and colleagues,127 patients given chemoradiation compared with radiation (5 Gy×5) had a significantly lower incidence of positive circumferential resection margin (4% vs 13%), but no significant difference in local failure (14% vs 9%) or 4-year survival (66% vs 67%). Furthermore, although the rate of pathological complete response was much higher (16% vs 1%), the incidence of sphincter preservation was not increased. However, because the number of patients (n=316) was small, surgeons were not encouraged to modify the operation on the basis of tumour response, and there was a lack of central review of the quality of the radiotherapy.
Use of adjuvant chemotherapy after preoperative chemoradiation has been contentious. Although data from randomised trials showed a 10—15% survival benefit with postoperative fluorouracil-based chemotherapy in colon and rectal trials, this result was not confirmed in the EORTC 22921128 and FFCD 9203129 randomised trials. The negative results might be partly attributable to the difficulty in patients tolerating full doses of chemotherapy after preoperative chemoradiation. Chemotherapy was better tolerated in the neoadjuvant than in the adjuvant setting in the GCR-3 phase II trial (table 2).42 A potential advantage of neoadjuvant chemotherapy is the early treatment of micrometastatic disease.
Conventional chemoradiation regimens include continuous-infusion fluorouracil or capecitabine (an oral fluorouracil prodrug). New cytotoxic and targeted treatments are being investigated (table 2).35—42 Most show higher rates of pathological complete response than with fluorouracil alone. However, acute toxicity was significantly higher without a benefit in the rate of pathological complete remission with the addition of oxaliplatin to continuous-infusion fluorouracil-based36 or capecitabine-based chemoradiation (ACCORD 12-040535). Local control and survival data were not available, but the rate of distant metastases was lower in the oxaliplatin-combination group than in the group not given oxaliplatin in the STAR trial.35
Most clinical series indicate improved outcome with increasing response to preoperative chemoradiation.130 Use of molecular markers131, 132 has had varying success in the prediction of response rates. Clinical or radiological responses to preoperative chemoradiation do not sufficiently correlate with pathological response.133 Adjuvant treatment should be based on the initial T and N stages. In one series, the value of radical surgery in patients (with cT1—3 disease) with a biopsy-proven complete response was questioned,134 and although not confirmed by other investigators remains a pertinent research question.
Novel fractionation and delivery techniques might improve outcomes in the future. Generally, hyperfractionated radiation improves the rates of pathological complete response but increases acute toxicity.135 Three-dimensional treatment allows planning and localisation of the target and normal tissues at all levels of the treatment volume, and to obtain dose-volume histograms.136, 137 Intensity-modulated radiotherapy can further reduce the volume of the small bowel in the field.138 The clinical benefit of this treatment compared with three-dimensional or conventional treatment is yet to be determined.
Current and simple guidelines or algorithms for the multimodality management of rectal cancer, including surgery and radiation, and all stages of disease have been reported by the US National Comprehensive Cancer Network.139
Adjuvant treatment for early stage disease
Surgery is the cornerstone for cure in localised colorectal cancer. In node-positive (stage III) disease, administration of adjuvant fluorouracil for 6 months reduces the risk of death by 30%, which is equivalent to an additional 10—15% survival gain.140 The alternative oral fluoropyrimidine, capecitabine, has shown similar efficacy to fluorouracil alone.141 The establishment of 3-year disease-free survival as a validated surrogate for 5-year overall survival142, 143 and primary endpoint has expedited the timely reporting of adjuvant trials and uptake of effective treatments. However, the magnitude of benefit in disease-free survival is not necessarily matched by that in overall survival because of various factors.143 Oxaliplatin (a third-generation platinum) added to infused fluorouracil versus infused fluorouracil alone improved 3-year disease-free survival by 7% in the MOSAIC study,144 leading to a 2·5% gain in overall survival at 6 years for stage II and III disease, and a survival increment of 4·2% in stage III alone.145 Results for disease-free survival were replicated in the NSABP C-07 study of fluorouracil and oxaliplatin.146 In the XELOXA study147 of oral capecitabine plus oxaliplatin versus fluorouracil and folinic acid (stage III disease), there was an improvement in 3-year disease-free survival (70·9% vs 66·5%, hazard ratio 0·80, p=0·0045) but a non-significant 5 year benefit in overall survival (3·4%). The choice between one drug (intravenous fluorouracil or oral capecitabine) or two will depend on the patient’s fitness or preference, potential for compliance, and toxicity considerations—eg, hand—foot syndrome with capecitabine, and risk of permanent peripheral sensory neuropathy with oxaliplatin (15·5% all grades of peripheral sensory neuropathy at 48 months after treatment145), with patient-reported improvement in hand peripheral sensory neuropathy but worsening of foot numbness, tingling, or discomfort by 18 months.148 Results from the MOSAIC study144 did not suggest a survival benefit with adjuvant oxaliplatin and fluorouracil in patients older than 65 years, a finding supported for individuals older than 70 years in an analysis of the ACCENT group database of more than 12 500 patients (17% older than 70 years) given adjuvant treatment in six randomised studies (including NSABP C-07 and MOSAIC).149 These data and toxicity considerations imply fluoropyrimidine monotherapy might be considered in older patients with stage III colorectal cancer.
Irinotecan added to fluorouracil did not significantly improve disease-free or overall survival,150—152 although there was a non-significant improvement with combination treatment in the PETAAC-3 trial.152
Adjuvant chemotherapy for node-negative (stage II) colon cancer (40% of resected cancers) has been controversial because of the small gains in survival for this subgroup in studies in which patients with stage II and III cancer were combined, although high-risk patients with stage II tumours (T4 tumours, obstructing presentation, poor differentiation, extramural venous invasion, fewer than 10—12 harvested lymph nodes, indeterminate or positive resection margins) are often offered treatment.153 However, in the QUASAR study154 of 3239 patients (with mostly stage II colorectal cancer) randomly assigned to fluorouracil and folinic acid or to observation (20% had central pathology review), there was a significant improvement in overall survival (risk reduction of 18% and 3·6% overall survival gain), with a similar benefit for colon and rectal cancers. This small benefit weighted against treatment toxicities and logistics, and comorbidities, should be included in discussions of adjuvant chemotherapy. Tests of microsatellite instability might contribute to the risk-benefit assessment of treatment in stage II disease. In QUASAR,154 patients with stage II colorectal cancer older than 70 years did not seem to benefit from chemotherapy, and the question is whether to treat or not to treat this age group. In the MOSAIC study, the benefit of adjuvant oxaliplatin and fluorouracil in stage II disease seemed small (no gain in 6-year overall survival, hazard ratio for 5-year disease-free survival 0·84), with a non-significant benefit in patients with high-risk stage II cancer (2·3% gain in 6-year overall survival, hazard ratio for 5-year disease-free survival 0·72).145 Central to the decision-making process for adjuvant treatment (monotherapy or oxaliplatin-based) in all patients (stage II and III disease, older patients, and those with comorbidities) is discussion with the patient, and incorporation of the patient’s preference after accurate communication of benefits and risks of treatment.
Of the targeted treatments assessed, addition of adjuvant edrecolomab (a monoclonal antibody against the epithelial cell adhesion molecule) and bevacizumab (a humanised monoclonal antibody against vascular endothelial factor [VEGF]) to chemotherapy did not improve disease-free survival.155, 156 Efficacy results from another study of adjuvant bevacizumab (AVANT study) are awaited, and an interim analysis of a randomised study of cetuximab (a monoclonal antibody targeted at the epidermal growth factor receptor [EGFR]) added to adjuvant fluorouracil and oxaliplatin has indicated a lack of benefit with the cetuximab combination.157
Disease relapse after surgery, with or without adjuvant chemotherapy, mostly occurs within 3 years.143 Intensive follow-up strategies for patients with colorectal cancer can improve survival, with the early detection of oligometastatic disease (commonly liver or lung) and potential for further radical treatment in a third of patients.158—160 5-year survival after liver and lung resection is about 36—58% and 27—41%, respectively.159, 160 Surveillance should be through a combination of clinical review, monitoring of serum carcinoembryonic antigen every 3—6 months for 3 years and then every 6—12 months until 5 years, imaging (most commonly CT) once a year for the first 3 years, and colonoscopy 1 year after surgery and then every 3—5 years.160—162
Treatment of metastatic disease
Palliative chemotherapy for metastatic colorectal cancer can improve survival, lessen symptoms, improve quality of life, and downsize liver-only or lung-only metastases in patients with potentially resectable disease. Survival has increased from 12 months with fluorouracil monotherapy to roughly 2 years with the addition of irinotecan, oxaliplatin, and targeted drugs. The use of infused fluorouracil added to oxaliplatin and to irinotecan has reduced toxicity and is commonly used.163 Fluorouracil can be safely substituted with capecitabine when combined with oxaliplatin without loss of efficacy.164, 165 For increments in survival, the sequence of drugs used at first presentation of disease and then on disease progression seems less important than is exposure to all active drugs during the treatment pathway.166 Although initial combination treatment is commonly used, first-line fluoropyrimidine monotherapy is appropriate in some patients.167, 168 When the aim is liver or lung resection, conversion regimens with high response rates are preferable.169 Treatment might continue until disease progression or for a fixed duration (usually 6 months), depending on toxicities, preference of the patient, and tumour response. Intermittent scheduling has also been investigated.170, 171
The main advance in the management of metastatic colorectal cancer in the past 5 years has been the addition of targeted treatments. Cetuximab, bevacizumab, and panitumumab (a fully human EGFR monoclonal antibody), the only licensed targeted drugs, have, however, had a relatively small effect on survival outcomes. Table 3 shows the main randomised studies and summarises the efficacy outcomes of these drugs when used as monotherapy or as part of combination treatment.
PFS=progression-free survival. OS=overall survival. EGFR=epidermal growth factor receptor. TTP=time to progression. NR=not reported. FOLFIRI=fluorouracil and irinotecan. FOLFOX=fluorouracil and oxaliplatin. ORR=overall response rate. CAPEOX=capecitabine and oxaliplatin. VEGF=vascular growth factor receptor. IFL=bolus fluorouracil and irinotecan. XELOX=capecitabine and oxaliplatin.
* Unless otherwise indicated.
† For comparison between control and investigational groups (all-comers and not according to KRAS status).
‡ Patients with wild-type or mutated KRAS were randomised in the intent-to-treat population, but data shown are for the primary and secondary efficacy analyses done in the KRAS wild-type population only.
§ Coprimary endpoints.
¶ 230 additional patients were treated with irinotecan-based chemotherapy but the primary efficacy analysis was restricted to the oxaliplatin cohort (n=823).
In chemorefractory patients, cetuximab showed activity when used alone, and reversal of irinotecan-resistance when used with irinotecan.172 Activity of cetuximab alone or in combination with irinotecan in chemorefractory patients has been confirmed in further studies173, 174, 188 and activity has now been demonstrated for cetuximab in combination with fluorouracil and irinotecan, and fluorouracil and oxaliplatin regimens in untreated patients (table 3).176—178 Crossover to a cetuximab-based regimen might have masked survival differences between treatment groups in pretreated patients, and subsequent treatments might have affected the survival results in untreated patients. First-line treatment with cetuximab added to fluorouracil and irinotecan marginally improved progression-free survival in the CRYSTAL study.176 However, retrospective subgroup analysis showed significantly improved response rates and progression-free survival in patients with liver-only metastases and KRAS wild-type tumours, and increased rates of liver resection with combination treatment. With longer follow-up, the difference in progression-free and overall survival between the two groups in patients with wild-type KRAS has increased and the difference in overall survival is now significant (table 3).189 By contrast, although comparison of oxaliplatin-based chemotherapy (investigator’s choice) with or without cetuximab in the COIN trial179 showed a higher response rate in the cetuximab combination group, it did not show a significant improvement in progression-free or overall survival even in patients with wild-type KRAS and BRAF. Panitumumab has been approved as monotherapy for pretreated patients.175 It significantly improved progression-free and overall survivals when given with fluorouracil and oxaliplatin to untreated patients with wild-type KRAS tumours (PRIME study).180 Panitumumab in combination with irinotecan and fluorouracil also resulted in a significant improvement in progression-free but not overall survival in pretreated patients with wild-type KRAS.181KRAS mutation status has been consistently identified as a predictor of patient response to EGFR-directed monoclonal antibodies (table 4), and cetuximab and panitumumab are now only offered to patients with wild-type KRAS colorectal cancer. Rash, diarrhoea, and hypomagnesaemia are characteristic toxicities of anti-EGFR drugs.
KRAS mutation status as a predictive marker of outcome to epidermal growth factor receptor (EGFR)-directed monoclonal antibodies
Data are number (%) or %, unless otherwise indicated. mAB=monoclonal antibody. BSC=best supportive care. FOLFIRI=fluorouracil and irinotecan. FOLFOX=fluorouracil and oxaliplatin. CAPEOX=capecitabine and oxaliplatin. HR=hazard ratio for comparison between control and EGFR-directed treatment. OX=oxaliplatin-based chemotherapy. NR=not reported.
* Unless otherwise indicated.
† Refers to the unselected intention-to-treat population.
‡ Have been prospectively analysed according to KRAS status.
Bevacizumab is an antiangiogenic monoclonal antibody and can also cause normalisation of tumour vasculature, thereby improving drug delivery to the target. Its side-effects include hypertension, gastrointestinal perforation, delayed wound healing, bleeding, and thromboembolism. Bevacizumab, when administered with chemotherapy that included bolus irinotecan and fluorouracil, improved overall survival by 4·7 months and response rates by 10% in untreated patients with metastatic colorectal cancer.182 However, these results were not replicated when bevacizumab was given with oxaliplatin-based chemotherapy to untreated patients,184 whereas the combination significantly prolonged survival in previously treated patients (table 3).183 Failure to continue combination treatment until disease progression and possible occurrence of VEGF rebound might have contributed to these contradictory findings.184 Whether bevacizumab should be continued after disease progression with a change of the cytotoxic drugs remains an important question, and an observational series suggested prolongation in survival with this strategy.194 Maintenance bevacizumab after initial response to combination treatment is being investigated, but this drug has little activity when used alone.183 The risk of postoperative complications, including delayed wound healing, is increased with bevacizumab. However, the risk seems to be low when an interval of 6 weeks from the last bevacizumab dose to surgery is allowed.195
Addition of cetuximab to capecitabine, oxaliplatin, and bevacizumab (CAIRO trial),187 and of panitumumab to bevacizumab in combination with irinotecan or oxaliplatin-based chemotherapy (PACCE trial)186 in untreated patients with metastatic disease worsened progression-free survival and increased toxicity, indicating a possible negative interaction of combining these targeted drugs despite encouraging results in a previous phase II trial (table 3).185
Bevacizumab received regulatory approval in 2004 for first-line treatment of metastatic colorectal cancer in combination with fluoropyrimidine-based chemotherapy, and was widely considered a standard first-line treatment. However, the licence for first-line cetuximab plus chemotherapy on the basis of the results of the CRYSTAL study176 and increased rates of liver resection in patients with wild-type KRAS tumours and initially unresectable liver-only metastases provides another treatment option. Nevertheless, the benefits of cetuximab compared with bevacizumab have not been proven in this setting. Regulatory approval was granted for cetuximab to be used as monotherapy or as combination therapy in 2004 in pretreated chemotherapy-resistant patients for whom there are few treatment options, and for panitumumab monotherapy in 2006—07 in patients with wild-type KRAS pretreated tumours. However, outside the USA, the cost has to some extent restricted the use of cetuximab, panitumumab, and bevacizumab; thus, identification of subgroups most likely to benefit from treatment could improve cost effectiveness. For instance, in the UK, cetuximab was only approved by the National Institute for Health and Clinical Excellence (NICE) for wild-type KRAS non-resectable liver-only metastatic colorectal cancer.196
Prognostic and predictive molecular markers
Prognostic biomarkers are associated with survival that is independent of the treatment effect. Predictive biomarkers indicate likely benefit of treatment. Markers can be prognostic and predictive. The most important development in molecular markers for metastatic colorectal cancer has been the validation of KRAS mutation status as predictive of non-response to EGFR-targeted drugs. In the adjuvant setting, prognostic and predictive molecular markers (microsatellite instability and 18q imbalance) could potentially be used to discriminate between molecular phenotypes in stage II disease (clinically heterogeneous), thereby contributing to the risk-benefit assessment of adjuvant treatment (table 5). However, complex pathways contribute to disease progression and, in general, single markers might not be entirely useful for prediction of efficacy and outcome. With high-throughput genome-wide screening, predictive and prognostic molecular signatures are increasingly being sought but, as yet, none have been validated for clinical use.
Genetic markers and their clinical consequences in colorectal cancer
MSI-H=high-level microsatellite instability. EGFR=epidermal growth factor receptor. mAB=monoclonal antibody. TS=thymidylate synthase. 2R=two tandom repeats. 3R=three tandem repeats. UTR=untranslated region. TSER=TS enhancer region. ERCC-1=excision-repair cross-complementing-1. VEGF=vascular-endothelial growth factor.
Roughly 40% of patients with metastatic colorectal cancer have somatic activating KRAS mutations. These mutations are highly predictive of non-response to EGFR inhibitors (table 4). The updated results of CRYSTAL189 showed a significant improvement in response rate, progression-free survival, and overall survival (23·5 months vs 20·0 months, p=0·0094) for patients with wild-type KRAS tumours given fluorouracil, irinotecan, and cetuximab compared with patients with mutant KRAS tumours who did not seem to benefit from treatment. The updated results of OPUS189 also showed a significant increase in response rate and progression-free survival (hazard ratio 0·567, 95% CI 0·375—0·856, p=0·006), but not in overall survival in patients with wild-type KRAS given cetuximab plus fluorouracil and oxaliplatin (table 4). The predictive value of KRAS mutation status was confirmed in a meta-analysis of CRYSTAL and OPUS.189 Similarly, KRAS mutation status is useful for prediction of the response to panitumumab.180, 181, 192 Importantly, patients with KRAS-mutated tumours given first-line oxaliplatin-based chemotherapy had worse progression-free survival and overall survival (table 4) in the PRIME study,180 worse progression-free survival in OPUS,177 and a non-significantly inferior overall survival in COIN.179 In randomised studies of irinotecan-based chemotherapy plus EGFR-directed monoclonal antibodies, a detrimental effect on survival in patients with KRAS mutant tumours has not been observed.181, 189KRAS mutation status should be established before starting treatment.
However, not all 60% of patients with wild-type KRAS will respond to treatment. Additional factors, such as amphiregulin and epiregulin, might contribute to treatment response; and mutation of BRAF or NRAS, or loss of PTEN or PIK3CA activation might contribute to resistance to EGFR-targeted monoclonal antibodies.197BRAF is the main downstream effector of KRAS. Mutations that activate BRAF arise in 8—10% of metastatic colorectal cancers and are mutually exclusive of KRAS mutations. BRAF mutation was associated with poor prognosis (reduced progression-free and overall survival) in patients (n=113) with metastatic colorectal cancer given anti-EGFR antibodies.198 The predictive value of BRAF mutations is yet to be prospectively assessed, and although the results of the CRYSTAL study199 suggested no association with resistance to first-line cetuximab in combination with chemotherapy, statistical power was low.
High-frequency microsatellite instability is present in almost 22% of stage II colorectal cancers compared with in 12% of stage III tumours.200 In a pooled analysis of 7642 patients treated with adjuvant fluorouracil, tumours with high-frequency microsatellite instability were associated with significantly improved prognosis compared with tumours that were microsatellite stable.201 Data for the prognostic effect of this microsatellite instability were contradictory in patients given irinotecan-based chemotherapy,200, 202 and subgroup analysis suggested a stronger effect in stage II than in stage III colorectal cancer, possibly attributable to stage-specific biological effects of microsatellite instability.200 Patients who have tumours with high-frequency microsatellite instability do not seem to benefit from adjuvant fluorouracil.203 These findings were corroborated in a pooled analysis, which also showed that deficient mismatch repair (a surrogate for high-frequency microsatellite instability) was associated with a significant reduction in overall survival (hazard ratio 3·15, p=0·03) in patients with stage II disease given adjuvant fluorouracil.204 Hence microsatellite-instability status might be used to decide which of these patients (about a fifth of those with stage II colorectal cancer) should not be treated with adjuvant fluorouracil.200
Results from studies have suggested an association between loss of heterozygosity at chromosome 18q with poor prognosis in patients with colorectal cancer.205—208 Although the microsatellite-stability status was not assessed in all the studies, it is an important covariable since loss of heterozygosity of 18q is rarely noted in tumours with high-frequency microsatellite instability. Allelic imbalance at 18q had a negative effect on overall survival in patients with stage III microsatellite-stable colorectal cancers,208 but this result was not replicated in other studies.209—212 The 18q region contains several important candidate genes, including SMAD7, SMAD4, SMAD2, and DCC, and, in stage III colon cancer, reduced SMAD4 expression was associated with poor prognosis with fluorouracil-based chemotherapy.213, 214 18q imbalance might also be a surrogate marker for the complex chromosomal instability phenotype arising in most colon tumours.215, 216 An investigation of the use of microsatellite instability and 18q loss of heterozygosity to decide which adjuvant treatment should be assigned in patients with stage II colorectal cancer is in progress (no treatment if tumour has high-frequency microsatellite instability or retention of 18q).
Other extensively studied potential prognostic and predictive markers include thymidylate synthase (the primary target of the active metabolite of fluorouracil), excision-repair cross-complementing-1 (implicated in resistance or sensitivity to platinum drugs), VEGF and its receptors, and the interleukins (table 5).
There have been considerable advances in understanding the molecular pathogenesis, in diagnosis (hereditary and sporadic), and in treatment of colorectal cancer. Despite the use of active targeted drugs for treatment of metastatic colorectal cancer in the past decade, and improvement of overall survival to nearly 2 years for non-resectable disease, cure rates remain low. Parallel development of predictive molecular and clinical markers is paramount to achieve the best outcomes from targeted treatments, and KRAS is the only validated predictive molecular marker in colorectal cancer for EGFR-directed monoclonal antibodies. Clinical and translational research that is in progress will hopefully help to provide the much promised hope of personalised medicine in the management of this cancer.
Search strategy and selection criteria
We searched Medline, PubMed, ASCO abstracts, ESMO abstracts, and the Cochrane database, between 2004 and 2009, for papers published in English. We used the search terms “colorectal cancer”, “colon cancer”, “rectal cancer”, “carcinogenesis”, “epidemiology”, “genetics”, “screening”, “diagnosis”, “staging”, “surgery”, “radiation therapy”, “chemotherapy” (“adjuvant”, “metastatic”, and “neoadjuvant”), and “molecular prognostic and predictive markers”. We cross-checked reference lists we found, and asked other colleagues to recommend references. We selected papers on the basis that they provided a major contribution to colorectal cancer or drew attention to evolving ideas, particularly papers in the past 5 years since publication of the previous seminar about colorectal cancer published in The Lancet in 2005.
All authors provided final review and approval for the Seminar, and input into responding to reviewers’ comments. DC co-wrote sections about adjuvant treatment for early disease and treatment of metastatic disease, and also provided overall structure and editing for the Seminar. WA wrote the section about screening. HJL wrote sections about molecular carcinogenesis, and prognostic and predictive molecular markers. HTL wrote the section about genetic epidemiology. BM wrote the section about radiation for rectal cancer. BN wrote the section about diagnosis and staging, and surgery. NS co-wrote sections about adjuvant treatment for early disease and treatment of metastatic disease, collated individual sections for the whole Seminar, and provided the search strategy.
Conflicts of interests
BM has been on speaker’s bureau for Sanofi-Aventis, Genentech, and Roche; and has been a consultant for Sanofi-Aventis. HJL is a consultant for Response Genetics. BMS is a consultant for ImClone and Merck, and holds stock options for Response Genetics. DC has received research funding from Sanofi-Aventis, Roche, Amgen, Pfizer, Merck, Novartis. WA, BN, and NS declare that they have no conflicts of interest.
DC is part funded by the National Institute for Health Research Biomedical Research Centre.
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