Colon Cancer
Abstract
Colorectal cancer had a low incidence several decades ago. However, it has become a predominant cancer and now accounts for approximately 10% of cancer-related mortality in western countries. The rise of colorectal cancer in developed countries can be attributed to the increasingly ageing population, unfavorable modern dietary habits and an increase in risk factors. New treatments for primary and metastatic colorectal cancer have emerged, providing additional options for patients, but these new treatment options have had limited impact on cure rates and long-term survival. For these reasons, and the recognition that colorectal cancer is long preceded by a polypoid precursor, new screening programs have gained momentum. .
Introduction
We live in an era with improved worldwide average living standards and increased access to adequate health care which had an effect on the average life expectancy in most regions of the world. However, although death rates from communicable diseases have improved globally, cancer-related mortality has increased by almost 40% over the past 40 years. A further 60% increase is expected in the next 15 years, with 13 million people estimated to die of cancer in 2030[1]. The main causes of cancer-related mortality have also changed, attributable to alterations in disease incidence, the introduction of screening programs and therapeutic improvements. Colorectal cancer was rare in 1950, but has become a predominant cancer in western countries, now accounting for approximately 10% of cancer-related mortality. Reasons explaining this increased incidence include an ageing population and the preponderance of poor dietary habits, smoking, low physical activity and obesity in western countries. The change in incidence is not only apparent in the rates of sporadic disease but also in some familial cancer syndromes.
New treatments for primary and metastatic colorectal cancer have been developed and include: laparoscopic surgery for primary disease; resection of metastatic disease affecting; radiotherapy; and neoadjuvant and palliative chemotherapy[2,3,4]. Despite advances in surgical and medical therapies, cure rates and long-term survival have changed little in the past several decades. Against this background, and given that colorectal cancer is preceded by a polypoid precursor (Fig. 1), screening programmes for early detection have gained momentum.
Figure 1: Colorectal neoplasia at different stages. a | A small sessile adenoma. b | An advanced, larger sessile adenoma. c | A large, dish-shaped, ulcerating sigmoid carcinoma.
Indeed, screening and early diagnosis are expected to have a substantial impact on colorectal cancer incidence and mortality in the next 15 years. Screening will only make these improvements with high uptake; accordingly, major improvements in non-invasive screening (for example, faecal immunochemical testing) are being investigated as alternatives to the current gold-standard, but invasive, screening methodology 〞 colonoscopy. Alongside these advances, the quality of screening colonoscopy has undergone substantial improvement in terms of technical changes and training, and quality assurance[5,6].
Epidemiology
Colorectal cancer is the second-most and third-most common cancer in women and men, respectively. In 2012, 614,000 women (9.2% of all new cancer cases) and 746,000 men (10% of new cancer cases) were diagnosed with colorectal cancer worldwide[7]. Combined, in both sexes, colorectal cancer is the third-most common cancer and accounts for 9.7% of all cancers excluding non-melanoma skin cancer. More than half of the cases occur in more-developed regions of world. The age-standardized incidence rate (ASRi) of colorectal cancer is higher in men (20.6 per 100,000 individuals) than in women (14.3 per 100,000 individuals). The majority of patients with sporadic cancer are >50 years of age, with 75% of patients with rectal cancer and 80% of patients with colon cancer being ≡60 years of age at the time of diagnosis.
Incidence varies geographically, with the highest incidence in Australia and New Zealand (ASRi: 44.8 and 32.2 per 100,000 men and women, respectively), whereas Western Africa (ASRi: 4.5 and 3.8 per 100,000) has the lowest incidence (Fig. 2). More-developed regions (Europe, Northern America, Australia, New Zealand and Japan; combined ASRi: 29.2 per 100,000) have a higher incidence than less-developed regions (all regions of Africa, Asia (excluding Japan), Latin America and the Caribbean, Melanesia, Micronesia and Polynesia; combined ASRi: 11.7 per 100,000)[7]. The seven world regions can be ranked according to increasing ASRi: from Africa (6.3 per 100,000), Asia (13.7 per 100,000), Latin America and the Caribbean (14.0 per 100,000), Micronesia and Polynesia (15.0 per 100,000), Northern America (26.1 per 100,000), Europe (29.5 per 100,000), to Australia and New Zealand (34.8 per 100,000)[7]. Within each of these regions, the ASRi of colorectal cancer can show marked variation. In Europe, Albania (8.4 per 100,000) and Ukraine (23.4 per 100,000) have a lower incidence, whereas Slovakia (42.7 per 100,000), Hungary (42.3 per 100,000) and Denmark (40.5 per 100,000) have high incidence. Asia has the greatest diversity with regard to the ASRi of colorectal cancer. The incidence is high in South Korea (45.0 per 100,000), Singapore (33.7 per 100,000) and Japan (32.2 per 100,000), but much lower in Nepal (3.2 per 100,000), Bhutan (3.5 per 100,000) and India (6.1 per 100,000). These variations are associated with different socioeconomic levels[8].
Figure 2: The age-standardized incidence and mortality rates in men and women (per 100,000 people) across geographical zones. Rates are consistently higher in males (m) than in females (f), and vary considerably between regions[7]. Highest rates occur in Australia and New Zealand, Europe and Northern America
In 2013, 771,000 people died as a result of colorectal cancer globally, making the disease the fourth-most common cause of cancer-related death worldwide after lung, liver and stomach cancer[9]. The age-standardized mortality rate (ASRm) of colorectal cancer in different countries reflects disease incidence. Mortality also depends on the stage distribution at diagnosis, which is influenced by the availability of a population screening programme and by the level of care in each country. The ASRm is almost twofold higher in more-developed regions (11.6 per 100,000) than in less-developed regions (6.6 per 100,000).
Risk factors
Both genetic and environmental factors play an important part in the aetiology of colorectal cancer. The majority of colorectal cancers are sporadic; approximately three-quarters of patients have a negative family history. In most western populations, the average lifetime risk for colorectal cancer is in the range of 3-5%. However, this risk almost doubles in individuals with a first-degree family member with colorectal cancer who was diagnosed at 50-70 years of age; the risk triples if the first-degree relative was <50 years of age at diagnosis. Risk further increases in individuals who have two or more affected family members. For sporadic colorectal cancer, this increased risk in the presence of affected family at least in part reflects low-penetrance genetic factors. Accordingly, positive family history has a role in approximately 15-20% of patients with colorectal cancer.
A range of environmental 〞 largely modifiable 〞 lifestyle factors influence the risk of developing colorectal cancer. The risk is increased by smoking, alcohol intake and increased body weight. With each unit increase of the body mass index, the risk for colorectal cancer increases by 2-3%[10]. In close conjunction, patients with type 2 diabetes mellitus also have an increased risk of colorectal cancer[11]. Moderate alcohol consumption (2-3 units per day) has been estimated to increase risk by 20%, whereas even higher alcohol consumption is associated with an up to 50% increased risk[12]. Prolonged heavy smoking has an effect of similar magnitude[13,14]. Intake of red meat and processed meat increases the risk of colorectal cancer by an estimated 1.16-fold per 100 g increase of daily intake[15]. By contrast, the consumption of milk, whole grains, fresh fruits and vegetables, as well as an intake of calcium, fibre, multivitamins and vitamin D, decrease the risk of colorectal cancer. The decrease of risk is estimated to be approximately 10% per daily intake of every 10 g of fibre, 300 mg of calcium or 200 ml of milk[15,16]. Daily physical activity for 30 minutes has a similar magnitude of effect[10,17]. Low-dose aspirin has also been associated with decreased risk of colorectal cancer[18].
The prevalence of these modifiable lifestyle factors can explain, to a considerable extent, the geographical and socioeconomic differences in colorectal cancer incidence[19]. Several studies have estimated that 16-71% of colorectal cancers in Europe and the United States are attributable to lifestyle factors[20,21,22]. Any benefit from lifestyle changes can be augmented by regular intake of aspirin and other NSAIDs28; however, this effect seems to depend on the host genotype[23,24]. Statin use might have a small preventive effect on the incidence of colorectal cancer[25,26], as does hormone therapy in postmenopausal women[27].
Diagnosis, Screening and Prevention
Diagnosis
A diagnosis of colorectal cancer either results from an assessment of a patient presenting with symptoms or as a result of screening. The disease can be associated with a range of symptoms, including blood in stools, change in bowel habits and abdominal pain. Other symptoms include fatigue, anaemia-related symptoms, such as pale appearance and shortness of breath, and weight loss. The predictive value of these symptoms for the presence of colorectal cancer in an elderly patient is limited, but they do warrant further clinical evaluation. With the widespread introduction of population screening for colorectal cancer, many individuals are diagnosed at the preclinical stage. In symptomatic patients, colonoscopy is the preferred method of investigation, but other endoscopic methods are also available or being developed (Box 2). For population screening, a range of other methods can be used for primary assessment, followed by colonoscopy in case of a positive test.
Box 2: Endoscopic techniques for the diagnosis of colorectal cancer
High-definition white-light endoscopy
- Current standard for colonoscopy, combining high-definition video endoscopes with high-resolution videoscreens
- Provides detailed images of the gastrointestinal mucosa
- Advantage of routine endoscopy; disadvantage that it provides no specific contrast for the detection of neoplastic lesions
Chromoendoscopy
- The use of a dye spray during gastrointestinal endoscopy to improve visualization
- Improves the detection of neoplastic lesions
- Time-consuming to spray the complete colon
- A new technique with dye incorporated into colon preparation is under investigation
Magnification endoscopy
- Endoscope with zoom-lens in the tip, which enables 6-150-fold enlargement of the mucosa
- Can characterize and determine the extension of neoplastic lesions
- Not suitable for screening of the complete colon
- Can be combined with other methods
Narrow-band imaging
- A technique that can also be built into white-light endoscopes
- Filters light to two bands, with a wavelength of 415 nm (blue) and 540 nm (green), respectively
- Longer wavelength light is less scattered and, therefore, penetrates deeper into the mucosa
- Blue light enhances superficial capillaries, whereas green light shows deeper, subepithelial vessels
- Can characterize and determine the extension of neoplastic lesions
- Does not increase neoplasia detection rates
Intelligent colour enhancement (FICE; Fujinon) and iScan (Pentax) imaging
- Similar techniques as narrow-band imaging, but with no filtering of the outgoing light
- Instead, processes the reflected light
Autofluorescence endoscopy
- A technique that can also be built into white-light endoscopes
- Based on the principle that illumination with a specific blue wavelength light can lead to excitation of tissue, which then emits light with a longer wavelength
- Wavelength of the emitted light is longer for neoplastic tissue
- Can be used to search for neoplastic lesions
Endomicroscopy
- A technique of extreme magnification endoscopy
- Enables in vivo visualization of individual glands and cellular structures
- Can evaluate neoplastic lesions
- Not suitable for scanning larger mucosal surfaces
Colonoscopy. Colonoscopy is the gold standard for the diagnosis of colorectal cancer. It has a high diagnostic accuracy and can assess the location of the tumour. Importantly, the technique can enable simultaneous biopsy sampling and, hence, histological confirmation of the diagnosis and material for molecular profiling. Colonoscopy is also the only screening technique that provides both a diagnostic and therapeutic effect. Removal of adenomas using endoscopic polypectomy can reduce cancer incidence and mortality. Indeed, the efficacy of colonoscopy for the reduction of colorectal cancer incidence and mortality was well demonstrated by the US National Polyp Study. Recent 20-year follow-up data from this study showed a reduction in colorectal cancer-related mortality of 53%, which is an encouraging result that has been echoed by a more-recent study. The quality of colonoscopy is a determining factor in the diagnostic yield of cancer and adenoma, which is the most certain way of avoiding interval cancers (that is, a tumour arising in between screening visits).
The image quality of colonoscopy has markedly improved over the past 20 years, from original fibre-optic to videochip endoscopes. Videochip endoscopes were further improved over the years, leading to higher resolution and wider angle of view. The current standard combines high-power endoscopes with high-resolution videoscreens to yield high-definition white-light endoscopy (hWLE). Although various technologies for further image enhancement in colonoscopy have been introduced over the past decade, none of them have been shown to improve the diagnosis of polyps and colorectal cancer compared with hWLE. Only chromoendoscopy (Box 2) has proven to be superior to hWLE in the identification of adenomas. Narrow-band imaging, imaging with the Fujinon Intelligent Colour Enhancement system (Fujinon Corporation, Saitama, Japan) and autofluorescence endoscopy are not advantageous over hWLE in the detection of adenomas or carcinomas. The Third Eye Retroscope device (Avantis Medical Systems, California, USA) was designed to address the fact that lesions behind mucosal folds in the gut are often missed. This endoscope provides a simultaneous retrograde view of the colon that complements the forward view of a standard colonoscope. Several pilot studies have indicated that it might be useful, but more data are needed. The invasive nature of colonoscopy poses a burden to screenees and patients, which might affect participation in screening programmes. In recent years, several alternative diagnostic methods have been introduced, such as capsule endoscopy and biomarker tests.
Capsule endoscopy. Capsule endoscopy uses a wireless capsule device that is swallowed by the screenee and enables examination of almost the entire gastrointestinal tract without the use of conventional endoscopy. Capsule endoscopy is useful in diagnosing adenomas and colorectal cancer. The first-generation capsule endoscopy was found to be able to detect polyps >6 mm in size with a sensitivity of approximately 60% and specificity of >80%. Cancer detection was achieved in 74% of patients with colorectal cancer. With the development of the second-generation capsule endoscopy for the colon (PillCam Colon2 (Given Imaging Ltd, Yokne'am Illit, Israel)), the frame speed was increased from a fixed speed of four pictures per second to a variable 4-35 pictures per second depending on capsule movement. The angle of view was widened from 156～ to 172～ on both ends of the capsule, providing a 344～ view. A large trial in the United States and Israel assessed the accuracy of this new capsule to diagnose colorectal neoplasia. With 884 patients included, sensitivity was shown to be 88% and specificity 82% for the detection of adenomas >6 mm in size.
CT colonography. CT colonography uses low-dose CT scanning to obtain an interior view of the colon. The technique is well established as a diagnostic modality for colorectal cancer. In a systematic review and meta-analysis that included >11,000 people from 49 centres, CT colonography was shown to have a sensitivity of 96% for the detection of colorectal cancer. This performance is similar to that of conventional colonoscopy. A recent study reported similar performance of CT colonography and capsule endoscopy in patients with previous incomplete colonoscopy. A large trial in 411 patients with obstructive cancers showed excellent performance of CT colonography for the evaluation of proximal synchronous lesions. An observational study based on data from England of 2,731 people with a positive guaiac faecal occult blood test (gFOBT, see below) showed that the detection rate of advanced neoplasia was significantly lower for subsequent CT colonography than for subsequent colonoscopy. Furthermore, the detection and accuracy rates for advanced neoplasia were better in high-volume centres. These findings underline the need for adequate quality assurance similar to measures implemented for colonoscopy screening.
CT colonography requires full bowel preparation (that is, clearance of the bowel), air inflation and a change in position of the patients during the examination. The discomfort to the screenee undergoing CT colonography is similar to colonoscopy in experienced hands, particularly because of the need for substantial bowel insufflation, but it has the advantage of obviating the use of sedation and can be used as part of the staging procedure in a confirmed case of colorectal cancer. However, CT colonography has low sensitivity for small (6-9 mm) and flat lesions. The technique is associated with high colonoscopy referral rates (up to 30%) and high rates of extra-colonic findings in non-cancer cases, which translate to unnecessary investigations and increased anxiety for individuals. The costs of CT colonography and the need for further investigation in a subset of screenees limit the usefulness of this method for population screening in most countries.
CT colonography has been recommended as one of the options for colorectal cancer screening in guidelines in the United States and Europe. In many countries, CT colonography has replaced double-contrast barium enema examination (the conventional X-ray-based imaging modality for the colon) and is increasingly being used as an alternative to conventional colonoscopy. However, CT colonography has not readily been accepted in Europe because of radiation exposure, costs, burden to patients and high colonoscopy referral rates. In the Asia-Pacific region, CT colonography is not recommended for colorectal cancer screening, except in those for whom total colonoscopy is not possible.
Biomarkers of colorectal cancer. Molecular detection of colorectal cancer offers a non-invasive test that is appealing to patients and clinicians as samples of multiple patients can be analysed in batch. The ideal molecular marker should be highly discriminating between cancer and advanced adenomas from other lesions, be continuously released into the bowel lumen or circulation, and disappear or reduce after the lesion is removed or treated. Indeed, assays using proteins, RNA and DNA in the blood, stool and urine have been developed but with varying degrees of success. Stool tests are based on the fact that early cancers as well as advanced pre-malignant lesions can bleed and shed cells into the bowel lumen, which can be detected. Blood tests obviate the handling of stool and urine and can be performed alongside routine checking of blood sugar and cholesterol in the elderly population.
SEPT9 belongs to a class of GTPases, and hypermethylation of its promoter region is associated with colorectal cancer; aberrant methylation of SEPT9 at the tissue level discriminates colorectal neoplasia from normal mucosa. Early case-control studies from referral centres showed that SEPT9 methylation testing yielded a moderate sensitivity of 50-70% for colorectal cancer, with a specificity of 85-90%. However, a more-recent larger scale study in the population with average risk of developing the disease suggested a colorectal cancer detection rate of <50% when using SEPT9 methylation testing. The reported detection of advanced colonic adenoma by SEPT9 methylation status is only approximately 10%. As such, SEPT9 assays are outperformed by current quantitative faecal immunochemical tests (FITs).
Mutations of APC and KRAS have been tested in DNA shed by epithelial cells and isolated from stool samples. The first-generation faecal DNA tests only gave satisfactory results with fair sensitivity for the detection of colorectal cancer but low sensitivity for the detection of advanced colonic adenomas. Since then, several technological improvements have been made, including the use of a stabilizing buffer, the addition of other more-discriminating markers (KRAS mutations, aberrant NDRG family member 4 (NDRG4), bone morphogenetic protein 3 (BMP3) methylation and the presence of actin), the use of more-sensitive analytical methods and the optimization of the determining algorithm 〞 all of which have improved the accuracy of the assay (see further description below). Other potentially useful markers under investigation include circulating tumour mRNA, microRNA and circulating cytokeratins.
Screening and prevention
Colorectal cancer is more suitable for population screening than any other malignancy owing to a combination of factors. First, the incidence of the disease is high, and outcome for a significant proportion of affected patients is poor despite intense, burdensome and often very costly treatments. Colorectal cancer also has a long preclinical stage. For instance, 7,151 Dutch men 55-75 years of age were newly diagnosed with colorectal cancer in 2012 (see the Dutch Cancer Registry: www.cijfersoverkanker.nl), which corresponds to approximately 0.2% of the 3.5 million people in that age group. Such an incidence is in line with similar annual incidences in other western European countries. However, colonoscopy screening studies generally tend to find prevalent colorectal cancer in 0.5-0.9% of the participants in the same age group. Although an increased willingness of symptomatic screenees might confound this difference, these data indicate that colorectal cancer on average progresses for several years before becoming symptomatic. Furthermore, colorectal cancer is preceded by colorectal adenoma. In individuals with sporadic (non-hereditary) disease, the progression from adenoma to cancer takes at least 5-10 years. The long preclinical stage of the disease offers a large window of opportunity for screening.
Second, colorectal cancer is also suitable for screening because adenomas and early cancers are detectable and treatable entities, which is in contrast to precursors of other highly common cancers of the breast, prostate and lung.
Last, both endoscopic removal of adenomas and treatment of early-stage cancers have a profound effect on colorectal cancer mortality. After a 20-year follow-up of the US National Polyp Study cohort, colorectal cancer-specific mortality was approximately 50% lower among subjects who at baseline had undergone endoscopic removal of adenomas than in an unscreened control cohort. Furthermore, the 5-year survival rates for patients with early-stage cancer are approximately 90%, compared with 10% for patients diagnosed with advanced-stage metastatic disease. Together, these factors form the background for various international guidelines on colorectal cancer screening. Screening in most countries aims to capture men and women who are 50-75 years of age, although different age ranges are being used in various programmes depending on the available resources. Adoption of lifestyle measures can also substantially affect colorectal cancer incidence.
Endoscopy. Given that imaging of the colon can confirm a diagnosis or exclude colorectal neoplasia, clinicians often favour these methods for screening purposes. Colorectal adenomas and early-stage cancers can directly be visualized by endoscopy, CT colonography or capsule endoscopy. A randomized comparison between CT colonography and colonoscopy for primary population screening has shown a slightly higher uptake of CT colonography, counterbalanced by a slightly lower sensitivity for advanced neoplasia. Capsule endoscopy screening might in the near future provide an alternative visualization method for primary screening. Overall, colonoscopy has the highest accuracy, is generally considered the gold standard for screening and is associated with several advantages (Table 2). Recent large observational studies showed that screening colonoscopy reduced the risk of colorectal cancer by approximately 80%, and had a similar effect on related mortality. This preventive effect of colonoscopy strongly depends on procedural quality, which can be measured in terms of adenoma detection rate of the performing endoscopist. Other measures for procedural quality include the level of bowel preparation, caecal intubation rates, complication rates, average sedative medication dose and patient burden scores. In a study from the United States, adenoma detection rates per colonoscopist ranged from 7% in the lowest quintile of detection to 50% in the highest quintile 〞 a difference that is associated with an almost twofold risk in interval cancer. The correlation between risk of post-colonoscopy cancer and adenoma detection rates was also reported in a study from Poland. Training and quality-assurance measures, and adherence to surveillance guidelines also have an effect on the rate of post-colonoscopy cancers.
Sigmoidoscopy, which images the rectum and sigmoid colon and can include the descending colon, has been shown in several randomized prospective trials to reduce the incidence of colorectal cancer by approximately 33% and reduce related mortality by 38-59%. This effect was obtained by single sigmoidoscopy screening, with further colonoscopy in those with signs of advanced polyps 〞 a finding that formed the basis for the current roll-out of nationwide primary sigmoidoscopy screening in England. The wide use of colonoscopy and sigmoidoscopy for primary screening in various countries supports the introduction of non-physician endoscopists who can perform diagnostic endoscopy according to international standards. Further studies are needed to assess performance and cost efficacy.
Population screening. Given the considerable rise in treatment costs, colorectal cancer screening is a cost-saving exercise in many countries. Screening can be carried out using a range of methods, both invasive and non-invasive. Most programmes are based on a single primary screening test, followed by colonoscopy in those who test positive. In other settings, screenees are offered a choice between different screening methods, which might increase or decrease participation rates depending on the local setting.
Population screening must consider more than just test accuracy, but should take test uptake and the demand on resources into account. Accordingly, screening results must be reported in terms of identification of subjects with advanced neoplasia per 1,000 invited and in numbers needed to scope. A very accurate test by definition has no effect on cancer incidence and mortality in a population if not widely applied. Similarly, limitations in endoscopy capacity preclude the use of colonoscopy for primary screening. For these reasons, many countries prefer a two-step approach in population screening, first using a non-invasive screening test to select a subgroup of screenees who are at high risk of cancer for subsequent colonoscopy. Typically, a faecal occult blood test is this primary screen, either using gFOBTs or FITs. FITs are now more widely used than gFOBTs because of easier handling, resulting on average in approximately 10% higher uptake, higher sensitivity for advanced neoplasia and automated analysis. Indeed, quantitative FITs offer the additional advantage that their cut-off points can be adjusted to match colonoscopy capacity. For an optimal impact on the population level, adequate quality assurance is needed over the full range of the screening programme, as is organized active call-recall screening.
Management
Surgery
Surgery is the mainstay curative treatment for patients with non-metastasized colorectal cancer. However, outcome is strongly related to the quality of surgery, the quality of preoperative staging and treatment selection. The dissection should ideally follow the embryological anatomical planes to ensure that the tumour and its principle zone of lymphatic spread are removed. Special attention should be given to the circumferential surgical resection margins. In more-advanced cases of rectal cancer, neoadjuvant treatment (for example, preoperative chemotherapy for T4 colon cancer, and chemoradiotherapy or radiotherapy for locally advanced cancer) can reduce tumour load and even tumour stage, and might be necessary to optimize the chances for a successful resection. Thus, a multidisciplinary approach before beginning treatment, based on adequate staging information, is mandatory.
Colon surgery. Laparoscopic resection of colorectal cancer has been shown to be as safe as open surgery. As with any surgical procedure, the team needs to be skilled in laparoscopic colorectal surgery and adequately select patients. Contraindications for laparoscopic approach are obesity, previous abdominal surgeries and advanced-stage disease. If, during the laparoscopic procedure, conversion to open surgery is necessary, the earlier this is done the better the outcomes.
Quality assurance. The resected tumour specimen can be used to judge the quality of surgery; if the margin around the specimen is free of cancer cells in both colon and rectal cancer, the surgery is considered high quality. The removal and assessment of the lymph nodes is another guide for determining whether the mesocolic or mesorectal resection is adequate. Internationally, removal of 12 lymph nodes is viewed as the cut-off value needed to provide adequate histopathological staging; the lymph nodes can also be used to prognosticate patients. However, the role of procedures to remove the sentinel node (the first lymph node or group of nodes draining the cancer) in colorectal cancer is still unclear.
References
[1] Kuipers, E. J., Rösch, T., & Bretthauer, M. (2013). Colorectal cancer screening—optimizing current strategies and new directions. Nature reviews Clinical oncology, 10(3), 130.
[2] Papamichael, D., Audisio, R. A., Glimelius, B., de Gramont, A., Glynne-Jones, R., Haller, D., ... & Rutten, H. (2014). Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013. Annals of oncology, 26(3), 463-476.
[3] Hurwitz, H., Fehrenbacher, L., Novotny, W., Cartwright, T., Hainsworth, J., Heim, W., ... & Ferrara, N. (2004). Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New England journal of medicine, 350(23), 2335-2342.
[4] Heemskerk‐Gerritsen, B. A., Rookus, M. A., Aalfs, C. M., Ausems, M. G., Collée, J. M., Jansen, L., ... & Mooij, T. M. (2015). Improved overall survival after contralateral risk‐reducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer: a prospective analysis. International journal of cancer, 136(3), 668-677.
[5] de Jonge, V., Nicolaas, J. S., Cahen, D. L., Moolenaar, W., Rob, J. T., Tang, T. J., ... & SCoPE Consortium. (2012). Quality evaluation of colonoscopy reporting and colonoscopy performance in daily clinical practice. Gastrointestinal endoscopy, 75(1), 98-106.
[6] Valori, R., Rey, J.-F., Atkin, W. S., Bretthauer, M., Senore, C., Hoff, G., . . . Minoli, G. (2012). European guidelines for quality assurance in colorectal cancer screening and diagnosis. First Edition--Quality assurance in endoscopy in colorectal cancer screening and diagnosis. Endoscopy, 44 Suppl 3, SE88-105. This paper describes the results of extensive international consensus on quality-assurance measures for colorectal cancer screening.
[7] Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., ... & Bray, F. (2015). Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International journal of cancer, 136(5), E359-E386.
[8] Rohani-Rasaf, M., Abdollahi, M., Jazayeri, S., Kalantari, N., & Asadi-Lari, M. (2013). Correlation of cancer incidence with diet, smoking and socio-economic position across 22 districts of Tehran in 2008. Asian Pac J Cancer Prev, 14(3), 1669-76.
[9] Global, G. B. D. (2015). regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet, 385(9963), 117-171.
[10] World Cancer Research Fund/American Institute for Cancer Research. Continuous update project report. Food, nutrition, physical activity, and the prevention of colorectal cancer. Diet and Cancer Report [online], (2011).
[11] Guraya, S. Y. (2015). Association of type 2 diabetes mellitus and the risk of colorectal cancer: A meta-analysis and systematic review. World Journal of Gastroenterology: WJG, 21(19), 6026.
[12] Fedirko, V., Tramacere, I., Bagnardi, V., Rota, M., Scotti, L., Islami, F., ... & Boffetta, P. (2011). Alcohol drinking and colorectal cancer risk: an overall and dose–response meta-analysis of published studies. Annals of oncology, 22(9), 1958-1972.
[13] Liang, P. S., Chen, T. Y., & Giovannucci, E. (2009). Cigarette smoking and colorectal cancer incidence and mortality: Systematic review and meta‐analysis. International journal of cancer, 124(10), 2406-2415.
[14] Botteri, E., Iodice, S., Bagnardi, V., Raimondi, S., Lowenfels, A. B., & Maisonneuve, P. (2008). Smoking and colorectal cancer: a meta-analysis. Jama, 300(23), 2765-2778.
[15] Song, M., Garrett, W. S., & Chan, A. T. (2015). Nutrients, foods, and colorectal cancer prevention. Gastroenterology, 148(6), 1244-1260.
[16] Dahm, C. C., Keogh, R. H., Spencer, E. A., Greenwood, D. C., Key, T. J., Fentiman, I. S., ... & Mishra, G. (2010). Dietary fiber and colorectal cancer risk: a nested case–control study using food diaries. Journal of the National Cancer Institute, 102(9), 614-626.
[17] Arem, H., Moore, S. C., Park, Y., Ballard‐Barbash, R., Hollenbeck, A., Leitzmann, M., & Matthews, C. E. (2014). Physical activity and cancer‐specific mortality in the NIH‐AARP Diet and Health Study cohort. International journal of cancer, 135(2), 423-431.
[18] Algra, A. M., & Rothwell, P. M. (2012). Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. The lancet oncology, 13(5), 518-527.
[19] Doubeni, C. A., Major, J. M., Laiyemo, A. O., Schootman, M., Zauber, A. G., Hollenbeck, A. R., ... & Allison, J. (2012). Contribution of behavioral risk factors and obesity to socioeconomic differences in colorectal cancer incidence. Journal of the National Cancer Institute, 104(18), 1353-1362.
[20] Erdrich, J., Zhang, X., Giovannucci, E., & Willett, W. (2015). Proportion of colon cancer attributable to lifestyle in a cohort of US women. Cancer Causes & Control, 26(9), 1271-1279.
[21] Platz, E. A., Willett, W. C., Colditz, G. A., Rimm, E. B., Spiegelman, D., & Giovannucci, E. (2000). Proportion of colon cancer risk that might be preventable in a cohort of middle-aged US men. Cancer Causes & Control, 11(7), 579-588.
[22] Aleksandrova, K., Pischon, T., Jenab, M., Bueno-de-Mesquita, H. B., Fedirko, V., Norat, T., ... & Dartois, L. (2014). Combined impact of healthy lifestyle factors on colorectal cancer: a large European cohort study. BMC medicine, 12(1), 168.
[23] Andersen, V., & Vogel, U. (2014). Systematic review: interactions between aspirin, and other nonsteroidal anti‐inflammatory drugs, and polymorphisms in relation to colorectal cancer. Alimentary pharmacology & therapeutics, 40(2), 147-159.
[24] Nan, H., Hutter, C. M., Lin, Y., Jacobs, E. J., Ulrich, C. M., White, E., ... & Caan, B. J. (2015). Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants. Jama, 313(11), 1133-1142.
[25] Bardou, M., Barkun, A., & Martel, M. (2010). Effect of statin therapy on colorectal cancer. Gut, 59(11), 1572-1585.
[26] Liu, Y., Tang, W., Wang, J., Xie, L., Li, T., He, Y., ... & Qin, X. (2014). Association between statin use and colorectal cancer risk: a meta-analysis of 42 studies. Cancer causes & control, 25(2), 237-249.
[27] Limsui, D., Vierkant, R. A., Tillmans, L. S., Wang, A. H., Weisenberger, D. J., Laird, P. W., ... & Harnack, L. J. (2012). Postmenopausal hormone therapy and colorectal cancer risk by molecularly defined subtypes among older women. Gut, 61(9), 1299-1305.
