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This page provides an overview of colorectal cancer (CRC) epidemiology, risk factors, and clinical presentation, and introduces topics currently shaping clinical discussion.
Epidemiology, risk factors and survival
CRC is one of the leading causes of cancer worldwide: the third most common cancer in men and second most common in women.1,2 Global incidence and mortality rates vary up to 10-fold and point towards widening disparities and an increasing burden in transition countries.2
Although there have been some improvements in CRC outcomes in recent years in more developed countries,2 the unmet clinical need remains high.
As populations age, risk-related lifestyle behaviours persist and diagnostics improve, global incidence and mortality are anticipated to rise to an estimated 2.2 million new cases and 1.1 million related deaths by 2030.2,3
Global CRC incidence and mortality1
*both sexes, all ages
Reproduced from IARC CRC factsheet 20181 (GLOBOCAN data)
CRC, colorectal cancer; IARC, International Agency for Research on Cancer
International guidelines endorse implementation of proactive screening programmes for CRC, with frequency of assessment guided by individual patient risk.4
A number of CRC risk factors have been identified, including: age; inflammatory bowel disease; family history (in a first-degree relative); elevated body mass index; reduced physical activity; alcohol consumption and cigarette smoking, as well as a number of dietary factors. High consumption of processed and red meat is thought to contribute to increased risk, whereas high fruit and vegetable intake is thought to confer protection.5
Age is considered to be the major unmodifiable risk factor for CRC and is central to screening protocols. Almost 70% of colon cancers occur in patients aged 65 years or over,4 and increased age (and more advanced disease at time of diagnosis) is consistently associated with poorer prognosis.6
Five-year survival has risen for colon and rectal cancers in most developed countries in recent years. It is generally lower, and shows much wider variation, across Africa, Asia and Central and South America, likely reflecting differences in early diagnosis and access to optimum treatment.7
Age-standardised, 5-year survival rates have reached 50–59% for both colon and rectal cancers across many countries. For colon cancer, 5-year survival is more than 60% in North America, Oceania, some European countries and a minority of Central and South America and Asia, but remains below 40% in India, Indonesia and Mongolia. Even greater variation is seen in rectal cancer survival rates: exceeding 70% in some countries (e.g. Cyprus, Iceland and Qatar), but reaching only 29% in India.7
Presentation and diagnosis
Patients with CRC can present with a range of symptoms, including changes in bowel habits, general or localised abdominal pain, weight loss without other specific causes, weakness, iron deficiency and anaemia. Symptoms are seldom CRC specific and tend to be associated with relatively large tumours at an advanced stage of disease.4
Endoscopy is the main procedure for diagnosis and can be carried out by either sigmoidoscopy (as >35% of tumours are located in the rectosigmoid) or total colonoscopy. Endoscopic investigation enables exact localisation and biopsy of the lesion, detection of (further) synchronous precancerous or cancerous lesions and removal of polyps. Pathological stage should be evaluated in line with the tumour, node and metastasis (TNM) classification system.4
The improvement in CRC outcomes observed in more developed countries is thought to be associated with the implementation of effective screening programmes to aid detection at earlier stages of disease, and with improved therapeutic management approaches.2,4
Guidance recommends screening programmes be adapted to population risk. In an average-risk population (defined as individuals of 50 years of age with no additional risk factors) recommended screening approaches include annual or biennial faecal immunochemical test, sigmoidoscopy every 5 years or colonoscopy every 10 years. More regular screening may be warranted in high-risk subpopulations.8
If colon cancer is diagnosed early, surgery (partial colectomy ± lymph nodes) is the standard of care, with adjuvant chemotherapy according to the patient’s overall risk profile. Where chemotherapy is used, common combinations include a doublet schedule with oxaliplatin and fluoropyrimidine.4 Early diagnosis of rectal cancer allows for a curative treatment approach including surgery and, often, chemoradiation.9
In metastatic disease the heterogenous nature of CRC ensures treatment remains a complex and individualised challenge, owing to the numerous genes (tumour protein p53 [TP53]; KRAS and BRAF) and pathways (WNT, RAS−MAPK, PI3K, TGF-β, p53 and DNA mismatch-repair) implicated in disease initiation and progression.10,11 Targeted agents are indicated in the majority of patients with metastatic CRC, with choice of treatment pathway informed by the molecular profile, prior therapy, tolerability and treatment goal (cytoreduction for conversion and local ablative treatment, for symptom control or because of aggressive biology, or disease control).12
HOT TOPICS IN CRC
Molecular subtypes in CRC: ready for clinical practice?
CRC is a heterogeneous disease with numerous genes and pathways involved in its initiation and progression.11 Transcriptomic characterisation of CRC subtypes offers the potential to overcome some of the therapeutic challenges of CRC heterogeneity by identifying biomarkers associated with treatment response that can inform more targeted therapeutic approaches.13,14
A number of characteristics and categorisation approaches are discussed in the CRC literature, including the use of transcriptomics to classify tumours by consensus molecular subtype (CMS).14 The CMS classification system comprises four distinct subgroups defined by gene expression levels: CMS1 (microsatellite instability immune), hyper-mutated, microsatellite unstable and strong immune activation; CMS2 (canonical), epithelial, chromosomally unstable, marked WNT and MYC signalling activation; CMS3 (metabolic), epithelial and evident metabolic dysregulation; and CMS4 (mesenchymal), prominent transforming growth factor-β activation, stromal invasion and angiogenesis.14
Various studies have confirmed CMS as a robust CRC classification system that has prognostic potential, but research is ongoing to establish its utility as a biomarker for treatment response.15–19
Frequency of CMSs in CRC14
CMS, consensus molecular subtype; MSI, microsatellite instability
Modifiable risk factors in CRC
A number of risk factors for CRC have been identified, including:4
While unmodifiable risk factors can be used to evaluate overall patient risk and inform the design of secondary prevention and screening strategies,4 primary prevention strategies targeting modifiable risk factors hold the potential to reduce CRC morbidity and mortality.20
A systematic review and meta-analysis of 145 articles (56 on diet and lifestyle) found that regular physical exercise can reduce the risk of CRC by approximately 40%. The review also identified a number of dietary factors that can affect CRC risk, including:20
Seeking to improve early diagnosis of CRC
A trend towards increased CRC incidence within the 40–44-year age group has been observed,4 raising questions about the possibility for missed diagnostic opportunities in younger populations.21
A retrospective study involving symptomatic patients (n=252) with recent CRC diagnoses (Stages 1–4) identified missed diagnostic opportunities in more than one-third (36.5%) of patients. The most common differential diagnoses in these patients were other gastrointestinal and genitourinary diseases (e.g. haemorrhoids and diverticulitis). In patients in whom diagnostic opportunities had been missed, the most common recorded symptoms were stomach pain, anaemia, and constipation. Independent risk factors for missed diagnostic opportunities included age (<50) (odds ratio [OR] = 2.29 [1.14–4.60]; p=0.02) and female sex (OR = 2.19 [1.16–4.16]; p=0.03). Lack of continuity of care also appeared to contribute to increased risk of missed diagnosis: each additional physician consulted by one patient more than doubled the risk of missed diagnosis (OR = 2.05 [1.53–2.74], p<0.001).21
Combined with the marked reduction in survival rates in patients diagnosed with metastatic compared with earlier stage CRC at time of diagnosis, these data reinforce the importance of optimising screening strategies and physician training to identify CRC signs and symptoms in all at-risk populations.21
Patient-reported outcomes in CRC: focus on preserving quality of life
Colorectal cancer is one of the most commonly diagnosed cancers worldwide and nearly half of patients will develop metastatic disease. As the goal of treatment in the metastatic setting is generally to extend survival while maximising the patient's health-related quality of life, patient-reported outcomes (PROs) play an important role in ensuring treatment strategies achieve the optimum benefit–risk profile.22,23
Benefits of using PROs in CRC22
PROs are common assessment measures in CRC treatment, but the need to standardise their use to assist in efficient and effective synthesis of the evidence was highlighted by authors of a European Society of Digestive Oncology workshop.22
The workshop authors identified PRO measures (PROMs) from a systematic review of prospective CRC surgical studies. Across the 104 studies, a total of 58 different PROMs were identified. Collectively, the measures featured 917 items and covered 51 outcome domains. The domains comprising the most items were ‘anxiety’ (9.2%), ‘fatigue’ (7.3%) and ‘physical function’ (6.9%). No single PRO domain was included in all PROMs. The most commonly used PROM was the EORTC QLQ‐C30 (in 50 studies), but most measures (69%; n=40) were used in only one study.23
Potential for immunotherapy in CRC
Tumour genomic profiling and identification of the CMS subtypes affords the potential for further tailoring of treatment in CRC. The use of targeted agents (such as those targeting RAS- or BRAF- mutated tumours) in metastatic CRC is already informed by tumour molecular/genomic profile.12
Another compelling use of molecular profiling in CRC is to identify microsatellite unstable tumours, which may be especially sensitive to immune checkpoint inhibitors. Microsatellite instability (MSI) leads to either insertion or deletion of repeating units, and is attributed to defects in the DNA mismatch repair (MMR) system. The MSI subgroup makes up approximately 15% of all CRCs, but its prevalence is stage dependent: 15% of stage II–III CRCs are MMR deficient (dMMR), but only 4–5% of stage IV CRCs. CRC patients with MSI high tumours present with a distinct clinical and pathological pattern, such as proximal colon location in younger patients, and early stage and poorly differentiated tumours that exhibit an abundance of tumour infiltrating lymphocytes. As a result of the robust immune response observed in these tumours, clinical trials are underway to evaluate the potential benefit of anti-programmed cell death 1 (PD-1) checkpoint inhibitor therapy in dMMR CRC.24
Although immunotherapy has so far not had the same impact on clinical practice in CRC as it has in other tumour types such as NSCLC, research is ongoing. This also includes evaluation of combination strategies, including the combination of immunotherapies with targeted therapies, and to identify other CRC subpopulations who may benefit from immune-targeted approaches.24,25
International Agency for Research on Cancer (IARC). http://gco.iarc.fr/today/data/factsheets/cancers/10_8_9-Colorectum-fact-sheet.pdf (Accessed April 2019).
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Page last updated: June 2019
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