Epidemiology, risk factors and survival

Prevalence

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 behaviors 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

*Both sexes, all ages.

Reproduced from IARC CRC fact sheet 2020¹ (GLOBOCAN data).
CRC, colorectal cancer; IARC, International Agency for Research on Cancer.

Risk factors

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.⁵

A number of other CRC risk factors have been identified, including:⁶

• Inflammatory bowel disease

• Family history (in a first-degree relative)

• Elevated body mass index

• Reduced physical activity

• Alcohol consumption

• Cigarette smoking

• Dietary factors, with high red meat consumption increasing risk, and high fruit and vegetable intake conferring protection

Survival

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-standardized, 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 countries in 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:⁴

• Changes in bowel habits

• General or localized abdominal pain

• Weight loss without other specific causes

• Weakness, iron deficiency and anemia

Symptoms are seldom CRC specific and tend to be associated with relatively large tumors at an advanced stage of disease.⁴

A complete work-up is carried out to achieve an accurate histological diagnosis of the primary tumor, assess the baseline characteristics of the patient and determine the extent of the disease.⁴ In the absence of a bowel obstruction or massive hemorrhage, a total colonoscopy is used for diagnostic confirmation of colon cancer.⁴ Endoscopic investigation enables exact localization and biopsy of the lesion, and detection and removal of (further) synchronous precancerous or cancerous lesions.⁴ Pathological stage should be evaluated in line with the tumor, node and metastasis (TNM) classification system.⁴

Clinical management

The improvement in CRC outcomes observed in more developed countries is thought to be associated with effective screening programs that aid detection at earlier stages of disease, and with improved therapeutic management approaches.^2,4

Guidance recommends screening programs 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 fecal 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 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 individualized challenge, owing to the numerous genes (tumor 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.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 characterization of CRC subtypes (e.g. consensus molecular subtypes [CMS]) offers the potential to identify biomarkers associated with treatment response that can inform targeted therapeutic approaches.^13,14

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

Adapted from Guinney J, et al. (2015)¹⁴

CMS, consensus molecular subtype; MSI, microsatellite instability

Modifiable risk factors in CRC

Modifiable risk factors for CRC include smoking, high red meat consumption, obesity and physical inactivity.⁴ Primary prevention strategies targeting modifiable risk factors have 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

• Increased CRC risk: excessive alcohol consumption and a cholesterol rich diet; a diet low in folic acid and vitamin B6 intake

• Decreased CRC risk: eating (legume seeds) ≥3 a week; eating brown rice at least once a week; lower meat consumption, and a diet containing dairy products and calcium

Frequent consumption of cooked green vegetables, nuts, dried fruit, pulses and brown rice were associated with lower risk of colorectal polyps.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. hemorrhoids and diverticulitis). In patients in whom diagnostic opportunities had been missed, the most common recorded symptoms were stomach pain, anemia and constipation. Missed diagnostic opportunities were more than twice as likely to occur in patients aged <50 years and female patients.²¹ 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.²¹

Combined with the marked reduction in survival rates for metastatic CRC, these data reinforce the importance of optimizing screening strategies and physician training to diagnose CRC as early as possible, particularly in at-risk populations.²¹

Patient-reported outcomes in CRC: focus on preserving quality of life

Nearly half of all patients with CRC will go on to develop metastatic disease. As the goal of treatment in the metastatic setting is generally to extend survival while maximizing the patient's health-related quality of life, patient-reported outcomes (PROs) play an important role in maximizing the benefit–risk profile of treatment.^22,23

Benefits of using PROs in CRC²²

1. PROs allow for early detection of distress in a patient

2. PROs provide a valuable opportunity for the patient to be heard

3. PROs have led to an increase in symptom-related actions taken by the oncologist/treating physician, when used in clinical practice

4. PROs allow for symptoms to be discussed more openly and frequently, in particular chronic and non-specific symptoms

5. Obtaining PRO information prior to a patient’s visit does not seem to increase the consultation time

PROs are common assessment measures in CRC treatment, but the need to standardize 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%). 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

Tumor 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 tumors) in metastatic CRC is already informed by tumor molecular/genomic profile.¹² 

Another compelling use of molecular profiling in CRC is to identify microsatellite unstable tumors, 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 tumors present with a distinct clinical and pathological pattern, such as proximal colon location in younger patients, and early stage and poorly differentiated tumors that exhibit an abundance of tumor infiltrating lymphocytes. As a result of the robust immune response observed in these tumors, 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 tumor types such as NSCLC, research is ongoing. This also includes evaluation of combination strategies, including the combination of immunotherapies with targeted therapies, and identification of other CRC subpopulations who may benefit from immune-targeted approaches.^24,25