**Author details**

Sanjay Saran Department of Endocrinology, SMS Medical College and Associated Group of Hospitals, Jaipur, Rajasthan, India

\*Address all correspondence to<EMAIL_ADDRESS>
© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


**4. Colorectal cancer screening uptake**

Participation in screening has varied greatly among different regions. The Netherlands showed the highest participation rate (68.2%) and some areas of Canada showed the lowest (16%). Participation rates were highest among women and in programs that used the iFOBT test. The iFOBT test has been the most widely test used in screening program worldwide nowadays. The advent of this test has increased participation rates and the detection of positive results [13].

In a large scale study conducted in Asia Pacific region, 27% of respondents aged 50 years and older had undergone previous CRC testing; the Philippines (69%), Australia (48%), and Japan (38%) had the highest participation rates, whereas India (1.5%), Malaysia (3%), Indonesia (3%), Pakistan (7.5%), and Brunei (13.7%) had the lowest rates [21].

### **5. Barriers for colorectal cancer screening**

Community with cancer tends to present to cancer services in the later stages of the disease, and this late presentation has severe, often fatal, consequences. Therefore, increasing awareness about cancer signs and symptoms could contribute to earlier presentation and improvements in cancer outcomes Despite the prevalence of colorectal cancer and the many screening tests available, the number of people going for these screening tests are very low [22]. This is rather alarming and many studies have been conducted worldwide to discover and analyze the causes of low turnout for colorectal cancer screening [23].

### **5.1 Poor knowledge of CRC symptoms and risk factors**

A majority of the studies found that the largest barrier towards colorectal cancer screening is poor knowledge of the general public towards the risk factors,

symptoms and screening tests available for CRC. A recent multi-center, international study involving 14 countries or regions in the Asia Pacific region reported considerable deficiencies in knowledge of CRC symptoms and risk factors, and suggested that this could lead to poor uptake of CRC screening tests. One research indicates that there is a lack of awareness among community about CRC symptoms, i.e. only 40.6% of 2379 participants recognized 'blood in stool' as a warning sign for CRC. Other causes of delayed detection and diagnosis include denial, negative perceptions of the disease, the over-reliance on traditional medicine, misperceived risk, emotional barriers and negative perceptions towards screening. Cancer awareness campaigns and their evaluation are sparse in low- and middle-income countries.

Many stated that they were too busy, or the tests were too time consuming. Thirdly, there is limited access to centers that provide such screening tests [23]. The most common barrier for screening is because FOBT test is unavailable in the primary care clinic. FOBT is in fact easily available and free in certain health care facilities but only few health clinics have this test. In most of the primary care health clinics, the test needs to be sent to nearest hospital laboratory and because of that it

Majority of patients will come to primary care as their first consult. Wellness clinic has been implemented in primary care clinics. This clinic is meant for patients to come for screening. However, the programme in the certain clinic is mainly targeting on screening cardiovascular risk factors such as diabetes, hypertension and hypercholesterolaemia. Little is done for cancer screening. Cervical cancer screening has the highest patient uptake (43%) because of the incorporation of Pap smear programme in maternal and child health clinic which is run in primary care

There are many people who do not perceive that they are at risk of getting CRC. This low perceived risk is attributable to several factors, such as not having a family history of CRC, not experiencing any signs or symptoms, living a healthy or lowrisk lifestyle or being free from health problems in general [23]. Another barrier that many studies report is the negative perception towards screening methods, with a more negative view towards more invasive procedures such as endoscopicbased procedures. Among the negative views reported were fear, pain experienced or perceived pain towards screening procedures, feeling of embarrassment, health damage, inconvenience and lack of confidence in screening efficacy. Fear of test result is a common barrier for any test. It is especially when most people relate cancer to untreatable and fatal disease. A study in Italy also showed the same finding where being concern with the test result is the most important reason of

Throughout the world there are widespread differences in CRC screening implementation status and strategy. Differences can be attributed to geographical variation in CRC incidence, economic resources, healthcare structure and infrastructure to support screening such as the ability to identify the target population at risk and cancer registry availability. Despite well-developed CRC screening guidelines, implementation of screening is markedly different among countries and regions worldwide [26]. What is more, there is also inequitable access to CRC screening, at least in relation to socioeconomic status and ethnicity. The mecha-

**Table 1** showed some evidence from previous studies on CRC screening and intervention modalities. Mixed of intervention through telephone counseling, a mail invitation, email/text-message reminder, health talk, video and brochure are some intervention has been done and showed a positive finding on CRC screening uptake. The government needs to take action for CRC screening programme and

become tedious and not commonly ordered [25].

*DOI: http://dx.doi.org/10.5772/intechopen.94396*

**5.4 Patient's negative perception towards CRC screening**

facilities [25].

*Public Health: Prevention*

patient's noncompliance.

nism, however, is not well understood [27].

**6. Intervention related to CRC screening**

**5.5 Others factor**

**9**

Studies from Hong Kong, Australia and USA also reported low levels of knowledge of CRC [22]. Other than that, those with poor educational backgrounds are more likely to have language and communication barriers, and have a harder time understanding materials or recommendations. Also identified being the male gender to have poorer CRC knowledge, as females have better health knowledge due to their traditional role as carers. With particular focus to a multiracial country, the language barrier becomes a prominent problem. Subjects have complained of the limited language diversity in cancer screening awareness material, hence result in poorer understanding. This in particular would be a problem for the older generation, as many are less multilingual than the younger generation; and this becomes a large problem as CRC has a higher prevalence among those above 50 years of age [23]. Few Asian countries have established nationwide CRC awareness and screening programs, with Taiwan, Korea, Singapore and Japan being the only Asian countries that have existing national CRC screening guidelines and programs [23].

## **5.2 Lack of physician's recommendation**

Another major factor of poor knowledge within the population is the severe lack of physician's recommendation to do CRC screening [23]. In Asia Pacific region, countries with low CRC screening participation were found to have the lowest physician recommendation rate [21]. According to an American study, failure of a clinician to suggest screening was identified as the most important barriers to CRC screening [24].

The most common barrier was "unavailability of the test". The two most common patient factors are "patient in a hurry" and "poor patient awareness". This may be related to the low availability of the test in the primary care setting and poor awareness and understanding of the importance of colorectal cancer screening among patients.

### **5.3 Lack of access of CRC screening**

A notable category of barriers that people face that hinders them from CRC screening participation is access barriers. One of them is financial constraints. Another is time constraint. In a busy clinic, long patient waiting time may lead to patient in a hurry and refusal despite being recommended. It is known that the conventional gFOBT is troublesome and embarrassing for patients to do. Another drawback of the test is patient has to be on certain food restriction and the test has to be repeated at least twice. Therefore, many countries have now moving towards using immunological test since it is less troublesome and better detection rate [25].

### *Public Health: Prevention DOI: http://dx.doi.org/10.5772/intechopen.94396*

symptoms and screening tests available for CRC. A recent multi-center, international study involving 14 countries or regions in the Asia Pacific region reported considerable deficiencies in knowledge of CRC symptoms and risk factors, and suggested that this could lead to poor uptake of CRC screening tests. One research indicates that there is a lack of awareness among community about CRC symptoms, i.e. only 40.6% of 2379 participants recognized 'blood in stool' as a warning sign for CRC. Other causes of delayed detection and diagnosis include denial, negative perceptions of the disease, the over-reliance on traditional medicine, misperceived risk, emotional barriers and negative perceptions towards screening. Cancer awareness campaigns and their evaluation are sparse in low- and middle-income

Studies from Hong Kong, Australia and USA also reported low levels of knowledge of CRC [22]. Other than that, those with poor educational backgrounds are more likely to have language and communication barriers, and have a harder time understanding materials or recommendations. Also identified being the male gender to have poorer CRC knowledge, as females have better health knowledge due to their traditional role as carers. With particular focus to a multiracial country, the language barrier becomes a prominent problem. Subjects have complained of the limited language diversity in cancer screening awareness material, hence result in poorer understanding. This in particular would be a problem for the older generation, as many are less multilingual than the younger generation; and this becomes a large problem as CRC has a higher prevalence among those above 50 years of age [23]. Few Asian countries have established nationwide CRC awareness and screening programs, with Taiwan, Korea, Singapore and Japan being the only Asian countries that have existing national

Another major factor of poor knowledge within the population is the severe lack of physician's recommendation to do CRC screening [23]. In Asia Pacific region, countries with low CRC screening participation were found to have the lowest physician recommendation rate [21]. According to an American study, failure of a clinician to suggest screening was identified as the most important barriers to CRC

The most common barrier was "unavailability of the test". The two most common patient factors are "patient in a hurry" and "poor patient awareness". This may be related to the low availability of the test in the primary care setting and poor awareness and understanding of the importance of colorectal cancer screening

A notable category of barriers that people face that hinders them from CRC screening participation is access barriers. One of them is financial constraints. Another is time constraint. In a busy clinic, long patient waiting time may lead to patient in a hurry and refusal despite being recommended. It is known that the conventional gFOBT is troublesome and embarrassing for patients to do. Another drawback of the test is patient has to be on certain food restriction and the test has to be repeated at least twice. Therefore, many countries have now moving towards using immunological test since it is less troublesome and better

CRC screening guidelines and programs [23].

**5.2 Lack of physician's recommendation**

**5.3 Lack of access of CRC screening**

countries.

*Colorectal Cancer*

screening [24].

among patients.

detection rate [25].

**8**

Many stated that they were too busy, or the tests were too time consuming. Thirdly, there is limited access to centers that provide such screening tests [23]. The most common barrier for screening is because FOBT test is unavailable in the primary care clinic. FOBT is in fact easily available and free in certain health care facilities but only few health clinics have this test. In most of the primary care health clinics, the test needs to be sent to nearest hospital laboratory and because of that it become tedious and not commonly ordered [25].

Majority of patients will come to primary care as their first consult. Wellness clinic has been implemented in primary care clinics. This clinic is meant for patients to come for screening. However, the programme in the certain clinic is mainly targeting on screening cardiovascular risk factors such as diabetes, hypertension and hypercholesterolaemia. Little is done for cancer screening. Cervical cancer screening has the highest patient uptake (43%) because of the incorporation of Pap smear programme in maternal and child health clinic which is run in primary care facilities [25].

### **5.4 Patient's negative perception towards CRC screening**

There are many people who do not perceive that they are at risk of getting CRC. This low perceived risk is attributable to several factors, such as not having a family history of CRC, not experiencing any signs or symptoms, living a healthy or lowrisk lifestyle or being free from health problems in general [23]. Another barrier that many studies report is the negative perception towards screening methods, with a more negative view towards more invasive procedures such as endoscopicbased procedures. Among the negative views reported were fear, pain experienced or perceived pain towards screening procedures, feeling of embarrassment, health damage, inconvenience and lack of confidence in screening efficacy. Fear of test result is a common barrier for any test. It is especially when most people relate cancer to untreatable and fatal disease. A study in Italy also showed the same finding where being concern with the test result is the most important reason of patient's noncompliance.

### **5.5 Others factor**

Throughout the world there are widespread differences in CRC screening implementation status and strategy. Differences can be attributed to geographical variation in CRC incidence, economic resources, healthcare structure and infrastructure to support screening such as the ability to identify the target population at risk and cancer registry availability. Despite well-developed CRC screening guidelines, implementation of screening is markedly different among countries and regions worldwide [26]. What is more, there is also inequitable access to CRC screening, at least in relation to socioeconomic status and ethnicity. The mechanism, however, is not well understood [27].


**1.2 Pathophysiology of AMD in humans**

Although incompletely understood, AMD is a complex disease that results from a mix of genetic predisposition, environmental factors, and age. There are many models that attempt to explain the pathophysiology of AMD, the underlying disease mechanisms of which are multifaceted and not mutually exclusive. These can be categorized as oxidative stress, inflammation, dysregulated antioxidants, lipid metabolism, and angiogenesis [13]. This chapter highlights the multifactorial etiology of RPE damage and dysfunction, a key event in AMD pathogenesis and briefly touches on other aspects of AMD pathophysiology [3].

A properly functioning RPE is important for retinal homeostasis because of the multiple roles it plays including: transportation of nutrients from the choroidal vasculature; absorption of stray photons of light; phagocytosis of photoreceptor outer segments; metabolism of fatty acids; formation of the blood-retinal barrier; regulation of subretinal water transport; and regeneration of visual pigments during the visual transduction cascade [14]. Some retinal changes that are characteristic of AMD include dysfunction of the RPE, sub-RPE deposition of lipids and proteins, neovascularization of the choroid or retina, and disciform scar formation [13]. Most people develop asymptomatic extracellular lipid deposition underneath the RPE. However, as these lesions enlarge they can cause dysfunction of the RPE [15]. Although an exact stepwise development of disease is not clear, early AMD is defined by the appearance of drusen under the RPE with thickening of Bruch's membrane (BrM). Consequently, this impairs the ability of the RPE to efflux fluids across BrM and to deliver nutrients such as glucose, vitamin A (all-*trans* retinal), and docosahexenoic acid (DHA), causing stress on the RPE and photoreceptors [15]. The impaired transport across BrM may exacerbate formation of drusen, thus causing a vicious cycle of pathology.

Moreover, the RPE is susceptible to oxidative stress from high oxygen utilization, prolonged exposure to visible light, lipid oxidation by photoreceptors and drusen, and cigarette smoking [4, 13]. During phototransduction, visual pigments called opsins use the chromophore 11-*cis* retinal to absorb photons of light. Upon absorption, the 11-*cis* configuration becomes all-*trans*, the initiating step for phototransduction. To convert the all-*trans* back to 11-*cis*, it must proceed through the retinoid cycle whereby the RPE re-isomerizes the molecule back to its 11-*cis* conformation. A byproduct of this cycle is A2E, which accumulates in lipofuscin — particularly in the macula — and reacts with oxygen to form free radicals. This may partly explain why the macula is preferentially affected in AMD [15]. Lipofuscin also accumulates in aging eyes which may exacerbate oxidative stress by forming free radicals and inhibiting the RPE's function of degrading organelles [4, 13]. In short, there are many etiologies of oxidative stress and the literature supports that it is an important part of AMD pathophysiology [13].

Identification of SNPs in several complement factor components sheds light on its role in AMD pathogenesis. The complement system is beneficial for its role in innate immunity and encouraging phagocytosis and removal of unwanted cellular material; however, dysregulation of this system can cause damage and inflammation in surrounding tissue [4]. Similarly, inflammation is a cascade of events that is beneficial in the short term in response to foreign and damaged material, yet chronic inflammation can be harmful and may contribute to the development of AMD [16]. There are many genetic variants of complement genes associated with AMD and one example is the Y402H polymorphism in the *CFH* gene. CFH normally regulates the alternate complement pathway by interfering with C3b and factor B interaction and inhibiting the formation of C3 convertase [17]. However, the

Y402H polymorphism prevents CFH from binding to BrM or to malondialdehyde, a byproduct of lipid peroxidation, ultimately causing unregulated complement activation and chronic inflammation [4, 13, 17].

Antioxidants scavenge reactive oxygen species (ROS) thereby attenuating oxidative stress. Nuclear factor erythyroid 2-related factor 2 (NRF2) is a transcription factor that upregulates antioxidants when signaled by oxidative stress. Studies of *Nrf2*−/− mice showed retinal damage and changes such as thickened BrM, sub-RPE deposits, and complement activation. Thus, antioxidants may protect against AMD, and in contrast, the loss of antioxidants, as shown in the *Nrf2*−/− mice, may exacerbate AMD progression [13].

In humans, the inner and outer retina are supplied by the retinal artery and choroidal circulation, respectively. The choroidal circulation is located beneath BrM, which acts as a physical barrier. Drusen accumulation may disrupt this barrier and when conditions favor angiogenesis, permeable blood vessels lacking endothelial tight junctions and pericytes can develop between the retina and choroidal blood vessels. These vessels can grow into the central retina, a process called choroidal neovascularization (CNV) as seen in exudative AMD [15, 18, 19]. Neovascularization may also originate from the retina in a process called retinal angiomatous proliferation (RAP) [17]. Vascular endothelial growth factor (VEGF) plays a major role in angiogenesis. There is sufficient evidence that points to the role of VEGF in exudative AMD pathogenesis, given the higher VEGF levels in AMD patients and the successful decrease in neovascularization with anti-VEGF agents [13]. Pigment epithelium-derived growth factor (PEDF) is an antiangiogenic molecule whose expression is reduced in eyes with AMD. This imbalance between angiogenic VEGF and antiangiogenic PEDF suggests that homeostasis of vascular factors is disrupted in exudative AMD [15]. In summary, AMD is a multifaceted disease with genetic and environmental risk factors that likely progresses due to a combination of oxidative stress and inflammation, combined with dysregulated antioxidants, lipid metabolism, and increased angiogenesis.

#### **1.3 Classification of AMD**

Disease classification can elucidate pathophysiological processes, prognosis, and guide in clinical decision-making. Drusen, the hallmark lesion of AMD, is visible by fundoscopy and can be classified by their size and border characteristics [15]. Specifically, drusen can be small (< 63 mm), intermediate (63–124 mm), or large (>124 mm). They can also be stratified as hard (well demarcated), soft (poorly demarcated), or confluent (contiguous) [20, 21]. Higher number and larger size of drusen portends greater likelihood of progression in AMD. Moreover, compared to hard drusen, soft drusen tend to be located in the macula and increase risk of progression [21].

AMD is categorized as non-exudative or exudative. There are many ways to stratify AMD, but this chapter uses the classification of the Age-Related Eye Disease Study (AREDS) as follows: no AMD (no or few small drusen), early AMD (multiple small drusen, few intermediate drusen, or mild RPE abnormalities), intermediate AMD (numerous intermediate drusen, at least one large drusen, or geographic atrophy without center foveal involvement), and advanced AMD (geographic atrophy with center foveal involvement or neovascular maculopathy) [22].

Each stage has defining characteristics. The advanced non-exudative form of AMD is known as geographic atrophy (GA) and is defined by slow progressive atrophy of the photoreceptors, RPE, and the choriocapillaris that form sharply demarcated lesions [23]. Advanced exudative AMD represents 10–15% of all AMD and is characterized by growth of choroidal blood vessels through BrM and into the *An Overview of Age-Related Macular Degeneration: Clinical, Pre-Clinical Animal Models… DOI: http://dx.doi.org/10.5772/intechopen.96601*

retina, consequently causing intraretinal or subretinal leakage, hemorrhage, and RPE detachment. These changes can cause acute vision loss [15, 18, 24]. Follow-up data from the AREDS found that progression to advanced AMD is associated with the following retinal risk factors: increased baseline drusen severity, the presence of a large drusen within 1 disc diameter of the fovea, the presence of bilateral medium drusen, the presence of advanced AMD in the fellow eye, and the simultaneous presence of AMD RPE abnormalities and large drusen [25].