Introduction

The incidence of colorectal carcinoma (CRC) is rapidly increasing in India and the world.1 Age-standardized death rate of CRC in India is 2.9 per 100,000 cases, making us the country with the fifth highest mortality rate globally. Understandably, our 5-year survival of CRC patients also ranks among the lowest, being less than 40%.2 Incidence is also increasing in the younger population.34 CRC is a disease, like most solid tumors, that has a well-recognized pathogenesis pathway toward the ultimate development of cancer. Since this usually takes several years, it is possible to detect CRC in early stages with a regular screening strategy. The well-established methodology recommended by guidelines globally is screening sigmoidoscopy/colonoscopy—and can reduce CRC mortality by up to 73%. Awareness, acceptance, and implementation of CRC screening remain a significant public health challenge, globally as well as in India. The challenge is compounded by the fact that population screening for CRC is not part of the Indian national cancer programs. We therefore decided to do this study to determine the actual real-world utility of screening colonoscopy in India. Based on the same, we also discuss pitfalls and strategies to improve early detection of CRC in the community setting.

Methodology

The authors formed a group to discuss the importance of collecting such real-world data and agreed to the final questions for the survey. Based on the American Medical Association (AMA) guidelines, the cutoff age for population colonoscopy screening was accepted as necessary for individuals aged ≥45 years. Accordingly, a Google Form was devised containing three multiple-choice questions (Table 1) and circulated among health care professionals using WhatsApp. Participation was voluntary. Replies were collected over 30 days and duplicates were deleted. The data collected were then tabulated and analyzed.

Results

Data collected were from a total of 2,199 unique individuals. This included 733 health care professionals and their parents. The results are shown in Table 1 and Fig. 1. Overall, 7.13% (98/1,374) of eligible individuals had actually undergone screening colonoscopy in the real world in India.

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Fig. 1: Screening colonoscopy use in the real world among educated Indians (N = 2,199).

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Discussion

Globally, an estimated 19.3 million new cancer cases and almost 10.0 million cancer deaths occurred in the year 2020.56 The incidence of CRC has been increasing in India, with some registries reporting a 20 to 124% increase per year.1 Comparing the global rates of CRC with those of lung cancer (18.7%), liver cancer (7.8%), breast cancer (6.9%), and stomach cancer (6.8%), CRC has a higher death rate of 13.7 per 100,000.1 According to the World Cancer Research Fund (WCRF), India ranks fifth in the world for CRC mortality with an age-standardized rate of 2.9 per 100,000 cases. Our 5-year survival of CRC patients also ranks among the lowest, being less than 40%.2 Thus, trends in incidence and mortality for CRC in India document that it is a real public health care challenge—especially in the states/union territories of Mizoram, Jammu and Kashmir, and Kerala. The southern cities of Thiruvananthapuram, Kollam, Chennai, and Bengaluru had a high incidence of the disease. In the Northeast of India, the lifetime risk of developing CRC is the highest (probability of 1 in 167 for both males and females78; Table 2; Fig. 2). Failure to screen and identify them early leads to the diagnosis at advanced stages of disease, contributing to the high mortality rate.

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Fig. 2: Colon and rectal cancer among the top three regions of India. NE, Northeast.

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Like most solid tumors, the pathogenesis of CRCs is a relatively long process that commences by the development of colorectal polyps in the background of normal mucosa, which then may acquire precancerous features (e.g., dysplasia), further become carcinoma in situ, and finally a malignant tumor.9 The risk is higher in patients with inflammatory bowel disease and hereditary syndromes associated with the development of CRC—like those with familial adenomatous polyposis, Lynch's syndrome. Mutations involving chromosomal instability (CIN) and microsatellite instability (MSI) are other pathways with higher lifetime risks.10111213 Interestingly, the incidence of CRC is increasing in younger adults. This is a global feature that has generated a lot of controversy and compelled guidelines to reduce the age for screening in the general population.1415

The current public health focus of the Ministry of Health, Government of India, is on noncommunicable diseases, including cancers. Details can be obtained from the official Web sites of the National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular Diseases and Stroke (NPCDCS); National Health Mission (NHM); and Ayushman Bharat—Ayushman Arogya Mandir. At present, the priority areas for cancer detection includes breast, cervical, and oral cancers. Screening for CRC is unfortunately not part of the national cancer programs.

The standard well-established method of CRC is screening sigmoidoscopy/colonoscopy. The U.S. Preventive Service Task Force (USPSTF) guidelines and available evidence support routine screening from ages 45 to 75 years, and individualized consideration of screening for ages between 76 and 85 years. USPSTF guidelines recommend several invasive (scopy), noninvasive imaging, indirect visualization, blood tests, and stool tests at varying intervals (from annual to every 10 years).1415 Randomized controlled trials (RCTs) and meta-analyses have demonstrated the efficacy of these techniques in the early identification of CRC.151617 The enhancement of patient outcomes is ascribed to the capability of detecting and excising precancerous polyps during the procedure. In the meta-analysis conducted by Bretthauer et al, it was established that sigmoidoscopy for CRC screening emerged as the sole screening modality for CRC that demonstrated an improvement in longevity and a decrease in all-cause mortality.18

However, this strategy is not without challenges. For instance, conventional colonoscopic screening misses approximately 26.3% of polyps.19 The uptake of screening colonoscopy is suboptimal even in the western world. The Affordable Care Act (ACA) recommends that 80% of the population should be covered to make population screening effective.20 However, only 59% of population coverage has been achieved so far according to published data.21 This is true even in places where the procedure is available free of cost (e.g., Singapore).22 In India, our survey shows that only 7.13% of 1,374 eligible persons actually underwent screening colonoscopy, even among the educated health care professionals and their parents.

Invasive procedure, need for prior preparation of the bowel, requirement for sedation, and the risk of missing out adenomas (up to 14%) are some of the factors that discourage individuals from undergoing the procedure. Also, there is a small risk of complications such as bleeding or bowel tears. The study by Tomaszewski et al evaluated the risk associated with British Columbia Colon Screening Program and concluded that the risk of a serious adverse event occurring 14 days after colonoscopy was 44 per 10,000 colonoscopies, including perforation (6 per 10,000), bleeding (26 per 10,000), and death (3 per 100,000).23 Rabeneck et al also reported that colonoscopy is associated with high risk of colon perforation, especially when done in conjunction with polypectomy.24 Marked discrepancies have also been observed in the impact of screening sigmoidoscopy between male and female populations.15 Females have been identified as having proximal lesions without discernible aberrations in the distal colon, which complicates the screening process via sigmoidoscopy, whereas males exhibit distal lesions that facilitate detection and subsequent referral for colonoscopy to ascertain the extent of the disease. Lack of awareness and limited knowledge were the primary barriers to colonoscopy screening, with fear and embarrassment being higher among women.25 Use of artificial intelligence to assist in adenoma detection has proven to be beneficial in almost all studies performed to date.2627 However, false negatives and false positives still abound. This can add to the emotional burden, increase anxiety, and result in additional tests with their respective toxicities (medical, financial) and occupy precious resources in chasing a bogey. In short, awareness, acceptance, and implementation of CRC screening remain a significant public health challenge, globally as well as in India. In a review by Akanbi et al, researchers concluded that in low- and middle-income countries (LMICs), knowledge about CRC and its screening methods is limited, particularly in rural areas and among lower socioeconomic groups.28 Jones et al, in a study conducted in South India, stated that provider recommendations can help address the low screening rates. If successful, it will reduce the mortality and economic burdens of CRC detected at an advanced stage.29 Efforts to improve awareness have included community-based programs aimed at educating the public about the benefits of early screening and the availability of various screening methods, such as colonoscopy and fecal immunochemical tests (FITs).3031 While current guidelines advocate for CRC screening to commence at the age of 45 years, recent trends indicate a rising incidence of CRC among younger adults aged 20 to 49 years might lead to the commencement of screening at a younger age.3233

A test is good only if it is used in the way that it is intended to be used. A gold standard, when used in only a small percentage of the population, defeats its public health purpose. Screening colonoscopy, as it is available and recommended today, is clearly not the right option for population, especially in India and other LMICs.

Enhancing the Uptake of Screening Colonoscopy/Sigmoidoscopy

Direct visualization techniques (DVTs; sigmoidoscopy and colonoscopy) were crying for help. Alternate visualization as well as imaging tools stepped in first (analog, digital, or artificial intelligence [AI] assisted digital).34 Advanced colonoscopy techniques present a promising avenue for enhancing the detection and removal of polyps. Such techniques include high-definition imaging, chromoendoscopy (use of contrast dyes to detect mucosal abnormalities), narrowband imaging (NBI; which uses optical filters to narrow the red light, thereby decreasing the penetration depth and results in a green-blue image that accentuates the mucosal vasculature and surface pattern morphology), and other newer devices like the G-EYE endoscope and full-spectrum endoscopy. These have shown to maximize adenoma detection and increase the scope for CRC detection.11

The next progress was the development of two other broad groups: stool-based and blood-based tests.35 Stool-based test include FIT, guaiac fecal occult blood test (gFOBT), and multitargeted stool DNA test (MT-sDNA).35 Blood-based tests consist of cell-free DNA analysis, methylated SEPT-9, and Guardant Health's Shield.353637Table 3 shows various screening methods available for CRC and their sensitivity, specificity, adherence, and additional remarks. Guardant Health's Shield utilizes genetic, epigenetic, and proteomics in circulating tumor DNA and was recently approved by the U.S. FDA (sensitivity of 91% in CRC, 20% in advanced adenoma, and specificity of 92%).38 This publication was extensively discussed in the Oncology beyond the Obvious webinar series on September 10, 2024.39Fig. 3 enumerates the various blood- and stool-based tests currently available.

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Fig. 3: Enhancing colorectal cancer (CRC) screening: blood-based and stool-based tests.

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Noninvasive tests like FOBT, gFOBT, FIT, and sDNA can be used as initial screening modalities, especially in people who are deferring invasive procedures like colonoscopy. The advantages of these are that the tests require no bowel preparation, dietary restrictions, or medication adjustments. Samples can be collected at home, making it more convenient and increasing adherence, posing no risk of damage to the colon.40 Coronado et al conducted an RCT demonstrating a 17.5% increase in CRC screening with blood-based testing compared with usual care. Liang et al found that offering a blood test as a secondary option increased screening by 7.5% among those who previously declined colonoscopy or FIT.41 However, a positive result still requires colonoscopy for confirmation.42 Delays in colonoscopy for positive FIT can lead to worse CRC outcomes, as demonstrated by Forbes et al. Therefore, a colonoscopy should be performed as soon as possible following a positive alternate screening test.4344

Conclusion

Colonoscopy/sigmoidoscopy remains the gold standard for CRC screening in the average-risk general population. However, its actual use is woefully inadequate in the real world globally. This is also true for LMICs like India. As a result, we have excessive deaths due to CRC in our people. Several factors contribute to this reality, including but not limited to colonoscopy being an invasive procedure, requiring diligent preparation, and being operator dependent. Expanding screening options to include noninvasive tests like stool-based and blood-based assays have the potential to improve rates of CRC screening and save lives. Tests like Guardant Health's Shield that identify high-risk individuals among the average-risk general population will persuade fence sitters to undergo the gold standard, namely, colonoscopy/sigmoidoscopy, and should be proactively used for people who can afford them (Table 4).