Colorectal cancer (CSC) is one of the most common malignant tumors in human beings, and its incidence and mortality rate rank third and fourth among all cancers, respectively. According to statistics, in 2008, there were 1,234,000 cases of CRC and 608,000 deaths worldwide; among them, men had 663,000 cases, accounting for 10% of all malignant tumors and ranking the third; women had 571,000 cases, accounting for 9.4% of all malignant tumors and ranking the second. The proportion of male incidence is significantly higher than that of female, and the ratio of male to female incidence is 1.4:1. In 2008, China had 220,000 cases of CRC and 109,000 deaths (http://globocan.iarc.fr).
Sixty percent of CRC cases occur in developed countries, and the highest incidence rate is in Australia/New Zealand. CRC has significant geographical distribution variability, with incidence rates up to 25 times higher or lower. China was originally a low incidence country for CRC, but in recent years, the incidence of colorectal cancer has been on the rise year by year in China, with the incidence rate ranking 5th among all tumor incidence rates, and the annual incremental rate of CRC incidence in large cities is even higher than the global average annual incremental rate. the age-standardized mortality rate of CRC continues to increase, unlike some tumors, such as lung, liver, and stomach cancer, whose mortality rates have been decreasing in recent years The trend of CRC mortality is decreasing in recent years.
CRC is a malignant tumor that is preventable, partially curable, and most of them can be treated to prolong survival time. However, because the symptoms of CRC are not obvious in the early stage, most of them are already in the middle or late stage when they are diagnosed, and once metastasis or recurrence occurs, their prognosis will be extremely poor. Therefore, the prevention and follow-up study of CRC need our attention urgently.
I. Prevention of colorectal cancer
Not all cancers can be prevented by the existing means to reduce the incidence of disease and death rate. The United States is a very good example of the effectiveness of interventions for CRC. The United States has been diagnosing and preventing CRC since the mid-1970s, mainly through health education to change the national poor dietary and lifestyle habits, improving CRC treatment methods and conducting screening.
In early 2010, the American Cancer Society and the North American Cancer Ranking Consortium jointly published an exciting report in the journal Cancer, stating that the incidence and mortality rates of CRC in the United States in the early 21st century had decreased by 22% and 26%, respectively, compared with the mid-1970s, and that half of the reasons for the decrease in incidence were due to changes in people’s lifestyle habits and the reduction of CRC risk factors. The other half is due to the introduction of CRC screening. Of the 26 percentage points of the reduction in morbidity and mortality, 14 percentage points came from dry CRC screening, while the other 9 and 3 percentage points came from reduced exposure to CRC risk factors and improved treatment, respectively [3].
The prevention of CRC is divided into two levels: first, primary prevention, etiological prevention; and second, secondary prevention, mainly screening.
1. High-risk factors for colorectal cancer
Although the true etiology of CRC is not yet clear, the risk factors for its development have been studied more thoroughly in China for more than 20 years, and it is believed that CRC is the result of the synergistic effect of environmental, dietary, and lifestyle and genetic factors.
1.1 Dietary factors
A high-fat diet and excessive intake of animal proteins, especially red meat, are the main risk factors for the development of CRC [4,5]. Studies have shown that the intake of red meat proteins leads to the occurrence of CRC mainly related to the way meat is processed, and meat processed at high temperatures is prone to the production of carcinogenic substances heterocyclic amines, and the intake of heterocyclic amines increases the incidence of CRC, and mutations in genes regulating heterocyclic amine metabolizing enzymes are also associated with the development of CRC. The most likely carcinogenic mechanism of a high-fat diet is increased excretion of bile acids, which ultimately increases exposure of the colorectal mucosa to toxins and cancer promoters.
Dietary fiber resists degradation by digestive enzymes in the body and is mainly composed of non-polysaccharides, found in vegetables, fruits, and grains. Fibrous matter dilutes carcinogens in the colon by making fecal volumes high; fibrous matter adsorbs bile salts (CRC promoters): fibrous matter is fermented by bacteria to produce short-chain fatty acids and lower pH, which is detrimental to cancer cell growth. Studies with large sample sizes have confirmed that a high-fiber diet is negatively associated with the development of CRC, with two studies from several European and American medical centers enrolling 33,971 (3,591 cases with adenomas) and 519,978, respectively, showing that a high-fiber diet reduces the risk of CRC by 27% and 40%, respectively [6,7].
Adenomatous polyps are increased in smokers, and the new Asia-Pacific CRC Working Group found 91 colorectal tumors and 24 progressive adenomas in 395 asymptomatic smokers, and only 76 colorectal tumors and 15 progressive adenomas in 452 nonsmokers. This suggests that the risk of colorectal tumors in smokers is about 1.5 times greater than in nonsmokers, and the risk of progressive adenomas is about 1.9 times greater than in nonsmokers.
In addition, trials have shown that dietary A, C, E, selenium, and calcium are beneficial for cancer prevention, especially calcium intake is beneficial for the prevention of colon cancer in women. Although the value of folic acid for the prevention of CRC is still controversial|[8-10], in general, the use of folic acid in the absence of early adenomas has a preventive effect on CRC; however, the effect on the prevention of recurrence after the removal of adenomas that have already appeared or adenomas is uncertain|[11,12]. Obesity and lack of physical activity were negatively associated, and controlled studies showed a positive association between total energy intake and the risk of colon cancer.
1.2 Disease factors
Chronic diseases such as chronic inflammation of the intestine, polyps, adenomas, and Crohn’s disease can be cancerous. It is estimated that colon cancer occurs in 3%-5% of chronic ulcerative colitis, and the cancer rate is 12.5% at 20 years of history and 40% at 30 years. It is believed that about 15-40% of colon cancers originate from colon polyps with a pre-cancerous course of 5-20 years, and the malignancy rate of adenomas in patients with familial adenomatous polyposis is 9.4% at the age of 25, 50% at the age of 30, and almost 100% before the age of 50, with a median age of malignancy of 36. Adenomas can also become cancerous, and their cancer rate is related to the size of the adenoma, pathological type, presence or absence of a tip, and degree of atypical hyperplasia, etc. Adenomas <1 cm have a cancer rate of <2%; adenomas >3 cm have a cancer rate of more than 40% [13]. The cancer rate of Crohn’s disease is lower than that of chronic ulcerative colitis, but much higher than that of the general population by 4 to 20 times. About 10% of Crohn’s disease carcinomas are multiple and therefore have a poor prognosis [14]. In addition, statistics have shown that: chronic diarrhea, mucus and blood stools; history of mental stimulation; history of cholecystectomy; history of appendicitis; history of appendicitis; history of constipation; family history of tumors; history of unclean water; history of red-hot fish; and history of laxative drugs are also high risk factors for CRC [15].
1.3 Genetic factors
Although most patients are disseminated, 15% of patients have a genetic basis. People with a family history of colorectal cancer have a higher risk of developing colorectal cancer than the general population, and those whose parents have colorectal cancer have a twofold higher risk of developing the disease than the general population, with a significantly lower age. From a comparative study of twins, the contribution of genetic factors in sporadic colorectal cancer amounted to 35%, and the cumulative risk of colorectal cancer in first-degree relatives of those with prior evidence of colon cancer was two times higher than that of first-degree relatives of those with prior evidence of rectal cancer. In the presence of familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HAP), the cumulative risk of colorectal cancer in the first-degree relatives of colon cancer precursors was 35%.
In families with a history of familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HNPCC), blood relatives are at high risk for colorectal cancer because both are autosomal dominant.
2. Primary prevention measures
It is believed that 80% of tumors are related to environmental factors and bad living habits, and CRC is one of them. In addition, colorectal cancer mostly starts with adenoma and has a long development process. If precancerous lesions can be detected and removed early, the occurrence of cancer can be effectively prevented. Therefore, the primary prevention of CRC includes not only the modification of poor living habits and possible chemoprevention, but also the primary prevention of adenomas at the beginning and the secondary prevention of adenomas after endoscopic removal.
2.1 Improving poor dietary and lifestyle habits, including
①Improve the diet structure and increase the intake of dietary fiber;
②Appropriate supplementation of calcium and vitamin D;
③For those with low blood folate level, take appropriate supplementation of folic acid;
④ Quit smoking; ⑤ Actively participate in physical activities, control body weight and prevent obesity.
2.2 Chemoprevention
High-risk group of colorectal tumor (>50 years old. Especially men, family history of colorectal tumor or other tumors, smokers, overweight, history of gallbladder surgery, history of schistosomiasis, etc.) can be considered to be treated with non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and selective cyclooxygenase-2 (COX-2) inhibitors [16]; however, attention should be paid to the adverse effects of the drugs. adverse drug reactions need to be noted. A prospective study by Chan et al [17] at Massachusetts General Hospital, Harvard Medical School, USA, not only confirmed the preventive effect of aspirin on CRC, but also suggested that the duration of aspirin use for prevention and the dose to minimize the risk of CRC should be taken continuously for at least 6 years at a dose of 325 mg, 2 times/d.
2.3 Aggressive treatment of precancerous disease
The precancerous lesions of colorectal cancer are relatively clear, mainly adenoma, familial adenomatous polyposis, ulcerative colitis, if these lesions can be removed at an early stage, it is expected to greatly reduce the occurrence of colorectal cancer. Most studies have concluded that more than 80% of colorectal cancers occur on the basis of preexisting adenomas. Therefore, any adenomas found on examination should be removed to prevent the occurrence of colorectal cancer in the future.
Colorectal adenoma (CRA) is the most predominant precancerous disease in CRC. The risk of progressive adenoma or advanced adenoma is higher. A progressive adenoma is defined as one of the following three conditions.
(i) polyps or lesions ≥10 mm in diameter;
(ii) choriocapillary adenoma, or mixed adenoma with >25% choriocapillary-like structures; (iii) high-grade intraepithelial neoplasia. Endoscopic removal of CRA, especially progressive adenomas, can prevent CRC to some extent, but CRA has a significant tendency to recur. Early scholars generally believed that endoscopic removal of CRA and endoscopic follow-up could reduce the incidence of CRC by more than 75%, but recent studies have found that this method is not as satisfactory.
Martinez et al. followed 9,167 patients after CRA removal for an average of 4 years and found that 46.7% of patients had recurrent CRA, 11.2% evolved into progressive CRA, and 0.6% evolved into CRC. the 3-year recurrence rate after removal of certain CRAs was as high as 40% to 50%. The results of a study from five medical centers in China showed that the 1-year recurrence rate after progressive CRA removal was as high as 59.46% and the 5-year recurrence rate was 78.07%.
Therefore, the corresponding follow-up after CRA removal should also be performed, and patients with progressive adenoma should undergo colonoscopy again after 3-6 months; patients with other polyps should undergo full colonoscopy again after 1 to 3 years (follow-up as shown in Figure 1 [20]). Prevention of recurrence after adenoma removal can be considered with pharmacological NSAIDs and selective COX-2 inhibitors. Calcium and vitamin D| supplementation, a high-fiber diet, and the intestinal metabolite short chain fatty acid (SCFA) may also have a preventive effect.
The goal of secondary prevention is early detection, early diagnosis, early treatment of precancerous lesions and early cancer. Generally speaking, two conditions need to be met for a cancer to be diagnosed and treated early to achieve a lower death rate. Firstly, there should be easy and effective examination means; secondly, after detecting precancerous lesions or early cancer, the precancerous lesions can be treated with effective interventions (e.g. colorectal adenoma can be detected by colonoscopy and can be treated by removal under colonoscopy), and for the early cancer detected, the disease and death rate of cancer can be reduced by effective treatment measures.
The survival rate of CRC is greatly improved when it is diagnosed at an early stage. Five-year productivity after surgery can be more than 90% for early-stage CRC, compared to less than 5% for late-stage. However, only 5% of CRC is diagnosed at an early stage, and 60% to 70% of CRC patients are already in the mid- to late-stage by the time they are detected, and the post-operative recurrence rate is as high as 30%, so improving the early diagnosis rate is the key to improving the survival rate of CRC patients.
The American Cancer Society (ACS), the American College ofGastroenterology (ACG), the Federal Colorectal Cancer Task Force (U.S. Multisociety TaskForce on Colorectal Cancer), and the National Comp Rehensive Cancer Network (NCCN) have each released The Multisociety TaskForce on Colorectal Cancer and the National Comp Rehensive Cancer Network (NCCN) have each published guidelines for colorectal screening. In addition, the United Kingdom, Canada, Singapore, and Korea also have their own screening guidelines. In Europe, 23 out of 37 countries have established national guidelines for colorectal cancer screening. The Chinese Society of Gastroenterology of the Chinese Medical Association formulated the consensus opinion on colorectal tumor screening, early diagnosis and treatment, and comprehensive prevention in China in October 2011.
The NCCN colorectal cancer screening guidelines divide the population into 3 groups according to the risk level of colorectal cancer.
1. General risk group: people aged 50 and above who have no history of colorectal adenoma, no history of inflammatory bowel disease, and no family history of colorectal cancer.
2.Higher risk group: Those who have a history of colorectal adenoma M wide based serrated polyp, colorectal cancer, endometrial cancer and ovarian cancer before the age of 60, or a history of inflammatory bowel disease, or a positive family history of colorectal tumor.
3.Hereditary high-risk group: people who have a history of colorectal cancer before the age of 50, or a family history of colorectal cancer aggregation, or a family history of hereditary nonpolyposiscolon cancer (HNPCC), or adenomatous polyposis of the colon (APC) gene-related polyposis (including classical FAP, mild FAP, Gardner syndrome, Turcot syndrome, etc.).
Available evidence suggests that colorectal cancer screening reduces mortality, with approximately 60% of Americans aged 50 years and older currently screened for CRC. 2012 ACP (American College of
Physicians) newly issued guidelines recommend individualized assessment of colorectal cancer risk in all adults, with core elements including.
1. Clinicians should conduct individualized colorectal cancer risk assessments in all adults. Risk factors for colorectal cancer incidence and mortality include older adults, black race, history of polyps, inflammatory bowel disease, colorectal cancer, and family history of colorectal cancer.
2. In adults at general risk, clinicians should begin colorectal cancer screening at age 50; in adults at high risk, screening should begin at age 40; or 10 years before the age at which the youngest affected relative was diagnosed with colorectal cancer. In these populations, the potential benefit of reduced deaths from early detection of colorectal cancer outweighs the potential risk of screening.
3. Screening for patients at average risk should include stool testing, bendable sigmoidoscopy, or fiberoptic colonoscopy. High-risk patients should undergo fiberoptic colonoscopy. Benefits, risks, and availability of specific screening tests, as well as patient preference, will influence the choice of screening test. For adults over 50 years of age at average risk, the recommended screening interval is 10 years for colonoscopy, 5 years for bendable sigmoidoscopy, virtual colonoscopy, and double-contrast barium enema, and 1 year for fecal occult blood testing.
4. Because the potential risk outweighs the potential benefit, clinicians should discontinue colorectal cancer screening for those older than 75 years of age or for adults with an expected survival of less than 10 years.
For hereditary high-risk groups, such as those with confirmed HNPCC, the NCCN colorectal cancer screening guidelines specifically state that colonoscopy should be initiated at the age of 20-25 years or 10 years prior to the earliest age of diagnosis of this disease in their family line, with surveillance starting as early as possible and repeated every 1-2 years. For women diagnosed with HNPCC, annual vaginal ultrasound or endometrial irrigation is also performed at the age of 25 to 35 years. cancer (HNPCC), also known as Lynch syndrome, accounts for 2% to 3% of all colorectal cancer cases. Its pathogenesis is mainly due to mutations in DNA mismatch repair genes (mainly MLHl, MSH2, MSH6, PMS2), and the lifetime risk of colorectal cancer for individuals carrying one HNPCC mutated gene is 80%.
The main clinical features of HNPCC are early age of tumor onset, usually colon cancer occurs before the age of 50 years, preferably in the proximal colon (cecum, ascending colon and transverse colon), with concurrent or heterozygous primary colon cancer, and common extraintestinal malignancies, the most common site of extraintestinal malignancies is the endometrium, followed by the stomach, small intestine, hepatobiliary system, upper urinary tract and ovaries, etc. The main risk of HNPCC is transmitted in an autosomal dominant manner The clinical prognosis of HNPCC is good, and early detection and treatment will greatly improve the prognosis of patients. For patients with suspected HNPCC, molecular diagnosis and genetic testing should be performed.
The consensus opinion on screening, early diagnosis, early treatment and comprehensive prevention of colorectal tumors in China formulated by the Chinese Society of Gastroenterology of the Chinese Medical Association believes that.
①Serological diagnosis of colorectal tumors (such as CEA and tumor antigen markers like CAl25 and CAl9-9) still lacks sensitive and specific methods.
A positive fecal occult blood test (FOBT) only indicates the need for further examination, but is not a means of confirming the diagnosis. The significance of fecal DNA and transferrin (TRF) tests for the diagnosis of colorectal tumors is limited. However, it is useful for screening of colorectal tumors.
CT colonoscopy (CTC) is a non-invasive test. It has unique advantages for those who cannot tolerate colonoscopy, but its early diagnostic value is limited.
④ Colonoscopy with pathology is the standard method to diagnose colorectal tumors. Adequate bowel preparation and careful observation at the time of retraction can help improve the detection rate of colorectal tumors. The endoscopic morphology of early stage CRC is divided into 2 basic types. Namely, augmented type and flat type. Those with flat type lesions found under endoscopy are recommended not to take biopsy.
II. Follow-up of colorectal cancer
It has been recognized that early detection, early diagnosis, early treatment and strengthening comprehensive treatment of gastrointestinal malignant tumors are two important aspects to improve the efficacy. With the progress of surgery and anesthesia technology, the resection rate and radical rate of colorectal cancer have been gradually improved, and the overall survival rate of colorectal cancer has also been continuously improved, with a 1-year survival rate of 92.3%, a 3-year survival rate of 73.9%, a 5-year survival rate of 65.1%, and a 10-year survival rate of 57.5% [26]. However, studies have shown that 30% to 40% of CRC patients will develop metastatic CRC, and about 1/3 of patients will die of recurrence [28]. If effective measures can be taken to prevent recurrence and timely detection of recurrence, and effective comprehensive treatment will potentially save a proportion of patients and prolong their survival, resulting in an improved overall 5-year survival rate.
Therefore there is a need to establish a standardized CRC follow-up system, however, follow-up after radical CRC remains controversial and there is still no consistent follow-up protocol. Today, the UK guidelines have only very minor follow-up comments – only imaging of the liver and colonoscopy are recommended [29]. Guidelines from the United States [30,31], Europe, and Canada, on the other hand, recommend follow-up to varying degrees, including clinical visits, CEA levels of tumor antigen markers, colonoscopy, and imaging of the chest and abdomen. In conclusion, a consistent and standardized follow-up system is lacking worldwide.
The main objective of post-operative CRC follow-up is to improve patient survival by early detection of recurrence in asymptomatic patients and to enable aggressive reoperation. It is important to note that the chances of reoperation in symptomatic patients with recurrence are in fact very low at about 1.7-7%. The secondary purposes of follow-up include: early detection and treatment of intestinal diseases (polyps, heterochronous tumors, etc.), resolution of surgery-related problems, psychological comfort for the patient, and accumulation of clinical research data.
These secondary follow-up implications are well understood, but whether the primary purpose of CRC follow-up can be achieved has been controversial. The available clinical evidence is not good enough to confirm the clinical significance of CRC follow-up. A panel of experts from the American Society of Clinical Oncology (ASCO) concluded from a review of 2500 publications on CRC follow-up that “there is an urgent need for high-quality clinical trials (to confirm the clinical significance of CRC follow-up).
Although there is still no consensus on the duration, intensity, or type of follow-up for post-operative CRC. However, based on the natural clinical pattern of CRC recurrence after surgery and recent advances in the treatment of CRC recurrence and metastasis, there is a general impression of postoperative follow-up of CRC. Approximately 80% of recurrences occur in the first 2 years after surgery, and approximately 90% of recurrences occur in the first 5 years after surgery. Patients are considered cured if they do not recur within 5 years after surgery. The incidence of heterochronous lesions is 0.35% per year and has a similar cure rate as the primary lesion. Approximately 20-40% of patients develop liver metastases, and 1 in 12 patients after radical surgery develop pulmonary metastases.
In contrast, there have been significant advances in interventions for recurrent metastatic CRC. In 1989, only 5% of patients with liver metastases were suitable for surgical resection [39]. Today, approximately 20% of patients with secondary liver metastases (and even more after downstaging with chemotherapy) can be considered for surgical treatment [40]. The 5-year survival rate of patients with liver metastases treated by surgery can be expected to reach 30%, while the median survival time of patients with liver metastases without treatment is only 6 months, and chemotherapy can extend the median survival time to 20 months. An epidemiological study concluded that 14.3% of patients with lung metastases were suitable for curative surgery [42] and their 3-year survival rate was 59.2%.
So how should the current follow-up after radical CRC surgery be performed? The follow-up recommendations given by the NCCN for colon cancer, 3rd edition, 2012, in the United States are as follows.
1.Follow up every 3-6 months for 2 years after surgery, and then every 6 months until a total of 5 years;
2. For patients with T2 and above, if further intervention is possible, CEA testing should be performed every 3-6 months for the first 2 years, and then every 6 months for a total of 5 years;
3. For patients at high risk of recurrence (e.g. tumors with lymphatic or vascular infiltration or poorly differentiated tumors), annual chest/abdominal/pelvic CT x 3-5 years;
4. Review colonoscopy within 1 year, or give colonoscopy within 3~6 months after surgery if preoperative colonoscopy was not performed. If high-risk adenoma is found, repeat colonoscopy after 1 year; if no high-risk adenoma is found, repeat within 3 years, and every 5 years thereafter.
5. PET-CT is not recommended as routine.
The Chinese consensus opinion on colorectal tumor screening, early diagnosis and treatment, and comprehensive prevention is that regular whole colonoscopy follow-up should be performed at the 3rd, 6th, and 12th months of the 1st year after endoscopic treatment of early CRC. If there is no residual or recurrence. If there is no residual or recurrence, follow up once a year thereafter; if there is residual or recurrence, additional surgical resection should be performed. Follow-up every 3 months (including serum oncological markers, FOBT, etc.): 1 colonoscopy per year after complete resection of the lesion. Staged resection of early CRC or precancerous lesions has the potential for recurrence and residual. Most recurrent or residual lesions occur mostly within the 1st year.
In recent years, with the advent of surgery and new generation of chemotherapeutic agents (oxaliplatin, irinotecan, etc.) and molecularly targeted drugs targeting EGFR, VEGFR, KRAS genes, etc., the treatment outcome of recurrent and metastatic advanced colorectal cancer has been further improved. While we continue to improve the effectiveness of cancer treatment, we also hope that early detection of recurrent metastatic disease through follow-up will lead to greater therapeutic benefit. Based on large scale and high quality clinical trial data, the development of a reasonable and standardized postoperative follow-up system for CRC is an urgent and important research issue now!