research paper on colon cancer

Advances in Colorectal Cancer Research

Colorectal cells grown into organoids, stem cell-derived human 'mini-organs' that are used to study human development and disease.

NCI-funded researchers are working to advance our understanding of how to prevent, detect, and treat colorectal cancer. They are also looking at what factors influence screening behaviors, how to address disparities, and the rising rates of colorectal cancer in younger people.

This page highlights some of the latest colorectal cancer research, including clinical advances that may soon translate into improved care, NCI-supported programs that are fueling progress, and findings from recent studies.

Prevention and Early Detection

Screening can prevent colorectal cancer through detection of precancerous growths, or polyps , which can be removed before they become cancerous. It can also allow colorectal cancers to be detected early, before they cause symptoms and when treatment may be more effective.

Colorectal cancer screening tests. These include colonoscopy , sigmoidoscopy , stool-based tests to detect hidden blood ( fecal immunochemical test ing (FIT) or fecal occult blood testing (FOBT)), and virtual colonoscopy . (See Screening Tests to Detect Colorectal Cancer and Polyps for more information.)

Despite the availability of effective colorectal cancer screening tests, some people choose not to get screened. Some reasons may be because of the personal nature of the procedures, a lack of recommendation by their doctor, perceived costs or lack of insurance, or the preparation involved for a colonoscopy.

Can Colorectal Cancer in Younger Adults Be Found Early?

Researchers find four “red flag” signs that may identify colorectal cancer early in younger adults.

Although not currently recommended for screening, there are new techniques under development such as:

• finding technologies that improve the genetic analysis of stool samples, which may reveal the presence of tumor DNA
• looking at changes in the gut microbiome and trying to identify specific bacteria that could potentially help identify patients at risk for colorectal cancer

Repeat screening or follow-up . The guideline for getting a screening colonoscopy is every 10 years. However, people who have noncancerous polyps detected at colonoscopy are generally asked to return for a repeat colonoscopy earlier than that.

NCI’s FORTE Colorectal Cancer Prevention Trial , is now looking at whether some people with one or two small polyps can wait 10 years before returning for another colonoscopy. By comparing two study groups, one with repeat colonoscopy after 5 years, and one with repeat colonoscopy after 10 years, researchers hope to learn whether waiting 10 years is as good at preventing colorectal cancer as follow-up exams after 5 years. 

For colorectal cancer screening to be effective, people need to follow up on abnormal test results. In one study, researchers found that people who had a positive at-home stool test to screen for colorectal cancer, but did not have a follow-up colonoscopy , were twice as likely to die from colorectal cancer as those who did have a follow-up colonoscopy.

NCI is funding research to better understand the many factors that can contribute to why a person may not have a follow-up test and how to increase repeat screening and follow-up colonoscopy after abnormal stool tests. Researchers are also studying how the many levels of the healthcare delivery system affect the decision to get screened.

Treatment for Colorectal Cancer

Surgically removing the cancer is the most common treatment for many stages of colorectal cancer. Chemotherapy,   radiation , targeted therapy , radiofrequency ablation , and cryosurgery are other treatments that may be used to treat colorectal cancer, depending on the stage.

Because of an increased risk of recurrence, differences in anatomy, and poorer prognosis , the treatment of rectal cancer may differ from that of colon cancer. Although surgery remains a common type of treatment for local and locally advanced rectal cancer, people with some stages may be treated with radiation, chemotherapy, and/or targeted therapy with or without surgery.

In addition to these standard treatments for rectal cancer, researchers continue to study both new treatments, such as immunotherapies, and new combinations of existing treatments in clinical trials.

One trial is comparing a standard treatment (chemoradiation followed by combination chemotherapy) with chemoradiation followed by combination chemotherapy that includes an additional chemotherapy drug.  The goal is to find out whether the additional chemotherapy drug may increase the likelihood of the cancer responding and possibly avoid the need for surgery. 

Immunotherapy for patients with Lynch syndrome or MSI-H colorectal cancer

Approximately 5% of colorectal cancer cases are due to Lynch syndrome , an inherited DNA repair disorder . People with this disorder have an increased risk of developing colorectal cancer, typically before they reach the age of 50. Lynch syndrome colorectal cancer tumors have many mutations, which may make them more susceptible to immunotherapies.

A genetic feature known as  microsatellite instability-high (MSI-H)  is seen in about 15% of patients with stages II and III colorectal cancer and about 5% with stage IV. MSI-H means that there are mistakes in the way the DNA is copied in cancer cells, which can make them grow out of control.

The immune checkpoint inhibitors nivolumab (Opdivo) , ipilimumab (Yervoy) , and pembrolizumab (Keytruda) have all been approved for the treatment of metastatic colorectal cancer in patients with Lynch syndrome and in patients with MSI-H cancers. 

The NCI-sponsored  COMMIT study is testing the addition of atezolizumab (Tecentriq)  to the combination of chemotherapy and the targeted therapy  bevacizumab (Avastin) , for treating patients that have defective DNA mismatch repair. The hope is that combining drugs that work in different ways will improve treatment results in patients with colorectal cancer.

Another NCI-sponsored trial is studying whether atezolizumab will improve outcomes in people with earlier-stage disease (specifically, stage III colon cancer) that is deficient in DNA mismatch repair. This trial will compare combination chemotherapy with or without atezolizumab.

For people with locally advanced rectal cancer who have MSI-H cancer, one trial is studying the effects of nivolumab and ipilimumab when given together with short-course radiation therapy . 

Combining immunotherapy with other treatments for patients without Lynch syndrome

Immune checkpoint inhibitors have been less effective in colorectal cancer patients without Lynch syndrome and whose cancers don't have mismatch repair deficiency . Scientists are currently testing various agents, such as chemotherapy drugs, targeted therapies and viruses, in combination with immune-based therapy to determine whether combining treatments would be effective in killing cancer cells.

Using targeted therapies for metastatic colorectal cancer

Using targeted therapies against genetic mutations that may drive tumor growth is another key area of research for metastatic colorectal cancer. The goal is to find agents that can block the activity of the abnormal proteins produced by these mutations. For example:

• The drug encorafenib (Braftovi ), which targets the BRAF protein, is approved for the treatment of some patients with colorectal cancer . This drug is used in combination with cetuximab (Erbitux) in adults with metastatic colorectal cancer whose tumors have a certain mutation in the BRAF gene and who have already undergone treatment.
• An NCI-supported trial showed that colorectal cancer that contains mutations in the BRAF gene responds to treatment with the drug vemurafenib (Zelboraf) in combination with cetuximab and irinotecan (Camptosar) . Vermurafentib targets mutant B-Raf proteins when combined with these two drugs.
• The NCI-sponsored SOLARIS trial is testing the addition of  vitamin D3 to the combination of chemotherapy and bevacizumab  for treating patients with metastatic colorectal cancer. 
• In January 2023, the Food and Drug Administration (FDA) approved the combination of two targeted drugs, tucatinib (Tukysa) and trastuzumab (Herceptin) for people with advanced colorectal cancer that produces an excess amount of a protein called HER2. (3% or less of people with advanced colorectal cancer have tumors that overexpress this protein.) In the clinical trial that led to the approval, called MOUNTAINEER, more than one third of people who received the drug combination had their tumors shrink or disappear. For another third, tumors stopped growing for some time.

Testing liquid biopsies

Liquid biopsies are a promising new approach being explored to detect, analyze, and track DNA, cells, and other substances shed from tumors into bodily fluids, such as blood and urine. Scientists are testing this method to detect colorectal cancer early, measure treatment responses, identify treatment resistance, and monitor for disease recurrence.

One example is the COBRA trial, which found that testing blood for fragments of genetic material (DNA) shed by tumors , known as circulating tumor DNA (ctDNA), could identify patients with stage IIA colon cancer who might benefit from additional treatment with chemotherapy after surgery.

An ongoing trial is studying ctDNA in people with stage II or III colon cancer. The goal is to determine whether and what type of chemotherapy will benefit patients who have had surgery for their colon cancer based on the presence or absence of ctDNA. 

NCI-Supported Research Programs

Many NCI-funded researchers at the NIH campus, and across the United States and world, are seeking ways to address colorectal cancer more effectively. Some research is basic, exploring questions as diverse as the biological underpinnings of cancer and the social factors that affect cancer risk. And some is more clinical, seeking to translate this basic information into improving patient outcomes. The programs listed below are a small sampling of NCI’s research efforts for colorectal cancer.

• The NCI-supported  genetic study, ENLACE, aims to learn more about colorectal cancer in people of Hispanic and Latino descent , with the ultimate goal of improving treatments for this population group. To achieve this, scientists are also testing ways to engage more people from this group in cancer research.
• The Population-based Research to Optimize the Screening PRocess (PROSPR) is an NCI-supported network conducting research to better understand how to improve the entire cancer screening process (recruitment, screening, diagnosis, referral for treatment) for lung, colorectal, and cervical cancer in community healthcare settings.
• Accelerating Colorectal Cancer Screening and Follow-Up Through Implementation Science (ACCIS) is intended to promote research in colorectal cancer screening, follow-up, referral-to-care and best practices for how multilevel interventions can be scaled-up in regions of the United States where screening rates are below national standards.
• Approaches to Identify and Care for Individuals with Inherited Cancer Syndromes are studies designed to increase screening, prevention, and early treatment of people at high risk of cancer due to an inherited genetic susceptibility .
• The NCI-funded Colon Cancer Family Registry (CCFR)  has established an international cohort of thousands of colorectal cancer patients, their relatives, and individuals at increased risk of colorectal and other cancers. Over 10,000 families from the United States, Canada, Australia, and New Zealand have been registered. The database includes more than 2,000 individuals with Lynch syndrome, from 781 families. 
• The goal of the Screen to Save Initiative , funded by NCI’s Center to Reduce Cancer Health Disparities , is to increase colorectal cancer screening in areas that need it most. Through community health educators, the program provides education and outreach to increase access to resources for those who may be affected by colorectal cancer.
• Dissemination of a Colorectal Cancer Screening Program Across American Indian Communities in the Southern Plains and Southwest United States is an effort to increase the use of colorectal cancer screening tests in American Indians. This project supports research on system-level changes and culturally appropriate media to promote screening, with the goal of closing the gap in colorectal cancer outcomes between the American Indian population and the general US population.
• NCI's  Gastrointestinal (GI) SPOREs focus on translational research in the gastrointestinal system. Currently, GI SPOREs focus on cancers of the colon, rectum, esophagus, liver, gastrointestinal stromal tumors (GIST), and pancreas, which account for the majority of new diagnoses.

Clinical Trials

NCI funds and oversees both early- and late-phase clinical trials to develop new treatments and improve patient care. Trials are available for colorectal cancer screening , to prevent  colon  and  rectal cancer , and treatment for colon cancer and rectal cancer. 

Colorectal Cancer Research Results

The following are some of our latest news articles on colorectal cancer research:

• ctDNA May Guide Who Needs Chemo After Colorectal Cancer Surgery
• ENLACE Study Explores Colorectal Cancer in Hispanic and Latino People
• Is AI Ready to Play a Leading Role in Colorectal Cancer Screening?
• Some People with Rectal Cancer Can Skip Radiation Before Surgery
• How Fatty Liver Disease Helps Cancer Thrive in the Liver
• Study Identifies Potential Warning Signs of Colorectal Cancer in Younger Adults

View the full list of Colorectal Cancer Research Results and Study Updates .

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Rapid rise seen in mental health diagnosis and care during and after pregnancy

by University of Michigan

Mental health issues during pregnancy or the first year of parenthood have a much greater chance of getting detected and treated now than just over a decade ago, a trio of new studies suggests.

But the rise in diagnosis and care hasn't happened equally across different groups and states, leaving some pregnant or postpartum individuals more likely to suffer through treatable symptoms that can put themselves and their newborn at risk.

In general, the studies show rises in diagnoses of anxiety, depression and post-traumatic stress disorder during pregnancy and the first year after giving birth in Americans with private insurance from 2008 to 2020. Treatment—both with psychotherapy and medications—also rose in this population.

The findings, published in three papers in the April issue of the journal Health Affairs , come from a team at the University of Michigan who study mental health in the perinatal period .

Their analysis groups multiple conditions diagnosed during this period under the label PMAD, short for perinatal mood and anxiety disorders. In general, PMAD includes depressive and anxiety disorders that occur any time during pregnancy and the postpartum year.

Key findings from 2008 to 2020 in privately insured people age 15 to 44:

• The rate of perinatal PTSD diagnosis quadrupled , to nearly 2% of all those pregnant or postpartum in 2020. Most of the rise was among those also diagnosed with PMAD; PTSD is considered an anxiety disorder in reaction to trauma.
• The rate of PMAD diagnoses nearly doubled , with the greatest increases seen since 2015. By 2020, 28% of those pregnant or postpartum received a PMAD diagnosis.
• The rate of suicidal thoughts or acts among pregnant and recently delivered people more than doubled overall, based on information reported to insurance companies. But the rate dropped among all those who had received a PMAD diagnosis.
• The rate at which patients who were pregnant or postpartum received psychotherapy—any form of talk therapy paid for by their private insurance—more than doubled. The rate of psychotherapy among those diagnosed with a PMAD condition increased 16% across the entire study period, with a clear increase after 2014.
• The rate of antidepressant medication prescriptions during pregnancy and the postpartum period rose overall , but the rate rose fastest among those diagnosed with a PMAD during pregnancy. The rate of antidepressant prescribing rose especially sharply after multiple guidelines for clinicians treating PMAD came out in 2015 and 2016. By 2020, just under half of those diagnosed with a PMAD received a prescription for an antidepressant.

"Taken together, these studies show a lot of movement in maternal mental health," said Stephanie Hall, Ph.D., a postdoctoral research fellow at the U-M Medical School Department of Psychiatry. "The landscape is different, at least as far as our health care system's ability to pick up on conditions and help people get treatment for them."

Hall is first author of the new papers on PTSD diagnosis and antidepressant prescribing in the perinatal period, and a co-author on the paper on PMAD diagnosis.

"If anything, the rates we're documenting for diagnosis and treatment are a floor, not a ceiling, based on what other studies have suggested about who is experiencing these symptoms," said Kara Zivin, Ph.D., a professor in the Medical School and School of Public Health who also holds positions with the VA Ann Arbor Healthcare System and Mathematica. "It's important that those who are struggling get help, because not getting care has consequences."

Zivin has spoken and written publicly about her own experience with a mental health crisis during pregnancy, including in Health Affairs.

Impacts of policy and guideline changes

The researchers say their findings suggest that many of the changes in diagnosis and care happened after increased insurance coverage through mental health parity laws and the Affordable Care Act, and after updated guidelines for clinicians emphasized increased use of screening, psychotherapy and medication.

Relevant guidelines include those issued by the American College of Obstetrics and Gynecology and the U.S. Preventive Services Task Force.

But they also note that increased societal awareness and acceptance of mental health conditions and care likely contributed to the trends seen in the new findings.

Another factor that could explain changes in diagnosis and treatment: the rise of collaborative care models , under which psychiatrists can offer expert consultations and resources to primary care teams caring for people of all ages with mental health conditions.

Since 2013, for instance, clinicians caring for pregnant and recently delivered individuals anywhere in Michigan can get assistance from the MC3 program run by Michigan Medicine, U-M's academic medical center.

The studies used data from private insurance companies, so they do not include people with low incomes covered by Medicaid, which covers about 40% of all births in the United States each year.

The data source also does not include those with other forms of government-funded insurance, those without insurance, and those with coverage by private insurance for less than two years.

So, the study findings mainly apply to those who have insurance through an employer (their own or that of another person who can cover them), and to those who bought private insurance individually, including after the launch of federal and state marketplaces under the ACA. The first marketplace plans offered coverage starting in 2014.

The studies include data for the first nine months of the pandemic, and the researchers hope to include more recent data in future studies.

Disparities in diagnosis and care

All of the studies show differences between groups of individuals in rates of diagnosis and treatment.

For instance, white individuals with PMAD were much more likely to receive antidepressant prescriptions during pregnancy than those of Black, Hispanic or Asian heritage. They were also more likely to be diagnosed with PTSD during the entire perinatal period, even though other research has shown that actual incidence of PTSD during the perinatal period is higher in people of color.

On the other hand, Black individuals as a group had the largest increase in PMAD diagnosis in the study period.

Of all age groups, people in the youngest group (15 to 24) had the largest increases in both PMAD diagnoses and antidepressant prescriptions during the study period. Those aged 15 to 26 were more likely to be diagnosed with PTSD than members of older age groups.

The PMAD diagnosis study also shows wide variation between states in the rate of individuals diagnosed with PMAD after the Affordable Care Act, compared with before.

The team plans to continue their state-level analysis, with new funding that will fuel studies of data from mental health surveys of individuals during the perinatal period. Their new research will look at changes over time in states where policies regarding reproductive care have gone into effect in recent years, including changes in abortion-related policies since the Supreme Court case that overturned the Roe vs. Wade decision in the Dobbs v. Jackson Women's Health Organization case in June 2022.

The researchers also plan to study the potential impact of other policy and clinical guideline changes.

The impact of telehealth-based perinatal mental health care since 2020, especially for those living in areas with shortages of mental health providers, also represents another important area to study, they say.

"Perinatal mental health has broad implications for babies and families," said Zivin. "The changes we've documented in these studies will have ripple effects for years to come."

Antidepressant Prescriptions Increased For Privately Insured People With Perinatal Mood And Anxiety Disorder, 2008–20, Health Affairs (2024), DOI: 10.1377/hlthaff.2023.01448 . www.healthaffairs.org/doi/10.1 … 7/hlthaff.2023.01448

Perinatal Mood And Anxiety Disorders Rose Among Privately Insured People, 2008–20, Health Affairs (2024), DOI: 10.1377/hlthaff.2023.01437 . www.healthaffairs.org/doi/10.1 … 7/hlthaff.2023.01437

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Colon cancer articles within Scientific Reports

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• v.33(3); 2022 Mar

The 100 Most-Cited Articles in the Field of Colorectal Diseases from 1955 to 2020: A Bibliometric Analysis

Chunmei zhang.

1 Medical Centre for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China

2 State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Hepatology Unit and Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China

Hanlong Zhu

The number of times that an article is cited could reflect its impact. This study aims to recognize and analyze the characteristics of the most frequently cited articles in the field of colorectal diseases.

We identified the 100 most-cited articles using the terms “colorectal,” “colon,” “rectal,” “IBD,” “ulcerative colitis,” “Crohn’s disease,” or “colonoscopy” in Web of Science. The articles were analyzed to evaluate the characteristics, including the number of citations, country of origin, the institution of origin based on the first author’s affiliation, study type, and others.

Of the top-cited publications, the number of citations ranged from 1575 to 9283, with a mean of 2504.11 citations. The journal with the greatest number of most-cited articles was the New England Journal of Medicine (n = 23), followed by Science (n = 14) and Nature (n = 12). These papers were published in 14 different countries, of which more than half were from the United States (n = 60). The most popular field was colorectal cancer (n = 45), followed by colon tumors (n = 21). Most of the papers were basic science studies (n = 43) and randomized controlled trials (n = 30). Regarding the level of evidence, there were 5 studies at level I, 29 at level II, and 5, 1, and 15 studies at levels III, IV, and V, respectively.

Our study could provide a historical perspective on scientific progress in the field of colorectal diseases. These 100 most-cited articles are of great significance for helping researchers understand this field over time.

Main Points

• Examination of top-cited articles is a tool that can help to identify and monitor outstanding scientific researches and landmark papers.
• The 100 most-cited papers in peer-reviewed biomedical journals in the field of colorectal disease are identified and analyzed.
• The most popular field is colorectal cancer (n = 45), followed by colon tumor (n = 21).
• Our study can give a historical perspective on the scientific progress of colorectal disease.

Introduction

The speed of updating knowledge is likely to increase as the internet becomes more accessible. Researchers could be overwhelmed by the amount of information and could find directions of interest for research difficult. Thus, there is an urgent need to explore ways that help researchers effectively access useful articles in their research fields.

In academia, the number of citations that an article receives does not necessarily mean it is the most influential. However, it could reflect how celebrated that article has been in its branch of learning, with the implication being that the more the number of times it is cited, the greater the paper’s worth. Although the value of citation counts has been debated, a high citation count is a direct proxy for a paper’s acceptance in its scientific field. Utilizing mathematical and statistical methods, bibliometric citation analysis can quickly filter out a large number of useful articles. 1

A classic citation is currently defined as a top-cited publication, as identified from the Science Citation Index or Social Sciences Citation Index. 2 At present, citation analysis has been widely used in various specialties, including gastric diseases, hepatology, urology, 3 -5 and others. To date, there is no comprehensive list of classic citations within the specialty of colorectal diseases. Therefore, the purpose of our study was to identify and evaluate the characteristics of top-cited publications concerning colorectal diseases and to try to gain insights into this area. The widely used databases for citation analysis include Web of Science (including its Science Citation Index), Scopus, and Google Scholar. 6 We acknowledge that Scopus and Google Scholar may provide relevant albeit different citation metrics. Compared with Web of Science, Scopus includes more journals and is convenient for keyword search and citation analysis, but its citation analysis is not sufficient. 7 Google Scholar can help retrieve even the most obscure information, but its use is marred by inadequate citation information that is updated less often. 6 Therefore, we chose the Web of Science (including the Science Citation Index) for our study.

Materials and Methods

Data sources and searches.

The Web of Science (including the Science Citation Index) database was searched using keywords such as “colorectal,” “colon,” “rectal,” ‘”BD,” “ulcerative colitis,” “Crohn’s disease,” and “colonoscopy” for manuscripts relating to colorectal diseases published since 1955 (the earliest year for which data were available) to the present; more keywords are shown in Table S1. We conducted our search on August 28, 2020, to avoid possible changes in the citation rate. Sorted into the category “Times Cited,” a list of the top-cited articles in the area of colorectal disease were determined. The full-text articles were obtained from PubMed, ScienceDirect, and EMBASE.

Study Selection and Data Extraction

The articles were selected by 2 researchers (C. Zhang and M. Luo), who read the abstracts to estimate whether they were related to colorectal diseases. The exclusion criteria were as follows: (1) articles in languages other than English and (2) articles focused on a wide range of areas without focusing entirely on colorectal disease. 3 , 8 Any discrepancy was resolved by a third investigator (H. Zhu). The 100 most-cited articles were included and analyzed. Data were extracted from each of the top-cited articles by 2 researchers (M. Luo and C. Zhang) using a predesigned Microsoft Excel template, with checks done by another researcher (J. Zhou). All the data were analyzed by 2 investigators (C. Zhang and M. Luo) with regard to authorship (only considering the first and second authors), institution, journal name, publication date, country of origin, number of citations, average citations per year, topic, study type (e.g., meta-analysis or systematic review, randomized controlled trial, prospective study, retrospective study, review, guideline, comment, or case report), and level of evidence. There are multiple methods of grading the level of evidence. 9 In our analysis, the level of evidence was determined using the Australian National Health and Medical Research Council evidence hierarchy. 10

Statistical Analysis

Tables and charts were created using Microsoft Word and Microsoft Excel, respectively. Data visualization was conducted using the VOSviewer (Leiden University, Leiden, The Netherlands) technique to create scientific landscapes and networks based on keyword frequency in titles and abstracts.

The top 100 most-cited articles in the field of colorectal disease between 1955 and 2017 were identified ( Table 1 ). The number of citations ranged from 1575 to 9283, with a mean of 2504.11 citations per article.

The Top-Cited 100 Articles on Colorectal Disease

Year, Country, and Number of Citations

The number of articles, citations per year, and country distribution are shown in Figures 1 and ​ and 2. 2 . The top 100 most-cited articles covered a wide range of countries, with the majority from the United States (n = 60), and the remainder from France (n = 10), the UK (n = 10), Canada (n = 4), the Netherlands (n = 3), Japan (n = 3), Belgium (n = 2), Denmark (n = 2), Australia (n = 1), Germany (n = 1), Finland (n = 1), Italy (n = 1), Sweden (n = 1), and Spain (n = 1) ( Figure 2 ). The United States had the highest number of citations (n = 156 142), and Sweden had the lowest (n = 1761). These articles were published between 1955 and 2017. The earliest article was published in 1955 by Truelove et al. in the British Medical Journal . 11 Siegel et al. 12 had the most recent article among the 100 most-cited articles, published in 2017 in the CA-A Cancer Journal for Clinicians . As shown in Figure 1 , from 1955 to 1988, only 7 articles were included, while more than 93% of the top-cited articles were published after 1989. For total citations, the trend per year was inconsistent with top-cited publications ( Figure 1 ).

The number and total citations of articles per year in the top 100 most-cited articles.

The number of the top 100 most-cited articles in different countries.

Authors and Journals

Fourteen authors published 2 or more articles ( Table 2 ). Among these, Fearon authored the most papers (n = 5). Twenty-one journals made contributions to the top-cited articles. The journals with the highest impact factor (IF) included the New England Journal of Medicine (NEJM) (IF = 74.699), Science (IF = 41.845), Nature (IF = 42.778), Gastroenterology (IF = 17.373), Cell (IF = 38.637), the Lancet (IF = 60.392), and the Journal of Clinical Oncology (IF = 32.956). Among them, 23 articles were published in NEJM (n = 64 941 citations), 14 in Science (n = 33 424 citations), 12 in Nature (n = 35 080 citations), 9 in Gastroenterology (n = 18 059), 7 in Cell (n = 23 946 citations), 7 in the Lancet (n = 15 156), and 6 in the Journal of Clinical Oncology (n = 13 159 citations). In addition, 9 journals published only 1 article ( Table 3 ).

Authors with Two or More Most-Cited Articles

Journals in Which the 100 Most-Cited Articles Were Published

a Journal impact factor was based on Thomson Reuters Web of Knowledge Journal Citation Reports Ranking (2019).

b Journals with 1 or 2 most-cited articles.

Institutions

With regard to institutions, the Johns Hopkins University School of Medicine published the largest number of articles (n = 12). The Harvard Medical School ranked second in the number of articles published (n = 5). The Mayo Clinic, the Memorial Sloan-Kettering Cancer Center, and the University of California contributed 3 papers each. There were 6 institutions with 2 papers, while other organizations had only 1 article each ( Table 4 ).

Institution with the Highest Number of Papers in the 100 Most-Cited Articles

Top Keywords and Research Directions Related to Colorectal Disease

There were 53 keywords that were used at least 5 times. The most commonly used keywords were cancer (n = 52), gene ( n = 25), mutation (n = 21), tumor (n = 20), data (n = 19), cell (n = 17), colon (n = 14), colon cancer (n = 14), Crohn’s disease (n = 14), role (n = 14), combination (n = 13), inflammatory bowel disease (n = 13), metastatic colorectal cancer (n = 13), overall survival (n = 13), progression (n = 13), week (n = 13), fluorouracil (n = 12), primary end point (n = 12), ulcerative colitis (n = 12), and chromosome (n = 11). The top-cited keywords among these are demonstrated in Figure 3 . Among these 100 classic articles, each article contains multiple research directions (with a total of 34 research directions), of which gastroenterology hepatology is the most researched, with 48 articles. This is followed by oncology (n = 44), biochemistry molecular biology (n = 26), genetics heredity (n = 23), general internal medicine (n = 22), cell biology (n = 21), science technology other topics (n = 16), and geriatrics gerontology (n = 10). There were 26 research directions with fewer than 10 articles, and 10 research directions appeared only once ( Figure S1 ).

Top used keywords related to colorectal disease in the top 100 most-cited articles.

Number of the top 100 most-cited articles in different research directions (at least 2 articles have been published in this research direction).

Research Area, Study Type, Level of Evidence

In terms of the research area, 72 articles focused on tumors. Among them, 45 papers (45%) involved colorectal tumors, 21 (21%) colon tumors only, and 6 (6%) rectal tumors only. The remaining 22 papers concentrated on colorectal inflammation, of which 9 (9%) papers were on Crohn’s disease, 3 (3%) on ulcerative colitis, and 10 (10%) on inflammatory bowel disease. Regarding study type, there were basic science studies (n = 43), randomized controlled trials (n = 30), reviews (n = 12), prospective studies (n = 3), guidelines and consensus (n = 2), retrospective studies (n = 1), case reports (n = 2), and meta-analyses (n = 1) ( Table 5 ). The types of clinical studies and level of evidence in the top-cited articles are summarized in Table 6 . There were 5 studies at level I, 29 at level II, and 5, 1, and 15 studies at levels III, IV, and V, respectively.

Field of Study Based on Types of Studies

RCTs, randomized controlled trials.

Levels of Evidence and Article Type Comprising the 100 Most-Cited Articles

The worldwide incidence of colorectal diseases, especially colorectal cancer and inflammatory bowel disease, has increased in recent years. 13 Therefore, a great deal of research has been done on colorectal diseases, including pathogenesis, epidemiology, genetics, and immunology. The number of citations of an article on a certain subject represents the influence and credibility of that article, and it also indicates the author’s academic achievement. 14 At present, the most-cited articles have been widely used in gastric diseases, hepatology, urology, 3 - 5 and other disciplines. For diseases of the digestive system, analysis of the top-cited articles has been performed in gastric cancer, 15 acute pancreatitis, 16 and ulcerative colitis. 17 However, no study has reported the most-cited articles in the field of colorectal diseases. Therefore, we aimed to analyze the characteristics of the 100 top-cited articles on colorectal diseases.

We found that the number of citations in colorectal disease literature was higher than that for some other digestive diseases, such as gastric cancer (n = 299-2893) and acute pancreatitis (n = 163-1281), 15 , 16 which confirms that colorectal diseases are a hot topic. In terms of country of origin and journal of publication, the citation characteristics for articles on colorectal diseases and other gastrointestinal diseases were similar. For example, the top-cited articles were primarily distributed in the United States, research on inflammatory conditions was mainly published in Gastroenterology , and cancer studies were generally published in NEJM . 15 - 17

In our study, the articles were distributed in various countries, with the United States occupying first place. In addition to having the most-cited articles every year, the United States also ranked first in the number of articles almost every year since 1986. The reasons for that may be as follows. First, a number of studies indicate that healthcare expenditure is closely linked to a country’s economic power, and the United States has the largest economy in the world. Second, it reflects the abundant funding support provided by the National Institutes of Health (25.29%), Health and Human Services (24.51%), the National Cancer Institute (11.67%), and other public and private sector agencies (Table S2). Finally, the United States has a rewards system for academia that encourages researchers to conduct basic and clinical studies, leading to such a substantial research contribution. 18

Colorectal cancer was the third most commonly diagnosed cancer in males and the second most commonly diagnosed cancer in females in developed countries, based on global cancer statistics in 2018. 13 In this study, we discovered that research on colorectal cancer accounted for a large proportion of the 100 landmark articles, which mainly concentrated on drugs and surgery. The combination of biological agents and chemotherapy was one of the hot topics in these 100 most-cited articles. 19 , 20 These included bevacizumab, cetuximab, the LV5FU2–oxaliplatin combination, fluorouracil-based combination chemotherapy, and irinotecan combined with fluorouracil and calcium folinate. Two articles indicated that laparoscopic surgery was better than open surgery for postoperative morbidity, hospitalization time, tumor recurrence, and cancer-related survival. 21 , 22 One study demonstrated that preoperative chemoradiotherapy for colorectal cancer had a good effect on local control, but it did not affect the overall survival rate. 23 In addition, several most-cited articles emphasized the importance of early diagnosis or screening of colorectal cancer and precancerous lesions using different modalities. The screening methods, including fecal occult blood testing with rehydration of the samples, 24 stool DNA tests, 25 and double-contrast barium enemas, 25 were mentioned in the 100 classic articles. The occurrence of colorectal cancer would be largely prevented by endoscopic resection if precancerous lesions, such as adenomatous polyps, were detected in screening. 26

Research related to genetics in colorectal cancer is also important, including oncogene activation ( K-RAS and EGFR ), 20 , 27 tumor suppressor gene inactivation ( P53 ), 27 mismatch repair gene mutations ( hMSH2 , PMS1 , and PMS2 ), 28 and excessive gene expression ( COX-2 and CD33 ). 29 , 30 From an etiological perspective, patients with familial adenomatous polyposis have a nearly 100% risk of colorectal cancer. 31 There were various stages of hyperplasia, adenoma, and cancerization in terms of morphological and corresponding chromosomal changes ( 5q , 17p , and 18q ). 32 These studies indicate that the development and progression of colorectal cancer is a multistage process with multiple gene mutations, which is currently the consensus among gastroenterologists.

The 100 top-cited articles were mainly published in 19 journals, which published the highest number of papers in these fields at the fastest speed and with the strictest standards. Most of the articles were published in NEJM . The reasons may be as follows. First, NEJM , a medical journal published by the American Massachusetts Medical Society, has published medical papers continuously for the longest time in the world. Second, NEJM is one of the most authoritative medical journals with a high impact factor (79.258 in 2017) and it has become the preferred choice of publication by excellent scholars worldwide. Science and Nature, both of which enjoy high reputations globally, also published many top-cited articles. These 3 kinds of journals mentioned above covered more than half of the articles in the classic citations of colorectal disease. NEJM was the main source of most clinical research, while Science and Nature were the main sources of basic research.

Different study designs could correspond to different levels of evidence, and assessing the levels of evidence helps guide clinical research and patient treatment. In our study, 61.8% of the articles were at levels I and II, of which RCTs accounted for 85.3%. Therefore, the majority of clinical trials among the top 100 cited articles were well designed. However, there were also 5, 1, and 15 studies at levels III, IV, and V, respectively; thus, more high-quality RCTs should be conducted in the field of colorectal diseases in the future.

We acknowledge that there were some limitations to this study. First, the articles in this field might not have been sought out entirely owing to the differences in the keywords and the insensitivity of the database search. We made efforts to input multiple combinations of colorectal disease keywords in Web of Science to detect as many relevant articles as possible. Second, we merely screened the articles published in English; hence papers with significance in other languages might have been missed. Third, the composition of the ranking list and the comparative ‘order and degree’ of publications are dynamic and constantly changing. Therefore, the 100 most-cited articles obtained at different times may vary, but the general trend will not change.

In conclusion, the study reviewed the 100 most-cited articles that reflected research progress and hot topics in the last 60 years in the field of colorectal disease, and the articles of significant findings that have contributed greatly to the occurrence and treatment of colorectal disease were confirmed. Therefore, these 100 most highly cited articles are meaningful for new researchers in understanding this field over a long period and are also helpful for researchers when searching for literature.

Supplementary Table 1.

The Search Words Used in Our Study

Supplementary Table 2.

Funding Resources for the 100 Most-Cited Articles

Ethics Committee Approval: N/A.

Informed Consent: N/A.

Peer-review: Externally peer-reviewed.

Author Contributions: Concept – C.Z., M.L., L.M.; Design – C.Z., M.L.; Supervision – H.Z., J.Z.; Fundings – L.M.; Materials – C.Z., M.L.; Data Collection and/or Processing – C.Z., M.L.; Analysis and/or Interpretation – C.Z., M.L.; Literature Search – C.Z., M.L.; Writing Manuscript – C.Z., M.L.; Critical Review – H.Z., J.Z., L.M.

Declaration of Interests: The authors have no conflict of interest to declare.

Funding: The authors declared that this study has received no financial support.