essay about colon cancer

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Colon cancer

Colon cancer can happen in any part of the colon. An exam of the whole colon using a long, flexible tube with a camera is one way to detect colon cancer and polyps. This exam is called a colonoscopy.

Colon cancer is a growth of cells that begins in a part of the large intestine called the colon. The colon is the first and longest part of the large intestine. The large intestine is the last part of the digestive system. The digestive system breaks down food for the body to use.

Colon cancer typically affects older adults, though it can happen at any age. It usually begins as small clumps of cells called polyps that form inside the colon. Polyps generally aren't cancerous, but some can turn into colon cancers over time.

Polyps often don't cause symptoms. For this reason, doctors recommend regular screening tests to look for polyps in the colon. Finding and removing polyps helps prevent colon cancer.

If colon cancer develops, many treatments can help control it. Treatments include surgery, radiation therapy and medicines, such as chemotherapy, targeted therapy and immunotherapy.

Colon cancer is sometimes called colorectal cancer. This term combines colon cancer and rectal cancer, which begins in the rectum.

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Many people with colon cancer don't have symptoms at first. When symptoms appear, they'll likely depend on the cancer's size and where it is in the large intestine.

Symptoms of colon cancer can include:

A change in bowel habits, such as more frequent diarrhea or constipation.
Rectal bleeding or blood in the stool.
Ongoing discomfort in the belly area, such as cramps, gas or pain.
A feeling that the bowel doesn't empty all the way during a bowel movement.
Weakness or tiredness.
Losing weight without trying.

When to see a doctor

If you notice lasting symptoms that worry you, make an appointment with a health care professional.

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Doctors aren't certain what causes most colon cancers.

Colon cancer happens when cells in the colon develop changes in their DNA. A cells' DNA holds the instructions that tell the cell what to do. The changes tell the cells to multiply quickly. The changes let the cells continue living when healthy cells die as part of their natural lifecycle.

This causes too many cells. The cells might form a mass called a tumor. The cells can invade and destroy healthy body tissue. In time, the cells can break away and spread to other parts of the body. When cancer spreads, it's called metastatic cancer.

Risk factors

Factors that may increase the risk of colon cancer include:

Older age. Colon cancer can happen at any age. But most people with colon cancer are older than 50. The numbers of people younger than 50 who have colon cancer has been growing. Doctors don't know why.
Black race. Black people in the United States have a greater risk of colon cancer than do people of other races.
A personal history of colorectal cancer or polyps. Having had colon cancer or colon polyps increases the risk of colon cancer.
Inflammatory bowel diseases. Conditions that cause pain and swelling of the intestines, called inflammatory bowel diseases, can increase the risk of colon cancer. These conditions include ulcerative colitis and Crohn's disease.
Inherited syndromes that increase colon cancer risk. Some DNA changes that increase the risk of colon cancer run in families. The most common inherited syndromes that increase colon cancer risk are familial adenomatous polyposis and Lynch syndrome.
Family history of colon cancer. Having a blood relative who has colon cancer increases the risk of getting colon cancer. Having more than one family member who has colon cancer or rectal cancer increases the risk more.
Low-fiber, high-fat diet. Colon cancer and rectal cancer might be linked with a typical Western diet. This type of diet tends to be low in fiber and high in fat and calories. Research in this area has had mixed results. Some studies have found an increased risk of colon cancer in people who eat a lot of red meat and processed meat.
Not exercising regularly. People who are not active are more likely to develop colon cancer. Getting regular physical activity might help lower the risk.
Diabetes. People with diabetes or insulin resistance have an increased risk of colon cancer.
Obesity. People who are obese have an increased risk of colon cancer. Obesity also increases the risk of dying of colon cancer.
Smoking. People who smoke can have an increased risk of colon cancer.
Drinking alcohol. Drinking too much alcohol can increase the risk of colon cancer.
Radiation therapy for cancer. Radiation therapy directed at the abdomen to treat previous cancers increases the risk of colon cancer.

Screening for colon cancer

Doctors recommend that people with an average risk of colon cancer consider starting colon cancer screening around age 45. But people with an increased risk should think about starting screening sooner. People with an increased risk include those with a family history of colon cancer.

There are several different tests that are used for colon cancer screening. Talk about your options with your health care team.

Lifestyle changes to reduce the risk of colon cancer

Making changes in everyday life can reduce the risk of colon cancer. To lower the risk of colon cancer:

Eat a variety of fruits, vegetables and whole grains. Fruits, vegetables and whole grains have vitamins, minerals, fiber and antioxidants, which may help prevent cancer. Choose a variety of fruits and vegetables so that you get a range of vitamins and nutrients.
Drink alcohol in moderation, if at all. If you choose to drink alcohol, limit the amount you drink to no more than one drink a day for women and two for men.
Stop smoking. Talk to your health care team about ways to quit.
Exercise most days of the week. Try to get at least 30 minutes of exercise on most days. If you've been inactive, start slowly and build up gradually to 30 minutes. Also, talk with a health care professional before starting an exercise program.
Maintain a healthy weight. If you are at a healthy weight, work to maintain your weight by combining a healthy diet with daily exercise. If you need to lose weight, ask your health care team about healthy ways to achieve your goal. Aim to lose weight slowly by eating fewer calories and moving more.

Colon cancer prevention for people with a high risk

Some medicines can reduce the risk of colon polyps or colon cancer. For instance, some evidence links a reduced risk of polyps and colon cancer to regular use of aspirin or aspirin-like medicines. But it's not clear what dose and what length of time would be needed to reduce the risk of colon cancer. Taking aspirin daily has some risks, including ulcers and bleeding in the digestive system.

These options are generally reserved for people with a high risk of colon cancer. There isn't enough evidence to recommend these medicines to people who have an average risk of colon cancer.

If you have an increased risk of colon cancer, discuss your risk factors with your health care team to see if preventive medicines are safe for you.

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Goldman L, et al., eds. Neoplasms of the small and large intestine. In: Goldman-Cecil Medicine. 26th ed. Elsevier; 2020. https://www.clinicalkey.com. Accessed Feb. 15, 2023.
AskMayoExpert. Colorectal cancer (adult). Mayo Clinic; 2022.
Rodriguez-Bigas, MA., et al. Overview of the management of primary colon cancer. https://www.uptodate.com/contents/search. Accessed Feb. 15, 2023.
Colon cancer. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelinesdetail?category=1&id=1428. Accessed Feb. 8, 2023.
NCCN guidelines for patients: Colon cancer. National Comprehensive Cancer Network. https://www.NCCN.org/patients. Accessed Feb. 14, 2023.
Palliative care. National Comprehensive Cancer Network. https://www.nccn.org/guidelines/guidelinesdetail?category=3&id=1454. Accessed Feb. 8, 2023.
Ami TR. Allscripts EPSi. Mayo Clinic. Feb. 1, 2023.
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The awkward conversation that led to my colon cancer diagnosis at age 38

It was November 2018, and I had been traveling nonstop for months. At 38, I was the owner of a 50-employee marketing firm. My company was depending on an important deal to come through, but it was in jeopardy. If I failed to save it, we might have to lay off staff. It was a horrifying thought. I was frazzled, jet-lagged and overwhelmed.

I woke up in another hotel bed at yet another conference I was attending to drum up new business and went to the bathroom as part of my normal morning routine. On this particular day, I looked in the toilet and I saw something abnormal. Could that be blood?

As a self-diagnosed hypochondriac, my first thought was cancer. A Google search calmed my nerves. There are many benign causes of blood in the toilet bowl, including hemorrhoids . So, it was probably nothing major. Yet my initial alarm also made me feel a little conflicted — should I tell someone or just ignore it? I didn’t have time for a health crisis.

While my important business deal was slipping away, the blood kept showing up. After several days, I realized I couldn’t brush it off much longer. My husband, Jesse, needed to know. Still, I was distracted by a quickly approaching meeting about another deal in San Francisco.

A few moments before the meeting started, I found myself standing in a doorway, calling Jesse. I often talked with him about my business challenges. He is a fellow business owner, and always a great sounding board for me. But this time, I realized that I was terrified — both about the meeting and the blood. Did I really need to tell him about the blood? What if it was just a hemorrhoid ? Fears of being “too dramatic” were flooding my brain. Even though my husband is supportive, discussing bathroom habits wasn’t the norm in our marriage. So, saying “Sweetie, I think I saw blood in my poop this week” was a jarringly uncomfortable thing to say.

We discussed the meeting, and then I paused and took a deep breath. I gathered up courage and got the words out. Once they were said, a weight lifted off me. He didn’t respond with words of disgust or dismiss my symptoms. We decided I should meet with our family doctor when I got home, and then a specialist if necessary. But the sense of relief was quickly replaced by an ominous sense of foreboding. Verbalizing my fears made them more real. Maybe that was the reason I was afraid of saying it out loud?

At home, I got the first available appointment with my family doctor. No hemorrhoid was found. The doctor said she wasn’t worried because I was only 38 — she sent me away. But since the bleeding persisted, and wasn’t caused by a hemorrhoid, I was still concerned.

Two weeks later, it was New Year’s Eve. Jesse and I wandered the aisles of Party City to pick up costumes for a zombie-themed New Year’s party later that night. Later that afternoon, I met with a gastroenterologist. New Year’s Eve is apparently a slow day for them, so they were able to fit me in.

As I shared my symptoms, I could see concern in the doctor’s face. “You’re not too young for colon cancer,” she said. “Two months of bleeding is too long, and a dull red color in your stool is consistent with bleeding higher up in your colon.” She put me at the top of the list for a colonoscopy .

I left the appointment in no mood to celebrate. I told Jesse I didn’t feel like going to the party, and recounted the conversation with my doctor. We moved the Party City bag into the garage and spent a quiet night on the couch, worrying about what the new year might bring.

Four days later, I groggily woke from a colonoscopy. When my doctor entered the room with a solemn expression, I instantly knew the news was not good. “We found a tumor, and it’s almost certainly cancerous,” she said.

I was unsurprised and also completely floored. On one hand, I felt vindicated because I had successfully advocated for my body, but I also couldn’t believe that my worst fear was actually happening. At the time, no one was talking about the rising risks of colon cancer in young people . At 38, I was too young to qualify for a preventative colonoscopy (they’re still not recommended until age 45 ). I didn’t have a family history of colon cancer, but apparently neither do the majority of people diagnosed, although it is a risk factor, according to the American Cancer Society . Only later did I learn that colon cancer kills more people each year than either breast or prostate cancer, according to the Centers for Disease Control and Prevention . It was a bigger threat than I imagined.

After my surgery to remove 10 inches of my colon.

The doctor told me it was good that I came in when I did. “If it’s not stage 4, you have a good chance of full recovery,” she said. “But treatment is going to be hard.”

For the next five days, Jesse and I waited for the test results to determine whether the cancer had spread. These were the most difficult days in the entire journey. Life seemed to be suspended as we nervously anticipated the phone call from my doctor.

Thankfully, my cancer was stage 3, and the survival odds were good. I had 10 inches of my colon surgically removed and underwent three months of grueling, high-dose chemotherapy. The treatment was intense emotionally and physically. I was so weak that a 10-minute walk sent me to bed for hours. I had months of nightmares about dying. But I survived through it all.

I also did chemotherapy for three months.

It’s been four years since I finished treatment, and my cancer hasn’t returned. This journey has turned my life upside down, but it also gave me a powerful sense of purpose. I brought in a new CEO to run my company so I could focus all of my energy on colon cancer prevention projects. I spoke at the White House as part of the Cancer Moonshot , an ambitious federal program to reduce cancer deaths by 50% over the next 25 years. I launched an initiative called Lead From Behind, resulting in a 36% increase in colonoscopy appointments nationwide . I never could have predicted I would spend my 40s proudly wearing a “Colonoscopy Enthusiast” T-shirt, and using my platform — and butt humor — to help prevent colon cancer in young people.

Verbalizing my bathroom experience was hard the first time I shared it with my husband, and is still a little weird every time I repeat it. But I’ve learned that it is so important to get over our fears and the stigmas when it comes to our bodies and our health. That awkward conversation that I forced myself to have with my husband led to an early and survivable diagnosis for me. But had I continued to be embarrassed, it might not have worked out that way. And I realized a simple but critical thing that keeps me talking about this today: The more awkward conversations we have now, the more people will live to talk about it later.

Do you have a personal essay to share with TODAY? Please send your ideas to [email protected] .

Brooks Bell is an entrepreneur, colon cancer survivor and advocate based in Raleigh, North Carolina. She currently serves on the boards of the CDC Foundation and the Research Triangle Foundation.

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Healthcare: Colon Cancer Essay

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Introduction

Causes of colon cancer, reducing the risk of colon cancer, reference list.

The colon refers to the longest section of the large gut and the most low-down section of the digestive arrangement in the human body. Within this part, water and salt are drawn out from solid desecrate ahead of it proceeding through the terminal section of the alimentary canal and leaving the body by way of the anus.

Cancer is a group of disorders typified by uncontrollable cell development, and colon cancer comes about when this uninhibited cell development kicks off with cells in the large intestine. For the most part, colon cancer disorder(s) begin to form small, nonmalignant growths referred to as adenomatous polyps that appear on the interior walls of the large tract (U.S. Preventive Services Task Force, March 2007, p. 361). A number of these cysts may develop into dangerous colon cancers with time if they are not gotten rid of during a procedure of endoscopy. Colon cancer cells will attack and harm hale and hearty tissue that is adjacent to the growth resulting in quite a several difficulties.

Following the formation of cancerous growths, the malignant cells may move by way of blood and lymph systems, extending to other sections of the body. These cancerous cells can develop in quite a several places, attacking and devastating other fit tissues in the body. This process is referred to as metastasis, and the outcome is a more severe situation that is very hard to take care of. Statistics show that in the United States close to 112,000 persons are identified to be having this disorder every year.

The warning signs of this disorder are pretty diverse and are contingent upon where the cancer is situated, where it has extended, and the size of the growth. It is widespread for those with the infection to have no signs in the initial periods of the disorder. Nonetheless, when the disorder develops, some signs manifest themselves. They mostly commence with diarrhea or constipation. These are followed by other symptoms which include, alterations in feces regularity, blood in feces, aches in the process of bowel movement(s), frequent urges to poop, inexplicable loss of weight, among others.

In cases where the disorder has extended to other parts of the body, further signs can occur in the affected sections. Such warning signs will rely on the area to which the disorder has spread, with the liver being the most frequent.

There are quite a several causes of this disorder and among them there features nutrition, obesity, and fitness of an individual. The types of foods that one majorly consumes determine whether they are at risk or not of developing this disorder (Su LJ, Arab L, 2004, p. 111). Research has established that diets containing high levels of fat and cholesterol, particularly from animals, put consumers at high risk of developing the disorder.

Obesity refers to a state in which a person surpasses their advocated weight. It is a step clear of being overweight, and it is a well-known cause of colon cancer. Studies have revealed that inactive lifestyles as well lead to the development of colon cancer.

The best place to begin is ensuring that one consumes the right foods. Foods rich in fiber are advocated, as well as fresh fruits, vegetables, and white meat. Red meat should be kept to a minimum (U.S. Preventive Services Task Force, March 2007, p. 364).

Alongside a healthy diet, people need to ensure that they exercise their bodies appropriately. All body systems work effectively through this and it also keeps complications like obesity at bay. Alcohol intake and smoking need to be kept to a minimum or even avoided as well.

Su LJ, Arab L (2004). Alcohol consumption and risk of colon cancer: evidence from the national health and nutrition examination survey I epidemiologic follow-up study. Nutr Cancer 50 (2): 111–9.

U.S. Preventive Services Task Force (2007). Routine aspirin or nonsteroidal anti- inflammatory drugs for the primary prevention of colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann. Intern. Med. 146 (5): 361–4.

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IvyPanda. (2022, March 29). Healthcare: Colon Cancer. https://ivypanda.com/essays/healthcare-colon-cancer/

"Healthcare: Colon Cancer." IvyPanda , 29 Mar. 2022, ivypanda.com/essays/healthcare-colon-cancer/.

IvyPanda . (2022) 'Healthcare: Colon Cancer'. 29 March.

IvyPanda . 2022. "Healthcare: Colon Cancer." March 29, 2022. https://ivypanda.com/essays/healthcare-colon-cancer/.

1. IvyPanda . "Healthcare: Colon Cancer." March 29, 2022. https://ivypanda.com/essays/healthcare-colon-cancer/.

Bibliography

IvyPanda . "Healthcare: Colon Cancer." March 29, 2022. https://ivypanda.com/essays/healthcare-colon-cancer/.

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Recent Advances in the Treatment of Colorectal Cancer: A Review

Affiliation.

1 Departments of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School.
PMID: 35082204
DOI: 10.1272/jnms.JNMS.2022_89-310

Colorectal cancer (CRC) is the third most common cancer worldwide, and surgical treatment remains the first-line treatment to provide a cure. In addition to the aging population, obesity, low physical activity, and smoking habits increase CRC risk. Despite advances in surgical techniques, chemotherapy, and radiotherapy, colorectal cancer remains the second leading cause of cancer-related deaths worldwide. For early-stage CRC, endoscopic treatment, including endoscopic mucosal resection and endoscopic submucosal dissection, has been performed. However, lymph node dissection is an integral part of surgical treatment for advanced-stage cancer because of the high incidence of lymph node metastasis. Conventional open surgery has evolved into laparoscopic and robotic surgery. Although prospective studies have confirmed the safety and feasibility of laparoscopic surgery for CRC, relevant treatment models of transverse colon cancer and rectal cancer still need to be further explored and validated. Furthermore, multidisciplinary treatment is needed to cure CRC completely. This review aimed to provide an update on recent advances in the surgical treatment of CRC.

Keywords: chemotherapy; colorectal cancer; endoscopy; navigation; surgery.

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A review of colorectal cancer in terms of epidemiology, risk factors, development, symptoms and diagnosis.

Simple Summary

Graphical Abstract

1. Introduction

2. epidemiology, 3. risk factors, 3.1. family and personal medical history, 3.1.1. family history and genetics, 3.1.2. inflammatory bowel disease (crohn’s disease; ulcerative colitis), 3.1.3. colon polyps, 3.1.4. diabetes mellitus, 3.1.5. cholecystectomy, 3.2. lifestyle, 3.2.1. dietary patterns.

Diet high in red and processed meat
Diet low in fiber, fruits and vegetables
Diet low in calcium, vitamin D and dairy products

3.2.2. Overweight and Obesity

3.2.3. physical inactivity, 3.2.4. cigarette smoking, 3.2.5. alcohol consumption, 3.3. others, 3.3.1. gut microbiota, 3.3.3. gender and race, 3.3.4. socioeconomics factors, 4. development factors, 5. symptoms, 6. diagnostic, 7. conclusions, author contributions, conflicts of interest.

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Published: 03 July 2024

Colon cancer diagnosis by means of explainable deep learning

Marcello Di Giammarco 2 , 3 ,
Fabio Martinelli 2 ,
Antonella Santone 1 ,
Mario Cesarelli 4 &
Francesco Mercaldo 1 , 2

Scientific Reports volume 14 , Article number: 15334 ( 2024 ) Cite this article

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Biomedical engineering
Cancer screening
Engineering

Early detection of the adenocarcinoma cancer in colon tissue by means of explainable deep learning, by classifying histological images and providing visual explainability on model prediction. Considering that in recent years, deep learning techniques have emerged as powerful techniques in medical image analysis, offering unprecedented accuracy and efficiency, in this paper we propose a method to automatically detect the presence of cancerous cells in colon tissue images. Various deep learning architectures are considered, with the aim of considering the best one in terms of quantitative and qualitative results. As a matter of fact, we consider qualitative results by taking into account the so-called prediction explainability, by providing a way to highlight on the tissue images the areas that from the model point of view are related to the presence of colon cancer. The experimental analysis, performed on 10,000 colon issue images, showed the effectiveness of the proposed method by obtaining an accuracy equal to 0.99. The experimental analysis shows that the proposed method can be successfully exploited for colon cancer detection and localisation from tissue images.

Prediction of the histology of colorectal neoplasm in white light colonoscopic images using deep learning algorithms

Automated histological classification for digital pathology images of colonoscopy specimen via deep learning

Diagnostic evaluation of a deep learning model for optical diagnosis of colorectal cancer

Introduction.

Colon cancer, also known as colorectal cancer, is a type of cancer that begins in the cells of the colon, which is a part of the large intestine. It typically starts as small, noncancerous clumps of cells called adenomatous polyps. Over time, some of these polyps can become cancerous 1 .

Colon cancer is one of the most common forms of cancer worldwide. The American Cancer Society ( https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-statistics.html ) estimates for the number of colorectal cancers in the United States for 2024 are: About 106,590 new cases of colon cancer (54,210 in men and 52,380 in women). Risk factors for developing colon cancer include age, family history of colorectal cancer, personal history of colorectal polyps or inflammatory bowel disease, certain genetic conditions, a diet high in red or processed meats, lack of physical activity, obesity, smoking, and heavy alcohol use.

Symptoms of colon cancer may include changes in bowel habits, persistent abdominal discomfort, unexplained weight loss, fatigue, and rectal bleeding. However, in the early stages, colon cancer may not cause noticeable symptoms, making regular screening important for early detection.

Screening for colon cancer often involves tests such as colonoscopy, sigmoidoscopy, and fecal occult blood tests. Early detection 2 is crucial in terms of reducing mortality rates and successful treatment. Early-stage cancers are typically smaller and confined to the inner layers of the colon, making them more amenable to curative treatment options such as surgery, radiation therapy, and chemotherapy. Furthermore, early-stage colon cancer may require less aggressive treatment compared to advanced-stage disease.

Adopting a healthy lifestyle, including a balanced diet, regular exercise, and avoiding known risk factors, can contribute to the prevention of colon cancer. Regular screenings are especially important for individuals with risk factors or those over the age of 50, as the risk of developing colon cancer increases with age.

Diagnosing colon cancer typically involves a combination of medical history evaluation, physical examination, and various diagnostic tests. The common method used for diagnosing colon cancer is represented by colonoscopy. During this procedure, a flexible tube with a camera on the end (i.e., the colonoscope) is inserted through the rectum to examine the entire colon. If polyps or suspicious areas are found, the doctor may take tissue samples (biopsies) for further examination under a microscope. Thus, if abnormal tissue is found during a colonoscopy or other imaging tests, a biopsy may be performed to analyze the cells under a microscope and confirm the presence of cancer.

The analysis of the biopsy is a time-consuming process performed by biologists and, for this reason, can produce misdiagnosis whether it is not performed by adequately trained medical personnel 3 .

For these reasons, in this paper, we propose a method aimed at detecting whether there is the presence of cancer in colon medical images. In particular, from the bioimages point of view, images obtained from colonoscopy are exploited, while in order to build a model aimed at discriminating between bioimages related to patients affected by colon cancer and healthy ones, we consider deep learning 4 , 5 , with particular regard to convolutional neural networks (CNN). While in the state-of-the-art literature, there are several proposals aimed at detecting cancer from bioimages exploiting deep learning, in the real-world practical clinic these methods are not adopted due to the lack of explainability. This is particularly important because many artificial intelligence models, such as deep neural networks, are often considered “black boxes” that make complex decisions without easily understandable reasoning. This is the reason why introduce, in the proposed method, the possibility to provide a visual explanation behind the model prediction, thus introducing explainable AI i.e., the capability of artificial intelligence systems to provide understandable and transparent explanations for their decisions and actions 6 . The visual explanation represents the research gap in the diagnostic field; so in this work, we dedicate particular attention to all qualitative aspects , applying different explainable AI techniques and, through similarity indices, try to “quantize” the qualitative results.

The paper proceeds as follows: in the next section a review of the state-of-the-art of adenocarcinoma deep learning detection; in “ The method ” we present the proposed method for the explainable detection of colon cancer from bioimages obtained from colonoscopy; in “ Experimental analysis and results ” we exploit the results and discuss them; and, finally, in the last section we present the conclusion and future research on this topic.

Related work

In this section, we present a review of the state-of-the-art research on the adoption of deep learning in the context of adenocarcinoma detection followed by a reasoned discussion.

Authors in 7 applied to the CRC-5000, nct-crc-he-100k and merged datasets on the ResNEt network obtaining 96.77%, 99.76% and 99.98% for the three publicly available datasets, respectively. Moreover, they tested their training strategy and models on the CRC-5000, nct-crc-he-100k and Warwick datasets. Respective accuracy rates of 98.66%, 99.12% and 78.39% were achieved by SegNet. However, the authors focused only on quantitative results and didn’t take into account the qualitative aspects. In the work of Musad et al. 8 , authors applied to CNNs architecture the same dataset, including the three folders of lung tissue and provided a 5-classes distinction obtaining 96.33% in accuracy. They applied the following techniques: wavelet and DFT (Discrete Fourier Transform) for the pre-processing steps and non-specified fully connected CNN for the classification task. From a medical point of view, analyzing lung and colon histological images into the same classification is not used in practice. Also in 9 , the same dataset was used. In this paper, authors reached 99% and 100%applying the DL network, suh as VGG16, VGG19, MobileNet, DenseNet169, and DenseNet201. These good performances were reproducible, but remain only from the metrics point of view. An interesting approach was explained in 10 . In their approach, the image classes (LC25000 datset) were trained from scratch with the DarkNet-19 model, and two optimization algorithms (Equilibrium and Manta Ray Foraging) and combined with the Support Vector Machine (SVM) method provided a performance of 99.69%. In the paper of Mehmood 11 , the LC250000 dataset was considered by a modified version of the AlexNet network for training and testing. In this way, performances reach 98.4% for a 5-way classification. Also in this, the reasons of mixing the lung and colon histological images are not clear and it is missed the visual explanation of these results. Three CNNs were trained and tested in 12 . They used three pre-trained CNN models, which are ShuffleNet V2, GoogLeNet, and ResNet18 also one simple customized CNN model. ShuffleNet V2 was the best model used to classify colon data, it gives 99.87% accuracy with the fastest training times of 1202.3 seconds. In the work of Sakr 13 , the input histopathological images (LC25000 dataset) were normalized before feeding them into their CNN model, and then colon cancer detection was performed. The result analysis demonstrates that their proposed deep model for colon cancer detection provides a higher accuracy of 99.50%, Bukhari and his collegues 14 provided two colon images datasets: LC250000 and Colorectal Adenocarcinoma Gland (CRAG) Dataset. In their study, three variants of CNN (ResNet-18, ResNet-34 and ResNet-50) have been employed to evaluate the images.The accuracy (93.91%) of ResNet-50 was the highest which is followed by ResNet-30 and ResNet-18 with the accuracy of 93.04% each. Last work 15 processed the LC25000 dataset. A shallow neural network architecture was used to classify the histopathological slides into squamous cell carcinomas, adenocarcinomas and benign for the lung. A similar model was used to classify adenocarcinomas and benign for the colon. The diagnostic accuracy of more than 97% and 96% was recorded for lung and colon respectively.

Table 1 compares the works covered in this section with the proposed approach in this study. It shows the important findings, the used dataset, and whether or not the authors consider explainability for the localization of disease into the images.

In this section, the proposed method for the detection of adenocarcinoma cancer coming from cell colon images is presented and shown in Fig. 1 .

Main steps of the proposed methodology.

Starting from the first step, the dataset’s choice represents one of the fundamental steps for the problem under analysis. For the classification of adenocarcinoma, authors choose a binary classification, considering a dataset was initially composed of 500 histological images of the colon cells for each class (benign tissue and adenocarcinoma) uploaded from Kaggle dataset website, loaded by Larxel, a Senior Data Scientist working at Hospital Israelita Albert Einstein, São Paulo, State of São Paulo, Brazil ( https://www.kaggle.com/andrewmvd/datasets ).

Figure 2 shows examples of colon cell histological images: benign tissue (Fig. 2 a) and adenocarcinoma cells (Fig. 2 b). For the medical contest, it is relevant that the images are generated and validated by specialists. In this way, the dataset is usable and reproducible for research purposes.

Representative images of the dataset: ( a ) benign tissue, ( b ) adenocarcinoma below.

The exploited dataset contains 5000 images for each class, as a data augmentation process was applied, using the Augmentor package. The applied data augmentation involves creating modified versions of the original samples by applying transformations like rotation, scaling, cropping, and flipping to increase the diversity of the data available for training. Augmentor package in Python is Compatible with Python 2 and 3 versions, and several kinds of image formats) simplifies this process by providing an easy-to-use interface for generating augmented data. Data augmentation guarantees an increase with a factor of ten of the sample images, providing the training step with a more useful and generalized dataset. Further information and methods regarding data augmentation in medical imaging contest are reported in 16 , 17 , 18 .

Other pre-processing techniques (for instance, denoising 19 ) are not taken into account, because the dataset reports with an adequate number of samples and good resolution. Further, pre-processing steps improve the computational costs and time consumption. The following step consists of the training of CNNs and the testing of these latter. All the training and testing phases, setting the hyperparameters and the sample splitting, generate a network model (for each architecture) through which results evaluation was obtained.

In the last two steps, the results evaluated from a quantitative to qualitative point of view were presented and discussed.

Quantitative results refer to the metrics, such as accuracy, precision, recall, loss, and Area Under the Curve (AUC). These results are supported by the confusion matrix computation and the graphical representation of the accuracy epoch and loss-epoch trends.

On the other hand, a qualitative analysis is conducted to explain the models developed. Class Activation Mapping (CAM) algorithms, specifically Grad-CAM and Score-CAM, generate heatmaps on input images, improving visual explainability and localization features. In conclusion, a structural similarity analysis was applied to these heatmaps.

CAM algorithms and visual explainability

Visual explainability for the resulting models was provided via CAM algorithms, specifically Grad-CAM and Score-CAM, as well as Structural Similarity Index Measures (SSIM).

In the context of CNNs and CAM algorithms, the selected layer for CAM is typically the final convolutional layer before the global average pooling layer or the fully connected layer in the network architecture. CAM algorithms aim to highlight the regions of an input image that contribute the most to the prediction made by the model. This is achieved by visualizing the activation maps of the final convolutional layer, which captures the spatial information learned by the network. The final convolutional layer is chosen because it retains spatial information about the input image while also abstracting high-level features learned by the network. By examining the activation maps of this layer, CAM techniques can localize the relevant features in the input image that are used by the model to make predictions. Some guidelines, during the qualitative evaluation of the models, help the data scientist to choose a better model that presents a visual explanation for medical staff. The considerations to take into account are related to:

knowledge about to images under exam (imaging techniques, disease features, and his severity degrees);

presence of the Region Of Interest (ROI) according to the presence of the disease;

the shape of these ROIs, for instance in histological images, the irregularity of the patterns can be crucial;

does not focus only on a few samples but evaluates the qualitative trends of the heatmaps for the entire sample set.

By highlighting the ROIs of the image that have contributed most to the classification; of medical content, the presence of the disease, for instance, the cancerous cells in colon images, CAM-based algorithms can enable us to understand the most discriminating feature of the images and to identify potential regions that have not yet been considered in current research, thereby directing future developments. Furthermore, concerning the pattern relevance throughout the classification process, the heatmaps are based on the VIRIDIS coloration ( https://cran.r-project.org/web/packages/viridis/vignettes/intro-to-viridis.html ).

In addiction, CAM algorithms and ROI analysis serve complementary roles in medical imaging analysis, with CAM providing insights into image interpretation and ROI analysis focusing on the detailed examination of specific regions within the image. While they are not directly correlated, they can be used synergistically to improve the understanding and utility of medical imaging data.

Looking in deeper detail at the two CAM algorithms: the Gradient-weighted Class Activation Mapping (Grad-CAM) 20 which applied the back-propagation of individual class weights, highlights ROIs, considering the gradient of the pixels in the images. A different method is used by the Score-weighted Class Activation Mapping (Score-CAM) 21 algorithm that based the heatmaps generation on the score i.e. the Channel-wise Increase of Confidence (CIC) parameter, which is used by Score-CAM to evaluate each feature map’s contribution based on the class score.

FastScore-CAM 22 is an enhancement or optimization of the Score-CAM method. It is designed to be computationally more efficient and faster to compute compared to Score-CAM. The term “Fast” in FastScore-CAM suggests that it introduces improvements in terms of speed or efficiency, making it more suitable for real-time or large-scale applications. It aims to retain the interpretability and accuracy of the original Score-CAM while addressing potential computational bottlenecks. In summary, FastScore-CAM is a variant of Score-CAM that is designed to be faster in terms of computation while preserving the interpretability of the original method.

The Structural Similarity Index Measure (SSIM) is a widely-used metric for quantifying the similarity between two images. It was introduced by Wang 23 in 2004. SSIM compares three aspects of images: luminance, contrast, and structure. It assesses the perceived change in structural information, which is crucial for human perception of image quality. In the DL contest, the SSIM approach was applied to improve the models’ level of explainability 24 . Conceptually, this technique “quantizes” the qualitative results coming from the overlapped heatmaps on cell colon histological images, providing values of similarity. These values indicate the degree of difference between two heatmaps created using the same model but different CAM techniques. The values of this index range from +1 to − 1, where a value of +1 denotes equality between the two images. The SSIM technique compares the images considering the differences in brightness, contrast, and potential distortions. In the proposed approach, we evaluate the qualitative model robustness, the MR-SSIM (Model Robustness SSIM) must have higher values.MR-SSIM refers to the application of the SSIM to evaluate the model robustness, so MR indicates only the final aims of the indices. This means that the comparison of two CAMs highlights the common pattern in the same image guaranteeing robustness for the classification model, and the explanation of the latter.

CAM algorithms and similarity indices introduce and explore qualitative aspects, and provide visual explainability to the AI “black box” model for medical and diagnosis point of view.

Experimental analysis and results

This section presents the dataset that was taken into account for the obtaining of quantitative and qualitative results. The latter were reported and discussed. The dataset we exploited is freely available for research purposes and is available at the following url ( https://www.kaggle.com/datasets/andrewmvd/lung-and-colon-cancer-histopathological-images/code ) on the Kaggle website. This dataset considers two main directories: one refers to the lung cancer images and the other to the colon cancer images. Coherently to the topic of the paper, we consider only the colon cancer folders, which are composed of two classes: benign tissue and adenocarcinoma (i.e., a binary classification is exploited). As discussed in “ The method ” the dataset was augmented, generating 5.000 histological images for each class (we consider a binary classification i.e., Adenocarcinoma and Benign_tissue). For the DL classification, the dataset was divided into an 80-10-10 splitting for the training, validation, and testing sets, respectively. The splitting division of the samples is the following:

80% of images (8.000) to the training dataset

10% of images (1.000) to the validation dataset.

10% of images (1.000) to the testing dataset.

For the training-testing phase, seven different deep learning architectures were been considered: ResNet50 25 , DenseNet 26 , VGG19 27 , Standard_CNN 28 , 29 , Inception-V3 30 , EfficientNet 31 and MobileNet 32 . The hyper-parameters are set to 50 epochs, 8 as batch, 0.0001 learning rate, and \(224 \times 224 \times 3\) image size. This combination is determined by evaluating several combinations on the networks under investigation.

We exploited the binary cross-entropy as loss function. As a matter of fact, using binary cross-entropy is specifically designed for binary classification problems, making it well-suited for tasks where the output variable has only two possible outcomes. Infact, binary cross-entropy is specifically designed for two-class classification problems where each input can belong to only one class among two mutually exclusive classes. Moreover, it mathematically penalizes the distance between the predicted probability distribution and the actual distribution of the class. This is the reason why it can be considered a good choice for optimizing models to predict class probabilities.

All training and testing were performed in a working environment using an Intel Core i7 CPU with 16 GB RAM.

In Table 2 are reported the metrics of the networks in terms of accuracy, precision, recall, F-Measure, AUC, and loss.

The classification results are shown in Table 2 .

From Table 2 two different groups of architectures were identified, based on the metrics results. The first one, which comprises the VGG19, the Standard_CNN, the ResNet50, and the DenseNet presents low results. These networks are not able to classify correctly the images, increasing the error possibility, and consequently are not reliable for the adenocarcinoma diagnosis; these networks will be excluded for further analysis.

On the other hand, the second group of CNNs, i.e. EfficientNet, MobileNet and Inception-V3 show optimal quantitative metrics, reaching almost 100% for accuracy, precision and recall. In other words, the classification applied through these architectures guarantees correct diagnosis for histological colon images. Additionally, these results confirm the author’s choice of not applying other pre-processing steps on the dataset, obtaining minor time consumption and computational cost.

To emphasize these results, Fig. 3 reported the confusion matrix considering the MobileNet network.

Confusion matrix of the MobileNet network.

The matrix in Fig. 3 demonstrates the model’s good performance, with greater values on the first diagonal, indicating that objects classified in a specific class are properly predicted in that class.

In Fig. 4 is shown for MobileNet network the epoch-accuracy and epoch-loss trends.

Epoch trends of the MobileNet network: ( a ) epoch-accuracy plot; ( b ) epoch-loss plot.

Good training phase results are shown in Fig. 4 a, with a minor decline observed during the validation phase (blue line). The training accuracy trend (red dotted line) demonstrates that the MobileNet model was able to identify the differences between images belonging to distinct classes. Figure 4 illustrates the opposite behavior that is acquired from the (training and testing) loss, providing more evidence that the model is correctly learning the distinctions between cells from benign tissue and those from adenocarcinoma. From these trends, it is possible to observe the convergence of loss, that is when the loss curve converges to a relatively stable value over epochs. This suggests that the model has learned the underlying patterns in the data and is not overfitting or underfitting. From both plots, it is present the alignment of training and validation curves. Indeed, ideally, the training and validation curves should follow a similar trend. This indicates that the model is generalizing well to unseen data.

Qualitative analysis

In this sub-section, the qualitative results were illustrated and discussed.

For these results, the quantitative approach is not valid because the qualitative aspect is not related to a quantified measure, but is based on the explanation conducted directly on the heatmaps overlapped on input images. So, to perform this evaluation, we have some guidelines presented in “ The method ”. After the heatmap generation on the three considered models and the three CAM algorithms; three different results were obtained.

Inception-V3 cannot able to generate heatmaps; this behavior is typical when a model does not recognize any common patterns in the images. From the qualitative point of view, this model is not able for a visual explanation.

EfficientNet model generates heatmaps, but by analyzing the entire sets of samples, it is possible to observe that all the highlighted heatmaps are identical, and in this case are focused on the right side as shown in Fig. 5 .

Grad-CAM of the EfficientNet model.

This behavior occurs when the models reveal a single pattern and repeat the same heatmaps for all the samples, not considering the variations in the input image. The same heatmaps appear also in the Score-CAM and FastScore-CAM. From a general point of view, CAM algorithms rely on the learned feature representations of the neural network model, which may not always align perfectly with the subtle visual cues associated with the presence of disease in medical images. If the model architecture or the training data does not adequately capture the relevant features indicative of the disease, the CAM-generated heatmaps may not accurately highlight the areas of interest. Considering that all the networks are trained and tested with the same dataset and with the optimal hyper-parameters combination, the main differences regarding the network architecture and the corresponding generated model. Moreover, in medical imaging classification, it is important to remember that the same networks work with good performances for all the medical images or all diseases. Consequentially, for each dataset and each classification task, an accurate comparison of CNNs is necessary.

For MobileNet, the obtained heatmaps are related to the presence of the ROIs corresponding to the presence of the disease, i.e. adenocarcinoma cell clusters, as shown in Fig. 6 .

In Fig. 6 were reported the heatmaps of the same samples for the three applied CAMs. The CAMs highlight three areas: in the upper, on the right side and in the bottom. varying the CAMs algorithm varies the intensity related to these common patterns, and these are referred to the presence of tumoral cell clusters. In such way, the heatmaps provide visual explainability and localization of the disease presence, improving reliability, trustworthiness and credibility from a medical point of view.

CAMs for MobileNet network of the same sample: ( a ) Grad-CAM, ( b ) Score-CAM, ( c ) FastScore-CAM.

Furthermore, the authors attempt to quantify the qualitative results and improve the model’s robustness by introducing the MR-SSIM. Table 3 displays the average similarity value among Grad-CAM, Score-CAM and FastScore-CAM heatmaps for each class, considering a couple of heatmap sets and obtaining the three possible combinations.

Table 3 compares heatmaps activated by Grad-CAM, Score-CAM, and FastScore-CAM algorithms on the same model, i.e., MobileNet. The MR-SSIM indices report 0.79 for the Grad-CAM/Score-CAM comparison and 0.76 for Score-CAM/FastScore-CAM as higher values. This means that the heatmaps produced by two distinct CAMs are highly similar, identifying the same locations with little changes in intensity.

When applying the SSIM to different CAM algorithms in adenocarcinoma biopsy images, the objective is to assess how well these algorithms highlight ROIs indicative of adenocarcinoma presence while preserving the structural details present in the original biopsy images. High values enhance os SSIM between two CAMs means that different CAM algorithms highlight the same areas (ROIs), improving in this way the visual explanation.

Conclusion and future works

In this paper, we designed and experimented with an automated approach for detecting adenocarcinoma in the colon tract by using histological images of colon cells. The results show that the deployed CNNs, specifically MobileNet, Inception-V3, and EfficientNet architectures, report optimal quantitative performances in terms of accuracy, precision, and recall (99% in each).

This work focuses on the qualitative aspects of tested models, using CAM algorithms to the visual localization of relevant and common patterns in the images related to the network classification and the cancer cell clusters in colon tissue. Furthermore, the use of three distinguished CAMs, i.e. Grad-CAM, Score-CAM, and FastScore-CAM, united to the index similarity; improves the reliability and the trustworthiness of AI in healthcare. This indicates that while deep learning prediction does not replace human decisions, it does aid in the consultation process during the diagnostic procedure.

Future studies will focus on different types of colon cancer generated by other imaging techniques (CT, MRI, echography, etc.) and combine them into an assembled DL model. Moreover, we will design a set of adversarial machine learning related to data poisoning to evaluate the DL bioimages classification resilience to these techniques. As a future work, more comparative evaluations can be performed after applying capsule network-based methods since they can keep spatial relationships of learned features and have been used recently in various works 33 , 34 and transformer-based approaches since they can obtain global information effectively 35 .

Data availability

The datasets generated and/or analysed during the current study are available in the “Lung and Colon Cancer” repository on Kaggle website, at the following link: https://www.kaggle.com/datasets/biplobdey/lung-and-colon-cancer .

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Acknowledgements

This work has been partially supported by EU DUCA, EU CyberSecPro, SYNAPSE, PTR 22-24 P2.01 (Cybersecurity) and SERICS (PE00000014) under the MUR National Recovery, Resilience Plan funded by the EU - NextGenerationEU projects, by MUR - REASONING: foRmal mEthods for computAtional analySis for diagnOsis and progNosis in imagING—PRIN, e-DAI (Digital ecosystem for integrated analysis of heterogeneous health data related to high-impact diseases: innovative model of care and research), Health Operational Plan, FSC 2014-2020, PRIN-MUR-Ministry of Health and the National Plan for NRRP Complementary Investments D \(^{\wedge }\) 3 4 Health: Digital Driven Diagnostics, prognostics and therapeutics for sustainable Health care and Progetto MolisCTe, Ministero delle Imprese e del Made in Italy, Italy, CUP: D33B22000060001.

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M.D.G. formal analysis, validation, software, Writing – Original Draft Preparation, Writing – Review & Editing. F.Mercaldo software, supervision, conceptualization, formal analysis, Writing – Original Draft Preparation, Writing – Review & Editing. A.S., F.Martinelli and M.C. investigation, formal analysis, data curation, Writing – Original Draft Preparation, Writing – Review & Editing.

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Di Giammarco, M., Martinelli, F., Santone, A. et al. Colon cancer diagnosis by means of explainable deep learning. Sci Rep 14 , 15334 (2024). https://doi.org/10.1038/s41598-024-63659-8

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40% of US cancer cases linked to lifestyle choices

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In a recent study published in CA: A Cancer Journal for Clinicians , a team of researchers analyzed nationally representative cancer incidence, risk factor prevalence, and mortality data to determine the number and proportion of various types of cancer cases and cancer-related mortality that could be attributed to modifiable risk factors.

Study: Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States, 201. Image Credit: africa_pink / Shutterstock

Despite substantial resources and efforts being invested in cancer research and an improved understanding of the mechanisms and pathology of cancer, the economic and health burden of cancer remains significant. A 2018 study by the same team of researchers examined the proportion of cancer cases and mortality that were attributable to modifiable risk factors, intending to improve cancer awareness and advocate for changes to control or prevent various types of cancer.

These modifiable risk factors include dietary and exercise-related factors, smoking behavior, alcohol consumption, exposure to ultraviolet (UV) radiation, as well as infections with various pathogens such as human papillomavirus (HPV), hepatitis B and C viruses, Epstein–Barr virus (EBV), Helicobacter pylori , and human immunodeficiency virus (HIV). However, new data has emerged since 2018 on the magnitude and nature of the associations between many of these modifiable risk factors and the risk of cancer, warranting a re-examination.

About the study

The present study analyzed cancer occurrence data from 2019 to evaluate the number and proportion of cases and deaths for 30 types of cancers (except for excluding non-melanoma skin cancers) and their association with a wide range of modifiable risk factors.

Despite the availability of data from 2020, the researchers used 2019 data to circumvent the low cancer diagnosis rates after cancer screening programs and diagnostic facilities were suspended or reduced due to the coronavirus disease 2019 (COVID-19) pandemic.

Data on new cases of invasive cancer from 2019 were obtained from cancer registries and surveillance programs run by the United States (U.S.) Centers for Disease Control and Prevention (CDC) and the National Cancer Institute. Data obtained from National Health and Nutrition Examination surveys from 2007 to 2016 were used to determine various modifiable risk factors.

A comprehensive list of modifiable risk factors was examined, including former and current smoking, body weight, low physical activity levels, exposure to second-hand smoke, increased consumption of processed and red meats, alcohol intake levels, and low intake of dietary fibers, dietary calcium, vegetables, and fruits.

While smoking is linked to numerous types of cancer, exposure to second-hand smoke increases the risk of bronchus and lung cancers. Dietary factors are predominantly associated with increased risk of colorectal cancer. Furthermore, UV radiation is a known risk factor for melanomas , and excess body weight, alcohol consumption, physical inactivity, and cigarette smoking are risk factors for multiple types of cancers.

Conclusions

Overall, the study found that almost 40% of all cancer cases in the U.S. in 2019 and close to 44% of cancer-related deaths could be attributed to modifiable risk factors, with cigarette smoking being the significant risk factor. Lung cancer was the predominant form of cancer attributed to modifiable risk factors.

The results emphasized that a growing number of cancer cases and mortality are linked to modifiable risk factors, and implementing lifestyle changes such as avoiding smoking, reducing alcohol and red and processed meat consumption, achieving adequate physical activity levels, and eating a healthy diet can substantially lower the overall cancer burden.

Islami, F., Marlow, E. C., Thomson, B., McCullough, M. L., Rumgay, H., Gapstur, S. M., Patel, A. V., Soerjomataram, I., & Jemal, A. (2024). Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States, 2019. CA: A Cancer Journal for Clinicians . DOI:10.3322/caac.21858, https://acsjournals.onlinelibrary.wiley.com/doi/full/10.3322/caac.21858

Posted in: Men's Health News | Medical Science News | Medical Research News | Women's Health News | Disease/Infection News

Tags: Alcohol , Breast Cancer , Calcium , Cancer , Cancer Diagnosis , Cervical Cancer , Cigarette , Colorectal , Colorectal Cancer , Coronavirus , covid-19 , Diagnostic , Diet , Esophageal Cancer , Exercise , Helicobacter pylori , Hepatitis , Hepatitis B , HIV , Hodgkin Lymphoma , Immunodeficiency , Liver , Lung Cancer , Lymphoma , Meat , Melanoma , Mortality , Nutrition , Pandemic , Pathology , Physical Activity , Research , Sarcoma , Skin , Skin Cancer , Smoking , Stomach , Stomach Cancer , Vegetables , Virus

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.

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COLORECTAL CANCER

Ernst j. kuipers.

1 Erasmus MC University Medical Center, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands

William M. Grady

2 Clinical Research Division, Fred Hutchinson Cancer Research Center; Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA

David Lieberman

3 Division of Gastroenterology and Hepatology, Oregon Health and Science University, Portland, OR, USA

Thomas Seufferlein

4 Department of Internal Medicine I, University of Ulm, Ulm, Germany

Joseph J. Sung

5 Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China

Petra G. Boelens

6 Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands

Cornelis J. H. van de Velde

Toshiaki watanabe.

7 Department of Surgical Oncology and Vascular Surgery, University of Tokyo, and the University of Tokyo Hospital, Tokyo, Japan

Colorectal cancer had a low incidence several decades ago. However, it has become a predominant cancer and now accounts for approximately 10% of cancer-related mortality in western countries. The ‘rise’ of colorectal cancer in developed countries can be attributed to the increasingly ageing population, unfavourable modern dietary habits and an increase in risk factors such as smoking, low physical exercise and obesity. New treatments for primary and metastatic colorectal cancer have emerged, providing additional options for patients; these treatments include laparoscopic surgery for primary disease, more-aggressive resection of metastatic disease (such as liver and pulmonary metastases), radiotherapy for rectal cancer and neoadjuvant and palliative chemotherapies. However, these new treatment options have had limited impact on cure rates and long-term survival. For these reasons, and the recognition that colorectal cancer is long preceded by a polypoid precursor, screening programmes have gained momentum. This Primer provides an overview of the current state of art knowledge on the epidemiology and mechanisms of colorectal cancer, as well as on diagnosis and treatment.

Introduction

We live in an era with improved worldwide average living standards and increased access to adequate healthcare that has considerably improved the diagnosis and treatment of diseases. These measures have had an impact on average life expectancy in most regions of the world. However, although death rates from communicable diseases have improved globally as a result of these medical improvements, cancer-related mortality has increased by almost 40% over the past 40 years. A further 60% increase is expected in the coming 15 years, with 13 million people estimated to die of cancer in 2030 1 . The main causes of cancer-related mortality have also changed, attributable to alterations in disease incidence, introduction of screening programmes and therapeutic improvements. Colorectal cancer was rather rare in 1950, but has become a predominant cancer in Western countries, now accounting for approximately 10% of cancer-related mortality. Reasons explaining this increased incidence include population ageing and the preponderance of poor dietary habits, smoking, low physical activity and obesity in western countries. The change in incidence is not only apparent in the rates of sporadic disease, but also in some familial cancer syndromes. Indeed, given that rates of Helicobacter pylori infection (a causative factor of gastric cancer) have fallen dramatically, colorectal cancer is now the predominant presentation of Lynch syndrome (a hereditary non-polyposis type of colorectal cancer), whereas carriers of this syndrome used to be predominantly affected by gastric cancer 2 – 4 .

New treatments for primary and metastatic colorectal cancer have been developed and include laparoscopic surgery for primary disease; resection of metastatic disease affecting, for example, the liver and lungs; radiotherapy for rectal cancer and some forms of metastatic disease; and neoadjuvant and palliative chemotherapy 5 – 7 . Despite advances in surgical and medical therapies, cure rates and long-term survival have changed little in the past several decades. Against this background, and given that colorectal cancer is preceded by a polypoid precursor ( Figure 1 ), screening programmes for early detection have gained momentum.

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(a) A small sessile adenoma. (b) An advanced, larger sessile adenoma. (c) A large, dish-shaped, ulcerating sigmoid carcinoma. The tumour covers most of the circumference, but has not yet led to substantial obstruction of the lumen.

Indeed, screening is expected to have a major impact on colorectal cancer incidence and mortality in the next 15 years, an effect that is unlikely to come from lifestyle interventions or from new therapeutics. Screening will only make these improvements with high uptake; accordingly, major improvements in noninvasive screening (for example, faecal immunochemical testing and faecal DNA testing) are being investigated as alternatives to the current gold standard, but invasive, screening methodology — colonoscopy. Alongside these advances, the quality of screening colonoscopy has undergone substantial improvement in terms of technical changes and training, and quality assurance 8 , 9 .

In this Primer, we provide an overview of the current knowledge on epidemiology and mechanisms underlying colorectal cancer, as well as on diagnosis and treatment, including surgical and medical approaches.

Epidemiology

Colorectal cancer is the second- and third-most common cancer in women and men, respectively. In 2012, 614,000 women (9.2% of all new cancer cases) and 746,000 men (10.0% of new cancer cases) were diagnosed with colorectal cancer worldwide 10 . Combined, in both sexes, colorectal cancer is the third-most common cancer and accounts for 9.7% of all cancers excluding non-melanoma skin cancer. More than half of the cases occur in more-developed regions of world. The age-standardized incidence rate (ASRi) of colorectal cancer is higher in men (20.6 per 100,000 individuals) than in women (14.3 per 100,000). The majority of patients with sporadic cancer are >50 years of age, with 75% of patients with rectal cancer and 80% of patients with colon cancer patients being ≥60 years of age at the time of diagnosis.

Incidence varies geographically, with the highest incidence in Australia and New Zealand (ASRi 44.8 and 32.2 per 100,000 men and women, respectively), whereas Western Africa (ASRi 4.5 and 3.8 per 100,000) has the lowest incidence ( Figure 2 ). More-developed regions (Europe, Northern America, Australia, New Zealand and Japan; combined ASRi 29.2 per 100,000) have a higher incidence than less-developed regions (all regions of Africa, Asia (excluding Japan), Latin America and the Caribbean, Melanesia, Micronesia and Polynesia; ASRi 11.7 per 100,000) 10 . The seven world regions can be ranked according to increasing ASRi, from Africa (6.3 per 100,000), Asia (13.7 per 100,000), Latin America and Caribbean (14.0 per 100,000), Micronesia/Polynesia (15.0 per 100,000), North America (26.1 per 100,000), Europe (29.5 per 100,000), to Oceania (34.8 per 100,000) 10 . Within each of these regions, the ASRi can show marked variation. In Europe, Albania (8.4 per 100,000) and Ukraine (23.4 per 100,000) have a lower incidence, whereas Slovakia (42.7 per 100,000), Hungary (42.3 per 100,000) and Denmark (40.5 per 100,000) have a high incidence. Asia has the greatest diversity with regard to the ASRi of colorectal cancer. The incidence is high in Korea (45.0 per 100 000), Singapore (33.7 per 100,000) and Japan (32.2 per 100,000), but much lower in Nepal (3.2 per 100,000), Bhutan (3.5 per 100,000) and India (6.1 per 100,000). These variations are associated with different socioeconomic levels 11 .

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Rates are consistently higher in men than in women, and vary considerably between regions. Highest rates occur in Australia and New Zealand, Europe and North America.

In 2013, 771,000 people died as a result of colorectal cancer globally 12 , making the disease the fourth most common cause of cancer-related death worldwide after lung, liver and stomach cancer 12 . The age-standardized mortality rate (ASRm) of colorectal cancer in different countries reflects disease incidence, which explains why the ASRm is higher in men (10.0 per 100,000) than in women (6.9 per 100,000). Mortality also depends on the stage distribution at diagnosis, which is influenced by the availability of a population-screening programme and by the level of care in each country. The ASRm is almost two-fold higher in more-developed regions (11.6 per 100,000) than in less-developed regions (6.6 per 100,000). The ASRm in both sexes ranged from 3.3 per 100,000 people in Western Africa to 14.9 per 100,000 people in Central and Eastern Europe; in men, this value ranged from 3.5 per 100,000 people in Western Africa to 20.3 in Central and Eastern Europe, whereas in women, ASRm ranged from 3.0 per 100,000 people in Western Africa to 11.7 per 100,000 people in Central and Eastern Europe. That is, Western Africa showed the lowest age-standardized mortality in the world and Central and Eastern Europe exhibited the highest mortality in the world, in both men and women. Worldwide, mortality due to colorectal cancer has increased with 57% between 1990 and 2013 12 . Since the 1980s, in several countries in Europe, North America and Asia, mortality has tended to decrease. This decrease might be attributable to the introduction of colonoscopy, which has improved detection and treatment of early lesions.

Risk factors

Both genetic and environmental factors play an important part in the aetiology of colorectal cancer. The majority of colorectal cancers are sporadic; approximately three-quarters of patients have a negative family history. In most Western populations, the average lifetime risk for colorectal cancer is in the range of 3–5%. However, this risk almost doubles in individuals with a first-degree family member with colorectal cancer who was diagnosed at 50–70 years of age; the risk triples if the first-degree relative was <50 years of age at diagnosis. Risk further increases in individuals who have two or more affected family members. For sporadic colorectal cancer, this increased risk in the presence of affected family at least in part reflects low-penetrance genetic factors. Accordingly, positive family history has a role in approximately 15–20% of patients with colorectal cancer.

Indeed, a specific subgroup of the patient population is formed by those affected by a hereditary colorectal cancer syndrome, accounting for 5–10% of all patients. The most common syndrome in this category is Lynch syndrome. This syndrome is caused by a mutation in one of the DNA mismatch-repair genes: MLH1, MSH2, MSH6, PMS2 or EPCAM . Impaired mismatch repair during replication gives rise to accumulation of DNA mutations, which occur, in particular, in microsatellite DNA fragments with repetitive nucleotide sequence. This microsatellite instability (MSI) can be identified by means of polymerase chain reaction (PCR) testing, which compares normal and tumour DNA of the same patient. Patients with Lynch syndrome used to be identified by means of clinicopathological criteria, such as the Amsterdam and Bethesda criteria 4 , 13 . However, clinical practice is shifting towards unrestricted testing of tumour material of all patients diagnosed before the age of 70 years by means of MSI PCR and immunohistochemistry for lack of expression of specific mismatch-repair proteins 14 , 15 .

The second most common hereditary colorectal cancer syndrome is familial adenomatous polyposis. This syndrome is caused by mutations in the adenomatous polyposis coli ( APC) gene, which controls activity of the Wnt signalling pathway 4 . Most patients with familial adenomatous polyposis develop very large numbers of colorectal adenomas and subsequent colorectal cancer at a young age. Other hereditary colorectal cancer syndromes are polyposis associated with mutations in the mutY DNA glycosylase ( MUTYH) gene, Peutz Jeghers syndrome, serrated polyposis and juvenile polyposis; the diagnosis and management of which have been discussed elsewhere 4 .

Chronic colitis due to inflammatory bowel disease (IBD) is also associated with increased risk of colorectal cancer. This risk increases with longer duration of IBD 16 . IBD explains only 1% of colorectal cancers in western populations, and a range of studies suggest that the incidence of colorectal cancer in those with IBD is decreasing because of effective anti-inflammatory treatments and improved surveillance 17 , 18 , although this observation is not yet unanimous 19 .

A range of environmental — largely modifiable — lifestyle factors influence the risk of developing colorectal cancer. The risk is increased by smoking, alcohol intake and increased body weight. With each unit increase of the body mass index, the risk for colorectal cancer increases by 2–3% 20 . In close conjunction, patients with type 2 diabetes mellitus also have an increased risk for colorectal cancer 21 . Moderate alcohol consumption (2–3 units per day) has been estimated to increase risk by 20%, whereas even higher alcohol consumption is associated with an up to 50% increased risk 22 . Prolonged heavy smoking has an effect of similar magnitude 23 , 24 . Intake of red meat and processed meat increases colorectal cancer risk by an estimated 1.16-fold per 100 g increase of daily intake 25 . By contrast, consumption of milk, whole grains, fresh fruits and vegetables, as well as intake of calcium, fibre, multivitamins and vitamin D, decrease risk. The decrease of risk is estimated to approximate 10% per daily intake of every 10 g fiber, 300 mg calcium or 200 ml milk 25 , 26 . Daily physical activity for 30 minutes has a similar magnitude of effect 20 , 27 . Low-dose aspirin has also been associated with decreased risk of colorectal cancer 28 .

The prevalence of these modifiable lifestyle factors can explain, to a considerable extent, the geographic and socioeconomic differences in colorectal cancer incidence 29 . Several studies have estimated that 16–71% of colorectal cancers in Europe and the United States are attributable to lifestyle factors 30 – 32 . Any benefit from lifestyle changes can be augmented by regular intake of aspirin and other nonsteroidal anti-inflammatory drugs 33 ; however, this effect seems to depend on host genotype 34 , 35 . Statin use might have a small preventive effect on colorectal cancer incidence 36 , 37 , as does hormone therapy in post-menopausal women 38 .

The variety of environmental factors that influence colorectal carcinogenesis is likely reflected in the heterogeneity of colorectal cancer, and has stimulated research into the so-called field of ‘molecular pathological epidemiology’, which focuses on the correlation between environmental and genetic factors, and between molecular tumour characteristics and disease progression 39 . Further research into the correlation between colonic microbiota and colorectal cancer will likely provide further insights (see below).

Mechanisms/pathophysiology

The environmental and genetic factors that cause colorectal cancer do so by promoting the acquisition of hallmark behaviours of cancer ( Box 1 ) in colon epithelial cells 40 , 41 . One way these hallmark cancer traits are acquired is through the progressive accumulation of genetic and epigenetic alterations that activate oncogenes and inactivate tumour suppressor genes. The loss of genomic and/or epigenomic stability has been observed in the majority of early neoplastic lesions in the colon (namely, aberrant crypt foci, adenomas and serrated polyps) and is likely a central molecular and pathophysiological event in the initiation and formation of colorectal cancer 42 , 43 . The loss of genomic and epigenomic stability accelerates the accumulation of mutations and epigenetic alterations in tumour suppressor genes and oncogenes, which drive the malignant transformation of colon cells through rounds of clonal expansion that select for those cells with the most aggressive and malignant behaviour 44 – 46 . A prevailing paradigm is that the cell of origin of most colorectal cancers is a stem cell or stem cell-like cell that resides in the base of the colon crypts 47 . In this model, mutations in oncogenes and tumour suppressor genes in these cells lead to the formation of cancer stem cells, which are essential for the initiation and maintenance of a tumour.

The hallmarks of cancer 40 , 41

Avoiding immune destruction: immune suppression in tumour microenvironment by induction of local cytokines
Evading growth suppressors: mutation and downregulation of growth-inhibiting factors and their receptors
Genome instability and mutation: inactivation of DNA repair mechanisms
Enabling replicative immortality: inhibition of mechanisms that induce senescence and induction of telomerase activity
Deregulating cellular energetics: aerobic glycolysis (Warburg phenomenon) and glutaminolysis
Tumour-promoting inflammation: induction of growth-promoting and angiogenesis-promoting factors by secreted proteins made by local inflammatory cells
Inducing angiogenesis: induction of the formation of new blood vessels
Resisting cell death: escape from autonomous and paracrine mediators of apoptosis and other forms of cell death (necrosis, necroptosis)
Activating invasion and metastasis: remodelling of extracellular matrix to promote cell motility and induction of epithelial–mesenchymal transition

In the colon, the evolution of normal epithelial cells to adenocarcinoma by and large follows a predictable progression of histological and concurrent epigenetic and genetic changes ( Figure 3 ). In the ‘classic’ colorectal cancer formation model, the vast majority of cancers arise from a polyp beginning with an aberrant crypt, which then evolves into an early adenoma (<1 cm in size, with tubular or tubulovillous histology). The adenoma then progresses to an advanced adenoma (>1cm in size, and/or with villous histology) before finally becoming a colorectal cancer. This process is driven by accumulation of mutations and epigenetic alterations and takes 10–15 years to occur but can progress more rapidly in certain settings (for example, in patients with Lynch syndrome) 48 . Notably, although the histology of conventional tubular adenomas is fairly homogeneous, the molecular biology of these polyps are heterogeneous, which might explain why some adenomas progress to colorectal cancer (approximately 10% of polyps) and some do not 49 , 50 .

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Currently, two discrete normal colon to colorectal cancer sequences have been identified. Both sequences involve the progression of normal colon epithelial cells to aberrant crypt foci, followed by early and advanced polyps with subsequent progression to early cancer and then advanced cancer. The ‘classic’ or traditional pathway (top) involves the development of tubular adenomas that can progress to adenocarcinomas. An alternate pathway (bottom) involves serrated polyps and their progression to serrated colorectal cancer has been described in the last 5–10 years. The genes mutated or epigenetically altered are indicated in each sequence; some genes are shared between the two pathways whereas others are unique (for example, BRAF mutations and CpG Island Methylator Phenotype (CIMP) only occur in the serrated pathway). The signalling pathways deregulated during the progression sequence are also shown, with the width of the arrow reflecting the significance of the signalling pathway in tumour formation.

APC , adenomatous polyposis coli; CIN, chromosomal instability; CTNNB1 , catenin-β1; FAM123B , family with sequence similarity 123B (also known as AMER1 ); FZD10 , frizzled class receptor 10; LRP5 , low-density lipoprotein receptor-related protein 5; MAPK, mitogen-activated protein kinase; MSI, microsatellite instability; PI3K, phosphatidylinositol 3-kinase; PI3KCA , phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit-α; PTEN , phosphatase and tensin homologue; SFRP , secreted frizzled-related protein; SMAD4 , SMAD family member 4; TGFβ, transforming growth factor-β; TGFBR2 , TGFβ _receptor 2.

Figure adapted from 229 , Nature Publishing Group.

Until 5–10 years ago tubular and tubulovillous adenomatous polyps were thought to be the only lesions capable of progressing to cancer. However, some colorectal cancers have been shown to evolve from a subset of polyps called sessile serrated polyps, which account for roughly 5–10% of all polyps. These serrated polyps arise by molecular and histological events that are distinct from tubular adenomas 51 – 53 and are classified into three categories: hyperplastic polyps, sessile serrated adenomas and traditional serrated adenomas 54 . The sessile serrated polyps have the potential to transform into colorectal cancers through the following sequence: hyperplastic polyp to sessile serrated polyp to adenocarcinoma 51 , 55 . Furthermore, serrated polyps that arise in the right colon (which includes the cecum, ascending colon and transverse colon) commonly show MSI and a form of epigenetic instability characterized by excessive aberrant CpG island DNA methylation, termed the CpG Island Methylator Phenotype (CIMP). By contrast, polyps that arise in the left colon (which includes the descending colon, sigmoid colon and rectum) are typically microsatellite stable but frequently carry mutations in KRAS and a subset of these polyps have an attenuated form of the CIMP 52 , 53 , 56 .

Given these molecular differences in the polyps and cancers they evolve into, a classification system for colorectal cancer has been proposed, with four subgroups of differing molecular features: hypermutable/microsatellite unstable (Hyp-MSI), hypermutable-microsatellite stable (Hyp-MSS), microsatellite stable (MSS) or chromosome unstable (CIN) and CIMP cancers 43 , 57 . The frequency of specific mutations can vary dramatically between the molecular subclasses, suggesting each has its own set of cooperating drivers 57 . However, the specific mutations and epigenetic alterations that define these molecular subgroups are still being determined. Some mutations, such as those in APC and SMAD family member 4 (SMAD4) , are common among all the molecular subgroups — suggesting a central role in colorectal cancer in general — whereas others are restricted to one subgroup (for example, BRAF in CIMP colorectal cancers) 58 .

In colorectal cancer, substantial heterogeneity in the specific mutations is evident between tumours, although the mutations seem to cluster in epistatically related groups (for example, genes involved in a certain signalling pathway) 59 – 61 . The most common alterations seen in colorectal cancer include those in APC, catenin-beta1 (CTNNB1), KRAS, BRAF, SMAD4, transforming-growth factor-beta receptor 2 (TGFBR2), TP53, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit-alpha (PIK3CA), AT-rich interactive domain 1A (ARID1A), SRY (sex-determining region Y) box 9 (SOX9), family with sequence similarity 123B (FAM123B; also known as AMER1 ) and ERBB2 , which promote tumorigenesis by perturbing the function of key signalling pathways, including the Wnt–β-catenin, epidermal growth factor (EGF)-mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) and TGF-β signalling pathways, or by affecting genes that regulate central behaviours of cells, such as DNA repair and proliferation 62 , 63 ( Table 1 ). Colorectal cancer is frequently initiated by alterations that affect the Wnt signalling pathway, and the ensuing neoplastic cells then progress upon deregulation of other signalling pathways, including the RAS–RAF–MAPK, TGF-β, and the PI3K–AKT pathways 61 , 64 .

Common genetic and epigenetic alterations in colorectal cancer *

Gene or biomarker	Chromosome	Function	Molecular lesion	Frequency (%)	Predictive?	Prognostic?	Diagnostic?
Tumour suppressors
	5	Regulates Wnt signalling pathway	Inactivating mutations	40–70	No	No	Familial Adenomatous Polyposis
	1	Member of SWI/SNF family, regulates chromatin structure and gene transcription	Inactivating mutations	15	No	No	NA
	3	Regulates Wnt signalling pathway	Activating mutations	1	No	No	No
	18	Netrin receptor; regulates apoptosis, deleted but not mutated in colorectal cancer, role in primary cancer still unclear	Deletion/LOH	9 (mutations)/ 70(LOH)	No	Possible	No
	X	Involved in Wnt signalling pathway	Inactivating mutations	10	No	No	No
	4	Regulates proteasome mediated protein degradation	Inactivating mutations	20	No	No	No
	10	Regulates PI3K–AKT pathway	Inactivating mutations, loss of protein by immunohistochemistry	10(mutation) 30 (loss of expression)	Possible	No	Cowdens syndrome
	10	Regulates GDNF signalling pathway	Inactivating mutations, aberrant DNA methylation	7 (mutation); 60(methylation)	No	No	No
	18	Regulates TGF-β and BMP pathways	Inactivating mutations, deletion	25	Possible	Possible	Juvenile Polypsis
	3	Regulates TGF-β pathway	Inactivating mutations	20	No	No	No
	17	Regulates expression of target genes involved in cell-cycle progression, DNA repair and apoptosis	Inactivating mutations	50	Possible	Possible	Li Fraumeni Syndrome
Proto-oncogenes
	7	Involved in MAPK signalling pathway	V600E activating mutation	8–28	Probable	Probable	Lynch syndrome
	17	Involved in EGF–MAPK signalling pathway	Amplification	35	No	No	No
	20	Regulates G-protein signalling	Mutation	20	No	No	No
	11	Regulates IGF signalling pathway	Copy number gain, loss of imprinting	7(mutations)/ 10(methylation)	No	No	No
		Regulates intracellular signalling via the MAPK pathway	Activating mutations in codon 12 or 13 but rarely in codons 61, 117 and 146	40	Yes	Possible	NA
	8	Regulates proliferation and differentiation	Amplification	2(mutations)/ 10 (CNV- gain)	No	No	No
	1	Regulates the MAPK pathway	Mutation in codon 12 or 13	2	Yes	No	No
	3	Regulates PI3K–AKT pathway	al and kina20Mutase mutations in kinase (exon 20) and helical(exon 9) domain	20	Probable	Possible	No
	1	Ligand for LGR family receptors, and activate Wnt signalling	Gene fusion translocation and	10	No	No	No
	17	Regulates apoptosis	Copy number gain	9(mutations)/ <5 (CNV gain)	No	No	No
	10	Regulates Wnt signalling	Gene fusion and translocation	10	No	No	No
Other molecular alterations
Chromosome Instability (CIN)	N/A	NA	Aneuploidy	70	Probable	Probable	No
CpG Island Methylator Phenotype (CIMP	N/A	NA	Methylation of >20% loci from a selected panel of markers	15	Probable	Probable	No
Microsatellite Instability (MSI)	N/A	NA	Unstable microsatellite repeats in consensus panel	15	Probable	Yes	Lynch syndrome
Mismatch Repair Genes	N/A	Regulate DNA mismatch repair	Loss of protein by immunohistochemistry; methylation; inactivating mutations	1–15	Possible	Probable	Lynch Syndrome
	17	NA	Methylation	>90	No	No	Serum based assay for cancer detection
	10, 16 and 4, respectively	NA	Methylation	75	No	No	Stool based test for early detection
18qLOH	18	NA	Deletion of the long arm of chromosome 18	50	Probable	Probable	No

APC , adenomatous polyposis coli; ARID1A , AT-rich interactive domain 1A; BMP , bone morphogenetic protein; CNV, copy number variation; CTNNB1 , catenin-β1; DCC , DCC netrin 1 receptor; EGF, epidermal growth factor; FAM123B , family with sequence similarity 123B; FBXW7 , F-box and WD repeat domain-containing 7, E3 ubiquitin protein ligase; GDNF, glial cell-derived neurotrophic factor; GNAS , guanine nucleotide-binding protein, α-stimulating complex locus; IGF , insulin-like growth factor; LGR, leucine-rich repeat-containing G protein-coupled receptor; LOH, loss of heterozygosity; MAPK, mitogen-activated protein kinase; N/A, not applicable; NDRG4 , NDRG family member 4; PI3K, phosphatidylinositol 3-kinase; PIK3CA , phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit-α; PTEN , phosphatase and tensin homologue; RSPO , R-spondin; SEPT9 , septin 9; SMAD4 , SMAD family member 4; SOX9 , SRY (sex-determining region Y) box 9; TCF7L2 , transcription factor 7-like 2; TGFβ, transforming growth factor-β; TGFBR2 , TGFβ _receptor 2; VIM , vimentin.

In addition to gene mutations, epigenetic alterations commonly occur in polyps and colorectal cancers and seem to cooperate with gene mutations to drive the polyp to cancer progression 59 , 65 , 66 . DNA methylation affects CpG-rich regions (CpG islands), which are often located in the 5′ region of genes and can result in transcriptional silencing through effects on transcription factor binding and changes in chromatin structure 67 . Modifications in DNA methylation related to the development of cancer (in general) include two fundamental changes: hypermethylation of CpG islands in gene promoters, which can silence tumour suppressor genes, and hypomethylation of repetitive genetic elements, which can lead to genomic instability or oncogene activation 68 . Hypermethylation, such as of the septin 9 (SEPT9) gene promotor, is also used for screening purposes (see below).

Importantly, the frequencies of many of these molecular features vary depending on the location of the tumour in the gut (from the ascending colon to the rectum) 69 , 70 . Some studies support a gradual gradient in change in frequency of the molecular alterations, whereas others suggest a more abrupt dichotomy. This has led to the traditional dichotomy of ‘proximal’ and ‘distal’ colorectal cancer versus adoption of a continuum model. Both models support the notion that the tumor microenvironment (the gut microbiome and inflammatory state of adjacent tissue) modulates the way these mutations affect cancer formation and disease progression. Thus, our current understanding of the pathogenesis of colorectal cancer is that the disease results from the accumulation of alterations in genes that then drive the formation of the tumour in the context of tumour-promoting factors derived from the adjacent tissue. This paradigm formed the basis for recent recommendation to determine the in situ immune cell infiltrate of the tumour as a prognostic marker alongside its (standard) TNM stage 71 . In close conjunction with these data, recent research has focused on the role of the gut microbiota in colorectal carcinogenesis. Indeed, studies have shown the enriched presence of Fusobacteria 72 , in particular in cancers with CIMP status 73 , which might be inversely related to the CD3+ T cells in colorectal cancers 74 . Together, these data form a basis for further research into the role of the colon microbiota and colon carcinogenesis.

Diagnosis, screening and prevention

A diagnosis of colorectal cancer either results from an assessment of a patient presenting with symptoms, or as a result of screening. The disease can be associated with spectrum of symptoms, including blood in stools, change in bowel habits and abdominal pain. Other symptoms include fatigue, anaemia-related symptoms such as pale appearance and shortness of breath, and weight loss. The predictive value of these symptoms for the presence of colorectal cancer in an elderly patient is limited, but they do warrant further clinical evaluation. With the widespread introduction of population screening for colorectal cancer, many individuals are diagnosed at a pre-clinical stage. In symptomatic patients, colonoscopy is the preferred method of investigation, but other endoscopic methods are also available or being developed ( Box 2 ). For population screening, a range of other methods can be used for primary assessment, followed by colonoscopy in case of a positive test.

Endoscopic techniques for the diagnosis of colorectal cancer

High-definition white-light endoscopy.

Current standard for colonoscopy, combining high-definition video endoscopes with high-resolution videoscreens
Provides detailed image of the gastrointestinal mucosa
Advantage of routine endoscopy, disadvantage that it provides no specific contrast for detection of neoplastic lesions

Chromoendoscopy

The use of a dye spray during gastrointestinal endoscopy to improve visualization
Improves detection of neoplastic lesions
Time-consuming to spray the complete colon
A new technique with dye incorporated into colon preparation is under investigation

Magnification endoscopy

Endoscope with zoom-lens in tip, which enables 6–150-fold enlargement of the mucosa
Can characterize and determine the extension of neoplastic lesions
Not suitable for screening of the complete colon
Can be combined with other methods

Narrow band imaging

Technique that can be built into white-light endoscopes
Filters light to two bands, with a wave length of respectively 415 nm (blue) and 540 nm (green)
Longer wavelength light is less scattered and, therefore, penetrates deeper into the mucosa
Blue light enhances superficial capillaries, whereas the green light displays deeper, subepithelial vessels
Does not increase neoplasia detection rates

Intelligent colour enhancement (FICE) imaging (Fujinon) and iScan imaging (Pentax)

Similar techniques as narrow band imaging, but no filtering of the outgoing light
Instead, processes the reflected light

Autofluorescence endoscopy

Technique that can also be built into white-light endoscopes
Based on the principle that illumination with a specific blue wavelength light can lead to excitation of tissue, which then emits light with longer wavelength
Wavelength of the emitted light is longer for neoplastic tissue
Can be used to search for neoplastic lesions

Endomicroscopy

Technique of extreme magnification endoscopy
Enables in vivo visualization of individual glands and cellular structures
Can evaluate neoplastic lesions
Not suitable for scanning larger mucosal surfaces

Colonoscopy

Colonoscopy is the gold standard for diagnosis of colorectal cancer. It has a high diagnostic accuracy and can assess the location of the tumour. Importantly, the technique can enable simultaneous biopsy sampling and, hence, histological confirmation of the diagnosis and material for molecular profiling. Colonoscopy is also the only screening technique that provides both a diagnostic and therapeutic effect. Removal of adenomas using endoscopic polypectomy can reduce cancer incidence and mortality 9 , 75 – 78 . Indeed, the efficacy of colonoscopy for reduction of colorectal cancer incidence and mortality was well demonstrated by the US National Polyp Study 77 , 79 . Recent 20-year follow-up data from this study showed a reduction in colorectal cancer-related mortality of 53% 77 , an encouraging result that has been echoed by a more-recent study 80 . The quality of colonoscopy is a determining factor in the diagnostic yield of cancer and adenoma, which is the most certain way of avoiding interval cancers (that is, a tumour arising in between screening visits) 9 , 76 , 81 , 82 .

The image-quality of colonoscopy has markedly improved over the past 20 years, from original fibre-optic to videochip endoscopes. Videochip endoscopes were further improved over the years, leading to higher resolution and wider angle of view. The current standard combines high-power endoscopes with high-resolution videoscreens to yield high-definition white light endoscopy (hWLE). Although various technologies for further image enhancement in colonoscopy have been introduced over the past decade, none of them has been shown to improve the diagnosis of polyps and colorectal cancer compared with white light colonoscopy 83 . Only chromoendoscopy ( Box 2 ), has proven to be superior to hWLE in identifying adenomas 84 . Narrow band imaging, imaging with the Fujinon Intelligent Color Enhancement system (Fujinon Corporation, Saitama, Japan) and autofluorescence endoscopy are not advantageous over hWLE in detecting adenomas or carcinomas 85 . The Third Eye Retroscope® device (Avantis Medical Systems, California, United States) was designed to address the fact that lesions behind mucosal folds in the gut are often missed. This endoscope provides a simultaneous retrograde view of the colon that complements the forward view of a standard colonoscope. Several pilot studies have indicated that it might be useful, but more data are needed 86 – 88 . The invasive nature of colonoscopy poses a burden to screenees and patients, which might affect participation in screening programmes. In recent years, several alternative diagnostic methods have been introduced, such as capsule endoscopy and biomarker tests.

Capsule endoscopy

Capsule endoscopy uses a wireless capsule device swallowed by the screenee, and enables examination of almost the entire gastrointestinal tract without the use of conventional endoscopy 89 – 92 . Capsule endoscopy is useful in diagnosing adenomas and colorectal cancer. The first-generation capsule endoscopy was found to be able to detect polyps ≥6 mm in size with a sensitivity of approximately 60% and specificity of >80% 89 . Cancer detection was achieved in 74% patients with colorectal cancer 89 . With the development of the second-generation capsule endoscopy for the colon (PillCam® Colon2 (Given Imaging Ltd, Yokne’am Illit, Israel), the frame speed was increased from a fixed speed of four pictures per second to a variable 4–35 pictures per second depending on capsule movement. The angle of view was widened from 156° to 172° on both ends of the capsule, providing a 344° view. A large trial in the United States and Israel assessed the accuracy of this new capsule to diagnose colorectal neoplasia. With 884 patients included, sensitivity was shown to be 88% and specificity 82% for detection of adenomas >6 mm in size 93 .

The European Society for Gastrointestinal Endoscopy Guideline for Colon Capsule Endoscopy recommends capsule endoscopy as a feasible and safe tool for visualization of the colonic mucosa in patients, who have undergone no or incomplete colonoscopies 92 . This recommendation was then also incorporated in the Asia-Pacific guidelines on colorectal cancer screening 94 . The indications for capsule endoscopy are at this moment limited to patients who refuse conventional colonoscopy and to those in whom a complete colonoscopy is not possible for anatomical reasons. The presence of a stenosis is a contraindication for capsule endoscopy as it could lead to capsule retention.

CT colonography

CT colonography uses low-dose CT scanning to obtain an interior view of the colon. The technique is well established as a diagnostic modality for colorectal cancer 95 . In a systematic review and meta-analysis that included >11,000 people from 49 centres, CT colonography was shown to have a sensitivity of 96% for colorectal cancer detection 96 . This performance is similar to that of conventional colonoscopy. A recent study reported similar performance of CT colonography and capsule endoscopy in patients with previous incomplete colonoscopy 97 . A large trial in 411 patients with obstructive cancers showed excellent performance of CT colonography for evaluation of proximal synchronous lesions 98 . An observational study based on data from England of 2,731 people with a positive guaiac faecal occult blood test (gFOBT, see below) showed that the detection rate of advanced neoplasia was significantly lower for subsequent CT colonography than for subsequent colonoscopy 99 . Furthermore, the detection and accuracy rates for advanced neoplasia were better in high-volume centres. These findings underline the need for adequate quality assurance similar to measures implemented for colonoscopy screening.

CT colonography requires full bowel preparation (clearance of the bowel), air inflation and change in position of the patients during the examination. The discomfort to the screenee of CT colonography is similar to colonoscopy in experienced hands, in particular because of the need of significant bowel insufflation 100 , but it has the advantage of obviating the use of sedation and can be used as part of the staging procedure in a confirmed case of colorectal cancer. However, CT colonography has low sensitivity for small (6–9mm) and flat lesions 101 . The technique is associated with high colonoscopy referral rates (up to 30%), and high rates of extra-colonic findings in non-cancer cases, which translate to unnecessary investigations and increased anxiety for individuals 102 , 103 . The costs of CT colonography, and the need for further investigation in a subset of screenees limit the usefulness of this method for population screening in most countries.

CT colonography has been recommended as one of the options for colorectal cancer screening in guidelines in the United State and Europe 104 , 105 . In many countries, CT colonography has replaced double-contrast barium enema (the conventional X-ray-based imaging modality for the colon) examination and is increasingly being used as an alternative to conventional colonoscopy. However, CT colonography has not readily been accepted in Europe because of radiation exposure, costs, burden to patients and high colonoscopy referral rates. In the Asia–Pacific region, CT colonography is not recommended for colorectal cancer screening unless in those for whom total colonoscopy is not possible 94 .

Biomarkers of colorectal cancer

Molecular detection of colorectal cancer offers a noninvasive test that is appealing to patients and clinicians as samples of multiple patients can be analysed in batch. The ideal molecular marker should be highly discriminating between cancer and advanced adenomas from other lesions, be continuously released into the bowel lumen or circulation, and disappear or reduce after the lesion is removed or treated. Indeed, assays using proteins, RNA and DNA in the blood, stool and urine have been developed but with varying degrees of success ( Table 1 ). Stool tests are based on the fact that early cancers as well as advanced premalignant lesions can bleed and shed cells into the bowel lumen, which can be detected. Blood tests obviate the handling of stool and urine and can be performed alongside routine checking of blood sugar and cholesterol in the elderly population.

The gene SEPT9 belongs to a class of GTPases, and hypermethylation of its promoter region is associated with colorectal cancer; aberrant methylation of SEPT9 at the tissue level discriminates colorectal neoplasia from normal mucosa. Early case–control studies from referral centres showed that SEPT9 methylation testing yielded a moderate sensitivity of 50–70% for colorectal cancer, with a specificity of 85–90% 106 . However, a more-recent larger scale study in population with average risk of developing the disease suggested a colorectal cancer detection rate of <50% when using SEPT9 methylation testing 107 . The reported detection of advanced colonic adenoma by SEPT9 methylation status is only approximately 10%. As such, SEPT9 assays are outperformed by current quantitative faecal immunochemical tests (FITs).

Mutation of APC and KRAS has been tested in DNA shed by epithelial cells and isolated from stool samples. The first-generation faecal DNA tests only gave satisfactory results with fair sensitivity for the detection of colorectal cancer but low sensitivity for the detection of advanced colonic adenomas 108 . Since then, several technological improvements have been made, including the use of a stabilizing buffer, the addition of other more-discriminating markers ( KRAS mutations, aberrant NDRG family member 4 (NDRG4), bone morphogenetic protein 3 (BMP3) methylation and presence of β-actin), the use of more-sensitive analytical methods and the optimization of the determining algorithm — all of which have improved the accuracy of the assay (see further description below) 109 . Other potentially useful markers under investigation include circulating tumour mRNA, microRNA and circulating cytokeratins 110 .

Screening and prevention

Colorectal cancer is more suitable for population screening than any other malignancy owing to a combination of factors 1 . Firstly, the incidence of the disease is high and outcome for a significant proportion of affected patients is poor despite intense, burdensome and often very costly treatments 111 . Colorectal cancer also has a long preclinical stage. For instance, 7,151 Dutch citizens aged 55–75 years were newly diagnosed with colorectal cancer in 2012 112 , which corresponds to approximately 0.2% of the 3.5 million people in that age group. Such an incidence is in line with similar annual incidences in other Western European countries. However, colonoscopy screening studies generally tend to find prevalent colorectal cancer in 0.5–0.9% of the participants in the same age group 54 , 63 , 64 . Although an increased willingness of symptomatic screenees might confound this difference, these data suggest that colorectal cancer on average progresses for several years before becoming symptomatic. Furthermore, colorectal cancer is preceded by colorectal adenoma. In individuals with sporadic (non-hereditary) disease, the progression from adenoma to cancer takes at least 5–10 years 113 . The long preclinical stage of disease offers a large window of opportunity for screening.

Second, colorectal cancer is also suitable for screening because adenomas and early cancers are detectable and treatable entities, which is in contrast to precursors of other highly common cancers of the breast, prostate and lung.

Last, both endoscopic removal of adenomas as well as treatment of early stage cancer have a profound impact on colorectal cancer mortality. After 20-year follow-up of the US National Polyp Study cohort, colorectal cancer-specific mortality was approximately 50% lower among subjects who at baseline had undergone endoscopic removal of adenomas than in an unscreened control cohort 77 . Furthermore, the 5-year survival rates for patients with early stage cancer are approximately 90%, compared with 10% for patients diagnosed with advanced-stage metastatic disease. Together, these factors form the background for various international guidelines on colorectal cancer screening. Screening in most countries aims to capture men and women aged 50–75 years, although different age ranges are being used in various programmes depending on the available resources 114 . Adoption of lifestyle measures can also significantly impact colorectal cancer incidence.

Given that imaging of the colon can confirm a diagnosis or exclude colorectal neoplasia, clinicians often favour these methods for screening purposes. Colorectal adenomas and early stage cancers can directly be visualized by endoscopy, CT colonography or capsule endoscopy 77 , 90 , 96 , 103 . A randomized comparison between CT colonography and colonoscopy for primary population screening showed a slightly higher uptake of the former, counterbalanced by a slightly lower sensitivity for advanced neoplasia 103 . Capsule endoscopy screening might in the near future provide an alternative visualization method for primary screening 90 . Overall, colonoscopy has the highest accuracy and is generally considered the gold standard for screening and is associated with a number of advantages ( Table 2 ). Recent large observational studies showed that screening colonoscopy reduced the risk for colorectal cancer by approximately 80%, and had a similar effect on related mortality 115 , 116 . This preventive effect of colonoscopy strongly depends on procedural quality, which can be measured in terms of adenoma detection rate of the performing endoscopist 76 . Other measures for procedural quality include the level of bowel preparation, caecal intubation rates, complication rates, average sedative medication dose and patient burden scores 9 . In a study from the United States, adenoma detection rates per colonoscopist ranged from 7% in the lowest quintile of detection to 50% in the highest quintile — a difference that is associated with an almost two-fold risk in interval cancer 81 . The correlation between risk of post-colonoscopy cancer and adenoma detection rates was also reported in a study from Poland 76 . Training and quality assurance measures, and adherence to surveillance guidelines also have an impact on the rate of post-colonoscopy cancers 75 , 117 .

Key performance indicators for organized screening with different modalities

Test	Advantages	Disadvantages	Refs
gFOBT	Cheap Low screenee burden Reasonable uptake	Limited sensitivity for advanced neoplasia Need for short screening intervals No effect on colorectal cancer incidence Qualitative, not automated Multiple sampling Moderate positive predictive value	, ,
FIT	Cheap Low screenee burden Quantitative, automated Single sample Sensitive for colorectal cancer Highest uptake Effect on incidence and mortality	Limited sensitivity for advanced adenoma Moderate positive predictive value Repeated screening needed (interval can likely be longer than for gFOBT) Temperature-dependent performance	, , , ,
Sigmoidoscopy	Sensitive for distal advanced neoplasia Long screening interval Effect on incidence and mortality	Low uptake Moderately sensitive for proximal advanced neoplasia Expensive	, , ,
Colonoscopy	Sensitive and specific Long screening interval Effect on incidence and mortality	Low uptake Expensive Burdensome Associated with complications	, , , ,
CT colonography	Sensitive and specific Long screening interval Likely effect on incidence and mortality	Low uptake Expensive Need for repeated lavage in case of advanced neoplasia Radiation exposure Burdensome	, , – , , ,
Multi-target faecal DNA test	Sensitive and specific	Uptake unknown Expensive Lack of prospective data	,

Sigmoidoscopy, which images the rectum and sigmoid colon and can include the descending colon, has been shown in several randomized prospective trials to reduce the incidence of colorectal cancer by approximately 33%, and reduce related mortality by 38–59% 1 , 118 – 120 . This effect was obtained by single sigmoidoscopy screening with further colonoscopy in those with signs of advanced polyps — a finding that formed the basis for the current roll-out of nationwide primary sigmoidoscopy screening in England. The wide use of colonoscopy and sigmoidoscopy for primary screening in various countries supports the introduction of non-physician endoscopists who can perform diagnostic endoscopy according to international standards 121 . Further studies are needed to assess performance and cost efficacy 122 .

Population screening

Given the considerable rise in treatment costs, colorectal cancer screening is in many countries a cost-saving exercise 123 . Screening can be done with a range of methods, both invasive and non-invasive ( Table 2 ). Most programmes are based on a single primary screening test, followed by colonoscopy in those who test positive 114 . In other settings, screenees are offered a choice between different screening methods, which might increase or decrease participation rates depending on the local setting 124 , 125 .

Population screening must consider more than just test accuracy, but should take test uptake and demand on resources into account. Accordingly, screening results must be reported in terms of identification of subjects with advanced neoplasia per 1,000 invited and in numbers needed to scope. A very accurate test by definition has no impact on cancer incidence and mortality in a population if not widely applied 1 , 111 . Similarly, limitations in endoscopy capacity preclude the use of colonoscopy for primary screening. For these reasons, many countries prefer a two-step approach in population screening, first using noninvasive screening test to select a subgroup of screenees who are at high risk of cancer for subsequent colonoscopy. Typically, faecal occult blood test is this primary screen 1 , either using gFOBTs or FITs. FITs are now more widely used than gFOBTs because of easier handling, resulting on average in approximately 10% higher uptake, higher sensitivity for advanced neoplasia and automated analysis 126 , 127 . Indeed, quantitative FITs offer the additional advantage that their cut-off points can be adjusted to match colonoscopy capacity 128 . For an optimal impact on the population level, adequate quality assurance is needed over the full range of the screening programme, as is organized active call–recall screening 1 .

The effect of uptake on the yield of screening was shown by a randomized study comparing primary colonoscopy and FIT screening in Spain 129 . The cancer detection rate was similar in both groups, but a considerable proportion of cancers in the colonoscopy group were actually detected by primary FIT after screenees first refused primary colonoscopy. Similarly, in a range of screening trials in the Rotterdam area, the highest detection rate was observed with repeated FIT screening 1 , 130 . This detection rate can be further increased with the use of two samples per screening round, especially in the first screening round 131 , although this approach is less cost-effective than screening with one sample 132 . gFOBT screening routinely makes use of a 1–2-year interval, the higher accuracy of FIT can allow for extension of the screening interval to 3 years 133 .

The performance of the aforementioned multi-target faecal DNA plus FIT testing was compared with FIT alone for detection of colorectal neoplasia 134 . All participants in the study underwent each of the ‘experimental’ screening methods and a confirmatory colonoscopy. The combined tests identified 60 of 65 patients (92%) with colorectal cancer and 321 of 757 patients (42%) with advanced adenomas; FIT alone detected 48 patients with colorectal cancer (74%, P = 0.002) and 180 patients with advanced adenomas (24% P <0.001) 134 . These results provide evidence for the accuracy of the DNA test in asymptomatic average-risk individuals, and led to FDA approval of the multi-target faecal DNA test plus FIT. However, the positive predictive value of the multi-target faecal DNA test was low (24%) for a non-invasive test, and the DNA test plus FIT yielded a 16.1% positivity rate versus 7.0% for FIT alone, thus necessitating 2.3-fold more colonoscopies in the DNA test plus FIT arm. If both tests were compared at the same positivity rate, a crucial determinant in countries with limited colonoscopy resources, the actual diagnostic yield and positive predictive value could have been approximated. This assumption is supported by previous studies that reported a similar number needed to screen to detect advanced neoplasia 135 . Finally, study design did not include a component to examine uptake of either test. For these reasons, further studies are needed to position the DNA test as a population screening method.

Surveillance after resection

Patients who have adenomatous polyps or colorectal cancer continue to be at risk for new neoplastic lesions after these have initially been removed — either because of biological or environmental factors, or both 136 . These patients could benefit from surveillance to detect and remove new lesions. Most evidence supporting this hypothesis is based on surveillance studies that have documented higher rates of tubular adenomas >10mm, adenomas with villous histology, high-grade dysplasia or cancer in patients with neoplasia at the baseline colonoscopy exam; the risk of developing subsequent tumours also depends on the size and histology of polyps at the index exam 136 – 138 . Furthermore, there is a relationship between the index lesion and subsequent risk of death from colorectal cancer 139 . Together, this body of data provides a strong justification for surveillance, but does not prove with certainty that surveillance will actually prevent recurrent cancer or reduce mortality.

Guidelines for surveillance in patients without hereditary syndromes vary in the United States and Europe 137 , 140 , 141 . The underlying premise of all such recommendations is that the baseline exam must be complete (including the caecum), with adequate bowel preparation, and that any detected lesions are removed completely. If the completeness of the resection or quality of the exam comes into question, early re-examination is recommended. The guidelines stratify risk based on the findings of the index examination ( Box 3 ). The US guidelines endorse a 10-year interval if the baseline exam is negative or if the patient only has hyperplastic polyps in the rectum or sigmoid colon. New evidence adds further support for this recommendation 80 , 142 . Interval faecal blood testing is generally not recommended, owing to a lack of evidence of benefit 137 , 140 .

Risk-stratified guidelines for surveillance after removal of adenomatous polyps or colorectal cancer

Colorectal cancer.

Patients with colorectal cancer should have intensive follow-up care
If a complete colonoscopy was not possible prior to surgical resection, colonoscopy should be offered within 3–6 months to detect synchronous lesions
If a complete colonoscopy was performed at baseline, patients with cancer should have colonoscopy at 1 year; if negative, every 3–5 years thereafter

High-risk adenoma

High-risk features include adenomas with high-grade dysplasia, villous histology, tubular adenoma ≥10mm in size, serrated lesions ≥10mm in size, serrated lesions with dysplasia or ≥3 adenomas
The risk of advanced neoplasia during surveillance is 15–20%, which is roughly 2–3-fold higher than individuals with 1–2 small (<10mm) tubular adenomas and 5–6-fold higher than individuals with no polyps at baseline colonoscopy 137
The US Multi-Society Task Force on Colorectal Cancer (USMSTF) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines recommend a 3-year interval for surveillance 137 , 140
The UK guidelines define highest-risk features as ≥5 small adenomas or ≥3 adenomas where at least one is >10 mm in size and recommends annual surveillance 141 based on data indicating a high likelihood of finding additional high-risk adenomas at 1 year 226
The UK guidelines define intermediate-risk features as 3–4 small (<10mm) adenomas or ≥1 large (≥10mm) adenomas, irrespective of histology, and suggest a 3-year screening interval

Low-risk adenoma

Individuals with 1–2 tubular adenomas <10mm in size represent a low-risk group
A statistically insignificant increase in risk, relative to patients with no polyps at baseline colonoscopy, are attributed to these patients
The UK guidelines recommend no specific follow-up 141 ; the ESGE guidelines recommend follow-up at 10 years 140 ; the USMSTF guidelines recommend surveillance at 5–10 years, with evidence supporting the 10-year interval if the index exam preparation was adequate 137
Serrated lesions <10mm in size with no dysplasia might also represent a low-risk lesion, but evidence is weak; the USMSTF recommends a 5-year interval for surveillance and the ESGE recommends a 10-year interval

Several longitudinal studies of patients after adenoma removal have provided some guidance for the optimal intervals for surveillance examinations 136 , 138 . Surveillance intervals are based on the findings at last colonoscopy ( Box 3 ). If the patient has an adenoma with high-risk features at baseline, but no polyp or an adenoma with low-risk features at surveillance, the next exam is recommended at 5 years. If the patient has an adenoma with low-risk features at baseline and at surveillance, the next exam interval is recommended at 5 years; if there is no polyp at surveillance, the next exam interval is 10 years. Finally, if a high-risk adenoma is found at surveillance, the next exam is recommended at 3 years. These recommendations are designed to reduce the frequency of surveillance for many individuals with low-risk lesions and are based on findings using high-quality colonoscopy. Complete examinations with good bowel preparation 9 are required, but the role of other mitigating factors during surveillance such as lifestyle, sex and race are unknown. Surveillance should be discontinued when the risks of performing the bowel preparation and/or colonoscopy could outweigh any potential benefit. These factors should also be considered in elderly patients with comorbid conditions that might limit life expectancy, diminish any potential benefit of polyp removal and increase risk of complications during the colonoscopy procedure 143 , 144 .

How to conduct surveillance of patients with serrated lesions is under debate. Understanding the natural history of these lesions requires accurate histological definition, endoscopic detection and longitudinal follow-up 145 . Furthermore, inter-observer variability in histological interpretation, wide variation in detection rates and virtually no longitudinal follow-up study of these patients have hindered surveillance assessment 146 . Nevertheless, some evidence suggests that this pathway accounts >20% of colorectal cancers and patients may be at risk for recurrent disease and, therefore, require surveillance after resection. Further studies have to substantiate the risk for recurrent polyps and define optimal surveillance schedules.

In addition to endoscopic surveillance after cancer resection, follow-up surveillance by measuring carcinoembryonic antigen (CEA) levels in the plasma and/or CT imaging might detect curatively treatable metastatic recurrence 147 . There have been concerns about the cost, benefit and number needed to test to achieve a survival benefit. A randomized study found that CEA testing resulted in 6.7% of patients receiving treatment with curative intent and CT resulted in 8.0% receiving treatment, which was significantly more than a group receiving minimum follow-up care that involved only targeted diagnostic assessment if symptomatic 148 . The actual survival benefit was probably small. The cost-effectiveness is also uncertain, but CEA testing is likely to be more cost-effective than CT, depending on the cost in different countries.

Although the molecular drivers of colorectal cancer have been described, where in the gut a tumour occurs has implications for treatment. That is, colon cancer and rectal cancer are two distinct cancers requiring different approaches, also depending on their stage. Cancer registries from different countries show huge differences in outcomes after treatment for colorectal cancer, although a trend for improvement is emerging 149 . Fortunately, increasing attention is being paid to quality assurance in cancer care 150 . Indeed, unravelling the effects of treatment on outcome is of utmost importance and, for this, population-based registries and audits are used to critically assess practice.

Surgery is the mainstay curative treatment for patients with non-metastasized colorectal cancer. However, outcome is strongly related to the quality of surgery 151 , 152 , the quality of pre-operative staging and treatment selection. The dissection should ideally follow the embryological anatomical planes to ensure that the tumour and its principle zone of lymphatic spread are removed. Special attention should be given to the circumferential surgical resection margins 152 , 153 ( Figure 4 ). In more-advanced cases of rectal cancer, neoadjuvant treatment (for example, preoperative chemotherapy for T4 colon cancer, and (chemo)radiotherapy for locally advanced cancer) can reduce tumour load and even tumour stage, and might be necessary to optimize the chances for a successful resection 150 , 152 , 154 . Thus, a multidisciplinary approach before beginning treatment, based on adequate staging information, is mandatory 151 , 153 , 155 , 156 .

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The mesocolon harbours the major blood vessels and draining lymph nodes; surgical planning involves considering the large blood vessels and the resection lines. For the caecum and the ascending colon (before the hepatic flexure), the main vessels are the ileocolic and right colic artery. The transverse colon begins at the hepatic flexure and ends at the splenic flexure; important vessels to consider in this region are the middle colic artery (via the superior mesenteric artery) arcading on the left side, with branches of the left colic artery (inferior mesenteric artery). The descending colon ‘bends’ at the sigmoid colon (at the left iliac crest) before continuing to the rectum. In the paracolic grooves, the parietal peritoneum is attached to the lateral border of the visceral peritoneum that overlies the colon and forms the surgical planes referred to as White Line of Toldt, which gives access to the avascular plane above Gerota’s fascia — the fascia on top of the retroperitoneum covering the kidney and ureter — without interfering with peri-renal space or ureters.

Preoperative assessment

When considering a patient for surgery, several factors such as their age, fitness, the perioperative management plan, tumour staging, type of surgery (including resection planes and reconstruction) and quality assurance are important. In terms of age, elderly patients with colorectal cancer have lower overall survival rates than their younger counterparts 149 . Indeed, postoperative mortality rates increase in elderly in the immediate postoperative period (first 30 days) and can double in the first 6–12 postoperative months 157 – 160 . However, ‘elderly patients’ as a group are heterogeneous, with varying comorbidities, degrees of fitness for surgery and risks for postoperative complications. Accordingly, age alone should not be a reason not to operate.

Before surgery of colorectal cancer, it is important to be informed about the whole colon to rule out synchronous cancers, which occur in some 4% of patients 161 . If preoperative endoscopy was incomplete owing to tumour obstruction, visualization of the colon should either be completed prior to surgery by CT colonography, or endoscopy should be performed in the 3 months following surgical resection 161 , 162 . Active search for distant metastases in the lungs and liver by means of chest and abdominal CT is also recommended before surgery 155 . CEA is preferably obtained before colorectal cancer surgery to provide a baseline value for postoperative surveillance. Genetic counselling is advised in young patients with a positive family history of colorectal cancer. Fast track protocols and laparoscopy should be considered to minimize the surgical trauma. In those with obstructive colorectal disease, abdominal CT imaging can also assess for T4 or stage IV disease. In patients with rectal cancer, preoperative MRI imaging of the pelvis is further recommended for planning purposes, as well as to distinguish the tumour in relation to the mesorectal fascia, and to assess T stage 163 . This information is necessary to select patients with T3c, T3d and T4 tumours for preoperative (chemo)radiotherapy.

Colon surgery

Laparoscopic resection of colorectal cancer ( Figure 5 ) has been shown to be as safe as open surgery 164 – 166 . As with any surgical procedure, the team needs to be skilled in laparoscopic colorectal surgery and adequately select patients. Contraindications for laparoscopic approach are obesity, previous abdominal surgeries and advanced-stage disease 151 , 152 , 165 . If, during the laparoscopic procedure, conversion to open surgery is necessary, the earlier this is done the better the outcomes.

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(a) A sigmoidectomy can be performed using three to six trocars. The laparoscopic exploration via the supraumbilical trocar (position 2) is a guide for the location of the other operating trocars. (X) The tumour location. (1) A 5 mm trocar in the left hypochondrium, for retracting the descending colon. (2) The first trocar to be introduced is a 12 mm trocar through the umbilical port. (3) A 12 mm trocar is used as an optical and operating port. (4) A 5 mm trocar is used for retracting tissue. (5) Carbon dioxide insufflation: pneumoperitoneum.

(b) The number of trocar ports for right colectomy varies from depending on the surgeon and operative difficulties. Trocar positioning is also variable, but our standard for a tumour in the caecum (shown in insert, position X) approach is to place (1) a 12 mm trocar in left hypochondrium as an optical or operating port. (2) The umbilical port side can be extended to a small laparotomy to extract the dissected colon and perform the extracorporeal anastomosis. (3) A 5 mm trocar is placed for operating and retracting the tissue (ascending colon or caecum). (4) A 5 mm trocar is used to retract the hepatic flexure, to expose ileocolic and right colic vessels, and perform the division. In both images, the patient’s head is at the top, their feet at the bottom.

In colon surgery, anatomical planes of the mesocolon with the parietal cavity wall and retroperitoneum should be followed to avoid damage of the ureters, duodenum, pancreas and spleen. Moreover the mesenteric margins are planned accurately, ensuring proficient vascularization of the remnant bowel loops for the anastomosis. A tension-free and torsion-free anastomosis must be created to avoid the feared complication of an anastomotic leakage.

Some patients might require perioperative placement of a stoma, in which the faeces are diverted into a bag on the outside of the body. Loop ileostomy or loop colostomy ( Figure 6 ), or permanent colostomies, are an essential part of surgery for rectal and sigmoid cancer, either to protect the anastomosis or when the distal rectum is resected. In cases of a rectal obstruction, a loop colostomy is placed on the right (ascending) side; a permanent stoma is placed in cases an abdominoperineal excision (APE; that is removal of the anus, rectum and part of the sigmoid colon along with the associated lymph nodes). Each stoma has its advantages and disadvantages; there is no strong argument for superiority of one over the other 167 . Complications of stomas are numerous and cumbersome for the patient, and include prolapse, retraction, dermatitis, leakage, para-stomal hernia, obstruction and anastomotic leakage after stoma closure.

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A colostomy is a surgical procedure in which a stoma (from the Greek for ‘mouth’ or ’opening’) is formed by drawing the healthy end of the large intestine (colon) through an incision in the anterior abdominal wall and suturing it into place. (a) For stoma positioning (sites 1–4), the subcostal line, lateral border of the rectal abdominus muscle, anterosuperior spine of the ilium, shape of the abdomen and abdominal creases (for example, when trousers and belt are worn, and while sitting) are considered. Ill-placed ostomies result in invalidating leakage and dermatitis. The position of an end ileostomy or a loop ileostomy is preferable in the right hypochondria (position 1); a loop transversostomy is preferred in the right upper quadrant (position 2) to preserve the left side upper and lower quadrants (positions 3 and 4, respectively) for a definitive end colostomy if necessary. (b) In end stoma formation, the inside of the intestinal loop with the mucosa is placed at the abdominal wall. End stomas provide only one lumen, commonly formed to stay. A well-placed ostomy is about 2–3 cm above the skin, which ensures that the faeces are not in contact with the skin. (c) In loop stoma formation, two openings are sewn into the skin: efferent and afferent. The afferent (in) limb produces the stool and the efferent (out) limb allows passage of flatus from the distal portion of the bowel.

In patients presenting with (sub)total obstruction due to a left-sided (descending) tumour, temporary pre-operative stenting can be considered to reduce perioperative morbidity and risks of surgery, but the risk of perforation must be considered 151 , 152 , 168 . Colostomy versus stent for palliation could be considered in patients presenting with obstruction and multiple distant metastases 151 , 152 , 169 .

Rectal surgery

There are several surgical approaches for patients with rectal cancer, depending on tumour stage. Each technique aims for adequate oncological treatment with complete tumour and local node resection to minimize locoregional and distant recurrence and optimize disease-free and overall survival. In addition, sphincter preservation and avoidance of a permanent stoma are important additional goals of rectal cancer treatment. Accordingly, a careful, balanced choice of treatment is needed for each individual patient.

For early stage rectal cancer, advances in minimally invasive techniques have reduced the number of open rectal resections and have improved functional outcome dramatically. Transanal endoscopic microsurgery (TEM) is just such a minimally invasive technique for local tumour excision of well-differentiated T1N0 tumors 170 – 172 . TEM is associated with better functional outcomes and is performed through the anus (and, therefore, does not leave an abdominal scar or require a stoma), but has the trade-off of higher local recurrences. Thus, TEM is not recommended for tumours that are unlikely to be completely resected, as well as for poorly differentiated tumours given their high risk of local recurrence. The technical complexity of TEM and the high costs of the apparatus led to the introduction of new transanal techniques, in particular transanal minimally invasive surgery (TAMIS). This technique makes use of a disposable multichannel port that is positioned transanally and provides access for conventional laparoscopic equipment 173 .

Total mesorectal excision (TME) is the gold standard surgical technique for rectal tumours staged T1, T2, and favorable T3 (T3 with negative nodal status (T3N0M0) and excluding low-seated rectal cancers, and T3c and T3d disease). In patients with unfavourable rectal tumors, TME surgery is only recommended after neoadjuvant therapy to reduce the risk of local recurrences. For tumour resection, the anatomical plane is the mesorectal fascia and the circumferential resection margin is just outside of this fascia ( Figure 7 ) 174 – 176 . The intact mesorectum, the fatty envelope that surrounds the rectal bowel wall, includes the draining lymph nodes. Complete resection involves removal of the bowel wall and these nodes. TME can be performed by open approach as well as laparoscopically; both have similar rates of locoregional recurrence, and disease-free and overall survival 165 . Rectal cancer surgery in locally advanced stages is associated with more blood loss; longer operation duration; more concomitant organ resections; and more postoperative complications such as anastomotic leakage, pelvic floor dysfunction, incontinence and genitourinary problems. However, robotic rectal resection may improve perioperative outcomes, such as reduction of perioperative blood loss, and is being explored 177 .

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The plane between the urogenitoury structures (prostate, urethra and seminal vesicle in men, and the vagina, uterus and ovaries in women) and the rectum is called Denonvilliers’ fascia. The dissection plane of the total mesorectal excision is sharp around the mesorectal fascia and surrounds the mesorectal fat, in which the draining lymph nodes and the rectum are located. The plane is avascular, and avoids the parasympatethic and sympathetic nerves in the pelvic lateral space, which coordinate sexual and urinary function. The superior hypogastric plexus is formed at the level of the sacral promontory, distally dividing in the hypogastric nerves. Together with the parasympathetic erigentes nerves, these form the inferior hypogastric (pelvic) plexus, which should not to be clamped during surgery to avoid damage. The pudendal nerve innervates the external sphincter, puborectalis muscle and external genitalia, among other structures.

Local recurrences after rectal surgery can be minimized using short-course radiotherapy 178 – 180 , although long-term data (12-year follow-up) showed no effect on overall survival for this approach 181 . The timing of surgery after short-course radiotherapy is important. Surgery after a longer waiting period is associated with fewer complications than immediate surgery after radiotherapy 182 . Importantly, neoadjuvant radiotherapy (that is, before surgery) is associated with an increased risk for low anterior syndrome (a complex of symptoms that include frequent and urgent stools, numerous bowel movements over a few hours, stool incontinence and sexual dysfunction) 183 .

Neoadjuvant radiotherapy (or chemoradiotherapy) can be proposed for patients with unfavourable T3 (upper and mid T3c, T3d and low T3b) rectal tumours: those that invade >5 mm into the mesorectal fat and/or approach within 2 mm of the mesorectal fascia as visualized on MRI. T4 and lymph node-positive rectal cancer need short-course fractionated radiotherapy or chemoradiotherapy depending on the patient and tumour characteristics 184 . After the primary radiotherapy or chemoradiotherapy, restaging by means of endoscopy and MRI is recommended for these patients. TME surgery can be possible when the tumour has been downsized sufficiently. In patients with advanced and recurrent rectal cancer, surgery should aim for complete resection and conventional surgical planes may not be adhered to 185 . In some patients, a clinical complete response can be achieved after chemoradiation alone. This raises the question whether surgery can be omitted in these patients. In the largest series of patients treated nonsurgically, high response rates were reported 186 . Other series had lower response rates 187 , 188 . Prospective research will be necessary for this group of patients. Indeed, in 2015, the prospective International Watch & Wait Database for rectal cancer was launched ( http://www.iwwd.org ); this initiative aims to produce assess whether nonsurgical approaches are valuable alternatives to surgery.

Finally, a prospective multicentre randomized trial in Japan comparing TME alone versus TME with dissection of lateral nodes was recently completed 189 . In this study, approximately 10% of patients had pathological pelvic sidewall lymph nodes. Given that preoperative radiotherapy on lateral nodes might not completely eradicate nodal metastases, TME surgery with lateral lymph node clearance might be justified.

Quality assurance

The resected tumour specimen can be used to judge the quality of surgery; if the margin around the specimen is free of cancer cells in both colon and rectal cancer, the surgery is considered high quality 174 , 175 . The removal and assessment of the lymph nodes is another guide for determining whether the mesocolic or mesorectal resection is adequate 153 . Internationally, removal of 12 lymph nodes is viewed as the cut-off value needed to provide adequate histopathological staging; the lymph nodes can also be used to prognosticate patients. However, the role of procedures to remove the sentinel node (the first lymph node or group of nodes draining the cancer) in colorectal cancer is still unclear.

Furthermore, quality assurance in colorectal cancer care has been defined for several aspects of the care continuum: performing trials, working in multidisciplinary teams, integrated care pathways, shared decision-making, auditing cancer care, centralization of complex procedures and international comparison of cancer outcomes. Auditing is a powerful instrument to improve cancer care. Especially for rectal cancer, survival and local recurrences have been shown to drastically improve with national auditing initiatives 150 , 190 , 191 . To reduce the differences in Europe, an international, multidisciplinary, outcome-based quality improvement project, European Registration of Cancer Care (EURECCA), was launched in 2007 156 . EURECCA aims to capture the best practices and promote uniform structured data collection and analysis to study outcomes of all patients with cancer. Although these analyses are used to feedback surgeons on the best techniques at hand, volume is another issue that has been shown to improve patient outcome in colorectal cancer management 192 .

Recovery after surgery

Perioperative protocols such as fast track and Enhanced Recovery After Surgery (ERAS) have been designed to minimize surgical complications 193 , 194 . The protocol describes the perioperative care pathway and lists elements of care for patients at various steps in the perioperative process. Considering these elements are supported by evidence to improve recovery time after surgery, ERAS was first implemented for patients undergoing colectomy 195 and includes elements such as preoperative counselling and bowel preparation, perioperative fluid management and prevention of ileus (obstipation and intolerance to oral intake) and postoperative glucose control and early mobilization. Indeed, for patients at high risk of postoperative ileus, enteral nutrition should be anticipated even before surgery 196 .

Systemic treatments for primary disease

The systemic treatment of patients with colorectal cancer has substantially developed over the past two decades, with major improvements in the neoadjuvant setting for rectal cancer, and adjuvant settings for cancer of the colon.

Neoadjuvant treatment

There is no accepted neoadjuvant treatment for colon cancer. However, for rectal cancer, neoadjuvant radiotherapy or chemoradiotherapy are recommended for intermediate-stage and advanced-stage cancer (for example, very low-tract anteriorly located cT2 lesions, most T3 lesions, some T4a lesions with limited peritoneal involvement, N+ lesions, cT3 lesions that invade the mesorectal fascia, and cT4a and cT4b lesions with positive lateral nodes) to reduce the rate of local recurrence. The neoadjuvant treatment can either be given as short-course radiotherapy followed by surgery or as chemoradiotherapy with 5-fluorouracil or capecitabine (an oral fluoropyrimidine). Although preoperative (chemo-)radiotherapy is more effective than postoperative treatment in reducing local recurrence, it does not improve overall survival 181 , 197 . Strategies that aimed to improve neoadjuvant treatment by intensifying the chemoradiotherapy regimen (for example, by combining 5-fluorouracil and oxaliplatin with radiotherapy instead of using 5-fluorouracil with radiotherapy) did not exhibit clear survival benefit, but increased toxicity 198 ; more research is needed.

Adjuvant treatment

The cure rate by surgery alone for T3, T4a, T4b and N0M0 colon cancers (Union for International Cancer Control (UICC) stage II) is high and only approximately 5% of patients benefit from adjuvant chemotherapy. However, guidelines endorsed by European and Japanese societies recommend considering adjuvant therapy in high-risk cases (that is, poorly differentiated tumours; when <12 lymph nodes were resected; in cases with vascular, lymphatic or perineural tumour invasion; in cases with obstructive or perforated tumours; or tumours with pT4 stage) 199 . By contrast, adjuvant treatment is standard for UICC stage III tumours (any T, N1–2 (3 or more positive nodes), M0); a combination of 5-fluorouracil (orally, as in the XELOX protocol, or intravenously as in the FOLFOX4 protocol) plus oxaliplatin is used. Currently, no data support that the addition of targeted therapies (such as epidermal growth factor receptor (EGFR)-specific or vascular endothelial growth factor (VEGF)-specific monoclonal antibodies) improves the outcome for patients in the adjuvant setting 199 . Data from pooled analyses suggest that patients >70 years of age might not benefit profoundly from oxaliplatin-based chemotherapy combinations in the adjuvant setting. These patients may benefit from fluoropyrimidine chemotherapy, similar to younger patients 200 . For rectal cancer, postoperative chemoradiotherapy can be applied if no preoperative treatment was given and if certain risk factors (including positive resection margins, perforation in the tumour area or defects in the mesorectum) are present; adjuvant chemotherapy typically uses fluoropyrimidines.

Metastatic disease

The survival of patients with metastatic disease has substantially improved over the past two decades and a median overall survival of 30 months has been achieved in clinical trials. This improvement in survival can be attributed to use of chemotherapeutics such as oxaliplatin and irinotecan, the introduction of targeted therapies that address specific properties of the tumour or its microenvironment and the incorporation of multidisciplinary approaches, including surgical resection of liver metastases.

Chemotherapy combinations

The chemotherapy backbone for first-line treatment of metastatic disease is typically a combination of 5-fluorouracil, leucovorin and either oxaliplatin (FOLFOX protocol) or irinotecan (FOLFIRI protocol). 5-Fluorouracil in the FOLFOX regimen can be replaced by capecitabine, but combination of capecitabine with irinotecan is more toxic than FOLFIRI. Doublet (two chemotherapeutic agents) and triplet (three chemotherapeutic agents) chemotherapy regimens consisting of 5-fluorouracil, leucovorin, oxaliplatin and irinotecan (the FOLFOXIRI protocol) have been shown to be efficacious 201 . As compared with single-agent fluoropyrimidine, combination chemotherapy achieves better tumour growth control. However, elderly and frail patients in particular might benefit from a sequential approach with initial single-agent fluoropyrimidine chemotherapy or combined fluoropyrimidine with VEGF-A-targeted therapy (bevacizumab; see below).

Targeted therapies

Alongside these combined chemotherapy regimens, targeted agents are used for metastatic colorectal cancer treatment. In particular, these include three major groups of drugs: monoclonal antibodies against EGFR (cetuximab and panitumumab), monoclonal antibodies against VEGF-A (bevacizumab), and fusion proteins that target multiple proangiogenic growth factors (for example, aflibercept) and small molecule-based multikinase inhibitors (for example, regorafenib).

Approximately 80% of all colorectal cancers express or overexpress EGFR; overexpression correlates with reduced survival and increased risk of metastases. The EGFR tyrosine kinase can be blocked by monocloncal antibodies specific to the extracellular domain of the receptor, decoy receptors that bind and block the soluble ligand, or small molecules that inhibit receptor dimerization or fit into the ATP binding pocket of its cytoplasmic tyrosine kinase domain. Most clinical data in colorectal cancer are available for receptor-blocking antibodies, such as cetuximab, which is a recombinant chimeric monoclonal IgG1 antibody, and panitumumab, which is a human EGFR-specific antibody. These antibodies show efficacy in chemotherapy-naive patients as well as in patients whose tumours are refractory to chemotherapy by improving the overall response rate of the tumours. These strategies also improve progression-free survival (PFS) and even overall survival in patients with metastatic colorectal cancer. However, a prerequisite for the efficacy of these agents is that the tumours do not harbour activating mutations in KRAS and NRAS 202 , 203 .

RAS is mutated in about half of all colorectal cancers, with codons 12 and 13 being most commonly affected; codons 61 and 146 of KRAS and codons 12, 13 and 61 of NRAS are affected to a lesser extent. HRAS mutations have so far not been described in colorectal cancer. The mutations render the Ras GTPase constitutively active; active Ras induces a plethora of tumorigenic intracellular signalling pathways. Thus, the Ras status of the tumour must be examined before treatment with EGFR-specific antibodies.

Tumours establish a vascular network of their own once they reach a critical size 204 . Accordingly, a major effector of tumour angiogenesis is the secreted glycoprotein VEGF-A, which binds to VEGFR-1 and VEGFR-2. VEGF-A is produced by many tumour and stromal cells, promotes proliferation and migration of endothelial cells and increases vessel permeability. VEGF is also a growth factor for various tumour cells. VEGF-specific therapies are used in metastatic colorectal cancer, but the precise mechanisms of action are not fully understood. These compounds might act by normalizing the dysregulated tumour vasculature, which would lead to improved tumour oxygenation and delivery of chemotherapy 205 . There are as yet no predictive biomarkers for anti-angiogenic agents.

Bevacizumab has demonstrated efficacy in combination with chemotherapy in the metastatic setting; combined with 5-fluorouracil and irinotecan, bevacizumab significantly improved median PFS and median overall survival of patients in a Phase III trial compared with chemotherapy alone 6 . The addition of bevacizumab also significantly improved median PFS in patients receiving a combination of fluoropyrimidine and oxaliplatin. Interestingly, the combination of bevacizumab and 5-fluorouracil/oxaliplatin also yielded a significant improvement in tumour response, median PFS and median overall survival compared to chemotherapy alone in patients with chemorefractory metastatic disease 206 . Bevacizumab is also one of the few compounds that confer a survival benefit to patients when treatment is continued even after disease progression 207 .

Aflibercept also targets angiogenesis. This drug is a recombinant fusion protein that consists of the VEGF-binding portions from the extracellular domains of human VEGFR-1 and VEGFR-2 fused to the Fc portion of the human IgG1 immunoglobulin. Aflibercept also binds the placenta growth factor (PLGF) and, therefore, has a somewhat broader antiangiogenic activity than bevcacizumab. Aflibercept has been shown to improve PFS and overall survival when used in combination with FOLFIRI in the second-line setting of treatment for metastatic disease 208 .

Metastatic resection

For patients with colorectal cancer who have isolated liver and/or lung metastases that are technically R0 resectable, surgery should be considered — particularly when the metastases are limited in number and size. The 5-year overall survival rate in this group is about 20% 209 , 210 , an impressive figure for metastatic disease. One clinical trial has used a perioperative FOLFOX protocol in this group of patients and showed an improvement in PFS, but no significant difference in overall survival compared with surgery alone 201 .

In the majority of patients with isolated liver and/or lung metastases, a R0 resection cannot be primarily achieved. However, if the metastases can be downsized and combined with adjuvant chemotherapy, the 5-year overall survival rate is similar to R0 resections 211 . In this situation, the most active chemotherapy should be employed to ‘convert’ the disease to a resectable state; FOLFOXIRI triplet chemotherapy regimen confers high response rate (approximately 60%) 212 . In a RAS wild-type population, chemotherapy doublets plus EGFR-specific treatment also result in high response rates. According to the data of the FIRE3 study, EGFR-specific antibodies in combination with FOLFIRI seem to induce more pronounced tumour shrinkage than FOLFIRI plus bevacizumab. Thus, this combination is an option if the tumour is RAS wild-type 213 .

If a more-active treatment with the intent to downsize metastases for secondary resectability is used, it is important to ensure that the tumour is regularly re-evaluated by a multidisciplinary team and resection of metastases is performed at the earliest time point when an R0 resection is possible. In doing so, chemotherapy toxicity is reduced and perioperative morbidity is minimized. The ‘disappearance’ of the metastases on CT imaging does not necessarily indicate a complete destruction of the metastases in most patients, and makes it difficult for the surgeon to completely resect all lesions 214 .

Further considerations

Patients with symptomatic or more-aggressive metastatic disease without chance of secondary metastatic resection benefit from active first-line treatment to achieve optimal tumour control. This can generally be achieved using doublet chemotherapy in combination with a targeted agent such as bevacizumab. In patients with RAS wild-type tumours, doublet chemotherapy together with an EGFR-specific antibody treatment can also be used. For those who respond to this ‘induction’ treatment, or who have a stable disease after 4–6 months of the treatment, the intensity of the treatment should be reduced to avoid excessive toxicity. This is particularly important if a FOLFOX protocol is used to avoid the cumulative neurotoxicity of oxaliplatin. A Phase III trial showed that after FOLFOX plus bevacizumab induction therapy, a maintenance strategy with fluoropyrimidine chemotherapy plus bevacizumab prolonged PFS without significantly improving overall survival compared to a complete treatment break 215 . Thus, active maintenance, but also treatment discontinuation, can be considered when tumours respond or are stable during a 4–6 months induction treatment and the tumour burden is not high.

In the palliative setting, a less-aggressive approach with monotherapy with fluoropyrimidine chemotherapy or a combination of fluoropyrimidine chemotherapy with bevacizumab is possible. Such a strategy requires the patient to be at low risk for rapid deterioration. Upon disease progression, treatment should be escalated and combination chemotherapy (together with bevacizumab) should be used. However, recent data from the FIRE3 and CALGB trials suggest that using a more-intensive treatment in the first-line setting can achieve a median overall survival of about 30 months in a RAS wild-type population. Such survival rates have so far not been reported in a sequential setting when treatment starts with just fluoropyrimidine chemotherapy with or without bevacizumab 201 .

In the second-line palliative setting, upon further disease progression, chemotherapy should be changed to a regimen not used in the first line (either FOLFOX/XELOX or FOLFIRI). A recent study showed that bevacizumab can be given after disease progression and improves overall survival in the second-line setting 207 . Apart from bevacizumab, aflibercept can be used in the second-line setting (in combination with FOLFIRI). Cetuximab or panitumumab can also be used if not previously used and if the tumour is RAS wild-type. For these compounds, efficacy beyond progression has not been demonstrated.

In cancers that are refractory to two lines of chemotherapy, EGFR-specific antibodies can be used if the tumour is RAS wild-type and an EGFR-specific antibody has not been used previously 202 . Regorafenib is an orally available multikinase inhibitor that has shown efficacy in patients who had previously been treated with all available therapies. Accordingly, it has become the standard in pre-treated patients 216 .

Quality of life

Colorectal cancer can manifestly impair quality of life through, for example, direct consequences of the disease, such as abdominal pain, change in bowel movements, blood loss and anaemia, fatigue, and weight loss. Furthermore, treatment incurs a burden to quality of life by means of surgery, chemotherapy and radiotherapy, which can be associated in the short-term with impaired nutrient intake and physical activity 217 . Indeed, weight loss and reduced physical condition is particularly relevant for elderly patients and those with co-morbidities, and should be adequately monitored during treatment and follow-up care.

Each treatment modality can be associated with further specific adverse effects and complications. One of the most feared surgical complications is the occurrence of leakage of the anastomosis, at the suture-line of the intestinal loops after removal of the tumour. This event usually requires further surgical or radiological intervention and is associated with significant morbidity and lengthening of hospital stay and mortality. Other more common complications of surgery are wound dehiscence (rupture of the wound along a surgical suture), and abdominal scar herniation. Overall, the impact on quality of life does not differ between open and laparoscopic surgery 133 . A range of stoma-related complications can also significantly impair social functioning and impair quality of life; these can sometimes be managed conservatively, but may require surgical revision of the stoma.

Treatment for rectal cancer is frequently associated with long-term complications. These include faecal incontinence and increased numbers of stools. These complications are well defined in the validated low anterior resection syndrome (LARS) score 218 . Pelvic floor problems are more frequent in rectal cancer patients receiving neoadjuvant (chemo) radiotherapy 219 . Toxicity is higher after chemoradiotherapy in comparison to radiotherapy alone 220 . Moreover erectile dysfunction in men and dyspareunia in women are common after rectal cancer treatment 221 , 222 .

With respect to chemotherapy, 5-fluorouracil is usually well tolerated, but oxaliplatin or irinotecan more often give rise to adverse effects such as neutropenia and diarrhoea. Targeted therapies have important adverse effects that must be considered. For the EGFR-specific antibodies, papulopustulous rash and paronychia (infection of the nail) occur within days of treatment, followed by skin atrophy after several weeks and alopecia that occurs within a few months. High-grade skin toxicity can involve pain and secondary infections. Antiangiogenic agents cause bleeding, arterial thromboembolic events, impaired wound healing, hypertension and proteinuria 6 . Aflibercept increases (to some extent) chemotherapy- induced adverse events such as diarrhoea, neutropenia and asthenia 208 .

Metastatic disease can give rise to a range of additional symptoms that affect quality of life, such as cachexia, loss of appetite, anaemia, liver failure, biliary obstruction and impaired pulmonary function 223 . These symptoms relate to duration of survival to some extent 223 . A range of interventions, with focus on management of pain, improvement of food intake and maintenance of physical activity benefit individual patient groups. For example, a systematic review of three studies reported that increased physical activity improved quality of life in patients with colorectal cancer 224 . Clinicians are aware of the potential major impact of colorectal cancer on many aspects of quality of life, and individualized options to improve this should be given 225 ( Box 4 ).

Supportive palliative care for patients with colorectal cancer

Maintenance of adequate nutrient intake.

Surgery and chemoradiotherapy can temporarily or for prolonged periods impair energy intake. Nutritional counselling and dietary monitoring can improve nutritional status, which benefits physical condition.

Pain relief

A substantial proportion of patients with advanced-stage disease require opioid treatment in the last months of their life. In a large UK study, approximately 20% of patients received intense opioid combination therapy. Such pain relief requires adequate patient monitoring, physician training and access to a dedicated pain treatment team 227 .

Physical condition maintenance

Various studies focusing on patients with advanced-stage colorectal as well as other cancers reported that exercise programmes can improve the patient’s physical condition, mobility and sleep, and reduce fatigue 27 , 228 .

Prevention of avoidable hospital admission

A considerable proportion of hospital admissions in patients with advanced-stage colorectal cancer are potentially avoidable by adequate support at home and hospice access. Potentially avoidable admissions seem to occur more often in elderly patients and those with end-stage disease.

Psychosocial support

Routine assessment at outpatient clinic visits or visits at home can help to identify patients who need specific psychosocial support in a timely manner.

Colorectal cancer has over the past several decades become one of the most common cancers, and its incidence is expected to continue to increase in coming years. Despite major advances in treatment, mortality from colorectal cancer remains high and 40–50% of patients eventually die because of their disease. As discussed above, colorectal cancer arises as a result of environmental factors and genetic factors cooperating to generate colon polyps that progress to colorectal cancer. The polyp to cancer progression sequence is primarily driven at the cellular level by gene mutations and epigenetic alterations and is now recognized to be a heterogeneous process. It is widely anticipated that insights into the unique gene alterations will lead to more-precise and individualized care for people with polyps and cancers, which will be guided by the molecular characterization of the individual’s colon tumour.

The future of cancer surgery for colorectal disease is aimed at minimizing surgical trauma and preserving organ function. Population-based studies to unravel the effects of multimodal strategies for elderly patients and those with comorbidities need to be undertaken. High-precision imaging will lead to image-guided techniques. Each patient is unique and surgery needs to be tailor-made, aimed at complete removal for cure. Feedback on performance is required to keep on improving our efforts.

Chemotherapy has made substantial progress in recent years. We can now individualize the treatment according to the type of metastases (isolated liver/lung metastases, resectable or primarily not resectable), the RAS mutation state of the tumour and the response to a given treatment (for maintenance strategies or therapeutic breaks). The Human Cancer Genome Atlas and various other genomic projects have identified a number of novel potential molecular targets and markers for colorectal cancer that might be used to guide more-specific treatments for subgroups of patients ( Figure 8 ).

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Object name is nihms769726f8.jpg

The Cancer Genome Atlas and various other genomics projects have identified several novel potential molecular targets and markers in colorectal cancer that might be used to guide specific treatments for subgroups of patients. These targets include the Wnt, transforming growth factor (TGF)-β and epidermal growth factor (EGF) receptor signaling pathways. Experimental agents targeting these molecules are included in grey boxes. APC, adenomatosis polyposis coli; BMP, Bone morphogenetic protein; BMPR, BMP receptor; CK1, casein kinase 1; Dsh, Dishevelled; GSK3, glycogen synthase kinase 3; LRP, low-density lipoprotein receptor-related protein; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; P (in a red circle), phosphate; PDK, 3-phosphoinositide-dependent protein kinase; PI3K, phosphatidylinositol 3-kinase; PIP 2 , phosphatidylinositol-(4,5)-bisphosphate; PIP 3 , phosphatidylinositol-(3,4,5)-trisphosphate; PTEN, phosphatase and tensin homologue; SFRP, Secreted frizzled-related protein 1; SMAD, SMAD family member; TGFβR, TGF)-β receptor.

These developments in surgery and chemo(radio)therapy will improve and further individualize treatment in the near future, which should prolong survival of patients. The largest impact on incidence and mortality will, however, come from widespread organized population screening. Screening programmes should aim for optimal uptake and smart use of available resources. Opportunistic screening programmes must be replaced by organized screening, together with incorporation of strict quality assurance measures. With such an approach, the foreseen rapid rise in colorectal cancer incidence and mortality could be reversed in the coming decade.

Author contributions

Competing interests

T.S. has received honoraria for lectures or advisory boards from Roche, Merck-Serono, Amgen and Bayer. All other authors declare no competing interests.

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Postpartum Depression—New Screening Recommendations and Treatments

1 University of Massachusetts Chan Medical School, Worcester
2 UMass Memorial Health, Worcester, Massachusetts
Medical News & Perspectives What to Know About the First Pill Approved for Postpartum Depression Rita Rubin, MA JAMA
Comment & Response Screening Recommendations and Treatments for Postpartum Depression—Reply Tiffany A. Moore Simas, MD, MPH, MEd; Anna Whelan, MD; Nancy Byatt, DO, MS, MBA JAMA
Comment & Response Screening Recommendations and Treatments for Postpartum Depression Itamar Nitzan, MD; Raylene Philips, MD; Robert D. White, MD JAMA

Perinatal mental health conditions are those that occur during pregnancy and the year following childbirth, whether onset of the condition(s) predates pregnancy or occurs in the perinatal period. Perinatal mental health conditions are the leading cause of overall and preventable maternal mortality and include a wide array of mental health conditions including anxiety, depression, and substance use disorders. 1 , 2 Perinatal depression specifically affects 1 in 7 perinatal individuals. 3 While commonly referred to as postpartum depression, it is more accurately called perinatal depression because its onset corresponds with prepregnancy (27%), pregnancy (33%), and postpartum (40%) time frames. 3

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Colon cancer, also known as colorectal cancer, is a type of cancer that begins in the cells of the colon, which is a part of the large intestine. It typically starts as small, noncancerous clumps ...
40% of US cancer cases linked to lifestyle choices
Please use one of the following formats to cite this article in your essay, paper or report: APA. Sidharthan, Chinta. (2024, July 14). 40% of US cancer cases linked to lifestyle choices.
COLORECTAL CANCER
Epidemiology. Colorectal cancer is the second- and third-most common cancer in women and men, respectively. In 2012, 614,000 women (9.2% of all new cancer cases) and 746,000 men (10.0% of new cancer cases) were diagnosed with colorectal cancer worldwide 10.Combined, in both sexes, colorectal cancer is the third-most common cancer and accounts for 9.7% of all cancers excluding non-melanoma skin ...
Postpartum Depression—New Screening Recommendations and Treatments
This Insights in the Women's Health series describes perinatal depression (occurring prepregnancy through postpartum periods) and new recommendations and treatment guidelines for this condition.

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