Rectal Cancer Symptoms, Stages, and Treatment – Patient Guide

Purpose and Scope of the Rectal Cancer Guide

This guide aims to provide a comprehensive, understandable source of information about rectal cancer. Rectal cancer has an important place among digestive system cancers and offers a high chance of treatment when diagnosed early. By examining its causes, symptoms, diagnostic methods, and treatment options in detail, this guide aims to assist both patients and healthcare professionals.

In addition to diagnosis and treatment, the guide focuses on strategies to improve quality of life. It will address exercise, rehabilitation, evidence-based complementary therapies, and the use of vitamins and supplements in detail. Our aim is to help patients better understand treatment and maximize their quality of life. Rectal cancer statistics in Türkiye and the latest research will also inform a resource relevant at both local and global levels.

This guide was prepared by Prof. Dr. Mustafa Özdoğan and his team using evidence from the latest clinical research, comprehensive reviews, and expert opinions. Its information is not intended to replace your physician's personalized advice. Your physician, who knows your medical history best, will guide you in determining the most suitable treatment plan.

Contents

1. What Is the Rectum?
2. Regions of the Rectum
3. What Is Rectal Cancer?
4. Differences Between Rectal and Colon Cancer
5. Rectal Cancer Incidence in Türkiye
6. Causes of Rectal Cancer (Etiology)
7. Risk Factors for Rectal Cancer
8. Symptoms of Rectal Cancer
9. Diagnostic Methods for Rectal Cancer
10. Imaging Techniques for Rectal Cancer
11. Hereditary Genetic Testing in Rectal Cancer
12. Rectal Cancer Stages and the TNM Staging System (Extent of Cancer Spread)
13. Importance of Staging in Treatment
14. Treatment Options for Rectal Cancer / Types of Surgery and Techniques
15. What Is Neoadjuvant Treatment in Rectal Cancer, and Why Is It Used?
16. Treatment Approaches for Localized and Locally Advanced Rectal Cancer
17. Major Problems During and After Radiotherapy and Their Management
18. Chemotherapy for Rectal Cancer and Management of Adverse Effects
19. Who Is Suitable for Neoadjuvant Long-course Chemoradiotherapy in Rectal Cancer?
20. What Is Total Neoadjuvant Therapy (TNT) in Rectal Cancer?
21. Applications of Total Neoadjuvant Therapy in Rectal Cancer
22. For Whom Is Conventional Chemoradiotherapy Preferred in Rectal Cancer?
23. Importance of Rectal Preservation in Rectal Cancer
24. What Should Patients Pay Attention to During Chemoradiotherapy for Rectal Cancer?
25. Role of Neoadjuvant Immunotherapy in Localized or Locally Advanced dMMR/MSI-high Rectal Cancer
26. Treatment of Metastatic (Stage Four) Rectal Cancer
27. Patients with Incurable pMMR / MSI-stable Metastatic Rectal Cancer (Not Suitable for Surgery Under Any Circumstances)
28. Sexual Problems Related to Surgery, Radiotherapy, and Chemotherapy in Rectal Cancer Patients
29. Individualized Treatment Selection in Metastatic Colorectal Cancer
30. Aims and Expectations of Systemic Treatment for Patients with Incurable pMMR / MSI-stable Metastatic Rectal Cancer
31. What Is NGS (Next Generation Sequencing)? What Is Its Role in Metastatic Rectal Cancer?
32. Coping with Sexual Problems and Treatment Methods
33. Exercise and Nutrition in Patients with Early-stage and Metastatic Rectal Cancer
34. Nutritional Recommendations for Overweight or Obese Patients with Nonmetastatic Early-stage Rectal Cancer
35. Exercise and Nutrition in Patients with Metastatic Rectal Cancer
36. Vitamins and Supplements in Colorectal Cancer
37. Ways to Reduce Rectal Cancer Risk
38. Importance of Psychological Support and Quality of Life in Rectal Cancer

What Is the Rectum?

 The rectum is a structure forming the final part of the digestive system and joining the anus.

Its anatomical and physiological definition and functions are as follows:

Definition of the Rectum: The rectum is the final portion of the large intestine, located between the sigmoid colon and the anal canal. It generally lies in the pelvic cavity and ends where it joins the anal canal.

Length of the Rectum: It is approximately 12-15 cm long on average.

Location of the Rectum: It lies within the pelvic bones, in the area known as the pelvis, behind the bladder.

Anatomical Structure of the Rectum: The rectum consists of serosal, muscular, and mucosal layers. Its upper and middle portions are covered by a serosal layer, while its lower portion has a mucosal layer.

Functions of the Rectum: The rectum temporarily stores the final waste products of digested food (feces). This storage allows stools to be passed regularly and at an appropriate time. As feces accumulate, the rectal walls stretch; this stimulates nerve endings and signals the need for a bowel movement. The rectum moves stool toward the anus and enables bowel control with the help of the anal sphincter muscles. These sphincters prevent involuntary emptying and relax when it is time to pass stool. The rectum also secretes mucus, which lubricates stool and makes defecation more comfortable. Its inner surface contains mucus-producing glands that allow stool to pass smoothly. When gas and stool accumulate, the rectum temporarily stores them. This accumulation controls the timing of the defecation reflex and gas release. Its capacity to expand allows temporary retention of stool and gas, helping a person control the need for a bowel movement.

The rectum's anatomical and functional features are important in assessing and treating many clinical conditions. In rectal cancer, for example, tumor location can directly affect prognosis and treatment strategies. Understanding rectal function and anatomy plays a critical role in diagnosis and treatment.

Below is a simplified view of gastrointestinal anatomy and the location of the rectum:

Division of the Rectum into Regions

Upper Rectum (Proximal Rectum): The upper rectum begins as a continuation of the sigmoid colon and generally encompasses the first 5-7 cm of the rectum. It is covered by a serosal layer (peritoneum) and lies within the pelvic bones. Upper rectal cancers generally have histopathological features similar to sigmoid colon cancers, and treatment usually focuses on surgery.

Middle Rectum: The middle rectum lies between the upper and lower rectum and is approximately 5-7 cm long. It contains both serosal and mucosal layers. This region is of particular clinical importance in terms of sensitivity to radiotherapy and chemotherapy. Cancers here are generally treated with neoadjuvant strategies. Radiotherapy and chemotherapy are used to shrink tumors and optimize them before surgery.

Lower Rectum (Distal Rectum): The lower rectum extends from the middle rectum to the anus and generally encompasses the final 5-7 cm. Because it transitions into the anal canal, it includes the mucosal layer and structures associated with the anal sphincter. Lower rectal cancers may be more aggressive because of their proximity to the anal sphincter (anus), and generally may require more extensive surgery or combined treatment.

Neoadjuvant chemoradiotherapy is frequently preferred for lower rectal cancers. In recent years, chemotherapy and radiotherapy given before surgery have enabled rates of disease eradication without surgery exceeding 30%. This approach shrinks tumors, allows a group of patients to recover without surgery, and makes surgery less invasive (destructive) in those who still require it.

Modern treatment approaches can prevent the need for a colostomy (permanent bag) in approximately one-third of patients undergoing surgery for lower rectal cancer. In addition, patients described as having high microsatellite instability (MSI-high) account for approximately 5% to 10% of all colorectal cancers; in this group, rates of disease eradication without surgery using immunotherapy alone approach 100%. Treatment of tumors in the distal rectum has therefore gained great importance in recent years.

What Is Rectal Cancer?

The rectum is the final six-inch (approximately 15 cm) portion of the large intestine and part of the digestive system consisting of the colon and rectum. Colon and rectal cancers arise from cells lining the inner bowel surface. Although rectal cancer begins similarly to colon cancer, treatment approaches differ because rectal anatomy and the disease's potential to spread are different.

Colon and rectal cancers are the fourth most common cancer type in the United States. In 2022, approximately 151,030 new cases were diagnosed and approximately 52,580 deaths occurred from these cancers. An individual's lifetime risk of developing colon or rectal cancer is approximately 4,1%. Treatment success in rectal cancer is very high when diagnosed at an early stage.

Differences Between Rectal and Colon Cancer

Although colon and rectal cancers are generally grouped together as "colorectal cancer", they occur in different parts of the body and have certain differences. These are reflected in location, patterns of spread, symptoms, and treatment methods.

Anatomical Differences

Colon: The first portion of the large intestine, approximately 1.5 meters long, where the final processing of digested food takes place before elimination. It consists of four main sections: ascending, transverse, descending, and sigmoid colon.

Rectum: The final 12-15 cm portion immediately after the colon. It temporarily stores stool and connects to the anus.

Cancer Location and Tendency to Spread

Colon cancer can develop in any part of the colon. As cancer cells begin to multiply, the tumor grows on the inner surface and can eventually spread into deeper layers.

Rectal cancer begins in the rectum. Because the rectum lies in the pelvis, its proximity to bones, blood vessels, and nerves can make surgery more complex, and the risk of cancer spread is higher.

Overview of Rectal Cancer

The main topics of our rectal cancer guide are briefly covered below. Each subsection is discussed in much greater detail later in the guide.

1. Symptoms of Rectal Cancer

Colon cancer generally presents with more general digestive problems such as abdominal pain, bloating, constipation, or diarrhea. Blood in the stool, unexplained weight loss, and chronic fatigue are also common symptoms.

Rectal cancer may produce more pronounced local symptoms, such as changes in bowel habits (frequent bowel movements, blood in stool, tenesmus—the feeling of incomplete emptying), pain around the anus, and rectal bleeding.

2. Diagnosis and Staging

Colon and rectal cancers are generally diagnosed with similar methods: colonoscopy, biopsy, and imaging such as CT and MRI establish a definitive diagnosis. In rectal cancer, additional MRI scans may be needed for detailed examination of the pelvis.

Staging is the same for both cancer types (stages 0-IV). However, the risk of spread to pelvic lymph nodes is higher during rectal cancer staging, so this area requires careful examination.

3. Treatment Methods

Colon cancer treatment generally involves surgical removal of the tumor (colectomy), followed by chemotherapy. The remaining bowel can generally return to normal function after surgery.

Rectal cancer treatment is supported by radiotherapy as well as surgery. Its pelvic location makes surgery more difficult, and some patients may need a permanent ostomy. Bowel function problems may also persist longer after surgery.

4. Surgical Differences

Colon cancer surgery generally removes the cancerous portion and joins the healthy bowel ends. This usually does not create a permanent change.

Rectal cancer surgery may require an ostomy (bringing the bowel to an opening outside the body), particularly in advanced stages, depending on tumor size and spread. Complete removal of the rectum may necessitate a permanent colostomy.

5. Risk of Recurrence

Rectal cancer has a higher risk of recurrence than colon cancer. This may reflect its structure within the pelvis and the difficulty of completely clearing disease during treatment.

Recurrence risk is lower in colon cancer, although it can vary according to stage and treatment success.

6. Prognostic Differences

Because rectal cancer generally involves more complex treatment, quality of life and the post-treatment period can be more challenging. Pelvic surgery and radiotherapy in particular can affect quality of life.

With early diagnosis and treatment, the chance of complete recovery is generally higher in colon cancer.

Rectal Cancer Incidence in Türkiye

Rectal cancer is among the common cancers in Türkiye and belongs to the colorectal cancer group. According to 2020 data, colorectal cancers are the third most common cancer type in Türkiye and a serious health problem in both men and women. Approximately 233.834 new cancer cases were diagnosed in Türkiye in 2020, with colorectal cancers accounting for a substantial proportion. Their high incidence underlines the importance of early diagnosis and treatment.

Colorectal cancers rank third among the most common cancers in men and also third in women. General cancer statistics in Türkiye show that one in four people is diagnosed with cancer before age 75, with colorectal cancers occupying an important place within this picture.

Causes of Rectal Cancer (Etiology)

Rectal cancer etiology is based on a complex network of interactions, shaped by the convergence of variables including genetic factors, environmental exposures, lifestyle choices, and infections.

1. Genetic Factors in Rectal Cancer

A substantial proportion of rectal cancer cases are associated with genetic susceptibility. Family history significantly increases risk, particularly for individuals with a first-degree relative who has had rectal or colorectal cancer. Hereditary syndromes such as Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer - HNPCC) and Familial Adenomatous Polyposis (FAP) involve genetic mutations that substantially increase rectal cancer risk. Errors in DNA repair mechanisms associated with these genetic disorders lead to the accumulation of carcinogenic changes in cells.

2. Environmental Factors in Rectal Cancer

Environmental exposures play an important role in rectal cancer development. Prolonged exposures in particular can trigger carcinogenic processes through cellular DNA damage. Contact with chemicals such as asbestos and heavy metals, for example, may increase cancer risk. Exposure to radioactive gases such as radon has also been described among risk factors.

3. Lifestyle and Diet in Rectal Cancer

Diet and lifestyle habits are determining factors in rectal cancer development. Major risk factors include a high-fat diet rich in red and processed meat, insufficient dietary fiber, excessive alcohol consumption, and smoking. Physical inactivity and obesity are also risk factors that promote carcinogenic processes in the bowel. High body mass index has also been associated with metabolic disorders such as insulin resistance and chronic inflammation.

4. Role of Infections in Rectal Cancer

Infections, particularly certain viruses and bacteria, may contribute to rectal cancer development. Human papillomavirus and Helicobacter pylori infections, for example, can lead to carcinogenic changes in the gastrointestinal system. These microorganisms may facilitate cancer development by directly damaging cellular DNA or through chronic inflammation. Rectal cancer causes are shaped by the interactions of these factors individually or in combination; assessment of both genetic and environmental risk factors is therefore important.

5. Importance of Age and Sex in Rectal Cancer

Rectal cancer risk increases substantially with age, with a higher incidence particularly in individuals over 50. This is considered a consequence of accumulated cellular DNA damage and declining immune effectiveness with age. Rectal cancer is also more common in men than women; this difference may partly reflect lifestyle factors and hormonal differences.

6. Association of Rectal Cancer with Smoking and Alcohol

Smoking and alcohol use are important lifestyle factors that increase rectal cancer risk. Carcinogens in tobacco can damage DNA in bowel cells. Alcohol, particularly when consumed excessively, is considered a risk factor for rectal and colon cancers. Chronic alcohol use facilitates cancer development through irritation of the intestinal mucosa and chronic inflammation.

7. Chronic Diseases and Immune System Problems in Rectal Cancer

Inflammatory bowel diseases, particularly chronic inflammatory conditions such as Crohn's disease and ulcerative colitis, increase rectal cancer risk. Persistent inflammation of the intestinal mucosa and cellular changes may lead to cancer. Diseases or treatments that suppress immunity, such as immunosuppressive drugs after organ transplantation, also increase risk. Weakened immunity makes it harder to recognize and eliminate cancer cells.

Awareness of these risk factors may help achieve earlier rectal cancer diagnosis and better treatment success by encouraging participation in screening, particularly among high-risk individuals.

Signs and Symptoms of Rectal Cancer

Rectal cancer may initially produce no clear symptoms, making early diagnosis difficult. As it progresses, both disease-specific and nonspecific symptoms may emerge.

1. Early Symptoms of Rectal Cancer

Early symptoms are generally mild and vague, often causing them to be overlooked. The most common is blood in the stool (rectal bleeding). Changes in bowel habits, such as diarrhea or constipation, and changes in the frequency or form of bowel movements may also occur early. A persistent urge to pass stool (tenesmus) or a feeling of incomplete bowel emptying can also be early signs.

2. Advanced Symptoms of Rectal Cancer

As disease progresses, symptoms become more pronounced and severe. Advanced symptoms include rectal pain, increased blood in stool, abdominal pain, and weight loss. Large tumors may cause bowel obstruction, leading to abdominal distension, nausea, vomiting, and serious complications requiring emergency surgery if obstruction is complete.

3. Specific and Nonspecific Symptoms of Rectal Cancer

Specific symptoms relate to the disease's direct effects: rectal bleeding, clear changes in bowel habits, and pain during defecation are considered disease-specific. Nonspecific symptoms are more general and may be confused with many other conditions. They include weakness, fatigue, loss of appetite, and anemia. Anemia develops from chronic blood loss and generally presents with fatigue and pallor.

Awareness of these symptoms can facilitate early diagnosis and improve treatment success. Individuals experiencing them should therefore seek medical advice.

Diagnostic Methods for Rectal Cancer

Early and accurate diagnosis is among the most important factors directly affecting treatment success. Diagnostic methods include various tests and procedures to determine stage and spread. This section explains the main methods used to diagnose rectal cancer.

1. Physical Examination in Rectal Cancer

Physical examination is the first step in diagnosis. Your physician assesses your general health and checks for abnormalities in the rectum or around the anus. In a simple test called a Digital Rectal Examination, the physician uses a finger to feel for masses or abnormalities. Pain or discomfort may occur, but the examination is generally brief and provides important information. It is also performed after preoperative treatments such as radiotherapy and chemotherapy to assess the tumor's response.

2. Laboratory Tests in Rectal Cancer

Laboratory tests assess general health, the function of organs such as the liver and kidneys, and levels of particular tumor markers.

a. Complete Blood Count (Hemogram)

This test measures the numbers of different blood cells. A low red blood cell count (anemia) in particular may indicate rectal bleeding or bowel cancer. In addition to red blood cells, called erythrocytes, it measures white blood cells, which regulate the immune system, and platelets, which are responsible for clotting.   

b. Carcinoembryonic Antigen (CEA), a Blood Tumor Marker in Rectal Cancer

Some cancers increase blood levels of particular proteins called tumor markers. CEA is a tumor marker used in rectal cancer diagnosis. Elevated levels may indicate cancer or the possibility of recurrence after treatment. However, elevated CEA does not always mean cancer, so it must be evaluated together with other diagnostic methods.

c. CA 19-9, a Blood Tumor Marker Test in Rectal Cancer

CA 19-9 is another tumor marker that can be elevated, particularly in gastrointestinal cancers. Although CA 19-9 is not routinely used to diagnose rectal cancer, its levels may sometimes rise in patients with this disease. Elevated CA 19-9 may indicate the need to investigate conditions such as liver and pancreatic metastases. However, elevated CA 19-9 is not limited to cancer, so assessment alongside other clinical findings is important.

These tests may also be performed periodically during treatment to monitor adverse effects and treatment effectiveness.

3. Imaging Techniques in Rectal Cancer (MRI, CT, PET, etc.)

Imaging is used to assess tumor size, location, and spread. These methods are vital to surgical planning and determining treatment strategies.

a. Magnetic Resonance Imaging (MRI) in Rectal Cancer

MRI uses radio waves and strong magnetic fields to image soft tissues in detail. In rectal cancer diagnosis, it is preferred for determining how deeply the tumor has spread into the rectal wall and whether it has reached nearby lymph nodes or organs. MRI is particularly suitable for evaluating details in the pelvis (lower abdomen).

Advantages of MRI and Research Data

MRI has high accuracy, such as 85-90%, in determining tumor stage. It has demonstrated clinical benefits in staging accuracy for rectal cancer patients. Its accuracy in assessing local invasion and spread to lymph nodes ranges from 76-89%. MRI is superior for assessing tumor distance and invasion of the rectal mesenteric fascia, which is important for improving surgical outcomes.

Changes in Tumor Spread (Stage) with MRI

MRI has the potential to change treatment planning in approximately 15-20% of patients by upstaging or downstaging the tumor, thus determining stage more accurately. This staging accuracy and potential rate of change are important particularly in planning neoadjuvant treatment, meaning treatment given before surgery.

b. Computed Tomography (CT) Scanning in Rectal Cancer

CT provides three-dimensional images of internal body structures. It is used to detect spread (metastasis) to neighboring or distant organs, such as the liver and lungs.

c. Positron Emission Tomography (PET) Scanning in Rectal Cancer

PET uses radioactive sugar (fluorodeoxyglucose) to identify areas where active cancer cells have spread. It assesses whether cancer has spread to other body regions and its response to treatment. PET combined with CT (PET-CT) provides both anatomical and metabolic information (tumor activity and viability), allowing a more definitive diagnosis.

Advantages of PET-CT

PET-CT is more sensitive than conventional CT because it can assess cancer's metabolic activity. In rectal cancer, it may change tumor stage by providing 15-20% additional information, particularly about lymph nodes and distant metastases. PET-CT has also been shown to have lower false-negative and false-positive rates, reducing incorrect staging.

4. Biopsy and Pathological Examination in Rectal Cancer

Biopsy is the most reliable method for a definitive diagnosis. A small tissue sample is taken from the rectum and examined microscopically. The pathologist confirms the presence and type of cancer cells. Results determine grade and histological characteristics, which are critical to treatment planning.

a. Endoscopic Biopsy in Rectal Cancer

A biopsy may be performed during endoscopic procedures such as colonoscopy or sigmoidoscopy. These allow the physician to examine the inner rectal and colonic surfaces and sample abnormal tissue when needed.

5. Genetic Tests and Biomarkers in Rectal Cancer

Genetic testing and biomarker analysis are increasingly important in determining personalized treatment approaches. Genetic tests in rectal cancer can be divided into two main categories:

6. Hereditary Genetic Testing in Rectal Cancer

Rectal cancer may sometimes arise from familial genetic susceptibility. Hereditary testing aims to identify these predispositions.

Association Between Rectal Cancer and Lynch Syndrome: Lynch syndrome is an inherited condition carrying a high risk of rectal and colon cancer as well as other cancers. People with a family history of rectal cancer or Lynch syndrome should be assessed through testing for this genetic condition. Lynch syndrome can increase rectal cancer risk and may require more frequent screening from an earlier age.

Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer, HNPCC) is an inherited cancer syndrome carrying increased risk of many cancers, including those of the colon, rectum, endometrium (uterus), stomach, ovaries, small intestine, brain, ureters, and renal pelvis. People with Lynch syndrome are particularly more likely to develop colon and rectal cancers, generally at younger ages. It results from inherited mutations in DNA repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) that correct DNA errors. These mutations can prevent cells from repairing errors in their genetic material and thereby lead to cancer. Consequently, lifetime colon and rectal cancer risk in people with Lynch syndrome is 50-80% higher than in the general population.

Lynch syndrome is diagnosed through genetic testing and assessment of family history. Molecular tests such as microsatellite instability (MSI) testing or immunohistochemistry are used to identify its presence. If abnormalities are detected, genetic counseling and confirmatory genetic tests are recommended.

7. Other Inherited Genetic Disorders in Rectal Cancer

Certain other genetic disorders can also increase rectal cancer risk. Tests to identify them may help individuals and families develop risk management strategies.

Tumor Genetic Sequencing Tests (NGS) in Rectal Cancer

Tumor genetic tests examine DNA taken directly from tumor tissue to understand the cancer's biological characteristics more fully. They provide important information for treatment planning.

Next-generation Tumor Genetic Sequencing (NGS)

NGS identifies genetic changes (mutations) in cancer cells. Mutations in genes such as KRAS, NRAS, and BRAF are tested particularly to predict response to specific targeted treatments in rectal cancer. Identifying these changes may help personalize treatment and predict whether a patient will respond to particular therapies.

Scientific evidence on rectal cancer frequently comes from studies including both colon and rectal cancers. In colorectal cancer (CRC), next-generation tumor sequencing has identified additional genetic targets beyond KRAS, NRAS, and BRAF mutations. These changes offer more personalized and effective treatment options. Other important genetic alterations that can be targeted in rectal cancer, and relevant treatment approaches, are explained below using evidence obtained from colorectal cancers:

HER2 overexpression: Overexpression of the HER2 (ERBB2) receptor occurs in approximately 2-3% of colon and rectal cancers.

• Trastuzumab: This monoclonal antibody, used in breast cancer treatment, has also shown activity in HER2-positive CRC patients.
• Pertuzumab: It increases effectiveness when used in combination with trastuzumab.
• Lapatinib and Tucatinib: These small-molecule tyrosine kinase inhibitors target the HER2 signaling pathway.
• Trastuzumab deruxtecan: A HER2-targeted antibody-drug conjugate (ADC). It contains a chemotherapeutic agent consisting of a topoisomerase I inhibitor linked to trastuzumab. By binding HER2-positive cells, it carries this chemotherapy agent inside, causing DNA damage and cell death. In the phase II DESTINY-CRC01 trial, trastuzumab deruxtecan produced a 45% objective response rate in previously treated patients with HER2-positive metastatic colorectal cancer. This demonstrates that HER2-targeted therapies may be effective in colorectal cancer and highlights trastuzumab deruxtecan's potential in this setting.

NTRK Fusions: Although rare, NTRK gene fusions occur in CRC as in various other solid tumors.

• Larotrectinib and Entrectinib: These drugs target NTRK gene fusions and are approved independently of tumor type. Various phase I and II studies have shown high response rates and durable responses. NTRK fusions are rare, occurring in 0.2-0.4% of all patients. Studies of larotrectinib in CRC patients with NTRK fusions found objective response rates of approximately 30-50%. Rates can vary according to tumor type and the patient's general condition.

PIK3CA Mutations: PIK3CA mutations occur in approximately 10-20% of colorectal cancer patients and activate the PI3K/AKT/mTOR pathway.

• Alpelisib: PIK3CA mutations are known to occur in approximately 10-20% of colorectal cancer patients. They contribute to tumor growth by affecting the PI3K pathway. Alpelisib has attracted attention as a PI3K inhibitor targeting these mutations. Its effectiveness has been investigated in various clinical studies. In FAIRLANE, for example, alpelisib plus panitumumab produced a 16% response rate in patients with PIK3CA mutations, and median progression-free survival was reported as 5.3 months. In CESAR, alpelisib plus cetuximab showed a 13.3% response rate and 3.7 months of progression-free survival. In ProSpect Trial, alpelisib plus irinotecan produced an 18.5% response rate and reported progression-free survival of 4.1 months.

Although these results are promising, response rates remain low and further research is needed. Future studies will guide more effective targeting of these mutations. mTOR Inhibitors: Drugs such as everolimus are used to inhibit this pathway. Early-phase studies have reported limited but appreciable activity with PI3K and mTOR inhibitors.

MET, ALK, and ROS Amplification and Mutations

Amplification, mutations, and fusions of the MET proto-oncogene are associated with uncontrolled tumor growth and metastasis. Certain rare genetic changes in colorectal cancer, particularly MET amplification and ROS1/ALK fusions, offer new targets in patients who may be treatment-resistant. Crizotinib and cabozantinib have been investigated as treatments directed at these targets.

• Crizotinib: Crizotinib has been studied in colorectal cancer patients with MET amplification or ROS1/NTRK fusions. In various phase II studies, for example, objective response rates in patients with MET amplification ranged from 10-20%. Promising results were also obtained in patients with ROS1 or NTRK fusions, but large-scale data are limited because these mutations are rare in colorectal cancer.
• Cabozantinib: Cabozantinib has been investigated in colorectal cancer patients with MET amplification or RET/NTRK fusions. Response rates of 15-25% were reported particularly in patients with MET amplification. Similar responses were also observed in patients with RET fusions.

Although both drugs showed activity in particular subgroups, response rates remain limited and further research is needed. They offer personalized treatment options directed at specific targets in advanced colorectal cancer.

BRAF V600E Mutation

A genetic alteration found in approximately 8-10% of patients, generally associated with a poor prognosis. It activates intracellular signaling pathways, causing uncontrolled tumor cell growth.

• BRAF Inhibitors: BRAF inhibitors, particularly encorafenib, may be effective in colorectal cancer with the BRAF V600E mutation. Alone, however, they generally produce limited responses because tumor cells may develop resistance through alternative pathways.
• Combination Treatments: Studies have shown greater effectiveness when BRAF inhibitors are combined with MEK inhibitors and anti-EGFR therapies. In BEACON CRC, for example, encorafenib, binimetinib, and cetuximab produced a 26% response rate, with mean progression-free survival reported as 4.3 months and overall survival as 9.3 months.

FGFR Alterations

Mutations and fusions in the Fibroblast Growth Factor Receptor (FGFR) gene are rare in CRC. This study investigated the frequency of FGFR2 and FGFR3 mutations in colorectal cancer. FGFR2 mutations occur in approximately 5-10% of colorectal cancers, while FGFR3 mutations are less frequent.

• Erdafitinib and Pemigatinib: The study emphasizes that FGFR inhibitors may increase response rates in some patients, although responses may generally be short-lived. It suggests that combination therapies and individualized approaches may make FGFR-targeted strategies more effective.

RET Fusions: RET gene fusions are rare but can be targeted when identified.

• Selpercatinib and Pralsetinib: These are used as RET inhibitors. Their effectiveness has been demonstrated in solid tumors with RET fusions, although colorectal cancer-specific data are limited.

Next-generation tumor sequencing contributes substantially to individualized colorectal cancer treatment. Detailed analysis of tumor profiles allows selection of appropriate targeted therapies and thereby improved effectiveness. Making comprehensive genetic testing routine in clinical practice and following current guidelines will allow patients access to the best treatment options.

Note: This information was compiled using scientific evidence and clinical studies available through October 2023. Treatment selection should always consider a multidisciplinary approach and current clinical guidelines.

Microsatellite Instability (MSI) Testing

MSI is a genetic alteration resulting from a defect in cellular DNA repair mechanisms. High MSI levels may indicate the potential for a better response to immunotherapy and may be an important factor in determining treatment options.

Genetic tests are critical both for assessing inherited risks and determining the tumor's molecular profile. They enable more targeted approaches to treatment decisions and patient management.

Diagnosis uses multiple methods to obtain a complete assessment. Each method serves a particular purpose according to disease characteristics, and several are generally combined for the most accurate diagnosis. Your physician will determine the methods most suitable for you and guide you through this process.

Minimal Residual Disease (MRD) Testing and Rectal Cancer

Minimal Residual Disease (MRD) refers to low levels of cancer cells remaining after treatment that cannot be detected by standard imaging or physical examination. In rectal cancer, MRD testing is a sensitive molecular analysis that may be used to assess response and predict recurrence risk.

Importance of MRD Testing in Rectal Cancer

• Assessment of Treatment Response: Post-treatment MRD testing plays a critical role in assessing response. Particularly after surgery and neoadjuvant treatment (chemotherapy and/or radiotherapy), it detects remaining microscopic cancer cells. MRD positivity indicates that disease has not been entirely eliminated and that cancer cells remaining despite treatment may increase recurrence risk.

• Determining Recurrence Risk: MRD testing may help assess recurrence risk after treatment. MRD-positive patients generally have a higher risk, potentially requiring additional treatment strategies. MRD-negative patients may have a lower risk. This enables personalized clinical decisions and follow-up strategies.

• Shaping Treatment Strategies:Post-treatment monitoring and intervention strategies may be developed according to MRD results. Additional treatment plans, such as further chemotherapy, radiotherapy, or targeted therapies, may be used for MRD-positive patients. For MRD-negative patients, plans may involve reducing treatment intensity or simplifying follow-up.

• Early Intervention and Monitoring: MRD testing may identify recurrence early, allowing early intervention. Positivity before clinical symptoms emerge may indicate a tendency for the disease to recur and provide an opportunity to intervene and begin treatment early. This may improve overall prognosis.

Rectal Cancer Stages and the TNM Staging System (Extent of Cancer Spread)

In rectal cancer, "stage" describes how far the cancer has progressed and whether it has spread elsewhere. Staging determines tumor size, spread to lymph nodes, and metastasis to distant parts of the body. The most widely used system is TNM staging, developed by the American Joint Committee on Cancer (AJCC).

TNM Staging System

T – Primary Tumor

TX: Primary tumor cannot be assessed

T0: No evidence of a primary tumor

Tis: Carcinoma in situ: invasion of the lamina propria

T1: Tumor invades the submucosa

T2: Tumor invades the muscularis propria

T3: Tumor invades the subserosa or nonperitonealized pericolic or perirectal tissues

T4: Tumor directly invades other organs or structures and/or perforates the visceral peritoneum

• T4a: Tumor perforates the visceral peritoneum
• T4b: Tumor directly invades other organs or structures

N – Regional Lymph Nodes

NX: Regional lymph nodes cannot be assessed

N0: No regional lymph node metastases

N1: Metastases in 1 to 3 regional lymph nodes

• N1a: Metastasis in 1 regional lymph node
• N1b: Metastases in 2–3 regional lymph nodes
• N1c: Tumor deposits (satellite nodules) in the subserosa or nonperitonealized pericolic or perirectal soft tissues, without regional lymph node metastases
• N2: Metastases in 4 or more regional lymph nodes
• N2a: Metastases in 4–6 regional lymph nodes
• N2b: Metastases in 7 or more regional lymph nodes

Lymph nodes in the rectal region are illustrated below:

M – Distant Metastasis

M0: No distant metastases

M1: Distant metastases present

• M1a: Metastasis confined to one organ (liver, lung, ovary, nonregional lymph nodes), without peritoneal metastases
• M1b: Metastases in more than one organ
• M1c: Peritoneal metastases with or without organ involvement

In rectal cancer, T stage has greater prognostic value than N stage: patients with stage IIIA disease (T1–2) have longer rectal cancer-specific survival than those with stage IIA (T3), IIB (T4a), or IIC (T4b) disease.

Stages of Rectal Cancer

Rectal cancer stages are generally divided into four main groups:

• Stage I: Cancer is present in the inner rectal layers and has not spread to surrounding tissues or lymph nodes. Surgery alone may generally be sufficient.

• Stage II: Cancer has extended beyond the rectal wall but has not spread to nearby lymph nodes. Chemotherapy and/or radiotherapy may be needed in addition to surgery.

• Stage III: Cancer has spread to nearby lymph nodes but not distant organs. Chemotherapy and radiotherapy are generally recommended in addition to surgery.

• Stage IV: Cancer has metastasized to distant organs, such as the liver or lungs. Treatment generally combines surgery, chemotherapy, targeted therapies, and/or immunotherapy.

Metastatic disease is classified as M1a when metastases involve only one site or solid organ, including lymph nodes outside the primary tumor's regional drainage area. M1b applies to spread to more than one distant site or solid organ, excluding peritoneal carcinomatosis. Patients with peritoneal metastases have shorter progression-free survival (PFS) and overall survival (OS) than those without peritoneal involvement.

Importance of Staging in Treatment

Stage plays a critical role in guiding treatment decisions.

• Early stage (Stages I and II): Surgery is generally the main treatment and may be curative (provide complete recovery) in some patients. Additional chemotherapy or radiotherapy may be used.
• Intermediate stage (Stage III): Systemic treatments (chemotherapy, radiotherapy) are generally used together with surgery.
• Advanced stage (Stage IV): Treatment is more complex, focusing on systemic therapies (chemotherapy, targeted therapies, immunotherapy) and sometimes surgery.

Staging is vital to planning treatment and predicting prognosis. Treatment is individualized and determined by staging results. Staging also includes examination of a tissue sample (biopsy) to determine tumor grade. Low-stage tumors tend to grow and spread slowly. Advanced-stage tumors, conversely, grow and spread rapidly and may therefore require more intensive treatment.

Treatment Options for Rectal Cancer

Place and Role of Surgery in Rectal Cancer

Surgery generally forms the cornerstone of treatment, aiming to remove the tumor and surrounding tissues completely. In early-stage rectal cancer, it increases the chance of recovery and reduces the risk of spread. Its role varies according to tumor type, stage, and general health. When determining surgical options, the physician needs to know how close the tumor is to the anus. This helps determine the type of surgery, and assessment of spread to the anal sphincter (the muscle structure that prevents stool release during bowel movements) is important.

Types of Surgery and Techniques in Rectal Cancer

• Polypectomy and Local Excision: Some early-stage rectal cancers and most polyps can be removed during colonoscopy. This procedure uses a long, flexible tube with a small video camera at its tip, inserted through the anus into the rectum. The cancer is removed with the polyp by cutting through its mushroom stalk-like base. A wire loop generally cuts the polyp from the rectal wall using an electrical current. If the rectal cancer is confined to the polyp and no tumor is found at the surgical margins, local excision is usually considered sufficient and the patient enters clinical follow-up. If tumor remains at the polyp's surgical margin and the disease is high-risk, the involved rectal area is removed through more extensive surgery.
• Laparoscopic Surgery in Rectal Cancer: Laparoscopic surgery is a minimally invasive approach performed through small incisions. It is associated with faster recovery and less pain.
• Open Surgery in Rectal Cancer: Traditional surgery uses a larger incision. In some situations, this allows removal of the tumor from a wider area.
• Transanal Surgery in Rectal Cancer: Used for early-stage tumors, this technique involves removing the tumor directly from the rectum.

This approach can remove early-stage (Stage I) rectal cancers. TAE is performed through the anal canal without an abdominal incision. It uses local anesthesia, with the patient awake. All layers of the rectal wall are cut to remove the cancer and surrounding healthy tissue. Because lymph nodes are not removed, radiotherapy and/or chemotherapy may be recommended afterward according to signs of cancer spread.

• Transanal Endoscopic Microsurgery (TEM): This may be used when early-stage cancers are higher in the rectum and beyond the reach of standard transanal resection. A specially designed magnifying device is inserted through the anus to perform precise transanal resection. This operation requires specialized equipment and training.
• Anterior Resection (Low Anterior Resection = LAR): Low anterior resection (LAR) may be recommended to preserve sphincter function in patients with CT2-4 rectal cancer and a normally functioning anorectal sphincter. Through several small abdominal incisions, the cancerous area and surrounding normal tissue are removed together with lymph nodes. The colon is then reconnected to the remaining rectum, avoiding a permanent colostomy.
• Coloanal Anastomosis: Complete removal of the rectum may be necessary for lower rectal cancers, particularly stages II and III. The colon is connected to the anus (coloanal anastomosis), allowing normal defecation. A colonic J-pouch or coloplasty may sometimes be created during the procedure to provide a storage area for stool. 
• Abdominoperineal Resection (APR): More extensive than LAR, this is recommended when the anal sphincter is affected. APR removes the rectum, anus, and surrounding tissues, including the sphincter muscle. A permanent colostomy is necessary: the bowel end is brought to an opening in the lower abdomen, and stool passes into a bag attached to the abdomen.
• Pelvic Exenteration: For patients with T4 rectal cancer (invasion of adjacent organs) without metastases, surgery removing the rectum and nearby organs to which cancer has spread is called pelvic exenteration. This is a major operation, and recovery may be prolonged.
• Diverting Colostomy: In some patients with advanced rectal cancer causing rectal obstruction, surgery may relieve the blockage. The cancerous rectal region is not removed; instead, the upper colon is connected to a stoma created in the skin.
• Possible Adverse Effects of Surgery: Adverse effects depend on the operation's extent and general health. Postoperative problems may include bleeding, infection, and blood clots. Poor healing of bowel connections, although rare, can cause serious complications.
• Colostomy or Ileostomy: Some patients may need a temporary or permanent colostomy (or ileostomy), requiring lifestyle adjustments. Specially trained ostomy nurses can provide guidance and refer patients to appropriate support groups. 

What Is Neoadjuvant Treatment in Rectal Cancer, and Why Is It Used?

Neoadjuvant treatment is given before surgery. It aims to shrink the tumor, make surgery more effective, and control cancer cells before they spread. In some patients, it also contributes to rectal preservation.

Preoperative Treatment Strategies

• Neoadjuvant Chemoradiotherapy: Chemotherapy and radiotherapy are combined to shrink the tumor and make it more suitable for surgery. This may reduce tumor size and improve surgical outcomes.
• Chemotherapy: This uses drugs to kill cancer cells or inhibit their growth. Neoadjuvant chemotherapy shrinks tumors and may increase the chance of surgical success.
• Radiotherapy: High-energy radiation destroys cancer cells. Neoadjuvant radiotherapy may shrink the tumor and make it suitable for surgery. It is often combined with chemotherapy. Although a short course can be used, the approach known as long-course treatment, given with chemotherapy over 6 weeks, is frequently preferred.
• Neoadjuvant Chemoradiotherapy (Combined Use of Chemotherapy and Radiotherapy): Neoadjuvant chemoradiotherapy includes both chemotherapy and radiotherapy. This combination can effectively shrink the tumor and achieve a better response to surgery. These neoadjuvant treatments administered before surgery offer the advantages of reducing tumor size and the risk of metastasis. However, chemoradiotherapy can also carry risks of side effects and complications. Patient monitoring is therefore important.

Treatment Approaches for Localized and Locally Advanced Rectal Cancer

In the treatment of rectal cancer, patients are evaluated in two main groups according to the disease profile: MSI-high and MSI-stable. Treatment strategies differ between these two groups. The proportions and treatment approaches for each group are discussed in detail below.

Patients with MSI-High (High Microsatellite Instability) Rectal Cancer

MSI-high (MSI-H) indicates a high degree of instability in the microsatellite regions of cancer cells. This characteristic is observed in approximately 10-15% of patients with rectal cancer. MSI-high patients constitute a subgroup whose tumors have the genetic potential to increase the immune response. Immunotherapies: Immunotherapies are an important treatment option for MSI-high patients. Immunotherapies such as PD-1 or PD-L1 inhibitors can be highly effective in MSI-high tumors.

Patients with MSI-Stable (Stable Microsatellites) Rectal Cancer

MSI-stable patients have cancer cells that show stability in their microsatellite regions. This group accounts for approximately 85-90% of patients with rectal cancer.

Neoadjuvant chemoradiotherapy is commonly used in MSI-stable patients with localized (Stage 2) and locally advanced (Stage 3) rectal cancer detected in the middle and especially the lower rectum. This treatment is used to reduce tumor size and improve treatment success before surgery.

In locally advanced rectal cancer, the rate of tumor shrinkage with neoadjuvant chemoradiotherapy can range from 70-80%, which may improve the success rate after surgery.

Treatment Strategies

Combinations of chemotherapy and radiotherapy are more effective in MSI-stable patients. In patients who respond to treatment, particularly those with tumors located distally, in the lower rectum, these combinations increase the likelihood of surgical tumor removal. They also increase the rate of becoming disease-free without surgery by achieving complete recovery in a group of patients (nearly one-third of patients).

Surgery and Postoperative Treatment

After surgery, adjuvant chemotherapy may be administered as an additional treatment. It is used to reduce the risk of disease recurrence, and the success rate is around 60-70%.

Treatment approaches in rectal cancer differ substantially according to the disease's microsatellite instability status. Immunotherapies are prominent for MSI-high patients, and high response rates have been observed with these treatments. For MSI-stable patients, neoadjuvant chemoradiotherapy and surgery are among the standard treatment methods. Personalized approaches suited to the characteristics of the disease should be used to achieve successful outcomes in the treatment of both groups.

Total Neoadjuvant Therapy (TNT) in Rectal Cancer

It can be defined as the combined use of chemotherapy, radiotherapy, and other treatments within a defined protocol. TNT is an approach in which chemotherapy and radiotherapy are administered together. This treatment aims to reduce the risk of recurrence after surgery by effectively shrinking the tumor.

Radiotherapy (Radiation Therapy) in Patients with Rectal Cancer

This section discusses radiotherapy treatment methods, equipment, and the management of side effects.

Radiotherapy in Rectal Cancer: Radiotherapy aims to destroy cancer cells using high-energy radiation. The radiation damages DNA, preventing cancer cells from dividing and multiplying. Radiotherapy is generally used to limit tumor growth and relieve symptoms. In rectal cancer, radiotherapy plays an important role in local disease control and in improving treatment success. In the treatment of rectal cancer, radiotherapy is generally used to reduce tumor size, achieve local tumor control before surgery, or destroy microscopic cancer cells remaining after surgery.

Treatment Planning: Before radiotherapy, the patient undergoes a detailed evaluation using imaging methods such as CT (computed tomography) or MRI (magnetic resonance imaging). This evaluation is necessary to identify the treatment area and ensure that healthy tissues are protected.

Simulation: The simulation stage used in treatment planning involves securing the patient in the correct position on the treatment table and precisely marking the treatment fields. A patient-specific mask or immobilization devices may be used at this stage.

Treatment Delivery: Radiotherapy is generally administered 5 days a week for a defined period (for example, 5-6 weeks). Each session lasts a few minutes, and the patient does not feel any pain during treatment.

Methods and Equipment Used in Radiotherapy: Different radiotherapy methods and equipment can be used in the treatment of rectal cancer. The differences between these devices are important in terms of the way treatment is delivered and the comfort provided to the patient.

External Beam Radiotherapy: The linear accelerator (LINAC) is the most commonly used device in external beam radiotherapy. It targets the cancerous area by producing high-energy X-rays. By precisely focusing the radiation beams on the tumor area, the linear accelerator minimizes damage to surrounding healthy tissues.

Intensity-Modulated Radiotherapy (IMRT): IMRT is a technique that precisely adjusts the radiation dose to follow the shape of the tumor. This method is used to reduce radiation damage to healthy tissues.

Image-Guided Radiotherapy (IGRT): IGRT is a method that verifies the tumor's position using real-time imaging during treatment. By accounting for tumor movement (for example, with breathing), this method improves the accuracy of radiation delivery.

Internal Radiotherapy (Brachytherapy): This method involves placing radioactive sources directly inside or near the tumor. Brachytherapy can generally be delivered at a low or high dose rate and is used particularly to protect healthy tissues surrounding tumors.

Differences Between Devices: Linear accelerators (LINAC) and IMRT allow radiation to be precisely targeted according to the shape and location of tumors. These devices are used to distribute the radiation dose for maximum tumor control with minimal side effects. Radiotherapy guided by real-time imaging (IGRT) improves treatment accuracy by using real-time imaging techniques to verify the tumor's position during treatment. This feature is particularly important when the tumor moves.

Treatment Duration and Number of Sessions: External beam radiotherapy is frequently used in rectal cancer. It is often administered concurrently with chemotherapy to eliminate the tumor completely before surgery or shrink it to improve surgical success, and to reduce regional disease recurrence after surgery in high-risk patients, thereby improving local control.

Brachytherapy generally requires fewer sessions and causes less damage to the healthy tissues surrounding the tumor.

Short-Course Radiotherapy (SCRT) and Conventional (Long-Course) Radiotherapy in the Treatment of Rectal Cancer: Dose, Treatment Duration, Side Effects, and Effectiveness

Radiotherapy methods used to treat rectal cancer include short-course radiotherapy (SCRT) and conventional long-course radiotherapy. These two approaches differ in their dose regimens, treatment durations, treatment effectiveness, and side effect profiles.

Short-course radiotherapy (SCRT) means delivering high-dose radiotherapy over a short period and is generally used before surgery in the treatment of rectal cancer.

Dose and Treatment Duration in Short-Course Radiotherapy

It generally involves a total dose of 25 Gy, delivered as 5 Gy per day for 5 days. The total treatment duration is 5 days, providing a rapid approach to completing treatment. This treatment method is frequently chosen before surgery to shrink the tumor and improve surgical success. The side effects of short-course radiotherapy generally develop in the short term and are mostly mild to moderate. They include proctitis caused by radiation-induced irritation of the rectal mucosa, diarrhea, abdominal pain, and mild skin reactions. In the long term, it can lead to complications such as pelvic fibrosis and sexual dysfunction. However, these side effects are generally more limited because of the short treatment duration.

Conventional long-course radiotherapy means delivering radiotherapy at lower doses over a longer period and is generally used as an alternative to short-course radiotherapy. It is usually administered at doses of 1.8-2 Gy/fraction, for a total of 45-50.4 Gy. Treatment generally lasts 5-6 weeks, meaning that the treatment process takes longer. This method can be used both as neoadjuvant treatment (before surgery) and as adjuvant treatment (after surgery).

More pronounced short-term side effects may include gastrointestinal symptoms (diarrhea, proctitis), urinary symptoms (burning and pain during urination, frequent urination), and skin reactions. Because treatment lasts longer, these side effects can accumulate over time and affect the patient's quality of life. Long-term side effects include fibrosis (tissue hardening) of healthy tissues in the pelvic region, sexual dysfunction, chronic changes in bowel movements, and, rarely, osteoradionecrosis.

Tumor Response and Pathological Complete Response Rate

Long-course chemoradiotherapy improves the success of surgery by shrinking the tumor and reducing its invasion into surrounding tissues, particularly in locally advanced rectal cancer. After chemoradiotherapy, pathological complete response (pCR) rates may be higher, which can improve patients' long-term survival rates.

Short-course radiotherapy and long-course chemoradiotherapy are effective radiotherapy methods used to treat rectal cancer. Short-course radiotherapy offers rapid treatment by delivering high-dose radiation over a short period, whereas long-course chemoradiotherapy may achieve higher rates of local control and pathological complete response with lower doses delivered over a longer period. The choice of treatment should be based on the patient's overall condition, tumor stage, surgical plan, and personal preferences. Clinical studies show that both approaches offer high effectiveness and tolerable side effect profiles in appropriate patient populations. Treatment decisions should be made collaboratively by a multidisciplinary team, taking patient-specific factors into account.

Major Problems During and After Radiotherapy and Their Management

Various side effects may occur during and after radiotherapy. These side effects can vary depending on factors such as the treatment dose and duration and the patient's overall health.

Skin Reactions (Burns and Irritation)

Radiotherapy can cause skin redness, dryness, peeling, and a burning sensation. Skin reactions are generally limited to the treatment area and may appear a few weeks after radiation treatment begins. Mild skin reactions can generally be managed with moisturizing creams and gentle skin care. In more severe cases, steroid creams or special dressings may be needed.

Bowel and Bladder Problems (Diarrhea and Changes in Bowel Movements)

Radiotherapy can affect the intestinal mucosa (surface lining), causing diarrhea, abdominal pain, and an increase in bowel movements.

Bladder Irritation (Cystitis)

Radiation-induced irritation of the bladder mucosa (surface lining) can cause frequent urination and a burning sensation when urinating.

Dietary changes (eating low-fiber foods) and antidiarrheal medications may be recommended for diarrhea. For patients with bladder irritation, increased fluid intake and medications to relieve bladder pain may be used.

Fatigue and Reduced Energy

Radiotherapy can affect the body's energy reserves, causing general fatigue and weakness. Regular light exercise, adequate sleep, and a balanced diet are recommended to cope with fatigue. Patients can also manage their energy better by planning their daily activities.

Pelvic Fibrosis, Adhesions, and Their Causes

Radiation can cause fibrosis and adhesions in tissues in the pelvic region, which can lead to painful bowel movements and sexual dysfunction. Managing fibrosis and adhesions may require physiotherapy, specific exercises, and surgery when necessary.

In the treatment of rectal cancer, radiotherapy is an important treatment method that improves tumor control and supports surgical success. However, managing side effects during and after treatment is very important for maintaining patients' quality of life. Working collaboratively with a multidisciplinary team during and after radiotherapy can improve treatment outcomes and patients' quality of life.

Chemotherapy in Rectal Cancer

Chemotherapy involves the use of drugs that kill cancer cells or prevent their growth. Some chemotherapy drugs used in rectal cancer are:

5-FU (5-Fluorouracil), Leucovorin, Oxaliplatin, Capecitabine, Irinotecan, Regorafenib, Trifluridine/Tipiracil, Bevacizumab.

Chemotherapy drugs are generally used in combination, which can improve treatment effectiveness.

Side Effects and Management of Chemotherapies Used in Rectal Cancer

Chemotherapy can cause side effects such as nausea, vomiting, hair loss, a weakened immune system, and mouth sores. These side effects are generally manageable and can be relieved with supportive treatments during therapy.

• Immunotherapy: Immunotherapy stimulates the immune system to recognize and destroy cancer cells. It is administered using antibodies specific to cancer cells or drugs that activate the immune system. Immunotherapy is particularly effective in localized or locally advanced rectal cancers with certain genetic characteristics defined as dMMR or MSI-high. Studies in the treatment of rectal cancer have shown that certain immunotherapeutic agents are highly effective in patients with dMMR- and/or MSI-high-positive rectal cancer.
• Targeted Therapies (Molecular Targets and Drugs): Targeted therapies act against specific molecular targets in cancer cells. Targeted therapies used in rectal cancer may address particular genetic alterations or molecular targets found in tumors.

Personalized Treatment Approaches

Personalized treatment involves treatment strategies tailored to the patient's genetic profile, tumor characteristics, and other individual factors. This approach can improve treatment effectiveness and reduce side effects. Personalized approaches include the most appropriate treatments identified using genetic tests and biomarkers.

Neoadjuvant Long-Course Chemoradiotherapy (LCCRT) in Rectal Cancer

This is a treatment method used in rectal cancer. It is administered to shrink the tumor and make it suitable for surgery. LCCRT includes both radiotherapy (radiation therapy) and chemotherapy (drug therapy).

Long-Course Radiotherapy Plan for Rectal Cancer

Radiotherapy: Radiotherapy sessions are given over 5-6 weeks. The total dose ranges from 45-54 Gy and is generally delivered in 25-28 sessions, 5 days a week (weekdays).

Chemotherapy Administered During Long-Course Radiotherapy for Rectal Cancer: The drug capecitabine is used. This drug is administered five days a week, at a daily dose of 825 mg/m².

Purpose of Treatment

The aim is to shrink the cancerous tissue (downstage it) and enable complete removal of the tumor during surgery (R0 resection). Some patients may achieve a complete response after treatment; in this case, a "clinical complete response (cCR)" can be achieved.

Who Is Suitable for Neoadjuvant Long-course Chemoradiotherapy in Rectal Cancer?

Patients with Performance Status (PS) 2: LCCRT may be preferred for patients with poorer overall health.

Patients Over 70 Years of Age: LCCRT can be administered to patients over 70 years of age, but factors such as age-related toxicity and treatment adherence should be considered. In this setting, LCCRT can be administered, followed by reassessment.

This treatment can be administered before surgery or after surgery as adjuvant treatment, that is, to protect against recurrence by reducing its risk. This patient group includes those at high risk of recurrence after surgery (patients with a high tumor volume, positive lymph nodes, and/or positive surgical margins). If a patient has only CRM positivity (a positive surgical margin) without other adverse radiological or histological findings, LCCRT may be an appropriate treatment option.

The treatment plan is determined by the multidisciplinary team according to the patient's condition, age, overall health, and other risk factors. The team decides whether LCCRT is the most appropriate option.

What Is Total Neoadjuvant Therapy (TNT) in Rectal Cancer?

Total neoadjuvant therapy is an innovative method used in the treatment of rectal cancer. TNT aims to shrink the tumor and improve treatment outcomes by comprehensively treating the disease before surgery. This approach combines both radiotherapy (radiation therapy) and chemotherapy (drug therapy).

In rectal cancer, TNT has gained scientific and clinical importance for several reasons: TNT provides aggressive treatment in the early stages of rectal cancer. The aim of this treatment is to eliminate the tumor completely and preserve the patient's rectum, and thus the anal region, which would otherwise be lost through surgery. In patients for whom this is not possible, it allows surgery on a smaller tumor. At the same time, by eliminating invisible micrometastatic disease that spreads through the body as the tumor develops, it may reduce the risk of subsequent recurrence.

Organ Preservation Strategies in Rectal Cancer

TNT can support organ preservation strategies for some patients. For example, by offering the option of omitting surgery in patients who achieve a pathological complete response (pCR), it can avoid unnecessary surgery and help preserve the organ. This can improve patients' quality of life and reduce postoperative complications.

Effectiveness for High-Risk Patients with Rectal Cancer

TNT stands out as an effective treatment option for high-risk patients with rectal cancer. In large and distally located tumors, the combination of chemotherapy and radiotherapy can help keep the disease under control.

Improving Outcomes in the Treatment of Rectal Cancer

Clinical studies have shown successful outcomes with TNT protocols. In particular, the RAPIDO and PRODIGE-23 studies demonstrated that TNT improves disease-related treatment success and reduces distant metastasis rates. 

The RAPIDO Study

In the RAPIDO study, a new treatment method administered to high-risk patients with rectal cancer produced better outcomes than standard treatment. With this new method, patients' disease-related treatment success decreased by 23.7%, while the risk of distant metastasis decreased by 20%. In addition, the rate of complete tumor elimination with this treatment increased to 28%, meaning that many patients became completely free of the tumor as a result of treatment.

The PRODIGE-23 Study

The PRODIGE-23 study compared two different treatment methods. The disease-free rate was 75.7% in patients receiving the new treatment method, compared with 68.5% in those receiving standard treatment. In other words, the new treatment method increased patients' chances of remaining disease-free.

Health Problems and the Recovery Process

TNT has the potential to reduce postoperative morbidity. The high risk of morbidity after partial or total mesorectal excision can be reduced through effective use of TNT. This may positively affect patients' recovery.

TNT is considered an important development in the treatment of rectal cancer. This comprehensive treatment method aims to shrink the tumor, reduce the risk of recurrence, and enable organ preservation strategies. The scientifically supported successes of TNT make it an important option in the treatment of rectal cancer.

Applications of Total Neoadjuvant Therapy in Rectal Cancer

1. Conventional Neoadjuvant Protocol

Chemotherapy: First, FOLFOX (5-Fluorouracil, Leucovorin, and Oxaliplatin) or FOLFIRINOX (5-Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan) chemotherapy is administered for 12 weeks.

Radiotherapy: After chemotherapy, radiotherapy is delivered for 5-6 weeks (25-28 sessions).

Rest: After radiotherapy, the patient rests for 6-8 weeks.

Assessment: After treatment, the patient is monitored if a complete response has been achieved. If a complete response has not been achieved, surgery is planned.

Subsequent Treatment: If a complete response has been achieved, monitoring continues; otherwise, systemic treatment (chemotherapy) is administered for 6 months after surgery.

2. Alternative Neoadjuvant Protocol

Short-Course Radiotherapy: At the start of treatment, high-dose, short-course radiotherapy is administered for 5 days.

Chemotherapy: Chemotherapy is administered for 18 weeks, beginning 11-18 days after radiotherapy.

Assessment: The patient is monitored if a complete response has been achieved 2-4 weeks after chemotherapy ends. If a complete response has not been achieved, additional radiotherapy is administered.

Total neoadjuvant therapy is a preferred approach, particularly for patients with high-volume and distally located rectal cancer that is not dMMR (mismatch repair deficient) or MSI-high (high microsatellite instability).

For Whom Is Conventional Chemoradiotherapy Preferred in Rectal Cancer?

Neoadjuvant Treatment Options: Total neoadjuvant therapy (TNT) is a widely used treatment method aimed at shrinking the tumor and improving treatment outcomes. However, conventional chemoradiotherapy may be preferred over TNT in some patient groups. These groups include:

Patients with Poorer Overall Health

Performance Status (PS) 2 or Higher

Conventional chemoradiotherapy may be preferred in patients with poorer overall health or performance status. These patients may not tolerate more aggressive TNT protocols.

Older Patients: Patients Over 70 Years of Age

Patients over 70 years of age may experience age-related problems with treatment side effects and tolerance. In this setting, conventional chemoradiotherapy may offer a lower risk of side effects and a better tolerance profile. However, the age threshold is not absolute, and the patient's overall health should be considered.

CRM-Positive Patients (When This Is the Only Risk Factor)

CRM-Positive (Circumferential Resection Margin) but Without Other Adverse Features: Conventional chemoradiotherapy may sometimes be appropriate in CRM-positive patients, particularly if no other serious adverse radiological or histological features are present. However, TNT may be recommended for CRM-positive patients; conventional chemoradiotherapy may be an alternative option for these patients.

Risks of Side Effects and Problems with Tolerance

The intensive and prolonged treatment regimens used in TNT may carry a high risk of side effects for some patients. Conventional chemoradiotherapy may be more appropriate for reducing side effects.

Conventional chemoradiotherapy is used as an alternative for patients in whom total neoadjuvant therapy cannot be administered or is not preferred. The patient's overall health, age, tolerance of side effects, and specific disease characteristics are important factors affecting treatment selection. The treatment approach for each patient is determined after evaluation by a multidisciplinary team.

Importance of Rectal Preservation in Rectal Cancer

In distal rectal cancer, preserving the rectum is very important for both treatment and the patient's quality of life. It means maintaining the ability to pass stool normally for the remainder of the patient's life without needing a bag attached to the abdomen. Some important points on this subject are:

1. Maintaining Quality of Life: Preserving the rectum directly affects the patient's quality of life. Particularly in tumors located in the lower rectum, surgical removal of the rectum can significantly affect stool control, and the patient may require a colostomy (placement of a stool bag on the abdominal wall). A colostomy can adversely affect the patient's social and psychological well-being, so preserving the rectum helps maintain a high quality of life.
2. Functional Outcomes: Preserving the rectum allows rectal and anal functions to be maintained as much as possible. After removal of the rectum, preserving anal sphincter function can be difficult, potentially leading to problems with defecation. Preserving the rectum maintains anal continence (the anus's ability to retain stool) and increases patients' chances of maintaining normal bowel habits.
3. Oncological Outcomes: Preserving the rectum is associated with oncological success. Particularly in early-stage cancers, adequate tumor removal with preservation of the rectum may reduce the risk of recurrence and improve long-term outcomes. However, because the tumor must be completely removed and the spread of cancer prevented, the extent and techniques of surgery must be carefully evaluated.
4. Psychological and Social Effects: Preserving the rectum is important for the patient's psychological well-being and social integration. The need for a colostomy and problems with stool control can affect patients' social lives and psychological state. Preserving the rectum can reduce these adverse effects and positively affect patients' social and psychological well-being.

Preserving the rectum is an important treatment goal in cancers of the distal rectum (the final, lower section of the rectum adjacent to the anus). This approach improves quality of life and functional outcomes and preserves patients' psychological and social well-being. Modern treatment methods and surgical techniques aim to achieve oncological success while allowing preservation of the rectum.

What Should Patients Pay Attention to During Chemoradiotherapy for Rectal Cancer?

In the treatment of rectal cancer, chemoradiotherapy means administering chemotherapy and radiotherapy together and is frequently preferred, particularly for locally advanced rectal cancer. This treatment process can be physically and emotionally challenging for patients. Patients should therefore pay attention to several important points during chemoradiotherapy.

• Following the Treatment Plan and Appointments: Chemoradiotherapy generally consists of radiotherapy 5 days a week and chemotherapy sessions at defined intervals. Adhering to the treatment plan is critical for treatment effectiveness. Patients should attend all appointments on time and follow the treatment schedule in full. If any change or delay occurs during treatment, patients should remain in regular contact with their treatment team. This is important for managing possible side effects and ensuring that treatment progresses as needed.
• Managing Side Effects: Chemoradiotherapy can cause side effects from both chemotherapy and radiotherapy. Managing these side effects helps make the treatment process more comfortable.
• Skin Reactions: Skin redness, irritation, and a burning sensation may develop in the radiotherapy treatment area. Patients should keep their skin clean and dry, use skin care products recommended by their doctor, and avoid tight clothing that could irritate the skin.
• Gastrointestinal (Stomach, Bowel, and Liver) Side Effects: Chemotherapy and radiotherapy can cause diarrhea, nausea, vomiting, and rectal irritation. Patients should follow the dietary plan recommended by their doctor and drink plenty of water. Eating low-fiber, easily digestible foods can help reduce gastrointestinal side effects.
• Fatigue: Many patients experience fatigue during treatment. It is therefore important for patients to prioritize rest, get enough sleep to maintain their energy levels, and rest when they feel tired.
• Blood Counts: Chemotherapy can affect blood cells, potentially increasing the risk of infection or bleeding. Patients should have regular blood tests and discuss the results with their doctors. They should contact a doctor immediately, particularly if they notice fever, bleeding, or signs of infection.
• Nutrition and Fluid Intake: During treatment, a healthy, balanced diet supports the body's recovery. It is important to eat protein-rich foods (meat, fish, eggs, dairy products) and vegetables. Adequate calorie intake should also be maintained, and nutritional supplements should be considered if nutritional deficiencies occur. Drinking plenty of water helps the body eliminate toxins and prevents dehydration that may occur during treatment. Patients should drink at least 8-10 glasses of water a day and make a point of drinking water before they feel thirsty.
• Physical Activity and Exercise: Regular light exercise (for example, walking or yoga) can help manage fatigue and improve overall health. However, patients should not overexert themselves and should decide on their exercise programs in consultation with their doctors.
• Psychological Support and Mental Health: Chemoradiotherapy can be physically and emotionally challenging. Receiving psychological support during this process can help manage stress and anxiety. Patients may consider seeing a therapist or counselor, joining support groups, or engaging in relaxing activities such as meditation.
• Support from Family and Friends: Emotional support from family and friends can help maintain patients' morale. Patients should not hesitate to share their feelings with loved ones and should ask for support when needed.
• Prescription Medications and Supplements: Medications prescribed by the doctor should be taken regularly throughout treatment. Patients should always consult their doctors before taking any vitamin, herbal supplement, or over-the-counter medication that could interact with chemotherapy or radiotherapy.
• Monitoring Side Effects and Reporting Them to the Doctor: It is important to monitor side effects that may occur during chemoradiotherapy and make daily notes of these symptoms. This can help the treatment team assess the severity of side effects and the response to treatment. Patients should contact their doctors immediately if serious side effects or unexpected symptoms develop. Early intervention can improve side effect management and the patient's adherence to treatment.
• Hygiene and Infection Prevention: Because the immune system may weaken during treatment, the risk of infection increases. Patients should wash their hands frequently, avoid crowded places, and avoid contact with people who have infections. They should also take care to avoid cuts and injuries.

Chemoradiotherapy for rectal cancer can be challenging, but appropriate management and attention can minimize its side effects and improve treatment effectiveness. It is important for patients to remain in close contact with their doctors during treatment, pay attention to nutrition and hydration, maintain physical activity, and receive emotional support. By following these recommendations, patients can undergo chemoradiotherapy more comfortably and effectively. Chemoradiotherapy can cause side effects from both chemotherapy and radiotherapy. Early recognition and appropriate management of these side effects help make the treatment process more comfortable.

The Role of Neoadjuvant Immunotherapy in Localized or Locally Advanced dMMR / MSI-High Rectal Cancer

dMMR (DNA mismatch repair deficiency) and MSI-high (high microsatellite instability) rectal cancers show high response rates to immunotherapies. In dMMR / MSI-high (MSI-H) rectal cancers, neoadjuvant immunotherapies are emerging as standard treatment options. Recent studies have shown promising results in this field and indicate a significant change in treatment approaches.

The Study by Cercek and Colleagues

In a prospective phase 2 study, all patients with dMMR locally advanced rectal cancer (LARC) achieved a complete clinical response (cCR) when treated with 9 cycles of dostarlimab (anti-PD-1). This made it possible to avoid chemotherapy, radiotherapy, and surgery. During follow-up, 100% of patients showed a complete clinical response, and no recurrence was reported over follow-up periods ranging from 0 to 36 months. This result indicates that immunotherapy has considerable treatment potential in dMMR/MSI-high rectal cancer. 

The NICHE Trial

In this study, patients with dMMR/MSI-high colon cancer were treated with the combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). Of 20 patients, 19 showed a major pathological response (MPR), while 12 achieved a pathological complete response (pCR). In the NICHE-2 study, treatment of 112 patients achieved a pathological complete response rate of 67% and a major pathological response rate of 98%, and no recurrence was observed in any patient.

Neoadjuvant Immunotherapies in dMMR / MSI Rectal Cancers

Studies have shown that immunotherapies (dostarlimab, sintilimab, etc.) are effective in dMMR / MSI-high rectal cancers and may replace radical surgery in some patients while improving quality of life.

Treatment Duration and Combinations

The roles of treatment duration and combination therapies in determining the effectiveness of neoadjuvant immunotherapy are being discussed. Although anti-PD-1 monotherapy generally appears sufficient in dMMR / MSI-high rectal cancers, more data are needed in colon cancer. It is important to monitor patients who respond to immunotherapy without requiring surgery. However, long-term outcomes are not yet clear, and close monitoring is necessary, taking the risks of local recurrence into account.

The Role of Biomarkers

Identifying biomarkers to predict the response to immunotherapies will play an important role in patient selection and treatment modifications. Neoadjuvant immunotherapies offer groundbreaking results in dMMR / MSI-high rectal cancers and may potentially allow patients to avoid chemotherapy, radiotherapy, and surgery. Research continues to gather more data on the effectiveness and long-term outcomes of these treatments in clinical practice.

Treatment of Metastatic (Stage Four) Rectal Cancer

The dMMR / MSI-High Patient Group with Metastatic Rectal Cancer

Immunotherapies are prominent among the treatment options for this group. These treatment approaches may be more effective depending on the disease's molecular characteristics and offer promising results, particularly for patients in this group.

Systemic Treatment in the dMMR / MSI-High Patient Group with Metastatic Rectal Cancer

Metastatic rectal cancer means that cancer has spread beyond the rectum. Patients identified as dMMR (mismatch repair deficient) or MSI-high (microsatellite instability-high) have a different genetic profile, which affects treatment approaches. In this patient group, systemic treatment is generally guided by immunotherapies. In dMMR / MSI-high patients, immunotherapies are prominent among standard treatment options. These treatments encourage the immune system to fight cancer cells.

PD-1/PD-L1 Inhibitors

Pembrolizumab (Keytruda) and Nivolumab (Opdivo): These drugs enable the immune system to recognize and destroy tumor cells. In dMMR / MSI-high patients, these treatments generally show high effectiveness. PD-1 inhibitors such as pembrolizumab and nivolumab are associated with high response rates in this patient group.

CTLA-4 Inhibitors

Ipilimumab (Yervoy): This drug increases immune system activity, producing an effective response against cancer cells. It is mostly used in combination with PD-1/PD-L1 inhibitors.

The KEYNOTE-177 Study: It showed that pembrolizumab provided a higher response rate and longer progression-free survival than chemotherapy in patients with dMMR / MSI-high rectal cancer.

The CheckMate 142 Study: The combination of nivolumab and ipilimumab was reported to provide a high objective response rate in dMMR / MSI-high patients and to improve effectiveness in patients who respond well to treatment.

Chemotherapies may be less effective than immunotherapies in dMMR / MSI-high patients, particularly as initial treatment. However, chemotherapy can be used in some patients when immunotherapy is ineffective. Chemotherapy regimens such as FOLFOX or FOLFIRI may be chosen according to the patient's overall health.

Targeted therapies address the tumor's specific genetic or molecular characteristics. However, because immunotherapies are generally more effective in dMMR / MSI-high patients, the use of targeted therapy is limited.

Systemic treatment for patients with metastatic rectal cancer and a dMMR / MSI-high profile is generally based on immunotherapies. Although PD-1/PD-L1 inhibitors can be highly effective in these patients, chemotherapy and targeted therapy are generally used in addition to immunotherapies or when needed. NGS tests play a critical role in personalizing the treatment plan and identifying the most appropriate treatment options. During treatment, it is important for patients and families to communicate openly with their doctors about treatment options and expectations.

The pMMR / MSI-Stable Patient Group with Metastatic Rectal Cancer

This group should be examined in greater detail in terms of treatment approaches. pMMR/MSI-stable patients can be divided into the following subgroups:

The Potentially Resectable (Oligometastatic) pMMR/MSI-Stable Patient Group with Metastatic Rectal Cancer

• Patients with Limited Liver Metastases: There is a limited number of metastases in the liver, and the tumors can be removed surgically. These patients can generally be cured with surgical treatment and additional adjuvant chemotherapy or radiotherapy options.
• Patients with Limited, Resectable Lung Metastases: These are patients with a limited number of lung metastases that can be surgically removed. Surgery followed by systemic treatment is recommended.
• Patients with Limited Peritoneal (Abdominal Lining) Metastases: These are patients with a limited number of metastases in the peritoneum. Surgery and additional treatment options are evaluated.

In all of these patient groups, chemotherapy and targeted therapies are administered before and/or after surgery in accordance with scientific evidence and the physician's preference.

The pMMR/MSI-Stable Patient Group with Metastatic Rectal Cancer and Unresectable Liver Metastases, but Eligible for Liver Transplantation

In this patient group, eligibility for liver transplantation is assessed even though the liver metastases cannot be surgically removed. The most important requirements are the absence of metastases in organs outside the liver and substantial benefit from systemic treatment before transplantation.

The TRANSMET study evaluated the effects of combining chemotherapy and liver transplantation in these patients.

In this study, chemotherapy regimens such as FOLFOX and FOLFIRI were used to shrink metastases and control disease progression. Patients generally receive chemotherapy before transplantation. Continued chemotherapy after transplantation also provides control of metastases.

Results of the TRANSMET Study

Overall Survival (OS): The 5-year overall survival rate was 57% in patients treated with liver transplantation, compared with 13% in patients receiving chemotherapy alone.

Progression-Free Survival (PFS): In patients who underwent liver transplantation, the 3-year PFS rate was 33% and the 5-year PFS rate was 20%. In patients treated with chemotherapy alone, these rates were 4% and 0%, respectively.

The TRANSMET study showed that adding liver transplantation to chemotherapy had positive effects on survival and disease control in patients with metastatic rectal cancer. Liver transplantation supports the shrinkage of metastases and improves long-term survival. However, patient selection must be performed by a multidisciplinary team, and patients should be monitored carefully during treatment. 

The Incurable pMMR/MSI-Stable Patient Group with Metastatic Rectal Cancer (Unsuitable for Surgery Under Any Circumstances)

This group consists of patients with extensive metastases or advanced disease who are unsuitable for surgery. Treatment is generally limited to systemic treatment and supportive care. Targeted therapy and chemotherapy options are evaluated for these patients.

What Is Systemic Treatment, and How Is It Administered?

Patients with metastatic rectal cancer who are unsuitable for surgery are generally treated with systemic treatment. This treatment seeks to be effective by targeting cancer cells throughout the body. Systemic treatment is as follows:

Chemotherapy

Chemotherapy drugs are used to kill cancer cells or stop their growth. They are generally administered through a vein (intravenously) in cycles lasting several weeks. The most common chemotherapy regimens are FOLFOX, consisting of 5FU, oxaliplatin, and leucovorin; FOLFIRI, consisting of 5FU, irinotecan, and leucovorin; FOLFIRINOX, consisting of 5FU, irinotecan, oxaliplatin, and leucovorin; CAPOX, consisting of capecitabine and oxaliplatin; trifluridine/tipiracil; and capecitabine monotherapy.

Targeted Therapy: This treatment targets specific characteristics of cancer cells. Drugs selected according to the cancer's genetic makeup seek to inhibit the growth of cancer cells. This treatment is generally administered in tablet form or intravenously.

What Is NGS (Next Generation Sequencing)? What Is Its Role in Metastatic Rectal Cancer?

NGS is a test that analyzes the genetic material of cancer cells. By examining the tumor's genetic alterations in detail, this test helps identify which treatment options may be more effective. NGS should be performed in the following circumstances: As soon as possible after diagnosis, it is performed to understand the cancer's genetic makeup and identify the most appropriate treatment option.

NGS results identify your tumor's genetic makeup and characteristics. Specific genetic alterations found in the tumor through NGS determine targeted treatment options. For example, specific drugs can be used for tumors with certain gene mutations. According to NGS results, existing treatment regimens may be changed or new treatment options added. For example, certain genetic alterations may be better treated with immunotherapies. NGS is decisive in developing a personalized treatment plan. NGS data help identify which treatments are most appropriate for your particular situation.

Patients with incurable rectal cancer are generally treated using systemic treatment methods. NGS tests guide treatment by identifying the cancer's genetic makeup and allow personalized treatment plans to be developed. During this process, it is important to discuss matters in detail with your doctor to determine the most appropriate treatment plan.

Individualized Treatment Selection in Metastatic Colorectal Cancer

Personalized approaches are critically important in the treatment of metastatic colorectal cancer. Genetic and molecular analyses used in treatment planning play an important role in determining patients' likelihood of responding and their eligibility for treatment.

Next-generation Tumor Genetic Sequencing (NGS)

NGS identifies genetic changes (mutations) in cancer cells. Mutations in genes such as KRAS, NRAS, and BRAF are tested particularly to predict response to specific targeted treatments in rectal cancer. Identifying these changes may help personalize treatment and predict whether a patient will respond to particular therapies.

Scientific evidence on rectal cancer is frequently obtained from studies that include both colon and rectal cancers. In the treatment of colorectal cancer (CRC), in addition to KRAS, NRAS, and BRAF mutations, different genetic targets have been identified through next-generation tumor genetic sequencing techniques. These genetic alterations offer patients more personalized and effective treatment options. Other important genetic alterations that can be targeted in rectal cancer and the treatment approaches directed at them are described below, based on scientific evidence obtained from colorectal cancers. 

The RAS Panel, BRAF, and NGS Data

RAS Mutations

RAS genes (KRAS and NRAS) are important genes that regulate the growth and proliferation of cancer cells. In colorectal cancer, RAS mutations can affect the response to treatment. KRAS and NRAS mutations, in particular, reduce the response to anti-EGFR (epidermal growth factor receptor) therapies. The presence of mutations in RAS genes is therefore used to determine patients' eligibility for anti-EGFR treatment. Anti-EGFR therapies (for example, cetuximab or panitumumab) are not recommended in patients with RAS mutations. Instead, antiangiogenic drugs (bevacizumab, aflibercept), which are other targeted treatment options, are added to regimens such as FOLFOX or FOLFIRI. In addition, better responses can be achieved using anti-EGFR therapies (cetuximab, panitumumab) in patients without RAS mutations.

BRAF V600E

BRAF mutations are associated with a poor prognosis in colorectal cancer and affect the response to treatment. Patients with a BRAF V600E mutation generally have a less favorable prognosis, and their treatment plans are shaped by the presence of this mutation. Targeted therapies such as BRAF inhibitors can be used in patients with BRAF mutations. In addition, patients with BRAF mutations generally need more intensive treatment approaches, and combination therapies are usually preferred.

When additional biomarkers such as HER2 amplification are detected in NGS results, HER2-targeted therapies can be added, as in the treatment of breast cancer. Appropriate targeted therapies for other mutations can also be identified.

In the treatment of metastatic colorectal cancer, the RAS panel, BRAF mutations, and NGS data play a critical role in determining personalized treatment approaches. By optimizing treatment options, these genetic and molecular tests can improve patients' responses and prognosis. A treatment plan tailored to each patient's genetic profile can significantly improve treatment effectiveness and the patient's quality of life.

HER2 Overexpression

Overexpression of the ER2 (ERBB2) receptor is observed in approximately 2-3% of colon and rectal cancers.

• Trastuzumab: This monoclonal antibody, used in breast cancer treatment, has also shown activity in HER2-positive CRC patients.
• Pertuzumab: It increases effectiveness when used in combination with trastuzumab.
• Lapatinib and Tucatinib: These small-molecule tyrosine kinase inhibitors target the HER2 signaling pathway.
• Trastuzumab deruxtecan: This is a HER2-targeted antibody-drug conjugate (ADC). It contains a chemotherapeutic agent consisting of a topoisomerase I inhibitor linked to trastuzumab. By binding to HER2-positive cells, it transports this chemotherapy agent into the cell and causes cell death by inducing DNA damage in the target cell. In the phase II study named DESTINY-CRC01, trastuzumab deruxtecan showed an objective response rate of 45% in previously treated patients with HER2-positive metastatic colorectal cancer. This demonstrates that HER2-targeted therapies can be effective in patients with colorectal cancer and highlights the potential of trastuzumab deruxtecan in this field.

NTRK Fusions: Although rare, NTRK gene fusions occur in CRC as in various other solid tumors.

• Larotrectinib and Entrectinib: These are drugs that target NTRK gene fusions and have been approved regardless of tumor type. Various phase I and II studies have shown that these drugs produce high response rates and lasting responses. NTRK fusions are rare, occurring in 0.2-0.4% of all patients. In studies of larotrectinib in CRC patients with NTRK fusions, the objective response rate ranged from approximately 30-50%. This rate may vary depending on the tumor type and the patient's overall condition.

PIK3CA Mutations: PIK3CA mutations occur in approximately 10-20% of colorectal cancer patients and activate the PI3K/AKT/mTOR pathway.

• Alpelisib: We know that PIK3CA mutations occur in approximately 10-20% of patients with colorectal cancer. These mutations contribute to tumor cell growth by affecting the PI3K pathway. Alpelisib stands out as a PI3K inhibitor that targets these mutations. Its effectiveness has been investigated in various clinical studies. For example, in the FAIRLANE study, the combination of alpelisib and panitumumab achieved a response rate of 16% in patients with PIK3CA mutations, and median progression-free survival was reported as 5.3 months. In the CESAR study, the combination of alpelisib and cetuximab showed a response rate of 13.3% and progression-free survival of 3.7 months. In addition, in the ProSpect Trial, the combination of alpelisib and irinotecan achieved a response rate of 18.5%, and progression-free survival was reported as 4.1 months.

Although these results are promising, it is important to emphasize that response rates remain low and that further research is needed. Future studies will guide us toward targeting these mutations more effectively. mTOR Inhibitors: Drugs such as everolimus are used to inhibit this pathway. Early-phase studies have reported limited but appreciable effectiveness with PI3K and mTOR inhibitors.

MET, ALK, and ROS Amplification and Mutations

Amplification, mutations, and fusions of the MET proto-oncogene are associated with uncontrolled tumor growth and metastasis. Certain rare genetic changes in colorectal cancer, particularly MET amplification and ROS1/ALK fusions, offer new targets in patients who may be treatment-resistant. Crizotinib and cabozantinib have been investigated as treatments directed at these targets.

• Crizotinib: The effectiveness of crizotinib has been investigated in patients with colorectal cancer with MET amplification or ROS1/NTRK fusions. For example, in various phase II studies, the objective response rate with crizotinib ranged from 10-20% in patients with MET amplification. Promising results were also obtained in patients with ROS1 or NTRK fusions, but extensive data are limited because these mutations are rare in colorectal cancer.
• Cabozantinib: Cabozantinib has been investigated in patients with colorectal cancer with MET amplification or RET/NTRK fusions. In particular, response rates of 15-25% have been reported with cabozantinib in patients with MET amplification. Similar responses have also been observed in patients with RET fusions.

Although both drugs have shown effectiveness in certain subgroups, it is important to emphasize that response rates remain limited and that further research is needed. These therapies offer personalized treatment options directed at specific targets in advanced colorectal cancer.

• BRAF V600E Mutation: This is a genetic alteration occurring in approximately 8-10% of patients and is generally associated with a poor prognosis. This mutation activates intracellular signaling pathways, causing uncontrolled growth of tumor cells.
• BRAF Inhibitors: BRAF inhibitors, particularly encorafenib, may be effective in patients with BRAF V600E-mutated colorectal cancer. However, when used alone, they generally provide a limited response because tumor cells can develop resistance through alternative pathways.
• Combination Treatments: Studies have shown that BRAF inhibitors are more effective when used in combination with MEK inhibitors and anti-EGFR therapies. For example, in the BEACON CRC study, the combination of encorafenib, binimetinib, and cetuximab achieved a response rate of 26%, and mean progression-free survival was reported as 4.3 months. Overall survival was measured as 9.3 months.

FGFR Alterations: Mutations and fusions in the fibroblast growth factor receptor (FGFR) gene are rare in CRC. This study investigated the frequency of FGFR2 and FGFR3 mutations in patients with colorectal cancer. FGFR2 mutations occur in approximately 5-10% of colorectal cancers, while FGFR3 mutations occur less frequently.

• Erdafitinib and Pemigatinib: The study emphasizes that FGFR inhibitors may increase response rates in some patients, although responses may generally be short-lived. It suggests that combination therapies and individualized approaches may make FGFR-targeted strategies more effective.

RET Fusions: RET gene fusions are rare but can be targeted when identified.

• Selpercatinib and Pralsetinib: These are used as RET inhibitors. Their effectiveness has been demonstrated in solid tumors with RET fusions, although colorectal cancer-specific data are limited.

Next-generation tumor sequencing contributes substantially to individualized colorectal cancer treatment. Detailed analysis of tumor profiles allows selection of appropriate targeted therapies and thereby improved effectiveness. Making comprehensive genetic testing routine in clinical practice and following current guidelines will allow patients access to the best treatment options.

Note: This information was compiled using scientific evidence and clinical studies available through October 2023. Treatment selection should always consider a multidisciplinary approach and current clinical guidelines.

Goals and Expectations of Systemic Treatment in the Incurable pMMR/MSI-Stable Patient Group with Metastatic Rectal Cancer

Systemic treatment is a treatment method that seeks to be effective by targeting cancer cells throughout the body. It aims to stop the spread of cancer, shrink existing tumors, and slow disease progression.

Systemic treatment helps control tumor growth and spread. This may slow disease progression and improve the patient's quality of life.

Cancer can cause various symptoms. Systemic treatment helps relieve these symptoms, making the patient more comfortable. For example, it can reduce problems such as pain, bleeding, or digestive difficulties.

Treatment aims to prolong life by stopping or slowing cancer progression. This allows the patient to receive treatment for longer and spend more time with their family.

Systemic treatment is assessed with tests performed at regular intervals to monitor whether the treatment is working. This allows the treatment plan to be changed when needed.

Systemic treatments may have some side effects, but these are generally temporary and treatable. It is important to remain in contact with your doctor to learn about side effects and how to manage them.

The treatment plan and drug selection are personalized according to factors such as the patient's overall health, tumor characteristics, and response to treatment. During treatment, your doctor can monitor the course of the disease and update the plan as needed.

Systemic treatment is an important treatment option for patients with metastatic rectal cancer who are unsuitable for surgery. Treatment can help control cancer, relieve symptoms, and prolong life. Open communication with the patient and their family about treatment can help manage the treatment process and cope with possible side effects.

Sexual Problems Related to Surgery, Radiotherapy, and Chemotherapy in Rectal Cancer Patients

Treatment of rectal cancer

Includes various approaches such as surgery, radiotherapy, and chemotherapy. Although these treatments play an important role in controlling and treating the disease, they can cause side effects that affect patients' quality of life. Sexual dysfunction is frequently encountered after rectal cancer treatment and can adversely affect patients' quality of life.

Surgical Treatment and Sexual Problems

Surgical treatment for rectal cancer varies depending on the tumor's location and size. Operations that require removal of all or part of the rectum (for example, abdominoperineal resection or total mesorectal excision) can cause sexual dysfunction, particularly in men.

Erectile Dysfunction (ED)

During surgery, nerves and blood vessels in the pelvic region may be damaged. In men, this can lead to erectile dysfunction (difficulty achieving an erection). The likelihood of damage to nerves leading to the penis is higher, particularly with more invasive operations such as abdominoperineal resection.

Ejaculation Problems and Changes in Orgasm

Male patients may experience difficulties with ejaculation and reduced orgasmic sensation after surgery. Some men may experience less satisfaction during orgasm after rectal cancer surgery.

Sexual Dysfunction in Women

In women, adhesions that may develop between pelvic organs after removal of the rectum can cause pain during sexual intercourse (dyspareunia). In addition, postoperative pelvic nerve damage can lead to vaginal dryness and difficulties with orgasm.

Radiotherapy and Sexual Problems

Radiotherapy is frequently used for local control of rectal cancer. However, radiotherapy delivered to the pelvic region can cause sexual dysfunction in both men and women.

Radiotherapy in Men

Radiotherapy delivered to the pelvic region increases the risk of erectile dysfunction. Radiation can damage penile blood vessels and nerves, potentially causing loss of erections over time. In addition, problems such as pain during ejaculation and reduced ejaculate volume may occur after radiotherapy.

Radiotherapy in Women

In women, pelvic radiotherapy can cause vaginal dryness, vaginal narrowing (stenosis), and pain during sexual intercourse (dyspareunia). Fibrosis and loss of elasticity in vaginal tissues are among the main causes of these symptoms. Early menopause may also develop after radiotherapy, which can lead to loss of libido and vaginal atrophy.

Chemotherapy and Sexual Problems

Chemotherapy is another frequently used method in the treatment of rectal cancer. Its effects on sexual function are generally more systemic and may be observed similarly in both men and women.

Loss of Libido

A commonly reported side effect during chemotherapy is reduced sexual desire (libido). This can develop as a result of the physical and psychological side effects of treatment.

Fatigue and Reduced Energy

Fatigue after chemotherapy is another factor that can limit sexual activity. As physical energy declines, the desire for sexual activity may also decrease.

Hormonal Changes

Chemotherapy can affect hormone levels. Men may experience a decrease in testosterone levels, while women may experience fluctuations in estrogen levels. These hormonal changes can adversely affect sexual desire and performance.

Coping with Sexual Problems and Treatment Methods

A multidisciplinary approach is needed to address sexual problems that develop after rectal cancer treatment. Patients can receive support from sexual health specialists, psychologists, and physiotherapists. Various methods can be used to treat sexual dysfunction, including PDE5 inhibitors (for example, sildenafil), vaginal moisturizers, dilator therapy, and hormone replacement therapy. Pelvic floor physiotherapy may also be effective in reducing sexual problems.

Rectal cancer treatment plays an important role in cancer control through methods such as surgery, radiotherapy, and chemotherapy. However, these treatments can have various adverse effects on sexual function. It is therefore very important for patients to be informed about their sexual health before and after treatment and to receive specialist support when necessary. Patients must be informed about sexual problems before treatment, and the healthcare team should encourage them to share these problems with the team and work toward finding solutions.

Exercise and Nutrition in Patients with Early-stage and Metastatic Rectal Cancer

Rectal cancer is a disease that requires various treatment strategies. The effects of exercise and nutrition in patients with early-stage and metastatic rectal cancer are gaining increasing importance as part of treatment.

Physical Activity

In patients with early-stage rectal cancer, exercise can accelerate recovery after treatment, improve overall health, and enhance quality of life. Exercise can help preserve muscle mass and support cardiovascular health after surgery.

Types of Exercise

Aerobic and strength exercises such as walking, light jogging, swimming, and resistance training are recommended. At least 150 minutes of moderate-intensity exercise per week is advised.

A Balanced Diet

A balanced, nutrient-rich diet is important for patients with early-stage disease. Fiber-rich foods (vegetables, fruits, whole grains) support the digestive system and prevent problems such as constipation.

Protein and Calories

Adequate protein and calorie intake supports recovery and provides energy. Protein requirements may increase, particularly after surgery.

Nutritional Recommendations for Overweight or Obese Patients with Nonmetastatic Early-stage Rectal Cancer

Nutritional management is an important part of treatment for overweight and obese patients diagnosed with early-stage rectal cancer. Weight control and healthy eating are critically important both for improving treatment outcomes and for reducing the risk of cancer recurrence.

Reducing the Risk of Recurrence

An association has been found between body mass index (BMI) and cancer recurrence in overweight and obese patients. Research indicates that a high BMI may increase the risk of cancer recurrence and adversely affect treatment outcomes. For example, a study conducted in 2022 found a strong association between obesity and colorectal cancer recurrence.

Metabolic Health

Obesity is associated with metabolic problems such as insulin resistance and inflammation. These conditions can promote cancer cell growth and affect the response to treatment. Losing weight can improve metabolic health and reduce the risk of recurrence.

A Low-Calorie, Nutrient-Rich Diet

A healthy diet in patients with cancer supports weight control and can improve overall health. Fiber-rich, low-calorie foods (vegetables, fruits, whole grains) support the digestive system and may help with weight loss.

Anti-Inflammatory Foods

Foods with strong anti-inflammatory properties (olive oil, fish containing omega-3 fatty acids, green leafy vegetables) may reduce cancer-related inflammation and support treatment.

Calorie Restriction

Reducing daily calorie intake can help with weight loss. Calorie restriction is recommended as an appropriate strategy for overweight and obese patients. Reducing calories can help decrease fat mass and maintain a healthy weight.

Fiber and Protein

Fiber-rich foods support digestive health and provide a lasting feeling of fullness. Adequate protein intake preserves muscle mass and supports recovery.

Limiting Sugar and Processed Foods

Limiting sugar and processed foods supports weight control and has positive effects on metabolic health. Processed foods are generally high in calories and low in nutritional value.

Regular Exercise

Exercise supports weight loss and improves metabolism. Performing at least 150 minutes of moderate-intensity exercise per week can support weight control and improve overall health.

Weight control and healthy eating are critically important during treatment for overweight and obese patients with early-stage rectal cancer. Losing weight and following a healthy diet can reduce the risk of cancer recurrence, improve treatment outcomes, and support overall health. Nutrition plans should be personalized and supported by the treatment team.

Exercise and Nutrition in Patients with Metastatic Rectal Cancer

Benefits of Exercise

In patients with metastatic rectal cancer, exercise can improve physical function, reduce fatigue, and help manage treatment side effects. Exercise can also have positive effects on psychological well-being. Exercise programs for patients with metastatic disease should be personalized. Low-impact exercises, such as gentle walking and stretching, are generally recommended. Exercises should be adapted to the patient's overall condition and treatment side effects.

Specific Nutritional Needs

Nutritional strategies for patients with metastatic disease should generally be adjusted according to treatment-related side effects and the course of the disease. For example, side effects such as loss of appetite, nausea, or diarrhea can affect the nutrition plan.

High-Calorie, High-Protein Foods

High-calorie, high-protein foods are recommended for patients with metastatic disease to prevent weight loss and address nutritional deficiencies. Eating frequent small portions and using liquid nutritional supplements may be helpful.

Studies have demonstrated the positive effects of exercise in patients with cancer. For example, a meta-analysis published in 2021 showed that exercise improved quality of life and reduced treatment-related side effects in patients undergoing cancer treatment. Exercise was found to be effective in reducing cancer-related fatigue and improving overall physical performance.

Research on nutrition indicates that high-protein, high-calorie diets, in particular, can support recovery in patients with cancer. A study in 2022 found that nutritional interventions improved overall health and positively affected treatment outcomes in patients with early-stage and metastatic cancer.

Exercise and nutrition are important parts of treatment for patients with early-stage and metastatic rectal cancer. Exercise has positive effects on physical and psychological well-being, while appropriate nutrition can support the course of the disease and help manage treatment side effects. Both strategies should be personalized and regularly evaluated by the treatment team.

Vitamins and Supplements in Colorectal Cancer

In the treatment of colorectal cancer, nutrition and vitamin supplements can support patients' overall health and contribute to treatment. In particular, it is important to understand whether certain vitamins and supplements have a role in cancer treatment and prevention.

The Role of Vitamin D: Vitamin D may reduce cancer risk by supporting immune system functions and regulating cell growth. Studies of colorectal cancer have found an association between low vitamin D levels and a higher risk of cancer. Studies indicate that adequate vitamin D levels may reduce the risk of colorectal cancer and improve patients' prognosis.

The Role of Folic Acid

Folic acid plays an important role in DNA synthesis and cell repair. It may be effective in reducing the risk of colorectal cancer. However, high doses of folic acid may carry certain risks, and caution is advised.

The Roles of Vitamins C and E

Vitamins C and E have antioxidant properties and protect cells from the harmful effects of free radicals. However, findings on the effects of vitamins C and E in the treatment of colorectal cancer are conflicting. Further research is needed on the effects of high doses of these vitamins on treatment.

The Role of Omega-3 Fatty Acids

Omega-3 fatty acids may reduce cancer risk through their anti-inflammatory properties and may be beneficial during treatment. Omega-3 supplements may support overall health by reducing inflammation in patients with colorectal cancer, but their benefit has not been clearly demonstrated in studies.

Vitamins and supplements in the treatment of colorectal cancer may support patients' overall health and contribute to treatment. Vitamin D, in particular, has the potential to reduce cancer risk and provide beneficial effects during treatment. More research is needed on the effects of other vitamins and supplements. Patients should discuss their use of vitamins and supplements with their doctors and follow personalized advice.

Ways to Reduce Rectal Cancer Risk

• Follow a healthy diet rich in plant-based foods. Limit red meat and processed foods. Obtain your nutrients from real foods rather than relying solely on supplements.
• Drink very little alcohol or none at all.
• Move more and rest less.
• Maintain a healthy weight. Tracking your weight, diet, calories, and activity levels can help you achieve your goals.
• Stop using tobacco. Ask your care team about options for quitting. Counseling and medications are generally available options.
• Obtain vitamin D from foods such as salmon, tuna, mackerel, and egg yolks. Your skin can also produce vitamin D when exposed to sunlight, but remember to use sunscreen when spending extended periods outdoors.

Importance of Psychological Support and Quality of Life in Rectal Cancer

A diagnosis of rectal cancer creates a considerable emotional burden for patients and their loved ones. This process is not limited to physical treatment; its psychological and social aspects must also be addressed. The physical challenges experienced during treatment highlight the importance of psychological support and strategies to improve quality of life.

The Need for Psychological Support

A cancer diagnosis can cause intense anxiety, fear, depression, and feelings of helplessness in patients. Patients with rectal cancer may face circumstances that substantially affect quality of life, such as an ostomy, particularly as a result of surgery. These physical consequences can profoundly affect patients' psychological state and increase the risk of social isolation.

Patients need psychological support immediately after diagnosis. Psychosocial support helps individuals cope with the disease and adhere to treatment. Psychotherapy can reduce patients' anxiety and depression, strengthen their mental health, and help them maintain a more positive attitude during treatment. Providing psychological support early helps patients navigate this challenging process more comfortably.

Maintaining Quality of Life

Rectal cancer treatment may involve intensive methods such as surgery, chemotherapy, and radiotherapy. These treatments are emotionally as well as physically challenging and can adversely affect patients' quality of life. Outcomes such as having an ostomy after surgery can negatively affect patients' body image and self-confidence. This may lead to social withdrawal, isolation, and depression.

A multidisciplinary approach is needed to maintain quality of life. Alongside physical rehabilitation and social support networks, psychological support plays an important role in improving patients' quality of life. Physical rehabilitation programs and support groups contribute to patients' recovery both physically and emotionally.

Support from Family and Loved Ones

Cancer deeply affects not only the patient but also their family and loved ones. Physical and emotional support from families is very important for adherence to treatment. Family-based psychological support can help the patient cope with feelings of loneliness and helplessness. Family members' use of psychological counseling services during this process will positively contribute to the patient's recovery.

Psychological Adjustment to Treatment

One of the most important roles of psychological support is helping patients adhere to treatment. Approaching treatment with a more positive outlook may also positively affect patients' response to treatment. Mental health professionals help patients with cancer manage their stress and anxiety using various techniques, including psychotherapy, relaxation exercises, and cognitive behavioral therapy.

Palliative Care and Psychological Support

Palliative care aimed at improving quality of life is very important for patients with advanced cancer. Palliative care aims not only to relieve pain and other physical symptoms but also to support the patient's emotional and mental health. Psychological support is an integral part of palliative care. Psychosocial support is a substantial help to the patient and their family in coping with the disease.