Colon and Rectum Carcinoma

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  • VIDEO
  • CONTENT
  • QUIZ
  • MATERIALS
  • Introduction
  • Epidemiology
  • Prevention
  • Screening
  • HNPCC
  • FAP
  • Etiology
  • Pathogenesis
  • Signs and Symptoms
  • Diagnosis
  • Staging
  • Treatment
  • pT1
  • Surgery
  • Adjuvant Chemotherapy
  • Perioperative Therapy
    for Rectal Cancer
  • Special Situations
  • mCRC
  • Metastasis and
    Palliative Situations
  • ICD
  • Research

Introduction to Colorectal Cancer

Definition

  • Nature of the Disease: Colorectal cancer, encompassing both colon and rectal cancer, involves uncontrolled cell growth in the colon or rectum.
  • Location: The colon, the first and longest part of the large intestine, and the rectum, where stool is stored, are the primary sites.
  • Development: Most colorectal cancers start as polyps on the inner lining of the colon or rectum. Some of these polyps may evolve into cancer over time.
  • Importance of Screening: Early detection through screening can identify and remove polyps before they become cancerous and is crucial for effective treatment.

Demographics and Onset

  • Age Factor: Typically affects older adults but can occur at any age.
  • Polyps as Precursors: Begins as small clumps of cells called polyps in the colon. Most polyps are non-cancerous, but some may develop into cancer.
  • Asymptomatic Nature: Polyps usually don’t cause symptoms, making regular screening vital for early detection and prevention of colon cancer.

Types of Polyps and Cancer

  • Polyp to Cancer Transformation: The likelihood of a polyp becoming cancerous varies based on its type.
  • Common Cancer Type: Most colorectal cancers are adenocarcinomas, starting in cells that produce mucus for lubricating the colon and rectum lining.
  • Other Tumor Types: Less common tumor types can also originate in the colon and rectum.

Risk Factors and Symptoms

  • Risk Factors: Includes age, personal history of colorectal polyps or inflammatory bowel disease, family history of colorectal cancer, and certain genetic syndromes.
  • Symptoms: May include changes in bowel habits, rectal bleeding, blood in the stool, abdominal discomfort, unexplained weight loss, and fatigue.

Colorectal Cancer: Epidemiology

  • Definition and Prevalence
    • Colorectal cancer includes both colon and rectal cancers.
    • It is the third most common cancer globally and the second leading cause of cancer-related deaths.
  • Statistics in the United States
    • Ranked as the third leading cause of cancer-related deaths for both men and women.
    • Estimated new cases in 2023: 106,970 (colon cancer) and 46,050 (rectal cancer).
    • Lifetime risk: approximately 1 in 23 for men and 1 in 26 for women.

Trends and Changes in Incidence

  • Overall Decline Since the 1980s
    • Decreasing incidence rates due to improved screening and lifestyle changes.
  • Increase Among Younger Population
    • Incidence rates increasing by 1% to 2% per year in people under 50 since the mid-1990s.
  • Global Perspective
    • In 2020, over 1.9 million new cases worldwide.
    • Highest rates observed in Hungary and Slovakia.

Risk Factors for Colorectal Cancer

  • Age
    • Most cases occur in individuals over 50 years old.
  • Genetic Factors
    • Family history of colorectal cancer or polyps.
    • Genetic syndromes like Lynch syndrome and familial adenomatous polyposis (FAP).
  • Lifestyle Factors
    • Lack of physical activity, unhealthy diet, obesity.
    • Smoking and excessive alcohol consumption.

Prevention and Screening

  • Importance of Regular Screenings
    • Key to early detection and prevention.
  • Healthy Lifestyle
    • Regular exercise, balanced diet, maintaining a healthy weight.
    • Avoidance of smoking and limiting alcohol consumption.

Prevention of colorectal cancer in the asymptomatic population

Lifestyle

  • Physical activity: Regular physical activity to reduce the risk of colorectal cancer (CRC).
  • Weight management: Weight loss in overweight people to reduce the risk of CRC.
  • Stopping smoking: Active promotion of non-smoking in the population.

Diet

  • Healthy diet: Characterized by high consumption of fruits and vegetables and reduced intake of red and processed meat. This diet is associated with a reduced risk of CRC.
  • Unhealthy diet: High consumption of red and processed meat, potatoes, and refined starch is associated with an increased risk of CRC.
  • Fiber intake: Daily intake of about 30 g of fiber is recommended to reduce the risk.
  • Alcohol consumption: Limiting alcohol consumption to reduce the risk of CRC.
  • Red and processed meat: High consumption is associated with an increased risk of CRC.
  • Coffee and tea consumption: No proven association with reduced risk of CRC, so no specific recommendation.
  • Fruits and vegetables: Recommendation of 5 portions per day, despite inconclusive data on CRC prevention.
  • Food preparation and components
  • Food preparation and fats: No proven association with CRC risk.
  • Acrylamide intake: No association with CRC risk has been found.

Medication

  • COX-2 inhibitors: Not recommended for the prevention of CRC in the asymptomatic population.
  • Statins: Should not be used for primary prevention of CRC.
  • Acetylsalicylic acid (aspirin): A daily dose of 300 mg or more over 5 years can reduce the risk of CRC after a latency of 10 years (based on a meta-analysis of two large studies).**

Summary

The following lifestyle and dietary changes are recommended to reduce the risk of colorectal cancer:

  • Regular physical activity
  • Weight management in overweight people
  • Stopping smoking
  • Healthy diet, characterized by high consumption of fruits and vegetables and reduced intake of red and processed meat
  • Daily intake of about 30 g of fiber
  • Limiting alcohol consumption

The following medications may also be effective in reducing the risk of colorectal cancer:

  • Aspirin (300 mg or more per day)

Colorectal Cancer Screening and Early Detection in Asymptomatic Population

Age Guidelines for Screening/Early Detection

  • Start Age: Screening for colorectal cancer in the asymptomatic population is recommended from the age of 50.
  • Upper Age Limit: No fixed upper age limit is set due to increasing life expectancy; decisions should be individualized based on health status.

Screening Methods

  • Distinction of Methods: Between those primarily detecting carcinomas (FOBT, genetic stool tests, M2-PK) and those capable of additionally detecting adenomas (colonoscopy, sigmoidoscopy, CT colonography, capsule endoscopy).
  • Methods:
    • Colonoscopy (Gold standard with highest sensitivity and specificity)
    • Sigmoidoscopy
    • FOBT (Fecal Occult Blood Test)
    • Genetic and other stool tests
    • CT Colonography
    • Capsule Endoscopy

Endoscopic Methods

  • Colonoscopy: Offers the highest sensitivity and specificity for early detection of colorectal neoplasms.
  • Sigmoidoscopy: Recommended for individuals refusing colonoscopy; quality-assured sigmoidoscopy should be combined with annual FOBT for detecting proximal carcinomas.
  • Capsule Colonoscopy: Not recommended for screening/early detection in the asymptomatic population.

Fecal Occult Blood Test (FOBT)

  • Administration: Annually for individuals with average colorectal cancer risk who do not prefer colonoscopy.
  • Positive Result: Necessitates a complete endoscopic examination of the colon.
  • Effectiveness: Annual FOBT is more effective than biennial testing in reducing mortality due to colorectal cancer.
  • With Colonoscopy Participation: FOBT and other measures become unnecessary.

Stool Tests

  • DNA Changes: Not recommended for colorectal cancer screening in the asymptomatic population.
  • M2-PK Stool Test: Not recommended for screening/early detection.

Imaging Methods

  • CT and MR Colonography: Not recommended for screening/early detection, except in cases of incomplete colonoscopy with a continued desire for complete colon evaluation.

Cost-Effectiveness

  • Both FOBT and Sigmoidoscopy, Colonoscopy, and the Combination of Sigmoidoscopy and FOBT: Considered cost-effective compared to screening/early detection methods for other diseases.

Summary

Early detection and screening of colorectal cancer in the asymptomatic population starting at age 50 are crucial. Colonoscopy remains the gold standard, while alternative methods such as sigmoidoscopy and FOBT also play significant roles. The choice of appropriate method should be based on individual assessment, considering the advantages and limitations of each option.

Hereditary Non-Polyposis Colorectal Cancer (HNPCC)/Lynch Syndrome

Overview

  • Monogenetic Colorectal Cancers: These are rare, accounting for less than 5% of all colorectal cancers.
  • Risk Group: Includes individuals from families meeting Amsterdam criteria or Bethesda criteria with Microsatellite Instability (MSI) and relatives potentially carrying mutations.
  • Amsterdam Criteria (AC1 and AC2):
    • At least three family members with HNPCC-associated carcinomas (colon/rectum, endometrium, small intestine, urothelium of ureter/kidney pelvis)
    • At least two successive generations affected
    • One family member is a first-degree relative of the other two
    • One member diagnosed before age 50
    • Exclusion of familial adenomatous polyposis
  • Revised Bethesda Criteria:
    • Colorectal cancer (CRC) diagnosed before 50 years of age
    • Synchronous or metachronous colorectal or other HNPCC-associated tumors at any age
    • CRC with MSI-H histology diagnosed before 60 years
    • CRC patient with a first-degree relative diagnosed with CRC or HNPCC-associated tumor before 50
    • CRC patient with at least two relatives diagnosed with CRC or HNPCC-associated tumor at any age

Genetic Aspects

  • Pathogenic Germline Mutation Carriers: Identified as Lynch Syndrome individuals.
  • Mutation Risks: High risk of developing colorectal (50-70%) or endometrial cancer (20-60%).
  • Lifetime Risk for HNPCC Mutation Carriers: 80-90% chance of developing at least one HNPCC-associated carcinoma, with CRC being the most common.
  • Age of Onset: Average age of CRC onset in HNPCC is around 44 years. Rare before 25 years.
  • Lifetime Risk for Specific Cancers:
    • Endometrial cancer: 40-60% risk for female carriers
    • Small intestine cancer: 4-8% cumulative risk
    • Biliary tumors: Increased but overall low risk
    • Pancreatic cancer: Rare but more frequent than in general population
    • Brain tumors (mainly astrocytomas and glioblastomas): Slightly increased risk

Screening and Diagnostic Procedures

  • Molecular Pathology Testing: Recommended for anyone meeting at least one revised Bethesda criterion, using immunohistochemical expression of DNA mismatch repair proteins or MSI testing.
  • MSI: Found in about 80% of tumors from patients meeting Amsterdam I/II criteria.
  • BRAF Mutation Analysis: Conducted for MLH1 protein loss in MSI-high tumors to exclude HNPCC.
    • BRAF mutation analysis is an essential diagnostic tool in colorectal cancer, especially for tumors with high MSI and loss of MLH1 protein.
    • This analysis helps in differentiating sporadic CRCs, which commonly exhibit the BRAF mutation, from HNPCC-associated CRCs, which do not.
  • Differentiating HNPCC from Sporadic CRC: HNPCC-associated CRCs do not exhibit BRAF mutations.

Recommendations for HNPCC Risk Individuals

  • Genetic Counseling: Suggested from the age of consent (usually 18), especially before 25 years.
  • Colorectal Screening: Annual colonoscopy starting at age 25.
  • For Female Carriers:
    • Transvaginal ultrasound for endometrial and ovarian cancer from age 25.
    • Endometrial biopsy annually from age 35.
  • Upper Gastrointestinal Endoscopy: Regularly from age 35.
  • Prophylactic Surgery: Not generally recommended but can be discussed individually.
  • Postoperative Surveillance: Continuation of preoperative colonoscopic surveillance pattern.

Prophylactic Surgery Discussions

  • Hysterectomy and Oophorectomy: Should be discussed with women at age 40 or five years before the earliest age of onset in the family.

Familial Adenomatous Polyposis (FAP) and Its Variants

Classic (Typical) FAP

  • Characterization: Presence of more than 100 colorectal adenomas.
  • Onset: Usually begins in the second decade of life.
  • Cancer Risk: Nearly 100% due to the multitude of adenomas.
  • Extracolonic Manifestations
    • Duodenal/Papillary Adenomas: Occur in about 75% of patients, considered precancerous.
    • Gastric Adenomas: Less common, incidence <10%.
    • Other Manifestations: Include abdominal and extra-abdominal desmoid tumors, thyroid cancers, CNS tumors (mostly medulloblastomas), hepatoblastomas, osteomas, epidermoid cysts, and retinal pigment anomalies.

Attenuated FAP (AFAP)

  • Distinction: Different from classic FAP, characterized by fewer than 100 adenomas and/or later onset.
  • Cancer Risk: Still very high, with polyps and cancers often developing later and frequently in the proximal colon.

MUTYH-Associated Polyposis (MAP)

  • Phenotype: Typically resembles AFAP with a very high lifetime risk of colorectal cancer.
  • Genetic Pattern: Autosomal recessive inheritance; hence low disease risk for children of a patient and heterozygous carriers.
  • Diagnosis: Primarily through molecular genetic testing.

Screening and Management for FAP and Variants

  • Family Members at Risk: Should undergo predictive genetic testing from age 10, following genetic counseling, if the family’s specific APC mutation is known.
  • Exclusion of Mutation: Regular cancer screening is not needed if the family’s identified mutation is ruled out in relatives.
  • Confirmed or Undetermined Mutation Carriers: Annual rectosigmoidoscopy from age 10; colonoscopy upon adenoma detection, repeated annually until proctocolectomy.
  • Prophylactic Surgery: Recommended for patients with classic FAP, preferably after puberty.

Surveillance Post-Surgery

  • Pouchoscopy: Regularly after proctocolectomy.
  • Rectal Stump: Regular rectoscopy in patients with retained rectum.
  • Upper Gastrointestinal Endoscopy: Starting between ages 25-30, repeated every three years or more frequently based on adenoma severity.

Desmoid Tumors Management

  • First-Line Therapy: Combination of Sulindac and Tamoxifen.
  • Advanced Cases: Consider chemotherapy, surgery, or radiation therapy.

Thyroid Surveillance

  • Annual Ultrasound: For female FAP patients from age 15.

Attenuated FAP Management

  • Depends on Age, Polyp Count, Histology: Consider colectomy for unmanageable polyposis. Annual colonoscopy for non-colectomized patients.

Hamartomatous Polyposis Syndromes

  • Includes: Peutz-Jeghers Syndrome, Familial Juvenile Polyposis, Cowden Syndrome, Hyperplastic Polyposis Syndrome, Hereditary Mixed Polyposis.
  • Rarity: Very rare, contributing to less than 0.1% of all CRCs.
  • Increased Risk: Both colorectal cancers and syndrome-specific intestinal and extraintestinal tumors.

Peutz-Jeghers Syndrome (PJS)

  • Overview
    • Inheritance: Autosomal dominant.
    • Characteristics: Presence of hamartomatous polyps in the gastrointestinal tract and mucocutaneous melanin pigmentations, especially noticeable periorally.
    • Genetic Mutation: Caused by mutations in the STK11/LKB1 gene.
  • Manifestations and Risks
    • Polyps Location: Predominantly found in the small intestine.
    • Complications in Childhood: Include acute abdomen due to intussusception, obstructive ileus, and chronic bleeding leading to anemia.
    • Cancer Risks: Significantly increased risk for intestinal and extraintestinal tumors, including colorectal, breast, gastric, small intestine, pancreatic, testicular, ovarian, and uterine cancers.
    • Lifetime Cancer Risk: Estimated at approximately 85-90%.
    • Gynecological Tumors: Elevated risk, with ovarian tumors often being SCTAT and non-epithelial, and cervical cancers predominantly adenoma malignum.

Familial Juvenile Polyposis (FJP)

  • Diagnosis Criteria: Five or more juvenile polyps in the colon, extracolonic juvenile polyps, or a juvenile polyp with positive family history.
  • Complications: Chronic gastrointestinal bleeding or exudative enteropathy with developmental delays in early childhood.
  • Genetic Mutation: Mutations in SMAD4 or BMPR1A genes.
  • Colorectal Cancer Risk: Up to 68%.
  • Management and Surveillance
    • Endoscopic and Histological Differentiation: Challenging due to similarities with hyperplastic polyps, lymphocytic infiltrates, and dysplastic components.
    • SMAD4 Mutation Carriers: Higher risk for stomach polyps and cancer, hereditary hemorrhagic telangiectasia (Morbus Osler-Rendu-Weber), and potentially pancreatic cancers.
    • Severe Early-Onset Cases: Consider juvenile polyposis of infancy.
    • Cowden Syndrome Differentiation: Based on predominant extraintestinal tumor spectrum and molecular genetics.

Cowden Syndrome (PTEN Hamartoma Tumor Syndrome)

  • Increased Risks: Particularly for breast and thyroid cancers. Recent data suggest elevated colorectal cancer risk (9% lifetime risk).
  • PTEN Mutation Association: Both Cowden Syndrome and Bannayan-Riley-Ruvalcaba Syndrome are associated with PTEN gene mutations.

Hereditary Mixed Polyposis (HMPS) and Hyperplastic Polyposis Syndrome (HPS)

  • Definition and Genetics: Poorly defined entities with limited understanding of genetic bases.
  • Cancer Risks: Associated with significantly increased colorectal cancer risk but clinical and genetic characteristics are not well characterized.
  • Treatment: Cases with identified PTEN or BMPR1A mutations should be considered atypical variants of Cowden Syndrome or FJP and managed accordingly.

Summary

FAP and its variants, including AFAP and MAP, present high risks for colorectal and other cancers, necessitating early genetic testing, regular screening, and proactive management. Surgical interventions and continuous surveillance play key roles in reducing cancer risk for these patients. The approach is tailored based on the specific type of polyposis and genetic findings.

Etiology of Colon Cancer: A Multifactorial Perspective

Genetic Factors

  • Significant Role in Colon Cancer Development: Genetic predispositions account for about 5% to 10% of colon cancers.
  • Hereditary Syndromes:
    • Lynch Syndrome (HNPCC): Most common inherited syndrome linked with colon cancer.
    • Familial Adenomatous Polyposis (FAP): Another key inherited syndrome.
    • MUTYH-Associated Polyposis (MAP): Less common inherited condition.
    • Hamartomatous Polyposis Conditions: Rare but notable genetic syndromes.

Environmental and Lifestyle Factors

  • Older Age: Majority of colon cancer cases occur in individuals over 50.
  • Lifestyle-Related Risks:
    • Sedentary lifestyle.
    • Overweight or obesity.
    • Heavy alcohol consumption.
    • Smoking.
  • Dietary Factors:
    • High intake of red and processed meats.
    • Low consumption of fruits, vegetables, and fiber.

Risk Factors and Screening Recommendations

Ulcerative Colitis and Colonic Neoplasia

  • Association with Colonic Neoplasia: Chronic ulcerative colitis (UC) is closely linked to colonic neoplasia. Risk factors include the extent, duration, and activity of the disease.
  • Risk Increase:
    • Pancolitis: 5-15 times higher risk than the general population.
    • Left-Side Colitis: Approximately threefold increased risk.
    • Proctitis/Proctosigmoiditis: No significant increase in risk.
  • Cancer Incidence Rate: Roughly 0.5% per year for 10-20 years duration, increasing to 1% per year thereafter.
  • Co-Occurrence with Primary Sclerosing Cholangitis: Significantly greater risk.
  • Pseudopolyps and Strictures: Potential independent risk factors.

Crohn’s Disease

  • Relative Risk of Colon Malignancy: Similar to extensive UC, especially in cases of pancolitis, though data are less consistent.

Abdominal Radiation and Gastrointestinal Neoplasms

  • Increased Risk in Adult Survivors of Childhood Malignancy: Particularly colorectal cancer post-abdominal radiation.
  • Screening Recommendation: Colonoscopy every five years for survivors who received 30 Gy or more, starting 10 years after radiation or at age 35.
  • Prostate Cancer Radiation Therapy: Associated with increased risk of rectal cancer.

Screening Recommendations Influenced by Race/Ethnicity and Gender

  • African Americans: Highest CRC rates in the US; earlier onset and higher frequency under age 50. Recommended to start CRC screening at age 45.
  • Gender Differences: Higher CRC mortality in men and more proximal distribution in women; no major guidelines currently recommend gender-stratified screening.

Other Factors

  • Acromegaly: Increased frequency of colonic adenomas and CRC, especially uncontrolled disease. Colonoscopy recommended at diagnosis.
  • Renal Transplantation: Linked with increased CRC risk; screening often starts at age 40 or five years post-transplant.
  • Diabetes Mellitus and Insulin Resistance: Associated with elevated CRC risk, but not influencing surveillance recommendations.
  • Androgen Deprivation Therapy: Suggests a possible increased CRC risk in long-term users.
  • Cholecystectomy: Associated with a slight increase in right-sided colon cancer risk.
  • Alcohol Consumption: Increased CRC risk, especially in moderate and heavy drinkers.
  • Obesity: Higher CRC risk and mortality, especially in men.
  • Other Risks: Include coronary heart disease, cigarette smoking, ureterocolic anastomoses, red meat consumption, and certain infections like H. pylori and Streptococcus bovis.
  • HIV-Positive Patients: Some reports suggest increased colorectal neoplasia incidence.
  • Prior Hodgkin Lymphoma Treatment: Associated with increased CRC risk.

Pathogenesis of Colon Cancer

Genetic and Epigenetic Changes

  • Adenoma-Carcinoma Sequence: A critical pathway in the development of colorectal cancer.
  • Key Genes Involved:
    • APC: Mutation leads to early adenoma formation.
    • TP53: Alterations contribute to the transition from adenoma to carcinoma.
    • KRAS: Mutations promote uncontrolled cell proliferation.
    • PI3KCA: Changes in this gene are involved in tumor growth and survival.
  • Impact on Cellular Regulation:
    • Tumor Suppressor Genes: Inactivation leads to loss of cell cycle control.
    • Oncogenes: Activation encourages uncontrolled cellular division and tumor development.

Environmental and Lifestyle Factors

  • Colonic Microbiome: Plays a role in the metabolism of dietary and environmental compounds.
  • Metabolites:
    • Carcinogenic Properties: Some metabolites can initiate or promote cancer development.
    • Tumor-Suppressive Properties: Others may have a protective effect against cancer formation.
  • Chronic Inflammatory Bowel Diseases:
    • Crohn’s Disease and Ulcerative Colitis: Increased risk of colon cancer due to chronic inflammation.

Sign and Symptoms

  • Onset: Patients often report a slow, insidious start with paradoxical diarrhea (alternating between diarrhea and constipation), bloating, more frequent bowel movements, blood in the stool (usually bright red for tumors in the sigmoid or rectum), mucus in the stool, pencil-thin stools, and nonspecific abdominal pain, especially when the tumor is located in the left hemicolon.
  • Pain: While pain is usually nonspecific, colicky pain may indicate impending obstruction, and constant pain may suggest local tumor spread with abdominal wall or surrounding organ infiltration. Occasional back pain may occur with retroperitoneal growth, as sometimes seen with tumors of the ascending colon.
  • Bleeding: Rectal bleeding can be either occult or apparent. The more proximal the tumor, the more altered and hidden the blood, often escaping the patient’s notice.
  • Weight Loss: An unspecific tumor symptom that is relatively rare in colon tumors. Substantial weight loss may suggest metastasis. In slim patients, the colon tumor might sometimes be palpable, especially if located in the intraperitoneal sections of the intestine and possibly infiltrating the abdominal wall.
  • Emergency Presentation: Colon cancer rarely presents as an emergency requiring treatment for complete luminal obstruction (clinical and radiological signs of large bowel ileus with typically empty rectal ampulla), bowel perforation, or circulatory-relevant hemorrhage.
  • Metastatic Disease
    • 20% of US patients present with distant metastasis.
    • Common metastatic sites: lymph nodes, liver, lungs, peritoneum.
    • Symptoms referable to these areas, including right upper quadrant pain and early satiety.
  • General Symptoms: Anorexia, weight loss, general weakness, sometimes fever due to necrosis and local infections.
  • Changes in Bowel Habits
    • Persistent constipation, most common with sigmoid colon cancer.
    • Diarrhea in mucin-secreting tumors.
    • Dyschezia (painful bowel movements) and tenesmus (feeling of incomplete bowel evacuation) with rectal cancer.
  • Iron Deficiency Anemia
    • Resulting from chronic, usually occult blood loss.
  • Unusual Presentations
    • Malignant fistula formation
    • fever of unknown origin
    • Abscesses
    • Streptococcus bovis bacteremia
    • Clostridium septicum sepsis.

Typical Clinical Symptoms Depending on Tumor Location in Colon Cancer

Right-Sided Colon Cancer

  • Symptoms:
    • Anemia, fatigue, decreased stamina
    • Diarrhea
    • Palpable resistance in the abdomen
    • Pain in the right middle/lower abdomen
    • Appendicitis-like complaints
    • Postprandial colicky discomfort
    • Weight loss

Left-Sided Colon Cancer

  • Symptoms:
    • Alternating diarrhea and constipation
    • Mucus/blood in the stool
    • Pencil-thin stools
    • Pain in the left middle/lower abdomen
    • Weight loss

Synchronous Cancers

  • Defined as two or more primary tumors.
  • Occur in 3 to 5% of patients with colon cancer.
  • Same prognosis as solitary malignancies when compared at the highest stage.

Metachronous Cancers

  • New tumors developing at least six months post initial diagnosis.
  • Occur in 1.5 to 3% of patients within the first five years, increasing over time.

Frequency of Initial Symptoms

  • Abdominal pain: 44%
  • Change in bowel habits: 43%
  • Hematochezia or melena: 40%
  • Weakness: 20%
  • Anemia without other GI symptoms: 11%
  • Weight loss: 6%

Diagnosis of Colorectal Cancer (CRC)

Initial Suspicion

  • Symptoms and Signs: CRC may be indicated by the symptoms and signs discussed previously.
  • Asymptomatic Cases: May be discovered through routine screening in average and high-risk individuals.

Diagnostic Procedures

  • Clinical Examination: Includes palpation of the abdomen, assessment of bowel sounds, and always a rectal examination.
  • Rectal Examination:
    • The rectum can be examined up to 10 cm using digital palpation.
    • About 10% of colorectal cancers can be detected using DRE.
  • Colonoscopy:
    • Most accurate test for symptomatic individuals.
    • Can localize, biopsy, and remove polyps.
    • Detects synchronous neoplasms.
    • Most cancers are protruding masses, but flat or depressed lesions are also possible.
    • Difficulty in visualizing nonpolypoid adenomas.
  • Air Contrast Barium Enema (BE) and Flexible Sigmoidoscopy:
    • Sometimes used to evaluate symptoms.
    • Lower diagnostic yield compared to colonoscopy.
  • CT Colonography:
    • Used when colonoscopy is not feasible due to technical reasons.
    • Provides a radiographic diagnosis but cannot biopsy or remove polyps.
  • Emerging Technologies:
    • Capsule colonoscopy may play a future role.

Post-Diagnosis Protocol

  • Examination of the Entire Large Bowel:
    • Necessary to check for synchronous lesions if CRC is found.
    • If preoperative full colonoscopy is not possible due to obstruction, a complete examination should follow soon after resection.

Screening

  • Starting Age: Screening should begin at the age of 40 with the fecal occult blood test (Haemoccult test) and a rectal examination.
  • Colonoscopy: From the age of 50, colonoscopies are recommended at intervals of several years and are covered by health insurance providers.
  • Fecal DNA Tests
    • Newer Tests: ColoAlert® and Cologuard®.
      • Detect tumor DNA in stool.
      • Higher sensitivity for detecting colon cancers and precancers compared to fecal immunochemical tests (FIT) but have more false positives.
  • CEA (Carcinoembryonic Antigen)
    • Preoperative and postoperative monitoring marker.
    • Not recommended for screening due to low sensitivity/specificity.

Recommended Investigations for Colorectal Cancer

InvestigationColon Cancer (KolonCa)Rectal Cancer (RektumCa)
Complete ColonoscopyXX
CEA (Carcinoembryonic Antigen)XX
Abdominal UltrasonographyXX
Chest X-Ray (Rö-Thorax)XX
Rigid RectoscopyX
MR (CT) of Pelvis with Distance of Tumor to Mesorectal FasciaX
Rectal Endosonography for Locally Limited TumorX
StadiumPrimärtumorLymphknotenstatusFernmetastasen
0TisN0M0
IT1, T2N0M0
IIAT3N0M0
IIBT4aN0M0
IICT4bN0M0
IIIAT1 – 2N1 (1-3 betroffene LK)M0
T1N2a (4-6 betroffene LK)M0
IIIBT3 – 4N1 (1-3 betroffene LK)M0
T2-3N2a (4-6 betroffene LK)M0
T1-2N2b (≥ 7 betroffene LK)M0
IIICT4aN2a (4-6 betroffene LK)M0
T3-T4aN2b (≥ 7 betroffene LK)M0
T4bN1-2M0
IVAjedes Tjedes NM1a (Fernmetastasen in einem Organ oder einer Lokalisation ohne Peritonealbefall)
IVBjedes Tjedes NM1b (Fernmetastasen in zwei oder mehr Organen oder Lokalisationen ohne Peritonealbefall)
IVCjedes Tjedes NM1c (Peritonealbefall mit oder ohne Fernmetastasen in anderen Organen oder Lokalisationen)
Klassifikation der Tumorstadien (UICC)

Localized Stage Colorectal Cancer Treatment

Management of Stages I and II Localized Colon Carcinoma (T1–3, N0, M0)

Surgical Resection as Primary Treatment

  • Efficacy: The majority of patients with stages I and II colon cancer are potentially cured through surgical resection.
  • Stage I:
    • Low risk of local or distant recurrence post complete resection.
    • Adjuvant chemotherapy does not typically improve survival.
  • Stage II:
    • Up to 46% may die from colon cancer even after complete resection.
    • Adjuvant chemotherapy considered for selected patients, especially:
      • Younger patients.
      • Tumors with “high-risk” histologic features.

Controversy and Future Directions

  • Adjuvant Chemotherapy in Stage II:
    • Controversial data on survival benefit.
    • Current focus on improved staging and prognostic tumor markers to better select patients who may benefit from adjuvant therapy.
  • Micrometastases Detection:
    • Improved staging methods to detect micrometastases could refine treatment approaches.

Key Considerations

  • Individualized Approach: Treatment decisions, especially regarding adjuvant chemotherapy in stage II, should be based on individual patient and tumor characteristics.
  • Importance of Accurate Staging: Crucial for determining the necessity of adjuvant therapy post-surgery.
  • Future Research: Ongoing efforts to identify more sensitive prognostic markers and improve staging techniques are essential to optimize treatment strategies for localized colon carcinoma.

Colon Cancer: Stages I-III

  • Curative Approach: The primary objective is complete surgical removal of the tumor.
  • Lymph Node Removal: Mandatory removal of at least 12 local lymph nodes.
  • Adjuvant Chemotherapy:
    • Stage III: Always indicated.
    • Stage II: Considered for patients with increased risk of recurrence.
  • Recurrence Risk Factors: Include lymphovascular invasion, blood vessel invasion, perineural invasion, fewer than 12 lymph nodes examined, tumor perforation, and tumor obstruction.
  • Treatment Regimen:
    • Stage II: Six months of adjuvant chemotherapy with a fluoropyrimidine, commonly Capecitabine due to ease of oral administration.
    • Stage III: Chemotherapy with Capecitabine and Oxaliplatin is recommended, if the patient’s condition permits.
  • Duration of Adjuvant Chemotherapy in Stage III: Depends on recurrence risk determined by TNM status; can be three or six months.

Rectal Cancer: Localized Stage

  • Treatment Approach: Similar to colon cancer but varies slightly based on the stage.
  • Stage I: Surgical removal of the tumor is typically sufficient.
  • Stage II-III:
    • Preoperative radiation or combined chemoradiotherapy.
    • Reduces postoperative recurrence rates and improves overall survival.
    • Most effective for tumors in the lower third of the rectum.
  • Tumors in Upper Rectum:
    • Tumors above 12 cm from the anus are usually not treated with preoperative radio(chemo)therapy and are managed similarly to colon cancer.
  • Stage III Management of Stage III Colon Cancer: Lymph Node Metastasis (Tany, N1, M0) Risk and Treatment Necessity
    • Increased Recurrence Risk: Patients with lymph node involvement (stage III) have a higher risk of both local and distant recurrence.
    • Adjuvant Chemotherapy: Strongly recommended for these patients to reduce recurrence and improve survival.
    Chemotherapy Regimens
    • 5-Fluorouracil (5-FU)–Based Treatments:
      • Historically the backbone of adjuvant therapy in stage III.
      • Used in combination with levamisole or leucovorin.
      • Proven to reduce recurrences and enhance survival.
    • Newer Agents and Approaches:
      • Capecitabine: An oral prodrug of 5-FU.
      • Irinotecan: A topoisomerase inhibitor.
      • Oxaliplatin: A platinum-based chemotherapy.
      • Angiogenesis Inhibitors: Target the blood vessels supplying the tumor.
      • Immunotherapy: Shows promise, particularly in specific genetic profiles of colon cancer.
  • Stage IV Advanced Stage Colorectal Cancer Treatment Overview
    • Incidence: Approximately 20% of patients have metastasized disease (synchronous metastasis) at diagnosis, with others developing metastases (metachronous metastasis) within three years post-diagnosis.
    • Prognosis: Survival is generally limited in stage IV colon cancer due to distant metastasis.
    • Potential for Curative Resection: In highly selected patients with isolated, resectable metastases, surgery (metastasectomy) can offer survival benefits.
    Metastasis and Resection
    • Liver Metastasis:
      • Most common site of metastasis.
      • Approximately 15% of patients with systemic disease have liver-limited metastasis.
      • Around 20% of these cases are potentially resectable for cure.
      • 5-year survival improvement (20 to 40%) compared to non-resected patients.
      • Hepatic resection may be combined or staged.
    • Lung Metastasis:
      • Occurs in about 20% of patients.
      • Long-term survival benefit (30 to 40%) in the small subset that is resectable.
    • Other Sites:
      • Successful resections reported in limited cases (e.g., ovarian, retroperitoneal metastases).
    Palliative Management
    • Non-resectable Stage IV Disease: Focus on palliation rather than cure.
    • Primary Tumor Management Controversy:
      • Traditional approach: Resect primary tumor to prevent complications (obstruction, bleeding).
      • Potential drawbacks: Surgery may delay chemotherapy.
      • New perspective: Some oncologists suggest chemotherapy without primary tumor resection.
    • Palliative Methods:
      • Colonic stenting for obstructing left colon lesions.
      • Diverting stoma for obstruction.
    • Importance of Adjuvant Chemotherapy: Essential for all patients, irrespective of surgery.
    Potentially Curative Approach in Select Cases
    • Solitary/Resectable Metastases: Mainly lung or liver metastases can be approached with a potentially curative intent.
    Palliative Treatment Approach
    • Objective: To extend life while maintaining or improving quality of life.
    • Palliative Resection of Primary Tumor: Not mandatory in the absence of symptoms.
    • Complications Management: Surgical intervention should be considered in cases of perforation, obstruction, or bleeding.
    • Palliative Stenting for Obstruction: Evaluated to avoid more extensive surgery and associated risks.
    Palliative Chemotherapy
    • Factors Influencing Treatment: Patient’s overall condition, tumor biology, mutation status (RAS, BRAF), and microsatellite instability.
    • First-Line Therapy for Fit Patients: Combination of chemotherapy (5-FU, Oxaliplatin, and/or Irinotecan) with targeted therapy (monoclonal antibodies).
      • RAS Wildtype Tumors: Use of anti-EGFR antibodies (Cetuximab, Panitumumab).
      • RAS or BRAF Mutations, Right-Sided Colon Cancer: Use of anti-VEGF antibody (Bevacizumab), given limited efficacy of Cetuximab and Panitumumab in these scenarios.
    Immunotherapy in Metastatic Stage
    • Background: KEYNOTE-177 study showed benefit in progression-free survival with Pembrolizumab (an immune checkpoint inhibitor) compared to standard therapy for untreated metastatic colorectal cancer patients with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR).
    • Overall Survival Data: Presented at ASCO 2021, showing a trend favoring immunotherapy, but not statistically significant, partly due to patients in the chemotherapy arm receiving immunotherapy post-progression (cross-over).
    • First-Line Therapy: Immunotherapy is the definitive first-line therapy for patients with MSI-H/dMMR metastatic colorectal cancer.
    Treatment Options for Recurrent/Refractory Colorectal Cancer Second-Line Therapy After First-Line Failure
    • Treatment Selection: Based on treatment goals, tumor biology, and the patient’s performance status.
    • Options:
      • Antiangiogenic Agents: Ramucirumab and Aflibercept.
      • Multikinase Inhibitor: Regorafenib.
      • Fluoropyrimidine: TAS-102.
      • BRAF Mutation: Second-line therapy includes BRAF-targeted treatment.
    BRAF-Targeted Therapy
    • Historical Context: Historically, patients with BRAF mutations have significantly shorter survival compared to those with BRAF wild-type.
    • Development of BRAF Inhibitors: Prompted by the poor outcomes associated with BRAF mutations.
    • BEACON Study:
      • Demonstrated the superiority of BRAF-targeted therapy over standard therapy in previously treated patients.
      • Examined Encorafenib (a BRAF inhibitor) and Binimetinib (a MEK inhibitor) in combination with Cetuximab.
      • The triple combination of Encorafenib/Binimetinib/Cetuximab was tested, but the dual combination of Encorafenib/Cetuximab was found to be equally effective in improving overall survival with a more favorable side-effect profile.
      Local Ablative Procedures for Liver Metastases in Colorectal Cancer Radiofrequency Ablation (RFA)
      • Indications:
        • Non-resectable liver metastases.
        • Patients unfit for surgical resection, especially post prior liver resection.
      • Efficacy:
        • Recent studies suggest that RFA may yield comparable outcomes to resection for solitary liver metastases smaller than 3 cm.
      Selective Internal Radiation Therapy (SIRT)
      • Application:
        • Used for disseminated liver metastases in colorectal cancer (CRC).
      • Considerations:
        • Suitable for patients without other treatment options.
        • Recommended to be performed within clinical trials only.
      Laser-Induced Interstitial Thermotherapy (LITT)
      • Efficacy:
        • Case series have shown it to be a safe and effective treatment for patients with inoperable liver metastases from CRC.
      • Comparison with RFA:
        • Currently, no data are available comparing the efficiency of LITT with percutaneous radiofrequency ablation.
      Summary
      • Local ablative procedures, such as RFA, SIRT, and LITT, offer alternative treatment options for liver metastases in colorectal cancer, particularly when surgical resection is not feasible or suitable for the patient. These methods are continually being evaluated and refined, with current evidence supporting their use in specific circumstances, especially as part of clinical trials. The choice of technique depends on various factors, including the size and number of metastases, patient’s overall health, and treatment availability.

Management of pT1 carcinomas of the colon

Histological evaluation of endoscopically removed polyps

  • pT1 carcinoma and R0 resection:
    • Low-risk case: No oncological re-resection necessary.
    • High-risk case: Radical surgical treatment recommended despite complete removal.

Risk stratification of pT1 carcinomas

  • Determination of low- and high-risk groups: Based on the likelihood of lymph node metastasis.
  • Lymph node metastasis rate: Between 0-20% for the overall group of T1 carcinomas.
  • Prognostic criteria:
    • Grading (G1, G2, G3, G4): G1 and G2 are considered low-risk.
    • Invasion in lymph or blood vessels (L0 V0): Absence of invasions determines the low-risk category.
    • Tumor budding.
    • Submucosal invasion: Early invasive forms (sm1 ≤ 1000 µm) have a low N+ risk.

Treatment of pT1 carcinomas

  • Local R0 situation: Verification through timely endoscopic-biopsy control (2-6 months) required.
  • Full-thickness endoscopic resection (FTRD): Can be used in selected cases for low-risk tumors.
  • In case of uncertain resection margin: Surgical resection required.

Incomplete removal of a low-risk pT1 carcinoma

  • Treatment strategy: Complete endoscopic or local surgical removal.
  • In case of uncertainty or impossibility of R0 resection: Oncological surgical resection necessary.

Follow-up and risk of recurrence

  • Risk of recurrence after endoscopic therapy of low-risk T1 carcinomas: Approximately 3% recurrence rate in the form of local recurrences or distant metastases.
  • Endoscopic follow-up: Done after six months for complete R0 removal of low-risk carcinomas (pT1, G1, G2, L0).
  • Complete colonoscopy: Recommended after 3 years.

Intraoperative Management and Surgical Approach for Colon Cancer

Intraoperative Liver Inspection and Palpation

  • Routine Procedure: Should be performed in all cases, even with unremarkable preoperative staging.
  • Intraoperative Sonography: Not justified for searching additional metastases if preoperative diagnostics are sufficient.
  • Histological Confirmation: Necessary if imaging doesn’t clearly categorize unclear liver lesions.
    • Preferably via needle biopsy through healthy liver parenchyma.
    • Incisional biopsies should be strictly avoided.
    • For smaller lesions, complete excision as an excision biopsy may be considered.

Sentinel Node Biopsy

  • Not mentioned in the given text: The role and details of sentinel node biopsy in colon cancer surgery are not provided in the excerpt.

Radical Surgical Therapy for Colon Carcinoma

Lymph Node Dissection

  • Metastasis Pattern: Involves initially longitudinal spread to paracolic lymph nodes, then to intermediate nodes along radial arteries, and finally to central nodes.
  • Extent of Resection: Determined by the spread to central lymph nodes; paracolic metastasis rarely extends beyond 10 cm.

Surgical Approach Based on Tumor Location

  1. Cecum and Ascending Colon Carcinomas:
    • Metastasis via ileocolic artery and right colic artery.
    • Central transection of these vessels required.
    • Omentum majus resection only needed if in direct tumor contact.
  2. Right Flexure and Right Transverse Colon Carcinomas:
    • Extended right hemicolectomy: Ligation of ileocolic artery, right colic artery, and middle colic artery.
    • Distal resection limit at left transverse colon.
    • Lymphadenectomy over the pancreas head due to potential metastasis.
  3. Middle Transverse Colon Carcinomas:
    • Metastasis via middle colic artery towards superior mesenteric artery and left colic artery towards inferior mesenteric artery.
    • Transverse resection includes both flexures.
    • Omentum resection and dissection of the greater curvature of the stomach needed.
  4. Distal Transverse Colon and Left Flexure Carcinomas:
    • Metastasis to the right via middle colic artery and to the left via left colic artery.
    • Central transection of both arteries.
    • Ascendo-sigmoidostomy for continuity restoration.
    • Dissection of left-sided omentum and greater curvature of the stomach.
  5. Descending Colon Carcinomas:
    • Metastasis via left colic and sigmoid arteries.
    • Left hemicolectomy with central transection of the inferior mesenteric artery.
    • Distal resection limit in the upper rectum, proximal limit at left flexure.
  6. Sigmoid Colon Carcinomas:
    • Metastasis via sigmoid arteries to the inferior mesenteric artery trunk.
    • Proximal colon transection in descending colon, adhering to rectal cancer guidelines for distal resection.
    • At least 5 cm distal safety margin and mesorectum transection without coning required.
    Surgical Therapy for Colon Carcinoma: Complete Mesocolic Excision (CME) Concept of CME
    • Complete Mesocolic Excision: Analogous to Total Mesorectal Excision (TME) for rectal cancer, CME is a surgical technique applied in colon cancer surgeries.
    • Objective: Achieves maximum local radicality and lymph node harvest.
    • Technique: Involves dissection in predefined anatomical layers with central transection of supplying vessels.
    • Preservation of Mesocolic Layers: Special attention is given to maintaining the integrity of the two mesocolic layers (referred to as “fasciae”).
    Importance of CME in Colon Cancer Surgery
    • Maximizing Outcomes: CME aims to enhance surgical outcomes by ensuring complete removal of the tumor and associated lymphatic tissue.
    • Anatomical Precision: The technique demands precise anatomical dissection to achieve effective tumor removal while preserving important structures within the mesocolon.
    Radical Surgical Therapy for Rectal Carcinoma Key Principles of Curative Treatment
    • Objective: Resection of the primary tumor with partial or total mesorectum removal, including regional lymphatic drainage (radical resection).
    • Local Measures: In strictly selected cases, curative resection can be achieved through local procedures.
    Surgical Procedures
    • (Deep) Anterior Rectal Resection: Suitable based on tumor location, depth of infiltration, and sphincter function.
    • Abdominoperineal Rectal Excision: Indicated for tumors with specific relation to the dentate line and levator muscle.
    • Intersphincteric Rectal Resection: Requires special expertise; often called abdominoperineal rectal resection.
      • Note: Deep anterior resection may frequently involve intersphincteric preparation for adequate distal safety margin, but it differs from the abdominoperineal approach.
    Sphincter Preservation and Quality of Life
    • Preference for Continence-Preserving Procedures: Weighing expected postoperative quality of life.
    • Permanent Colostomy: Recommended for poor sphincter function, performed with or without rectal excision, depending on the safety margin from the pelvic floor.
    Oncological Principles
    • Lymphatic Drainage Removal: Involves transecting the inferior mesenteric artery at least distal to the left colic artery origin.
    • Central Ligation of Inferior Mesenteric Artery: Not prognostically significant but often done for left colon mobilization.
    • Complete Mesorectal Excision (TME):
      • Essential for middle and lower third rectal carcinomas.
      • Partial mesorectal excision for upper third.
    • Surgical Margins: Adherence to appropriate safety margins.
    • En-Bloc Resection: For tumor-adherent organs to prevent local tumor cell spread.
    • Nerve Preservation: Hypogastric nerves and hypogastric plexuses should be spared to maintain autonomic functions.
    Resection Techniques Based on Tumor Location
    • Upper Rectal Third: Partial mesorectal excision 5 cm distal to the tumor margin; horizontal transection without proximal thinning (no coning).
    • Middle and Lower Rectal Thirds: Total mesorectal excision (TME) to the pelvic floor, sparing the superior hypogastric plexus and hypogastric nerves.
    Tumor Grading and Safety Margin
    • Low-Grade Tumors: 1-2 cm safety margin is sufficient for well or moderately differentiated tumors in the lower third.
    • High-Grade Tumors (G3/4): A larger safety margin is recommended.
    After Neoadjuvant Radiochemotherapy
    • Reduced Tumor Mass: Crucial for sphincter preservation; decision on surgical procedure should be made post-therapy.
    • Complete Response: In rare cases, surgery can be omitted post-neoadjuvant therapy, provided the patient is informed and agrees to rigorous follow-up.
    Reconstruction after Total Mesorectal Excision
    • Options: Straight colo-anal anastomosis, colon J-pouch, transverse coloplasty, or side-to-end anastomosis.
    • Functionality: Colon J-pouch generally has the best functional outcome. Transverse coloplasty is inferior, while side-to-end anastomosis may be comparable to J-pouch.
    Abdominoperineal Rectal Excision
    • Indication: For low-lying tumors infiltrating the anal canal/sphincters where sphincter-saving surgery isn’t possible.
    • Technique: “Cylindrical” resection including levator ani muscle.
    Postoperative Considerations
    • Wound Healing: Primary plastic covering with a myocutaneous flap may reduce perineal wound complications.
    • Diversion Stoma: Temporary stoma should be considered for radical surgery with TME and deep anastomosis, using either colostomy or ileostomy.
    Local Surgical Tumor Excision
    • Indications: Suitable for pT1 carcinomas with a diameter up to 3 cm, good or moderate differentiation, and no lymphovascular invasion (Low-Risk Histology), ensuring complete removal (R0).
    • High-Risk T1 and T2 Carcinomas: Not recommended due to higher risk of lymph node metastases (10–20%).
    Laparoscopic versus Open Resection
    • Feasibility: Laparoscopic resection can be performed with similar oncological outcomes as open surgery, provided there’s appropriate expertise and patient selection.

Indications for Adjuvant Treatment in Colon Cancer

Prerequisites for Adjuvant Therapy

  • Complete Resection: R0 resection (no residual tumor) of the primary tumor is a prerequisite.
  • Pathohistological Staging: Particularly determining the pN status (lymph node involvement).
  • Lymph Node Examination: At least 12 regional lymph nodes should be examined for pN0 classification (UICC 2002).
  • Exclusion Criteria: Immunocytological findings of isolated tumor cells in bone marrow biopsies or lymph nodes, and cytological tumor cell findings in peritoneal lavage, do not indicate adjuvant therapy outside of clinical studies.

Indications Based on Cancer Stage

  • Stage I: Adjuvant therapy is not indicated.
  • Stage II and III: Patients should preferably be enrolled in controlled studies to gain insights into indications and optimal adjuvant therapy.
  • Non-Study Patients: For those treated outside clinical trials, documentation of recurrences, survival rates, and side effects is crucial.

Requirements for Adjuvant Chemotherapy

  • Expertise: Requires experience and knowledge of dose reduction schemes for managing toxicity.

Contraindications for Adjuvant Chemotherapy in Colon Cancer

  • General Condition: Poorer than 2 (ECOG).
  • Uncontrolled Infections.
  • Liver Cirrhosis: Child B and C.
  • Severe Coronary Heart Disease: Heart failure (NYHA III and IV).
  • Pre-Terminal or Terminal Renal Failure.
  • Compromised Bone Marrow Function.
  • Other Significant Comorbidities: Affecting life expectancy.
  • Inability to Participate in Regular Follow-Up.

Age Limitations for Adjuvant Chemotherapy

  • No Age-Based Exclusion: Adjuvant chemotherapy should not be omitted solely based on age.
  • Patients Over 75 Years: Insufficient evidence to support routine adjuvant chemotherapy.

Adjuvant Chemotherapy in Colon Cancer

Timing of Initiation

  • Postoperative Start: Adjuvant chemotherapy should begin as soon as possible after surgery.
  • Typical Timeline: In randomized studies, treatment started within 8 weeks postoperatively.
  • Impact of Delay: Starting adjuvant therapy later than 60 days post-surgery may lead to reduced overall survival.

UICC Stage III

  • Mandatory Chemotherapy: Patients with R0 resected stage III colon cancer should receive adjuvant chemotherapy.
  • Evidence of Benefit: Significant survival advantage demonstrated in numerous randomized studies.

UICC Stage II

  • Optional Chemotherapy: Can be considered for patients with curatively resected stage II colon cancer.
  • Benefit Assessment: The absolute benefit in 5-year survival lies between 2-5% without risk factors. No significant survival advantage observed in studies for stage II patients without adjuvant chemotherapy.

UICC Stage II with Risk Factors

  • Selected High-Risk Situations: T4 stage, tumor perforation/rupture, emergency surgery, insufficient lymph node examination.
  • Benefit of Chemotherapy: Mixed evidence. Some studies show no benefit, while others like the MOSAIC study indicate a non-significant improvement in 10-year disease-free survival with FOLFOX4 compared to 5FU/FS in high-risk populations.

Microsatellite Status Determination

  • Essential in Stage II: Microsatellite status should be assessed before deciding on adjuvant chemotherapy.
  • MSI-H Status: Adjuvant chemotherapy should not be performed in stage II patients with high microsatellite instability (MSI-H).
  • Other Parameters: CEA levels, differentiation grade, 18q loss, isolated tumor cells in lymph nodes or bone marrow, DNA ploidy, TS/p53 expression, lymphovascular invasion, and molecular genetic analyses should not be used to decide on adjuvant chemotherapy.

Summary

Adjuvant chemotherapy in colon cancer is recommended post-surgery, especially within 8 weeks, to improve survival outcomes. In stage III, chemotherapy is essential due to proven benefits. In stage II, its utility depends on the presence of risk factors, with mixed evidence regarding its benefit. The decision for adjuvant therapy in stage II should be informed by the microsatellite status, particularly avoiding chemotherapy in MSI-H cases. Other molecular and pathological parameters are not recommended for determining the need for adjuvant therapy.

Chemotherapy Protocols for Colon Cancer

Stage III Colon Cancer

  1. Oxaliplatin with 5-FU/Folinic Acid (FS)
    • Recommendation: Use Oxaliplatin-based therapy for adjuvant treatment.
    • Therapy Schemes:
      • FOLFOX4: Folinic Acid, 5-FU (bolus and infusion), with Oxaliplatin. 12 cycles, every 2 weeks.
      • Modified FOLFOX6: Oxaliplatin with Folinic Acid and 5-FU (bolus and continuous infusion). 12 cycles, every 2 weeks.
      • XELOX: Oxaliplatin and oral Capecitabine. 8 cycles, every 3 weeks.
    • Efficacy: Addition of Oxaliplatin improves 7-year overall survival from 67% to 73%.
    • Note: Oxaliplatin is not recommended for patients over 70 years.
  2. Monotherapy with Fluoropyrimidines
    • Indication: If Oxaliplatin is contraindicated.
    • Preference: Oral fluoropyrimidines over infusion schemes; bolus regimens should be avoided due to higher toxicity.
    • Example: Capecitabine, 2 x 1250 mg/m² body surface, orally, for 14 days in a 3-week cycle, for 8 cycles.
    • Efficacy: Comparable to or possibly superior to Mayo Clinic regimen in disease-free survival.
  3. Adjuvant Therapy in Stage II
    • Recommendation: If adjuvant chemotherapy is performed for stage II tumors, Fluoropyrimidine monotherapy should be used.

Duration of Adjuvant Therapy

  • Consideration of Toxicity: Regular monitoring of (neuro)toxicity against therapeutic benefits is crucial.
  • Low Recurrence Risk (T1-3 N1): A 3-month Oxaliplatin-containing therapy following the CAPOX/XELOX scheme is recommended.

Fluoropyrimidines are a group of chemotherapy drugs that are primarily used to treat various types of cancer, including colon cancer, breast cancer, and gastrointestinal cancers. These drugs work by inhibiting the synthesis of DNA and RNA in cancer cells, which prevents them from growing and dividing. Some of the most commonly used fluoropyrimidines include:

  1. 5-Fluorouracil (5-FU): One of the oldest and most widely used fluoropyrimidines. It’s often given intravenously and used in combination with other drugs.
  2. Capecitabine (Xeloda): An oral drug that is converted into 5-FU in the body. It’s used to treat various types of cancer, including colorectal and breast cancer.
  3. Tegafur: Often used in combination with other drugs, it is a prodrug of 5-FU and used in various chemotherapy regimens.

Summary

For stage III colon cancer, Oxaliplatin combined with 5-FU/Folinic Acid is strongly recommended, showing significant improvement in long-term survival. In cases where Oxaliplatin is contraindicated, a monotherapy with Fluoropyrimidines, preferably oral Capecitabine, is advised. In adjuvant therapy for stage II colon cancer, Fluoropyrimidine monotherapy should be considered. The duration of therapy should be carefully balanced with the potential for toxicity, especially in patients with a low risk of recurrence.

Perioperative Therapy for Rectal Cancer

Neoadjuvant Therapy

Stage I (UICC Stage I, cT1-2N0)

  • No preoperative therapy recommended.
  • Low rates of local recurrence and distant metastasis following radical surgery alone with total mesorectal excision (TME) for tumors in the lower/middle third and partial mesorectal excision (PME) for tumors in the upper third.

Stage II/III (cT3/4 and/or cN+)

  • Neoadjuvant radiochemotherapy or short-term radiotherapy recommended for tumors in the lower and middle rectal third.
  • Exceptions for primary resection:
    • cT1/2 tumors with questionable lymph node involvement.
    • cT3a/b tumors with limited perirectal fat tissue infiltration and no imaging evidence of lymph node metastasis.
  • For tumors in the upper rectal third without risk factors for local recurrence: Primary operation and adjuvant therapy similar to colon cancers.
  • For risk factors in the upper rectal third: Preoperative radio-/radiochemotherapy can be considered.

Neoadjuvant Radiotherapy Methods

  • Short-term radiation with 5 x 5 Gy followed by immediate surgery or conventional fractionated radiochemotherapy (1.8-2.0 Gy up to 45-50.4 Gy) with a 6-8 week interval until surgery.
  • For patients aiming for downsizing, short-term radiation with an extended interval (up to 12 weeks) to surgery (with/without neoadjuvant chemotherapy) can be performed.
  • For T4 tumors, proximity to the mesorectal fascia, or deep tumors with intended sphincter preservation: Preoperative radiochemotherapy recommended.

Timing of Surgery

  • Surgery should occur 6-8 weeks after neoadjuvant radiochemotherapy.
  • After short-term radiation (5 x 5 Gy), surgery should be either within 10 days from the start of radiotherapy or after 4-8 weeks.

Neoadjuvant Chemotherapy

  • Neoadjuvant chemotherapy before or after radiochemotherapy (or as sole neoadjuvant therapy without radio-/radiochemotherapy) should not be performed outside of clinical studies.
  • For synchronous metastasis, short-term RT with 5 x 5 Gy followed by neoadjuvant chemotherapy and surgery at an interval can be performed.

Adjuvant Therapy for Rectal Cancer Following Primary Surgery

UICC Stage I (pT1/2N0)

  • No adjuvant therapy recommended after an R0 resection.

For Histopathologically Confirmed Risk Factors for Local-Regional Recurrence

  • Risk factors include: R1 resection, intraoperative tumor tear, positive circumferential resection margin (pCRM+), inadequate TME quality, pT4, pT3c/d, pN2, extranodal tumor deposits in mesorectum, pT3 in lower rectal third.
  • Adjuvant radiochemotherapy recommended in these cases.

Stage II/III Without Adjuvant Radiochemotherapy

  • If no adjuvant radiochemotherapy is performed after primary R0 resection in Stage II/III, adjuvant chemotherapy should be considered.
  • The indications and regimens for adjuvant chemotherapy should follow those used for colon cancer.

Post-Neoadjuvant Radiochemotherapy

  • No clear recommendation can be made for or against adjuvant chemotherapy following neoadjuvant radiochemotherapy for rectal cancer, due to the current state of available data.
  • Therapeutic Approach for Metastasis and Palliative SituationsTherapeutic Approach for Metastasis and Palliative Situations For Patients in Good General Condition
    • Intensive Treatment: Suitable for surgery or chemotherapy.
    • Resectable Tumor Manifestations: Primary metastasectomy is recommended if favorable risk factors are present.
    For Patients Where Surgery is Not Initially Feasible
    • Systemic Chemotherapy: Effective chemotherapy should be given, aiming for maximum tumor reduction.
    • Chemotherapy Regimen: Depends on the molecular pathological profile of the tumor. RAS Wildtype tumors’ treatment also considers the primary tumor’s location.
    Palliative Medicine
    • Objective: To improve the quality of life for patients and families facing life-threatening illnesses through prevention and relief of suffering via early identification and impeccable assessment and treatment of pain and other physical, psychosocial, and spiritual problems.
    Medication Indication
    • Initiation: Medicinal tumor therapy should start upon metastasis detection, regardless of metastasis-related symptoms.
    • Consideration: Potential contraindications, including age, must be considered.
    Decision Algorithm for Optimal First-Line Therapy
    • Factors to consider:
      • General Condition: Tolerance for intensive therapy.
      • Disease Extent and Location: Includes resectability and local-regional intervention.
      • Molecular Biology of Tumor: Determines optimal targeted therapy.
    Initial Molecular Biological Diagnostics Before Therapy Initiation
    • Objective: To characterize the disease for prognostic assessment and predictive information for therapy selection.
    • Analyses: RAS genes KRAS and NRAS mutation status, BRAF gene, and microsatellite instability status (MSS or MSI-H).
    BRAF Mutation
    • Prevalence: About 8-12% of metastatic colorectal cancer (mCRC) patients.
    • Implications: BRAF V600 mutations often co-occur with MSI. MSI presence suggests sporadic defects in mismatch repair (dMMR).
    Pharmacogenetic Diagnostics Before First-Line Therapy
    • UGT1A1: Not routinely recommended before palliative chemotherapy with Irinotecan, except in specific conditions like Gilbert’s syndrome.
    • DPD Deficiency: Diagnostic option before Fluoropyrimidine therapy. Routine evaluation of DPYD*2A polymorphism can be conducted.
    Testing for Microsatellite Instability (MSI)
    • Effectiveness: High efficacy of Pembrolizumab, a checkpoint inhibitor, in treating mCRC with MSI-H.
    Primary Resectable Disease in Reduced General Condition
    • Operability Assessment: Regularly re-evaluate if initially inoperable.
    Primary Non-Resectable Disease in Reduced General Condition
    • Focus: Primarily palliative, symptomatic treatment.
    • Treatment Options: Initial treatment with Fluoropyrimidine + Bevacizumab or a reduced chemotherapy doublet (± Bevacizumab).
    • Alternative for RAS-WT Tumors: Anti-EGFR monotherapy.
    Poor General Condition Due to Tumor
    • Consideration: Intensified tumor therapy might be used even with poor ECOG status if the condition is primarily tumor-related.
    Treatment for Patients Suitable for Intensive Therapy
    • Objective: Access to the most effective and tolerable therapy.
    • Parameters for Decision Making: Surgical criteria (operability, resectability), prognostic criteria.
    • Technical Resectability: Primary metastasectomy for resectable disease with favorable prognosis. Systemic therapy first for resectable disease with unfavorable prognosis.
    Timing of Resection
    • Procedure: If stabilization is achieved with systemic therapy, resection should be pursued within 2-3 months.
    Small Metastases
    • Approach: Small metastases (≤1cm) should be primarily removed as they might disappear under initial chemotherapy and become undetectable.
    Neoadjuvant Therapy for Resectable Liver Metastases
    • Recommendation: Not advised. Clinical benefit not firmly established.
    Adjuvant/Additive Therapy After Metastasis Resection
    • Guideline: No adjuvant/additive chemotherapy after metastasis resection.
    Primary Non-Resectable Metastasis
    • Approach: Begin with systemic tumor therapy.
    • Selection: Choose the most effective therapy based on tumor and patient characteristics.
    Systemic Therapy Choices Based on Molecular Pathology and Tumor Location
    • RAS Wildtype: For left-sided primary colon cancer, use chemotherapy doublet + anti-EGFR therapy in first-line treatment.
    • BRAF Mutation: Prioritize effective chemotherapy or clinical trial enrollment.
    • MSI: Consider checkpoint inhibitors in later treatment lines.
    • HER-2 Amplification: Follow treatment based on RAS and BRAF mutation status.
    Conducting First-Line Chemotherapy
    • Standard Approach: Use Fluoropyrimidine-based regimens like FOLFIRI, FOLFOX, FOLFOXIRI, or Capecitabine (with Oxaliplatin).
    • Combination Therapy: Choose based on therapeutic goals, molecular characteristics, and tumor location.
    • Reduced General Condition: Use Fluoropyrimidine monotherapies, typically combined with Bevacizumab.
    Second-Line Therapy
    • Focus: Choose based on effectiveness and side effects of prior therapy.
    Sequential Therapy
    • Strategy: Optimal therapy sequence depends on RAS status and primary tumor location.
    • Additional Treatments: Consideration of Trifluridin/Tipiracil and Regorafenib in advanced treatment stages.
    Local Ablative Procedures for Liver Metastases Treatment Thermoablation
    • Evidence Base: Cohort studies and retrospective analyses show no difference in survival between resection and thermoablation for metastases up to 3-4 cm in diameter.
    • Other Local Treatments: Including stereotactic radiation (SBRT), brachytherapy, cryotherapy, and irreversible electroporation (IRE), have limited or no evidence of efficacy.
    Locoregional Effective Procedures
    • Selective Internal Radioembolization (SIRT): Can be used for treating disseminated liver metastases in colorectal cancer (CRC) when no other equivalent therapy option is available.
    • Hepatic Intraarterial Chemotherapy (HAI): Specific method of delivering chemotherapy directly to the liver.
    • Hyperthermic Intraperitoneal Chemotherapy (HIPEC):
      • Indications: For patients with isolated and limited peritoneal carcinomatosis.
      • Requirements: Peritoneal cancer index (PCI) < 20, no extra-abdominal metastases, possibility of macroscopic complete removal or destruction of all tumor manifestations.
      • Specialized Center: Treatment should be carried out in a specialized center.
      • HIPEC Implementation: Should be conducted within clinical studies.
    Under Chemotherapy for Metastasis and Palliative Situation
    • Regular Assessment: All patients should undergo regular assessment of disease and therapy-induced side effects with targeted symptom treatment.
    • Primary Goal: Extend progression-free survival and overall survival with low toxicity and good quality of life.
    • Patient Guidance: Regular instruction for patients on effective self-management of symptoms is recommended.

Special Situations in Surgical Therapy for Colorectal Cancer

Surgical Therapy for Peritoneal Carcinosis

  • Criteria for Cytoreductive Surgery and HIPEC:
    • Peritoneal Cancer Index (PCI) < 20.
    • No extra-abdominal metastases.
    • Possibility of complete macroscopic removal or destruction of all tumor manifestations.
    • Performed in a specialized center.
    • Preferably conducted within clinical trials.

Multivisceral Resection

  • In Cases of Tumor Adherence to Neighboring Organs:
    • Unclear if adherence is due to infiltration or peritumoral inflammation.
    • Avoid biopsies and frozen section examinations to prevent local tumor cell spread.
    • En bloc resection of affected organs is recommended.
    • Total pelvic exenteration may be necessary for rectal cancer.

Multiple Colorectal Carcinomas

  • Approach:
    • Avoid routine colectomy; tailor the approach to individual tumor requirements.
    • May involve multiple anastomoses.

Emergency Operations

  • Indications: Ileus, tumor perforation, or bowel perforation by stenosing tumor.
  • Approach:
    • Aim for oncological radical resection akin to elective procedures, depending on the situation.

Resection of Liver Metastases

  • Simultaneous Resection:
    • Likely does not affect long-term survival compared to a staged approach in appropriately selected patients.
    • Higher postoperative mortality risk in patients with comorbidities or older age (>70 years).

Key Points

  • Peritoneal Carcinosis: Cytoreductive surgery followed by HIPEC is viable under specific conditions, with a preference for conducting it within clinical trials.
  • Multivisceral Resection: Recommended for tumors adhering to adjacent organs, with a focus on avoiding local tumor cell dissemination.
  • Multiple Colorectal Carcinomas: Tailored surgical approach rather than routine colectomy, possibly requiring multiple anastomoses.
  • Emergency Surgeries: Oncological radical resection is the goal, similar to elective surgeries, adapted to the emergency context.
  • Liver Metastases Resection: Simultaneous resection in selected patients does not impact long-term survival but may increase postoperative mortality, especially in older or comorbid patients.

Multimodal Approach for Multiple Synchronous Liver Metastases

Two-Stage and Multimodal Approach

  • Strategy: For multiple synchronous liver metastases, a two-stage approach combining surgery and systemic therapy is recommended.

Considerations for Simultaneous Resection of Liver Metastases and Primary Tumor

  • Access to Liver in Right-Sided Colon Resections:
    • Typically straightforward due to patient positioning and incision, except in very obese patients or those with a large fatty liver.
  • Access Challenges in Left-Sided Colon and Rectal Surgeries:
    • More difficult due to typical patient positioning with elevated pelvis.
  • Peripherally Located Metastases:
    • Resection feasible during surgeries for left-sided colon and rectum, with minimal additional challenges.
  • Formal Right-Sided Resections:
    • E.g., right hemihepatectomy, are more feasibly performed during right-sided colon resections due to better access.
  • Small, Isolated Metastases:
    • Often followed by further metachronous metastases.
    • Even with technical resectability, it may be justified to observe for further liver metastases development and potentially interpose systemic chemotherapy.

Special Situations in Colorectal Cancer Management

Extensive Metastasis with Asymptomatic Primary Tumor

  • Approach for Stage IV Patients: In cases with extensive liver metastases and an asymptomatic primary tumor (no symptoms of obstruction or transfusion-requiring bleeding), primary chemotherapy can be initiated without resecting the primary tumor.

Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

  • Prophylactic Colectomy/Proctocolectomy: Not recommended for mutation carriers.
  • Subtotal Colectomy: Should not be routinely performed but can be considered on an individual basis.
  • Postoperative Surveillance: Continuation of regular colonoscopic monitoring post-oncologically resective surgery, following the pre-operative surveillance pattern.

Familial Adenomatous Polyposis (FAP)

  • Standard Operation: Restorative proctocolectomy with ileal pouch and lymph node dissection based on the carcinoma’s location.
  • Alternative Approaches: Proctocolectomy or limited resection may be performed depending on sphincter insufficiency or incurable tumor conditions.
  • Attenuated FAP with Discrete Rectal Involvement: Ileorectal anastomosis recommended.

Ulcerative Colitis-Related Carcinoma

  • Standard Operation: Restorative proctocolectomy with ileal pouch, if oncologically and functionally sensible.
  • Microsatellite Instability Testing: Optional in cases suspicious for HNPCC.

Carcinoma Grading Based on MSI-H

  • Poorly Differentiated Adenocarcinomas:
    • Immunohistochemical testing for hMLH1 and hMSH2 expression recommended.
    • If hMLH1 or hMSH2 are deficient, classify as low-grade carcinomas.
  • Colorectal Carcinomas with High-Grade Microsatellite Instability (MSI-H):
    • Generally have a more favorable prognosis and lower rate of distant metastasis compared to those with microsatellite stability (MSS) or low-grade microsatellite instability (MSI-L).

Molecular Pathology in Metastatic Colorectal Cancer (mCRC)

RAS Genes (kRAS)

  • Presence of RAS Mutation: Recommended treatment is a doublet chemotherapy with or without Bevacizumab.
  • RAS Wildtype in Right-Sided CRC: A doublet chemotherapy with or without Bevacizumab is also recommended.
  • RAS Wildtype in Left-Sided CRC: Doublet chemotherapy with or without Panitumumab and Cetuximab is advised, which has been shown to improve overall survival.

BRAF Mutations

  • BRAF Mutations: Particularly BRAF-V600 mutation is associated with a very poor prognosis, hence an intensified chemotherapy triplet with or without Bevacizumab is recommended early on.

Microsatellite Status

  • Patients with Microsatellite Instability: A monotherapy with Pembrolizumab is recommended as it has been shown to extend progression-free survival compared to chemotherapy (André et al. 2020).

Treatment Strategies for mCRC

  • Patients in Good General Condition:
    • Primary resection of both the primary tumor and metastasis with curative intent is recommended, possibly in combination with chemotherapy.
    • Even with limited metastasis to one or two organs, curative treatment approaches exist.
  • Non-resectable Metastasis Initially:
    • Systemic chemotherapy with regular reevaluation for resection is suggested, which may potentially be curative.
  • Patients in Poor General Condition:
    • Less intensive therapies with fewer side effects are preferred, focusing on extending survival rather than cure.
  • Patients Unable to Tolerate Therapy:
    • Supportive symptomatic therapy, or “best supportive care,” is provided.

Palliative Surgery in Metastatic Colorectal Cancer

Gastric Outlet Obstruction and Small Bowel Ileus

  • Conservative Treatment: Considered for small bowel ileus when surgery is not absolutely indicated, as spontaneous resolution occurs in 70% of cases, particularly with adhesions as the cause.
  • Regular Patient Assessment: Essential for reevaluation of treatment approach.
  • Surgical Options: Include tumor resection with primary anastomosis, bypass surgery, or stoma, depending on the patient’s condition and life expectancy.

Tumor Resection with Primary Anastomosis

  • Indication: Recommended if the tumor is accessible and can be fully resected with clear margins.
  • Conditions for Anastomosis: Feasible if intra-abdominal tumor burden is low, the patient is in good general health, and no stenosis is detected beyond the anastomosis.

Bypass Surgery

  • Indication: Considered when resection is not feasible or multiple strictures are present, and enough healthy bowel exists both proximal and distal to the stenosis.

Stoma

  • Indication: Last resort if neither resection nor bypass is possible.
  • Procedure: The most distal bowel segment is brought out, with at least 150 cm of remaining small bowel to prevent short bowel syndrome. A double-barreled stoma is typically created for potential decompression in both directions.

Median Survival for Surgical Procedures

  • Tumor Resection: 7.2 months.
  • Ileostomy: 3.4 months.
  • Bypass Surgery: 2.7 months.
  • Note on Data Interpretation: There might be a selection bias influencing these results.

Ablauf-PEG for Non-Surgical Candidates

  • Indication: Considered for patients not suitable for surgery.

Large Bowel Obstruction

  • Tumor Resection: Recommended for accessible tumors, especially in the right-sided or transverse colon. Often combined with an end colostomy in palliative cases.
  • Colostomy: Considered when palliative resection is not feasible.
  • Stent Implantation: Evaluated mainly for stenoses in the left-sided colon.

Stent-Related Considerations

  • Types: Covered and non-covered stents, each with specific indications and complication risks.
  • Complications: Perforation risk present with both types.
  • Meta-Analysis Findings: Higher mortality and stoma rates post-surgery; perforations and late complications more common post-stent placement.

Palliative Surgery for Perforated Tumor

  • Indication: Absolute surgical indication for acute abdomen with perforation.
  • Approach: Rapid surgical exploration, with resection and possible stoma creation based on intraoperative findings.

Palliative Surgery for Bleeding Tumor

  • Treatment: Initial stabilization, followed by resection for definitive bleeding control, considering associated morbidity and mortality risks.
  • Alternative Treatments: Transanal minimally invasive surgery (TAMIS) or radiation for rectal tumors, with a high recurrence rate of symptoms.

Therapeutic Approach for Metastasis and Palliative Situations

For Patients in Good General Condition

  • Intensive Treatment: Suitable for surgery or chemotherapy.
  • Resectable Tumor Manifestations: Primary metastasectomy is recommended if favorable risk factors are present.

For Patients Where Surgery is Not Initially Feasible

  • Systemic Chemotherapy: Effective chemotherapy should be given, aiming for maximum tumor reduction.
  • Chemotherapy Regimen: Depends on the molecular pathological profile of the tumor. RAS Wildtype tumors’ treatment also considers the primary tumor’s location.

Palliative Medicine

  • Objective: To improve the quality of life for patients and families facing life-threatening illnesses through prevention and relief of suffering via early identification and impeccable assessment and treatment of pain and other physical, psychosocial, and spiritual problems.

Medication Indication

  • Initiation: Medicinal tumor therapy should start upon metastasis detection, regardless of metastasis-related symptoms.
  • Consideration: Potential contraindications, including age, must be considered.

Decision Algorithm for Optimal First-Line Therapy

  • Factors to consider:
    • General Condition: Tolerance for intensive therapy.
    • Disease Extent and Location: Includes resectability and local-regional intervention.
    • Molecular Biology of Tumor: Determines optimal targeted therapy.

Initial Molecular Biological Diagnostics Before Therapy Initiation

  • Objective: To characterize the disease for prognostic assessment and predictive information for therapy selection.
  • Analyses: RAS genes KRAS and NRAS mutation status, BRAF gene, and microsatellite instability status (MSS or MSI-H).

BRAF Mutation

  • Prevalence: About 8-12% of metastatic colorectal cancer (mCRC) patients.
  • Implications: BRAF V600 mutations often co-occur with MSI. MSI presence suggests sporadic defects in mismatch repair (dMMR).

Pharmacogenetic Diagnostics Before First-Line Therapy

  • UGT1A1: Not routinely recommended before palliative chemotherapy with Irinotecan, except in specific conditions like Gilbert’s syndrome.
  • DPD Deficiency: Diagnostic option before Fluoropyrimidine therapy. Routine evaluation of DPYD*2A polymorphism can be conducted.

Testing for Microsatellite Instability (MSI)

  • Effectiveness: High efficacy of Pembrolizumab, a checkpoint inhibitor, in treating mCRC with MSI-H.

Primary Resectable Disease in Reduced General Condition

  • Operability Assessment: Regularly re-evaluate if initially inoperable.

Primary Non-Resectable Disease in Reduced General Condition

  • Focus: Primarily palliative, symptomatic treatment.
  • Treatment Options: Initial treatment with Fluoropyrimidine + Bevacizumab or a reduced chemotherapy doublet (± Bevacizumab).
  • Alternative for RAS-WT Tumors: Anti-EGFR monotherapy.

Poor General Condition Due to Tumor

  • Consideration: Intensified tumor therapy might be used even with poor ECOG status if the condition is primarily tumor-related.

Treatment for Patients Suitable for Intensive Therapy

  • Objective: Access to the most effective and tolerable therapy.
  • Parameters for Decision Making: Surgical criteria (operability, resectability), prognostic criteria.
  • Technical Resectability: Primary metastasectomy for resectable disease with favorable prognosis. Systemic therapy first for resectable disease with unfavorable prognosis.

Timing of Resection

  • Procedure: If stabilization is achieved with systemic therapy, resection should be pursued within 2-3 months.

Small Metastases

  • Approach: Small metastases (≤1cm) should be primarily removed as they might disappear under initial chemotherapy and become undetectable.

Neoadjuvant Therapy for Resectable Liver Metastases

  • Recommendation: Not advised. Clinical benefit not firmly established.

Adjuvant/Additive Therapy After Metastasis Resection

  • Guideline: No adjuvant/additive chemotherapy after metastasis resection.

Primary Non-Resectable Metastasis

  • Approach: Begin with systemic tumor therapy.
  • Selection: Choose the most effective therapy based on tumor and patient characteristics.

Systemic Therapy Choices Based on Molecular Pathology and Tumor Location

  • RAS Wildtype: For left-sided primary colon cancer, use chemotherapy doublet + anti-EGFR therapy in first-line treatment.
  • BRAF Mutation: Prioritize effective chemotherapy or clinical trial enrollment.
  • MSI: Consider checkpoint inhibitors in later treatment lines.
  • HER-2 Amplification: Follow treatment based on RAS and BRAF mutation status.

Conducting First-Line Chemotherapy

  • Standard Approach: Use Fluoropyrimidine-based regimens like FOLFIRI, FOLFOX, FOLFOXIRI, or Capecitabine (with Oxaliplatin).
  • Combination Therapy: Choose based on therapeutic goals, molecular characteristics, and tumor location.
  • Reduced General Condition: Use Fluoropyrimidine monotherapies, typically combined with Bevacizumab.

Second-Line Therapy

  • Focus: Choose based on effectiveness and side effects of prior therapy.

Sequential Therapy

  • Strategy: Optimal therapy sequence depends on RAS status and primary tumor location.
  • Additional Treatments: Consideration of Trifluridin/Tipiracil and Regorafenib in advanced treatment stages.

Local Ablative Procedures for Liver Metastases Treatment

Thermoablation

  • Evidence Base: Cohort studies and retrospective analyses show no difference in survival between resection and thermoablation for metastases up to 3-4 cm in diameter.
  • Other Local Treatments: Including stereotactic radiation (SBRT), brachytherapy, cryotherapy, and irreversible electroporation (IRE), have limited or no evidence of efficacy.

Locoregional Effective Procedures

  • Selective Internal Radioembolization (SIRT): Can be used for treating disseminated liver metastases in colorectal cancer (CRC) when no other equivalent therapy option is available.
  • Hepatic Intraarterial Chemotherapy (HAI): Specific method of delivering chemotherapy directly to the liver.
  • Hyperthermic Intraperitoneal Chemotherapy (HIPEC):
    • Indications: For patients with isolated and limited peritoneal carcinomatosis.
    • Requirements: Peritoneal cancer index (PCI) < 20, no extra-abdominal metastases, possibility of macroscopic complete removal or destruction of all tumor manifestations.
    • Specialized Center: Treatment should be carried out in a specialized center.
    • HIPEC Implementation: Should be conducted within clinical studies.

Under Chemotherapy for Metastasis and Palliative Situation

  • Regular Assessment: All patients should undergo regular assessment of disease and therapy-induced side effects with targeted symptom treatment.
  • Primary Goal: Extend progression-free survival and overall survival with low toxicity and good quality of life.
  • Patient Guidance: Regular instruction for patients on effective self-management of symptoms is recommended.
  • Investigations
  • ECOG

Recommended Investigations for Colorectal Cancer

InvestigationColon Cancer (KolonCa)Rectal Cancer (RektumCa)
Complete ColonoscopyXX
CEA (Carcinoembryonic Antigen)XX
Abdominal UltrasonographyXX
Chest X-Ray (Rö-Thorax)XX
Rigid RectoscopyX
MR (CT) of Pelvis with Distance of Tumor to Mesorectal FasciaX
Rectal Endosonography for Locally Limited TumorX

Karnofsky and ECOG Performance Status Scales

Karnofsky IndexECOG IndexDescription
100%0No complaints, no signs of disease.
90%Capable of normal activity; few or no symptoms.
80%1Normal activity with effort possible. Clear symptoms.
70%Self-sufficient. Normal activity or work not possible.
60%2Some help needed, independent in most areas.
50%Help and medical care often sought.
40%3Disabled. Qualified help needed.
30%Severely disabled. Hospitalization necessary.
20%4Very sick. Intensive medical measures required.
10%Moribund. Inexorable physical decline.
0%5Death.

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