Colorectal Cancer
Sandra Van Schaeybroeck, Mark Lawler, Brian Johnston, Manuel Salto-Tellez, Jack Lee, Paula Loughlin, Richard Wilson and Patrick G. Johnston
Summary of Key Points
Epidemiology
• Colorectal cancer (CRC) is the second most common cancer in women and the third most common cancer in men worldwide.
• Within economically developed countries, the lifetime risk of developing CRC is 1 in 20.
• Because of increased screening rates, the incidence of CRC is declining for men and women in the United States.
• The incidence is 15 times higher in adults older than age 50 years, compared with those younger than age 50 years.
• Inherited genetic syndromes (hereditary nonpolyposis colorectal cancer [HNPCC] and familial adenomatous polyposis [FAP]: fewer than 10% of cases) and inflammatory bowel disease (IBD) in concert with dietary and environmental exposures increases risk for CRC.
• The 5-year overall survival rate has greatly improved in the last 2 decades, and is now approximately 65%, with variations across racial and ethnic subgroups.
Screening and Prevention of CRC
• High level of physical activity decreases the risk of CRC by up to 50%.
• Diets high in fiber and low in red, processed meat may alter risk of CRC.
• Calcium/vitamin D supplementation might have preventive effects.
• Aspirin and cyclooxygenase (COX)-2 inhibitors may prevent polyps and CRC, but are only recommended in high-risk patients.
• Premenopausal hormone replacement therapy reduces the incidence of CRC, but increases the risk of breast cancer and cardiovascular complications.
• There are mixed results in studies of the effects of statins on CRC risk.
• Colonoscopy is the mainstay of screening and a useful tool in the diagnosis of CRC. Sigmoidoscopy may reduce CRC incidence and mortality.
• Fecal occult blood is an acceptable screening tool.
• Virtual colonoscopy, the detection of abnormal DNA within stool sample and capsule endoscopy are potentially new screening tests.
• Screening is based on risk categories that take into account age; race; personal history of IBD, polyps, or cancer; family history of CRC; and presence of hereditary syndromes.
Diagnosis and Staging
• CRC is often insidious in development, underscoring the importance of screening.
• Altered bowel habits, blood per anum, fatigue, anemia, and weight loss are frequent symptoms.
• Obstruction is the most common acute surgical problem (approximately 30% of left-sided lesions present with an obstruction).
• Approximately 5% of CRC patients will be diagnosed with synchronous cancer. The liver is the most common site for synchronous metastasis.
• Approximately 20% to 40% will have synchronous polyps with cancer primary.
• Computed tomography (CT) scan, magnetic resonance imaging (MRI), and positron emission tomography (PET) are imaging tools used in the staging of CRC.
• Intraoperative ultrasound is the most sensitive method to evaluate liver for metastases.
• Tumor size is not as critical as depth of invasion and nodal status in determining prognosis.
• High histologic grade, lymphatic invasion, venous invasion, and involvement of surgical resection margins are independent adverse prognostic factors.
Molecular Pathogenesis
• The “Vogelgram” highlights the involvement of specific oncogenes and tumor suppressor genes in the colorectal adenoma to carcinoma transition, and involves APC, KRAS, TP53, and DCC.
• The APC tumor suppressor gene is defective in more than 80% of colon adenomatous polyps and cancers. KRAS, TP53, and BRAF are mutated in 40% to 50%, approximately 50%, and 8% of CRC, respectively.
• Deletions of 18q21 (location for DCC, SMAD2 and SMAD 4) also play a role in CRC carcinogenesis.
• Chromosomal instability (CIN) and microsatellite instability (MSI) pathways are closely associated to this adenoma-to-carcinoma model, and involve genes in the Wnt signaling and DNA mismatch repair pathways, respectively.
• Defective DNA mismatch repair is responsible for 15% to 20% of CRC; hereditary syndromes (e.g., HNPCC); in 3% to 5% of cases, MSI positivity correlates with the inherited colon cancer HNPCC or Lynch syndrome.
• Integrating genomics and transcriptomics into our standard of care remains a challenge, but is a critical component of a framework to establish a comprehensive personalized medicine strategy for the cancer patient.
Surgical Treatment
• The use of an enhanced recovery program (ERP) is important in the management of patients undergoing elective colonic resections.
• Treatment may consist of en bloc resection of the anatomically defined portions of the colon with in-continuity draining nodes to the root of the mesocolon.
• It is now recommended that, if available, a laparoscopic resection should be offered as an alternative to an open resection where both are available.
• The absence of mechanical bowel preparation is not associated with a greater risk of perioperative morbidity or mortality. Curtailed carbohydrate loading, deep vein thrombosis prophylaxis, and a single dose of prophylactic antibiotics are recommended before surgery.
• Experienced surgeons and the use of high-volume hospitals improve the chance of good surgical outcome.
• The role of surgical resection in management of CRC metastases has led to improved outcomes for patients.
Surveillance
• Eighty percent to 90% of recurrences are detected in the first 3 years following curative surgery. Fewer than 5% of recurrences occur after 5 years.
• Many of these recurrences are solitary or limited, and when resected completely, can still cure at least 35% of patients.
• A high percentage of first recurrence occurs in the liver and lung, are asymptomatic, and can be detected from a rising carcinoembryonic antigen (CEA) or CT imaging.
• Of those patients who are closely followed for evidence of recurrence, 20% are candidates for salvage surgery. These patients have a 5-year disease-free survival rate of 18.6% compared with only 5.6% when metastatic disease is diagnosed because patients became symptomatic.
Adjuvant Therapy in Early Stage Colorectal Cancer
• Fifty percent to 60% of patients who undergo successful surgery for CRC have residual micrometastatic disease.
• The goal of adjuvant therapy is to eradicate residual local disease. Recommended length for therapy is 6 months.
• Combined 5-fluorouracil (5-FU) plus leucovorin regimens with oxaliplatin have further improved overall survival in patients with stage III CRC.
• Adjuvant 5-FU regimens are also used in high-risk stage II CRC patients. MSI is now considered as a robust prognostic marker, in particular in stage II CRC MSI-H patients, who have a favorable clinical outcome and do not seem to benefit from adjuvant 5-FU-based chemotherapy.
• In contrast to metastatic CRC, all clinical trials investigating a potential role of epidermal growth factor receptor (EGFR)- and vascular endothelial growth factor (VEGF)-targeted therapies have failed in the adjuvant setting.
• Adjuvant radiation therapy has no standard role but may be considered (in conjunction with chemotherapy) in selected cases in which resection of T4 lesions leaves potentially positive circumferential resection margins.
Management of Metastatic Disease
• Patients with metastatic disease, in particular liver metastases, should be evaluated to determine if curative resection with or without perioperative chemotherapy treatment is possible.
• Infusional 5-FU plus leucovorin with irinotecan and EGFR monoclonal antibody (mAB) cetuximab has improved overall survival to 24.9 months in patients with chemo-naive KRAS wild-type CRC tumors.
• Infusional 5-FU plus leucovorin with irinotecan or oxaliplatin in combination with the VEGF mAB bevacizumab has increased median overall survival to more than 25 months.
• The multikinase inhibitor regorafenib has shown to increase survival in patients who have been previously treated with 5-FU, oxaliplatin, irinotecan, anti-VEGF, and anti-EGFR agents.
• KRAS is the first predictive biomarker approved for metastatic CRC. Novel adaptive clinical trial design, incorporating putative prognostic/predictive markers in prospective randomized phase II or III CRC studies, will enable a clinical validation of these biomarkers and facilitate their incorporation into routine medical practice.
1. What is the recommended adjuvant treatment following resection of stage III colorectal cancer (CRC)?
2. KRAS testing in CRC is relevant for treatment with:
3. The genetic basis for hereditary nonpolyposis colorectal cancer (HNPCC) is:
4. The diagnostic approach of obstructing colorectal tumor include
5. Stage II colorectal cancer is offered adjuvant chemotherapy
1. Answer: B. Phase III trials, such as MOSAIC and NSABP C-07, have shown a significant benefit in progression-free survival and overall survival from 5-FU+OXA treatment compared with 5-FU+LVtreatment. PETACC-3 trial showed no benefit form addition of irinotecan to 5-FU+LV treatment in the adjuvant setting. NSABP C-07 and N0147 trials showed no benefit from addition of Avastin or cetuximab to FOLFOX treatment in the adjuvant setting.
2. Answer: B. Several phases II and III trials, such as CRYSTAL and OPUS, showed that KRASMT CRC tumors do not benefit from addition of epidermal growth factor receptor (EGFR)-targeted monoclonal antibody strategy to standard chemotherapy. It is now recommended that all patients with metastatic colorectal cancer who are candidates for anti-EGFR–targeted therapies, should be tested for KRAS mutations, and if KRAS mutant, should not receive anti-EGFR–targeted strategies. No studies have shown the value of KRAS as a predictive biomarker to chemotherapy or antiangiogenic therapy. KRAS is not a prognostic biomarker, approved in early stage CRC.
3. Answer: C. The genetic basis of hereditary nonpolyposis colorectal cancer is a germline mutation in one of several genes involved in the mismatch repair system, most commonly hMSH2 or hMLH1, but also hPMS1, PMS2, or hMSH6. HNPCC has an autosomal dominant mode of inheritance, with less than 50% penetrance. Molecular genetic testing leading to subsequent clinical management recommendations currently exist for patients with HNPCC.
4. Answer: D. Barium should not be used. It can become inspissated in the colon distal to the obstruction and if a perforation occurs, entry of barium into the peritoneal cavity can lead to a life-threatening barium peritonitis. Colonoscopy and sigmoidoscopy are contraindicated because of risk for perforation.
5. Answer: C. In patients with stage II colon cancer, additional clinicopathological findings are considered when assessing the need for adjuvant chemotherapy, including histologic grade, intramural lymphovascular invasion, extramural vascular invasion, perineural invasion, 12 or fewer lymph nodes sampled, and evidence of obstruction and/or perforation. In stage II CRC, only the MSI-L/MSS subgroup may benefit from adjuvant 5-FU treatment.
