Colorectal Cancer

Epidemiology, Lynch syndrome and other hereditary risks, presentation, and multimodality treatment by stage

Key Points

• CRC is the 3rd most common cancer and 2nd leading cause of cancer death in the US; incidence in adults <50 has risen significantly.
• Lynch syndrome (mismatch repair deficiency) accounts for ~3% of CRC; familial adenomatous polyposis (FAP) accounts for <1%.
• Most CRCs are asymptomatic early; common presenting symptoms include rectal bleeding, change in bowel habits, and iron-deficiency anemia.
• MSI-H/dMMR status is critical — it predicts response to immune checkpoint inhibition and qualifies patients for immunotherapy.
• Stage I–II colon cancer is treated with surgery alone in most cases; oxaliplatin-based adjuvant chemotherapy is standard for high-risk stage II and all stage III.
• Rectal cancer management differs from colon cancer — neoadjuvant chemoradiation or short-course RT is standard for T3/T4 or node-positive disease.
• RAS and BRAF mutation status guides biologic therapy selection in metastatic CRC.

Epidemiology & Incidence

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related death in the United States for both men and women combined. In 2024, approximately 154,270 new CRC cases and 52,180 deaths were projected. Colon cancer accounts for ~72% of cases; rectal cancer for ~28%. The most concerning epidemiologic trend is the sharp rise in incidence among adults under 50 — young-onset CRC has increased by ~2% annually since the mid-1990s, prompting the USPSTF and American Cancer Society to lower the recommended screening start age to 45. The etiology of…

Genetic Predispositions & Risk Factors

Approximately 5% of CRC is attributed to well-defined hereditary syndromes: Lynch Syndrome (Hereditary Non-Polyposis CRC, HNPCC): Caused by germline mutations in DNA mismatch repair (MMR) genes — MLH1, MSH2, MSH6, PMS2, or EPCAM. Accounts for ~3% of all CRC. Lifetime CRC risk: 25–75% depending on gene. Also associated with endometrial (highest lifetime risk in women), ovarian, gastric, urothelial, and small bowel cancers. The Amsterdam II Criteria and revised Bethesda Guidelines are used for clinical identification; universal MMR/MSI tumor testing is now recommended for all CRC at diagnosis.…

Clinical Presentation

CRC is often asymptomatic in early stages, which is why screening is so critical. When symptoms do occur, they vary by tumor location: Right-sided (ascending/cecal) colon cancer: Tends to present with iron-deficiency anemia (occult bleeding from large fungating tumors), fatigue, weight loss, and a right-sided abdominal mass. Frank rectal bleeding is less common because stool is still liquid. These tumors are frequently detected at more advanced stage due to absence of obstructive symptoms. Left-sided (descending/sigmoid) colon cancer: More likely to cause changes in bowel habits…

Staging Overview

CRC is staged using the AJCC 8th Edition TNM system: Stage I: T1–2 N0 M0 (tumor invades submucosa or muscularis propria, no nodal involvement) Stage IIA: T3 N0 M0 (tumor invades pericolorectal tissues) Stage IIB: T4a N0 M0 (penetrates visceral peritoneum) Stage IIC: T4b N0 M0 (invades adjacent structures) Stage IIIA: T1–2 N1–2a M0 Stage IIIB: T3–4a N1–2, T2–3 N2b M0 Stage IIIC: T4a N2b, T4b N1–2, M0 Stage IVA: Any T, any N, M1a (one metastatic site/organ) Stage IVB: Any T, any N, M1b (two or more sites) Stage IVC: Any T, any N, M1c (peritoneal metastasis ± other sites) Essential biomarkers:…

Stage I–II Treatment

Stage I (T1–2 N0): Surgical resection with adequate margins and regional lymphadenectomy (minimum 12 nodes examined) is curative in >90% of cases. No adjuvant chemotherapy is indicated. Transanal local excision (TAE/TEM) may be considered for selected T1 rectal cancers with favorable pathologic features (no LVI, no PNI, well-differentiated, negative margins). Stage II (T3–4 N0): Surgical resection remains the backbone. Adjuvant chemotherapy with FOLFOX (oxaliplatin + leucovorin + 5-FU) or CAPOX (capecitabine + oxaliplatin) is recommended for high-risk stage II features, which include: T4…

Stage III Treatment

Stage III colon cancer (any T, N1–2, M0): Standard of care is surgery followed by 6 months of adjuvant FOLFOX or CAPOX. The MOSAIC and XELOXA trials established the survival benefit of adding oxaliplatin. Three months of CAPOX is non-inferior to 6 months for low-risk stage III (T1–3 N1), while 6 months is preferred for high-risk stage III (T4 or N2) per IDEA collaboration data. Stage III rectal cancer: Multimodal therapy is essential to reduce local recurrence and enable sphincter preservation: • Long-course neoadjuvant chemoradiation (CRT): 45–50.4 Gy in 25–28 fractions with concurrent…

Stage IV (Metastatic) Treatment

Metastatic CRC (mCRC) is heterogeneous; a meaningful subset of patients with liver-limited or lung-limited disease can achieve cure with aggressive multidisciplinary treatment. Oligometastatic/resectable disease: Synchronous or metachronous liver or lung metastases that are technically resectable should be evaluated for combined colon/rectal resection + metastasectomy. 5-year survival rates of 25–40% are reported for R0 resection of limited liver metastases. Perioperative FOLFOX (EORTC 40983 trial) improves PFS. Hepatic arterial infusion (HAI) pump chemotherapy is offered at specialized…