Colorectal Carcinoma

Meet the patient

A 68-year-old man arrives with three months of tiredness and a vague fullness in his right iliac fossa. His GP checked a blood count and found a microcytic anaemia with a low ferritin — iron deficiency with no obvious cause. He has not seen blood in his stool and his weight is steady. He is, in his own words, "fine apart from being a bit pale".^[1]

The tumour is almost certainly in his caecum. The two questions that decide his next two weeks are the two that decide every colorectal cancer stem: where is it? (the symptom pattern answers before the scope) and has it spread? (CT and, for a rectal lesion, MRI answer before the surgeon). Hold those two questions and the rest of the page slots into place.^[1]

Right is anaemia, left is obstruction, rectum is bleeding

Where the tumour sits in the bowel dictates how it declares itself, and the pattern is the first mark-scorer in any stem. The right colon has a wide lumen and liquid contents, so it hides; the left colon narrows and the stool firms up, so it obstructs; the rectum bleeds where you can see and feel it.^[1]

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The classic trap: iron-deficiency anaemia in an adult male or a postmenopausal woman is right-sided colorectal cancer until a colonoscope proves otherwise. Attributing it to diet or "just getting older" is the recurring trainee error that delays the diagnosis by months.^[1]

Everyone forgets: never label rectal bleeding as haemorrhoids without a digital rectal examination — and, in anyone over 40, without a scope. Piles are common and coexist with cancer; the bleeding you are reassuring the patient about may be the tumour.^[1]

The atypical presentations are the ones that hurt patients, because they are missed:^[1]

• Acute large-bowel obstruction — distension, no flatus or stool, colicky pain, an empty rectum on DRE. The commonest surgical emergency arising from CRC.
• Perforation — sudden severe pain and peritonism, free gas on an erect chest X-ray; at the tumour, or as a diastatic blow-out of the caecum behind an obstructing left-sided lesion.
• A young patient under 45 with a right-sided tumour — think Lynch syndrome before you think "too young for cancer". The incidence in younger adults is rising, which is exactly why screening moved to 45.^[1]

The adenoma-carcinoma sequence — the 10-to-15-year window that screening exploits

Every CRC you will ever meet began as a benign adenoma, and took 10 to 15 years to turn malignant — which is the single fact that makes screening work. Normal colonic mucosa collects mutations in a predictable order, each step pushing it further along the path from polyp to cancer.^[1]

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1. APC loss on 5q — initiates the adenoma by dysregulating the Wnt pathway and accumulating beta-catenin.
2. KRAS mutation on 12p — drives the small adenoma into a large one.
3. TP53 loss on 17p — converts the large adenoma into invasive carcinoma.^[1]

That decade-long window is the whole rationale for screening and polypectomy. Snip the adenoma at colonoscopy and the cancer never forms — prevention by removal, which is why a screening colonoscopy is the only modality that is both diagnostic and therapeutic.^[1]

The second pathway is MSI-H (microsatellite instability): a defective mismatch-repair system lets replication errors accumulate fast, producing right-sided, mucinous, poorly differentiated tumours bristling with tumour-infiltrating lymphocytes — and, paradoxically, a better stage-for-stage prognosis.^[1]

Spread follows a predictable order — direct extension through the bowel wall (the T stage), lymphatic to regional nodes (epicolic, paracolic, intermediate, principal — the N stage), haematogenous through the portal vein to the liver then the lungs, and transcoelomic drop-metastases to the peritoneum and ovary (Krukenberg).^[1]

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How common, and who is sitting in your clinic

CRC is the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide; lifetime risk in the general population is about 4 to 5 percent. Risk splits cleanly into what you cannot change and what you can.^[1]

Non-modifiable: age (over 90 percent of cases are 50 or older), family history (one first-degree relative roughly doubles risk), the hereditary syndromes (Lynch, FAP), and long-standing inflammatory bowel disease — especially ulcerative colitis with pancolitis beyond 8 to 10 years.^[1]

Modifiable: red and processed meat, low fibre intake, smoking, alcohol, obesity, and physical inactivity. The lifestyle lecture is dull, but it is real evidence.^[1]

Lynch vs FAP — the two syndromes that change the screening age

Up to 10 percent of CRC is hereditary, and the two syndromes every final-prof candidate must distinguish are Lynch and FAP — because each changes the age screening starts, the operation you offer, and the counselling of the family.^[1]

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Lynch is the commonest hereditary CRC syndrome — 2 to 4 percent of all CRC, and the diagnosis you must not miss in a young right-sided tumour. The Amsterdam II criteria select the families: three or more relatives with CRC or a Lynch-associated cancer, one a first-degree relative of the other two, across two generations, with at least one diagnosed under 50.^[1]

Lynch in depth — the mismatch-repair defect and why it mattersShowHide

The defective mismatch-repair machinery produces microsatellite instability (MSI-H), accelerating the adenoma-carcinoma sequence to roughly 2 to 3 years per adenoma versus 10 years in sporadic cancer. Despite this, stage for stage the prognosis is better — and MSI-H tumours respond to immune checkpoint inhibitors in the metastatic setting. Every CRC resected should have MMR and MSI testing on the specimen.^[1]

FAP is the one you cannot miss in adolescence: an APC mutation carpets the colon with hundreds of adenomas, and without prophylactic colectomy by the early twenties the lifetime cancer risk approaches 100 percent. Screen the duodenum too (Spigelman stage) and watch for desmoid tumours.^[1]

The bedside round — DRE first, always

Examination rarely makes the diagnosis; the scope does. But the digital rectal examination is the one bedside act that must never be skipped in any patient with rectal bleeding or an altered habit. A low rectal tumour is a hard, irregular, non-tender mass, often with contact bleeding on the glove, and it changes the operation from a restorative resection to a permanent colostomy.^[1]

Beyond DRE: a right iliac fossa mass (a caecal tumour), hepatomegaly (liver metastases), ascites (peritoneal disease), and distension (obstruction). On general examination look for pallor, cachexia, a Virchow node in the left supraclavicular fossa, and a Sister Mary Joseph nodule at the umbilicus — each a sign of advanced disease.^[1]

Investigations — scope it, stage it, type it

Three jobs, in order: confirm the tumour, stage the tumour, and type the tumour's biology. Colonoscopy with biopsy is the gold standard — it visualises the whole colon, biopsies the lesion, finds the 3 to 5 percent of synchronous tumours, and removes incidental adenomas. If the prep is poor or the lumen obstructed, CT colonography is the fallback.^[1]

Staging is CT chest, abdomen and pelvis (liver and lung metastases, local invasion, nodes) plus, for any rectal cancer, an MRI rectum — the only way to read the depth of wall invasion, the circumferential resection margin against the mesorectal fascia, and extramural vascular invasion. Serum CEA is checked pre-operatively as a baseline; it monitors response and recurrence, it never makes the diagnosis.^[1]

Molecular typing guides therapy. MMR and MSI status on the tumour flags Lynch (refer genetics), predicts better prognosis, and identifies the MSI-H metastatic tumours that respond to pembrolizumab. RAS (KRAS and NRAS) and BRAF testing in metastatic disease decides who may receive an anti-EGFR antibody — only RAS wild-type tumours respond.^[1]

TNM in one breath — and the rules that decide neoadjuvant

Learn the stage groups, then learn the three rules that sit on top of them and change management. The AJCC 8th edition groups tumour depth (T), nodal involvement (N) and metastasis (M) into the stages that set survival and treatment intent.^[1]

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The three rules that decide neoadjuvant therapy and surgical extent:^[1]

• Circumferential resection margin (CRM) — in rectal cancer, the closest distance from tumour to mesorectal fascia on MRI. A margin under 1 mm is threatened and mandates long-course chemoradiotherapy before TME.
• Extramural vascular invasion (EMVI) — tumour in vessels beyond the muscularis propria on MRI; an independent poor prognostic factor.
• The 12-node rule — a minimum of 12 lymph nodes must be examined for accurate staging. Fewer means understaging and under-treatment, and it is the single most reproducible marker of an adequate oncological resection.^[1]

TME for rectum, high-tie 12 nodes for colon

Surgery is the only curative treatment for localised CRC, and the operation is decided by where the tumour sits. The colon gets a segmental resection with a high vascular tie and 12 nodes; the rectum gets a total mesorectal excision.^[1]

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For colon cancer, the segmental resection follows the arterial supply: a right hemicolectomy (caecum, ascending, proximal transverse) ligates the ileocolic, right colic and middle colic vessels with a primary ileocolic anastomosis; a left hemicolectomy (descending, sigmoid) ligates the inferior mesenteric artery branches; an extended right hemicolectomy covers the mid-transverse colon; synchronous tumours or FAP demand a subtotal or total colectomy.^[1]

For rectal cancer, the operation is total mesorectal excision. Heald's TME removes the entire mesorectum — lymphatics and nodes — inside an intact fascial envelope, securing a clear circumferential margin. It is the single advance that dropped local recurrence from 20 to 30 percent to under 10 percent, and it has been the global standard for forty years.^[5]

The rectal operation forks on the height of the tumour:^[5]

• Anterior resection for upper and mid-rectal tumours (above roughly 5 to 6 cm from the anal verge) — restores continuity with a colorectal or coloanal anastomosis, protected by a temporary defunctioning ileostomy.
• Abdominoperineal excision of rectum (APER) for low tumours involving the sphincter — removes rectum and anus, leaving a permanent end colostomy. ELAPE reduces positive CRM rates.
• Transanal endoscopic microsurgery (TEMS or TAMIS) for an early T1 lesion (well-differentiated, no lymphovascular invasion, under 3 cm) in an unfit patient — local excision only.^[5]

The oncological principles are non-negotiable: a proximal high vascular tie (the "high tie") for an adequate lymph-node harvest, a minimum of 12 nodes examined, 5 cm proximal and distal margins, and en-bloc resection of any adherent adjacent organ (T4). Fewer than 12 nodes is not a technical footnote — it is understaging.^[1]

Neoadjuvant for rectal cancer — short course or long course

For stage II to III rectal cancer (T3 to T4 or node-positive), pre-operative therapy downstages the tumour and cuts local recurrence. Two regimens, chosen by the tumour and the centre.^[1]

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A complete clinical response after long-course CRT opens the watch-and-wait door — intensive surveillance instead of surgery in selected, motivated patients. It is a specialist decision, not a default, and the patient must understand the trade-off.^[1]

Adjuvant FOLFOX for stage III — the MOSAIC rule

Node-positive (stage III) colon cancer gets adjuvant chemotherapy; node-negative stage II generally does not. The MOSAIC trial is the evidence every candidate is expected to name: adding oxaliplatin to 5-FU and leucovorin (FOLFOX4) improved three-year disease-free survival from 65.3 to 78.2 percent in stage II to III colon cancer.^[3]

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The six-year update matters because it settled who actually benefits in overall survival — stage III did, stage II did not. So reserve adjuvant chemotherapy for stage III, and for the high-risk stage II patient (T4, fewer than 12 nodes, perforation or obstruction, poorly differentiated, lymphovascular invasion) only after an individualised discussion. MSI-H stage II has an excellent prognosis and may not benefit from 5-FU at all.^[4]

Stage IV (metastatic) disease is treated with palliative systemic therapy: first-line FOLFOX or FOLFIRI plus bevacizumab (any RAS status), or an anti-EGFR antibody (cetuximab or panitumumab) only if RAS wild-type and left-sided. Pembrolizumab is first-line for MSI-H or dMMR metastatic CRC. Surgery or stenting addresses obstruction; resectable liver metastases are resected.^[1]

The drug doses — FOLFOX, CAPOX, FOLFIRI, and the biologics

These are the standard adult regimens, dosed on body surface area and adjusted for toxicity, organ function and performance status. Cross-check renal function for capecitabine and irinotecan, and UGT1A1 status for irinotecan where available.^[1]

FOLFOX — oxaliplatin added to infusional fluorouracil and leucovorin (FOLFOX4), given for six months after curative resection in the MOSAIC adjuvant trial and used first-line in metastatic disease (PRIME used FOLFOX4 as its comparator backbone):^[3][9]

• Cumulative sensory neurotoxicity is the dose-limiting toxicity. In MOSAIC, grade 3 sensory neuropathy affected 12.4 percent of patients during treatment, falling to 1.1 percent at one year of follow-up — the reason oxaliplatin exposure is capped and the duration question exists at all.
• Febrile neutropenia is uncommon — 1.8 percent on FOLFOX4 in MOSAIC.
• Per-cycle drug doses vary between FOLFOX variants (FOLFOX4, mFOLFOX6); always check the local protocol before prescribing.

CAPOX (XELOX) — the oral adjuvant alternative to FOLFOX for resected stage III colon cancer, given for six months as oxaliplatin 130 mg/m² IV on day 1 plus capecitabine 1,000 mg/m² orally twice daily on days 1 to 14, every 3 weeks (NO16968: seven-year disease-free survival 63 percent with XELOX versus 56 percent with bolus fluorouracil/folinic acid).^[6]

FOLFIRI — the irinotecan doublet for metastatic disease, every 2 weeks: irinotecan 180 mg/m², leucovorin 400 mg/m², and 5-FU 400 mg/m² IV bolus followed by 2,400 mg/m² as a 46-hour infusion — the standard biweekly FOLFIRI backbone used in current metastatic trials.^[13]

Single-agent capecitabine — oral adjuvant monotherapy for resected stage III colon cancer, an alternative to bolus 5-FU/leucovorin: 1,250 mg/m² orally twice daily on days 1 to 14 of each 3-week cycle, for 24 weeks (X-ACT: at least equivalent disease-free and overall survival).^[7]

Bevacizumab (anti-VEGF) — added to first-line chemotherapy in metastatic disease: 5 mg/kg IV every 2 weeks with irinotecan-based therapy in the pivotal trial, which improved median survival to 20.3 months. It is the targeted alternative to EGFR inhibitors in right-sided tumours.^[8][10]

Cetuximab and panitumumab (anti-EGFR antibodies) — reserved for metastatic disease with KRAS/NRAS/BRAF wild-type, left-sided primary tumours, given in conjunction with chemotherapy; EGFR inhibition can extend survival in that selected population. Panitumumab plus FOLFOX4 improved progression-free survival versus FOLFOX4 alone in wild-type KRAS metastatic colorectal cancer (PRIME).^[10][9]

Pembrolizumab (anti-PD-1) — first-line treatment of unresectable or metastatic MSI-H or dMMR colorectal cancer: it improved progression-free survival over chemotherapy in the KEYNOTE-177 randomised phase 3 trial and is the standard first-line option in this biomarker-defined group.^[11]

Duration questions (IDEA). The IDEA collaboration pooled six randomised phase 3 trials comparing 3 versus 6 months of adjuvant chemotherapy for stage III colon cancer; overall, non-inferiority of the 3-month duration was not shown. Weigh any shorter oxaliplatin schedule against the cumulative sensory neuropathy quantified above.^[14]

The emergency presentation — obstruction or perforation

Treat the acute abdomen and the sepsis first; decide the operation second. The obstructing or perforated CRC is the commonest surgical emergency arising from colorectal cancer, and the first hour is resuscitation, not theatre.^[1]

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The Hartmann procedure — resection of the perforated or obstructed segment, an end colostomy, and a closed rectal stump — trades restoration of continuity for survival in the unstable, unprepared patient. It is the safe default for the emergency left colon.^[1]

Screening — start at 45, scope the bleed

The USPSTF in 2021 lowered the screening start age from 50 to 45, reflecting the rising incidence of CRC in adults under 50. Screen everyone from 45 to 75; from 76 to 85 the decision is individual; stop at 85.^[2]

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The FIT rule that saves (and costs) the most: any positive FIT mandates a colonoscopy — never re-test. Roughly half of FIT-positive patients have a neoplastic finding on colonoscopy, and 5 to 7 percent have cancer. Repeat-testing a positive FIT is the recurring avoidable error.^[1]

Named traps — the recurring trainee errors

These are the errors that delay diagnosis, understage the tumour, or harm the patient. Name them and you will not make them.^[1]

• Iron-deficiency anaemia in an adult male or postmenopausal woman labelled as dietary — colonoscopy to exclude a right-sided CRC, every time.
• Rectal bleeding attributed to haemorrhoids without a DRE — and without a scope in anyone over 40. Piles coexist with cancer; the bleed you are reassuring may be the tumour.
• Forgetting Lynch syndrome in a young patient with a right-sided tumour — take a three-generation pedigree and test the tumour for MMR and MSI.
• An inadequate lymph-node harvest under 12 — understaging, under-treatment, and an oncologically inadequate operation.
• A rising CEA after curative resection ignored — it is the earliest marker of recurrence; image and investigate.^[1]

Complications — by disease and by operation

CRC harms the patient directly (obstruction, perforation, bleeding, metastases) and the operation harms them too (anastomotic leak, nerve injury, stoma problems). Both lists are examinable.^[1]

• Local disease complications — obstruction (the commonest surgical emergency), perforation with peritonitis or abscess, fistula (colovesical with pneumaturia, colovaginal), and chronic or acute bleeding.
• Metastatic — liver (commonest, resectable in roughly 20 percent), lungs, peritoneum (pseudomyxoma peritonei from mucinous tumours), and bone (late).
• Surgical — anastomotic leak (3 to 5 percent, presenting days 5 to 7 with fever, pain and tachycardia; higher in low rectal anastomoses, malnutrition and steroids), stoma complications (parastomal hernia, retraction, necrosis), ureteric injury in rectal surgery, and sexual and urinary dysfunction from autonomic nerve damage during TME.^[1][5]

The anastomotic leak — recognise it on day 5 to 7ShowHide

A patient who was recovering well after a colorectal anastomosis develops fever, abdominal pain and tachycardia around day 5 to 7. This is an anastomotic leak until proven otherwise — CT with water-soluble contrast, resuscitation, antibiotics, and most often a return to theatre for defunctioning or revision. Risk is highest in low rectal anastomoses, the malnourished, and the patient on steroids, which is why a defunctioning ileostomy protects a low anastomosis.^[1]

Prognosis, follow-up, and the CEA that warns you first

Stage at diagnosis is the dominant prognostic factor — stage I around 90 percent five-year survival, stage IV around 15 percent. Node-negative patients with clear margins are generally cured by surgery alone.^[1]

Other prognostic markers: MSI-H or dMMR (better), BRAF mutation in metastatic disease (worse), perineural and lymphovascular invasion, a positive CRM in rectal cancer (high local recurrence), a high pre-operative CEA, and obstruction or perforation at presentation — all worse.^[1]

Follow-up after curative resection is CEA-led. Check CEA every 3 to 6 months for 3 years then 6-monthly to 5 years (a rising trend prompts imaging for recurrence), CT CAP annually for 3 to 5 years, and a surveillance colonoscopy at 1 year then 3-yearly to catch metachronous tumours.^[1]

The mantra, and the mnemonic

^[1]

The mantra: screen at 45, scope the bleed, take 12 nodes.^[1][2]

Ward-round test — three stems

Stem 1 — the pale man with the full right iliac fossa (answer)ShowHide

A 68-year-old man, three months of tiredness, a microcytic iron-deficiency anaemia with a low ferritin, no visible rectal bleeding. What is the next investigation, and why is the tumour likely right-sided? Model: Colonoscopy — the iron-deficiency anaemia in an adult male is right-sided colorectal cancer until proven otherwise. The right colon has a wide lumen and liquid stool, so it bleeds occultly and presents late with anaemia rather than obstruction. Biopsy the lesion, stage with CT CAP, and plan a right hemicolectomy with an ileocolic anastomosis if localised.^[1]

Stem 2 — bright blood on the paper in a 52-year-old (answer)ShowHide

A 52-year-old reports bright red blood on the toilet paper and dripping into the bowl, attributed by a colleague to "his piles". What must you do before accepting that diagnosis? Model: A digital rectal examination, then a proctoscopy or colonoscopy — never label rectal bleeding as haemorrhoids without examining and scoping. Haemorrhoids are common and coexist with cancer; a rectal tumour is palpable as a hard, irregular, contact-bleeding mass on DRE, and a proximal tumour is invisible to DRE. At 52 he is above the screening age, so colonoscopy is both diagnostic and therapeutic.^[1][2]

Stem 3 — a 38-year-old with a right-sided mucinous tumour (answer)ShowHide

A 38-year-old woman has a resected right-sided, mucinous, poorly differentiated CRC with tumour-infiltrating lymphocytes. What is the likely syndrome, and what changes in her surveillance and her family's? Model: This phenotype — young, right-sided, mucinous, MSI-H — is Lynch syndrome until germline testing proves otherwise. Test the tumour for mismatch repair (IHC for MLH1, MSH2, MSH6, PMS2) and microsatellite instability; confirm with germline testing and refer genetics. She needs colonoscopic surveillance every 1 to 2 years and consideration of an extended colectomy for metachronous risk; her first-degree relatives cascade-screen from age 25 to 30, or 10 years before the youngest affected relative. Counsel endometrial and ovarian risk. Do not attribute a young right-sided tumour to bad luck.^[1]

References14ShowHide

1. [1]Dekker E, Tanis PJ, Vleugels JLA, et al. Colorectal cancer Lancet, 2019.PMID 31631858
2. [2]Davidson KW, Barry MJ, Mangione CM, et al. Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement JAMA, 2021.PMID 34003218
3. [3]André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer N Engl J Med, 2004.PMID 15175436
4. [4]André T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial J Clin Oncol, 2009.PMID 19451431
5. [5]Votava J, Kachlik D, Hoch J Total mesorectal excision - 40 years of standard of rectal cancer surgery Acta Chir Belg, 2020.PMID 32200705
6. [6]Schmoll HJ, Tabernero J, Maroun J, et al. Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer: Final Results of the NO16968 Randomized Controlled Phase III Trial J Clin Oncol, 2015.PMID 26324362
7. [7]Twelves C, Scheithauer W, McKendrick J, et al. Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy Ann Oncol, 2012.PMID 21896539
8. [8]Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer N Engl J Med, 2004.PMID 15175435
9. [9]Douillard JY, Siena S, Cassidy J, et al. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer Ann Oncol, 2014.PMID 24718886
10. [10]Sakata S, Larson DW Targeted Therapy for Colorectal Cancer Surg Oncol Clin N Am, 2022.PMID 35351276
11. [11]Diaz LA, Shiu K, Kim T, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study Lancet Oncol, 2022.PMID 35427471
12. [12]Tan CJ, Dasari BV, Gardiner K Systematic review and meta-analysis of randomized clinical trials of self-expanding metallic stents as a bridge to surgery versus emergency surgery for malignant left-sided large bowel obstruction Br J Surg, 2012.PMID 22261931
13. [13]Lee KW, Han SW, Kim TW, et al. A Phase 1b/2a Study of GC1118 with 5-Fluorouracil, Leucovorin and Irinotecan (FOLFIRI) in Patients with Recurrent or Metastatic Colorectal Cancer Cancer Res Treat, 2024.PMID 38062706
14. [14]André T, Meyerhardt J, Iveson T, et al. Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials Lancet Oncol, 2020.PMID 33271092