Cancer - colorectal
Description
- Adenocarcinoma in >95%
- Colon vs rectum are different diseases - rectal disease needs MRI, neoadjuvant therapy and a different surgical plan
Three molecular pathways
| Pathway | % | Mechanism | Features |
|---|---|---|---|
| Chromosomal instability | ~85% | APC -> KRAS -> TP53 (adenoma-carcinoma) | Left-sided, classic polyp sequence |
| Microsatellite instability (dMMR) | ~15% | MMR loss (germline Lynch, or somatic MLH1 hypermethylation) | Right-sided, mucinous, TILs, poorly differentiated |
| CpG island methylator (CIMP) / serrated | overlaps | BRAF V600E, sessile serrated lesions | Right-sided, elderly, F>M |
Sidedness matters therapeutically
| Right (proximal) | Left (distal) + rectum | |
|---|---|---|
| Molecular | BRAF, MSI-H, CIMP | RAS, chromosomal instability |
| Presentation | Anaemia, weight loss, mass; late | Obstruction, PR bleed, change in habit |
| Prognosis (metastatic) | Worse | Better |
| Anti-EGFR benefit | Minimal - do not use | Best |
MSI-H phenotype
- Proximal colon, large bulky local tumour, synchronous tumours more often
- Rarely metastasises distantly - stage-for-stage better prognosis
- Bimodal age: <50 (Lynch) or elderly (sporadic MLH1 methylation)
- Exquisitely immunotherapy-sensitive
Epidemiology
- ~15,500 new cases/yr AU; 2nd commonest cause of cancer death
- Lifetime risk ~1 in 13; median age ~70
- Incidence rising sharply in under-50s (~2-4%/yr) while falling in screened ages - do not dismiss rectal bleeding in a young patient
- Family history: 1 FDR = ~2x risk; 2 FDRs or 1 FDR <50 = 3-6x
- ~5% hereditary syndrome; ~20% familial clustering without an identified gene
Aetiopathogenesis
Risk factors
- Age, family history, prior adenoma/CRC
- IBD - UC pancolitis and Crohn's colitis; risk with duration, extent, PSC, ongoing inflammation
- Diet - processed and red meat, low fibre
- Obesity, T2DM, sedentary
- Smoking, alcohol
- Prior abdominopelvic radiotherapy, acromegaly, ureterosigmoidostomy
Lynch syndrome (HNPCC)
- AD, germline MMR mutation -> MSI
| Gene | Frequency |
|---|---|
| MSH2 | ~41% |
| MLH1 | ~37% |
| MSH6 | ~13% |
| PMS2 | ~9% |
- Also EPCAM deletion (silences MSH2)
- Right-sided, young, rapid adenoma-carcinoma progression (hence interval cancers despite surveillance)
- Lifetime CRC risk ~50-70% (MLH1/MSH2), lower for MSH6/PMS2
- *MSI is not specific to Lynch - ~15% of sporadic CRC is dMMR via MLH1 promoter hypermethylation + BRAF V600E*
- BRAF V600E mutation or MLH1 methylation -> sporadic, not Lynch
Polyposis syndromes
| Gene | Inheritance | Features | |
|---|---|---|---|
| FAP | APC | AD | >100 adenomas from teens; CRC ~90% by 45 untreated; desmoids, CHRPE, duodenal/ampullary Ca, osteomas (Gardner), medulloblastoma (Turcot) |
| Attenuated FAP | APC | AD | 10-100 polyps, later onset |
| MUTYH-associated polyposis | MUTYH biallelic | AR | Base excision repair of oxidative damage (8-oxoG); phenocopies attenuated FAP |
| Peutz-Jeghers | STK11 | AD | Hamartomas, mucocutaneous pigmentation, intussusception |
| Juvenile polyposis | SMAD4/BMPR1A | AD | SMAD4 also causes HHT |
| Serrated polyposis | - | - | Multiple/large sessile serrated lesions
Diagnosis
Presentation
- Change in bowel habit, PR bleeding, iron deficiency anaemia, obstruction, perforation
- Iron deficiency anaemia in any man or postmenopausal woman = colonoscopy until proven otherwise
Confirming and staging
- Complete colonoscopy + biopsy - must visualise the whole colon
- Synchronous cancers in 2-4%; if obstructed, complete within 6 months of resection
- CT chest/abdomen/pelvis for distant staging
- Rectal cancer: pelvic MRI is the reference standard for T stage, mesorectal fascia involvement (CRM) and EMVI
- CT chest justified - rectal cancer metastasises to lung more than colon does
- Liver MRI more sensitive than CT for liver metastases
- PET-CT has no role in routine staging without known/suspected metastatic disease
- CEA at baseline - only useful for surveillance if raised pre-op
Molecular testing
- MMR/MSI status on every colorectal cancer
- IHC for MLH1/MSH2/MSH6/PMS2 loss, or PCR MSI panel - either acceptable
- MLH1 loss -> reflex BRAF V600E +/- MLH1 methylation to separate sporadic from Lynch
- Metastatic disease: RAS (KRAS + NRAS), BRAF, HER2, MSI
Screening
- National Bowel Cancer Screening Program: biennial iFOBT, age 45-74 (invited from 50; 45-49 on request since July 2024)
- dec CRC mortality ~15-25%; positive iFOBT -> colonoscopy within 30 days
- Family history (2 FDRs, or 1 FDR <50): colonoscopy 5-yearly from age 50, or 10 years before the earliest family diagnosis - whichever is earlier
- Lynch: colonoscopy 1-2 yearly from age 25, or 5 yr before the earliest family cancer
- FAP: annual flexible sigmoidoscopy/colonoscopy from age 10-12; gastroduodenoscopy from 25
- IBD: surveillance colonoscopy from 8 yr of colitis, interval by risk
Management
A. Localised colon cancer
- Surgical resection with en bloc mesenteric lymphadenectomy
- >=12 nodes required for adequate staging
- Adjuvant chemotherapy by stage
| Stage | Adjuvant |
|---|---|
| I | None |
| II low-risk | None (and *chemotherapy harms MSI-high stage II* - do not give) |
| II high-risk | Single-agent fluoropyrimidine (capecitabine or 5-FU). High risk = T4, perforation, obstruction, poor differentiation, <12 nodes, LVI, high pre-op CEA |
| III | FOLFOX or CAPOX (MOSAIC: oxaliplatin doublet > 5-FU alone) |
- Duration (IDEA): 3 months CAPOX for low-risk stage III (T1-3 N1) - equivalent efficacy, far less neuropathy; 6 months for high-risk (T4 or N2)
- ctDNA-guided adjuvant therapy (DYNAMIC, Australian) reduces chemotherapy use without compromising recurrence-free survival in stage II - entering practice, not yet standard funding
B. Rectal cancer
- Determined by MRI: threatened CRM, T3c-4, N+, EMVI -> neoadjuvant therapy
- Total neoadjuvant therapy (TNT) - all chemo + chemoradiation before surgery
- Better compliance, higher complete response, more organ preservation
- Total mesorectal excision is the operation
- Watch and wait for a sustained clinical complete response - avoids permanent stoma; needs intensive surveillance
- dMMR/MSI-H rectal cancer: neoadjuvant PD-1 blockade (dostarlimab) alone -> very high clinical complete response, many avoid surgery and radiotherapy entirely
- The most important recent change - always check MMR before booking a rectal resection
C. Metastatic disease
Is it resectable?
- Oligometastatic (liver/lung) -> resect with curative intent - 5-yr survival 30-50%
- Borderline -> conversion chemotherapy to downsize, then resect
- Also: ablation, SIRT, HIPEC for selected peritoneal disease
Unresectable/high volume -> systemic therapy
- Backbone FOLFOX or FOLFIRI (FOLFOXIRI if fit and aiming for conversion)
- Add a biological by molecular profile and sidedness:
| Biomarker | Therapy |
|---|---|
| MSI-H/dMMR | Pembrolizumab first line (KEYNOTE-177) - beats chemotherapy; durable |
| RAS wild-type + LEFT-sided | Cetuximab or panitumumab (anti-EGFR) |
| RAS mutant, or right-sided | Bevacizumab (anti-VEGF) |
| BRAF V600E | Encorafenib + cetuximab (+/- binimetinib) - poor prognosis group |
| HER2 amplified | Trastuzumab + tucatinib/pertuzumab |
- Later lines: trifluridine-tipiracil + bevacizumab, regorafenib
- *Anti-EGFR only works if RAS wild-type* - a RAS mutation leaves the pathway constitutively active downstream of the receptor
D. Targeted therapy toxicity
- Bevacizumab - hypertension, proteinuria, arterial thromboembolism, impaired wound healing (stop 6 wk before surgery), bleeding 2-3%, GI perforation
- Cetuximab/panitumumab - papulopustular acneiform rash in 60-90%, rash intensity predicts response
- Sunscreen, prophylactic doxycycline + topical steroid; hypomagnesaemia; infusion reactions
- Oxaliplatin - cold-triggered acute dysaesthesia, cumulative sensory neuropathy (dose-limiting)
- Irinotecan - early cholinergic diarrhoea (atropine), late diarrhoea (loperamide); UGT1A128 poor metaboliser*
- 5-FU/capecitabine - mucositis, hand-foot syndrome, coronary vasospasm; *DPYD deficiency -> life-threatening toxicity; test before starting*
E. Chemoprevention
- Regular aspirin dec long-term (20-yr) CRC incidence and mortality
- Lynch syndrome: aspirin (CAPP2 - 600 mg/day up to 4 yr; >2 yr use gave ~59% risk reduction)
F. Surveillance after curative resection
- Clinical review + CEA 3-monthly for 2 yr, then 6-monthly to 5 yr
- CT C/A/P 6-monthly for 2 yr, then annually to 5 yr
- Colonoscopy at 1 year, then every 2-3 yr if clear
Associations
Lynch syndrome extracolonic cancers
- Endometrial - commonest extracolonic (esp. MSH6); often the sentinel cancer
- Ovarian, gastric, small bowel, hepatobiliary
- Urothelial - renal pelvis and ureter (esp. MSH2)
- Pancreas, brain (Turcot - glioblastoma), sebaceous adenoma/carcinoma (Muir-Torre)
Other
- IBD (UC > Crohn's colitis), primary sclerosing cholangitis
- Streptococcus gallolyticus (bovis) bacteraemia/endocarditis -> always colonoscope
- Clostridium septicum bacteraemia
- Acromegaly
- Ureterosigmoidostomy
- Prior abdominal/pelvic radiotherapy
Natural history & complications
- 5-yr survival: stage I ~95%, II ~80-85%, III ~65%, IV ~15% (higher if resected oligometastatic)
- Adenoma -> carcinoma takes ~10 years sporadically; far faster in Lynch - hence 1-2 yearly, not 5-yearly, colonoscopy
- FAP untreated: CRC risk ~90% by 45; most need colectomy in late teens/early twenties
Recurrence
- ~80% of recurrences within 3 years - hence front-loaded surveillance
- Liver is the dominant metastatic site (portal drainage); rectal cancer also lung (systemic venous drainage below dentate line)
- Rising CEA on surveillance -> CT +/- PET to find resectable recurrence
Prognostic markers
- Stage (dominant), nodes examined, LVI/PNI, perforation/obstruction
- BRAF V600E - poor prognosis in metastatic disease
- MSI-H - better prognosis in stage II/III, and predicts immunotherapy benefit
- Persistent post-operative ctDNA - strongest predictor of recurrence
Complications
- Obstruction, perforation, fistula, bleeding
- Peritoneal disease -> malignant obstruction; consider stent vs stoma vs surgery
- Post-op: anterior resection syndrome, stoma complications, sexual/urinary dysfunction after TME
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