GI cancer Flashcards
With regards to colonoscopy - what reduces risk of developing colorectal cancer
- Higher adenoma detection rate at colonoscopy by a skilled physician - each 1% increase in adenoma detection rate A/W 3% decrease in risk of cancer
Gene mutations associated with:
- Peutz-Jeghers
- Familial adenomatous polyposis
- HNPCC
- Peutz-Jeghers → STK11 (LKB1)
- FAP → MUTYH
- HNPCC → MSH2
Epidemiology colorectal cancer,
2nd most highest diagnosed cancer (behind breast and prostate)
Median age diagnosis 70
Increased incidence in patient’s <50 years (⅓rd patients) → ? increased obesity, increase in antibiotics use, sedentary lifestyle
Bowel screening
FOB test, every 2 years in 50-74 year olds
Test for human globin in stool
8% have a +ve result → colonoscopy. One in 29 diagnosed with cancer (most common cause of positive result → haemorrhoids, diverticular disease)
41% Australian’s eligible have taken the test
Risk factors colorectal cancer
- IBD → UC. Crohn’s risk likely due to pancolitis and similar to UC
- Previous abdominopelvis radiation
- Screening 5 years after radiation or at 30 years
- Obesity (early adulthood weight gain)
- Diabetes and insulin resistance (independent of obesity)
- Meat consumption (?processed meats)
- Family history (1st degree relative diagnosed before 45 years
Genetic conditions that lead to polyposis and notes on mismatch repair
FAP, MUTYH-Associated polyposis
< 1% CRC
>100 polyps with 90% risk of developing CRC by 45 years (FAP)
Due to loss of adenomatous polyposis coli (APC) gebe on chromosome 5
MAP due to loss of MUTYH gene → failure of base excision pathway
Lynch syndrome (HNPCC)
3% CRC
Loss of MLH1 (can be sporadic due to promotor methylation), MSH2, PMS2, MSH6 → presence of repeat sequences DNA → microsatellite instability
Lifetime risk if 50% in MLH1 deficienct
Mismatch repair
Large increases in DNA sequences → referred to as microsatellites
Leads to mutator phenotype, development of neoantigens
Engagement of the immune system leads to these being better CRC
Neoantigens are good for immunotherapy permitting points of differentiation
Significance of bowel anatomy in colorectal cancer
- Arterial supply of colon determines operation and level of resection (anastomotic integrity critical)
- Venous supply suggests metastatic pattern e.g. rectal cancer more commonly → lungs due to venous drainage direct into IVC
- Surgery diagnostic, pathologically stages the tumours, and can cure the patient
- Measures of surgery are margins (aim for R0 resection) and lymph node yield → most guidelines minimum 14 lymph nodes
Notes on rectal cancer
- Local recurrence an issue due to proximity to other structures (bladder, vaginal vault)
- T3-T4 neoadjuvant chemoradiotherapy due to risk of local recurrence. Either short course RTX or long course chemoradiotherapy (in combo with radiosensitising chemo → 5FU, capecitabine). Long course superior for local tumour response, local control and disease free control.
- Improve chance of R0 resection. Patients who achieve a complete response have an excellent prognosis (16-27%)
- Non-randomised data on these patients → successful management without surgery 0 risk of relapse approx 15.7% at 3 years, 95% sucessfully undergo salvage therapy
Role of staging in adjuvant chemotherapy
- Adjuvant chemo for Stage 3 colorectal cancer (lymph node positive) and high risk stage 2 disease
- T4 disease (extending into peritoneum), presenting with obstruction or perforation, inadequate node sampling, presence of lymphovascular or perineural invasion
- Benefit in stage 2 disease not clear and area of controversy
Circulating tumour DNA
- Assesses the presence of circulating tumour DNA in those who have had a curative procedure → should not have ctDNA if you’ve had a definitive operation
- Those ctDNA positive post-op with almost all recur → has been shown to demonstrate response and recurrence to adjuvant therapy in Stage 2 disease
- Current studies to look at using it as a toole to escalate or de-escalate therapy in locally advanced rectal cancer
- Recent study → assessing high risk stage 2 disease on basis of ctDNA rather than high risk features as listed above → if positive adjuvant chemo. Less patients recevied adjuvant chemo and demonstrated to be non-inferior at 2 years
Notes on adjuvant chemotherapy
- Mop up micro-metastatic disease
- Fit patients - adjuvant chemo with fluoropyrimidine (5FU or capecitabine) and oxaliplatin i.e. FOLFOX or CAPOX
- FOLFOX fortnightly, 46 hr infusion of 5FU
- 5FU requires leucovorin to increase it’s half life (impaired metabolism of 5FU)
- Capecitabine → PO analogue of 5FU, administered twice daily, for 2-3 weeks
- DPYD deficiency - used to metabolise fluoropyrimidines, 1% population deficient → leads to gross over-exposure → severe mucositis, neutropaenia, can be fatal
Surveillance guidelines in colorectal cancer
- ASCO Guidelines
- Those who haven’t had a full colonscopy at diagnosis require one at conclusion of treatment
- Then at 3 years, then 5 yearly
- Physical exam, with CEA (expressed in 70% CRC) 3 monthly for 3 years, then 6 monthly
- CT CAP annually for 3 years
Management of metastatic colorectal cancer
- Stage 4 disease - 4a = confined to one metastatic organ, 4b = multiple organ involvement
- 25% colorectal cancer present as denovo metastatic disease, 50% of those with local disease will relapse
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Pattern of metastatic spread influenced by:
- Primary tumour site (left, right, rectum)
- R) sided cancers present later with metastatic disease
- Mutation status (RAS/RAF) - predictive and prognostic
- Absence of RAS/RAF mutations (i.e. RAS/RAF wild-type) predictive of response to EGFR directed therapy
- BRAF mt poor prognosis → rapid development of chemotherapy resistance and often nodal spread
- MMR status - MSI-H (dMMR) do poorly
- Primary tumour site (left, right, rectum)
- Stage 4b disease → palliative chemotherapy
- FOLFOX and FOLFIRI (5FU, leucovorin, irinotecan) or capecitabine
- Combined with a targeted agent (no role for targeted treatments in adjuvant chemo)
- VEGF inhibitors → bevacizumab
- EGFR → cituximab, panitumimab
- Stage 4a → aim at cure. Most common site of met liver (56%), lung (5%) and peritoneum
- 3 months neoadjuvant chemo prior to resection (evidence not strong and no established survival benefit)
- Aggressive surgical approach → 5YS 40%. 10% in chemotherapy alone
Notes on pembrolizumab in colorectal cancer
Keynote 177
- PFS more than 8 months longer for pembrolizumab compared with chemotherapy alone, 40% risk reduction in disease progression
