GI malignancy Flashcards
2 histologic subtypes of oesophageal ca
Squamous (mid-proximal)
Adenocarcinoma (distal, GEJ) *Western countries more common
Risk factors for oesphageal ca
SCC
Smoking
Excess ETOH
HPV (weak)
Adenocarcinoma Barrett's Obesity Smoking Absence of H.pylori
Gastric cancer 2 main subtypes
95% adenocarcinomas
Diffuse - undifferentiated (30% of cases)
- Proximal stomach
- Associated with linitus plastica
- Inferior prognosis
Intestinal - well differentiated (reducing but still more common ~50%)
- Evolves from chronic gastritis
- Elderly male
- More favourable prognosis
Risk factors gastric ca
H pylori, smoking, high salt intake, obesity, EBV
CDH1 mutation (hereditary diffuse gastric ca)
Lynch syndrome
Polyposis syndrome - FAP, Peutz-Jeugers
Hereditary diffuse gastric ca
Autosomal dominant
CDH1 mutation
Prophylactic total gastroectomy recommended between 18-40 years
Women with CDH1 mutation increased risk of breast ca
How to stage gastric cancer?
TNM
Rx localised oesophageal/gastric ca
Resectable
- Neoadjuvant chemo (docetaxel/5FU/oxaliplatin) –> surgery
Unresectable
- Definitive chemoradiotherapy
Asian population benefit from chemo post resection
Rx advanced/metastatic oesophageal/gastric ca
HER2 neg
1st line: platinum + fluoropyrimidine
HER2 positive (poor prognosis)
1st line: platinum + fluoropyrimidine + trastuzumab
Many anti-HER2 agents have shown NEGATIVE results
If no response to first line, generally poor prognosis
Dumping syndrome post gastrectomy
GI and vasomotor symptoms due to rapid emptying of gastric contents into small bowel
Can be early or late dumping
Early (10-30 min after): abdo discomfort, nausea, diarrhoea, bloating
Late (4 hours after): hypoglycaemia (excess insulin release)
Management: mainly lifestyle modification
Vitamin deficiencies after upper GI surgery
Vitamin B, iron deficiency –> anaemia
Fat soluble vitamins A, D, E, K
Majority of pancreatic ca is located where?
70% pancreatic head
Risk factors pancreatic ca
Smoking
ETOH +++
High BMI
Chronic DM (especially with weight loss)
Genetic predisposition pancreatic ca
Familial component 10% of cases
Peutz-Jeghers syndrome
Lynch syndrome
BRCA 1/2
staging pancreatic ca
TNM
Treatment pancreatic ca
1) Resectable
2) Borderline resectable
3) Metastasis/unresectable
Depends on resectability
10-15% resectable –> surgery + adjuvant chemo
30-40% borderline resectable –> consider neoadjuvant chemotherapy (not mainstream) –> surgery
50-60% metastasis/unresectable - -> chemotherapy + systemic therapy +/- radiotherapy
Chemo: doublet or triple regimen e.g. Nab-paclitaxel/gemcitabine, FOLFIRINOX (5FU/oxaliplatin/irinotecan)
PARP and BRCA mutation
Explain pathophysiology in pancreatic ca
BRCA repairs double strand DNA breaks = homologous recombination repair
PARP repairs single strand DNA breaks
If one strand breaks, and we inhibit PARP, it is unable to be repaired. Single strand breaks eventually turn into double strand breaks –> mutated BRCA is unable to undergo homologous recombination repair –> cell death
PARP inhibitor toxicity
Fatigue
nausea
anaemia
GI symptoms - abdo pain, diarrhoea
Rx BRCA mutated metastatic pancreatic ca
PARP inhibitor - olaparib
Complications of pancreatic ca
Biliary obstruction 75%
- Biliary stenting/percutaneous drainage
Gastric outlet obstruction 25%
- Enteric stent/PEG, duodenal bypass
Abdo pain (invade into coeliac plexus) - Consider coeliac plexus neurolysis/radiotherapy
Pancreatic exocrine insufficiency - steatorrhoea, abdo cramps
- Creon replacement therapy
Thromboembolic disease
GI bleed due to invasion into adjacent structures (poorer prognosis)
- Endoscopic, radiotherapy, angiographic embolisation
Which factor is the most important in determining suitability to commence chemotherapy?
ECOG performance status
GIST features
Mesenchymal tumour related to CT/SM Spindle shaped cells 95% express c-kit mutation Rare ca, but most common sarcoma of the GIT Stomach > small intestine
Prognostic factors GIST
Large tumour size
High mitotic count
Non-gastric locations
Rx GIST
TK inhibitors
Imatinib –> dose escalation –> sunitinib –> Regorafenib
GIST histology
Spindle shaped cells, 95% express C-KIT mutation
HCC risk factors
HBV, HCV
Chronic ETOH
NAFLD, NASH
Genetic haemochromatosis
HCC screening involves
All liver cirrhotic patients
Abdo USS + AFP every 6/12
Diagnosis of HCC
Arterial hypervascularity and ‘wash out’ on portal venous phases (multi-phase CT)
Rising AFP
Biopsy in selected cases - increasingly done now due to better techniques(due to risk of seeding)
Management HCC
1) BCLC A+B
2) BCLC C
3) BCLC D
Depends on resectability
1) BCLC A+B
Resection, transplant = best cure
- Resection is difficult in portal HTN. Transplant preferred.
Locoregional therapies (TACE, ablation, RT) = not curative but can be a bridge to curative therapies
2) BCLC C
Systemic therapy in advanced disease
- Child pugh A (good liver function) only
- PDL1 inhibitor (Atezolizumab) + Anti-VEGF (bevacizumab) 1st line
3) BCLC D
Best supportive care
HCC and liver transplant follow which criteria?
Milan criteria
- Single tumour ≤5cm or ≤3 nodules ≤3cm
Expanded criteria (UCSF criteria)
- Single lesion ≤6.5cm
- ≤3 nodules, each ≤4.5cm
- Total tumour diameter ≤8cm
CRC most common histology is….
> 90% adenocarcinoma
Histologic variants include mucinous and signet ring cell carcinoma = inferior prognosis
3 main types of CRC
3 main types
- Sporadic 65%
- FHx but no associated gene identified 25%
- Hereditary 5% - HNPCC ie Lynch syndrome, FAP
Features of Chromosomal instability (CIN) in CRC
Something wrong with the actual chromosome/gene
APC gene - FAP
KRAS gene
TP53 gene
Lt sided colon
Younger male
Features of CpG island methylator phenotype (CIMP) in CRC
MLH1 promoter hypermethylation
Rt sided colon + transverse colon up to splenic flexure
Can be associated with MSI high, BRAF mutation
Older females
Features of MSI high in CRC
Loss of MMR protein (most due to MLH1 methylation)
CIMP and MSI are correlated. 70% of MSI-high CRC are also CIMP-high
Key differentiation is BRAF mutation which is strongly associated with sporadic origin i.e. CIMP
What are the 3 carcinogenic pathways in CRC?
1) Adenoma-carcinoma sequence
- Small adenoma –> large adenoma –> cancer
- CIN-high
- 90% of sporadic CRC
2) Serrated pathway
- Hyperplastic polyp –> sessile serrated adenoma –> cancer
- CIMP-high
- 10% of sporadic CRC
3) Inflammatory pathway
- <2% of all CRC
Lynch syndrome/HNPCC
How common?
What is it?
Where is the mutation?
3% of CRC
Genetic syndrome
Autosomal dominant with high penetrance
Rt sided colon cancer (early onset), endometrial ca, ovarian ca
Mutation in mismatch repair genes (MMR): MLH1, MSH2, EPCAM, MSH6, PMS2
[From high to low risk]
MMR usually goes and repair genes –> when it doesn’t work, small genetic mutations accumulate –> ‘microsatellite instability’
Often poorly differentiated, mucinous and infiltrating lymphocytes
Diagnosis lynch syndrome
Amsterdam criteria “3-2-1’ rule
At least 3 relatives with associated lynch syndrome cancer (CRC, endometrial, small bowel, ureter, or renal pelvis)
2 successful generations should be affected
1 should be diagnosed before age 50
Surveillance and surgical management of lynch syndrome
Surveillance colonmoscpy every 1-2 years
Commence at age 25 or 5 years younger than the youngest affected family members if <30 years
Extended resection generally favoured. Annual surveillance required for residual colon.
High dose Aspirin prophylaxis 600mg daily for 2 years reduce Lynch-syndrome associated cancers
FAP features
How common? Cause? Clinical features Risk of CRC Associated cancers
<1%
Germline APC mutation
Autosomal dominant with high penetrance
Polyps ++++
Distal left sided colon, beginning from adolescence
Risk of CRC 100% by age 40
Other associated ca: papillary thyroid, gastric ca, ileal carcinoid
Surveillance and surgical management for FAP
Colonoscopy from age 10-15
In classical FAP, sigmoidoscopy is adequate since adenoma occur simultaneously throughout the colorectum
Once an adenoma is identified, annual colonoscopy until colectomy
Colectomy at age 15-25
NSAID chemoprophylaxis if surgery inappropriate
Population screening CRC
Immunochemical FOBT
Age 50-74
Every 2 years
Current screening participation 40%
Cost effective
Improve CRC mortality
Diagnose at earlier stage
Screening for people with FHx CRC
3 categories
1 - near average risk
- iFOBT every 2 years from age 50-74 (same as general population)
2 - moderately increased risk
- iFOBT every 2 years from age 40-49
- Colonoscopy every 5 years from age 50-74
3 - potentially high risk
- iFOBT every 2 years from 35-44
- Colonoscopy every 5 years from age 45-74
Fluoropyrimidine toxicities
Includes 5-FU infusion, oral capecitabine
Diarrhoea, hand-foot syndrome, coronary artery spasm
DPD enzyme - exaggerated toxicities which can be life threatening - diarrhoea, mucositis, myelosuppression
Irinotecan toxicities
Diarrhoea, neutropenia, myelosuppression
Acute cholinergic syndrome (early onset diarrhoea) Rx atropine
UGT1A enzyme deficiency - toxicities
Oxaliplatin toxicities
Diarrhoea, neutropenia
Acute neurotoxicity - aggravated by exposure to cold, sensory and motor. Cold induced pharyngolaryngeal dysethesia 1-2%
Chronic neurotoxicity mainly sensory, usually reversible
Advanced/metastatic CRC KRAS mutation
40% mCRC
Ligand binds to EGFR receptor –> downstream signalling K-RAS –> RAF –> MEK –> ERK —> DNA transcription –> cell proliferation, survival, cancer
If you have a KRAS mutation, blocking EGFR (cetuximab/panitumumab) is not sufficient to block downstream pathways
EGFRi - cetuximab/panitumumab toxicities
Acneiform rash
Diarrhoea
Electrolyte derangement
Skin and nail toxicities
Bevacizumab in CRC
MOA
Toxicities
Monoclonal ab against VEGF-A
Inhibits new vessel growth, normalises tumour blood flow and allows chemo to be delivered to the tumour
Used in conjunction with chemo
Toxicities: HTN, proteinuria, GI perforation, VTE, delayed wound healing
BRAF V600 mutation in mCRC management
Aggressive
Poor prognosis
Single BRAFi is not good enough
Encorafenib (BRAFi) + cetuximab (EGFRi) + Binimetinib (MEK inhibitor) - not standard of care at the moment but great results in 2nd line and beyond
MSI-h in mCRC management
PD1 inhibitor with pembrolizumab
1st line
Types of pancreatic ca
Adenocarcinoma (95%)
Neuroendocrine
Lymphoma
Sarcoma
Clinical presentation of pancreatic ca
Head of pancreas (70%)
- Obstructive jaundice
Others
- Epigastric/back pain
- LOW, LOA
- Fatigue
- Malabsorption
Often vague sx leading to late presentation
Tumour marker for pancreatic Ca
CA19-9 (also for other GI ca)
Role of PARP inhibitors in pancreatic ca with BRCA mutation
Increased PFS but not overall survival
Hence not currently PBS funded
How to stage HCC?
Barcelona clinic liver cancer staging
Combines tumour stage, liver function and ECOG
Risk factors for CRC
IBD
- Especially those with PSC (UC)
Previous abdominopelvic radiation
Obesity
Diabetes/insulin resistance
Processed meats
How does mutation in mismatch repair gene cause CRC?
Mismatch repair gene mutation –> deficient mismatch repair –> large increases in DNA sequences referred to as ‘microsatellites’ –> frameshift mutation –> CRC
Treatment of T3/T4 rectal cancer
Neoadjuvant chemotherapy (to reduce risk of recurrence given proximity to other organs) –> wait 10 weeks –> surgery –> adjuvant chemotherapy
How to follow up curatively treated CRC?
Those who haven’t had a full colonoscopy at diagnosis require one at the conclusion of treatment, then at 3 years, then 5 yearly
Physical exam with CEA 3 monthly for 3 years, then 6 monthly
CTCAP annually for 3 years
Compare right sided and left sided CRC
Right sided
- More aggressive, worse prognosis
- BRAF mutations
- More active immune cells promoting immunogenicity
Left sided
- RAS/RAF mutations
Treatment of early stage CRC (stage 1 and 2)
Curative surgery +/- adjuvant chemotherapy (benefit is ~5% in stage 2 high risk patients)
If MSI high, no need for adjuvant chemotherapy
Treatment of stage 3 CRC (lymph node positive)
Surgery + adjuvant chemotherapy (5FU/capecitabine + oxaliplatin) for 3-6/12
Treatment of stage 4 CRC
Oligometastatic and resectable
Surgery +/- adjuvant chemotherapy (5FU/capecitabine + oxaliplatin)
Treatment of stage 4 CRC
Oligometastatic and partially resectable
Neoadjuvant chemo –> surgery –> adjuvant chemo
Treatment of stage 4 CRC
Unresectable disease
Doublet chemotherapy (5FU/capecitabine PLUS oxaliplatin or irinotecan)
If RAS/RAF wildtype: add EGFR inhibitor (panitumumab or cetuximab)
If RAS/RAF mutation: add VEGF inhibitor (bevacizumab)
If MSI high (not yet PBS approved): immunotherapy (pembrolizumab or nivolumab or ipilimumab with nivolumab)
Cancer genetic testing is now available for 3 conditions. What are they?
1) All high grade serous ovarian ca (non-mucinous) <70 years
2) All triple neg breast ca <50 years
3) Breast ca with manchester score >15 (>10% pre test probability of BRCA1/2 mutation)
