GIT Malignancy Flashcards
Oesophageal Cancer subtypes and associated distribution?
Squamous cell carcinoma (proximal third)
Adenocarcinoma (distal, GEJ)
Oesophageal cancer subtypes and associated risk factors?
SCC:
- Smoking
- Excvessive etoh
- HPV (weak)
Adeno
- Barrett’s
- Obesity
- Smoking
- Absence of H pylori
Hereditary Oesophageal cancer syndromes?
Howel Evans Syndrome
- AD, RHBDF2 gene
NEPPK (non-epidermolytic palmoplantar keratosis)
- Essentially howel-Evans syndrome without the palmoplantar keratosis
- AD, RHBDF2 gene
Familial Barretts oesophagus
- AD
Bloom Syndrome
- AR, BLM/RECQL3 gene
Fanconi Anaemia
- AR
- BRCA2, FANCD1, FANCN gene
Main type of gastric cancer and subtypes?
95% Gastric Ca are adenocarinomas
2 main subtypes:
- Intestinal - most common, well differentiated. Chronic inflammatory process fro chronic gastritis -> cancer. Elderly male. Good prognosis
- Diffuse - Undifferentiated, located in proximal stomach. Associated with lichen plastica. Poor prognosis
Hereditary gastric cancer syndromes (some also associated with other forms of cancers ie CRC)?
Hereditary diffuse gastric cancer
- AD
- CDH1 gene
- Need prophylactic gatrectomy
Lynch Syndrome (aka HNPCC)
- AD
- EPCAM, MLH1, MSH2, MSH 6, PMS2
Juvenile possibly syndrome (JPS)
- AD
- SMAD4, BMPR1A
Peutz Jegher syndrome (PJS):
- AD
- STK11
Familial Adenomatous Polyposis (FAP)
- AD
- APC gene
Treatment for Resectable oesophageal and gastric cancers?
Oesophageal / GEJ:
- neoadjuvant carboplatin/paclitaxel, resection, adjuvant immunotherapy
GEJ / gastric:
- Perioperative chemo (FLOT4)
Gastric:
- Adjuvant capecitabine plus oxaliplatin (CAPOX) chemo
Treatment for unresectable oesophageal cancers?
Definitive chemotherapy with platinum + flurouracil
Treatment for advanced / metastatic esophageal / gastric cancers?
HER2 Negative ~80%
- 1st line - a platinum + fluropyrimidine + immunotherapy
HER2 amplified - IHC 3+, or IHC 2+ / ISH +ve (~20%)
- 1st line - a platinum + fluropyrimidine + trantuzumab
Two types of dumping syndrome and their associated symptoms?
Early Dumping - occurs 30 mins post meal
- Cause - hyperosmolar content into small bowel draws water in
- GIT Sx - abdo discomfort, nausea, dia, bloating
- Vasomotor symptoms - Flushing, palp / tachycardia, sweating
Late Dumping - occurs after several hours
- Cause - carb dump leading to hyper insulin state and hypoglycemia
- GIT Sx: - Hypoglycemia
Vasomotor Symptoms - tired, faint, hunger, sweatign (low BSL Sx)
Dumping syndrome management?
Lifestyle and diet modification:
- small regular meals, rather than big meals
- delay fluid intake until at least 30 mins following meal
- Avoid high GI carbs
- Lie down after meal - avoids hypovolaemia symptoms
Pharm
- Short acting somatostatin anologues (ie octreotide)
- Acarbose in late dumping (nil effect in early dumping)
Surgical
- Nil
Pancreatic cancer most common location?
70% located in panc head
Pancreatic cancer subtypes?
Adenocarcinoma (95%)
NET (5%)
Pancreatic cancer risk factors?
Smoking
heavy etoh
high BMI
Long term DM
Inherited GIT cancer syndromes that increase risk of pancreatic cancer?
Familial component in 10% of cases of pancreatic cancer cases
- Peutz-Jegher syndrome
- Lynch syndrome
- BRCA1/2 mutation - more so BRCA2 mutation
Explain the role of BRCA genes and PARP proteins and the MOA of PARP inhibitors?
BRCA1/2 are tumor suppressor genes that play a fundamental role in a DNA repair pathway called homologous recombination repair
Mutations can be germline or somatic (tumor only) variants
PARPs are a large family of proteins which facilitate DNA repair in pathways involving single strand breaks.
Inhibition of PARPs with a PARP inhibitor leads to accumulation of single strand breaks which eventually results in double strand breaks (synthetic lethality)
- therefore PARP inhibitors are only good in pts with BRCA mutations
What is synthetic lethality?
Synthetic lethality is a type of genetic interaction where the combination of two genetic events results in cell death or death of an organism
For example, combination of BRCA1/2 mutation and PARP inhibition leads to cell death
Pancreatic cancer prognosis and treatment?
Very poor prognosis even if early Dx
Treatment:
- resectable - upfront surgery followed by adjuvant chemo
- Boarderline resectable - consider neoadjuvant chemo followed by surgery (emerging)
- Locally advance / metastatic - chemoradiotherapy / systemic therapy
Olaparib is associated with significant increase in PFS in metastatic pancreatic cancer compared to placebo
Pancreatic cancer complications?
Biliary obstruction (common, 70%)
- Biliary stenting or PTC insertion
Gastric outlet obstruction (10-25%)
- Enteric stenting, PEJ tube insertion
- Duodenal bypass surgery if prognosis >3-6 months
Tumor associated abdo pain
- usually due to coeliac plexus involvment
- Consider coeliac plexus neurolysis (block that results in damage to nerves) / radiotherapy
Thromboembolic disease
- very thrombotic cancer. currently no need for prophylactic anticoagulation
GI bleeding
Gastro intestinal stromal tumours (GIST) basic details?
Mesenchymal tumour related to connective tissue / smooth muscle
Rare cancer, but most common form of GI sarcoma
Occurs in stomach (50-60%), small intestines (30-40%), but can arise anywhere in GI tract
Characterized by spindle shaped cells
Genetic mutation associated with GIST?
95% express KIT
- activating mutation in KIT or PDGFRA gene
Treatment of GIST?
Imatinib -> dose escalation -> sunitinib -> regorafenib -> ripretinib
Risk factors for HCC?
Major risk factor is chronic liver disease:
- HBV
- HCV
- Chronic etoh consumption
- NAFLD (including NASH)
- genetic haemochromatosis
What does HCC screening involve and who should be screened?
HCC screening in at risk individuals (ie pts with CLD)
Screening involves 6 monthly AFP and liver USS
Diagnosis of HCC?
HCC is one of the only cancers that can be Dx based on imaging (nil tissue required)
- Quad phase CT - single lesion with arterial hypervascularity and wash out on portal venous phase
Other components of Dx include:
- rising AFP
- Biopsy in selected cases
Treatment of HCC?
Resection or transplantation (curative potential)
Locoregional therapies (nil curative but can be bridge to curative therapies)
- TACE, ablation, RT
Systemic therapies in pts with unresectable metastatic HCC (advanced disease)
- Atezolizumab (PDL1) + bevacizumab (VEGF). Otherwise Lenvatinib (VEGFR1,2,3) or sorafenib
- Not much benefit with systemic cytotoxic chemo
- Systemic therapy only offered to CPA cirrhosis pts (not decompensated disease)
Transplant criteria for HCC?
Milan criteria or UCSF criteria
UCSF criteria:
- single nodule <6.5cm diameter
- </=3 modules, each </= 4.5cm each. Total dia </= 8cm
Colorectal Cancer histological variants?
Adenocarcinoma (>90%)
Mucinous
signet ring carcinoma
Classification / main types of CRC?
Sporadic (60-65%)
Familial (25%)
- familial association however nil identified gene defects
Hereditary
- HNPCC
- FAP
Main features in CRC carcinogenesis?
Chromosomal instability (CIN)
- errors during mitosis leading to abnormalities in chromosomal number and structure
CpG island Methylator Phenotype (CIMP)
- MLH1 promotor hypermethylation
Microsatelite instability (MSI)
- Loss of MMR genes (MLH1, MSH2
- CIMP and MSI are strongly corrolated
- BRAF mutation strongly associated with sporadic CRC (ie BRAF mut = sporadic)
Gene defects in HNPCC / Lynch syndrome?
Mutations in MMR genes: MLH1, MSH2, MSH6, PMS2
- MSH2 and MLH1 are in >90% of cases
Basic details of HNPCC / lynch syndrome?
AD inheritance, high penetrance
Results in right sided colon cancer
Often poorly differentiated, mucinous and infiltrating lymphocytes
MMR gene defects: MLH1, MSH2, MSH6, PMS2
Diagnostic criteria for HNPCC / Lynch Syndrome?
Amsterdam criteria (3-2-1 rule)
- at least 3 relative with any lynch syndrome associated cancer
- at least 2 consecutive generations affected
- at least one relative Dx before age of 50yrs
Surveillance and surgery in HNPCC / Lynch syndrome?
Surveillance from age of 25yrs, or 5 years younger than youngest affected family member
Surveillance C scope every 1-2 years
Surgical management with extended colectomy (subtotal or total colectomy preferred)
Annual survailence of residual colon
NSIAD chemoporphylaxis (aspirin 600mg daily)
Basic details of FAP? Associated cancers?
AD inheritance, high penetrance
Results in 100s of distal left sided polyps from adolescence
Risk of CRC is 100% at age >40yrs
Other associated cancers
- papiliary thyroid
- Gastric
- Ileal Carcinoid
Gene defect in FAP?
Germline APC mutation
Surveillance and surgery in FAP?
Endoscopic survailence from age 10-15yrs (or earlier if GI symptoms)
Sigmoidoscpy sufficient due to predominate left sided polyps
Colectomy usually between age 15 and 25yrs
NSAID chemoprophylaxis when surgery inappropriate
Population screening for CRC?
FOBT every 2 years from age 50 - 74yrs
Low participation 40% of population currently
Treatment of CRC?
Locally advanced (stage II or III) disease
- Neoadjuvant chemoradiotherapy, followed by surgery (total mesorectal excision) +/- adjuvant chemotherapy
- Total neoadjuvant therapy involves systemic chemo and chemoradiation before surgery (ie systemic chemo with Folfirinox, then cRT, then surgery)
Folfirinox = folinic acid, furouricil, irinotecan, oxaliplatin
Locally advances (stage II or III) disease with “high risk” features
- High risk features include: T4 disease, poorly differentiated, presence of obstruction, perforation etc
- Neoadjuvant chemoradiotherapy, followed by surgery (total mesorectal excision) + adjuvant chemotherapy
- Adjuvant chemo with 3-6/12 fluropyrimidine (5-FU/capecitabine) + oxaliplatin
- limited role for irinotecan / bevacizumab / EGFRi in adjuvant setting
Advanced / metastatic CRC - targeted therapies
- mCRC with KRAS mutation (KRAS found in 70% of mCRC) -> KRASi (Divarasib) +/- EGFRi
- mCRC with EGFR mutation -> first line chemo + EGFRi (cetuximab, panitumumab)
- mCRC with VEGF mutation -> first line chemo + VEGFi (Bevacizumab)
- mCRC with BRAF mutation -> BRAFi (encorafenib) + EGFRi (cetuximab) + MEKi (Binimetinib)
- mCRC with MSI-h -> 1st line PD-1 inhibitor (pembrilizumab)
Common GIT chemotherapy agents related toxicities?
Fluropyrimidines (5-FU, capecitibine, etc)
- Diarrhoea, hand foot syndrome, coronary artery vasospasm
Oxaplatin
- Acute neurotoxicity agrevated by exposure to cold
- cold induced pharyngolaryngeal dysesthesia
EGFR cancer pathway downstream components?
EGFR (cell surface receptor)
KRAS
BRAF V600E
MEK
ERK
Activation leading to stimulation of cell growth and cancer
