GenSurg.nz

Gastric adenocarcinoma

Section: UGI Sub-section: Gastric Curriculum: Curriculum, page 96

Definition

  • Malignant epithelial tumours of the gastric mucosa with glandular differentiation
    • Includes Siewert & Stein III
      • Anything > 2cm from GOJ
    • Excludes cardia (which is treated as GOJ/Oesophageal)

Epidemiology

  • Incidence
    • 7/100,000 in NZ
    • Māori & PI > European 20/100,000
  • M > F 2:1
    • Except diffuse type F>M 1.2:1
  • Rare < Age 50
  • 2nd most common cancer world-wide
    • Incidence decreasing, esp. in West (? due to H. pylori management)
  • Incidence highest in Japan (>40/100,000)
    • In migrants: subsequent generations (after 1st) acquire risk rate of their new environment

Risk factors

  • Male
  • Lifestyle factors
  • Environmental (dietary) factors
  • Infectious
  • Genetics
    • Blood group A
      • Increased risk (RR ≈ 1.2) (Diffuse type)
  • Other Risk Factors
    • Hypertrophic gastropathy (Menetrier’s disease)
    • Pernicious anaemia
    • Previous gastric surgery
    • Adenomatous gastric polyps
    • Hyperplastic polyps

Lifestyle Risk Factors

  • Cigarette smokers:
    • 2-3x increased risk of proximal Gastric Ca
  • High EtOH intake
  • Low socioeconomic status
  • Obesity

Environmental (Dietary) Risk Factors

  • High salt, smoked meats, poorly preserved food
    • Nitrates in the food converted to carcinogenic N-nitroso compounds by bacteria in the stomach
      • Note N-nitroso compounds also in cigarette smoke
    • Synergism with H. pylori
      • H. pylori promotes growth of bacteria that increase N-nitroso compounds
      • H. pylori inhibits secretion of ascorbic acid, (see below)
  • Fruit & vegetables → Protective
    • Release ascorbic acid
    • Ascorbic acid removes carcinogenic N-nitroso compounds and scavenges free radicals.
  • Calcium, Vitamin A, Vitamin C (anti-oxidant activity) → Protective
    • Stop conversion of nitrates to nitrites

Infectious Risk Factors

  • H. Pylori
  • EBV associated Gastric Ca
    • Present in carcinoma cells

Genetic Risk Factors

Hereditary diffuse gastric carcinoma syndrome

  • Autosomal dominant, Penetrance 70-80%
  • Germline mutations in CDH1 (16q) gene
    • Encodes the cell adhesion protein E-cadherin
  • Predisposition to
    • Diffuse-type Gastric Cancer
    • Lobular Breast Cancer
    • Signet Ring Colon Cancer
  • Management
    • Prophylactic Total Gastrectomy after age 20 recommended
      • Surveillance Gastroscopy from 16
      • Lifetime risk 80%, average age of cancer 38
    • Breast screen from age 35
      • Cumulative lifetime risk 50%
    • Recommend colonic screening
  • Diagnosis
    • For diagnosis (Familial condition) must have at least
    • 2 family members with one being diagnosed < 50
    • OR 3 family members

Other Genetic Risk Factors

  • Familial adenomatous polyposis

    • 85% of patients have Fundic Gland Polyps
      • 40% of these have dysplasia
    • Also much higher frequency of potentially malignant duodenal polyps
    • Surveillance Gastroscopy recommended

  • Menetrier’s Disease

    • Overview
      • Hypoproteinaemic Hypertrophic Gastropathy
      • Rare, acquired disease, Pre-malignant
      • Characterised by massive gastric folds in the fundus and body
      • Gives mucosa cobblestone or cerebriform appearance (looks like brain!)
    • Pathology
      • Foveolar Hyperplasia
        • Expansion of surface mucous cells, and loss of parietal cells
        • Typical changes seen on endoscopy
      • Protein loss from the stomach
      • Excessive mucus production
      • Hypo or achlorhydria (gland atrophy)
    • Aetiology
      • Unknown - ? CMV infection in children, ? H.Pylori in adults
    • Presentation
      • Epigastric pain, vomiting, weight loss, anorexia, peripheral oedema
    • Investigations
      • Gastroscopy and biopsy to R/O gastric carcinoma or lymphoma
      • Can do 24hr pH monitoring to detect low acid levels
    • Management
      • Anticholinergics, PPIs, Octreotide, H.pylori eradication
        • Inconsistent results
      • Consider total gastrectomy if
        • Massive ongoing protein loss despite medical therapy
        • Dysplasia or carcinoma on biopsy

  • Genes implicated in Gastric Ca:

    • C-met, c-erbB2, K-sam, E-cadherin
    • Microsatellite instability seen in 20-30% of intestinal type Gastric Ca
    • E-Cadherin reduction/absence seen in 50% of diffuse type Gastric Ca

Other Risk Factors

  • Pernicious Anaemia – 3-4x increased risk
    • Achlorhydria and mucosal atrophy with antral/intestinal metaplasia
  • Previous gastric surgery → RR 2
    • Roux-en-Y or previous peptic ulcer disease surgery
    • Due to
      • Alkaline duodenal gastric reflux
      • Or Bacterial overgrowth (increased conversion of nitrates)

Adenomatous Gastric polyps

  • 10-20% risk of developing carcinoma
  • Increases with size of polyp
  • Polypectomy sufficient if no in-situ or malignant cancer
  • Often has atypia
    • If > 2cm, sessile or proven cancer then should be treated as per Gastric cancer
  • Hyperplastic polyps associated increased risk
    • Probably because they form in stomach with established gastritis

Classification Systems

Systems

  • Siewert and Stein
    • For GOJ cancers
  • Lauren Classification
    • Microscopic/Histological
  • WHO Classification
  • Bormann’s Morphologic Classification
  • Paris classification

Siewert & Stein Classification

  • System of anatomical classification used for adenocarcinomas of the GOJ
    • Type I:
      • Tumour center 1-5cm above GOJ
      • Usually arises from Barrett’s
      • Lymphatic spread to Mediastinal and Coeliac LNs
    • Type II:
      • Arises 1cm proximal or 2cm distal to the GOJ
    • Type III: Proximal Stomach
      • Center of tumor lies 2-5cm below the junction, but invades the cardia area

Lauren Classification

  • Microscopic/Histological Classification system
    • Intestinal Type
      • Environmental → Gastric atrophy/intestinal metaplasia
      • M > W
      • Increasing age
      • Haematogenous spread
      • Microsatellite instability/APC gene mutation/P16/P53 inactivation
    • Diffuse type
      • More commonly familial and with blood group A
      • W>M, younger pts
      • Poorly differentiated, signet ring cell, transmural/lymphatic spread
      • Decreased E-Cadherin

WHO Classification

  • Histological Classification
    • Based on degree of resemblance to metaplastic intestinal tissue
  • Adenocarcinoma
    • Papillary
    • Micropapillary
    • Tubular
    • Mucinous
    • Signet Ring Cell
      • Contains > 50% Signet Ring Cells

Bormann’s Classification

  • Morphologic classification based on gross appearance of tumour
  • Type 0: Superficial (15%)
    • Usually seen as early gastric CA Protruded / superficial elevated / flat / superficial depressed / excavated types
    • Classified according to Murakami classification (similar to Paris)
  • Type 1: Polypoid (25%)
    • Large bulky growth
  • Type 2: Flat lesion with borders (25%)
  • Type 3: Ulcerated but flat borders
  • Type 4: Diffusely infiltrating/lateral spreading
    • Linitis plastica (10%)
      • Type 4 that involves whole stomach
  • Type 5: Doesn’t fit into categories above

Paris classification

Morphologic system for superficial gastric cancers/ Early Gastric Cancers

Clinical

  • Often asymptomatic, until advanced
    • Most present late
    • 65% T3/T4 stage
    • 85% LN mets at diagnosis
    • 50% present with unresectable locally advanced or metastatic
  • 95% with anorexia & weight loss ± vague abdo pain, N+V, early satiety (linitis plastica)
  • 50% non-specific symptoms, e.g. dyspepsia
    • NB: Only 1-2% of pts with dyspepsia have Gastric Ca finding
  • Ulcerated tumours may cause bleeding → hematemesis, melena, UGIB
    • 40% have some form of GI bleeding – anaemia or haematemesis
  • Advanced tumours may present with:
    • Palpable abdo mass
    • Cachexia
    • Bowel obstruction
    • Ascites / oedema
    • Hepatomegaly
    • Involvement of other organs from peritoneal seeding:
      • Ovaries: Krukenberg tumour
      • Pelvic cul-de-sac “Blumer’s shelf”
      • LN Metastasis
        • Supraclavicular LN = Virchow’s node ≡ Troisier’s sign
        • Left Axillary LN (Irish’s node)
      • Periumbilical node / metastatic deposit (Sister Mary-Joseph’s nodule)
      • Trousseau’s sign (migratory thrombophlebitis) – more common with Pancreatic Cancer
      • Acanthosis nigricans
      • Sign of Leser-Trélat

Pathology

Carcinoma Sequence

  • Invasive gastric carcinoma preceded by a cascade of precancerous lesions

Tumour Pathogenesis

  • 95% of Gastric Cancer = Adenocarcinoma

  • Others: Lymphoma (2%), GIST

  • Location

    • Antrum (50-60%) > Cardia (near GOJ) > Body
      • Trend is for more proximal location
    • Most cancers found on the lesser curve
      • As are benign gastric ulcers
      • However an ulcer on the greater curve is more likely to be malignant

  • Intestinal Type Gastric Ca

    • M > F (2:1), typically older age
    • Gland formation: well to poorly differentiated tumours
    • Haematogenous spread more common (than Diffuse)
    • Grow in expanding, rather than infiltrative, patterns
    • Occur secondary to chronic atrophic gastritis & intestinal metaplasia
    • H. pylori infection & Infiltration with MALT and neutrophils
      • Leads to damage to epithelial cells
      • Alterations in cell cycle with increased apoptosis and cellular proliferation
        • Results in atrophic gastritis
      • Nuclear and architectural abnormalities with progressive mutations leading to carcinoma.
    • Associated with cancer of cardia & distal oesophagus + antrum
    • Better prognosis than diffuse
    • Common genetic mutations:
      • KRAS, P53, APC, MMR genes, HER2

  • Diffuse Type Gastric Ca

    • M = F, younger, incidence increasing
    • Familial (Hereditary Diffuse Gastric Carcinoma) version
    • Less related to environmental influences
    • More associated with blood group A
    • Histology:
      • Poorly differentiated, lacks gland formation, composed of signet ring cells
      • Scattered, poorly cohesive cells with diffuse infiltration
      • Often exhibiting deep infiltration of stomach wall
      • May exhibit pronounced desmoplasia & associated inflammation with relative sparing of overlying mucosa
    • Metastasizes early via lymphatics > LN and transperitoneal spread
    • May arise from single-cell mutations within normal gastric glands
    • Linitis plastica more common
    • Prognosis poorer
    • Common gene mutations:
      • E-cadherin (50%), P53, C-met amplification, N-cadherin over exposure

  • Pathological Grade

    • Probably has less prognostic implication than in other cancers
      • Well differentiated
      • Moderately differentiated
      • Poorly differentiated
      • Anaplastic
    • Predominant patterns: Papillary, tubular, poorly differentiated, signet-ring cell, mucinous
    • Cytokeratin positive immunohistochemistry

Molecular pathology

  • Adenocarcinoma of stomach identified by histopathological markers. Positive for CK7, CDX2 (usually intestinal type). Negative for CK20, CK5/6, CK14, p63 and p40.
  • HER2 testing – metastatic gastric cancer could be eligible for Trastuzumab
  • VEGFR – could be eligible for ramucirumab
  • c-MET is a transmembrane tyrosine kinase receptor, amplified at higher frequency in diffuse-type gastric cancer. FGFR2 amplification also detected. Trials of these inhibitors have not been successful.
  • p53 mutation in 60% gastric carcinoma
  • APC 30-40% of moderately & well differentiated intestinal type. <2% of poorly differentiated diffuse-type gastric carcinoma
  • MSI 15-38%. MSH2, MLH1, MSH6, PMS1 & PMS2.

Stage

Early Gastric Cancer

  • 90% 5-yr survival
  • T1 = Limited to mucosa / submucosa
    • Regardless of LN status
    • NB: Lymphatics run in submucosa
    • Important to differentiate intramucosal from high grade dysplasia and intramucosal from submucosal
  • LN metastasis in 2-3% for intramucosal
    • Poor predictors for LN involvement:
      • LVI
      • Ulceration
      • Tumour > 30mm
    • With none of above, < 1% had LN involvement
  • LN metastasis in 20-30% for submucosal lesions
  • Rarely diagnosed at this early stage in Western countries

Advanced Gastric Cancer

  • T2-T4
    • Invasion into muscularis propria or beyond
    • Classified by Borrmann classification
  • 5-yr survival 20-30% in western population
  • Usually ulcerated with raised everted edge (Borrmann I-III)
    • cf Punched out benign peptic ulcer
  • Linitis plastica (Leather-bottle stomach)
    • Borrmann IV
    • Diffuse infiltration producing a thickened shrunken stomach with no visible change of lining mucosa

Modalities of Spread

  • Direct spread through wall (local invasion)
  • Lymphatic spread to regional LN
    • Risk factors:
      • Age at diagnosis, > 20mm tumour, depressed type, undifferentiated, LVI or submucosal invasion
  • Haematological spread
    • Surprisingly differentiated tumours at higher risk than poorly differentiated.
  • Transperitoneal spread:
    • e.g. Krukenberg tumour = ovarian infiltration by signet ring cells

TNM Staging

T stage

CategoryT criteria
TXPrimary tumor cannot be assessed
T0No evidence of primary tumor
TisCarcinoma in situ: Intraepithelial tumor without invasion of the lamina propria, high-grade dysplasia
T1Tumor invades the lamina propria, muscularis mucosae, or submucosa
T1aTumor invades the lamina propria or muscularis mucosae
T1bTumor invades the submucosa
T2Tumor invades the muscularis propria*
T3Tumor penetrates the subserosal connective tissue without invasion of the visceral peritoneum or adjacent structures¶Δ
T4Tumor invades the serosa (visceral peritoneum) or adjacent structures¶Δ
T4aTumor invades the serosa (visceral peritoneum)
T4bTumor invades adjacent structures/organs
N stage
NXRegional lymph node(s) cannot be assessed
N0No regional lymph node metastasis
N1Metastases in 1 or 2 regional lymph nodes
N2Metastases in 3 to 6 regional lymph nodes
N3Metastases in 7 or more regional lymph nodes
N3aMetastases in 7 to 15 regional lymph nodes
N3bMetastases in 16 or more regional lymph nodes
M Stage
M0No distant metastasis
M1Distant metastasis
  • Invasive adenocarcinoma = Invasion into lamina propria
  • Resectable via EMR = T1a
  • If invasion into submucosa (T1b), need surgery

Distal Nodes (i.e. M1 Disease)

  • Retropancreatic
  • Pancreaticoduodenal
  • Peri-pancreatic
  • Superior Mesenteric
  • Middle Colic
  • Para-Aortic
  • Retroperitoneal

Staging by TNM

When T is…And N is…And M is…Then the stage group is…
TisN0M00
T1N0M0I
T2N0M0I
T1N1, N2, or N3M0IIA
T2N1, N2, or N3M0IIA
T3N0M0IIB
T4aN0M0IIB
T3N1, N2, or N3M0III
T4aN1, N2, or N3M0III
T4bAny NM0IVA
Any TAny NM1IVB

Screening

  • Mass screening in high incidence regions
    • E.g. Japan
  • High Risk patients should be screened 1-2yrly
    • American Society for Gastrointestinal Endoscopy recommendation
      • History gastric cancer
      • FAP
      • Peutz-Jeghers
      • Menetrier’s disease
  • If chronic atrophic gastritis and Gastric intestinal metaplasia
    • Surveillance scope every 3yrs

BPAC Guidelines Screening for Hereditary Diffuse Gastric Ca https://bpac.org.nz/2018/gastric-cancer.aspx#main-nav

Investigations

Endoscopy

  • Most sensitive and specific diagnostic method
  • EMR as both staging and treatment

CT scan

  • Do in all
    • Identification of LNs or metastases
  • Good for liver metastasis detection
  • Only able to detect ≈ 25% of peritoneal mets
    • vs ≈ 85% by laparoscopy

EUS

  • Recommended in pts without metastatic disease
  • Gold standard for T staging
    • Most reliable non-surgical method for evaluating depth of invasion of gastric cancer
    • Particularly T1 lesions
    • Use in consideration for EMR vs surgery
  • Also good for detecting regional lymph node involvement
    • EUS guided FNA helps to determine if reactive or metastatic nodes

Staging Laparoscopy and Peritoneal Washings

  • Consider in
    • All fit patients being considered for resection

    • T1

    • Without metastatic disease on CT
    • Who would not otherwise need a gastrectomy for symptoms
  • Do in any patient being considered for neoadjuvant therapy
  • Esp. useful assessment if suggestion of locoregional spread, large tumour or at GOJ
  • Detects peritoneal/metastatic disease in 20-30% of pts with disease beyond T1
    • Pts best palliated by chemo, so will change management
  • Higher in T4 disease and linitis plastica
  • Peritoneal cytology
    • At least 200ml of normal saline instilled
    • Placed across different quadrants of abdo, i.e. left and right sub-phrenic space, Pouch of Douglas
    • Fluid should be dispersed
    • Aspirations from different parts of the body
    • 50ml should be sent for analysis
    • NB: Positive washings only does not mean patient is incurable
    • +ve cells → ↓ prognosis (but not in Stage IA)
    • Median survival 10-13 months (or 15 months with chemo)
      • cf patients with overt mets (9 month overall survival)
  • Indication for neoadjuvant treatment if no gross mets but washings positive
    • Should repeat laparoscopy and washings at completion of treatment

FDG-PET CT

  • Controversial, does not replace staging laparoscopy
    • Not funded in NZ
  • Issues with loss of GLUT1 receptors
    • Unhelpful if primary not FDG avid
  • Funded for GOJ (mandatory part of that staging)
  • Gastric cancers not as PET avid as oesphgeal

Peri-op Assessment and Management

  • Balance between patient (comorbidities/fitness) and disease (stage) factors.
  • Need to identify factors that will change treatment options available and factors that can be improved to optimize outcomes
    • Cardiac testing for any patients with symptoms/risk factors
    • Pulmonary function testing
    • Renal function
    • Nutritional Assessment
    • Other Optimisation

Cardiac Testing

  • Do cardiac testing for any patients with symptoms/risk factors
    • 10% of patients undergoing oesophagogastric surgery will have a cardiac event
  • ECG
  • Stress testing – exercise or pharmacological
  • Assess for exercise induced ischemia or cardiac function that limits exercise (valvular, cardiomyopathy etc)
  • Cardio/respiratory fitness testing (CPEX)
    • Provides a safe, reliable, repeatable, non-invasive, objective, individual assessment of combined pulmonary, cardiac, and circulatory function.
    • Anaerobic threshold
      • Usually about ½ way through test, where 02 demand exceeds supply and muscles generate ATP anaerobically
      • Detected by increased CO2 as HCO3 used to buffer excess H+ generated
    • VO2 max been found to closely correlate with occurrence of post-operative cardiopulmonary complications.
      • Target > 800mL/m2

Respiratory and Renal Testing

  • Pulmonary Function Testing
    • Post op pulmonary complications = 15-50%
    • Can be optimized by early physiotherapy, early mobilization and incentive spirometry
    • Spirometry best test to determine lung function
      • Low FEV1 and FVC has been shown to correlate with poor pulmonary outcome

Renal function

  • Pts on dialysis are not appropriate surgical candidates
  • Patients with pre-existing renal disease should be optimised pre-op and involvement of nephrologist

Nutritional Assessment

  • Pre-operative malnutrition and associated immunosuppression shown to have increased risk of adverse outcomes
    • Esp. risk of infection/mortality
  • Best adjunct to improve nutrition is surgically placed feeding jejunostomy
    • No compromise to gastric conduit
    • No risk of stent migration/perforation or disruption of radiotherapy
    • Well tolerated by patients compared to NJ tube
  • Malnutrition Definition
    • BMI < 18.5
    • Weight loss > 10% over the last 3-6 months
    • BMI < 20 and weight loss 5% over last 3-6 months
  • Enteral feeding preferred
    • Improved gut oxygenation and colonization with healthy flora
      • Reduces risk of septic complications
    • Also cheaper

Other Optimisation

  • Anticoagulation:
    • Increased risk, although not much can do to change
  • Smoking cessation for a minimum 8 weeks prior
  • Optimise Hb with iron supplementation or transfusion
  • Encourage regular cardiovascular exercise
    • Pre-op exercise shown to improve function however not definitively shown to reduce complications
  • Encourage weight loss if obese
  • B-Blocker
    • May improve ventricular dysfunction and reduce risk of perioperative arrhythmia

Intra/Post Operative Care

  • Lung isolation techniques
    • Single lung ventilation using double lumen tube
    • Tidal volume should be minimized and PEEP added to minimize lung injury
  • Early extubation recommended if possible
  • Minimise intraoperative blood loss and fluids given
    • Goal directed therapy
  • Adequate post op analgesia
    • Thoracic epidural highly effective
      • Should avoid hypotension with epidural
      • Minimize bolus doses, reduce rate and ensure patient euvolemic + vasopressors when required.

Care pathways

::::Carepathway.png

  • Important for post-op care as common goals for all involved and targets for patients

Management

General Principles

  • Always involve an MDM
    • Surgeon, radiologist, pathologist, oncologist,
  • Early Gastric Cancer = T1 N0
  • Advanced Gastric Cancer = Anything else
  • Goal of surgery
    • Excise cancer with clear longitudinal and circumferential margins
    • 3cm intestinal type
    • 5cm diffuse type
  • Prophylactic gastrectomy in patients with E-cadherin mutation

Example Management Algorithm

Endoscopic Management

Three stages:

  • Endoscopy assessment + biopsy +/- EUS
    • Paris classification to assess deeper involvement
      • Presence of ulceration
        • Histology
          • Degree of differentiation/LVI
          • If poor or undifferentiated > surgery
          • Classified by ‘Vienna classification system’ to guide management of GI neoplasia
  • Endoscopic resection attempt (ESD)
  • Surveillance if complete resection
    • 6/12 1st year then annually

Endoscopic mucosal resection

  • Pioneered in Japan
  • Suitable for Early Gastric Ca
  • If none of the factors suggesting increased risk of metastasis are present
    • Poor differentiation
    • LVI
    • Ulceration

    • 30mm

  • Perforation rate ≈ 4%
    • Can be repaired by endoscopic clipping or omental patch
    • No evidence of increased dissemination risk if perforation
  • If +ve margin after EMR → Surgery required
  • USA guidelines suggest EMR for Tis or T1a
    • i.e. limited to muscularis mucosae only (not into submucosa)
  • Formal surgery (without preop chemo) for T1b

Neoadjuvant Therapy

  • Neoadjuvant chemotherapy is standard of care for all EXCEPT

    • NCCN guidelines:
      • Tis or T1a → ER or surgery (if medically fit)
      • T1b → Surgery
      • T2 or higher, any N → Perioperative chemotherapy (preferred) or surgery alone

  • MAGIC Trial 2006 NEMJ

    • Inclusion: Adenocarcinoma of stomach, GOJ, or lower oesophagus, T2+, any N
    • ECF (Epirubicin, Cisplatin, 5FU) 3 x before and 3 x courses after surgery
      • Only 40% received post-op course
    • Increased R0 resection
      • 10% higher
    • Reduction in T stage and nodal status
    • Improved overall survival at 5 yrs – 36% vs 23%
    • Issues – Staging issues, R2 resection rate 32% vs 17%

  • FLOT4-AIO Trial

    • Inclusion: Adenocarcinoma of stomach, GOJ, T2+, any N
    • Compared FLOT4 (4 cycles pre/post) vs. ECF (MAGIC) or ECX (capecitabine) (3 cycles pre/post)
    • Overall survival better – 50 months vs 36 months
    • High tolerance of FLOT not replicated clinically

  • TOPGEAR trial

    • RCT gastric + GOJ - ChemoRTx vs Chemo - Chemo was ECF or FLOT4
    • No difference in overall survival or progression free survival
    • No benefit from the addition of radiotherapy to neoadjuvant chemotherapy

  • FLOT if good performance status

  • ECF if lesser performance status

Adjuvant Therapy

  • Adjuvant Chemotherapy
  • Adjuvant Chemoradiotherapy
  • Radiotherapy after surgery:
    • Considered if ≥ R1 resection (NCCN 2009)

Adjuvant Chemotherapy

Given as part of Magic protocol

  • 3 x pre-op and 3x post-op cycles ECF
    • Epirubicin, Cisplatin, 5-FU
      • NB: Significant difficulty with post-op compliance
      • Only 30% complete entire 3 cycles
  • Given as part of FLOT4
  • If no neoadjuvent treatment then FOLFOX or FLOT4 or CAPOX
    • For T2N0 with high risk features and above
      • High histologic grade or the presence of lymphovascular or perineural invasion, or age <50) who have had an adequate lymphadenectomy

Adjuvant Chemo/Radiotherapy

  • Indications for Adjuvant Chemo/radio therapy (NCCN )
    • Controversial
    • T3-4
    • Node-positive disease if they have undergone less than a D2 dissection
    • Incomplete (microscopically incomplete or macroscopically incomplete resection
  • Intergroup 0116 Trial
    • For ≥T3 / N1 tumours of stomach (80%) and GOJ (20%)
    • Treated with post-op Chemoradiotherapy
    • 5-FU + Leucovorin + radiotherapy 5/52 (“MacDonald Protocol”)
    • Median survival 27 vs 36 months
    • Survival at 3yrs = 40% vs 50%
    • Improved DFS (OR=1.5) and mortality (OR=1.35) compared to surgery alone
    • Distant mets = most common form of recurrence in adjuvant group (33 vs 18%) cf LR more common in surgery only group (30 vs 20%)
    • But this study has been criticized as 40% of pts had a D0 resection, only 10% had D2 resection
    • Greatest benefit may be in high-risk pts treated with inadequate resections, ? just overcoming inadequate surgery
  • Herceptin/ Trastuzumab
    • Approved for HER-2 overexpression in metastatic gastric or gastro-oesophageal cancer
    • 10-30% +ve for HER2

Surgery

Resection

  • Early gastric cancer in middle of stomach (T1) can be treated with pylorus preserving sub-total gastrectomy
    • 3cm prox to pylorus and small upper gastric remnant (for reservoir)
    • Need to preserve Anterior Vagal n.
    • Aim to achieve 3-5cm margins in intestinal-type
    • At least 5cm margins in diffuse-type
  • Total Gastrectomy (whole stomach and cardia) for proximal tumours
  • Distal Gastrectomy (2/3 stomach and pylorus) for lower middle and distal tumours
    • Minimum 2cm margin to GOJ (maintain function)
    • Short Gastric Arteries preserved
    • No survival benefit for total over distal gastrectomy for distal cancers
  • Only resect adjacent pancreas if directly involved in tumour in order to achieve R0 resection
    • Should have careful patient selection for this as high morbidity and may not strongly improve survival as generally poor prognostic tumours anyway
  • No benefit of liver resection for isolated mets as high recurrence or distant spread
  • Spleen not routinely resected, only if hilum involved

Lymphadenectomy in gastric cancer

At NSH we perform a D1 plus - 1-7 + 8 and 9 as standard

  • At least 16 LN are necessary to accurately stage a tumour
    • T1a tumours 3% LN involvement
    • T1b = 18% involvement
    • T4a = 80% involvement
  • Controversy re: limited vs extended LN dissection
    • Removal of at least the Station 1-6 -level nodes (D1) improves 5-yr survival (20 → 34%)
  • D3 = D2 + D3 – not recommended!
  • Dutch Gastric Cancer Group Trial phase III:
    • D1 vs D2 5yr survival rates similar (~ 45%)
  • D2 Disadvantages
    • More post-op complications (45 vs 30%)
    • More post-op deaths (10% vs 5%)
    • Longer hospital stays
  • D2 Advantages
    • Survival difference in patients with N2 / stage II & IIIA disease (D2 better)
    • Risk of recurrence greater in D1 than D2 group (40 vs 30%)
    • Unfortunately, ‘N2’ disease cannot be reliably identified pre-op
  • Greatest contributing factor to post-op M&M in D2 group was addition of pancreaticosplenectomy
    • “D2 resection without pancreaticosplenectomy may be better than a standard D1”
  • Other Western studies
    • Survival benefit for D2 without pancreaticosplenectomy
    • Italian Gastric Cancer study Group (IGCSG), Austrian study, Spain - Post-op mortality after D2 ≈ 3-5%
  • ANZGOSA recommendation
    • Splenectomy if greater curvature involved with tumour
    • Distal pancreatectomy only if direct tumour involvement

D1 Resection

  • Early gastric cancer (T1) should be treated with D1 gastrectomy
  • D1 dissection entails gastrectomy and the resection of both the greater and lesser omenta
    • Stations 1 to 6 (+ now includes 7, left gastric)
  • Includes the lymph nodes along
    • Right (1) and Left (2) cardiac
    • Lesser (3) and Greater (4) Curvature
    • Suprapyloric (5) along the Right Gastric Artery
    • Infrapyloric area (6)

D1 Plus Resection

  • D1 plus
    • Levels 7, 8a, 9
  • Standard of care for Stages II & IIIa because
  • Safe (provided pancreaticosplenectomy not done)
  • Gives prognostic information
  • Japanese survival stats – D2 mortality <1%

D2 Resection

  • D2 dissection is a D1 plus all the nodes along the left gastric artery, common hepatic artery, celiac artery, splenic hilum, and splenic artery
  • Station 7
    • Left Gastric Artery (N1) – should be removed in all gastrectomy (including distal)
  • Station 8
    • Common Hepatic Artery (N2)
  • Station 9
    • Coeliac Trunk (N2)
  • Station 10
    • Splenic Hilum (N2)
    • Not necessary to resect for all cancers, as often diff to resect without splenectomy
    • Recommended for proximal gastric cancers on greater curvature
  • Station 11
    • Splenic Artery
  • Station 12
    • Hepatoduodenal nodes

Reconstruction

  • Factors to Consider
    • For high-risk patients (patient or disease factors)
      • Choose safety over function
    • For low-risk patients (disease factors and well patient)
      • Given longer life expectancy and lower chance of recurrence consider functional quality of reconstruction
    • Consider feeding jejunostomy
      • NB: ANZGOSA lec says not to routinely for subtotals

Reconstruction After Distal Gastrectomy

Roux–en–Y

  • Best reconstruction option

  • Pros:

    • No bile reflux
    • Relatively safe anastomosis
    • Low risk of obstruction if reoccurrence

  • Cons:

    • Difficult to ERCP/Duodenoscopy
    • Nutritional problems
    • Dumping syndrome
    • Two anastomosis Billroth I

  • Pros:

    • Physiologic passage
    • Simple anastomosis
    • Preserved endoscopic access
    • Preferred for distal small tumours with sufficient residual stomach volume and low chance of recurrence

  • Cons:

    • Duodenal reflux
    • Risk of leak reasonable (some tension on anastomosis)
    • Obstruction if recurrence Billroth II

  • Pros:

    • Only one anastomoses
    • Can still access proximal duodenum endoscopically

  • Cons:

    • Risk of bile reflux
    • Afferent Loop Syndrome

  • Reconstruction After Total Gastrectomy

    • Roux-en-y is the standard reconstruction
    • Oesophagojejunostomy performed
    • Safe, simple and good functional outcomes
    • Cons = Early satiety, risk of nutritional deficiencies

Palliative Therapy

  • Locally advance or metastatic disease
  • Chemotherapy:
    • Survival improvement from 3-5 months to 8-12 months compared to supportive care.
    •    Combination therapy better than single.
      • ECF widely used
        • EOX (epirubicin-oxaliplatin-capecitabine) better tolerated.
      • FOLFOX or CAPOX (recommend by uptodate)
  • Monoclonal antibodies
    • Trastuzumab (Herceptin)
      • for HER2 over-expression
      • Antibody against human epidermal growth factor receptor 2 (HER2, aka ERBB2)
        • ToGA trial: Survival benefit of 13.8 (trastuzumab + chemo) vs 11.1 months (chemo alone)
    • dMMR/MSI-H tumors
      • Check point inhibitors improves OS and can induce durable treatment responses
      • Pembrolizumab etc
    • Ramucirumab (VEGRF-2 inhibitor) used as part of second line with paclitaxel

Palliative Interventions

  • Main indications for procedures are complications of advanced gastric cancer
  • Treatment should be focussed on maximal palliation and minimal morbidity
  • Perforation
    • Requires surgical intervention
    • Primary closure of perforation usually not possible
    • Graham patch may be an option
    • Especially given likely poor functional status of patient
    • Gastrectomy is an option if it can be done with minimal morbidity
  • Bleeding
    • Endoscopic measures first line (as any other UGIB)
    • Multiple attempts reasonable if patient is stable
    • Could consider angiography
    • If unstable, and other means haven’t worked, surgery indicated
    • Tailor resection to situation
    • Limited resection to grossly negative margins if life expectancy limited
  • Obstruction
    • Endoscopic dilatation and stent placement can provide good short-term palliation
    • Tumour progression and stent migration limit efficacy long-term
    • Chemo-radiotherapy can be used to attempt to relieve obstruction
    • Response rates 50%
    • If longer survival predicted, consider palliative bypass with gastrojejunostomy

Prognosis/Natural History

  • Diffuse-type worse than intestinal-type
  • Early Gastric Ca → Excellent prognosis: 10YS 90% (or ≈ 70% if LN +ve)
  • Four patterns of metastasis:
    • Lymphatic
    • Haematological
    • Peritoneal
    • Direct invasion (T4b)
  • Localized, node -ve Gastric Ca treated with surgery alone → 75% 5YS
    • cf. node +ve Gastric Ca → 10-30% 5YS
  • Advanced disease – M1 or unresectable = 6-12 months
    • Overall 5YS: 20-30%
    • In advanced stage with curative intent surgery: med survival = 24mths (20-30% 5YS)
  • Following palliative procedures: median survival = 10 months
  • In pts without palliative treatment: median survival = 5 months
    • Surgical morbidity ≈ 32% & mortality ≈ 3.5%
    • Recurrence rate 50% in patients resected with curative intent
  • Rate of locoregional recurrence is related to T stage; rate of distant mets to N stage
    • Most common peritoneal disease in T4 cancers
  • Higher risk in diffuse than intestinal type gastric cancer

Prognostic Factors

  • LN status
    • Number provides a better prognostic indication than anatomic location
    • LN +ve >20% (i.e. +ve / removed nodes) = Single most important prognostic factor
  • Increased size
    • Associated with LN metastasis & decreased 5Yr survival
  • T category (serosal penetration most important)
  • Tumour location
    • Proximal 1/3 may represent a distinct entity with poorer prognosis
    • GOJ tumours 5YS ≈ 5%
    • Tumours tend to be larger, have extensive wall penetration, venous invasion, nodal mets & more advanced stage
    • May require a different surgical approach based on a potentially different biological behaviour
  • Resection margins (R0 vs R1/R2)
  • LVI
  • Age >70yrs
  • ? genetic markers (p53, E-cadherin, CD-34, c-ErbB2, CA 72-4, CEA)
  • Pathologic grade (well/mod/ poor differentiated / anaplastic) has little prognostic significance

Follow-up

  • After Subtotal Gastrectomy
    • Surveillance of gastric remnant recommended for 10-15yrs
    • Cancer of gastric remnant
    • Usually at the anastomotic site
    • May be due to irritation from exposure to duodenal contents
    • Eradication of H. pylori post-op decreases RR

Oesophageal + Gastric Comparison

Post-operative Complications

Anastomotic Leak

  • Most commonly at oesophagojejunostomy
  • Due to ischemia/tension
  • Diagnose with gastrograffin swallow
  • Drain and conservative management if stable
  • NBM/NJ tube
  • If no drain or patient septic
    • Return to OT
    • Drain + repair if possible
    • Feeding jejunostomy if not already placed

Duodenal stump leak

  • Rare
  • Risks – ischemia, afferent limb obstruction
  • Easily diagnosed if prophylactic drain placed (If bile ++)
  • Needs return to OT
    • Place Foley in duodenum to control fistula
    • Or suction drain adjacent to small defect
    • Decompression NJ then up duodenum to decompress

Pancreatic Fistula

  • Increased risk with
    • D2 resection/bursectomy, pancreatectomy or splenectomy
    • Always place prophylactic drains during above surgery over pancreatic border
  • Diagnose by amylase in drain fluid
    • Usually dark red wine colour
  • No evidence octreotide prevents fistula formation
  • Management
    • Adequate drainage +/- irrigation of abscess cavity once walled off

Haemorrhage

  • Early
    • Return to OT
  • Late
    • Usually due to intra-abdominal infection
    • Leads to pseudoaneurysm of splenic artery
      • Manage with Angiography + Embolisation
      • Preferred as repeat surgery after infection is risky

Late Complications

Early Dumping Syndrome

  • Occurs within 20-30mins after meal
  • More common than late dumping
  • More GI and less cardiovascular effects.
  • Symptoms related to serotonin and bradykinin release
    • GI
      • Nausea/vomiting, epigastric discomfort, crampy pains + explosive diarrhoea
    • Cardio
      • Tachycardia, palpitations, diaphoresis, fainting, dizziness, flushing, blurred vision
    • Pathophysiology
      • Rapid transit of high osmotic load into small bowel
      • Draws fluid in → Visceral distension → Release of vasomotor mediators
      • Vasomotor (serotonin & bradykinin) release causes
        • Weakness, dizziness, faint, pallor, sweat
  • Most common after Billroth II (especially if >2/3 resected)
  • Investigations
    • Contrast study to demonstrate rapid emptying or provocation test by ingesting 200ml of 50% glucose & water
  • Management
    • Dietary change
    • Avoid sugary foods, small frequent meals, separate liquids from solids, high protein/fat meals
    • Octreotide can help – inhibits hormonal response & delays gastric emptying
    • Surgery – consider interposition of 10-20cm jejunum

Late Dumping Syndrome

  • Occurs 2-3 hours post-meal
    • Related to high carbohydrate load into small bowel
    • Get rapid glucose absorption and profound insulin release that overshoots glucose
    • Rebound hypoglycaemia
    • Triggers Adrenal Gland to secrete Catecholamines
  • Diaphoresis/tremors/tachycardia
    • Just like hypoglycaemic shock symptoms
  • Management
    • Small frequent meals & less carbs
  • Surgical option of jejunal interposition

Nutritional Issues

  • Fat malabsorption
    • Lack of mixing with duodenal bile/pancreatic enzymes
    • Get steatorrhea
    • Treat with Creon
  • Vit B12 deficiency
    • Lack of IF produced by Parietal Cells
    • Slow decline in body stores
    • Megaloblastic anaemia at 24 months if not replaced
    • Treat with 1mg Hydroxocobalamin IM 3-monthly
  • Vit D deficiency
    • Due to fat malabsorption
    • Exacerbated by Ca2+ malabsorption (proximal duo)
    • Increased risk of osteoporosis
    • Treat with oral calcium and calcitriol
  • Iron
    • Predominantly absorbed duodenum and proximal jejunum
    • Requires deoxidization to Fe2+ form (from Fe3+) for best absorption
    • Tx with oral or IV supplementation

Post-Gastrectomy Syndromes

  • Physiologic derangements cause by
    • Loss of reservoir function
    • Interruption of pyloric sphincter mechanism
    • Vagal nerve transection
  • 25% of patients may develop some symptoms
  • Only approx 1% permanently disabled by symptoms
  • Metabolic Disturbance
    • Afferent Loop Syndrome
    • Efferent Loop Obstruction
    • Alkaline (Bile) Reflux Gastritis
    • Gastric Atony
    • Retained Antrum Syndrome

Other Metabolic Disturbances

  • Billroth II worst
  • Anaemia
    • Seen in 30% by 5yrs, due to ↓intake & malabsorption of:
  • B12
    • Due to ↓ IF ± bacterial overgrowth
  • Iron
    • Due to ↓ gastric acid & ↓ duodenal absorption (= optimal site)
  • Folate
    • Achlorhydria → ↑ gastric pH, above optimal for folate absorption
  • Osteoporosis/osteomalacia
    • ↓ Ca – also absorbed primarily in duodenum (+/- ?↓Vit D)→ Bone disease
  • Fat malabsorption causes fatty acids to bind to calcium in GI tract and inhibit absorption
    • Increased gallstones – calcium malabsorption
    • Fat malabsorption
  • In Billroth 2 fats bypass duodenum
    • Treat with pancreatic enzymes

Afferent Loop Syndrome

  • Typically after a Billroth II but can also be seen in the BP limp of a [R&Y
  • Mechanical partial obstruction of long afferent limb
    • Cannot empty its contents
    • Fills with biliary & pancreatic secretions
    • Leading to pain
    • Build-up eventually decompresses into stomach
    • Leading to vomiting and relief of symptoms
    • Usually related to long (>30-40cm) and antecolic afferent limb
  • Symptoms
    • Epigastric pain
    • If severe may reflux into stomach and cause bilious vomiting
      • If chronic can get Blind Loop Syndrome
        • Bacterial overgrowth, binding to B12 and deconjugated bile acids
        • Resulting in
          • Megaloblastic Anaemia and Fat Malabsorption
    • Requires surgical intervention – convert to Roux-en-Y

Efferent Loop Syndrome

  • Rare
  • Usually due to herniation of limb behind the anastomosis from R to L
  • Get colicky LUQ pain, bilious vomiting, abdominal distension
  • Diagnosis with contrast study
    • Failure of barium to enter efferent limb
  • Management
    • Operative - reduce the hernia and close the mesenteric defect

Bile Reflux Gastritis

  • Common especially for Billroth 2
  • Investigations
    • HIDA – see biliary reflux into stomach
    • Endoscopy – beefy, friable red mucosa
  • Management
    • Medical to control symptoms though generally poor outcomes
    • Surgical - convert to Roux-en-Y
      • Should preferentially do Roux-en-Y in first operation

Gastric Atony

  • After truncal vagotomy, can occur even with pyloroplasty or gastrectomy
  • Need to exclude other causes
    • Diabetic gastropathy
    • NM disorder
    • Post op adhesions
    • Internal hernia
    • Afferent loop obstruction
  • Investigations
    • Scintigraphic assessment of gastric emptying/fluoroscopy study
  • Management – usually medical
    • Metoclopramide
      • Prokinetic effects - dopamine antagonist and cholinergic enhancing activity
      • Facilitates release of acetylcholine from enteric cholinergic neurons
    • Erythromycin
      • Binds to motilin receptors on GI smooth muscle cells, causing increased motility
    • If atony refractory to medical therapy, may need gastrectomy

Retained Antrum Syndrome

  • Usually, antrum left in duodenal stump
  • Get recurrent ulcers
  • Investigation
    • Technetium scan + SPECT
  • Treatment
    • Resect antral tissue that is retained

Graph View

Backlinks