Gastric Cancer

Anatomy

• The stomach begins at the gastroesophageal (GE) junction
• Ends at the pylorus

Three parts

• Fundus(Cardia)—> cranial portion
• Body
• Pyloric portion(Antrum)
  • A plane passing through the incisura angularis on the lesser curvature divides the remainder of the stomach into the body and the pyloric portion (antrum).

• The anterior surface of the stomach is covered with peritoneum of the greater sac.
• Posteriorly is covered with peritoneum of the lesser sac or mental bursa.
• GEJ —> either no or variable visceral peritoneal

• The hepatogastric ligament or lesser omentum is attached to the lesser curvature and contains the left gastric artery and the right gastric branch of the hepatic artery.
• Vascular Supply:
  • Celiac axis.
    • originates at or below T12 (75%) and at or above L1 (25%)
    • Branches:
      • Left gastric artery—>upper right portion of the stomach
      • Common hepatic artery
        • Right gastric artery —> right portion of the stomach and the right gastroepiploic branch supplying the lower portion of the greater curvature
      • Splenic artery
        • Left gastroepiploic —>
          • Upper portion of the greater curvature
        • Short gastric arteries —>
          • Fundus

• Most lymphatics drain ultimately to the celiac nodal area
• Other at risk nodal area:
  • Splenic hilum
  • Suprapancreatic nodal groups
  • Porta hepatis
  • Gastroduodenal areas.

Epidemiology

• Significant decline in the incidence of gastric cancer in both sexes in Western countries
• Steady and rapid increase in the incidence of proximal and GE junction tumours; especially in white males.

Risk factors

• High intake of smoked and salted foods
• Low intake of fruits and vegetables
• Low socioeconomic status
• Decreased use of refrigeration
• Pernicious anemia
  • 5% to 10% of patients with pernicious anemia developing Ca
• Prior subtotal gastrectomy(2% to 5% risk)
  • Latency periods of 15 to 40 years
• Villous adenomas : premalignant
  • hyperplastic or hamartomatous polyps—>more frequently& benign
• Helicobacter pylori —> 3-6 times risk
  • distal gastric ca
  • intestinal type ca
  • only a minority get ca
• Gastric Ulcer —> NO RISK
• Peutz-Jeghers syndrome
• FAP - Familial adenomatous polyposis
• HNPCC syndrome (microsatellite instability gene [MSI])
• Li-Fraumeni Syndrome
• Gene mutations:
  • p53, c-met, k-sam, E-cadherin gene (CDH1), bcl-2, and erb-B2

Patterns of Spread

Direct Extension

• Omenta
• Pancreas
• Diaphragm
• Transverse colon/mesocolon
• Duodenum
• Jejunum
• Spleen
• Liver
• Superior mesenteric & celiac vessels
• Abdominal wall
• Left adrenal gland
• Kidney

Lymphatic

• Abundant lymphatic channels within submucosa and subserosal
  • Microscopic or subclinical spread beyond the visible gross lesions (intramural spread) occurs commonly via the lymphatic channels==>Frozen sections of the gastric resection margins is obtained intraoperatively
  • It is difficult to perform a complete nodal dissection
• Gastric Lymphatics
  • 1, 2 Perigastric
  • 3, 4 Lesser and greater curvature
  • 5 Suprapyloric (right gastric)
  • 6 Infrapyloric
  • 7 Left gastric
  • 8 Common hepatic
  • 9 Celiac
  • 10 Splenic hilum
  • 11 Splenic
  • 12 Hepaticoduodenal

Lymph nodes accepted as distant metastases: posterior pancreatic (13), sup. mesenteric [14], middle colic (15), paraaortic (16), portal, retroperitoneal

Hematologic

• Venous drainage is primarily to the liver by the portal system.
  • In as many as 30% of patients

Peritoneal Involvement

Clinical Presentation

• Loss of appetite
• Abdominal discomfort
• Weight loss
• Weakness from anemia
• Nausea & vomiting
• Melena

• Duration of symptoms
  • 40% —> <3m
  • 20% —> >1yr

• Signs:
  • Abdominal mass
  • Sister mary-joseph nodule ( peri-umbilical nodular metastasis )
  • Supraclavicular LN ( left ) = Virchow's node
  • Rectal shelf (peritoneal seeding) - blumer's shelf metastasis

Diagnostic Work-Up

• Upper gastrointestinal (GI) radiography and endoscopy
  • direct vision
  • cytology
  • biopsy
  • infiltrative (linitis plastica), small (<3 cm), or cardia lesions are more difficult to diagnose endoscopically

• Double-contrast x-ray studies may reveal small lesions limited to the inner layers of the gastric wall

• Best method for depth determination —> endoscopic US
  • Intramural versus extramural extension
  • Less accurate in LN

• Abdominal CT
  • Local extension
  • LN mets
    • accuracy ~ 50%
  • CT in general overstages the T category and understages the N category

• R/O distant metastases:
  • CXR
  • LFT
  • CT Chest if proximal extensive gastric ca
    • Mediatinal LN?

• The value of laparoscopy in the staging of gastric cancer still is being defined.

Staging

Pathology

• Adenocarcinomas (90%-95%)
• Lymphomas(usually unfavourable histology —>2nd most common
• Leiomyosarcomas (2%)
• Carcinoid tumors (1%)
• Adenoacanthomas (1%)
• Squamous cell carcinomas (1%)

Site of origin:

• Antrum/distal stomach (~ 40%)
• Proximal & GE junction (~ 35%)
• Body (~ 25%)

Increased frequency of cardia lesions. Cardia lesions may have different epidemiologic factors, exhibit different tumor biology, and have an inferior prognosis from lesions in the other sites.

Borrmann's five types:

Type	Tumour	Prognosis
I	polypoid-fungating	favourable
II	ulcerating surrounded by elevated borders	favourable
III	gastric wall invaded
IV	linitis-plastica(diffusely infiltrative)	poor prognosis
V	unclassifiable	poor prognosis

Prognostic Factors

• The most important —> tumour extent
• stage IV —> universally fatal
• Lymph node involvement
  • Number & locations(adjacent to primary or not)

• Cardia lesions —> worse
• Flow cytometry is also prognostically valuable
• Aneuploidy is associated with:
  • Unfavorable tumor location
  • LN metastasis
  • Tumor invasion

• Loss of tumor suppressor gene function
  • Inactivation of the p53 gene
    • Located on the short arm of chromosome 17
• Alteration in mismatch repair genes ==> replication error through out the genome
  • hMSH3
    • On chromosome 2
  • hMLH1
    • On chromosome 3
  • Both in hereditary nonpolyposis colorectal cancer
• Proto-oncogenes
  • C-met —> encodes hepatocyte growth factor ( potent endogenous promoter of gastric epithelial cell growth )
    • in men older than 50
  • K-sam —> encodes a tyrosine kinase receptor
    • in female younger than 40
  • Both in scirrhous carcinoma

• Peptide receptors ( ER, EGFR )
  • Poor prognosis
  • associated with linitis plastic
  • higher rates of primary tumour infiltration rate
  • poor differentiation

MANAGEMENT

Surgery

• Primary therapy
• Resection of gastric and nodal area
• Subtotal gastrectomy
  • Preferred treatment for lesions in the body or antrum
    • 5cm clear margin required
  • Removes:
    • 80% of the stomach
    • First portion of the duodenum
    • Gastrohepatic and gastrocolic omenta
    • Nodal tissue adjacent to the three branches of the celiac axis
• Total gastrectomy
  • Extensive or proximal Ca
  • In proximal third and greater curvature
    • Risk of metastasis to splenic hilum
    • Reuire splenectomy
  • Involvement of the body or tail of the pancreas
    • Distal pancreatectomy & splenectomy
  • Invasion of the transverse mesocolon
    • Often requiring transverse colectomy
  • Involvement of the spleen
    • Splenectomy
  • Involvement of left lobe of the liver
    • Wedge resection with a 1-cm or wider clearance

Routine total gastrectomy does not improve survival but does increase morbidity & mortality

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• Carcinomas limited to the mucosa or submucosa (Tis or T1N0M0) (~30% in Japan and <5% in US)
  • Surgery alone
• More invasive carcinomas
  • Only 25% to 40% of patients will have potentially curative procedures.

The optimal extent of lymph node dissection for gastric cancer remains controversial. ( 15 needs to be removed )

Extended node dissection seems reasonable when it can be performed by experienced surgeons without significant additional surgical morbidity or mortality.

• Postoperative symptoms
  • Heartburn
  • Dumping syndrome
  • Decreased absorption of fats, iron, and calcium
  • Loss of intrinsic factor ==> vitamin B12 deficiency
  • F/U post-op:
  • ==> Dietary supplements (iron, calcium)
  • Monitoring for osteoporosis
  • Monthly vitamin B12 injections

Surgery alone outcome

• DIsease limited to mucose and submucosa —> ~90%
• Early stage —> up to 80%
• More invasive cancers:
  • Antrum : 31%
  • Mid-stomach : 24%
  • Cardia : 16%
• Survival decreases proportional to the degree of invasion or nodal involvement
  • N1 or N2 +
    • 5-year OS: 10%-30%
  • N3-N4: OS <10%

Improvements in survival with the addition of adjuvant chemoradiation to surgical resection.

Relapse Patterns after “Curative Resection”

• Surgical bed
  • Anastomoses
  • Gastric remnant
  • Duodenal stump
• Regional LN
• Distant failures

• Lesions of GE junction
  • Liver and lungs are common sites of DM
• If no extension to Esophagus —> Mets are usually to liver only

Adjuvant treatment could potentially benefit at least 20% of patients.
Effective systemic therapy is also essential to improve the outcome for resected high-risk gastric cancer patients in view of the risks of both intra-abdominal (liver and peritoneal) and extra- abdominal metastasis (lung, other).

Adjuvant Chemotherapy

• Adjuvant single-agent chemo: no benefit
• Mitomycin-C ( Spanish trial ) has shown survival benefit.
• Adjuvant epirubicin, 5-FU, and leucovorin (the EFL regimen): OS benefit

Perioperative Chemotherapy (MAGIC Trial)

• 503 patients
• Resectable adenocarcinoma
  • Stomach (372 pts)
  • GE junction (58 pts)
  • Lower esophagus (73 pts)
• Randomized:
  • Surgery alone
  • Surgery plus three cycles of preoperative epirubicin, cisplatin, and infusional 5-FU (ECF regimen) and three cycles of postoperative ECF therapy

• Result:
  • Significant improvement in survival in chemo group —> (median survival 24 vs. 20 months, 5-year OS 36% vs. 23%, p = .009)
  • Overall, 103 patients completed all six cycles of chemotherapy

Adjuvant Irradiation

• British adjuvant trial
  • Adjuvant EBRT reduced locoregional failures
  • No OS benefit

• Trials from Japan and China
  • IORT —> some OS benefit

• The British Stomach Cancer Group (BSCG) study —> role od adj RT
  • No OS benefit, less locoregional recurrence

Pre-op RT

• Russia and China trials
• Survival benefit

Postoperative EBRT Plus Chemotherapy

Phase III Trials: Mayo Clinic, U.S. GI Intergroup 0116

• A prospective randomized trial
• 62 patients with a poor prognosis after complete resection of gastric cancers
• Randomized between:
  • Surgery alone
  • Surgery followed by EBRT plus concomitant 5-FU (37.5 Gy in 24 fractions over 4 to 5 weeks; 5-FU, 15 mg/kg/day 1 to 3 by IV bolus)
• Result:
  • Favor Adjuvant group
    • Better OS —> 5yr OS ( 20% vs 4% )
    • Less locoregional (54% incidence with surgery alone vs. 39% with irradiation plus 5-FU).

Adenocarcinoma
Gastric Ca
GEJ
T2-4N0 & T1-4N1-3; 85% of patients were Node (+)
Arms: Surgery vs Surgery CRT ( Chemo = 5d of 5FU+Leucorverin —> 45Gy/25 + concurrent CRT 4d per week #1 and 5d per week #5 —> 2cycles of chemo 5d q1m)
F/U of this study: 5yr

	Surgery alone	Sx+CRT
3yr Recurrence Free Survival	50%	30%
3yr OS	50%	40%
Median Survival	36m	27m
Percentage of Local Recurrence in those who recurred	30%	20%
Percentage of Regional relapse in those who recurred	70%	65%
Percetange of Extra-abdominal relapse in those who recurred	13%	33%
Grade III-IV toxicity	30%	40%

Because of conflicting results in prior small phase III studies, a U.S. GI Intergroup trial (INT 0116) was initiated to evaluate postoperative combined 5-FU–based chemotherapy and irradiation to the gastric bed and regional nodes versus surgery only in resected but high-risk gastric cancer patients.163 Eligible patients had completely resected ACA of the stomach or GE junction with complete penetration of the muscularis propria (T2-4N0) or involved nodes (T1-4N1-3). After an en bloc resection, 556 patients were randomized to either surgery alone or postoperative combined modality therapy. This con- sisted of one 5-day cycle of 5-FU and leucovorin followed by concurrent chemoradiation (45 Gy in 25 fractions plus con- current 5-FU and leucovorin, 4 days/week 1, 3 days/week 5) followed by two additional 5-day cycles of 5-FU and leuco- vorin given at 1-month intervals. Nodal metastases were present in 85% of patients. With median follow-up of 5 years, RFS at 3 years is 48% for adjuvant treatment and 31% for observation ( p = .001); 3-year OS is 50% for treatment and 41% for observation ( p = .005) (see Table 45-5). The median survival in the surgery-only group was 27 months, as compared with 36 months in the chemoradiation group. The median duration of RFS was 30 months in the chemoradiation group and 19 months in the surgery-only group (Fig. 45-3).
Patterns of relapse were based on the site of first relapse only and were categorized as local, regional, or distant. Local recurrence occurred in 29% of the patients who experienced relapse in the surgery-only group and 19% of the chemoradia- tion patients with relapse. Regional relapse—typically abdom- inal carcinomatosis—was reported in 72% of those who experienced relapse in the surgery-only group and 65% of those who had relapse in the chemoradiation group. Extra- abdominal distant metastases were diagnosed in 18% of those who had relapse in the surgery-only patients and 33% of the chemoradiation patients. Treatment was tolerable, with three toxic deaths (1%). Grade 3 and 4 toxicity occurred in 41% and 32% of cases, respectively.
The results of this large randomized phase III U.S. GI Intergroup trial demonstrate a clear survival advantage to the use of postoperative chemoradiation in high-risk patients who have undergone resection of their disease.163 Further- more, the results strongly support the integration of post- operative chemoradiation into the routine care of patients with curatively resected high-risk carcinoma of the stomach and GE junction. This approach is now viewed by many as the standard of care in the United States.
Quality control of irradiation field design in the INT 0116 trial was conducted during the cycle of chemotherapy given before the start of concurrent chemoradiation.164 The upfront quality control provided the mechanism to correct most of the major or minor deviations (35% incidence) in field design before the start of treatment and resulted in only a 6.5% final major deviation rate. Utilization of upfront quality control may have been a key factor in achieving a positive survival advantage for adjuvant chemoradiation. Postoperative Chemoradiation Plus D2 Resection
The final results of the phase III British and Dutch multicenter trials evaluating the value of extended lymphadenectomy (D1 vs. D2 resection) demonstrated that D2 resection produced greater morbidity with no impact on survival. In spite of these negative results, because D2 resections were not commonly performed as a component of surgery in the U.S. GI Inter- group phase III gastric adjuvant trial, some have questioned whether chemoradiation would give added benefit after a D2 resection.
The potential role of postoperative chemoradiation in D2 resected patients was evaluated in a series of 990 patients treated in Seoul, South Korea165 (Table 45-6 and see web-only Table 45-3). Surgery alone was used in 446 patients, and post- operative chemoradiation was given to 544 patients (disease and patient characteristics and method of chemoradiation paralleled the INT 0116 trial). Both disease control and sur- vival were improved in patients who received trimodality treatment (median survival 95.3 vs. 62.6 months, 5-year OS 57% vs. 51%, p = .02; 5-year RFS 54.5% vs. 47.9%, p = .016; locoregional relapse 14.9% vs. 21.7%, p = .005). Five-year RFS and OS were consistently better with trimodality treatment for each stage grouping.
Preoperative EBRT Plus Chemotherapy
Although no randomized trials testing preoperative EBRT plus chemotherapy for gastric cancer have yet been published, three phase III trials for patients with esophagus cancer (alone or combined with GE junction or cardia lesions) included patients with adenocarcinoma. This includes studies by Walsh and associates,166 Urba and coauthors,167 and the U.S. GI Inter- group trial published by Tepper and colleagues.168
In the Dublin trial by Walsh and associates,166 patients with ACA of the esophagus and gastric cardia were randomized to either immediate surgery (control arm) or preoperative EBRT plus 5-FU and cisplatin (40 Gy in 15 fractions; 5-FU, 15 mg/kg/day for 5 days weeks 1 and 6 as a continuous infu- sion or approximately 600 mg/m2/day for 5 days; cisplatin 75 mg/m2 on the first day of each 5-FU infusion), followed by surgical resection 8 weeks after completion of EBRT plus chemotherapy. A highly significant difference in survival was observed with combined modality therapy (intent to treat: median survival 16 vs. 11 months; 3-year OS, 32% vs. 6%; p = .01; actual treatment: median survival 32 vs. 11 months; p = .001; 3-year OS, 37% vs. 7%; p = .006). Survival rates for the control group of patients were inferior to those from other historical data.
Urba and coauthors167 at the University of Michigan found a borderline survival advantage for patients treated with preoperative chemoradiation versus surgery alone. Preopera- tive treatment involved 5-FU, cisplatin, and vinblastine given concurrently with EBRT (45 Gy/1.5 Gy twice daily for 3 weeks). Patients with either squamous cell carcinoma (SCC) or ACA were eligible, but 75 of the 100 randomized patients had ACA. Survival differences favoring trimodality treatment versus surgery alone did not appear until several years of follow-up (3-year OS, 30 vs. 16%; p = .15 Cox regression; 0.09 log-rank multivariate analysis).
A confirmatory U.S. GI Intergroup trial (CALGB 9781) included patients with either esophagus or GE junction cancers (either SCC or ACA); this trial was stopped pre- maturely because of poor accrual. Despite the low accrual, patients randomized to trimodality treatment had a survival benefit when compared with patients randomized to surgery alone (median survival 54 vs. 21.6 months; 5-year OS 39% vs. 16%, p = .008).168
Summary: Adjuvant EBRT Alone or Plus Chemotherapy
In summary, postoperative chemoradiation163,164 has been demonstrated to be superior to surgery alone for resectable gastric and GE junction cancers in randomized phase III trials. There are also randomized phase III data to suggest a benefit to preoperative irradiation that need to be confirmed.155 Future preoperative irradiation trials should evaluate the addition of concurrent and maintenance chemotherapy. Postoperative chemoradiation trials are evaluating more aggressive chemo- therapy both as concurrent and maintenance components of treatment.