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					 Gastric Cancer:
Current Concepts
         David Shin
Dept of Surgery Grand Rounds
       August 24, 2005
                Epidemiology
   Gastric cancer was the fourth most common
    cancer in the world in 2004, and is expected to
    remain fourth in 2005.
   Worldwide there are 930,000 new cases and
    700,000 deaths per year. Sixty percent of new
    cases occur in developing countries.
   There is tremendous geographic variation, with
    the highest death rates in Chile, the former
    Soviet Union, China, and Japan.
                 Epidemiology
   In the United States gastric cancer is the 15th
    most common cancer, with 21,860 new cases
    expected this year, and 11,550 deaths.
   The incidence of gastric cancer has declined
    significantly worldwide in the last century, with a
    marked decline in the US since the 1930s.
                Epidemiology
   In New York State there were an average of
    1955 cases annually between 1998-2002, with
    1070 deaths.
   Male to female ratio of 2:1 in the US; 3:2 in New
    York.
   Median age at diagnosis is 65 years (40-70).
    Incidence increases with age, peaking in the 7th
    decade.
                 Risk Factors
   Diet
     Low fat or protein consumption
     Salted meat or fish

     High nitrate consumption

     High complex carbohydrate consumption
                  Risk Factors
   Environment
     Poor food preparation (smoked/salted)
     Lack of refridgeration

     Poor drinking water (well water)

     Smoking
                     Risk Factors
   Social
       Low social class (except in Japan)
   Medical
     Prior gastric surgery
     H. pylori infection

     Gastric atrophy and gastritis

     Adenomatous polyps

     Male gender
                    Risk Factors
   Helicobacter pylori
     Presence of IgG to H. pylori in a given population
      correlates with local incidence and mortality from
      gastric cancer.
     Different strains elicit different antibody responses.
      The cagA strain causes more mucosal inflammation
      and thus a higher risk of gastric cancer than cagA-
      negative strains.
                   Risk Factors
   Adenomatous polyps
     10-20% risk of developing cancer, especially in
      lesions greater than 2 cm.
     Multiple lesions increase the risk of developing
      cancer.
     Presence of polyps increase the chance of
      developing cancer in the remainder of mucosa.
     Endoscopic surveillance is required after removal of
      polyps.
            Decreasing Incidence




   Improved nutrition and refrigeration of foods
   Lower incidences of H. pylori due to increased antibiotic
    use and cleaner water/sanitation leading to decreased
    transmission of disease
   Earlier detection and treatment in certain countries
                      Anatomy
   Most of the blood supply to the stomach is from
    the celiac artery.
   Four main arteries:
     Left and right gastric along the lesser curvature
     Left and right gastroepiploic along the greater
      curvature.
   Blood supply to the proximal stomach also
    comes from the inferior phrenic and short
    gastric arteries
                     Anatomy
   Occasionally (15-20%) an aberrant left hepatic
    artery arises from the left gastric – a concern if
    the left gastric needs to be divided.
   The extensive anastomotic connections between
    these arteries allow, in most cases, three of the
    four vessels to be ligated as long as the arcades
    between the curvatures are not disturbed.
                       Anatomy
   Venous drainage parallels the arterial supply
     Left and right gastric veins drain into the portal vein
     Right gastroepiploic drains into the SMV

     Left gastroepiploic drains into the splenic vein
                      Anatomy
   Lymphatic drainage is into four zones:
     Superior gastric
     Suprapyloric
     Pancreaticolienal
     Inferior gastric/subpyloric

   All four drain into the celiac group of nodes and
    into the thoracic duct.
   Gastric cancers drain into any of these groups
    regardless of location of the tumor.
                             Anatomy
   Innervation:
       Parasympathetic via the vagus.
            Left anterior and right posterior.
       Sympathetic via the celiac plexus.
                          Anatomy
   Stomach has five layers:
       Mucosa
           Epithelium, lamina propria, and muscularis mucosae*
     Submucosa
     Smooth muscle layer

     Subserosa

     Serosa
            Clinical Presentation
   Symptoms are often absent in early stages, and
    when present are often ignored, missed, or
    mistaken for another disease process.
     Vague discomfort and/or indigestion
     Epigastric pain that is constant, non-radiating, and
      unrelieved by food ingestion.
   Proximal tumors may present with dysphagia.
   Antral tumors may present with outlet
    obstruction.
           Clinical Presentation
   Diffuse mural disease may present with early
    satiety due to decreased distensibility.
   Up to 15% of patients develop hematemesis and
    40% are anemic at presentation.
           Clinical Presentation
   Unfortunately most patients present in later
    stages of disease, with evidence of metastatic or
    locally advanced tumor.
     Palpable abdominal mass, ovarian mass,
      supraclavicular or periumbilical lymph nodes.
     Obstruction from tumor invasion into transverse
      colon.
     Hepatomegaly, jaundice, ascites, and cachexia.
                    Diagnosis
   Endoscopy is the diagnostic method of choice.
     With multiple biopsies (seven or more) the
      diagnostic accuracy approaches 98%.
     Cytologic brushings can also be obtained.

     Size, morphology, and location of tumor can be
      documented, as well as any other mucosal
      abnormalities.
Endoscopy
Endoscopy
                          Diagnosis
   Double contrast barium
    swallow has 90%
    accuracy and is cost
    effective.
       No ability to distinguish
        between malignant and
        benign ulcers.
                    Diagnosis
   Endoscopic Ultrasound (EUS) is a newer
    modality that is being used in some center to
    help stage the tumor.
   Extent of wall invasion and lymph node
    involvement can be assessed.
   Overall accuracy is 75%.
     Poor for T2 tumors (38%)
     Better for T1 (80%) and T3 (90%)

   Remains operator dependent.
           Preoperative Workup
   Once diagnosis of gastric cancer has been made,
    CT scan is useful for evaluation of any distant
    disease.
     Limited in detecting early primary and small (<5mm)
      metastatic tumors.
     Accuracy of lymph node staging ranges from 25 to
      86%.
   If CT scan is negative, then laparoscopy is
    recommended as the next step in evaluation.
           Preoperative Workup
   Laparoscopy detected metastatic disease in 23 to
    37% of patients deemed eligible for curative
    resection by CT scan.
   Laparoscopy improves palliation in these
    patients by avoiding unnecessary laparotomy in
    about one fourth of patients presumed to have
    local disease on CT scan.
                     AJCC Cancer Staging Manual, Sixth Edition

                      Stomach
(Lymphomas, sarcomas, and carcinoid tumors are not included.)
                     AJCC Cancer Staging Manual, Sixth Edition

                      Stomach
(Lymphomas, sarcomas, and carcinoid tumors are not included.)
                     AJCC Cancer Staging Manual, Sixth Edition

                      Stomach
(Lymphomas, sarcomas, and carcinoid tumors are not included.)
                     Treatment
   Surgical resection remains the mainstay of treatment
    and is the only curative option.
   More recently pre- and post-chemoradiation therapy
    has been scrutinized to see if there is any benefit to
    survival.
   The issue of extent of resection appears to have been
    settled. As long as adequate tumor margins are
    achieved, subtotal gastrectomy has the same survival as
    total, with decreased morbidity.
          Neoadjuvant Therapy
   Radiation alone
     1970’s in Russia 152 patients were randomly
      assigned to surgery alone or preop radiation with 20
      Gy a week prior to surgery. Five year survival rates
      were 30% and 39% respectively.
     In 1998 a Chinese group reported a prospective
      series of 370 patients who underwent surgery only or
      had 40 Gy preop radiation. Five year survival was
      19.8% vs 30.1% with radiation. Resectability and
      radical resection rates were also improved.
           Neoadjuvant Therapy
   Radiation alone
     In both studies reported perioperative mortality and
      anastamotic leak rates were not significantly
      different.
     Further studies in radiation alone were largely
      abandoned in favor of studies including
      chemotherapy.
Neoadjuvant Therapy
          Neoadjuvant Therapy
   Chemotherapy alone
     A randomized Netherlands study (DGCT) was
      unable to show any difference with preop
      chemotherapy. This may be in part due to the
      regimen used – FAMTX (FU, doxyrubicin,
      methotrexate).
     In the U.K. the MAGIC trial using ECF (epirubicin,
      cisplatin, FU) has shown promising preliminary
      results, with 10% more resectable cases and
      improved disease-free survival.
          Neoadjuvant Therapy
   Combined chemoradiation therapy
     Has shown a beneficial impact on surgical outcomes
      in esophageal and rectal cancers, making it an
      attractive approach for gastric cancer as well.
     The M.D. Anderson Cancer Center reported several
      studies, one in 2004 where patients who underwent
      preop chemoradiotherapy – FU, leucovorin,
      cisplatin, and 45 Gy in 25 fractions over 5 weeks –
      achieved pathological complete and partial response
      in 64% of all operated patients.
           Neoadjuvant Therapy
   Chemoradiation therapy
     These patients showed a significantly longer median
      survival of 64 months in comparison to 13 months
      in patients who did not reach complete or partial
      response.
     Further clinical trials are warranted to further show
      any benefit of neoadjuvant chemoradiation.
                Surgical Treatment
   Aggressive resection of gastric cancer is justified in the
    absence of distant metastatic spread.
   The surgery is tailored mainly to the location of the
    tumor and known pattern of spread.
   R0 resection should be achieved, with a minimum of
    6cm margins from gross tumor.
       R0 – tumor free margins
       R1 – microscopic disease
       R2 – gross tumor at margins
   Minimum of 15 nodes should be removed.
            Surgical Treatment
   Tumors in the cardia and proximal stomach
    account for 35-50% of gastric adenocarcinomas.
    For these tumors a total gastrectomy should be
    performed, as opposed to proximal gastric
    resection which is associated with higher
    morbidity and mortality rates.
   Distal tumors may be removed by distal
    gastrectomy as long as adequate margins are
    achieved.
                Surgical Treatment
   The extent of lymphadenectomy remains controversial.
   The JGCA classifies the lymph node basins into 16
    basins, and are grouped according to the location of the
    primary tumor as either D1, D2, or D3 nodes. In
    general:
       D1 – removal of group 1 nodes along the lesser and greater
        curvature.
       D2 – D1 plus group 2 nodes along the left gastric, common
        hepatic, celiac, and splenic arteries.
       D3 – D2 plus para-aortic and distal lymph nodes
Lymph Node Stations
              Surgical Treatment
   A 1993 survey by the ACS showed a 77.1% resection
    rate in 18,365 patients, with a postoperative mortality
    rate of 7.2% and 5-year survival rate of 19%. Of these
    only 4.7% were D2 dissections.
   In comparison, the Japanese routinely perform D2
    dissections, with 5-year survival rates above 50%.
    Although earlier detection accounts for much of the
    survival benefit, when comparing cancers in the same
    stage, the Japanese continue to have improved survival.
                Survival Outcomes
120

100

80
                                                    US
60
                                                    Japan
40

20

 0
      Stage I     Stage II   Stage III   Stage IV
             Surgical Treatment
   Based on this and other retrospective data, four
    randomized studies comparing D1 to D2
    dissections have been conducted.
   All four trials, including two large ones from the
    Netherlands and Britain all show the same data;
    that D2 dissection significantly increases
    morbidity and mortality without any significant
    increase in survival.
            Surgical Treatment
   Splenectomy and pancreatectomy were found to
    be important risk factors for morbidity and
    mortality after D2 dissection.
   In the DGCT trial a subgroup analysis of
    patients who underwent D2 without
    splenectomy and/or pancreatectomy had a
    significantly improved survival benefit.
   A randomized British trial also supported these
    findings in stage II and III disease.
            Surgical Treatment
   Based on these findings, many groups are
    recommending “over-D1” lymphadenectomy
    for gastric cancers in Western society.
   The large difference between the Japanese
    results and Western results remains largely an
    enigma.
            Surgical Treatment
   Choice of reanastamosis depends on extent of
    resection.
   Very distal gastrectomies may be reanastamosed
    via a Billroth I, II, or Roux-en-Y.
   Subtotal gastrectomies will require a Billroth II
    or Roux-en-Y.
   Total gastrectomies are best served with a Roux-
    en-Y anastamosis.
Surgical Treatment
Surgical Treatment
            Surgical Treatment
   In the U.S. 20 to 30% of patients present with
    stage IV disease.
   Palliative treatment should be geared toward
    relief of symptoms with minimal morbidity,
    usually non-operative.
   Laser recanulization and endoscopic dilatation
    with or without stent placement has shown
    success in relieving outlet obstruction.
              Adjuvant Therapy
   A 1999 review of the National Cancer Database
    reported that only 29% of patients undergoing
    gastrectomy for cancer had some form of
    adjuvant therapy.
   This shows the lack of convincing data up to
    that point that adjuvant therapy increase survival
    in gastric cancer.
             Adjuvant Therapy
   In 2001 the Southwest Oncology Group trial
    was published, showing for the first time in a
    large prospective randomized trial a survival
    benefit for patients undergoing gastrectomy for
    cancer.
   Median survival was 27 months in the surgery
    only group, and 36 months after
    chemoradiotherapy.
              Adjuvant Therapy
   Survival was improved only in the D0 and D1
    groups.
   Details on late toxicity have yet to be followed
    up on and reported.
   Radiation toxicity had been improved with the
    use of IMRT (intensity modulated RT),
    especially renal toxicity.
Adjuvant Therapy
                    Outcomes
   What can you expect?
   Patients who have undergone a potentially
    curative resection have an average 5-year
    survival of 24 to 57%.
   More useful survival rates are stratified by stage
    of disease.
                   Outcomes
   Recurrence rates remain high, from 40 to 80%
    depending on the series being quoted.
   Locoregional failure rate 38 to 45%, with most
    recurrence in the gastric remnant at the
    anastamosis, gastric bed, and lymph nodes.
   Surveillance is important. Patients should be
    followed every 4 months for the first year, then
    6 months for 2 more years. Yearly endoscopy
    should be performed for subtotal gastrectomies.
            Choice of Operation
   Open gastrectomy with lymph node dissection –
    at least D1 – is the current operative standard.
   Laparoscopic gastrectomy has been shown to be
    safe with similar survival for patients with distal
    cancer.
   Learning curve needs to be overcome, which
    may be difficult with the decreasing number of
    gastric cancer cases in the U.S.
End

				
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