gastric cancer: current concepts david shin dept of surgery grand rounds august 24, 2005

Gastric Cancer: Gastric Cancer: Current ConceptsCurrent Concepts

David ShinDavid Shin

Dept of Surgery Grand Dept of Surgery Grand RoundsRounds

August 24, 2005August 24, 2005

EpidemiologyEpidemiology Gastric cancer was the fourth most Gastric cancer was the fourth most

common cancer in the world in 2004, common cancer in the world in 2004, and is expected to remain fourth in 2005.and is expected to remain fourth in 2005.

Worldwide there are 930,000 new cases Worldwide there are 930,000 new cases and 700,000 deaths per year. Sixty and 700,000 deaths per year. Sixty percent of new cases occur in developing percent of new cases occur in developing countries.countries.

There is tremendous geographic There is tremendous geographic variation, with the highest death rates in variation, with the highest death rates in Chile, the former Soviet Union, China, Chile, the former Soviet Union, China, and Japan.and Japan.

EpidemiologyEpidemiology

In the United States gastric cancer In the United States gastric cancer is the 15is the 15thth most common cancer, most common cancer, with 21,860 new cases expected this with 21,860 new cases expected this year, and 11,550 deaths.year, and 11,550 deaths.

The incidence of gastric cancer has The incidence of gastric cancer has declined significantly worldwide in declined significantly worldwide in the last century, with a marked the last century, with a marked decline in the US since the 1930s.decline in the US since the 1930s.

EpidemiologyEpidemiology

In New York State there were an In New York State there were an average of 1955 cases annually average of 1955 cases annually between 1998-2002, with 1070 between 1998-2002, with 1070 deaths.deaths.

Male to female ratio of 2:1 in the Male to female ratio of 2:1 in the US; 3:2 in New York.US; 3:2 in New York.

Median age at diagnosis is 65 years Median age at diagnosis is 65 years (40-70). Incidence increases with (40-70). Incidence increases with age, peaking in the 7age, peaking in the 7thth decade. decade.

Risk FactorsRisk Factors

DietDiet Low fat or protein consumptionLow fat or protein consumption Salted meat or fishSalted meat or fish High nitrate consumptionHigh nitrate consumption High complex carbohydrate High complex carbohydrate

consumptionconsumption


EnvironmentEnvironment Poor food preparation (smoked/salted)Poor food preparation (smoked/salted) Lack of refridgerationLack of refridgeration Poor drinking water (well water)Poor drinking water (well water) SmokingSmoking


SocialSocial Low social class (except in Japan)Low social class (except in Japan)

MedicalMedical Prior gastric surgeryPrior gastric surgery H. pyloriH. pylori infection infection Gastric atrophy and gastritisGastric atrophy and gastritis Adenomatous polypsAdenomatous polyps Male genderMale gender


Helicobacter pyloriHelicobacter pylori Presence of IgG to Presence of IgG to H. pylori H. pylori in a given in a given

population correlates with local population correlates with local incidence and mortality from gastric incidence and mortality from gastric cancer.cancer.

Different strains elicit different Different strains elicit different antibody responses. The antibody responses. The cagAcagA strain strain causes more mucosal inflammation and causes more mucosal inflammation and thus a higher risk of gastric cancer than thus a higher risk of gastric cancer than cagA-cagA-negative strains.negative strains.


Adenomatous polypsAdenomatous polyps 10-20% risk of developing cancer, 10-20% risk of developing cancer,

especially in lesions greater than 2 cm.especially in lesions greater than 2 cm. Multiple lesions increase the risk of Multiple lesions increase the risk of

developing cancer.developing cancer. Presence of polyps increase the chance Presence of polyps increase the chance

of developing cancer in the remainder of of developing cancer in the remainder of mucosa.mucosa.

Endoscopic surveillance is required after Endoscopic surveillance is required after removal of polyps.removal of polyps.

Decreasing IncidenceDecreasing Incidence

Improved nutrition and refrigeration of foodsImproved nutrition and refrigeration of foods Lower incidences of Lower incidences of H. pyloriH. pylori due to increased due to increased

antibiotic use and cleaner water/sanitation antibiotic use and cleaner water/sanitation leading to decreased transmission of diseaseleading to decreased transmission of disease

Earlier detection and treatment in certain Earlier detection and treatment in certain countriescountries

AnatomyAnatomy

Most of the blood supply to the Most of the blood supply to the stomach is from the celiac artery.stomach is from the celiac artery.

Four main arteries:Four main arteries: Left and right gastric along the lesser Left and right gastric along the lesser

curvaturecurvature Left and right gastroepiploic along the Left and right gastroepiploic along the

greater curvature. greater curvature. Blood supply to the proximal stomach Blood supply to the proximal stomach

also comes from the inferior phrenic also comes from the inferior phrenic and short gastric arteriesand short gastric arteries

AnatomyAnatomy

Occasionally (15-20%) an aberrant left Occasionally (15-20%) an aberrant left hepatic artery arises from the left hepatic artery arises from the left gastric – a concern if the left gastric gastric – a concern if the left gastric needs to be divided.needs to be divided.

The extensive anastomotic connections The extensive anastomotic connections between these arteries allow, in most between these arteries allow, in most cases, three of the four vessels to be cases, three of the four vessels to be ligated as long as the arcades between ligated as long as the arcades between the curvatures are not disturbed.the curvatures are not disturbed.

AnatomyAnatomy

Venous drainage parallels the Venous drainage parallels the arterial supplyarterial supply Left and right gastric veins drain into Left and right gastric veins drain into

the portal veinthe portal vein Right gastroepiploic drains into the Right gastroepiploic drains into the

SMVSMV Left gastroepiploic drains into the Left gastroepiploic drains into the

splenic veinsplenic vein

AnatomyAnatomy

Lymphatic drainage is into four zones:Lymphatic drainage is into four zones: Superior gastricSuperior gastric SuprapyloricSuprapyloric PancreaticolienalPancreaticolienal Inferior gastric/subpyloricInferior gastric/subpyloric

All four drain into the celiac group of All four drain into the celiac group of nodes and into the thoracic duct.nodes and into the thoracic duct.

Gastric cancers drain into any of these Gastric cancers drain into any of these groups regardless of location of the groups regardless of location of the tumor.tumor.

AnatomyAnatomy

Innervation:Innervation: Parasympathetic via the vagus.Parasympathetic via the vagus.

Left anterior and right posterior.Left anterior and right posterior. Sympathetic via the celiac plexus.Sympathetic via the celiac plexus.

AnatomyAnatomy

Stomach has five layers:Stomach has five layers: MucosaMucosa

Epithelium, lamina propria, and muscularis Epithelium, lamina propria, and muscularis mucosae*mucosae*

SubmucosaSubmucosa Smooth muscle layerSmooth muscle layer SubserosaSubserosa SerosaSerosa

Clinical PresentationClinical Presentation Symptoms are often absent in early Symptoms are often absent in early

stages, and when present are often stages, and when present are often ignored, missed, or mistaken for another ignored, missed, or mistaken for another disease process.disease process. Vague discomfort and/or indigestionVague discomfort and/or indigestion Epigastric pain that is constant, non-Epigastric pain that is constant, non-

radiating, and unrelieved by food ingestion.radiating, and unrelieved by food ingestion. Proximal tumors may present with Proximal tumors may present with

dysphagia.dysphagia. Antral tumors may present with outlet Antral tumors may present with outlet

obstruction.obstruction.

Clinical PresentationClinical Presentation

Diffuse mural disease may present Diffuse mural disease may present with early satiety due to decreased with early satiety due to decreased distensibility.distensibility.

Up to 15% of patients develop Up to 15% of patients develop hematemesis and 40% are anemic at hematemesis and 40% are anemic at presentation.presentation.

Clinical PresentationClinical Presentation

Unfortunately most patients present in Unfortunately most patients present in later stages of disease, with evidence of later stages of disease, with evidence of metastatic or locally advanced tumor.metastatic or locally advanced tumor. Palpable abdominal mass, ovarian mass, Palpable abdominal mass, ovarian mass,

supraclavicular or periumbilical lymph supraclavicular or periumbilical lymph nodes.nodes.

Obstruction from tumor invasion into Obstruction from tumor invasion into transverse colon.transverse colon.

Hepatomegaly, jaundice, ascites, and Hepatomegaly, jaundice, ascites, and cachexia.cachexia.

DiagnosisDiagnosis

Endoscopy is the diagnostic method Endoscopy is the diagnostic method of choice.of choice. With multiple biopsies (seven or more) With multiple biopsies (seven or more)

the diagnostic accuracy approaches 98%.the diagnostic accuracy approaches 98%. Cytologic brushings can also be Cytologic brushings can also be

obtained.obtained. Size, morphology, and location of tumor Size, morphology, and location of tumor

can be documented, as well as any other can be documented, as well as any other mucosal abnormalities.mucosal abnormalities.

EndoscopyEndoscopy

DiagnosisDiagnosis

Double contrast Double contrast barium swallow barium swallow has 90% accuracy has 90% accuracy and is cost and is cost effective.effective. No ability to No ability to

distinguish distinguish between malignant between malignant and benign ulcers.and benign ulcers.

DiagnosisDiagnosis

Endoscopic Ultrasound (EUS) is a Endoscopic Ultrasound (EUS) is a newer modality that is being used in newer modality that is being used in some center to help stage the tumor.some center to help stage the tumor.

Extent of wall invasion and lymph Extent of wall invasion and lymph node involvement can be assessed.node involvement can be assessed.

Overall accuracy is 75%.Overall accuracy is 75%. Poor for T2 tumors (38%)Poor for T2 tumors (38%) Better for T1 (80%) and T3 (90%)Better for T1 (80%) and T3 (90%)

Remains operator dependent.Remains operator dependent.

Preoperative WorkupPreoperative Workup

Once diagnosis of gastric cancer has Once diagnosis of gastric cancer has been made, CT scan is useful for been made, CT scan is useful for evaluation of any distant disease.evaluation of any distant disease. Limited in detecting early primary and Limited in detecting early primary and

small (<5mm) metastatic tumors.small (<5mm) metastatic tumors. Accuracy of lymph node staging ranges Accuracy of lymph node staging ranges

from 25 to 86%.from 25 to 86%. If CT scan is negative, then laparoscopy If CT scan is negative, then laparoscopy

is recommended as the next step in is recommended as the next step in evaluation.evaluation.

Preoperative WorkupPreoperative Workup

Laparoscopy detected metastatic Laparoscopy detected metastatic disease in 23 to 37% of patients disease in 23 to 37% of patients deemed eligible for curative deemed eligible for curative resection by CT scan.resection by CT scan.

Laparoscopy improves palliation in Laparoscopy improves palliation in these patients by avoiding these patients by avoiding unnecessary laparotomy in about unnecessary laparotomy in about one fourth of patients presumed to one fourth of patients presumed to have local disease on CT scan.have local disease on CT scan.

AJCC Cancer Staging Manual, Sixth Edition

Stomach(Lymphomas, sarcomas, and carcinoid tumors are not included.)

TreatmentTreatment

Surgical resection remains the mainstay of Surgical resection remains the mainstay of treatment and is treatment and is the onlythe only curative option. curative option.

More recently pre- and post-chemoradiation More recently pre- and post-chemoradiation therapy has been scrutinized to see if there therapy has been scrutinized to see if there is any benefit to survival.is any benefit to survival.

The issue of extent of resection appears to The issue of extent of resection appears to have been settled. As long as adequate have been settled. As long as adequate tumor margins are achieved, subtotal tumor margins are achieved, subtotal gastrectomy has the same survival as total, gastrectomy has the same survival as total, with decreased morbidity.with decreased morbidity.

Neoadjuvant TherapyNeoadjuvant Therapy

Radiation aloneRadiation alone 1970’s in Russia 152 patients were 1970’s in Russia 152 patients were

randomly assigned to surgery alone or randomly assigned to surgery alone or preop radiation with 20 Gy a week prior to preop radiation with 20 Gy a week prior to surgery. Five year survival rates were 30% surgery. Five year survival rates were 30% and 39% respectively.and 39% respectively.

In 1998 a Chinese group reported a In 1998 a Chinese group reported a prospective series of 370 patients who prospective series of 370 patients who underwent surgery only or had 40 Gy preop underwent surgery only or had 40 Gy preop radiation. Five year survival was 19.8% vs radiation. Five year survival was 19.8% vs 30.1% with radiation. Resectability and 30.1% with radiation. Resectability and radical resection rates were also improved.radical resection rates were also improved.


Radiation aloneRadiation alone In both studies reported perioperative In both studies reported perioperative

mortality and anastamotic leak rates mortality and anastamotic leak rates were not significantly different.were not significantly different.

Further studies in radiation alone were Further studies in radiation alone were largely abandoned in favor of studies largely abandoned in favor of studies including chemotherapy.including chemotherapy.


Chemotherapy aloneChemotherapy alone A randomized Netherlands study (DGCT) A randomized Netherlands study (DGCT)

was unable to show any difference with was unable to show any difference with preop chemotherapy. This may be in preop chemotherapy. This may be in part due to the regimen used – FAMTX part due to the regimen used – FAMTX (FU, doxyrubicin, methotrexate).(FU, doxyrubicin, methotrexate).

In the U.K. the MAGIC trial using ECF In the U.K. the MAGIC trial using ECF (epirubicin, cisplatin, FU) has shown (epirubicin, cisplatin, FU) has shown promising preliminary results, with 10% promising preliminary results, with 10% more resectable cases and improved more resectable cases and improved disease-free survival.disease-free survival.


Combined chemoradiation therapyCombined chemoradiation therapy Has shown a beneficial impact on surgical Has shown a beneficial impact on surgical

outcomes in esophageal and rectal cancers, outcomes in esophageal and rectal cancers, making it an attractive approach for gastric making it an attractive approach for gastric cancer as well.cancer as well.

The M.D. Anderson Cancer Center reported The M.D. Anderson Cancer Center reported several studies, one in 2004 where patients several studies, one in 2004 where patients who underwent preop chemoradiotherapy – who underwent preop chemoradiotherapy – FU, leucovorin, cisplatin, and 45 Gy in 25 FU, leucovorin, cisplatin, and 45 Gy in 25 fractions over 5 weeks – achieved fractions over 5 weeks – achieved pathological complete and partial response pathological complete and partial response in 64% of all operated patients.in 64% of all operated patients.


Chemoradiation therapyChemoradiation therapy These patients showed a significantly These patients showed a significantly

longer median survival of 64 months in longer median survival of 64 months in comparison to 13 months in patients comparison to 13 months in patients who did not reach complete or partial who did not reach complete or partial response.response.

Further clinical trials are warranted to Further clinical trials are warranted to further show any benefit of neoadjuvant further show any benefit of neoadjuvant chemoradiation. chemoradiation.

Surgical TreatmentSurgical Treatment Aggressive resection of gastric cancer is Aggressive resection of gastric cancer is

justified in the absence of distant metastatic justified in the absence of distant metastatic spread.spread.

The surgery is tailored mainly to the location The surgery is tailored mainly to the location of the tumor and known pattern of spread.of the tumor and known pattern of spread.

R0 resection should be achieved, with a R0 resection should be achieved, with a minimum of 6cm margins from gross tumor.minimum of 6cm margins from gross tumor. R0 – tumor free marginsR0 – tumor free margins R1 – microscopic diseaseR1 – microscopic disease R2 – gross tumor at marginsR2 – gross tumor at margins

Minimum of 15 nodes should be removed.Minimum of 15 nodes should be removed.

Surgical TreatmentSurgical Treatment

Tumors in the cardia and proximal Tumors in the cardia and proximal stomach account for 35-50% of gastric stomach account for 35-50% of gastric adenocarcinomas. For these tumors a adenocarcinomas. For these tumors a total gastrectomy should be performed, total gastrectomy should be performed, as opposed to proximal gastric as opposed to proximal gastric resection which is associated with resection which is associated with higher morbidity and mortality rates.higher morbidity and mortality rates.

Distal tumors may be removed by distal Distal tumors may be removed by distal gastrectomy as long as adequate gastrectomy as long as adequate margins are achieved.margins are achieved.


The extent of lymphadenectomy remains The extent of lymphadenectomy remains controversial. controversial.

The JGCA classifies the lymph node basins The JGCA classifies the lymph node basins into 16 basins, and are grouped according to into 16 basins, and are grouped according to the location of the primary tumor as either the location of the primary tumor as either D1, D2, or D3 nodes. In general:D1, D2, or D3 nodes. In general: D1 – removal of group 1 nodes along the lesser D1 – removal of group 1 nodes along the lesser

and greater curvature.and greater curvature. D2 – D1 plus group 2 nodes along the left gastric, D2 – D1 plus group 2 nodes along the left gastric,

common hepatic, celiac, and splenic arteries.common hepatic, celiac, and splenic arteries. D3 – D2 plus para-aortic and distal lymph nodesD3 – D2 plus para-aortic and distal lymph nodes

Lymph Node StationsLymph Node Stations


A 1993 survey by the ACS showed a 77.1% A 1993 survey by the ACS showed a 77.1% resection rate in 18,365 patients, with a resection rate in 18,365 patients, with a postoperative mortality rate of 7.2% and 5-year postoperative mortality rate of 7.2% and 5-year survival rate of 19%. Of these only 4.7% were survival rate of 19%. Of these only 4.7% were D2 dissections.D2 dissections.

In comparison, the Japanese routinely perform In comparison, the Japanese routinely perform D2 dissections, with 5-year survival rates D2 dissections, with 5-year survival rates above 50%. Although earlier detection above 50%. Although earlier detection accounts for much of the survival benefit, when accounts for much of the survival benefit, when comparing cancers in the same stage, the comparing cancers in the same stage, the Japanese continue to have improved survival.Japanese continue to have improved survival.

Survival OutcomesSurvival Outcomes

0

20

40

60

80

100

120

Stage I Stage II Stage III Stage IV

USJapan


Based on this and other retrospective Based on this and other retrospective data, four randomized studies data, four randomized studies comparing D1 to D2 dissections have comparing D1 to D2 dissections have been conducted.been conducted.

All four trials, including two large ones All four trials, including two large ones from the Netherlands and Britain all from the Netherlands and Britain all show the same data; that D2 dissection show the same data; that D2 dissection significantly increases morbidity and significantly increases morbidity and mortality without any significant mortality without any significant increase in survival.increase in survival.

Surgical TreatmentSurgical Treatment Splenectomy and pancreatectomy were Splenectomy and pancreatectomy were

found to be important risk factors for found to be important risk factors for morbidity and mortality after D2 morbidity and mortality after D2 dissection.dissection.

In the DGCT trial a subgroup analysis of In the DGCT trial a subgroup analysis of patients who underwent D2 without patients who underwent D2 without splenectomy and/or pancreatectomy had splenectomy and/or pancreatectomy had a significantly improved survival benefit.a significantly improved survival benefit.

A randomized British trial also A randomized British trial also supported these findings in stage II and supported these findings in stage II and III disease.III disease.


Based on these findings, many Based on these findings, many groups are recommending “over-D1” groups are recommending “over-D1” lymphadenectomy for gastric lymphadenectomy for gastric cancers in Western society.cancers in Western society.

The large difference between the The large difference between the Japanese results and Western results Japanese results and Western results remains largely an enigma.remains largely an enigma.


Choice of reanastamosis depends on Choice of reanastamosis depends on extent of resection.extent of resection.

Very distal gastrectomies may be Very distal gastrectomies may be reanastamosed via a Billroth I, II, or reanastamosed via a Billroth I, II, or Roux-en-Y.Roux-en-Y.

Subtotal gastrectomies will require a Subtotal gastrectomies will require a Billroth II or Roux-en-Y.Billroth II or Roux-en-Y.

Total gastrectomies are best served Total gastrectomies are best served with a Roux-en-Y anastamosis.with a Roux-en-Y anastamosis.


In the U.S. 20 to 30% of patients In the U.S. 20 to 30% of patients present with stage IV disease.present with stage IV disease.

Palliative treatment should be geared Palliative treatment should be geared toward relief of symptoms with minimal toward relief of symptoms with minimal morbidity, usually non-operative.morbidity, usually non-operative.

Laser recanulization and endoscopic Laser recanulization and endoscopic dilatation with or without stent dilatation with or without stent placement has shown success in placement has shown success in relieving outlet obstruction.relieving outlet obstruction.

Adjuvant TherapyAdjuvant Therapy

A 1999 review of the National A 1999 review of the National Cancer Database reported that only Cancer Database reported that only 29% of patients undergoing 29% of patients undergoing gastrectomy for cancer had some gastrectomy for cancer had some form of adjuvant therapy.form of adjuvant therapy.

This shows the lack of convincing This shows the lack of convincing data up to that point that adjuvant data up to that point that adjuvant therapy increase survival in gastric therapy increase survival in gastric cancer.cancer.


In 2001 the Southwest Oncology In 2001 the Southwest Oncology Group trial was published, showing Group trial was published, showing for the first time in a large for the first time in a large prospective randomized trial a prospective randomized trial a survival benefit for patients survival benefit for patients undergoing gastrectomy for cancer.undergoing gastrectomy for cancer.

Median survival was 27 months in Median survival was 27 months in the surgery only group, and 36 the surgery only group, and 36 months after chemoradiotherapy.months after chemoradiotherapy.


Survival was improved only in the Survival was improved only in the D0 and D1 groups.D0 and D1 groups.

Details on late toxicity have yet to be Details on late toxicity have yet to be followed up on and reported.followed up on and reported.

Radiation toxicity had been Radiation toxicity had been improved with the use of IMRT improved with the use of IMRT (intensity modulated RT), especially (intensity modulated RT), especially renal toxicity.renal toxicity.

OutcomesOutcomes

What can you expect?What can you expect? Patients who have undergone a Patients who have undergone a

potentially curative resection have potentially curative resection have an average 5-year survival of 24 to an average 5-year survival of 24 to 57%.57%.

More useful survival rates are More useful survival rates are stratified by stage of disease.stratified by stage of disease.

OutcomesOutcomes Recurrence rates remain high, from 40 to Recurrence rates remain high, from 40 to

80% depending on the series being quoted.80% depending on the series being quoted. Locoregional failure rate 38 to 45%, with Locoregional failure rate 38 to 45%, with

most recurrence in the gastric remnant at most recurrence in the gastric remnant at the anastamosis, gastric bed, and lymph the anastamosis, gastric bed, and lymph nodes.nodes.

Surveillance is important. Patients should Surveillance is important. Patients should be followed every 4 months for the first be followed every 4 months for the first year, then 6 months for 2 more years. year, then 6 months for 2 more years. Yearly endoscopy should be performed for Yearly endoscopy should be performed for subtotal gastrectomies.subtotal gastrectomies.

Choice of OperationChoice of Operation

Open gastrectomy with lymph node Open gastrectomy with lymph node dissection – at least D1 – is the current dissection – at least D1 – is the current operative standard.operative standard.

Laparoscopic gastrectomy has been Laparoscopic gastrectomy has been shown to be safe with similar survival for shown to be safe with similar survival for patients with distal cancer.patients with distal cancer.

Learning curve needs to be overcome, Learning curve needs to be overcome, which may be difficult with the which may be difficult with the decreasing number of gastric cancer decreasing number of gastric cancer cases in the U.S.cases in the U.S.

EndEnd

gastric cancer: current concepts david shin dept of surgery grand rounds august 24, 2005

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