gastric cancer

A Case History

• AH 55 yrs gentleman from Nabhania• C/O

– Abdominal pain• 3 months duration app.

• O/E– Nil abnormal

• Non ulcer dyspepsia Rx

A Case History

• No relief after a few weeks of therapy• Next investigation of choice?

– Fecal occult blood– UGI endoscopy– CT scan– Rapid serological test for H pylori– Serum gastrin level

Or this investigation?

Endoscopy

• Points to remember– Allows direct visualization– Biopsy

• >=10 biopsies– EUS– May miss some lesions

• Two investigations are complementary

Bowels MJ et al: BMJ 2001;323:1413

The Concern of The Son

• The nature of the disease of his father• Is it communicable?• Why did my father get it?• Was it initially missed?• Is the incidence of cancer highest in Al-

Qassim region?

Dr. Shad Salim AkhtarMBBS, MD, MRCP(UK), FRCP (Edin), FACP(USA)

Member AUICC FellowsConsultant Medical OncologistMedical DirectorPrince Faisal Oncology CenterKing Fahd Specialist HospitalBuraidah. Al-Qassim KSA

Gastric CancerThe

Standard Therapy

Gastric Ca In Al-Qassim 94-2000

94 = 1195 = 996 = 497 = 1198 = 699 = 800 = 1001 = 1202 = 4

Others = 2300

Gastric = 75

Year No

Lung 1,103,000Stomach 647,000Liver 549,000Colon & Rectum 492,000Breast 373,000Esophagus 338,000Cervix 233,000Pancreas 213,000Prostate 204,000Leukemia 195,000All sites 62,000,000

Parkin J et al. Eur J Cancer 2001; 37:S4

The Estimated Global Deaths for year 2000 (both sexes)

Changes in gastric ca related mortality in Europe

Russian Fed MRussian Fed F

East Europe MEast Europe F

XEU Solid line M (Male)XEU dashed line F (Female)

Levi F etal. Ann Oncol 2004; 15:338

SEER data 1973-1999 Submitted 2001

Incidence rate of gastric ca per 100,000 (USA)

Reduced Incidence of Gastric Ca Reasons?

• Better living conditions?• Increased consumption of fruits and

vegetables?• Incidence of distal tumors has decreased?• Decreased intake of salted, pickled,

smoked chemically preserved foods?• Decreased incidence mainly in developing

countries?

Average age adjusted mortality US Males 1930-2000. Ahmedin J et al. CA Cancer J Clin 2004;54:8–29

Ahmedin J et al. CA Cancer J Clin 2004;54:8–29Average age adjusted mortality US females 1930-2000.

Etiological Factors+ve -ve

Salt Ascorbic acidHelicobactor B- CaroteneCarcinogen?Risk factors include:

Pernicious anemia Ch Atrophic gastritis

Barrett’s esophagus Partial gastrectomy

Menetrier’s disease E cadherin gene abnormality

Gastric adenomatous polyposis

Family history of gastric ca Blood group A

Low socioeconomic status Cigarette smoking

Bowels MJ et al: BMJ 2001; 323:1413

Helicobacter pylori organisms between the domes of epithelial cells

Calam J etal. BMJ 2001; 323:980

Relation of H pylori infection to UGI conditions

Autoregulation of acid secretion Calam J etal. BMJ 2001;323:980

H pylori Induced Hypoacidity

• Predisposes to distal cancer

• Genetically determined

• Possibly due to inflammation

• Reversed after eradication of H pylori

• H pylori also impairs absorption of Vit. C

Hanson L etal. N Engl J Med 1996; 335:242-9

29,287 Pts

24,456 Pts

Uemura Naomi etal. N Engl J Med 2001; 345:784

Relationship of H pylori with Gastric Cancer Development

Relationship of H pylori with Gastric Cancer Development

Uemura Naomi etal. N Engl J Med 2001; 345:784-9

1246 Pts

280 Pts

Gastric Cancer Location

Factors Cardia CorpusIncidence Rising DecliningH. pylori + ++++Social status Upper LowerHistology Diffuse IntestinalDNA content Aneup+S phase DiploidSpread Early Hemat Late LocoReg

Alberts SR etal. Ann Oncol 2003; 14:s31

Was the Diagnosis Delayed?Symptom Frequency %

• Weight loss 61.6• Abdominal Pain 51.6• Nausea/Vomiting 34.3• Anorexia 32.0• Dysphagia 26.1• Malena 20.2• Early satiety 17.5• Ulcer type pain 17.1• Lower limb edema 5.9

Wanebo H etal Ann Surg 1993;218:58318365 pts with gastric cancer

Early gastric cancer Sparayed with 0.2% indigo carmine dye

Burn marks around the tumour Lesion removed with 1 cm margin

Gastric Cancer Histopathology

• Early cancers in eastern countries• Western experience• High grade dysplasia Cancer• No such reports from Japan & Korea• British Society of GE 1990..Hey Guys!!!!• Changes in histopathological classification

needed

Hohenberger P etal. The Lancet 2003; 362:305

75%Within 8 months

Category• 1 Negative for neoplasia• 2 Indefinitive for neoplasia• 3 Non invasive low grade neoplasia• 4 Non invasive high grade neoplasia

– 4.1 High grade adenoma– 4.2 Non invasive carcinoma– 4.3 Suspicious for invasive carcinoma

• 5 Invasive neoplasia– 5.1 Intramucosal carcinoma– 5.2 Submucosal carcinoma or beyond

Woodward M et al. Eur J Gastroenterol Hepatol 2001; 13:233-7

Advances in DiagnosisVienna Classification of Epithelial Neoplasia of GIT

Most Important Prognostic factorin Year 2004

Depth of InvasionDepth of Invasion

Most Important Prognostic FactorDepth of Invasion

Sasako M. J Clin Oncol 2003; 21:274S

Incidence of Metastasis and 5-Year Survival Rate- Related to Depth of Invasion NCC Hosp Japan 1972-91

Tis=(16)

T3=(464)

T2=(265)

T1=(168)

T Stage versus SurvivalMSKCC Prospective Gastric CA Database

TNM Staging System

N0 N1 N2 N3M0 T1 I a I b II IV

T2 I b II III a IVT3 II III a III b IVT4 III a IV IV IV

M1 IV IV IV IV


15 or more nodes to be examined

NX <15 nodes exam; N1 1-6 +; N2 7-15 +; N3 >15 regional nodes +

Staging Investigations

• Routine• Others as we know • Aim

– Extent of invasion– Nodal status– Distant metastasis

Frequency of Nodal Metastasis

%N+

Accuracy of Various Investigations to Assess TNM features

Category CT EUS Hydro CT LapT 25-66% 71-92% 51% 47%

N 25-68% 55-87% 51% 60-90%

M 65-72% 79% 80-90%


• Used for 4 decades prior to 60-70s• New techniques introduced 90s• Detection of advanced cancer

– CT 58% – EUS 63% – Lap 92%

• Alteration in treatment plan in 30%• Best tool prior to surgery

Does Laparoscopy Help?

Feussner H etal. In Hohenberger P, Staging Laparoscopy 2002. 83-95

Accuracy of Various Investigations to Assess TNM features

Category CT EUS Hydro CT LapT 25-66% 71-92% 51% 47%

N 25-68% 55-87% 51% 60-90%

M 65-72% 79% 80-90%


Staging Laparoscopy Steps• Visual turn around of cavity

– Peritoneal cavity– Liver surface

• Serosal invasion– Visual– Biopsy

• Open lesser sac to confirm resectability• Lavage of greater sac• Lap USG under direct vision

– Sub diaphragmatic liver segments\– Lymph nodes

• Perigastric • coeliac axis• hepatoduodenal ligament

• Biopsy any suspicious lymph nodes

D’Ugo DM etal. Surg Endosc 1997; 11:1159

Back To Our Patient

• Routine normal• Abdominal USG • CT scan • What was done?• What is the best treatment for such

patients?

Pattern of Failure

Local/Regional all 88%Distant 25%Local/Regional only 54%

Gunderson etal. Int J Radioation Oncol Biol 1981; 81:1

Standard Therapy of Gastric Cancer in 2004

CURATIVE CURATIVE RESECTIONRESECTION

Global Consensus-2004Good Good

LOCAL CONTROLLOCAL CONTROL

Is Essential To Is Essential To Cure Gastric Cure Gastric

CancerCancer

Gastric Cancer Surgery Controversies

• Gastrectomy– Total vs Subtotal?

• Splenectomy– To do or not to do?

• Extension of lymph node dissection– D1 vs D2?

• Neoadjuvant therapy (before surgery)– Role or no role?

Extent of GastrectomyTotal Gastrectomy (TG) vs Subtotal Gastrectomy

Surgery Number Mortality% Morbidity% 5 yr SurvTG 93 3.2 32 48SG 76 1.3 34 48

TG 303 2 13 62.4SG 315 1 9 65.3

Gouzi et al. Ann Surg 1989:209:162

Bozetti et al. Ann Surg 1999;230:170

Multivariate analysis by Bozetti confirmed deleterious effects of total gastrectomy

Conclusion• Subtotal gastrectomy except if

– Proximal tumor– Diffuse lesion

• No splenectomy unless– Greater curvature lesion

• Proximal 3rd

• >=T2– Organ invasion

• Preserve pancreatic tail except if– Organ invasion Degiuli J. N Clin Oncol 1998; 16:1490

Maryuma. World J Surg 1995; 19:532

Survival in US vs Japanese Pts

US 1982-1987 Japan 1971-1985Stage No (%) 5 yr

Surv (%)No (%) 5 yr

Surv (%)I 2004(17.8) 50.0 1453 (45.7) 90.7

II 1976(17.5) 29.0 377 (11.9) 71.7

III 3945(35.0) 13.0 693 (21.8) 44.3

IV 3342(29.7) 3.0 653 (20.6) 9.0

Alberts SR etal. Ann Oncol 2003; 14(s2):ii31

Japanese Terms of Staging• R =Residual disease

– R0 no residual disease– R1 microscopic residual tumor– R2 macroscopic residual disease

• D =Extent of lymph node dissection– D1 Perigastric – D2 +Celiac axis, hep & spl art, spl hilum– D3 removes N1, N2 and N3 level nodes

• Stomach is divided into three sectors– Upper third (C)– Middle third (M)– Lower third (A)

Japanese Concepts

• Early gastric cancer ~ 40%• D2 is a standard procedure• D3 for advanced cancers• Retrospective data confirming superiority

of these surgical procedures• Lymph node involvement is an indicator• Are we seeing a stage migration?

RCT of D1 vs D2 Resection

No Morbidity Mortality 5 yr SurvD1 380 25 4 45

D2 331 43 10 47

D1 200 28 6.5 35

D2 200 46 13 33P Value <0.001 P Value 0.004 NS

Cuschieri A et al. Br J Cancer 1999; 79:1522Bonenkamp JJ et al. N Engl J Med 1999; 340:908

Is there a survival advantage? Dutch Trial YES!!!

Risk Factors for Postoperative Mortality

• Kanofsky index 0.0001• Concomitant diseases 0.0001• Lymph node metastasis 0.001• Tumour diameter 0.001• Experience of the surg dept 0.001• Age 0.028

Need for centralizing the services

Bottcher et al. Chirug 1994; 65:298

Ongoing RCT Comparing Extent of ResectionType No Morbidity MortalityD1 76 11.0 1.3

D2 86 16.3 0

D1 109 7 0

D2 111 17 0

M Degiuli, Turin Italy

C W Wu, Tapei Taiwan

Who Needs Extensive Dissection? Can We Know In the Year 2004?

• Computerized database• Sentinel lymph node biopsy

• Genomic study

Selection for Nodal Surgery

• Maruyama computer program– Data from app 8000 pts– Indicators to predict nodal metastasis

• Depth of infiltration• Size• Location• Grading• Type• Macroscopic appearance

– Diagnostic accuracy ~74-94%

Guadagani S et al. World J Surg 2000; 24:1550

Selection for Nodal Surgery Sentinel lymph node biopsyNo Method Detection

rate (%)Sensitivity (%)

Node positive (%)

145 99Tc Sn colloid

95 92 17

62 ICG 100 87 2474 ICG 99 90 14

Kitagawa Y etal. Br J Surg 2002; 89:604Ichikurs T etal. World J Surg 2002; 26:318Hiratsuka M etal. Surgery 2001; 129:335

ICG = Indocyan green

Lymph nodes of Pts from Dutch Trial ASCO Presentation

Resected Gastric Cancer

5 years survival

• Node negative 40-60%• Node positive 5-30%

Adjuvant Chemotherapy

Is it effective?

Meta-analysis of Postoperative Adjuvant Trials

No of trials No Patients Mortality O.R. 95% CI11 2096 0.88 0.78-1.08

13 1990 0.80 0.66-0.97

21 3658 0.82 0.75-0.89

17 3118 0.72 0.62-0.84

Hermans J etal. J Clin Oncol 1993; 11:1441Earle CC etal. Eur J Cancer 1999; 35:1059Marie etal. Ann Oncol 2000Panzini etal. Tumori 2002

• FAM• EAP+5FU• EPI+5FU/LV• FAMTX• CPT-11/CDDP• Docetaxel/CDDP/5FU• ECF• Gem/CPT-11• 5FU CI/CDDP

Adjuvant ChemotherapyEffective Drugs Available

ECF vs FAMTX

ECF (111 pts) FAMTX (108 pts)CR+PR 50 (45%) 23 (21%)*CR 7 (6%) 2 (2%)PR 43 (39%) 21 (19%)SD 23 (27%) 23 (21%)Med Surv 8.7 mo 6.1 mo

Webb etal. J Clin Oncol 1997; 15:261

*p value <0.002

Gastro-esophageal junction adenocarcinoma patients

PEGASUSPan European Gastric Adjuvant

Study with Uniform SurgerySurgery

ChemotherapyHD Infusional 5-FU/Docetaxel/CPT-11

D1+ Lymph node dissectionPreservation of spleen and pancreatic tail

Observation

Post operative Adjuvant Therapy

Not a standard “yet”

Site of Relapse

Local and regional failure 70-90%

Gunderson et al. J Clin Oncol 1995

Adjuvant Local Therapy

Intra peritoneal therapy • Drugs tried

– Cisplatin– Mitomycin C– 5FU+Mitomycin C

• No survival benefit• Added postop morbidity and mortality

Yao JC & Ajani JA. Ann Oncol 2002; s2:7

Adjuvant Chemo-radiotherapy

No of pts 603; Negative margins essential; 47 ineligible for therapy

Macdonald JS. J Clin Oncol 2003; 21(23s):276sUpdated results similar

Macdonald JS. J Clin Oncol 2003; 21(23s):276s

Updated results similar

Post-operative Adjuvant Chemo-radiotherapy

• Improves survival– Disease free (44% improvement)– Overall (28% improvement)

• Acceptable toxicity– Mainly hematological

• Probably standard for the surgical techniques employed outside Japan

• May form the basis for future comparison

Gastric Cancer Spectrum In The West What Can Be Done?

• pT3 tumors in UK study 44%• III/IV disease in German study 59%• III/IV disease in Am Col Surg 67%• Comp Res rate in adv disease <50%• Median survival at 5 yrs ~30%

Neo Adjuvant TherapyWhat Should It Do?

• Improve resectability• Down stage the disease• Improve survival

MAGIC Trial

Observation3XECFAllum W etal. Proc Am Soc Clin Oncol 2003; 22:249 (Abst 998)

Operable Gastric Cancer

Randomize

3XECF Surgery

Surgery

MAGIC TRIAL

CSC SPatients having surgery 212 (85%) 232 (92%)

Median time to surgery 99 days 14 days

Proportion of curative resection

79%* 69%**p = 0.018

Allum W etal. Proc Am Soc Clin Oncol 2003; 22:249 (Abst 998)

MAGIC Trial

Improvement in survival

Ongoing Adjuvant Trials

Group No of pts targeted

Therapy

MRC 500 ECF pre & post op

France 250 CDDP/CI 5-FU

EORTC 360 CDDP/5-FU

Swiss/Italian 250 Docetaxel/CDDP/CI 5-FU

New Trends!!!• EGFR inhibitors• MOAB

– Cetuximab (C-225)• TKIs

– ZD-1839 (Iressa)– OSI-774 (Tarceva)

• Flavopiridol– Pan CDK inhibitor

Improvements in Future• Minimizing morbidity

– Patient selection– Organ preservation

• Local control– D1+disection– Minimum 15 nodes– Centralization

• Survival– Surgery– Radiotherapy– Chemotherapy

This Dream May Come True Soon

Lymph Node Metastasis Related to Depth of Tumor Invasion

Sasako M. J Clin Oncol 2003; 21:274S

gastric cancer

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