Gastric CancerCA Cancer J Clin 2005; 55: 10-33CA Cancer J Clin 2005; 55: 75Stewart: World Cancer Reports IARC Press, Lyon 2003

Worldwide:4th most common malignancy2ndleading cause cancer mortality 60% of cases from developing countries 90% cases are adenocarcinoma

Philippines Gastric Cancer

8th leading site in both sexes 5th in males and 10th in females

Epidemiology

Race/Ethnicity Male Female Male FemaleWhite 10.8 5.0 5.8 2.8  White

Hispanic18.4 10.3 9.9 5.4

White non-Hispanic

9.7 4.1 5.4 2.6

African American 18.8 9.9 13.3 6.3Asian/Pacific Islander 21.9 12.4 11.9 7.0Native American/Native Alaskan

15.7 8.9 7.3 4.1

Latino 17.8 10.0 9.7 5.3

INCIDENCE MORTALITY

 Gastric Cancer Incidence and Mortality Rates per 100,000 Cases(Age Adjusted) in the United States, 1997-2001

Environmental Risk factors H. pylori infection Dietary Factors Cigarette Smoking Alcohol Low Socioeconomic Status

Premalignant Conditions Chronic Atrophic Gastritis Intestinal Metaplasia Gastric Dysplasia Gastric Polyps Previous Gastrectomy Gastric Ulcer

WORK-UP

Abdominal CT with contrast PET/CT or PET scan(optional) Endoscopic ultrasound(optional) CBC and chemistry profile Chest imaging

NCCN Clinical Practice Guidelines in Oncology V.2.2009

Clinical Features Gastric cancers that do not penetrate

into the muscularis propria are asymptomatic in up to 80% of cases

When symptoms do occur, they tend to mimic PUD

Clinical Features Poor prognosis of gastric cancer -

Cancer is quite advanced by the time symptoms develop

Except in Japan, screening is not performed in most part of the world

Clinical Features

Weight Loss

Abdominal Pain

62% 52%

Less common symptoms: nausea, vomiting, anorexia, dysphagia,

melena,and early satiety

Cancer of the stomach. A patient care study by the American College of Surgeons.Wanebo HJ; Kennedy BJ; Chmiel J; Steele G Jr; Winchester D; Osteen R

Ann Surg 1993 Nov;218(5):583-92.

Physical Findings Physical findings are usually normal

Cachexia and signs of bowel obstruction are the most common abnormal findings

Occasionally it is possible to detect an epigastric mass, hepatomegaly, ascites, and lower extremity edema

P.E. : ADVANCED DISEASE

Umbilicus Sister Mary Joseph Nodule

Ovaries Krukenberg’sTumor

Left supraclavicular sentinel node

Virchow’s Node

Pouch of Douglas Rectal shelf of Blumer

SISTER MARY JOSEPH NODULE VIRCHOW’S NODE

At diagnosis, advanced cancer has usually metastasized: Liver: 40% lung, peritoneum, and bone marrow

Gastric cancer has also been reported to metastasize to the kidney, bladder, brain, bone, heart, thyroid, adrenal glands, and skin.

STAGING

CT SCAN

Overall accuracy for staging of gastric cancer: 43-82%

Not suitable to assess the tumor depth and metastatic lymph nodes

NCCN Clinical Practice Guidelines in Oncology V.2.2009

Not recommended routinely for preoperative staging

Used in conjunction with CT scan

Higher specificity (92%) but lower sensitivity (56%) than CT scan in the detection of local lymph node involvement

CLINICAL STAGING: PETNCCN Clinical Practice Guidelines in Oncology V.2.2009

Useful in assessing depth of tumor invasion

Accuracy: T staging- 65-92% N staging- 50-95%

CLINICAL STAGING: EUSNCCN Clinical Practice Guidelines in Oncology V.2.2009

Useful to evaluate metastases on the peritoneum and CT-occult metastases

Limitations include two-dimensional evaluation and limited use in the identification of hepatic metastases and perigastric lymph nodes

Laparoscopic stagingNCCN Clinical Practice Guidelines in Oncology V.2.2009

Peritoneal cytology

Cytogenetic analysis of peritoneal fluid to identify occult carcinomatosis

NCCN Clinical Practice Guidelines in Oncology V.2.2009

STAGE AT THE TIME OF DIAGNOSIS

Japan1

ResectableLocally advancedMetastatic

Western countries2

ResectableLocally advancedMetastaticUnstaged

25−30%10–15%25–30%

30–35%

17%15% 68%

1. http://www.ncc.go.jp/en/ncch/annrep/2000;2. sanofi-aventis Internal Epidemiology Data.

GASTRIC CANCER: PRIMARY TREATMENT

Carcinoma in situ(Tis)

Or

Tumor invasion of the lamina propia (T1a)

Medically fit

Medically unfit

Surgery or Endoscopic mucosal

resection (EMR)

Endoscopic mucosal resection (EMR)

NCCN Clinical Practice Guidelines in Oncology V.2.2009

GASTRIC CANCER: PRIMARY TREATMENT

Medically fit,Potentially resectable

tumorNo distant

metastases(M0)

Tumor invades submucosa

(T1b)

Tumor invades muscularispropi

a or deeper (T2-4)

Surgery

Surgery Or

Preoperative chemotherapy

Or Preoperative

chemoradiation

Surgery

NCCN Clinical Practice Guidelines in Oncology V.2.2009

CRITERIA OF UNRESECTABILITY FOR CURE

Locoregionally advanced Level 3 or 4 lymph node highly suspicious

on imaging or confirmed by biopsy Invasion or encasement of major vascular

structures

Distant metastasis or peritoneal seeding (including positive peritoneal cytology)

NCCN Clinical Practice Guidelines in Oncology V.2.2009

GASTRIC CANCER: PRIMARY TREATMENT

Medically fit,Unresectable

tumorNo distant

metastases(M0)

RT, 45-50.4Gy+ concurrent 5 FU based

radiosensitization

Or

Chemotherapy

NCCN Clinical Practice Guidelines in Oncology V.2.2009

GASTRIC CANCER: PRIMARY TREATMENT

Medically unfit,

No distant metastases(M0)

RT, 45-50.4Gy+ concurrent 5 FU based

radiosensitization

Or

Palliative therapy

NCCN Clinical Practice Guidelines in Oncology V.2.2009

GASTRIC CANCER: PRIMARY TREATMENT

Distant metastasis

Palliative therapy

NCCN Clinical Practice Guidelines in Oncology V.2.2009

GASTRIC CANCER: PRIMARY TREATMENT

Distant metastasis

Palliative therapy

GradeECOG0 Fully active, able to carry on all pre-disease performancewithout restriction

1 Restricted in physically strenuous activity but ambulatory and able to carryout work of a light or sedentary nature, e.g., light housework, office work

2 Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours

3 Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours

4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair

5 Dead

KARNOFSKY PERFORMANCESTATUS SCALE

Able to carry on normal activity and to work; no special care needed.

Unable to work; able to live at home and care for most personal needs; varying amount of assistance needed.

Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly.

Despite the fact that many advances have occurred in the managementof gastric cancer, it continues to carry a poor prognosis, amplifyingthe importance of palliative chemotherapy

When compared withbest supportive care alone, combination chemotherapy yieldsa significant advantage in the management of advanced gastriccancer

ADVANCES IN TREATMENT OF ADVANCED GASTRIC CA

Better understanding of the molecular basis of cancer

Development of rationally designed molecular targeted therapies

Interfere with the signaling cascades involved in cell differentiation, proliferation, and survival.

HER2/neu 185-kDa transmembrane tyrosine kinase

(TK) receptor and a member of the epidermal growth factor receptors (EGFRs) family

HER2/neu The binding of different ligands to the

extracellular domain of HER2 initiates a signal transduction cascade that can influence many aspects of tumor cell biology: cell proliferation apoptosis adhesion migration differentiation

Extracellular Domain

Transmembrane Domain

Intracellular Domain

EGF Pathway EGFR: transmembrane protein

Tyrosine Kinase Domain

Adapted from:Ciardiello F, et al. N Engl J Med. 2008;358:1160-1174.

EGF Pathway EGFR family

EGFR HER2 HER3 HER4

Adapted from:Ciardiello F, et al. N Engl J Med. 2008;358:1160-1174.

EGF Pathway Receptor specific ligands

EGFTGFαβ-cellulinHB-EGFEpiregulinAmphiregulin

EGFR HER2 HER3 HER4

NRGsβ-cellulinHB-EGF

NRGs

Adapted from:Ciardiello F, et al. N Engl J Med. 2008;358:1160-1174.

ProliferationApoptosis Resistance

Transcription

TGFα Interleukin-8 bFGF VEGF

MetastasisAngiogenesis

Shc

PI3K

RafMEKK-1

MEKMKK-7

JNK ERK

Ras

mTOR

Grb2

AKT

Sos-1

EGF Pathway

In carcinomas, HER2 acts as an oncogene

High-level amplification of the gene induces protein overexpression in the cellular membrane and subsequent acquisition of advantageous properties for a malignant cell

Role of HER2 in the development of numerous types of human cancer

HER2 overexpression and/or amplification have been detected in 10%-34% of invasive breast cancers

HER2 overexpression and/or amplification have also been observed in colon, bladder, ovarian, endometrial, lung, uterine cervix, head and neck, esophageal, and gastric carcinomas

Correlate with the clinical outcome, confer poor prognosis, and also constitute a predictive factor of poor response to chemotherapy and endocrine therapy

TRASTUZUMAB Monoclonal antibody which specifically

targets HER2 protein by directly binding the extracellular domain of the receptor

Trastuzumab enhances survival rates in both primary and metastatic HER2-positive breast cancer patients

The efficacy of trastuzumab in breast cancer patients has led to investigate its antitumor activity in patients with HER2-positive cancers, including gastric adenocarcinomas

ToGA trial About 22% of patients with

advanced gastric cancer were found to have tumors that overexpressedHER2

ToGA trial About 22% of patients with advanced

gastric cancer were found to have tumors that overexpressed HER2

phase III trial, 594 patients with HER2-positive advanced gastric cancer were randomized to receive standard chemotherapy alone or chemotherapy plus trastuzumab (Herceptin)

ToGA met the primary end point:

Reduced the risk of death by 26% when combined with a reference chemotherapy

Trastuzumab prolongs the median survival by 2.7 months in patients with HER2-positive advanced GC