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Gastric Cancer CA Cancer J Clin 2005; 55: 10-33 CA Cancer J Clin 2005; 55: 75 Stewart: World Cancer Reports IARC Press, Lyon 2003. Worldwide :4 th most common malignancy 2 nd leading cause cancer mortality 60 % of cases from developing countries 90 % cases are adenocarcinoma.

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slide1
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 malignancy

2ndleading cause cancer mortality

  • 60% of cases from developing countries
  • 90% cases are adenocarcinoma
philippines
Philippines
  • Gastric Cancer
    • 8th leading site in both sexes
    • 5th in males and 10th in females
epidemiology
Epidemiology

 Gastric Cancer Incidence and Mortality Rates per 100,000 Cases

(Age Adjusted) in the United States, 1997-2001

INCIDENCE

MORTALITY

environmental risk factors
Environmental Risk factors
  • H. pylori infection
  • Dietary Factors
  • Cigarette Smoking
  • Alcohol
  • Low Socioeconomic Status
premalignant conditions
Premalignant Conditions
  • Chronic Atrophic Gastritis
  • Intestinal Metaplasia
  • Gastric Dysplasia
  • Gastric Polyps
  • Previous Gastrectomy
  • Gastric Ulcer
work up
WORK-UP

NCCN Clinical Practice Guidelines in Oncology V.2.2009

  • Abdominal CT with contrast
  • PET/CT or PET scan(optional)
  • Endoscopic ultrasound(optional)
  • CBC and chemistry profile
  • Chest imaging
clinical features
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 features1
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 features2

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.

Clinical Features

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

and early satiety

physical findings
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
slide13

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.
ct scan
CT SCAN

NCCN Clinical Practice Guidelines in Oncology V.2.2009

  • Overall accuracy for staging of gastric cancer: 43-82%
  • Not suitable to assess the tumor depth and metastatic lymph nodes
clinical staging pet
CLINICAL STAGING: PET

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 eus
CLINICAL STAGING: EUS

NCCN Clinical Practice Guidelines in Oncology V.2.2009

  • Useful in assessing depth of tumor invasion
  • Accuracy: T staging- 65-92% N staging- 50-95%
laparoscopic staging
Laparoscopic staging

NCCN 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
peritoneal cytology
Peritoneal cytology

NCCN Clinical Practice Guidelines in Oncology V.2.2009

  • Cytogenetic analysis of peritoneal fluid to identify occult carcinomatosis
stage at the time of diagnosis

17%

15%

68%

STAGE AT THE TIME OF DIAGNOSIS

Japan1

Resectable

Locally advanced

Metastatic

Western countries2

10–15%

25−30%

Resectable

25–30%

Locally advanced

30–35%

Metastatic

Unstaged

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

gastric cancer primary treatment
GASTRIC CANCER: PRIMARY TREATMENT

NCCN Clinical Practice Guidelines in Oncology V.2.2009

gastric cancer primary treatment1
GASTRIC CANCER: PRIMARY TREATMENT

NCCN Clinical Practice Guidelines in Oncology V.2.2009

criteria of unresectability for cure
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 treatment2
GASTRIC CANCER: PRIMARY TREATMENT

NCCN Clinical Practice Guidelines in Oncology V.2.2009

gastric cancer primary treatment3
GASTRIC CANCER: PRIMARY TREATMENT

NCCN Clinical Practice Guidelines in Oncology V.2.2009

gastric cancer primary treatment4
GASTRIC CANCER: PRIMARY TREATMENT

NCCN Clinical Practice Guidelines in Oncology V.2.2009

slide32

GradeECOG

0 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 performance status scale
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.
slide34

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

slide35

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

advances in treatment of advanced gastric ca
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
HER2/neu
  • 185-kDa transmembrane tyrosine kinase (TK) receptor and a member of the epidermal growth factor receptors (EGFRs) family
her2 neu1
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
egf pathway
EGF Pathway

EGFR: transmembrane protein

Extracellular Domain

Transmembrane Domain

Intracellular Domain

Tyrosine Kinase Domain

Adapted from:

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

egf pathway1
EGF Pathway

EGFR family

EGFR

HER2

HER3

HER4

Adapted from:

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

egf pathway2
EGF Pathway

Receptor specific ligands

NRGsβ-cellulinHB-EGF

EGFTGFαβ-cellulinHB-EGFEpiregulinAmphiregulin

NRGs

EGFR

HER2

HER3

HER4

Adapted from:

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

egf pathway3

Angiogenesis

Metastasis

Shc

Grb2

Sos-1

PI3K

Ras

MEKK-1

Raf

AKT

MEK

MKK-7

mTOR

ERK

JNK

Apoptosis Resistance

Transcription

Proliferation

EGF Pathway

TGFα Interleukin-8 bFGF VEGF

slide44

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
slide45

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
slide46

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

slide47

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

trastuzumab
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
slide49

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
ToGA trial
  • About 22% of patients with advanced gastric cancer were found to have tumors that overexpressedHER2
toga trial1
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)
slide52

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