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
Gastric Cancer 8th leading site in both sexes 5th in males and 10th in females
Epidemiology
Race/Ethnicity Male Female Male Female
White 10.8 5.0 5.8 2.8
White Hispanic
18.4 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 6.3
Asian/Pacific Islander 21.9 12.4 11.9 7.0
Native 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
Resectable
Locally advanced
Metastatic
Western countries2
Resectable
Locally advanced
Metastatic
Unstaged
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