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Worldwide :4 th most common malignancy 2 nd leading cause cancer mortality

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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Worldwide :4 th most common malignancy 2 nd leading cause cancer mortality

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  1. 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

  2. Philippines • Gastric Cancer • 8th leading site in both sexes • 5th in males and 10th in females

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

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

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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. P.E. : ADVANCED DISEASE

  12. SISTER MARY JOSEPH NODULE VIRCHOW’S NODE

  13. 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.

  14. STAGING

  15. 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

  16. 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

  17. 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%

  18. 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

  19. Peritoneal cytology NCCN Clinical Practice Guidelines in Oncology V.2.2009 • Cytogenetic analysis of peritoneal fluid to identify occult carcinomatosis

  20. 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.

  21. GASTRIC CANCER: PRIMARY TREATMENT NCCN Clinical Practice Guidelines in Oncology V.2.2009

  22. GASTRIC CANCER: PRIMARY TREATMENT NCCN Clinical Practice Guidelines in Oncology V.2.2009

  23. 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

  24. GASTRIC CANCER: PRIMARY TREATMENT NCCN Clinical Practice Guidelines in Oncology V.2.2009

  25. GASTRIC CANCER: PRIMARY TREATMENT NCCN Clinical Practice Guidelines in Oncology V.2.2009

  26. GASTRIC CANCER: PRIMARY TREATMENT NCCN Clinical Practice Guidelines in Oncology V.2.2009

  27. GASTRIC CANCER: PRIMARY TREATMENT

  28. 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

  29. 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.

  30. 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

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

  32. 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.

  33. HER2/neu • 185-kDa transmembrane tyrosine kinase (TK) receptor and a member of the epidermal growth factor receptors (EGFRs) family

  34. 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

  35. 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.

  36. EGF Pathway EGFR family EGFR HER2 HER3 HER4 Adapted from: Ciardiello F, et al. N Engl J Med. 2008;358:1160-1174.

  37. 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.

  38. 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

  39. 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

  40. 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

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

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

  43. 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

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

  45. ToGA trial • About 22% of patients with advanced gastric cancer were found to have tumors that overexpressedHER2

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