Gastric cancer

INTRODUCTION,ANATOMY,CLASSIFICATION,STAGING,&MANAGEMENT OF GASTRIC CANCER

1. GASTRIC CANCER DR.SUNIL KAMBLE ASSISTANT PROFESSOR DEPT.OF GEN.SURGERY MNR MEDICAL COLLEGE,SANGAREDDY

2. Introduction Major cause of cancer mortality worldwide. Cure rate 5-10% Better results in Japan Rarely disseminates INCIDENCE UK- 15/100 000 per year US-10/100 000 per year

3. Eastern Europe-40/100 000 per year Japan-70/100 000 per year In some geographical areas of China incidence is double than Japan Incidence is falling 1% per year Proximal gastric cancer more in high socioeconomic group and not associated with H.Pylori infection.

4. ANATOMY

5. Five layers Mucosa , submucosa , muscular layer, subserosal layer, serosal layer . Peritoneum of greater sac covers anterior surface A portion of lesser sac drapes posteriorly over stomach . The GE junction has limited serosal covering.

6. The site of the lesion is classified on basis of relationship to long axis of stomach. 40% lower part 40% middle part 15% upper part 10% more than one part

7. Zone I (inferior gastric) drains into the subpyloric and omental nodes Zone II (splenic) drains into the pancreaticosplenic nodes Zone III (superior gastric) drains into the superior gastric nodes Zone IV (hepatic) drains into the suprapyloric nodes

8. RISK FACTORS

9. Histology 95% adenocarcinoma 4% lymphoma 1% leiomyosarcoma (GIST-malignant gastrointestinal stromal tumors) Rare – carcinoid, angiosarcoma , squamous cell carcinoma. As metastatic lesion from Colon/Pancreas Melanoma/Breast

10. GASTRIC ADENOCARCINOMA Lauren System Diffuse Type Intestinal Type

11. Diffuse type C ell cohesion absent, with individual cells infiltrating and thickening stomach wall without forming a discrete mass. M ore often in younger age group. Develops throughout stomach, including cardiac → loss of distensibility of gastric wall (“ linitis plastica ” or " leather bottle" appearance), with a far more ominous prognosis.

12. Above: low power view, with poorly differentiated cancer arising from mucosa and diffusely infiltrating all layers of gastric wall Right: ↑ magnification, with effacement of lamina propria of gastric mucosa

13. L initis plastica carcinoma diffusely infiltrates entire gastric wall without forming an intraluminal mass;wall typically thickened ~ 2-3 cm, with leathery, inelastic consistency.

14. Intestinal Type Cohesive neoplastic cells forming gland - like tubular structures Frequently ulcerative More commonly in antrum - prepylorus , cardia - fundus and lesser curvature of stomach, and often preceded by prolonged pre - cancerous process

15. Bormann Classification Polypoid Ulcerating Ulcerating / Infiltrating Infiltrating ( Linnitus Plastica )

16. Japanese Endoscopic Society (JES) Classification

17. International Union Against Cancer(UICC) staging of gastric cancer Primary Tumour (T) T1 – Tumor invades lamina propria / submucosa T1a- lamina propria T1b-submucosa T2 – Tumor invades muscularis propria T3 – Tumor involves subserosa T4a – Tumor perforates serosa T4b – Tumor invades adjacent organs

18. Regional Lymph Nodes (N) N0 : No lymph nodes N1 : M etastasis in 1 - 2 regional nodes N2 : M etastasis in 3 - 6 regional nodes N3a : Metastasis in 7 - 15 regional nodes N3b : Metastasis in more than 15 regional nodes

19. Distant Metastasis (M) M0 : No distant metastasis M1 : D istant metastasis (this includes peritoneum and distant lymph nodes)

20. A tumor may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without perforation of the visceral peritoneum covering these structures. In this case, the tumor is classified T2. If there is perforation of the visceral peritoneum covering the gastric ligaments or the omentum , the tumor should be classified T3 .

21. Positive peritoneal cytology is classified as M1. The adjacent structures of the stomach include the spleen, transverse colon , liver, diaphragm , pancreas, abdominal wall, adrenal gland, kidney, small intestine, and retroperitoneum .

22. ANATOMIC STAGE / PROGNOSTIC GROUPS (STOMACH) STAGE T N M I A T 1 N0 M0 I B T2 TI N0 N1 M0 M0 II A T3 T2 T1 N0 N1 N2 M0 M0 M0 II B T4a T3 T2 T1 N0 N1 N2 N3 M0 M0 M0 M0 III A T4a T3 T2 N1 N2 N3 M0 M0 M0 III B T4b T4b T4a T3 N0 N1 N2 N3 M0 M0 M0 M0 III C T4b T4b T4a N2 N3 N4 M0 M0 M0 IV ANY ANY M1

23. Residual tumour (R) The absence or presence of residual tumor after treatment. Rx – Presence of residual tumor cannot be assessed R0 – No residual tumor R1 – Microscopic residual tumor R2 – Macroscopic residual tumor

24. Histological Typing Ulcerated carcinoma (25%) Deep penetrated ulcer with shallow edges Usually through all layers of the stomach Polipoid carcinoma (25%) Intraluminal tumors , large in size Late metastasis Superficial spreading carcinomas (15%) Confinement to mucosa and sub-mucosa Metastasis 30% at time of diagnosis Better prognosis

25. Linitis plastica (10%) Varity of SS but involves all layers of the stomach Early spread with poor prognosis Advanced carcinoma (35%) Partly within and outside the stomach Represents advanced stage of most of the fore mentioned carcinomas

26. Siewert Classification of EG junction tumours

27. The lymphatic drainage routes differ for type I versus types II and III lesions. T he lymphatic pathways from the lower esophagus pass both cephalad (into the mediastinum) and caudad (toward the celiac axis). In contrast, the lymphatic drainage from the cardia and subcardial regions is toward the celiac axis, splenic hilus , and para -aortic nodes.

28. Thus, the Siewert classification provides a practical means for choosing among surgical options. For type I tumors, esophagectomy is required, T ypes II and III tumors can be treated by transabdominal extended gastrectomy (resection of the stomach and distal intra-abdominal esophagus ).

29. Clinical Course Directly, via lymphatics, or hematogenously Direct extension into omentum , pancreas, diaphragm, transverse colon, and duodenum . If lesion extends beyond wall to a free peritoneal surface, peritoneal involvement is frequent.

30. Abundant lymphatic channels in submucosal and subserosal layers allow for easy spread . The submucosal plexus is prominent in esophagus, the subserosal plexus prominent in duodenum, which allows for proximal and distal spread . Liver mets common, from hematogenous spread .

31. CLINICAL FEATURES Advanced disease – indigestion, nausea, dysphagia, early satiety, anorexia, weight loss . Weight loss, nausea & vomiting – tumours of pylorus Dysphagia & early satiety – diffuse lesions originating in cardia Upper abdominal discomfort (vague, postprandial fullness to steady pain) – extensive tumour

32. Physical Examination All physical signs are late events. - Palpable stomach with succussion splash Hepatomegaly Virchow nodes Sister Mary Joseph nodes Irish nodes Malignant ascites W eight loss P allor from bleeding and anemia .

33. Late complications include: Pleural effusions, Peritoneal effusions, Gastric outlet obstruction, GE obstruction, Small bowel obstruction, Bleeding, Jaundice, Cachexia. Unusual clinical features: Migratory thromboplebitis , Microangiopathic hemolytic anemi a

34. INVESTIGATIONS Screening: Double Contrast Barium Study Diagnostic Endoscopy Serum Tumour markers Local assessment: Upper GI Endoscopy Endoscopic Ultrasound Assessment for distal disease: X-ray chest CT – Thorax/Abdomen/Pelvis MRI

35. Laboratory Studies Complete blood count identifies anemia, which may be caused by bleeding, liver dysfunction, or poor nutrition . 30 % have anemia . Electrolytes and liver function tests.

36. Double Contrast Barium Study Useful alternative to endoscopy Has similar sensitivity in detection of gastric cancer Used as mass screening tool in Japan

37. Flexible Upper GI Endoscopy Obtains tissue for diagnosis . Detects large tumors, but only occasionally detects extension into esophagus or duodenum, especially if small or submucosal .

38. Imaging Studies CXR: done to evaluate for metastases & pleural effusion CT scan or MRI of chest, abdomen, pelvis: evaluate local disease process, and areas of spread. Unresectable or not Accurately predicts stage 66-77%. Poor nodal status prediction .

39. Endoscopic Ultrasound Useful when CT fails to show T3, T4, or metastatic disease. Used with neoadjuvant chemotherapy to stratify patients Can achieve resolution of 0.1 mm. Cannot reliably distinguish between tumor and fibrosis. Staging accuracy -75 % Poor for T2 lesions (38%) Better for T1(80%), T3 (90%)

40. Diagnostic Laparoscopy Inspect peritoneal surfaces, liver surface . Peritoneal lavage & biopsy can also be taken. Identification of advanced disease avoids non-therapeutic laparotomy in 25 %. Indications for laparoscopy Lymphadenopathy on CT GE junction tumours Diffuse tumours

41. PET Scan Less sensitive but more specific than CT for local LN metastases Potential role for early response assessment to neo-adjuvant Rx.

42. Screening Patients at risk for gastric cancer should undergo yearly endoscopy and biopsy Familial adenomatous polyposis Hereditary nonpolyposis colorectal cancer Gastric adenomas Menetrier’s disease Intestinal metaplasia or dysplasia Remote gastrectomy or gastrojejunostomy

43. Widely practiced in Japan (25% of gastric cancers). The early screening programs used double-contrast radiography 40 %–60% of cancers diagnosed by the screening programmes are early cancer with no lymphatic metastasis . A low level of serum pepsinogen I significantly associated with gastric cancer

44. Pepsinogen I concentration of less than 70 ng /mL, and a ratio of pepsinogen I:pepsinogen II of less than 3, are useful indicators, with a sensitivity of 84.6% and a specificity of 73.5 %. Although an elevated gastrin level of greater than 200 ng /L appears to be specific, the sensitivity is low (30%), which precludes its use as a screening tool.

45. Prognostic Features Stage – Stage, invasion and lymph node involvement are the most significant prognostic factors. Clinical classification – Superficial cancer > Focal cancer > Infiltrative cancer. Grade – high histologic grade – poor prognosis Flow cytometry – Diploid (18 months) > Aneuploid tumours (5 months) Nature & extent of resection – R0 > R1 > R2

46. MANAGEMENT Smoking avoidance or cessation . Diets rich in fruit , vegetables and fibre . Avoidance of salted , smoked and poorly preserved foods . Eradication of H. pylori . Mass screening is a viable strategy in high risk populations . Antioxidants,Green Tea

47. R isk for lymph node metastasis is important when evaluating treatment options for patients with Early Gastric Cancer (EGC). Thus , once tumors penetrate into the submucosa , the risk for nodal metastasis increases with tumor size . Tumor size Lymph node mets – Incidence < 1 cm 7.9% 1.1 – 2.0 cm 13.3% 2.1 – 3.0 cm 15.55% 3.1 – 4.0 cm 23.3% STAGE 1 DISEASE

48. Early Gastric Cancer – Treatement Options Endoscopic M ucosal Resection (EMR) Endoscopic Submucosal Dissection (ESD) Endoscopic Laser Ablation (ELA) Limited surgical resection Gastrectomy

49. Endoscopic M ucosal Resection Candidates for EMR: Tumors that have extremely low metastatic potential D ifferentiated , superficial type IIa (slightly elevated lesions), ≤ 2 cm in diameter. Differentiated, superficial type IIc (slightly depressed lesions), without ulcer formation, ≤ 1 cm in diameter. Located in an easily manipulated area. Tumors invading the submucosa are at increased risk for metastasizing to lymph nodes and are not usually considered candidates for EMR. En bloc resection rate i s significantly lower with conventional EMR for tumors ≥11 mm than for tumors ≤10 mm

50. Endoscopic Submucosal Dissection ESD has been developed for en bloc removal of large ( usually more than 2 cm), flat GI tract lesions . Superior to conventional EMR.

51. Advantages of ESD over EMR For lesions ≥ 11 mm in size, en bloc resection rates were significantly higher Possible to get histologically complete resection Reduced local recurrence rates Disadvantages of ESD over EMR Longer operating time Frequent intraoperative bleeding (can be reducer using various knives). Higher risk of perforation in case of ulcerated lesion

52. Endoscopic Laser Ablation Photodynamic therapy (PDT) Uses meso -tetrahydroxyphenylchlorin ( mTHPC ) as the photosensitiser in superficial gastric cancer. Types of Laser Coagulation used: Argon plasma coagulation ( at 60 W for 15 s/cm 2 ) contact Nd:YAG laser irradiation (40-60 joules) Day care procedure Useful for tumours situated in difficult areas Early gastric cancers that are obscurely demarcated are good indicators for low output laser therapy

53. Gastrectomy Patients who have intramucosal tumors with Poor histologic differentiation Size greater than 3 cm Tumor penetration into the submucosa Diffuse gastric cancer

54. STAGE II AND III DISEASE To achieve a microscopically and macroscopically complete resection (R0).

55. Treatement Modalities Surgery Perioperative chemotherapy Neoadjuvant chemotherapy Adjuvant chemotherapy Intraperitoneal chemotherapy Adjuvant radiotherapy Intraoperative radiotherapy Adjuvant chemoradiation

56. Mid & Distal Gastric Tumours 5-cm grossly negative margin around the tumor Microscopically negative surgical margins (R0) When gastrectomy is performed with curative intent, frozen-section assessment of proximal and distal resection margins . Distal Gastrectomy is comparable to Subtotal Gastrectomy , in terms of morbidity, mortality & oncologic outcome.

57. Mobilization of the greater curvature with omentectomy and division of the left gastroepiploic artery

58. Infrapyloric mobilization with ligation of the right gastroepiploic artery and vein as it enters the gastrocolic trunk

59. Suprapyloric mobilization with ligation of the right gastric artery

60. Duodenal transection

61. Lymphadenectomy with dissection of the porta hepatis , common hepatic artery, left gastric artery, celiac axis, and splenic artery and ligation of left gastric artery

62. Gastric transection

63. Proximal G astric Cancer Optimal surgical procedure for patients with localized tumors of the esophagogastric junction and proximal stomach is a matter of considerable debate Trans-abdominal approach with Resection of lower esophagus and proximal stomach Total gastrectomy Abdominal + thoracic approach

64. R0 Resection Can be achieved by a gastric-preserving approach, partial gastrectomy is preferred over total gastrectomy . Gastric-preserving R0 approach may minimize the risks of specific sequelae of total gastrectomy Early satiety, Weight loss, and Need for vitamin B12 supplementation .

65. Extent of Lymphadenectomy N1 – 3 to 6 N2 – 1, 2, 7, 8 & 11 N3 – 9, 10 & 12 N1 nodes are within 3cm of the tumor N2 nodes are along hepatic & splenic arteries N3 are more distant nodes To avoid under staging of gastric CA, a minimum of 15 nodes should be resected with the gastrectomy specimen.

66. “D” Nomenclature Describes extent of resection and lymphadenectomy D1 – Removes tumour and all nodes within 3cm of tumor (Tumour + N1). D2 – D1 plus hepatic, splenic, celiac, and left gastric nodes (Tumour + N1 + N2). D3 – D2 plus omentectomy , splenectomy, distal pancreatectomy , clearance of porta hepatis nodes (Tumour + N1 + N2 + N3). D1 dissection is the minimally accepted dissection.

67. The Japanese surgeons define any lymph nodal dissection less than a D2 dissection as suboptimal . Surgeons in the western hemisphere are of the opinion that there is no significant survival difference between D1 and D2 dissection .

68. Indications for Splenectomy If macroscopic disease can be resected & the operation is potentially curative then en bloc splenectomy or pancreaticosplenectomy is worthwhile . If it is more palliative then this benefit must be weighed against the potential complications of splenectomy and more extensive operation.

69. Distal Pancreatectomy Associated with marked increase in morbidity & mortality with or without splenectomy Indications for pancreatectomy : Direct invasion of the tail of the pancreas Likelihood of splenic artery nodal involvement

70. Peri -operative Chemotherapy Chemotherapy consisted of three preoperative and three postoperative cycles of intravenous epirubicin (50 mg/m2 bsa ) and cisplatin (60 mg/m2) on day 1, and a continuous intravenous infusion of fluorouracil (200 mg/m2 meter per day) for 21 days.

71. As compared with the surgery group, the perioperative‐chemotherapy group had a higher likelihood of overall survival (five‐year survival rate, 36 percent vs. 23 percent) and of progression‐free survival ( 0.53 to 0.81; P<0.001 ). Rates of postoperative complications were similar in the perioperative‐chemotherapy group and the surgery group (46 percent and 45 percent, respectively), as was the 30 day mortality after surgery.

72. Neo-adjuvant Chemotherapy Rationale –to downstage the disease and favor an R0 resection and also to treat occult micrometastases . No definite evidence of the effectiveness of neoadjuvant chemotherapy in resectable gastric cancer

73. Adjuvant Chemotherapy Meta‐analyses assessing the safety and efficacy of different adjuvant chemotherapeutic regimens in patients with gastric carcinomas who have undergone gastrectomy have found adjuvant chemotherapy to have a small survival benefit.

74. Intraperitoneal Chemotherapy A significant improvement in survival was associated with hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) alone or HIIC combined with early postoperative intraperitoneal chemotherapy (EPIC ). HIIC with or without EPIC after resection of advanced gastric primary cancer is associated with improved overall survival at the cost of increased risk of intra‐abdominal abscess and neutropenia .

75. Radiotherapy (RT) RT alone has not proved useful in treating gastric cancer. RT (4000 cGy in 4 weeks) in combination with 5-FU (15 mg/kg IV on first 3 days of RT), however, appears to improve survival over RT alone in pts with localized but unresectable cancers.

76. Intraoperative Radiation Therapy (IORT) IORT allows high dose of radiation to tumour bed or residual disease while permitting the exclusion of mobile radiosensitive normal tissues from the area irradiated. Selected pts may benefit from IORT, particularly when combined with supplemental external-beam radiation and chemotherapy.

77. Adjuvant Chemoradiation A Dutch phase I/II study performed to determine the maximal tolerated dose (MTD) and toxicity profile of postoperative radiotherapy with concurrent daily cisplatin and capecitabine treated patients. Capecitabine 1000 mg/m 2 b.i.d . for 2 weeks. Subsequently , patients received capecitabine (250‐650 mg/m 2 orally b.i.d , 5 days/week) and cisplatin (3‐6 mg/m 2 i.v. , 5 days/week) according to an alternating dose‐escalation schedule.

78. Radiotherapy was given to a total dose of 45 Gy in 25 fractions . Gastric cancer outcome could be improved with more effective and intensified postoperative chemoradiotherapy .

79. STAGE IV DISEASE Therapeutic Goal Palliation Improved quality of life

80. Treatment Modalities Endoscopic palliation Surgical resection Intestinal bypass procedures Palliative chemotherapy Palliative radiotherapy

81. Endoscopic Palliation The tumour mass obstructing the gastrointestinal lumen can either be Evaporated using lasers , or The tract opened using baloon dilators , or Self expanding stents can be placed across the obstruction to restore the bowel continuity.

82. Palliative Surgery C onsidered in circumstances such as tumor obstruction , perforation , and bleeding. If gastrectomy is performed, gross disease immediately adjacent to the stomach should be removed. Leaving behind a primary tumor mass in the stomach not only invites bleeding and perforation but also diminishes the likelihood of response to subsequent palliative chemotherapy.

83. Alternatively, a bypass procedure or gastrojejunostomy can be performed. However , gastric resection is not indicated in patients with a poor chance of survival, and the final decision is usually dictated by the overall clinical conditions of the patients .

84. Palliative Chemotherapy Chemotherapy significantly improves survival in comparison to best supportive care. In addition, combination chemotherapy improves survival compared to single‐agent 5‐FU, but the effect size is much smaller .

85. Among the combination chemotherapy regimens studied, best survival results are achieved with regimens containing 5‐FU, anthracyclines and cisplatin of which, ECF ( epirubicin , cisplatin and continuous infusion 5‐FU) is tolerated best. Regimens including FU as bolus exhibit a higher rate of toxic deaths than regimens using a continuous infusion of FU, such as epirubicin , cisplatin , and continuous‐infusion FU.

86. Palliative Radiotherapy Gastric adenocarcinoma is relatively radioresistent & requires high doses of radiation with toxic effects to surrounding organs. RT may be useful for palliating pain, vomiting due to obstruction, gastric haemorrhage , and metastasis to bone and brain.

87. PROGNOSIS 5-year survival rate (%) for a curative resection is Recurrences continuing for at least 8 years after surgery

88. Complications Mortality 1-2 % Anastamotic leak, bleeding, ileus, transit failure, cholecystitis , pancreatitis, pulmonary infections, and thromboembolism . Late complications -dumping syndrome, vitamin B-12 deficiency, reflux esophagitis, osteoporosis .

89. References Textbook of Gastroenterology, Yamada, 5 th edition Sleisenger and Fordtran’s Gastrointestinal & Liver Diseases, 9 th edition Principles and Practice of Oncology, DeVita , 9 th edition Mastery of Surgery, 6 th edition

90. Bailey and Love short practice of surgery-26 th edition Sabiston textbook of Surgery , 20 th edition Schwartz textbook of Principles of Surgery, 10 th edition Gray’s Anatomy, 40 th edition Skandalakis Surgical Anatomy, 2004