Gastric Cancer: Epidemiology
Surgery and Regional Therapy Gastric cancer is second leading cause of cancer Timothy J. Kennedy, MD specific mortality world wide (989,600 cases; 738,000 Montefiore Medical Center deaths) accounting for 8% new cancer cases Assistant Professor of Surgery Fourth leading cause of cancer death in the United Upper Gastrointestinal and Pancreas Surgery States (21,320 cases; 10,540 deaths) December 15, 2012 Incidence in Japan 8x higher than US More common in men More common in Asians, blacks, native americans and US hispanics Peak age is 7th decade Incidence of proximal gastric cancer increasing 1
Risk factors
Etiology H-pylori infection (90% intestinal type and 30% diffuse type) Exposure to carcinogens (tobacco, salt, nitrites) Pernicious anemia Obesity Adenomatous Polyp Previous gastric surgery Familial history of gastric cancer
4 Molecular Pathogenesis Molecular Pathogenesis Diffuse Type (linitis plastica) Histologic Types (Lauren Classification) Poorly differentiated signet ring cells Intestinal Type (well differentiated) Loss of expression of E-cadherin, a key intercellular Arises from gastric mucosa adhesion molecule which maintains organization of Most common in high risk patient populations epithelial tissue Related to environmental factors Arises within lamina propria of stomach wall and grows in infiltrative/submucosal pattern Associated with older patients and distal tumors Associated with females, younger patients and Incidence is decreasing proximal tumors Better prognosis Associated with early metastases Incidence is increasing 5 6
Gastric carcinogenic sequence Hereditary Diffuse Gastric Cancer Inherited form of diffuse type gastric cancer QRUPDOJDVWULFPXFRVD CDH1 mutations identified in 30-50% of affected ൻ ൸+S\ORULLQIHFWLRQ kindreds DWURSKLFJDVWULWLV Autosomal dominant trait with high penetrance ൻ Lifetime cumulative risk for gastric cancer is between LQWHVWLQDOPHWDSODVLD 40 and 67% in men and 60-83% in women ൻ Affected patients develop gastric cancer at early age G\VSODVLD (average 38) ൻ Asymptomatic carriers of germline truncating mutations LQYDVLYHDGHQRFDUFLQRPD in E-cadherin should have prophylactic gastrectomy, aalthough age is unclear 8 Clinical Features Diagnosis
Clinical Presentation Upper gastrointestinal endoscopy is best test for Vague abdominal pain, weight loss, anemia and anatomic localization of tumor and tissue diagnosis early satiety are most common presenting During endoscopy any gastric ulcer should be biopsied symptoms Single biopsy has 70% sensitivity for diagnosing an Massive bleeding and perforation rare existing gastric cancer 25% of patients have a gastric ulcer Seven biopsies from ulcer base and margin All gastric ulcers should be followed to complete increases sensitivity to >98% healing and those that do not heal should undergo Diagnosis of diffuse type gastric cancer endoscopically resection can be difficult because it is submucosal lesion Screening not cost effective in low risk groups 9 10
Staging Clinical Staging
Two major classification systems Directs the initial approach to therapy Most elaborate is the Japanese classification , Patients with locoregional disease (Stage I-III) are based upon anatomic location, particularly of lymph potentially curable node stations If tumor invades through submucosa (T2 or higher) or Most commonly used pathologic staging system is there is high suspicion of nodal involvement patient AJCC/UICC system should be referred for multidisciplinary evaluation T Stage – depth of gastric wall invasion Patients with stage IV disease are usually referred for N Stage – number of nodal metastases identified palliative therapy depending on symptoms and functional status M Stage – presence of distant metastases
11 12 Abdominopelvic CT Endoscopic Ultrasound (EUS)
Dynamic CT imaging should be performed to evaluate for Most reliable nonsurgical method for evaluating depth of Regional and distant nodal disease invasion of primary gastric cancers. Local extension to adjacent organs Accuracy of EUS for differentiation of individual tumor Liver metastases stages (T1 to T4 tumors) ranges from 77% to 93%. Peritoneal metastases Experience of operator markedly influences these rates. CT accurately assess T stage in only 50-70% of patients; EUS provides a more accurate prediction of T stage than Sensitivity for regional nodal metastases is limited for nodes CT. <0.8cm; in addition false positives can be attributed to In contrast accuracy for nodal staging (65 to 90%) is only inflammatory lymphadenopathy slightly greater than CT Sensitivity for nodal metastases ranges from 65 to 97% EUS guided FNA of suspicious nodes adds to this and specificity from 49 to 90% accuracy 13 14
FDG-PET Imaging Diagnostic laparoscopy
Role of PET is controversial and evolving Utilized to assess for small volume peritoneal carcinomatosis Can be used to confirm malignant involvement of CT detected lymphadenopathy Peritoneal cytology utilized to look for microscopic free peritoneal tumor cells Most diffuse type gastric cancers are not FDG avid 25% of patients with T3 – T4 or N(+) have radiographic More sensitive than CT for detection of distant occult disease identified by laparoscopy metastases but poor for peritoneal carcinomatosis Only 4% of T1 – T2 or N0 disease have any findings on May be useful in assessment of response of tumors to laparoscopy neoadjuvant treatment Utilized prior to administration of neoadjuvant chemotherapy
15 16 Peritoneal Cytology Peritoneal Cytology
Bentrem. Ann Surg Oncol 2005
371 R0 resections with staging laparoscopy and washings Incidence, Risk factors, Prognostic value of positive cytology
Peritoneal Cytology T Stage Correlates with (+) LN
Positive peritoneal washings as only site of M1 disease T1a - <5% and patients with gross metastatic disease fare equally T1b – 20% poorly T2 – 50% Surgical resection with therapeutic intent in the presence T3 – 70% of known M1 disease portends a poor outcome T4 – 90%
The absence of detectable M1 disease after systemic chemotherapy is associated with a survival benefit
20 TNM Classification Stage Grouping
Stage T N M Tis: Cancer cells only in mucosa N0: No spread to LN 0 Tis N0 M0 T1a: into lamina propria or muscularis mucosa N1: 1-2 regional LN IA T1 N0 M0 T1b: into the submucosa N2: 3-6 regional LN IB T1 N1 M0 T2: into muscularis propria N3: >7 regional LN T2 N0 M0 T3: into the subserosa II T1 N2 M0 T4a: into serosa T2 N1 M0 T4b: into nearby organs or structures T3 N0 M0 IIIA T2 N2 M0 T3 N1 M0 T4 N0 M0 Mo: No distant mets IIIB T3 N2 M0 M1: Distant mets IV T4 N1–3 M0 T1–3 N3 M0 Any T Any N M1
21 22
Survival by AJCC stage – curative resection
1.0
0.8 Surgical Management I N=659 0.6 II N=385 III N=583 IV N=131 0.4 Dysplasia
0.2
0.0 0 24 48 72 96 120 144 168 Months 24
Progression of LGD/HGD to Cancer Progression of Dysplasia ______$XWKRU \HDU /*'SURJUHVVLRQ PHDQLQWHUYDO +*'SURJUHVVLRQ PHDQLQWHUYDO Progression in low grade dysplasia is from 0% - 23% in 6DUDJDHWDO \HDUV PRQWKV various studies /DQVGRZQHWDO 1$ PRQWKV Progression in high grade dysplasia is 60 - 85% in 5XJJHHWDO \HDU PRQWKV multiple studies 'L*UHJRULRHWDO \HDUV PRQWKV Most experts recommend endoscopic surveillance in )HUWLWWDHWDO PRQWKV PRQWKV patients with LGD 5XJJHHWDO \HDUV PRQWKV Most experts recommend endoscopic or surgical .RNNRODHWDO 1$ PRQWKV resection for management of patients with evidence of 5XJJHHWDO PRQWKV PRQWKV HGD 26 Progression of Dysplasia > 1 year endoscopic followup of 90 low-grade and 16 high-grade gastric dysplasia cases Low-grade: 53.3% regression 31.1% no change Surgical Management 15.4% progression 8.8% progression to cancer (mean 48 months [21-85]) High-grade: 0/16 regression Early Gastric Cancer 5/16 no change 11/16 progression to cancer (mean 34 months [13-72]) Rugge, et al., Gut 2003 28 Early Gastric Cancer (EGC) Endoscopic Resection of EGC Developed 20 years ago, defined over the last two EGC defined as adenocarcinoma limited to mucosa decades as an alternative to gastrectomy for early and submucosa regardless of LN involvement (T1Nx) gastric cancers Reflects that EGC represents a more favorable/curable Endoscopically developing a plane submucosally and subset of gastric cancers compared to more invasive resecting affected tissue in one piece gastric cancers (T2-T4Nx) Advantages include decreased morbidity and mortality, EGC identified more often now with the upward trend potential increased quality of life post procedure reflecting mass screening and improved technology Disadvantages include increased risk of nodal disease, Still uncommon in US given lack of screening metachronous disease, incomplete resection endoscopy in low risk patient population Early Gastric Cancer (EGC) In Western countries early gastric cancers comprise <15% of gastric cancers diagnosed Frequency of early gastric cancer: Surgical Management Japan - 78 cases/100,000 United States - 10 cases/100,000 Locoregional Disease 31 32 Gastrectomy Indicators of Unresectability Distant metastatic disease Resection offers best chance for survival for patients with localized gastric cancer Invasion of major vascular structure such as aorta, celiac axis, hepatic artery or proximal splenic artery As previously discussed adjuvant or perioperative chemotherapy or chemoradiotherapy can improve Bulky lymphadenopathy fixed to pancreatic head that outcomes over surgery alone may require pancreaticoduodenectomy Optimal therapy depends on accurate staging of extent Lymph nodes considered outside surgical resection of disease field such as porta hepatis, aortocaval, inferior or posterior to pancreas or mediastinal (3rd or 4th echelon nodes in the Japanese nomenclature) 33 34 Surgical resection Two main surgical issues in surgical management of curable gastric cancer Extent of gastric resection – depends on location of Extent of Surgical Resection lesion within stomach Extent of lymphadenectomy – depends on extent of lymph node involvement Distal Tumors 36 Distal Gastric Adenocarcinoma Total versus Subtotal Gastrectomy Two studies have prospectively randomized patients to French Study total versus subtotal gastrectomy for surgical treatment Randomized 169 patients with tumors of distal stomach of distal gastric cancer Five year survival was no different between groups Studies show no benefit for total gastrectomy Complication and perioperative mortality rates similar (32 and compared to subtotal gastrectomy 1.3% for total and 34 and 3.2% for subtotal) Italian Gastrointestinal Study Group Randomized trial of 618 patients with tumors of distal stomach No difference in 5 year survival between patients having a subtotal or total gastrectomy (65% vs. 62%) Morbidity and mortality data were not reported 37 38 Proximal gastric adenocarcinoma Total gastrectomy with Roux-en-Y esophagojejunostomy is preferred treatment over a Extent of Surgical Resection proximal gastrectomy Roux-en-Y is associated with much lower risk of reflux esophagitis compared to 1/3 of patients who Proximal Tumors develop reflux esophagitis after proximal gastrectomy Proximal subtotal gastrectomy may fail to remove lymph nodes along lesser curvature which are most common site of nodal matastases 39 40 Extent of Lymphadenectomy 42 Extent of Lymph Node Dissection One of most controversial areas in surgical management of gastric cancer D1 LN dissection involves a perigastric LN dissection (stations 1-6) 43 44 Extent of Lymph Node Dissection One of most controversial areas in surgical management of gastric cancer D1 LN dissection involves a perigastric LN dissection (stations 1-6) D2 lymphadenetomy is an extended LN dissection that entails removing all nodes along the hepatic, left gastric, celiac and splenic arteries (stations 1-11) 45 46 Extent of Lymph Node Dissection One of most controversial areas in surgical management of gastric cancer D1 LN dissection involves a perigastric LN dissection (stations 1-6) D2 lymphadenetomy is an extended LN dissection that entails removing all nodes along the hepatic, left gastric, celiac and splenic arteries (stations 1-11) D3 is a superextended lymphadenectomy and involves a D2 lymphadenectomy plus removal of nodes within porta hepatis and periaortic regions (station 1-16), also termed D2 lymphadenectomy plus periaortic nodal dissection (PAND) 47 48 Extent of Lymphadenectomy Extended Lymphadenectomy Japanese surgeon routinely perform extended Two arguments against routine use of extended lymphadenectomy due to survival benefit lymphadenectomy: demonstrated in Eastern literature Higher associated morbidity and mortality Randomized studies in Western series demonstrated Lack of a survival benefit for extended increased morbidity with D2 LN dissection but no lymphadenectomy in most large randomized studies benefit in terms of improved survival over D1 LN dissection Need at least 16 nodes to properly stage patient 50 D1 versus D2 LN dissection D1 versus D2 LN dissection Dutch Trial MRC Trial (Medical Research Council) Largest randomized trial from Dutch Gastric Cancer Group Random assignment trial of 400 patients to D1 or D2 Randomized 711 patients treated with curative intent to D1 vs. D2 LN dissection lymphadenectomy Japanese surgeon trained and monitored operative procedures of Post-op morbidity and mortality higher in D2 group 11 Dutch surgeons (46% vs. 28% and 13% vs. 6%) Postoperative morbidity (43% vs. 25%) and mortality (10% vs. Five year survival rates were similar (33% versus 4%) higher in D2 group 35%) Most recent 15 year follow up revealed: Overall survival – 21% in D1 versus 29% in D2 (p=0.34) Lower local regional recurrence rates with D2 (22% in D1 versus 12% in D2) Gastric cancer related death higher in D1 group (48% vs. 37%) 51 52 D1 versus D2 LN dissection D2 versus D3 LN dissection Many clinicians considered above trials flawed JCOG trial 9501 Dutch trial assumed increase in survival from 20- 32% - likely an overestimate of potential benefit Multicenter Japan Clinical Oncology Group (JCOG) randomly assigned 523 patients to a D2 versus a D3 40% of patients with early gastric cancer LN dissection. (unexpected high proportion unanticipated ) who would be unlikely to derive benefit Complication rate in D3 group significantly higher (28% vs. 21%) although no differences in major Both studies significantly underpowered for the complications or mortality (0.8% in both arms) group of patients with N2 disease who would be expected to derive a long term benefit. Five year recurrence free survival (63% in both groups) and overall survival (70% vs. 69%) were no Operative mortality of 10-13% would not be better after extended lymphadenectomy expected in high volume centers 53 54 Laparoscopic Gastrectomy Theoretical Advantages Decreased pain Predominantly utilized for early gastric cancer Shorter hospital stay Role in advanced gastric cancer is unclear Less intraoperative blood loss Types of gastric operations: Fewer complications Staging – diagnostic laparoscopy with peritoneal washings Quicker recovery of intestinal function Resection Improved cosmesis Laparoscopic Subtotal gastrectomy Laparoscopic Total gastrectomy Laparoscopic Proximal Gastrectomy Palliative Bypass Concerns Results Oncologic equivalence? A multitude of retrospective reports and case control Adequacy of lymph node dissection and surgical reports comparing laparoscopic and open gastrectomy margins for the treatment of early gastric cancer from both Western and Eastern countries Longer operative time All studies demonstrated laparoscopic gastrectomy to Need for advanced instrumentation be safe with equivalent results to open surgery Long learning curve At least 5 prospective randomized studies comparing laparoscopic and open gastrectomy for early gastric cancer Studies Results Author Year Country LADG ODG Site Recon A meta-Analysis of these studies revealed : Kitano el al 2002 Japan 14 14 Distal B-I Lee et al 2005 Korea 24 23 Distal B-I LADG associated with less blood loss, less analgesic Hayashi et al 2005 Japan 14 14 Distal B-I requirements and lower rate of complications Huscher et al 2005 Italy 30 29 Distal B-II or Roux LADG associated with longer operative time and Kim et al 2008 Korea 82 82 Distal B-I decreased number of lymph nodes harvested No difference demonstrated for resumption of oral intake, duration of hospital stay, tumor recurrence or mortality Ohtani et al. J Gastrintest Surg 2010 Surgeon and Institution Experience Institutional Volume United states Intergroup Trial 0116 provided Recent study in state of Texas looked at 1800 sobering overview of current surgical practice in gastrectomies performed in 214 hospitals over a 3 patients with resectable gastric cancer year period. Of 556 patients, 54% Intraperitoneal Chemotherapy for Gastric Cancer Peritoneal metastases are a common site of spread for Regional Therapy gastric cancer Patients with gastric cancer and peritoneal carcinomatosis have a very poor prognosis with Peritoneal Carcinomatosis median survival of 3 months without treatment Systemic chemotherapy is largely ineffective against peritoneal carcinomatosis 63 64 Hyperthermic Intraperitoneal HIPEC and Gastric Cancer Chemotherapy (HIPEC) Best quality study is randmoized controlled trial by Utilized in combination with cytoreductive surgery for Kuramoto et al treatment of advanced cancers limited to peritoneal cavity Randomized patients with positive peritoneal cytology and no macroscopic peritoneal disease to surgery All visible tumor from the peritoneal cavity is removed aolne versus surgery and HIPEC. (cytoreductive surgery or debulking) Revealed improved survival with addition of HIPEC. Sterile solution containing heated chemotherapeutic agent is continuously circulated through the abdominal cavity for set period of time 66 Montefiore-Einstein Center for CRS and HIPEC Cancer Care Phase II Trial Role of CRS and HIPEC in patients with macroscopic peritoneal disease is unclear Cytoreduction + Hyperthermic Intraperitoneal Mitomycin C + Standard Systemic Chemotherapy in Studies looking at this are mostly retrospective, poorly Patients with Peritoneal Carcinomatosis designed and conclusions on efficacy of this treatment are unproven Eligible patients are patients with ECOG performance cytologically or biopsy proven carcinomatosis from gastric cancer (other histologies included in trial are appendiceal, colorectal, pseudomyxoma and peritoneal mesothelioma). 67 Phase II Trial Primary Objective is to evaluate technical parameters including completeness of cytoreduction, achievement of hyperthermia, Thank you. morbidity and mortality. Secondary objectives are to evaluate progression free survival, overall survival, and quality of life. 70