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Neoplastic diseases of the Stomach/Pancreas/Liver

John D. B. Dockins, MD Friday Academic Session 12/17/10

Gastric Cancer - Anatomy - Overview - Epidemiology - Staging - Surgery - Combined Modality Treatment - Treatment Guidelines - Summary



Cancers of UGI Tract - Stomach - Esophagus - GE junction Major Health Problem Worldwide 2009 US Stats - 37,600 new cases - 25,150 deaths

Rampant in Many Countries worldwide - 4th most common Worldwide - Japans most common cancer in men Incidence declining since WWII

- One of least common in US

- 21,130 new cases 2009 - 10,620 eventual deaths 2009 Gastric Adenocarcinoma - Cardiac origination dominates in West - Non-cardiac/Distal dominates East (Japan, Korea, former USSR)

Often Dx at advanced stage - Japan/Korea earlier detection ( screening) Environmental risk factors - H. Pylori - Smoking - High salt intake - Dietary factors Genetic factors - Higher risk with family history - 1-3% associated with inherited syndromes - E-Cadherin mutations in 25% of a hereditary diffuse gastric cancer (genetic counseling recommended)

2 Major classifications - Japanese (elaborate, anatomy, nodes) - AJCC and UICC (Western Hemisphere) - 15 LN recommended for adequate staging

Baseline Stage useful in tx strategy

- 50% present w/advanced disease (poor outcome) - Poor performance status, mets., Alk Phos. > 100 U/L

Localized, resectable disease - Outcome based on surgical stage - 70-80% pts. have regional +LN mets. (# has profound influence on survival)

Pre-op Staging
Clinical staging has greatly improved with diagnostic modalities CT- routinely used (43-82%) sensitivity for T stage PET-CT - Lower detection rate than CT alone - Lower sensitivity than CT for LN involvement (56% vs. 78%)

- Improved specificity (92% vs. 62%)

- higher accuracy in pre-op staging (68%) vs. CT(53%) or PET(47%) PET not adequate as primary detection or staging modality

Pre-op Staging
EUS - assesses tumor depth - T stage accuracy 65-92% - N stage accuracy 50-95% (operator dependent) - Distant nodal evaluation suboptimal

- Good for occult metastasis - MSKCC study 657 staged laparascopically - Metastatic dz. in 31% of patients

- Limitations were 2D evaluation and detecting hepatic mets. and perigastric LN

- Usually reserved for medically fit with resectable dz. - May be used in unfit if there is consideration for adding radiation to chemo

Pre-op Staging
Cytogenetic analysis - Reports suggest (+) peritoneal cytology is an independent predictor for risk of recurrence following curative resection

Primary treatment for early stage gastric cancer is surgery Standard goal is complete resection with adequate margins (4cm or greater) Type of resection (subtotal vs. total) and extent of lymphadenectomy is controversial

Primary goal is to accomplish complete resection with (-) margins (R0) - R1 microscopic residual dz. - R2 - macroscopic residual dz. - 50% reach R0 resection of primary lesion Subtotal gastrectomy is preferred approach for distal gastric cancers - Similar outcome as total gastrectomy

- Significantly fewer complications

Proximal or total gastrectomy both indicated for proximal gastric cancer - associated with post-op nutritional impairment

Clinical Staging with CT +/- EUS is done pre-op T1b- T3 tumors distal, total, or subtotal gastrectomy T4 tumors- en-block resection of involved structures Routine splenectomy should be avoided - Slightly morbidity and mortality in pts. undergoing total gastrectomy + splenectomy vs. total gastrectomy - Marginal survival benefit - Studies do not support prophylactic splenectomy to remove macroscopically negative LN Placement of feeding jejunostomy considered for those receiving post-op chemoradiation

Unresectable disease - Peritoneal involvement - Distant metastasis - Locally advanced disease (involvement or encasement of major blood vessels) Limited gastric resection is acceptable for symptomatic palliation of bleeding (+ margins acceptable) Palliative gastric resection should not be performed unless pt. is symptomatic and LN dissection not required

Gastric bypass with gastrojejunostomy to proximal stomach used for palliation of symptomatic obstruction
Feeding jejunostomy or venting gastrotomy may also be considered

LN dissection Controversial Nodal stations defined in proximity to stomach - D0 no effort to resect LN (palliative)

- D1 perigastric LN
- D2 LN along main tunks of celiac axis

Japanese surgeons advocate D2 LN dissection - report overall survival Several Western trial have investigated D2 LN dissection on outcome British Medical Group - D2 vs D1 LN dissection - postop morbidity - no benefit in overall survival or recurrence free survival Dutch Group - D1 vs D2 LN dissection (Japanese instructor) - no benefit in overall survival Both trials incorporated distal pancreatectomy and splenectomy - Probably influenced long-term mortality

Retrospective analysis comparing D2 vs D1 without pancreaticosplenectomy demostrate favorable survival in D2 group Benefit of aggressive lymphadenectomy is more accurate staging MSKCC - number of LN, not location is important in prognosis - N1 1-6 LN - N2 7-15 LN - N3 - > 15 LN - 15+ LN improve prognostication and outcome Likely due to improved staging (dont erroneously pts. With occult metastasis

Endoscopic Mucosal Resection (EMR) - Major advance in endoscopic surgery - used for Tis or T1a tumors - require limited resection (5yr survival>90%) - Limited in US Indications - well or moderately differentiated tumors - no ulceration - no invasive findings - tumors <30mm

Promising, Routine use limited to clinical trials (no Class 1 data comparisons
Proper patient selection is key

Laparascopic resection offers advantages - blood loss - pain and hospitalization - recovery - return of bowel funtion Hulscher and colleagues - open vs. laparascopic subtotal gastrectomy - 59 pts. - Mortality 3.3 vs 6.7 - 5yr OS rates 59.8 vs 55.7 - DFS 57.3 vs 54.8 Not statistically significant More trials needed

Combined Modality Treatment

Adjuvant Therapy MSKCC analysis of 1172 pts. Undergoing RO curative resection - 42% incidence of recurrent disease after long term follow-up - 54% locoregional - 51% distant loci - 79% picked up w/in 2yrs. - median time of death 6 months

High likelyhood of recurrence has stimulated interest in combined modality therapies for resected gastric cancer

Combined Modality Treatment

Adjuvant chemotherapy +/- radiation has failed to demostrated benefit survival However, adjuvant chemoradiation is suggested as standard of care in US Intergroup 0016 trial - compared post-op 5-FU, leucovorin and external beam radiation to observation - overall and disease free survival

- Flawed quality control

- Recommended D2 dissection (10% got it) - 54% had less than D1 dissection

- Probably equal to outcomes of extensive LN dissection (>15LN)

Combined Modality Treatment

Neoadjuvant Therapy - Review of Intergroup 0116 - only 64% were able to complete therapy Potential benefits of pre-op chemotherapy Oncologic benefit of chemo or chemorads controversial MAGIC trial compared pre-op chemo to surgery alone - suggest resectability and more durable overall survival - radiation not used Parameters guiding appropriate selection of patient currently unavailable

Treatment guidelines
Management requires multidisciplinary approach (Medical, Surgical, Radiation Oncology, Nutritionist, Endocopist) Workup - Usually present with anemia, weight loss, N/V, and/or bleeding -H&P - CXR - Upper endoscopy - CBC - CMP - CT +/- PET - EUS if potentially resectable H.Pylori testing

Treatment guidelines
Initial Workup classifies pts. Into 3 groups Localized (Tis or T1a) Locoregional (Stage 1-3) - Medically fit w/potential for resection - Medically fit but unresectable - Medically unfit Metastatic (Stage 4 or M1)

Treatment guidelines
Primary treatment - EMR or surgery for medically fit (Tis or T1) - Surgery for medically fit and T1b tumors - Advancd tumors receive perioperative chemotherapy (Calss 1) or pre-op chemoradiation (Class 2B) for T2 and higher tumors in medically fit - RT (45-50.4Gy) with senstization or palliative chemotherapy for medically fit patient with unresectable disease - Medically unfit or fit with unresectable disease need restaging after completion of therapy If complee response, may be observed or offered surgery if appropriate

Treatment guidelines
Post-op Treatment - Based on surgical margins and nodal status

- Tis, T1NO, T2NO may be observed

- T2N0 with high risk features require postop chemorads - T3< require chemorads

Bleeding endoscopy or angioembolization Ostruction gastrojujunostomy, stenting, PEG Pain- RT and pain meds N/V - antiemetics

Hepatobiliary Cancer
- Anatomy - Epidemiology - Staging - Surgery - Combined Modality Treatment - Treatment Guidelines - Summary

Hepatocellular Carcinoma - most common hepatobiliary cancer Risk factors - Chronic Hepatitis B/Hepatitis C

- hereditary hemochromatosis, porphyria cutanea tarda, alpha 1 antitrypsin disorder

- autoimmune hepatitis - Non-alcoholic fatty liver disease - excessive alcohol intake - aflatoxin Most cases risk factor for HCC mimic risk factors for liver cirrhosis

Screening for HCC - AFP and liver U/S most widely used - U/S alone is better than AFP alone - Combined modalities better At- risk populations - periodic screening with U/S and AFP testing every 612mo - Additional imaging (CT with contrast) recommended with AFP level or findings of liver mass nodule

Diagnosis and Work-up

HCC is asymptomatic for most of its course Symptoms Usually nonspecific jaundice anorexia malaise upper abdominal pain

Signs - Hepatomegaly - Ascites - Paraneoplastic syndromes (hyperlipidemia, Hypercalcemia, Hypoglycemia

Diagnosis and Workup

Imaging HCC lesions are hypervascular Derive most of blood supply from hepatic artery Triphasic helical CT Trphasic cortrast MRI

Classic imaging profile is intense arterial uptake followed by contrast washout or hypodensity in delayed phase Pts w/liver mass on U/S should receive one or more imaging modalities - 1-2cm nodule needs two imaging modalities - classic arterial enhancement in 2 modalities is considered diagnostic of HCC - Tissue sampling recommended when classic pattern not observed or seen with only one modality

Diagnosis and Workup

Biopsy - May not be required - Needle core biopsy (preferred) or FNA is recommended in some cases FNA - may have lower complication rate - rapid staining and examining samples - Highly dependent on operator skill - possible high false negative and false positive rates NCB - more invasive - provides cytology and architecture - additional histological tests may be performed Use of biopsy is limited - nondiagnostic biopsies should be followed closely - change in size of a nodule warrants additional imaging or biopsy

Diagnosis and Workup

Initial Workup - Multidisciplinary team - Hepatitis panel - Comorbidity assessment

- Imaging studies to look for mets.

- evaluation of Hepatic function and presence of portal HTN Common sites of metastasis - Lung

- Abdominal LN
- Bone

Diagnosis and Workup

Chest Imaging and bone scan recommended as part of initial workup Triphasic CT or MRI - tumor burden - metastatic disease - vascular invasion - portal HTN - size, location and estimate of liver remnant in relation to total volume

Diagnosis and Workup

Liver function Testing serum bilirubin AST/ALT Alk Phos. PT/PTT/INR albumin protein

Child-Pugh classification

- 3 classes according to likelihood of survival

Diagnosis and Workup

Model for End-Stage Liver Disease (MELD) - numerical scale - ranges from 6 (less ill) to 40 (gravely ill) - sometimes used in place of Child-Pugh classification to asses prognosis in liver cirrhosis

- used by UNOS for transplant waiting list stratification

3 types of HCC identified Nodular - associated with cirrhosis - well circumscribed nodules Massive - usally non-cirrhotic liver - occupies large area - with or w/out satellite nodules Diffuse - Less common - diffuse involvement of many small indistinct nodules

Vascular invasion major predictor of outcome after resection Pt. with HCC must be carefully evaluated - Underlying liver dz complicates management - different types of HCC may impact tx. response - Treatmentnecessitates involvement of large teams (Hepatologist, IR, Transplant surgeons, pathologists, etc.)

Partial Hepatectomy - potentially curative in early stage HCC who are eligible - can be performed with low morbidity and mortality (5% or less) - some studies report 5yr survival over 50% - 70% with good functional reserve - High incidence of recurrence - Careful patient selection is essential Resection recommended only in setting of preserved liver function

- Child-Pugh score A - No portal HTN - Child-Pugh score B may be considered in selected cases (normal LFTs)

Liver Transplantation - attractive, potentially curative option for pts. With early HCC - removes detectable and undetectable LN - treats cirrhosis - avoids complications associated with a small FLR - UNOS specify that candidates for transplant should not be candidates for resection Initial tx. Of choice in early HCC and moderate to severe cirrhosis (Child class B and C)

Local Regional Therapy directed at inducing selective tumor necrosis Has not been established as comparable to transplant or hepatectomy Alation - Chemical exposure (ethanol, acetic acid) - temperature (RFA, cryoablation, microwave) - can be performed laparascopically, open or percutaneous - most common methods are RFA percutaneous ethanol injection (PEI) - low complication rate (4% and 0%)

Embolization - based on tumor blood supply - catheter based infusion of particles targeted to the branch of hepatic artery feeding tumor - Limited to segment, subsegment, or lobe - all HCC tumors may be amenable to embolization provided that the blood supply may be isolated - Unresectable/inoperable disease - not amenable to ablation - absence of extrahepatic disease - >5cm, inoperable embolization, 3-5cm inoperable ablation + embolization

Systemic therapy- Generally reserved for very advanced liver disease Usually only given to unresectable HCC in presence of clinical trial Sorafenib- recommended for Child Class A

- unresectable - not suitable for transplant - local disease only in pts non-operable

Cross sectional imaging every 36months for 2yrs, then annually
AFP levels if initially elevated should be measured every 3mo for 2yrs, then every 6mo

Reevaluation undertaken for progression or recurrence

Gallbladder cancer
Risk factors - Gallstones

- chronic inflammation
- calcification (porcelain gallbladder)

Diagnosis and Workup

Often diagnosed at advanced stage - aggressive tumor - clinical presentation mimics biliary colic or chronic cholecystitis - Often dx. as incidental finding at surgery or on pathology review following cholecystectomy Workup of suspicious mass on U/S or jaundice - LFTs, evaluation of hepatic reserve - CEA Ca 19-9 (not specific) - CT abdomen to assess extent and nodal disease - Chest XR or CT - Cholangiography (MRCP preferred over ERCP or PTC unless intervention planned)

Pathology and Staging

80% adenocarcinomas - often have early spread to lymph nodes and bloodstream Poor prognosis - 5yr survival 39% stage 1 - 1% stage 4

Surgery only curative modality All pts. needCT/MRI and chest imaging prior to surgery Staging laparoscopy should beconsidered prior to laparotomy Recommended surgery for known diagnosis cholecystectomy en-bloc hepatic resection lymphadenectomy with or without bile duct excision Portahepatis,retroduodenal, gastrohepatic ligament Nodal disease outside of this area is unresectable

Surgery for tumor detected after cholecystectomy - 74% found to have residual dz during reexploration - Recommend extended cholecystectomy - T1a may be observed (no muscle involvement)

- T1b or greater require metastatic workup, then hepatic resection and lymphadenectomy
- Should not be performed by inexperienced surgeon or unknown resectability Unresectable disease - biopsy to confirm diagnosis - biliary drainage - possible chemotherapy or chemoradiation (usually in clinical trial) - supportive care

Tumors originating from epithelium of bile duct Distinguished by anatomic site Intrahepatic

- peripheral cholagiocarcinomas - located within hepatic parenchyma

Extrahepatic hilar cholangiocarcinomas(Klatskins tumors) usually near junction of left and right hepatic ducts more common hilar is most common type

Risk factors - No predisposing factors have been identified in most patients - May be associated with chronic inflammation

- chronic calculi
- Primary sclerosis cholangitis - Choledochal cysts - liver fluke infections - gallstones not related - Hep C may be associated with intrahepatic forms

Diagnosis and workup

Typically asymptomatic Intrahepatic likely to present with - fever - weight loss - abdominal pain - biliary obstruction uncommon - may be detected as isolated intrahepatic mass on imaging

Extrhepatic likely to present with - jaundice followed by obstruction

Diagnosis and Workup

Workup - LFTs - CEA and Ca 19-9 (not specific) - Delayed contrast CT/MR (helpful in determining resectability) - Chest imaging - Cholangiography in patients with jaundice (MRCP vs. ERCP vs. PTC)

Pathology and staging

>90% adenocarcinomas Divided into 3 types - Mass forming - periductal - intraductal

Intrahepatic cholangiocarcinoma - Complete resection on curative modality - most pts. Not candidates for surgery due to advanced dz. At presentation Surgery involves removing entire lobe or segment along the involved duct

R0 resetion associated with longer survival rates

20-43% 5yr survival R0 resections may be observed

R1 or R2 need individualized therapy

Unresectable disease chemo, chemorads, clinical trial, supportive care

Extrahepatic cholangiocarcinomas - complete resction main curative strategy Surgical procedure based on location - Proximal 1/3 hilar resection with lymphadenectomy and en-bloc liver resection - Mid 1/3 major bile duct excision with lymphadenectomy, assessment of margins - Distal 1/3 Pancreaticoduodenectomy R0 resection may be observed, chemo, or chemorads (no standard) Liver transplant only other possible curative modality for extrahepatic cholangiocarcinoma - unresectable dz. - normal biliary function

Distal strictures - ERCP with brushing and stenting Unresectable disease - biliary drainage (PTC or ERCP +stent) - biopsy - clinical trial, chemo, or chemorads (no standard) Metastatic disease as above

No data to support aggressive surveillance Imaging every 6mo to 2yrs Although most pts. With hepatobiliary cancers found at advanced stage, all should be evaluated for treatment

Careful selection and multidisciplinary approach are essential

Pancreatic Adenocarcinoma
36,800 die each year 4th MCC death in US men and women Peak incidence 7th and 8th decades African American have higher incidence than whites


Pancreatic adenocarcinoma
Risk factors - Cigarette smoking - Increased BMI

- incresed meat and dairy products

- occupational exposure to chemicals(benzidine and betanaphthylamine)

- chronic pancreatitis
- alcohol intake

Pancreatic adenocarcinoma
Familial pancreatic cancer is rare
- 5-10% may have genetic predisposition - May be associated with BRCA2 mutations - Assess family history

Diagnosing and staging

Ductal adenocarcinoma >90% of pancreatic malignancies Presenting symptoms - weight loss - jaundice - floating stools - pain - dyspepsia - nausea - depression No early warning signs May be considered in diabetics presentin>50 or with unusual manifestations Pts. Should undergo helical or spiral CT with pancreatic protocol if pancreatic cancer is suspected

CT best and most widely used - Triphasic (arterial, late arterial, venous) - Thin slices Helps to distinguish resectable vs. unresectable

CT is primary means through which stage is determined

70-85% determined to have resectable tumors by CT were able to undergo resection (specificity > sensitivity) MRI may be sued if CT isnt possible EUS is complementary to CT Chest imaging

Laparoscopy is a a valuable staging tool may pick up implants missed by CT Tumor antigens - Ca 19-9 should be performed after biliary decompression - low postop Ca 19-9 levels and declining levels ater surgery are associated with improved survival

Staging and resectability

Patients with stage 0, 1, or 2 are generally considered resectable Some surgeons will resect patients with stage 3 tumors Pts. With tumor confined to the pancreas and resected LN w/o vascular invasion are candidates for surgery

Neoadjuvant therapy is not routinely performed - may be used in locally invasive disease - 10% downstaging
Adjuvant therapy is the standard of care with chemotherapy +/- radiation

Pancreaticoduodenectomy is treatment - delayed gastric emptying in 15% Postop chemotherapy is given Palliation may involve biliary drainage for recurrent or metastatic disease Sympathetic denervation may be performed for intractable pain

NCCN guidelines Cameron