MORE GI CANCER
| SURGICAL THERAPY FOR GASTRIC CANCER —D. Scott Lind, MD, Cecil F. Whittaker Professor and Chief of Surgical
Oncology, Medical College of Georgia, Augusta
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| Factors associated with reduction in incidence of gastric cancer in United States: decreased consumption
of salted, pickled, and smoked foods; increased consumption of fresh fruits and vegetables; use of refrigerator and improved
living conditions; decrease in Helicobacter pylori transmission
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| Minimally invasive techniques: sentinel lymph node biopsy (SLNB)—speaker believes SLNB has role in gastric
cancer; has become standard of care for melanoma and breast cancer; laparoscopic gastrectomy—widely used in Japan
due to endemic gastric cancer; laparoscopic staging—British Medical Research Council (MRC) trial and Dutch Gastric
Cancer Trial examined extent of lymphadenectomy and compared D1 to D2 resection; neither trial showed benefit from more
aggressive dissection; endoscopic mucosal resection—pioneered in Japan for early gastric cancer; endoscopic ultrasonography
(EUS)—better at determining T stage than computed tomography (CT); shows size and appearance of nodes;
can guide fine needle aspiration
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| Neoadjuvant chemotherapy: favored by speaker for T3 and T4 lesions or node-positive disease; some data support
improved overall survival and local regional control in patients who respond well
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| Laparoscopic staging: goal to detect occult M1 disease typically missed by CT; gastric cancer has high tendency to
spread peritoneally, and peritoneal disease not picked up well by CT; in certain subsets of patients, laparoscopic staging
can lead to revised and more accurate staging in 20% to 30% of patients, and may prevent unnecessary laparotomy; goal
to visualize all peritoneal surfaces and look at peritoneal cytology
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| Gastric resection: controversy about extent of gastric resection; Italian gastrointestinal (GI) tumor study group randomized
>600 patients with distal gastric cancer to total or subtotal gastrectomy and found no difference in overall survival; patients with
part of stomach preserved had better nutritional outcomes; for proximal tumors (insidious proximal spread in submucosal lymphatics),
speaker favors total gastrectomy and 4- to 6-cm proximal margin; because pylorus good deterrent to spread into
duodenum, subtotal gastrectomy done for distal tumors (facilitates reconstruction); tumors of cardia and gastroesophageal
(GE) junction—in United States, increasing in incidence, particularly in white men; not associated with Barrett’s esophagus
(etiology unclear); biologic behavior aggressive; technically difficult; gastrectomy with transhiatal exposure of esophagus usually
allows adequate margins without entering chest for anastomosis; with more proximal tumors, thoracotomy sometimes required;
transhiatal esophagectomy with abdominal and left neck incision occasionally required
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| Roux-en-Y gastric bypass: standard reconstruction after total gastrectomy; Roux limb should be 45 to 60 cm to avoid
alkaline reflux esophagitis; not done for less than total gastrectomy due to delayed gastric emptying in Roux syndrome
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| Braun enteroenterostomy: subtotal gastrectomy; bile diverted away from stomach as in Roux-en-Y; Vogel studied
≈100 patients undergoing Braun enteroenterostomy with dual scanning (looking at gastric emptying and bile reflux into
stomach) and had good results, but speaker believes clinical outcome correlation remains to be proven
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| Gastric reservoir: goal to improve nutritional status; however, literature shows no significant difference in weight,
anastomotic leak, Visick score (assesses quality of life after gastric surgery), or reported mortality; speaker does not use
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| D2 resection: in United States, resectability rate of gastric cancer ≈70%; D2 resection standard of care in Japan, but most US
surgeons not trained in procedure; mortality higher in United States despite less extensive dissection, probably due to low number
of procedures done and fact that disease diagnosed earlier in Japan
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| Biologic differences in gastric cancer: speaker not sure whether cancers in United States different from those in Japan;
stage migration may play role (better staging leads to better outcomes); Western patients usually older, heavier, and
have more comorbidities, leading to worse outcomes; improved medical therapies in United States have dramatically reduced
number of gastric resections
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| Lymphatic drainage of stomach: meticulously studied by Japanese; categorized into 16 stations correlating to D dissections
(most US surgeons trained in D1 dissection); for TNM staging system, need ≥15 nodes to accurately stage patient;
Japanese think 25 minimum
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| Extent of lymphadenectomy: British MRC Trial, Dutch Gastric Cancer Trial (randomized prospective trials with several
hundred patients each); with more extensive dissections (included pancreatic and splenic resections), morbidity (fistulas, infections)
and mortality in both trials statistically higher; no difference in overall survival; trials somewhat flawed but did lead
to more accurate staging and improved local control; recent Japanese study showed morbidity very low in their hands (10%-
20%)
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| Endoscopic mucosal resection: developed by Japanese; more sophisticated techniques now available for staining and
outlining resection, as well as devices that facilitate resection
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| Sentinel node biopsy: based on fact that principal or sentinel node is first node of tumor spread; if this node tumor-free,
95% likelihood remaining nodes also without tumor; can spare patients with negative SLNB morbidity of lymphatic dissection;
also enables more accurate staging and mapping of lymphatics so only nodes involved with tumor removed;
learning curve involves combination of techniques; literature in Japan shows high false-negative rate; however, speaker
thinks this is manifestation of learning curve
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| Laparoscopic resection: now option for surgical treatment of colorectal cancer; advantages apply to gastric resection;
shorter hospital stay, less pain, improved pulmonary and immune function; disadvantages include longer surgery, cost,
and steeper learning curve
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| Conclusion: EUS and laparoscopy important staging tools; total gastrectomy not always required; D2 resection not yet of
proven benefit; minimally invasive approaches should be integrated into practice; need better chemotherapy regimens;
need to predict more precisely who will benefit from chemotherapy by genetic profiling and phenotyping of tumors,
which also targets therapy and enables molecular staging
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| CURRENT CONCEPTS IN PANCREATIC CANCER —Thomas N. Wang, MD, PhD, Associate Professor, Surgical Oncology,
Medical College of Georgia, Augusta
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| Pancreatic cancer: mortality and morbidity high; 30500 new cases annually and growing rapidly; fourth leading cause of
cancer deaths in United States; age-adjusted mortality tripled over last 70 yr in United States, Japan, and Europe; only 10% to
15% resectable at diagnosis; 5-yr survival 23% in resected patients; for everyone with pancreatic disease, 5-yr survival probably
4%
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| Treatment: streamlined approach needed; objectives 1) find patients that can be resected, 2) determine which patients
unresectable to avoid subjecting them to Whipple procedure and associated morbidity and mortality; comprehensive
clinical assessment—at Medical College of Georgia (MCG), speaker takes careful history, looking at risk factors for
pancreatic cancer, including malaise, weight loss, and pain; new-onset diabetes can point to new pancreatic cancer; look
for jaundice and ascites; some patients mildly depressed; order baseline chest x-ray, baseline laboratory survey, and abdominal
CT
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| Tumor markers: carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 available; not specific and
probably should not be used for diagnosis or to determine resectability; use as follow-up in treated patients to determine
whether recurrence has occurred
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| Imaging studies: CT— mainstay; use newer generation CT imaging with dual contrast (rapid bolus of intravenous [IV]
as well as oral [PO] contrast) and thin cuts (1-1.2 mm through entire pancreas); provides anatomy of pancreas with relationship
to vasculature to determine resectability; magnetic resonance imaging (MRI)—not very useful for determining
resectability; good noninvasive modality for looking at pancreatic duct, common bile duct, and intrahepatic ducts;
EUS—useful tool for diagnosis and staging; studies show probably better than CT for finding tumors <3 cm; with EUS-
guided biopsy, can make tissue diagnosis to triage patients for neoadjuvant chemotherapy; in treatment, EUS can be used
in stenting and for injecting celiac plexus for neurolysis for pain and for injecting tumor with molecularly targeted agents;
endoscopic retrograde cholangiopancreatography (ERCP)—used extensively; certain findings in imaging and brushings
can help make diagnosis; patients who present with jaundice triaged to ERCP; positron emission tomography
(PET)—new modality still in development; used as follow-up after surgery, but this may be changing; several studies
show it may be good for tumors <2 cm, whereas CT better for tumors >5 cm
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| Computed tomography: dual-phase high-resolution CT with multiple detectors allows determination of relationship of
tumor to adjacent blood vessels and to celiac axis, hepatic arteries, and gastroduodenal artery; desirable to have cancer located
away from superior mesenteric artery and fat plane separating superior mesenteric artery and vein; if vein involved,
cancer not unresectable because vein can be removed and interposition graft placed; flow through superior mesenteric vein
absolutely necessary; absence of flow through superior mesenteric vein-portal vein confluence indicates cancer unresectable
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| Pretreatment algorithm: places patients in 4 categories, 1) unresectable pancreatic cancer or metastatic disease; get
tissue diagnosis (US-guided biopsy of liver if liver metastases present or EUS biopsy of pancreatic head) to start chemotherapy
or chemoradiation therapy; 2) resectable pancreatic cancer; place in neoadjuvant chemoradiation therapy trial
(tissue diagnosis needed); 3) resectable pancreatic cancer not requiring chemotherapy or chemoradiation therapy; patients
go straight to surgery, no tissue diagnosis necessary; 4) suspected but unproven pancreatic cancer; discuss options with
patient; preemptive surgery strongly advised
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| Treatment algorithm: in patients with locally advanced or metastatic cancers, surgery contraindicated; go directly to
biopsy and chemotherapy or chemoradiation therapy; for patients with resectable tumors, perform biopsy, followed by
preoperative chemoradiation therapy, restaging CT, surgery, and adjuvant chemotherapy; if biopsy inconclusive, perform
pancreaticoduodenectomy; if preoperative chemotherapy not indicated, forgo biopsy and go directly to Whipple procedure
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| Whipple procedure: use standard method so nothing left out; speaker’s team mobilizes right colon, head of pancreas,
and second, third, and fourth portions of duodenum until left side of aorta reached; transect bile duct, gastroduodenal artery,
stomach, and jejunum; flip everything to be resected over to right side of superior mesenteric vessels; finally,
transect pancreas and do retroperitoneal dissection; most important for oncologist to make sure retroperitoneal margin
transected neatly to enable accurate determination by pathologist of whether microscopic disease left
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| Vein and tumor inseparable: sometimes occurs despite CT; 3 approaches, 1) do less clean dissection, leaving tumor
behind, 2) try to take tumor off, damaging vein and causing bleeding, suture, remove remaining tumor, and leave tumor behind,
3) controlled vein resection (speaker favors); remove tumor with vein en bloc, followed by transposition graft from
internal jugular vein; study of venous resection—31 patients with vein resection and 45 patients with no vein resection;
found survival comparable (vein resection group somewhat better but not statistically significant); reconstruction—end-
to-side pancreaticojejunostomy, choledocojejunostomy, and gastrojejunostomy; speaker avoids use of G-tube, J-tube, and
drains
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| Natural history: recurrence rate 80% to 90% (micrometastatic disease usually present at time of Whipple); median survival
18 to 24 mo; surgical mortality 5%; hospital stay 2 wk; long recovery period (2 mo); outcome very poor (speaker
thinks because retroperitoneal margin very small [millimeters or microns], so that even if margin negative, micrometastases
most likely already present)
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| Adjuvant therapy protocols: GI tumor study group (1987) showed 2-yr survival 46% (median survival 18 mo) with
adjuvant chemotherapy, which compared favorably to resection alone (12 to 15 mo); Yeo found 21-mo median survival;
European study found similar results; Virginia Mason Medical Center (Seattle) study—used “immunochemotherapy,”
ie, added interferon to regimen of cisplatin (Platinol-AQ), external beam radiation therapy, and 5-fluorouracil (5-FU);
small initial phase 1 trial showed new group had 2-yr actuarial survival of 84%, compared to 54% in historical trials of
conventional therapy; expanded study to 43 patients and published results in 2003, showing 5-yr survival as high as 50%
to 60%; double to triple survival with traditional chemotherapies
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| American College of Surgeons Oncology Group trial (ACOSOG) 5031 phase 2 study: interferon-based
adjuvant chemoradiation for resected pancreatic adenocarcinoma; based on Virginia Mason trial; patients who had Whipple
procedure treated 6 to 8 wk later with external beam radiation therapy, 5-FU, and interferon; after 4 wk, second and
third trials of 5-FU; ongoing multi-institutional study
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| Molecularly targeted therapies: vascular endothelial growth factor (VEGF) secreted by tumor and surrounding
stroma and promotes angiogenesis; VEGF can cause vessel abnormality, increase vessel oncotic pressure, retard effect of
chemotherapy, and make tumors radioresistant; studying effects of VEGF inhibitors; recombinant humanized monoclonal
antibody bevacizumab (Avastin) new agent that binds to VEGF; shown to increase response rate when used with
gemcitabine; appears to prevent VEGF from binding to its receptor, preventing tumors from developing abnormal vasculature,
and promoting effectiveness of chemotherapy; data show increased survival; new ACOSOG Z5041 phase 2 trial
comparing pre- and postoperative therapy with bevacizumab
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| Cytokines: speaker working on matrix metalloproteinases and cytokines that seem to promote upregulation of proteases
to allow tumors to invade; ability of tumors to invade promotes angiogenesis and allows production of proteases that help
tumors go through endothelium; cytokine macrophage inflammatory protein-3 alpha (MIP-3 α) can upregulate matrix
metalloproteinase-9 (MMP-9), which plays role in tumor invasion into stroma and vessels; may be able to prevent tumor
invasion by adding monoclonal antibodies against receptor for MIP-3α or against MMP-9
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Educational Objectives
| The goal of this activity is to educate the listener about issues in gastrointestinal (GI) cancer. After hearing and assimilating
this program, the clinician will be better able to:
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 | 1. Review developments in management of gastric cancer.
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| 2. Understand potential role for sentinel lymph node biopsy in gastric cancer.
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| 3. Familiarize clinician with issues in treatment of pancreatic cancer.
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| 4. Consider new approaches to treatment of pancreatic cancer.
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| 5. Understand new developments in adjuvant chemotherapy for pancreatic cancer.
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Discussed on This Program
Bevacizumab [Avastin]
Cisplatin (CDDP) [Platinol A-Q]
Fluorouracil (5-fluorouracil, 5-FU) [Adrucil, Carac, Efudex, Fluoroplex]
Suggested Reading
Albo D et al: Antiangiogenic therapy. Curr Pharm Des10:27, 2004; Buscail L et al: Interventional endoscopic ultrasound
in pancreatic diseases. Pancreatology 6:7, 2006; Campbell AS et al: Macrophage inflammatory protein-3alpha
promotes pancreatic cancer cell invasion. J Surg Res 123:96, 2005; Carboni F et al: Gastrointestinal stromal tumors of
the stomach. A ten-year surgical experience. J Exp Clin Cancer Res 22:379, 2003; Chang F et al: Endoscopic ultrasound-guided
fine needle aspiration cytology of pancreatic neuroendocrine tumours: cytomorphological and immunocytochemical
evaluation. Cytopathology 17:10, 2006; Etoh T et al: Laparoscopic gastrectomy for cancer. Dig Dis 23:113,
2005; Gipponi M: Clinical applications of sentinel lymph-node biopsy for the staging and treatment of solid neoplasms.
Minerva Chir 60:217, 2005; English, Italian. Ichikura T et al: Individualized surgery for early gastric cancer guided by
sentinel node biopsy. Surgery 139:501, 2006; Ishizaki M et al: Evaluation of sentinel node identification with isosulfan
blue in gastric cancer. Eur J Surg Oncol 32:191, 2006; Epub 2006 Jan 18. Jhala D et al: Endoscopic ultrasound guided
fine needle aspiration of the pancreas. Adv Exp Med Biol 563:91, 2005; Kaushik N et al: Isolated pancreatic tuberculosis
diagnosed by endoscopic ultrasound-guided fine needle aspiration: a case report. JOP 7:205, 2006; Mackay S et al:
Management of gastric cancer. Aust Fam Physician 35:208, 2006; Meyer Ch et al: Gastric cancer: the French survey.
Acta Gastroenterol Belg 65:161, 2002; Noble M et al: Techniques and results of neurolysis for chronic pancreatitis and
pancreatic cancer pain. Curr Gastroenterol Rep 8:99, 2006; Samarasam I et al: Palliative gastrectomy in advanced
gastric cancer: is it worthwhile? ANZ J Surg 76:60, 2006; Schumacher IK et al: Current concepts in gastric cancer surgery.
Saudi Med J 23:62, 2002; Siddiqui AA et al: The role of endoscopic ultrasound in the diagnosis and staging of
pancreatic adenocarcinoma. J Okla State Med Assoc 98:539, 2005; Wang TN et al: Fibroblasts promote breast cancer
cell invasion by upregulating tumor matrix metalloproteinase-9 production. Surgery 132:220, 2002; Wayne JD et al:
Limited gastric resection. Surg Clin North Am 85:1009, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship
with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty reported
nothing to disclose.
Drs. Lind and Wang were recorded at the Medical and Surgical Approaches to GI Disorders, presented July 25-29, 2005,
in Amelia Island, FL by the Medical College of Georgia. The Audio-Digest Foundation thanks the speakers and the sponsor
for their cooperation in the production of this program.
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