GI CANCER: PART 2
From 11th Annual Medical and Surgical Approaches to GI Disorders, Kiawah Island, SC
| PANCREATIC CANCER —Thomas N. Wang, MD, PhD, Associate Professor of Surgery, Medical College of Georgia,
Augusta
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| Introduction: prognosis for pancreatic cancer extremely poor; incidence—ranks ninth in incidence of total diagnosed
cancers annually and fourth in cancer-related mortality; 5-yr survival <5% (lowest of all types of cancers); reasons for
poor prognosis—aggressive; diagnosis often made late (surgery not possible for most); vague abdominal complaints, or
symptoms often present 6 mo before diagnosis
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| Risk factors: age at onset—most patients (80%) diagnosed in seventh or eighth decade of life; person <40 yr of age has
<1% chance of having pancreatic cancer; new-onset diabetes—elderly patient presenting with new-onset diabetes should
have pancreatic cancer in differential diagnosis; debate whether diabetes causing pancreatic cancer or pancreatic cancer
causing diabetes; majority opinion that pancreatic cancer predisposes individual to diabetes; Italian study—in majority of
patients with diabetes and pancreatic cancer, diabetes occurred ≤2 yr before diagnosis of pancreatic cancer or at time of diagnosis;
when cancer resected, diabetes resolved in majority of patients; history of upper gastrointestinal (GI) surgery—
causes 5-fold increase in risk of developing pancreatic cancer; possible reasons include upregulation of some trophic neurohormones,
eg, gastrin (amount of gastrin increased after distal or total gastrectomy and related to different types of pancreatic
cancer, gastric carcinoids, and gastric adenocarcinoma); another possible reason is nondegradation of nitrosamines due
to lack of gastric acid or absence of stomach; history of chronic pancreatitis—increases risk 26-fold; cigarette
smoking—dependent on amount smoked (<1 pack daily, 1.5-fold increased incidence; >2 packs daily, 10-fold increase);
family history—associated with familial diseases such as familial atypical multiple mole melanoma syndrome, mutation of
BRCA2 (breast cancer susceptibility gene), Peutz-Jeghers syndrome, familial pancreatitis; 2- to 3-fold increase in risk if
first-degree relative has pancreatic cancer
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| Diagnosis: differentiation from other abdominal pathologies requires high index of suspicion, awareness of key epidemiologic
risk factors, and immediate investigation prompted by multiple key clinical features (including jaundice, abdominal
pain, nausea, and symptoms of biliary obstruction) and epidemiologic criteria mentioned earlier (new-onset
diabetes, chronic pancreatitis, previous upper GI surgery); early use of high-resolution imaging studies; repeated serologic
and radiographic testing if necessary
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 | Imaging studies: computed tomography (CT)—most commonly used to determine whether patient has resectable or suspicious
pancreatic mass or cancer; endoscopic ultrasonography (EUS)—enables tissue diagnosis of pancreatic cancer,
if necessary, and evaluation for nodal disease or regional metastatic disease; ability to perform US and biopsy at same
time big advantage, especially if considering neoadjuvant chemotherapy or chemoradiation therapy; endoscopic retrograde
cholangiopancreatography (ERCP)—especially helpful if unable to make diagnosis with initial tests; positron
emission tomography (PET)—not used in speaker’s hospital to make diagnosis, but useful if pancreatic cancer or metastatic
disease suspected in imaging study (avoids unnecessary laparotomy); important as adjuvant study after surgery to
evaluate for presentation of metastatic disease in future; CT criteria for resectability—absence of extrapancreatic disease
or metastasis; absence of encasement or obstruction of celiac, hepatic, or superior mesenteric arteries; absence of occlusion
of superior mesenteric or portal veins; criteria controversial in other regions of United States
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| Algorithm for treatment: once cancer suspected on CT and by history, perform imaging work-up to determine
whether metastatic disease present (if so, patient sent directly for chemotherapy); usually use US-guided fine-needle aspiration
(FNA) of liver if lesion present; with locally advanced tumor that seems unresectable and occlusion of vein or evidence
of invasion of arteries, EUS-guided FNA performed to determine tissue diagnosis to randomize patient for
chemoradiation (possibly for downstaging of tumor for resectability in future); few patients make it to surgery after this
point (in speaker’s series of >100 patients, only 10% of patients made it to surgery); if tumor resectable, 2 options; can
randomize into prospective trials looking at neoadjuvant chemoradiation therapy (need EUS-guided FNA of pancreas to
make tissue diagnosis, give chemotherapy, restage patient, perform pancreaticoduodenectomy [Whipple procedure], followed
by adjuvant chemotherapy if necessary); in majority of patients, if unable to make diagnosis, but still have mass in
head of pancreas with high index of suspicion for cancer, go directly to surgery (Whipple procedure); in occasional patient
without pancreatic mass but high index of suspicion (eg, presents with jaundice or heterogeneous lesion), perform
further studies, including repeat CT or EUS, or ERCP to check ducts, and biliary stenting to help with palliative efforts;
biopsy performed if necessary
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| Surgical treatment: pancreaticoduodenectomy; resection performed in clockwise fashion; reassemble in counterclockwise
fashion; perform end-to-side pancreaticojejunostomy, end-to-side choledochojejunostomy, and end-to-side gastrojejunostomy;
speaker does not use feeding tubes or drains (results comparable)
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| Natural history of resectable pancreatic cancer: recurrence high; usually have micrometastatic disease at time of
surgery; median survival 18 to 24 mo; surgical mortality high; length of hospital stay 2 wk; recovery period 2 mo; results
poor (tumor too close to retroperitoneal structures, allowing rapid metastasis); if micrometastasis present at time of surgery,
patient needs chemotherapy and possibly chemoradiation therapy
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| Treatment research: GI Tumor Study Group (GITSG) trial—demonstrated that addition of external-beam radiation
therapy (EBRT) and 5-fluorouracil (5-FU) significantly improved survival of patients with pancreatic cancer (still only
19%); present treatment has to include adjuvant therapy; Virginia Mason Clinic trial (2000)—looked at newer type of
adjuvant treatment (5-FU, cisplatin, and interferon-2 alpha [IFN2-α) and demonstrated significant improvement in 5-yr
survival (60%; dramatically different from GITSG trial); American College of Surgeons Oncology Group (ACOSOG)
Z5031 trial (phase 2)—ongoing; looking at IFN-based adjuvant chemoradiation therapy; after surgery, patients treated
with EBRT and chemotherapy (5-FU, cisplatin, and IFN2-α), and after 4 wk, treated again with 5-FU; bevacizumab
(Avastin)—used in colorectal cancers (primary and metastatic); monoclonal antibody directed at vascular endothelial
growth factor (VEGF); binds to VEGF, preventing it from binding to its receptor; Dr. Kindler (2004)—multicenter
phase 2 clinical trial looking at bevacizumab and gemcitabine vs gemcitabine alone in metastatic pancreatic cancer (nonresectable);
response rate with addition of bevacizumab 21% (vs 5% with gemcitabine alone); median follow-up 6.2 mo;
median survival 74% at 6 mo, 53% at 1 yr; ACOSOG Z5041 trial—looking at bevacizumab to treat resectable primary
pancreatic cancer; used preoperatively (neoadjuvant) and as adjuvant treatment; patients with resectable primary adenocarcinoma
of head of pancreas by CT (important criterion) randomized to bevacizumab and gemcitabine vs gemcitabine alone;
preoperative CT restaging followed by pancreaticoduodenectomy 8 to 12 wk posttreatment, then postoperative chemoradiation
(bevacizumab, capecitabine, and EBRT); future treatment research—netrin-1 seems to stimulate endothelial
cell migration (may be directional cue with important role in neuronal development); angiogenesis necessary for pancreatic
cancer to develop; platelet-derived growth factor (PDGF) allows for capillary formation by increasing numbers of
endothelial cells; Deleted in colorectal cancer (Dcc) gene—produces molecule that is specific receptor for netrin-1;
tumor-suppressor gene; present in large amounts in pancreatic cancer and endothelial cells; increasing netrin-1 results in
dose-dependent increase in endothelial cell migration; effect blocked by adding antibody to Dcc
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| SURGICAL UPDATE ON GASTRIC CANCER —D. Scott Lind, MD, Jarrell Distinguished Professor and Chief, Surgical
Oncology, Department of Surgery, Medical College of Georgia, Augusta
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| Introduction: difference between Eastern and Western hemispheres in incidence, presentation, and management of gastric
cancer; in United States, incidence and mortality rate decreased dramatically over last century, tends to be diagnosed
late, and surgical management less aggressive; decreased incidence in United States attributed to change in diet (decreased
intake of salted, pickled, and smoked foods; increased consumption of fruits and vegetables); development of refrigeration
and improved living conditions (decreased Helicobacter pylori transmission [involved in pathogenesis of other upper GI
diseases])
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| Staging: important in selection of optimal treatment; CT—mainstay; test of choice for visceral metastases and contiguous
organ involvement, but has limitations; not good for determining whether small lymph nodes contain metastases and
whether lymph nodes enlarged due to tumor or inflammation; not good in peritoneal dissemination (gastric cancer has
high propensity for transgastric spread through wall, with tumor implantation in peritoneum); also not best for determining
T stage to plan therapy; EUS—best method to determine T stage; for early lesions, can help in planning for local
therapy; for late lesions (T3 and T4), laparoscopic staging used; staging techniques complementary; may have decreased
sensitivity after chemotherapy and irradiation (because of scarring and inflammation); PET—most gastric adenocarcinomas
avidly take up fluorodeoxyglucose (FDG); sensitivity equivalent to CT in determining metastatic disease but
somewhat better for lymph nodes; plays role in assessing response to additional therapy (shows functional and metabolic
activity); laparoscopic staging—because of propensity for transverse spread, can change staging in 20% to 30% of patients
if used appropriately; can be used to better stage patients on neoadjuvant protocol; can help avoid unnecessary laparotomy,
unless patient candidate for palliative gastric resection; best in T3 and T4 lesions identified by EUS (allows
visualization of peritoneal surfaces; obtain cytology and rapid assay intraoperatively); combined with laparoscopic US,
can compensate for lack of tactile sensation and limited surface inspection
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| Surgical treatment: resection of primary tumor and draining lymph nodes primary therapy; if tumor proximal or diffuse,
total gastrectomy preferred; gastric cancer has high propensity to travel in submucosal lymphatics proximally, and pylorus
effective barrier for distal spread (need 5-cm margin proximally); involves total gastrectomy for proximal tumors; distal
tumors can be treated with subtotal gastrectomy (facilitates construction of anastomosis and may lessen sequelae from total
gastrectomy); Italian study—>600 patients randomized to total or subtotal gastrectomy; mortality same, but quality of
life somewhat better in subtotal group; in United States—proximal migration of tumors; although overall incidence decreasing
dramatically, increasing incidence of biologically aggressive tumors of cardia (reason unknown) in subgroup of
young white patients; can usually perform gastrectomy without thoracotomy; if need to go higher, sometimes have to enter
right chest and remove esophagus to get clear margin; with total gastrectomy, standard reconstruction Roux-en-Y esophagojejunostomy
(diverts bile away from esophagus); with subtotal gastrectomy, Billroth II anastomosis (possible bile gastritis
and development of stump cancer); Roux stasis syndrome—nausea and intermittent vomiting related to bypassing
of duodenal pacemaker and myoelectric activity in small bowel; Braun enteroenterostomy—reduces bile reflux in stomach,
but results in slight impairment of gastric emptying (easier to treat); little data to support long-term effect on clinical
outcome; gastric reservoir—to possibly improve nutritional status; number of prospective studies show no significant
short-term difference in mortality, anastomotic leak, and Visick score
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| Gastric cancer in United States vs Japan: in United States, most patients (two thirds) present with T3 and T4 lesions,
and 90% have node-positive disease; resectability rate 70%; in Japan, 66% of patients present with early gastric
cancer confined to mucosa and submucosa; in United States, <5% of resections D2 resections (standard of care in Japan);
mortality higher and 5-yr survival lower in United States; disparity attributed to inherent biologic differences, fact that
Western patient tends to be older, heavier and with more comorbidities, and volume-outcome differences (more gastric
resections performed in Japan); Japan Research Society for Gastric Cancer (JRSGC)—extensively studied lymphatic
drainage of stomach and divided into 16 nodal stations (correspond to N groupings); goal to get 1 station ahead of where
disease located; British Medical Research Council Trial and Dutch Gastric Trial—showed morbidity and mortality
of extended dissection higher, with no improvement in overall survival, but staging more accurate; morbidity and mortality
tied to concomitant distal pancreatectomy and splenectomy
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| Minimally invasive approaches to staging and treatment: endoscopic mucosal resection—more sophisticated
techniques performed in Japan; sentinel node biopsy—if sentinel node tumor-free, 95% likelihood that rest of
nodes in base tumor-free (can spare node-negative patients morbidity of node dissection; premise in melanoma and
breast cancer; question whether premise holds true in gastric cancer); sentinel node biopsy allows more intense pathologic
examination of node, but clinical significance questionable; laparoscopic resection—advantages include
shorter hospital stay, less pain, and improved pulmonary and immune function; disadvantages include steep learning
curve, increased cost, and increased operative time; combining techniques (eg, laparoscopic resection and sentinel
node biopsy) done in Japan but need multi-institutional validation trials
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| Summary: significant differences between Eastern and Western hemispheres in incidence, presentation, and management;
EUS, laparoscopy, PET, and CT important staging tools; total gastrectomy not always required; although data show D2
resection not of proven benefit, may be subset in which it is; minimally invasive approaches being integrated into practice
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Educational Objectives
| The goal of this program is to educate the listener about the epidemiology, diagnosis, and treatment of pancreatic and
gastric cancer. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Recognize the risk factors for pancreatic cancer and discuss why its prognosis is extremely poor.
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| 2. Employ the treatment algorithm and procedures for pancreatic cancer.
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| 3. Describe future treatments and developments in pancreatic cancer.
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| 4. Assess current surgical options for treating gastric cancer.
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| 5. Discuss minimally invasive approaches to staging and treatment of gastric cancer.
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Discussed on This Program
Bevacizumab [Avastin]
Capecitabine [Xeloda]
Cisplatin (CDDP) [Platinol-AQ]
Fluorouracil (5-fluorouracil, 5-FU) [Adrucil, Carac, Efudex, Fluoroplex]
Gemcitabine HCl [Gemzar]
Interferon alfa-2a, recombinant (rIFN-A; IFLrA) [Roferon-A]
Interferon alfa-2b (recombinant) (IFN-alpha 2; rIFN-⓬ α-2-interferon) [Intron A]
Suggested Reading
Ajani JA: Standard of care for gastric cancer based on meta-analysis? Treading on thin ice or it is very nice! J Clin
Oncol 24:5473, 2006; Amin Z et al: Diagnosing pancreatic cancer: the role of percutaneous biopsy and CT. Clin
Radiol 61:996, 2006; available. Derosier LC et al: Treatment with gemcitabine and TRA-8 anti-death receptor-5
mAb reduces pancreatic adenocarcinoma cell viability in vitro and growth in vivo. J Gastrointest Surg 10:1291,
2006; Ito Y et al: Evaluation of acute intestinal toxicity in relation to the volume of irradiated small bowel in patients
treated with concurrent weekly gemcitabine and radiotherapy for locally advanced pancreatic cancer. Anticancer
Res 26:3755, 2006; Knab B et al: Intensity-modulated radiotherapy for neoadjuvant treatment of gastric cancer.
Med Dosim 31:292, 2006; Krishnan S et al: Prognostic factors in patients with unresectable locally advanced pancreatic
adenocarcinoma treated with chemoradiation. Cancer 107:2589, 2006; Latchford A et al: Peutz-Jeghers
syndrome and screening for pancreatic cancer. Br J Surg 93:1446, 2006; Matsumoto J et al: Exocrine function following
the Whipple operation as assessed by stool elastase. J Gastrointest Surg 10:1225, 2006; Oba K et al: Efficacy
of adjuvant chemotherapy using oral fluorinated pyrimidines for curatively resected gastric cancer: a meta-
analysis of centrally randomized controlled clinical trials in Japan. J Chemother 18:311, 2006; Papadia FS et al:
Gastric Cancer and Roux-en-Y Gastric Bypass. Obes Surg 16:1552, 2006; Riall TS et al: Pancreatic cancer in the
general population: improvements in survival over the last decade. J Gastrointest Surg 10:1212, 2006; Rustgi AK:
The molecular pathogenesis of pancreatic cancer: clarifying a complex circuitry. Genes Dev 20:3049, 2006;
Toshimitsu H et al: Molecular features linked to the growth-inhibitory effects of gemcitabine on human pancreatic
cancer cells. Oncol Rep 16:1285, 2006; Tran QN et al: Endoscopic ultrasound-guided celiac plexus neurolysis for
pancreatic cancer pain: a single-institution experience and review of the literature. J Support Oncol 4:460, 2006;
Winter JM et al: 1423 pancreaticoduodenectomies for pancreatic cancer: a single-institution experience. J Gastrointest
Surg 10:1199, 2006; Xie DR et al: Meta-analysis on inoperable pancreatic cancer: A comparison between
gemcitabine-based combination therapy and gemcitabine alone. World J Gastroenterol 12:6973, 2006; Yahagi N et
al: How useful is EUS in patients with gastric cancer? Nat Clin Pract Gastroenterol Hepatol 3:666, 2006; No abstract
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. Wang and Lind were recorded at Medical and Surgical Approaches to GI Disorders, held July 10-14, 2006, at
Kiawah Island, SC. The Audio-Digest Foundation thanks the speakers and the Medical College of Georgia, Division
of Continuing Medical Education and School of Medicine for their cooperation in the production of this program.
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