Ampullary Carcinoma: Treatment and Prognosis

8/13/2019 Ampullary Carcinoma: Treatment and Prognosis

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14/11/13, 21:47Ampullary carcinoma: Treatment and prognosis

Pgina 1 de 24http://www.uptodate.com/contents/ampullary-carcinoma-treatment-duodenectomy&selectedTitle=3%7E47&view=print&displayedView=full

Official reprint from UpToDate

www.uptodate.com2013 UpToDate

AuthorsDavid P Ryan, MDHarvey Mamon, MD, PhDCarlos Fernandez-del Castillo, MD

Section EditorKenneth K Tanabe, MD

Deputy EditorDiane MF Savarese, MD

Ampullary carcinoma: Treatment and prognosis

Disclosures

All topics are updated as new evidence becomes available and our peer review processis complete.Literature review current through:Oct 2013. | This topic last updated:Nov 8, 2013.

INTRODUCTION Periampullary tumors are neoplasms that arise in the vicinity of the ampulla of Vater. Neoplasms

that arise in this site can originate from the pancreas, duodenum, distal common bile duct (CBD), or the structures of

the ampullary complex.

The ampulla of Vater is formed by the duodenal aspect of the sphincter of Oddi muscle, which surrounds the

confluence of the distal CBD and main pancreatic duct as well as the papilla of Vater, a mucosal papillary mound at

the distal insertion of these ducts on the medial wall of the duodenum (figure 1). Ampullary carcinomas are defined

as those that arise within the ampullary complex, distal to the confluence of the distal common bile duct and the

pancreatic duct (figure 2).

It can be difficult to distinguish a primary ampullary carcinoma from other periampullary tumors preoperatively.

However, true ampullary cancers have a better prognosis than periampullary malignancies of pancreatic or bile duct

origin. Resectability rates are higher, and five-year survival rates are approximately 30 to 50 percent in patients with

limited lymph node involvement. In contrast, fewer than 10 percent of patients with completely resected node-

positive pancreatic cancer are alive at two years. Thus, an aggressive approach to diagnosis and treatment of

periampullary tumors is needed to ensure that patients with these comparatively favorable cancers are treated

optimally.

This topic review will cover the treatment and prognosis of ampullary carcinomas. The epidemiology, biologic

behavior, clinical manifestations, diagnosis and staging are covered separately. (See "Ampullary carcinoma:

Epidemiology, clinical manifestations, diagnosis and staging".)

TREATMENT FOR LOCALIZED DISEASE The only potentially curative treatment for ampullary carcinoma is

surgical resection. Complete tumor resection with negative margins (R0 resection) is a prerequisite for cure.

Pancreaticoduodenectomy Pancreaticoduodenectomy (Whipple operation) is considered the standard approach

for ampullary cancer (figure 3). This can be done as a pylorus-preserving procedure or as a conventional

pancreaticoduodenectomy, which includes an antrectomy (figure 4). Although some authors claim advantages of a

pylorus-preserving procedure because of a shorter operative time and less intraoperative blood loss [1], this is based

on European variations of the technique which require creation of a Roux-en-Y to anastomose separately the gastric

from the pancreatic and biliary anastomosis. Otherwise, there are no differences in long-term survival, and some

series have shown higher incidence of delayed gastric emptying with the pylorus preservation. The impact of a

pylorus-preserving procedure on long-term gastrointestinal function is less certain. Some studies suggest an

improved nutritional state (as reflected by faster weight gain in the first postoperative year), but results have been

inconsistent. (See "Pancreaticoduodenectomy (Whipple procedure): Techniques"and "Surgery in the treatment of

exocrine pancreatic cancer and prognosis", section on 'Pancreaticoduodenectomy'.)

Surgical outcomes from pancreaticoduodenectomy for ampullary cancer have improved over time. In contemporary


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single-institution series, rates of potentially curative resection have increased from approximately 80 to over 90

percent [2-6]. Long-term survival is possible after pancreaticoduodenectomy, even for patients with lymph node

metastases or invasion beyond the duodenal wall (T3 disease, (table 1)). (See 'Prognosis'below.)

Although pancreaticoduodenectomy has been associated with high perioperative morbidity and mortality rates in the

past, contemporary series show that in experienced hands, perioperative (30-day) mortality rates are between 0 and

5 percent [2-10]. Perioperative morbidity rates are between 20 and 40 percent, with the most common problems

being pneumonia, intraabdominal infection, anastomotic (pancreatic) leak, and delayed gastric emptying [11,12].(See 'Complications'below.)

These improved outcomes have been attributed to better operative technique and postoperative care. One of the

most important reasons for this is the greater experience of a limited number of surgeons who perform the procedure

regularly in high-volume institutions [13-15]. Good outcomes have been described even in patients older than 80

years in such centers. However, even within high-volume hospitals, operative mortality rates from

pancreaticoduodenectomy vary considerably depending upon the experience of the individual surgeon [16].

Preoperative biliary drainage The most common presenting symptom of ampullary carcinoma is obstructive

jaundice (80 percent) caused by compression of the distal bile duct by the tumor. (See "Ampullary carcinoma:

Epidemiology, clinical manifestations, diagnosis and staging".)

The role of preoperative biliary drainage in patients with periampullary tumors is controversial. Because obstructive

jaundice can impair hepatic, renal, and immune function, it was hoped that preoperative relief of jaundice would

correct these defects and decrease postoperative morbidity and mortality rates from pancreaticoduodenectomy.

However, the available data from randomized trials of preoperative drainage versus no drainage are conflicting.

Furthermore, three meta-analyses examining the benefit of preoperative biliary drainage for patients with obstructive

jaundice have come to different conclusions, with one finding neither an adverse nor a favorable impact of

preoperative stenting on the incidence of postoperative morbidity or mortality, another finding an overall adverse

impact of stenting on the postoperative complication rate, and the third, significantly fewer postoperative

complications in the stented group but no impact on postsurgical mortality. (See "Pancreaticoduodenectomy

(Whipple procedure): Techniques"and "Surgery in the treatment of exocrine pancreatic cancer and prognosis".)

In the specific setting of ampullary cancer, the benefit of preoperative biliary drainage was addressed in a

retrospective series of 82 patients undergoing potentially curative surgery at a single hospital in Singapore; 35 were

drained preoperatively and 47 were not [17]. Preoperative drainage was associated with a significantly reduced

incidence of postoperative wound infection (3 versus 26 percent), but there was no favorable impact on other

postoperative complications or survival.

Uncertainty as to the benefit of preoperative drainage has led to differing approaches. Some surgeons routinely

decompress jaundiced patients with an endoscopically placed stent prior to surgery. However, others reserve biliary

decompression for selected patients in whom surgery will be delayed or those with debilitating pruritus or a clinical

picture of cholangitis with fever and leucocytosis.

In practice, the majority of patients who present with obstructive jaundice will have been stented by a

gastroenterologist before the diagnosis is established and it is known whether or not the patient is a surgical

candidate; the surgeon usually has little influence on the decision. For those who are not stented, our preference is

to proceed with ERCP and stenting only when there is high grade jaundice (>15 mg/dl of bilirubin) and surgery will

not take place within the following week.

The prognostic implication of obstructive jaundice at presentation on prognosis is discussed below. (See 'Obstructive

jaundice'below.)

Complications The most frequent treatment-related complication of pancreaticoduodenectomy is pancreatic

fistula, and the rates are higher for patients with ampullary cancer than for pancreas cancer because the pancreaticparenchyma is typically normal in ampullary carcinoma. Other complications include delayed gastric emptying,


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hemorrhage, sepsis, bile leaks, and postoperative diabetes as a result of pancreatic resection. (See

"Pancreaticoduodenectomy (Whipple procedure): Techniques".)

Local resection Many patients with ampullary cancer are elderly and have significant comorbidities. This has

generated interest in less aggressive surgical options, such as local resection or ampullectomy for selected patients.

Experience with this approach is limited to small published series, in which most of the patients were considered

high-risk candidates for surgery [2,18-28]. Comparison of these studies with each other is limited by different

eligibility criteria for ampullectomy and the fact that the extent of surgery (eg, "ampullectomy" versus "local

resection") has not always been clearly specified.

In the aggregate, the available data indicate that local resection is associated with lower morbidity than

pancreaticoduodenectomy, but at the expense of higher recurrence rates and inferior survival, at least in the setting

of invasive disease [11,21,23,29-33].

The largest series included 37 patients who were planned for ampullectomy rather than pancreaticoduodenectomy at

Memorial Sloan-Kettering Cancer Center because of significant comorbidity or a small ampullary lesion (median 1.5

cm, range 0.4 to 4.2 cm) that was thought to represent a benign adenoma after a preoperative biopsy [31].

Intraoperatively, eight cases were converted from ampullectomy to pancreaticoduodenectomy because of disease

extent or a frozen-section finding of invasive tumor. Eight of the 29 patients treated by ampullectomy alone hadinvasive tumor on the final histology; seven recurred, and only one was alive at last follow-up. In contrast, of the 91

patients undergoing pancreaticoduodenectomy during the same time period for invasive adenocarcinoma, 68 were

still alive at the end of the study period, 49 without recurrence.

Early, low-grade tumors In contrast to pancreaticoduodenectomy, ampullectomy does not accomplish

removal of the regional lymph nodes. Because of the low rate of nodal metastases (less than 4 percent in most

series), some have suggested that local resection is a reasonable approach for well-differentiated small (


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Summary While potentially curative in the setting of ampullary adenomas, all three modalities of nonsurgical

treatment provide palliative rather than curative benefit for patients with ampullary carcinoma. These methods are

appropriate only for patients who are not operative candidates and those who refuse surgery.

PROGNOSIS The outcome of resected ampullary cancer depends upon the extent of local invasion, status of thesurgical margins, and the presence or absence of nodal metastases [5,11,48-50]. Five-year survival rates following

pancreaticoduodenectomy range from 64 to 80 percent for patients with node-negative disease, and from 17 to 50

percent for node-positive disease [2,4,7-11,13,18,29,30,51-56].

Five-year overall survival in one retrospective single-institution series, stratified according to surgical stage (table 1)

was as follows [11]:

About two-thirds of patients surviving five years after pancreaticoduodenectomy for ampullary carcinoma are also

alive at 10 years [57].

Outcomes tend to be somewhat worse in population-based analyses. As an example, five-year survival rates

stratified by stage at presentation from a series of 1301 patients with ampullary cancer reported to the National

Cancer Institute SEER (Surveillance, Epidemiology and End Results) database between 1988 and 2003 are

presented in the table (table 2) [50].

These survival data are better than similar presentations for pancreatic cancer, particularly for those with node-

positive disease. It is unclear whether this represents a true difference in biology or earlier presentation of ampullary

cancers due to earlier biliary obstruction. (See "Ampullary carcinoma: Epidemiology, clinical manifestations,

diagnosis and staging", section on 'Epidemiology and biologic behavior'.)

by the inadequacy of biopsy in terms of correct pathologic characterization of the lesion (and therefore its risk

of harboring lymph node metastases) and the inability to predict successful, margin-negative endoscopic

resection [20,41-44].

Endoscopic debulking has been used mainly preoperatively to permit stent insertion and decompression of the

biliary tree. The controversy surrounding the need for preoperative biliary decompression is discussed above

(see 'Preoperative biliary drainage'above).

Laser ablation offers the potential for control of local tumor growth in patients who are unfit for more aggressive

therapy. In one such series of 12 patients with ampullary cancer, duodenal obstruction was relieved in one, and

the longest survival was 36 months (median 21 months) [45].

Compared with laser ablation, photodynamic therapy (PDT) eradicates local tumor with less surrounding tissue

destruction. PDT uses a photosensitizing drug (a hematoporphyrin derivative, Photofrin), which is

disproportionately retained by malignant tissue after intravenous administration. Irradiation with visible light via

a light-transmitting catheter (light-guide) placed through an endoscope and targeted at the tumor energizes the

photosensitizing molecule within the tumor and catalyzes oxygen free-radical generation leading to cell death

[46]. The major side effect of PDT is prolonged cutaneous photosensitivity after the procedure, requiring the

patient to avoid sunlight and wear appropriate clothing to protect the skin for several weeks after treatment.(See "Photodynamic therapy for ablation of Barrett's esophagus".)

In the largest series of PDT involving 10 patients with ampullary cancer, remission was achieved for 8 to 12

months in three who had small tumors confined to the ampulla [47]. Tumor bulk was greatly reduced in four

additional patients, while little effect was observed in the remaining three.

Stage I 84 percent

Stage II 70 percent

Stage III 27 percent

Stage IV 0 percent


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Prognostic factors The following sections will summarize the available data on predictors of recurrence.

Histology In addition to depth of tumor invasion (the T stage, (table 1)) and nodal status, high-grade histology

and positive surgical margins are associated with a worse prognosis [2,6,9,11,18,54,55,58-64]. The incidence of

positive margins is low (3 percent in one series [6]), particularly when compared to the incidence of positive margins

in resected pancreatic adenocarcinoma (40 percent in the same series).

Whether there is a correlation between prognosis and morphologic type (ie, intestinal versus pancreaticobiliary) is

unclear; the available data are conflicting, with some suggesting no difference, and others, a worse prognosis for the

pancreaticobiliary type [65-67].

More recent data suggest that adenocarcinomas of the ampulla of Vater can be subdivided according to histologic

subtype and immunohistochemical staining pattern into distinct subsets with differing biologic behavior. In a

retrospective study of a cohort of 72 patients treated for ampullary adenocarcinoma in Sydney, Australia, those with

a histomolecular pancreaticobiliary phenotype (CDX-negative, MUC1 positive) had a significantly worse outcome

than did those with an intestinal phenotype (CDX-positive, MUC1-negative), median survival 16 versus 116 months

[67]. When histomolecular phenotype was combined with the lymph node status, three subsets of ampullary

adenocarcinomas emerged with significantly different survival outcomes:

The results were comparable in two additional independent cohorts of 90 patients from Glasgow, Scotland, and 46

from Verona, Italy.

Whether and how this information could be used to individualize treatment decisions, particularly with regard toadjuvant therapy, is unclear. The impact of adjuvant therapy on outcomes according to histomolecular phenotype

could not be addressed in the study since only a minority of patients (64 of 208) in all three cohorts received

adjuvant chemotherapy, and it was not randomly assigned. More evidence on the influence of histomolecular

phenotypes in ampullary cancer is needed before conclusions can be drawn [68]. At present, adjuvant therapy

recommendations for patients with ampullary cancer follow guidelines established for pancreatic cancer rather than

intestinal cancer. (See 'Adjuvant therapy'below.)

Nodal metastases The presence of nodal involvement portends a worse prognosis. However, among patients

with nodal metastases, the number of affected nodes, particularly compared to the total number of examined nodes,

is also of prognostic importance [6,60,69-71]:

Five-year survival was also predicted by the LNR:

Patients with a node-negative, non-pancreaticobiliary histomolecular phenotype tumor had an excellentprognosis (five-year survival 88 percent).

Patients with a node-positive, pancreaticobiliary phenotype had a poor prognosis (five-year survival 20

percent).

The remaining patients (node-positive, non-pancreaticobiliary phenotype, node-negative pancreaticobiliary

phenotype) had an intermediate prognosis (five-year survival 47 percent).

In a report of 66 patients undergoing resection for an ampullary cancer, five-year survival rates were similar

among the 13 patients with two or fewer positive lymph nodes and the 38 with node-negative disease

(approximately 50 percent) [60]. In contrast, none of the 15 patients with three or more involved nodes

remained alive beyond 28 months.

The number of involved nodes divided by the total number of examined nodes is referred to as the lymph node

ratio (LNR). One study evaluated the utility of using the LNR for predicting recurrence and survival in 90

patients who underwent resection of ampullary carcinoma [69]. The median number of resected nodes was 16,

and patients with 16 or more examined nodes had a significantly lower recurrence rate and better five-year

survival (81 versus 45 percent) than patients whose pathology material contained 16 or fewer nodes.


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In contrast to other GI tumor sites, the number of lymph nodes does not influence N stage (table 1) [72]. The

implications of these data on the extent of lymph node dissection (ie, whether there is a role for extended

lymphadenectomy) are unclear. A prospective, randomized study of 62 patients who underwent resection of

ampullary carcinoma found no difference in the five-year survival in the group undergoing standard versus extended

lymphadenectomy (56 versus 60 percent) [73]. The authors concluded that the added morbidity of extended

lymphadenectomy could not be justified by the better oncologic outcomes. We agree with this conclusion, and do not

routinely perform extended lymphadenectomy in these patients. The surgeon and pathologist should aim to dissect

and analyze at least 12 lymph nodes.

Obstructive jaundice Patients who present with obstructive jaundice tend to have a worse prognosis. In one

study, five- and ten-year survival rates were 70 and 49 percent, respectively, in patients who did not present with

obstructive jaundice versus 34 and 29 percent, respectively, in patients who were jaundiced at presentation [74].

These data could be interpreted as demonstrating that early detection of ampullary carcinoma prior to the onset of

obstructive jaundice is associated with a better oncologic outcome. The role of preoperative biliary drainage in

patients who present with obstructive jaundice is addressed above (see 'Preoperative biliary drainage'above).

Intraoperative blood transfusion In a systematic review, patients who required intraoperative transfusion of

more than three units of red blood cell units had worse outcomes than those requiring less blood [75]. However,

patients who require transfusion tend to be sicker as a group (or their tumors are more advanced, requiring more

intraoperative dissection) than those who do not require transfusion. Therefore, the independent contribution of

intraoperative blood transfusion to outcomes remains uncertain.

Tumor marker elevation Elevated preoperative levels of the serum tumor markers CA 19-9 and CEA are

associated with a poorer prognosis relative to individuals with normal values [52,76]. In one study, the optimal cutoff

levels of CA 19-9 to stratify risk for disease recurrence was >150 units/mL in non-jaundiced patients and >300

units/mL in the presence of cholestasis [76]. (See "Ampullary carcinoma: Epidemiology, clinical manifestations,

diagnosis and staging", section on 'Serum tumor markers'.)

Patterns of recurrence In many series, recurrences are about evenly split between locoregional recurrence and

distant spread [10,77], although others note a predominance of distant metastases [52,63]. The risk factors for

locoregional and distant recurrence are slightly different. This was shown in a series of 127 patients who underwent

pancreaticoduodenectomy with regional lymphadenectomy for ampullary carcinoma [10]. The median time to

recurrence was 11.4 months, and the risk factors for locoregional recurrence were the presence of pancreatic

invasion and tumor size. In contrast, lymph node metastasis was the sole risk factor for distant recurrence. Bothpancreatic invasion and lymph node involvement were significant predictors of inferior survival.

The most common site of distant spread is the liver, but other sites include peritoneum, bone, supraclavicular lymph

nodes and lung [10,52,77].

ADJUVANT THERAPY Despite the high rate of potentially curative resections in contemporary series, more than

one-half of patients die from recurrent disease, suggesting the need for effective adjuvant therapy. There are few

published data to guide the use of adjuvant therapy in patients with resected ampullary cancer.

Chemoradiotherapy Benefit from postoperative chemoradiotherapy in patients with completely resected disease

has been suggested in several uncontrolled series [58,78-83]. In one of the largest reports from the Mayo Clinic, 29

of 125 patients who underwent definitive surgery for an ampullary cancer received adjuvant RT with concurrent 5-FU, while the remainder received no adjuvant therapy [78]. In multivariate analysis, lymph node status emerged as

LNR = 0 75 percent

LNR >0 to 0.2 49 percent

LNR >0.2 to 0.4 38 percent

LNR >0.4 0 percent


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the only significant predictor of outcome. Overall survival rates at one, three, and five years in the adjuvant therapy

group were 91, 54, and 48 percent, compared to 66, 22, and 11 percent in the control group. Within the high-risk

node-positive subgroup (n = 54), the 24 patients who received adjuvant therapy survived significantly longer than the

30 who did not receive it.

On the other hand, other retrospective comparisons [84,85], and the only phase III randomized trial that included a

substantial number of patients with ampullary carcinoma have failed to show a benefit for postoperative

chemoradiotherapy. In a trial from the EORTC, 218 patients with resected pancreatic or other periampullary cancerswere randomly assigned to postoperative RT (40 Gy in split courses) plus concurrent 5-FU (25 mg/kg per day by

continuous infusion) or observation [86]. For the 104 periampullary cancers (which included cancers of the ampulla,

distal common bile duct or duodenum), there was no difference in the two-year survival rate (67 versus 63 percent)

or in the incidence of locoregional recurrence in the treated patients compared to controls. (See "Adjuvant and

neoadjuvant therapy for exocrine pancreatic cancer", section on 'EORTC study'.)

Chemotherapy alone The benefit of adjuvant chemotherapy for resected ampullary adenocarcinomas was

directly studied in the international ESPAC-3 trial, in which 428 patients with periampullary malignancies (297

ampullary, 96 bile duct, 35 other) were randomly assigned to one of three arms: observation alone, leucovorin-

modulated 5-FU (six courses of leucovorin 20 mg/m IV bolus followed by 5-FU 425 mg/m , daily for five days, once

per month), or single agent gemcitabine(1000 mg/m weekly for three of every four weeks for six months) [87]. Acomplete (R0) resection was achieved in 84 percent of patients, and 59 percent had node-positive disease.

The use of adjuvant chemotherapy was associated with a potentially meaningful overall survival advantage but it

was not statistically significant (median 43 versus 35 months, HR 0.86, 95% CI 0.66 to 1.11). Although of a greater

magnitude, the difference in median survival between gemcitabine-treated and observed patients was still not

statistically significant (median 46 versus 35 months, HR 0.77, 95% CI 0.57-1.05). However, in secondary

multivariate analysis adjusting for predefined prognostic variables, there was a statistically significant survival benefit

for any chemotherapy (HR for death 0.75, 95% CI 0.57-0.98) and for gemcitabine alone (HR 0.70, 95% CI 0.51-

0.97). Furthermore, when the analysis was restricted to patients with ampullary cancer, those treated with

gemcitabine had a median survival that was almost twice as long as those in the observation group (median 71

versus 41 months); the median survival in the FU/leucovoringroup was 57.8 months. Posthoc analysis did not show

differential treatment responsiveness based upon histologic subtype.

There was no difference in overall survival between the chemotherapy arms, but grade 3 or 4 stomatitis (11 versus 0

percent) and diarrhea (14 versus 4 percent) were significantly more common with leucovorin-modulated FU, and

there were more serious adverse effects in the FU group as well.

The only other randomized trial that addressed the benefit of adjuvant chemotherapy was a multicenter randomized

trial from Japan that compared surgery with and without postoperative chemotherapy (two courses of mitomycinC

plus infusional 5-FU, followed by prolonged oral administration of 5-FU until tumor progression) in 508 patients with

pancreaticobiliary tract cancer (56 with ampullary cancer) [88]. A significant survival benefit for adjuvant

chemotherapy was seen in the patients with gallbladder cancer (5-year survival 26 versus 14 percent), but not inthose with ampullary cancer (five-year survival 28 versus 34 percent in the chemotherapy and control groups,

respectively).

Summary The results of clinical trials are not definitive, and there is no consensus regarding the optimal

management of patients after resection of an ampullary cancer. Recommendations for management of ampullary

carcinoma are not included in published guidelines from either the NCCN [39] or ESMO [40].

Many clinicians do not recommend adjuvant chemoradiotherapy or chemotherapy for resected ampullary cancers,

citing the more favorable prognosis of ampullary as compared to other biliary tract cancers [59,89] and the lack of

data from randomized trials proving a survival advantage. However, we suggest that these patients be managed in a

manner similar to the approach used for resected pancreatic cancer, even for those who have the intestinalhistomolecular phenotype. (See 'Histology'above.)

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The approach differs in Europe and in the United States. Based upon the ESPAC-1 trial [90], which showed that 5-

FU-containing chemotherapy (but not chemoradiotherapy) prolongs survival in resected pancreatic cancer, results of

the German CONKO trial [91] showing a survival benefit from adjuvant gemcitabinein the same patient population,

and the report of the ESPAC-3 trial, which suggests a potentially clinically meaningful but statistically insignificant

improvement in overall with adjuvant gemcitabine or leucovorin-modulated 5-FU [87], most European clinicians use

chemotherapy alone after resection of either a pancreatic or ampullary cancer. (See "Adjuvant and neoadjuvant

therapy for exocrine pancreatic cancer".)

The American approach differs with regard to chemoradiotherapy. We treat all patients with resected ampullary

cancer stage IB or higher (table 1) like we do those with resected pancreatic adenocarcinoma using concurrent

chemoradiotherapy with infusional 5-FU. Given the risk for distant recurrence and the results from RTOG 9704 [92],

combined with those from the German CONKO trial [91], we also add a course of gemcitabineadjuvant

chemotherapy to chemoradiotherapy, as we do in patients with pancreatic adenocarcinoma, although this approach

remains unproven for resected ampullary tumors. (See "Adjuvant and neoadjuvant therapy for exocrine pancreatic

cancer".)

As with pancreatic cancer, the optimal way to sequence 5-FU-based chemoradiotherapy and gemcitabinealone is

unclear. An acceptable regimen is that used in RTOG 9704, which consists of three weekly doses of gemcitabine

alone (1000 mg/m per week), followed by chemoradiotherapy with concurrent infusional 5-FU (250 mg/m daily),and starting three to five weeks later, three months of single agent gemcitabine (1000 mg/m weekly for three of

every four weeks) [92]. (See "Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer".)

Initial 5-FU-based chemoradiotherapy followed by four months of gemcitabinealone is an acceptable alternative, as

is concurrent 5-FU-based chemoradiotherapy alone, an approach used for resected extrahepatic

cholangiocarcinoma. (See "Treatment of localized cholangiocarcinoma: Surgical management and adjuvant

therapy".)

POSTTREATMENT SURVEILLANCE Posttreatment surveillance to detect recurrent or persistent disease is

performed at regular intervals, although the optimal surveillance strategy is undefined [39]. NCCN guidelines are not

available. Many clinicians follow patients every six months for five years and annually thereafter. Follow-up visitsusually include history and clinical examination, and serum tumor markers (typically CEA and CA 19-9). The utility of

periodic CT scan of the abdomen is unclear.

While the need for endoscopic surveillance is universally accepted, most published recommendations are similar to

those reported after local resection of ampullary adenomas. A reasonable approach is surveillance endoscopy every

six months for two years, then annually for an additional three to five years. (See "Treatment of ampullary

adenomas".)

CHEMOTHERAPY FOR ADVANCED DISEASE Limited data exist to guide physicians in the choice of

chemotherapy, largely because of the rarity of this disease. Much of the data on chemotherapy for advanced

ampullary cancer are in combined series that include patients with small bowel, pancreatic and ampullary

adenocarcinomas, or more commonly, ampullary plus biliary tract cancers. However, particularly because of recent

advances in treatment of advanced disease, the distinction as to whether periampullary tumors are of intestinal,

biliary, or pancreatic origin is particularly important for the selection of the treatment approach. (See "Treatment of

small bowel neoplasms", section on 'Unresectable or metastatic disease'and "Systemic therapy for advanced

cholangiocarcinoma"and "Chemotherapy for advanced exocrine pancreatic cancer", section on '5-FU plus irinotecan

and/or oxaliplatin'.)

There is no consensus on the best management for patients with advanced ampullary carcinoma. Patients with

ampullary cancer were included in the ABC trial of gemcitabinewith and without cisplatin, although they represented

a small minority [93]. There was a significant survival advantage to the combination both in terms of progression-free

and overall survival, compared to gemcitabine alone. Many consider this to represent the standard regimen foradvanced ampullary as well as biliary tract cancers, although others disagree, treating these patients more like those

with advanced pancreatic cancer or small bowel adenocarcinoma [94]. (See "Systemic therapy for advanced

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Metastatic disease Distinction as to whether periampullary tumors are of intestinal, biliary, or pancreatic origin is

particularly important in patients with metastatic disease as the approach differs. The optimal regimen for systemic

therapy of true ampullary tumors has not been established. Based upon the results of the ABC trial, the combination

of gemcitabineplus cisplatinis a reasonable approach for patients who are able to tolerate it. Others use a single

agent gemcitabine initially (table 4) followed by an oxaliplatin-based regimen, or vice versa, in a manner similar to

treatment of pancreatic cancer. (See 'Chemotherapy for advanced disease'above.)

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14. Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital volume and surgical mortality in the United States. NEngl J Med 2002; 346:1128.

The optimal way to sequence 5-FU-based chemoradiotherapy and gemcitabinechemotherapy is unclear.

An acceptable regimen is that used in the RTOG 9704 trial [92], which consists of three weekly doses of

gemcitabine alone (1000 mg/m per week), followed by chemoradiotherapy using concurrent infusional 5-

FU. Although the RTOG trial used 250 mg/m daily continuously, many clinicians, including our group,

consider this too toxic and use 225 mg/m daily, five days per week. Following chemoradiotherapy and

starting three to five weeks later, three months of single agent gemcitabine (table 3) are given. An

alternative approach that is often used for pancreatic cancer is to administer all six months of

chemotherapy upfront and to pursue concurrent fluoropyrimidine-based chemoradiotherapy only forpatients who remain free of metastatic disease. (See "Adjuvant and neoadjuvant therapy for exocrine

pancreatic cancer", section on 'Gemcitabine-based approaches'and "Treatment protocols for

hepatobiliary cancer".)

2

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15. Birkmeyer JD, Warshaw AL, Finlayson SR, et al. Relationship between hospital volume and late survival afterpancreaticoduodenectomy. Surgery 1999; 126:178.

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24. Gray G, Browder W. Villous tumors of the ampulla of Vater: local resection versus pancreatoduodenectomy.South Med J 1989; 82:917.

25. Sharp KW, Brandes JL. Local resection of tumors of the ampulla of Vater. Am Surg 1990; 56:214.

26. Newman RJ, Pittam MR. Local excision in the treatment of carcinoma of the ampulla of Vater. J R Coll SurgEdinb 1982; 27:154.

27. Kahn MB, Rush BF Jr. The overlooked technique of ampullary excision. Surg Gynecol Obstet 1989; 169:253.

28. Asbun HJ, Rossi RL, Munson JL. Local resection for ampullary tumors. Is there a place for it? Arch Surg 1993;128:515.

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30. Tarazi RY, Hermann RE, Vogt DP, et al. Results of surgical treatment of periampullary tumors: a thirty-five-yearexperience. Surgery 1986; 100:716.

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34. Bttger TC, Boddin J, Heintz A, Junginger T. Clinicopathologic study for the assessment of resection forampullary carcinoma. World J Surg 1997; 21:379.

35. Woo SM, Ryu JK, Lee SH, et al. Feasibility of endoscopic papillectomy in early stage ampulla of Vater cancer.J Gastroenterol Hepatol 2009; 24:120.

36. Yamaguchi K, Enjoji M. Carcinoma of the ampulla of vater. A clinicopathologic study and pathologic staging of109 cases of carcinoma and 5 cases of adenoma. Cancer 1987; 59:506.

37. Clary BM, Tyler DS, Dematos P, et al. Local ampullary resection with careful intraoperative frozen sectionevaluation for presumed benign ampullary neoplasms. Surgery 2000; 127:628.

38. Hornick JR, Johnston FM, Simon PO, et al. A single-institution review of 157 patients presenting with benignand malignant tumors of the ampulla of Vater: management and outcomes. Surgery 2011; 150:169.

39. National Comprehensive Cancer Network (NCCN) guidelines. Available at: www.nccn.org (Accessed on May15, 2013).

40. Eckel F, Jelic S. Biliary cancer: ESMO clinical recommendation for diagnosis, treatment and follow-up. AnnOncol 2009; 20(4 suppl):iv46.

41. Kozarek RA. Endoscopic resection of ampullary neoplasms. J Gastrointest Surg 2004; 8:932.


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42. Boix J, Lorenzo-Ziga V, Moreno de Vega V, et al. Endoscopic resection of ampullary tumors: 12-year reviewof 21 cases. Surg Endosc 2009; 23:45.

43. Menzel J, Poremba C, Dietl KH, et al. Tumors of the papilla of Vater--inadequate diagnostic impact ofendoscopic forceps biopsies taken prior to and following sphincterotomy. Ann Oncol 1999; 10:1227.

44. Yamaguchi K, Enjoji M, Kitamura K. Endoscopic biopsy has limited accuracy in diagnosis of ampullary tumors.Gastrointest Endosc 1990; 36:588.

45. Fowler AL, Barham CP, Britton BJ, Barr H. Laser ablation of ampullary carcinoma. Endoscopy 1999; 31:745.

46. Sibata CH, Colussi VC, Oleinick NL, Kinsella TJ. Photodynamic therapy in oncology. Expert OpinPharmacother 2001; 2:917.

47. Abulafi AM, Allardice JT, Williams NS, et al. Photodynamic therapy for malignant tumours of the ampulla ofVater. Gut 1995; 36:853.

48. Benhamiche AM, Jouve JL, Manfredi S, et al. Cancer of the ampulla of Vater: results of a 20-year population-based study. Eur J Gastroenterol Hepatol 2000; 12:75.

49. Sellner FJ, Riegler FM, Machacek E. Implications of histological grade of tumour for the prognosis of radicallyresected periampullary adenocarcinoma. Eur J Surg 1999; 165:865.

50. O'Connell JB, Maggard MA, Manunga J Jr, et al. Survival after resection of ampullary carcinoma: a nationalpopulation-based study. Ann Surg Oncol 2008; 15:1820.

51. Neoptolemos JP, Talbot IC, Shaw DC, Carr-Locke DL. Long-term survival after resection of ampullarycarcinoma is associated independently with tumor grade and a new staging classification that assesses localinvasiveness. Cancer 1988; 61:1403.

52. Todoroki T, Koike N, Morishita Y, et al. Patterns and predictors of failure after curative resections of carcinomaof the ampulla of Vater. Ann Surg Oncol 2003; 10:1176.

53. Willett CG, Warshaw AL, Convery K, Compton CC. Patterns of failure after pancreaticoduodenectomy forampullary carcinoma. Surg Gynecol Obstet 1993; 176:33.

54. Talamini MA, Moesinger RC, Pitt HA, et al. Adenocarcinoma of the ampulla of Vater. A 28-year experience.Ann Surg 1997; 225:590.

55. Delcore R Jr, Connor CS, Thomas JH, et al. Significance of tumor spread in adenocarcinoma of the ampulla ofVater. Am J Surg 1989; 158:593.

56. Shutze WP, Sack J, Aldrete JS. Long-term follow-up of 24 patients undergoing radical resection for ampullarycarcinoma, 1953 to 1988. Cancer 1990; 66:1717.

57. Yamaguchi K, Enjoji M, Tsuneyoshi M. Pancreatoduodenal carcinoma: a clinicopathologic study of 304patients and immunohistochemical observation for CEA and CA19-9. J Surg Oncol 1991; 47:148.

58. Lee JH, Whittington R, Williams NN, et al. Outcome of pancreaticoduodenectomy and impact of adjuvanttherapy for ampullary carcinomas. Int J Radiat Oncol Biol Phys 2000; 47:945.

59. Albores-Saavedra J, Schwartz AM, Batich K, Henson DE. Cancers of the ampulla of vater: demographics,morphology, and survival based on 5,625 cases from the SEER program. J Surg Oncol 2009; 100:598.

60. Roder JD, Schneider PM, Stein HJ, Siewert JR. Number of lymph node metastases is significantly associatedwith survival in patients with radically resected carcinoma of the ampulla of Vater. Br J Surg 1995; 82:1693.

61. Mori K, Ikei S, Yamane T, et al. Pathological factors influencing survival of carcinoma of the ampulla of Vater.Eur J Surg Oncol 1990; 16:183.

62. Park JS, Yoon DS, Kim KS, et al. Factors influencing recurrence after curative resection for ampulla of Vatercarcinoma. J Surg Oncol 2007; 95:286.

63. Kim RD, Kundhal PS, McGilvray ID, et al. Predictors of failure after pancreaticoduodenectomy for ampullarycarcinoma. J Am Coll Surg 2006; 202:112.

64. Qiao QL, Zhao YG, Ye ML, et al. Carcinoma of the ampulla of Vater: factors influencing long-term survival of127 patients with resection. World J Surg 2007; 31:137.

65. Zhou H, Schaefer N, Wolff M, Fischer HP. Carcinoma of the ampulla of Vater: comparativehistologic/immunohistochemical classification and follow-up. Am J Surg Pathol 2004; 28:875.

66. Kim WS, Choi DW, Choi SH, et al. Clinical significance of pathologic subtype in curatively resected ampulla ofvater cancer. J Surg Oncol 2012; 105:266.


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67. Chang DK, Jamieson NB, Johns AL, et al. Histomolecular phenotypes and outcome in adenocarcinoma of theampulla of vater. J Clin Oncol 2013; 31:1348.

68. Arroyo GF. Histomolecular phenotypes of adenocarcinoma of the ampulla of vater: more evidence is required.J Clin Oncol 2013; 31:3842.

69. Falconi M, Crippa S, Domnguez I, et al. Prognostic relevance of lymph node ratio and number of resectednodes after curative resection of ampulla of Vater carcinoma. Ann Surg Oncol 2008; 15:3178.

70. Sierzega M, Nowak K, Kulig J, et al. Lymph node involvement in ampullary cancer: the importance of the

number, ratio, and location of metastatic nodes. J Surg Oncol 2009; 100:19.

71. Sakata J, Shirai Y, Wakai T, et al. Number of positive lymph nodes independently affects long-term survivalafter resection in patients with ampullary carcinoma. Eur J Surg Oncol 2007; 33:346.

72. American Joint Committee on Cancer Staging Manual, 7th, Edge SB, Byrd DR, Compton CC, et al (Eds),Springer, New York 2010. p.235.

73. Yeo CJ, Cameron JL, Lillemoe KD, et al. Pancreaticoduodenectomy with or without distal gastrectomy andextended retroperitoneal lymphadenectomy for periampullary adenocarcinoma, part 2: randomized controlledtrial evaluating survival, morbidity, and mortality. Ann Surg 2002; 236:355.

74. Kamisawa T, Tu Y, Egawa N, et al. Clinicopathologic features of ampullary carcinoma without jaundice. J ClinGastroenterol 2006; 40:162.

75. Yao HS, Wang Q, Wang WJ, Hu ZQ. Intraoperative allogeneic red blood cell transfusion in ampullary canceroutcome after curative pancreatoduodenectomy: a clinical study and meta-analysis. World J Surg 2008;32:2038.

76. Smith RA, Ghaneh P, Sutton R, et al. Prognosis of resected ampullary adenocarcinoma by preoperative serumCA19-9 levels and platelet-lymphocyte ratio. J Gastrointest Surg 2008; 12:1422.

77. Balachandran P, Sikora SS, Kapoor S, et al. Long-term survival and recurrence patterns in ampullary cancer.Pancreas 2006; 32:390.

78. Bhatia S, Miller RC, Haddock MG, et al. Adjuvant therapy for ampullary carcinomas: the Mayo Clinicexperience. Int J Radiat Oncol Biol Phys 2006; 66:514.

79. Mehta VK, Fisher GA, Ford JM, et al. Adjuvant chemoradiotherapy for "unfavorable" carcinoma of the ampullaof Vater: preliminary report. Arch Surg 2001; 136:65.

80. Chakravarthy A, Abrams RA, Yeo CJ, et al. Intensified adjuvant combined modality therapy for resectedperiampullary adenocarcinoma: acceptable toxicity and suggestion of improved 1-year disease-free survival.Int J Radiat Oncol Biol Phys 2000; 48:1089.

81. Krishnan S, Rana V, Evans DB, et al. Role of adjuvant chemoradiation therapy in adenocarcinomas of theampulla of vater. Int J Radiat Oncol Biol Phys 2008; 70:735.

82. Kim K, Chie EK, Jang JY, et al. Role of adjuvant chemoradiotherapy for ampulla of Vater cancer. Int J RadiatOncol Biol Phys 2009; 75:436.

83. Palta M, Patel P, Broadwater G, et al. Carcinoma of the ampulla of Vater: patterns of failure following resectionand benefit of chemoradiotherapy. Ann Surg Oncol 2012; 19:1535.

84. Sikora SS, Balachandran P, Dimri K, et al. Adjuvant chemo-radiotherapy in ampullary cancers. Eur J Surg

Oncol 2005; 31:158.85. Zhou J, Hsu CC, Winter JM, et al. Adjuvant chemoradiation versus surgery alone for adenocarcinoma of the

ampulla of Vater. Radiother Oncol 2009; 92:244.

86. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection ofcancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancercooperative group. Ann Surg 1999; 230:776.

87. Neoptolemos JP, Moore MJ, Cox TF, et al. Effect of adjuvant chemotherapy with fluorouracil plus folinic acid orgemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3periampullary cancer randomized trial. JAMA 2012; 308:147.

88. Takada T, Amano H, Yasuda H, et al. Is postoperative adjuvant chemotherapy useful for gallbladdercarcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected

pancreaticobiliary carcinoma. Cancer 2002; 95:1685.89. Nathan H, Pawlik TM, Wolfgang CL, et al. Trends in survival after surgery for cholangiocarcinoma: a 30-year

population-based SEER database analysis. J Gastrointest Surg 2007; 11:1488.


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90. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapyafter resection of pancreatic cancer. N Engl J Med 2004; 350:1200.

91. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patientsundergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 2007; 297:267.

92. Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcitabine chemotherapy before and afterfluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlledtrial. JAMA 2008; 299:1019.

93. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. NEngl J Med 2010; 362:1273.

94. Jiang ZQ, Varadhachary G, Wang X, et al. A retrospective study of ampullary adenocarcinomas: overallsurvival and responsiveness to fluoropyrimidine-based chemotherapy. Ann Oncol 2013; 24:2349.

Topic 2506 Version 15.0


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GRAPHICS

Sphincter of Oddi in relation to the ampulla of Vater

Diagram of the anatomy of the sphincter of Oddi and ampulla of Vater. Themuscle fibers of the spincter of Oddi surround the intraduodenal segmentof the common bile duct and the ampulla of Vater. A circular aggregate ofmuscle fibers, known as the sphincter choledochus (or sphincter ofBoyden), keeps resistance to bile flow high, and thereby permits filling of

the gallbladder during fasting and prevents retrograde reflux of duodenal

contents into the biliary tree. A separate structure, called the sphincterpancreaticus, encircles the distal pancreatic duct. The muscle fibers of thesphincter pancreaticus are interlocked with those of the sphinctercholedochus in a figure eight pattern.


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Locations ampullary tumors


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Conventional pancreaticoduodenectomy (Whipple procedure)


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Pylorus-preserving pancreaticoduodenectomy


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TNM staging for ampullary carcinoma

Primary tumor (T)

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

Tis Carcinoma in situ

T1 Tumor limited to the ampulla of Vater or sphincter of Oddi

T2 Tumor invades duodenal wall

T3 Tumor invades pancreas

T4 Tumor invades peripancreatic soft tissues or other adjacent organs or structures other

than pancreas

Regional lymph nodes (N)

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Regional lymph node metastasis

Distant metastasis (M)

M0 No distant metastasis

M1 Distant metastasis

Anatomic stage/prognostic groups

Stage 0 Tis N0 M0

Stage

IA

T1 N0 M0

Stage

IB

T2 N0 M0

Stage

IIA

T3 N0 M0

Stage

IIB

T1 N1 M0

T2 N1 M0

T3 N1 M0

Stage

III

T4 Any N M0

Stage

IV

Any T Any N M1

Note: cTNM is the clinical classification, pTNM is the pathologic classification.Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The

original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published

by Springer New York, Inc.


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Gemcitabine for nonmetastatic pancreatic and biliary cancer

Cycle length: 4 weeks.

Drug

Dose

and

route

AdministrationAdministration

schedule

Gemcitabine 1000

mg/m

IV

Dilute in 100 mL normal saline (concentration

no greater than 40 mg/mL) and administer

over 30 minutes.

Weekly for three

weeks followed by one

week of rest.

Pretreatment considerations:

Emesis risk:LOW. Refer to UpToDate topic on "Prevention and treatment of chemotherapy-

induced nausea and vomiting".

Infection prophylaxis:Primary prophylaxis with granulocyte colony stimulating factors not

indicated (risk of neutropenic fever 3500 cells/mm and platelets are 100,000 cells/mm . During therapy, the dose of

gemcitabine should be decreased by 25 percent if the absolute neutrophil count decreases to


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This table is provided as an example of how to administer this regimen; theremay be other acceptable methods. This regimen must be administered by aclinician trained in the use of chemotherapy. The clinician is expected to use his

or her independent medical judgment in the context of individualcircumstances to make adjustments, as necessary.IV: intravenous; CBC: complete blood count.

References:

1. Oettle H, et al. JAMA 2007; 297:267.2. Gemzar (gemcitabine hydrochloride). US FDA approved manufacturer's package insert. US

National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on November

28, 2011).


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Pulmonary toxicity:A variety of manifestations of pulmonary toxicity have been reported.

Discontinue gemcitabine immediately and permanently. Refer to UpToDate topic on "Pulmonary

toxicity associated with antineoplastic therapy: Cytotoxic agents".

If there is a change in body weight of at least 10 percent, dose should be recalculated

for all drugs.

This table is provided as an example of how to administer this regimen; there

may be other acceptable methods. This regimen must be administered by aclinician trained in the use of chemotherapy. The clinician is expected to use his

or her independent medical judgment in the context of individualcircumstances to make adjustments, as necessary.IV: intravenous; CBC: complete blood count. * In the original protocol, the gemcitabine dose could be increased by 25 percent up to, but notexceeding, a dose of 1250 mg/m after the first cycle, provided the absolute neutrophil count and

platelets exceed 1500 cells/mm and 100,000/mm , respectively, and nonhematologic toxicity was less

than or equal to WHO Grade 1 .

References:

1. Burris HA, et al. J Clin Oncol 1997; 15:2403.

2. Oettle H, et al. Ann Oncol 2005; 16:1639.

3. Stathopoulos GP, et al. Br J Cancer 2006; 95:587.4. Herrmann R, et al. J Clin Oncol 2007; 25:2212.

5. Gemzar (gemcitabine hydrochloride). US FDA approved manufacturer's package insert. US

National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on November

28, 2011).

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Ampullary Carcinoma: Treatment and Prognosis

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