Ampullary Carcinoma: Treatment and Prognosis

Ampullary carcinoma: Treatment and prognosis
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Official reprint from UpToDate www.uptodate.com 2013 UpToDate
Ampullary carcinoma: Treatment and prognosis Authors David P Ryan, MD Harvey Mamon, MD, PhD Carlos Fernandez-del Castillo, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is 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 nodepositive 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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Section Editor Kenneth K Tanabe, MD
Deputy Editor Diane MF Savarese, MD
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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 pancreatic parenchyma 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 had invasive 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 (<6 mm) tumors that do not penetrate through the ampullary musculature (ie, Tis, T1, (table 1)) [28,34-37]. However, the majority of the patients reported in these series had ampullary adenomas, and few had carcinomas. A major concern is the inferior cancer-specific survival following local resection of small ampullary invasive carcinomas in the analysis from Sloan-Kettering described above [35]. Furthermore, in other series, 45 percent of patients with pathologically confirmed T1 invasive ampullary adenocarcinomas had lymph node metastases [38]. Thus, while local ampullary excision could be considered for high-risk patients with well-differentiated T1 ampullary cancers that are less than 6 mm based on endoscopic ultrasound (EUS), a more aggressive surgical approach is preferred by most surgeons for invasive tumors, including well-differentiated T1 lesions, as long as the patient is a reasonable candidate for pancreaticoduodenectomy. In our view, local resection (ampullectomy with lymph node sampling) is a reasonable alternative to pancreaticoduodenectomy for selected patients with noninvasive (pTis) tumors (table 1). However, pancreaticoduodenectomy is preferred for any invasive adenocarcinoma, if the patient can tolerate this approach. Recommendations for management of ampullary carcinoma are not included in published guidelines from either the National Comprehensive Cancer Network (NCCN) [39] or the European Society for Medical Oncology (ESMO) [40]. Minimally-invasive nonsurgical therapies Minimally invasive nonsurgical therapies for ampullary carcinoma include endoscopic snare resection, Nd:YAG laser ablation, and photodynamic therapy. The literature on these techniques in the setting of ampullary carcinoma is limited to single-case reports and small series. Endoscopic snare resection (papillectomy) is an effective means of treating ampullary adenomas. (See "Treatment of ampullary adenomas".) Endoscopic papillectomy has been attempted in early stage (Tis, T1) well differentiated ampullary cancers without angiolymphatic invasion [35]. However, acceptance of this method for definitive treatment is hampered
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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. 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 the surgical 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]: Stage I 84 percent Stage II 70 percent Stage III 27 percent Stage IV 0 percent 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 nodepositive 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'.)
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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: Patients with a node-negative, non-pancreaticobiliary histomolecular phenotype tumor had an excellent prognosis (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). 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 to adjuvant 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]: 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. Five-year survival was also predicted by the LNR:
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LNR = 0 75 percent LNR >0 to 0.2 49 percent LNR >0.2 to 0.4 38 percent LNR >0.4 0 percent 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. Both pancreatic 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 5FU, while the remainder received no adjuvant therapy [78]. In multivariate analysis, lymph node status emerged as
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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 cancers were 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, leucovorinmodulated 5-FU (six courses of leucovorin 20 mg/m2 IV bolus followed by 5-FU 425 mg/m2, daily for five days, once per month), or single agent gemcitabine (1000 mg/m2 weekly for three of every four weeks for six months) [87]. A complete (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 0.510.97). 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/leucovorin group 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 mitomycin C 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 in those 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 intestinal histomolecular 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 5FU-containing chemotherapy (but not chemoradiotherapy) prolongs survival in resected pancreatic cancer, results of the German CONKO trial [91] showing a survival benefit from adjuvant gemcitabine in 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 gemcitabine adjuvant 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 gemcitabine alone is unclear. An acceptable regimen is that used in RTOG 9704, which consists of three weekly doses of gemcitabine alone (1000 mg/m2 per week), followed by chemoradiotherapy with concurrent infusional 5-FU (250 mg/m2 daily), and starting three to five weeks later, three months of single agent gemcitabine (1000 mg/m2 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 gemcitabine alone 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 visits usually 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 gemcitabine with 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 for advanced 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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cholangiocarcinoma", section on 'Gemcitabine plus cisplatin' and "Chemotherapy for advanced exocrine pancreatic cancer" and "Treatment of small bowel neoplasms", section on 'Unresectable or metastatic disease'.) SUMMARY AND RECOMMENDATIONS It can be difficult to distinguish a primary ampullary carcinoma from other periampullary tumors (mainly pancreatic carcinoma or distal cholangiocarcinoma) preoperatively. However, true ampullary cancers have a better prognosis than pancreatic head cancers or distal cholangiocarcinomas. Resectability rates are higher, and five-year survival rates are 30 to 50 percent in selected patients with limited lymph node involvement. 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. (See 'Introduction' above and "Ampullary carcinoma: Epidemiology, clinical manifestations, diagnosis and staging".) Primary treatment We recommend pancreaticoduodenectomy rather than local resection for most patients with invasive ampullary carcinomas (Grade 1B). (See 'Pancreaticoduodenectomy' above.) We suggest local ampullary excision rather than pancreaticoduodenectomy for patients with noninvasive ampullary tumors (pTis, (table 1)) (Grade 2B). Ampullectomy is also a reasonable approach for poor surgical candidates who have a well-differentiated T1 tumor that is less than 6 mm in size (based upon endoscopic ultrasound [EUS]). However, a more aggressive surgical approach is preferred for patients who are candidates for pancreaticoduodenectomy because of better outcomes. (See 'Local resection' above.) Nonsurgical treatment modalities (ie, endoscopic snare resection, laser ablation, photodynamic therapy) provide palliative rather than curative benefit for patients with ampullary carcinoma. These methods should be restricted to patients who are not operative candidates and those who refuse surgery. (See 'Minimally-invasive nonsurgical therapies' above.) Adjuvant therapy There is no consensus regarding the optimal management of patients after resection of an ampullary adenocarcinoma. There are scant data to guide adjuvant treatment decisions, and the true benefit of such therapy remains uncertain. Nevertheless, many clinicians, including our group, treat these patients in a similar manner as those with resected pancreatic head adenocarcinomas. We offer adjuvant therapy to all patients with resected ampullary cancer stage IB or higher (table 1). (See 'Adjuvant therapy' above.) The approach differs in Europe and in the United States: Based upon the ESPAC-1 trial, which showed that 5-FU-containing chemotherapy (but not chemoradiotherapy) prolongs survival in resected pancreatic cancer, the German CONKO trial showing a survival benefit from adjuvant gemcitabine in the same patient population, and a preliminary report of the ESPAC-3 trial, suggesting a potentially clinically meaningful but statistically insignificant improvement in overall survival with adjuvant gemcitabine or leucovorin-modulated 5-FU in ampullary cancer, most European clinicians use chemotherapy alone after resection of an ampullary neoplasm. (See "Adjuvant and neoadjuvant therapy for exocrine pancreatic cancer".) The American approach more often includes chemoradiotherapy as well as adjuvant chemotherapy. The following represents our approach to patients with resected ampullary tumors: Eligible patients should be encouraged to enroll in clinical trials evaluating the potential benefits of chemotherapy and/or chemoradiotherapy as well as new therapies. Off-protocol, we suggest a combination of concurrent chemoradiotherapy and chemotherapy for patients with resected ampullary cancers stage IB or higher (table 1) rather than observation alone (Grade 2C). During the concurrent chemoradiotherapy portion, we prefer infusional 5-FU, and we use gemcitabine alone for the chemotherapy portion.
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The optimal way to sequence 5-FU-based chemoradiotherapy and gemcitabine chemotherapy 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/m2 per week), followed by chemoradiotherapy using concurrent infusional 5FU. Although the RTOG trial used 250 mg/m2 daily continuously, many clinicians, including our group, consider this too toxic and use 225 mg/m2 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 for patients 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".) 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 gemcitabine plus cisplatin is 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.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Diener MK, Knaebel HP, Heukaufer C, et al. A systematic review and meta-analysis of pylorus-preserving versus classical pancreaticoduodenectomy for surgical treatment of periampullary and pancreatic carcinoma. Ann Surg 2007; 245:187. 2. Allema JH, Reinders ME, van Gulik TM, et al. Results of pancreaticoduodenectomy for ampullary carcinoma and analysis of prognostic factors for survival. Surgery 1995; 117:247. 3. Bettschart V, Rahman MQ, Engelken FJ, et al. Presentation, treatment and outcome in patients with ampullary tumours. Br J Surg 2004; 91:1600. 4. Yeo CJ, Sohn TA, Cameron JL, et al. Periampullary adenocarcinoma: analysis of 5-year survivors. Ann Surg 1998; 227:821. 5. Roberts RH, Krige JE, Bornman PC, Terblanche J. Pancreaticoduodenectomy of ampullary carcinoma. Am Surg 1999; 65:1043. 6. Sommerville CA, Limongelli P, Pai M, et al. Survival analysis after pancreatic resection for ampullary and pancreatic head carcinoma: an analysis of clinicopathological factors. J Surg Oncol 2009; 100:651. 7. Duffy JP, Hines OJ, Liu JH, et al. Improved survival for adenocarcinoma of the ampulla of Vater: fifty-five consecutive resections. Arch Surg 2003; 138:941. 8. Brown KM, Tompkins AJ, Yong S, et al. Pancreaticoduodenectomy is curative in the majority of patients with node-negative ampullary cancer. Arch Surg 2005; 140:529. 9. Howe JR, Klimstra DS, Moccia RD, et al. Factors predictive of survival in ampullary carcinoma. Ann Surg 1998; 228:87. 10. Hsu HP, Yang TM, Hsieh YH, et al. Predictors for patterns of failure after pancreaticoduodenectomy in ampullary cancer. Ann Surg Oncol 2007; 14:50. 11. Beger HG, Treitschke F, Gansauge F, et al. Tumor of the ampulla of Vater: experience with local or radical resection in 171 consecutively treated patients. Arch Surg 1999; 134:526. 12. Yeo CJ. Pylorus-preserving pancreaticoduodenectomy. Surg Oncol Clin N Am 1998; 7:143. 13. Matory YL, Gaynor J, Brennan M. Carcinoma of the ampulla of Vater. Surg Gynecol Obstet 1993; 177:366. 14. Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital volume and surgical mortality in the United States. N Engl J Med 2002; 346:1128.
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15. Birkmeyer JD, Warshaw AL, Finlayson SR, et al. Relationship between hospital volume and late survival after pancreaticoduodenectomy. Surgery 1999; 126:178. 16. Birkmeyer JD, Stukel TA, Siewers AE, et al. Surgeon volume and operative mortality in the United States. N Engl J Med 2003; 349:2117. 17. Abdullah SA, Gupta T, Jaafar KA, et al. Ampullary carcinoma: effect of preoperative biliary drainage on surgical outcome. World J Gastroenterol 2009; 15:2908. 18. Monson JR, Donohue JH, McEntee GP, et al. Radical resection for carcinoma of the ampulla of Vater. Arch Surg 1991; 126:353. 19. Chappuis CW, Divincenti FC, Cohn I Jr. Villous tumors of the duodenum. Ann Surg 1989; 209:593. 20. Rattner DW, Fernandez-del Castillo C, Brugge WR, Warshaw AL. Defining the criteria for local resection of ampullary neoplasms. Arch Surg 1996; 131:366. 21. Branum GD, Pappas TN, Meyers WC. The management of tumors of the ampulla of Vater by local resection. Ann Surg 1996; 224:621. 22. Isaksson G, Ihse I, Andrn-Sandberg A, et al. Local excision for ampullary carcinoma. An alternative treatment for patients unfit for pancreatectomy. Acta Chir Scand 1982; 148:163. 23. Schlippert W, Lucke D, Anuras S, Christensen J. Carcinoma of the papilla of Vater. A review of fifty-seven cases. Am J Surg 1978; 135:763. 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 Surg Edinb 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. 29. Chareton B, Coiffic J, Landen S, et al. Diagnosis and therapy for ampullary tumors: 63 cases. World J Surg 1996; 20:707. 30. Tarazi RY, Hermann RE, Vogt DP, et al. Results of surgical treatment of periampullary tumors: a thirty-five-year experience. Surgery 1986; 100:716. 31. Roggin KK, Yeh JJ, Ferrone CR, et al. Limitations of ampullectomy in the treatment of nonfamilial ampullary neoplasms. Ann Surg Oncol 2005; 12:971. 32. Lindell G, Borch K, Tingstedt B, et al. Management of cancer of the ampulla of Vater: does local resection play a role? Dig Surg 2003; 20:511. 33. Grobmyer SR, Stasik CN, Draganov P, et al. Contemporary results with ampullectomy for 29 "benign" neoplasms of the ampulla. J Am Coll Surg 2008; 206:466. 34. Bttger TC, Boddin J, Heintz A, Junginger T. Clinicopathologic study for the assessment of resection for ampullary 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 of 109 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 section evaluation 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 benign and 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 May 15, 2013). 40. Eckel F, Jelic S. Biliary cancer: ESMO clinical recommendation for diagnosis, treatment and follow-up. Ann Oncol 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 review of 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 of endoscopic 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 Opin Pharmacother 2001; 2:917. 47. Abulafi AM, Allardice JT, Williams NS, et al. Photodynamic therapy for malignant tumours of the ampulla of Vater. Gut 1995; 36:853. 48. Benhamiche AM, Jouve JL, Manfredi S, et al. Cancer of the ampulla of Vater: results of a 20-year populationbased 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 radically resected 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 national population-based study. Ann Surg Oncol 2008; 15:1820. 51. Neoptolemos JP, Talbot IC, Shaw DC, Carr-Locke DL. Long-term survival after resection of ampullary carcinoma is associated independently with tumor grade and a new staging classification that assesses local invasiveness. Cancer 1988; 61:1403. 52. Todoroki T, Koike N, Morishita Y, et al. Patterns and predictors of failure after curative resections of carcinoma of the ampulla of Vater. Ann Surg Oncol 2003; 10:1176. 53. Willett CG, Warshaw AL, Convery K, Compton CC. Patterns of failure after pancreaticoduodenectomy for ampullary 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 of Vater. Am J Surg 1989; 158:593. 56. Shutze WP, Sack J, Aldrete JS. Long-term follow-up of 24 patients undergoing radical resection for ampullary carcinoma, 1953 to 1988. Cancer 1990; 66:1717. 57. Yamaguchi K, Enjoji M, Tsuneyoshi M. Pancreatoduodenal carcinoma: a clinicopathologic study of 304 patients 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 adjuvant therapy 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 associated with 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 Vater carcinoma. J Surg Oncol 2007; 95:286. 63. Kim RD, Kundhal PS, McGilvray ID, et al. Predictors of failure after pancreaticoduodenectomy for ampullary carcinoma. 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 of 127 patients with resection. World J Surg 2007; 31:137. 65. Zhou H, Schaefer N, Wolff M, Fischer HP. Carcinoma of the ampulla of Vater: comparative histologic/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 of vater 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 the ampulla 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 resected nodes 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 survival after 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 and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma, part 2: randomized controlled trial 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 Clin Gastroenterol 2006; 40:162. 75. Yao HS, Wang Q, Wang WJ, Hu ZQ. Intraoperative allogeneic red blood cell transfusion in ampullary cancer outcome 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 serum CA19-9 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 Clinic experience. 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 ampulla of Vater: preliminary report. Arch Surg 2001; 136:65. 80. Chakravarthy A, Abrams RA, Yeo CJ, et al. Intensified adjuvant combined modality therapy for resected periampullary 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 the ampulla 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 Radiat Oncol Biol Phys 2009; 75:436. 83. Palta M, Patel P, Broadwater G, et al. Carcinoma of the ampulla of Vater: patterns of failure following resection and 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 of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg 1999; 230:776. 87. Neoptolemos JP, Moore MJ, Cox TF, et al. Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial. JAMA 2012; 308:147. 88. Takada T, Amano H, Yasuda H, et al. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? 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 chemotherapy after 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 patients undergoing 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 after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA 2008; 299:1019. 93. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010; 362:1273. 94. Jiang ZQ, Varadhachary G, Wang X, et al. A retrospective study of ampullary adenocarcinomas: overall survival 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. The muscle fibers of the spincter of Oddi surround the intraduodenal segment of the common bile duct and the ampulla of Vater. A circular aggregate of muscle fibers, known as the sphincter choledochus (or sphincter of Boyden), 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 sphincter pancreaticus, encircles the distal pancreatic duct. The muscle fibers of the sphincter pancreaticus are interlocked with those of the sphincter choledochus 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 T0 Tis T1 T2 T3 T4 Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor limited to the ampulla of Vater or sphincter of Oddi Tumor invades duodenal wall Tumor invades pancreas Tumor invades peripancreatic soft tissues or other adjacent organs or structures other than pancreas
Regional lymph nodes (N)

NX N0 N1 Regional lymph nodes cannot be assessed No regional lymph node metastasis Regional lymph node metastasis
Distant metastasis (M)

M0 M1 No distant metastasis Distant metastasis
Anatomic stage/prognostic groups

Stage 0 Stage IA Stage IB Stage IIA Stage IIB Tis T1 T2 T3 T1 T2 T3 Stage III Stage IV T4 Any T N0 N0 N0 N0 N1 N1 N1 Any N Any N M0 M0 M0 M0 M0 M0 M0 M0 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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Five-year survival in a series of 1301 patients with ampullary cancer reported to the SEER* registry between 1988 and 2003
Stage at presentation
Ia Ib IIa IIb III IV N stage N0 N1 518 749 48 21 59 28
N
218 255 252 483 38 15 60 57 30 22 27 0
Five-year survival percent

OS 74 66 41 30 34 0 CSS
OS: overall survival; CSS: cause-specific survival. * SEER: Surveillance, Epidemiology and End Results database of the National Cancer Institute. Modified from: O'Connell, et al. Ann Surg Oncol 2008; 15:1820.
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Gemcitabine for nonmetastatic pancreatic and biliary cancer [1]

Cycle length: 4 weeks.
Drug
Gemcitabine
Dose and route

1000 mg/m 2 IV
Administration
Dilute in 100 mL normal saline (concentration no greater than 40 mg/mL) and administer over 30 minutes.
Administration schedule
Weekly for three weeks followed by one week of rest.
Pretreatment considerations:
Emesis risk: LOW. Refer to UpToDate topic on "Prevention and treatment of chemotherapyinduced nausea and vomiting". Infection prophylaxis: Primary prophylaxis with granulocyte colony stimulating factors not indicated (risk of neutropenic fever <1 percent). Refer to UpToDate topic on "Use of granulocyte colony stimulating factors in patients with chemotherapy-induced neutropenia". Dose adjustment for baseline liver or renal dysfunction: A lower starting dose may be needed for patients with liver impairment. Refer to UpToDate topic on "Chemotherapy hepatotoxicity and dose modification in patients with liver disease".
Monitoring parameters:
CBC with differential and platelet count weekly during treatment. Assess basic metabolic panel (including serum creatinine) and liver function prior to each cycle and otherwise as indicated during treatment.
Suggested dose alterations for toxicity:

Myelotoxicity: This regimen should not be initiated unless the white blood cell count is >3500 cells/mm 3 and platelets are 100,000 cells/mm 3[1]. During therapy, the dose of gemcitabine should be decreased by 25 percent if the absolute neutrophil count decreases to <1000 cells/mm 3 but 500 cells/mm 3, or the platelets decrease to <100,000/mm 3 and 50,000/mm 3[2]. The US FDA approved product information recommends holding gemcitabine for an absolute neutrophil count <500 cells/mm 3 or platelets <50,000/mm 3[2]. Hepatotoxicity: Gemcitabine is commonly associated with a transient rise in serum transaminases, but these are seldom of clinical significance. There is insufficient information from clinical studies to allow clear dose recommendations in these patients. Hemolytic-uremic syndrome (HUS): In clinical trials, HUS was reported in 0.25 percent of patients receiving gemcitabine. Consider diagnosis if the patient develops hemolysis and severe thrombocytopenia, with or without renal failure or central nervous system findings. Discontinue gemcitabine immediately and permanently. Refer to UpToDate topic on "Causes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults". 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.
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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 a clinician trained in the use of chemotherapy. The clinician is expected to use his or her independent medical judgment in the context of individual circumstances 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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Gemcitabine for metastatic pancreatic and biliary tract cancer [1]

Cycle length: 8 weeks for first cycle, then 4 weeks.
Drug
Gemcitabine*
Dose and route

1000 mg/m 2 IV
Administration
Dilute in 100 mL normal saline (concentration no greater than 40 mg/mL) and administer over 30 to 60 minutes.
Administration schedule
Weekly for seven weeks followed by one week of rest in the first cycle, then weekly for three weeks followed by one week of rest in all subsequent cycles.
Pretreatment considerations:
Emesis risk: LOW. Refer to UpToDate topic on "Prevention and treatment of chemotherapyinduced nausea and vomiting". Infection prophylaxis: Primary prophylaxis with granulocyte colony stimulating factors not indicated (incidence of neutropenic fever <1 percent [1-4]). Refer to UpToDate topic on "Use of granulocyte colony stimulating factors in patients with chemotherapy-induced neutropenia". Dose adjustment for baseline liver or renal dysfunction: A lower starting dose may be needed for patients with liver impairment. Refer to UpToDate topic on "Chemotherapy hepatotoxicity and dose modification in patients with liver disease".
Monitoring parameters:
CBC with differential and platelet count weekly during treatment. Assess basic metabolic panel (including serum creatinine) and liver function tests prior to each cycle and otherwise as indicated during treatment.
Suggested dose alterations for toxicity:

Myelotoxicity: This regimen should not be initiated unless the white blood cell count is greater than 3500 cells/mm 3 and platelets are greater than or equal to 100,000 cells/mm 3[1]. During therapy, the dose of gemcitabine should be decreased by 25 percent if the absolute neutrophil count decreases to <1000 cells/mm 3 but 500 cells/mm 3, or the platelets decrease
to <100,000/mm 3 and 50,000/mm 3[5]. The US FDA approved product information recommends holding gemcitabine for an absolute neutrophil count <500 cells/mm 3 or platelets <50,000/mm 3[5]. Hepatotoxicity: Gemcitabine is commonly associated with a transient rise in serum transaminases, but these are seldom of clinical significance. There is insufficient information from clinical studies to allow clear dose recommendations in these patients. Hemolytic-uremic syndrome (HUS): In clinical trials, HUS was reported in 0.25 percent of patients receiving gemcitabine. Consider diagnosis if the patient develops hemolysis and severe thrombocytopenia, with or without renal failure or central nervous system findings. Discontinue gemcitabine immediately and permanently. Refer to UpToDate topic on "Causes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults".
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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 a clinician trained in the use of chemotherapy. The clinician is expected to use his or her independent medical judgment in the context of individual circumstances 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 not exceeding, a dose of 1250 mg/m2 after the first cycle, provided the absolute neutrophil count and platelets exceed 1500 cells/mm3 and 100,000/mm3, respectively, and nonhematologic toxicity was less than or equal to WHO Grade 1[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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Ampullary Carcinoma: Treatment and Prognosis

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Ampullary carcinoma: Treatment and prognosis

Official reprint from UpToDate www.uptodate.com 2013 UpToDate

Section Editor Kenneth K Tanabe, MD

Deputy Editor Diane MF Savarese, MD