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Evaluation of adjuvant chemoradiation therapy for ampullary adenocarcinoma: the Johns Hopkins Hospital - Mayo Clinic collaborative study

Evaluation of adjuvant chemoradiation therapy for ampullary adenocarcinoma: the Johns Hopkins... Background: The role of adjuvant chemoradiation therapy for ampullary carcinoma is unknown. Previous literature suggests that certain populations with high risk factors for recurrence may benefit from adjuvant chemoradiation. We combined the experience of two institutions to better delineate which patients may benefit from adjuvant chemoradiation. Methods: Patients who underwent curative surgery for ampullary carcinoma at the Johns Hopkins Hospital (n = 290; 1992-2007) and at the Mayo Clinic (n = 130; 1977-2005) were reviewed. Patients with <60 days of follow-up, metastatic disease at surgery, or insufficient pathologic data were excluded. The final combined study consisted of 186 patients (n = 104 Johns Hopkins, n = 82 Mayo). Most patients received 5-FU based chemoradiation with conformal radiation. Cox proportional hazards models were used for survival analysis. Results: Median overall-survival was 39.9 months with 2- and 5-year survival rates of 62.4% and 39.1%. On univariate analysis, adverse prognostic factors for overall survival included T3/T4 stage disease (RR = 1.86, p = 0.002), node positive status (RR = 3.18, p < 0.001), and poor histological grade (RR = 1.69, p = 0.011). Patients who received adjuvant chemoradiation (n = 66) vs. surgery alone (n = 120) showed a higher rate of T3/T4 stage disease (57.6% vs. 30.8%, P < 0.001), lymph node involvement (72.7% vs. 30.0%, P < 0.001), and close or positive margins (4.6% vs. 0.0%, P = 0.019). Five year survival rates among node negative and node positive patients were 58.7% and 18.4% respectively. When compared with surgery alone, use of adjuvant chemoradiation improved survival among node positive patients (mOS 32.1 vs. 15.7 mos, 5 yr OS: 27.5% vs. 5.9%; RR = 0.47, P = 0.004). After adjusting for adverse prognostic factors on multivariate analysis, patients treated with adjuvant chemoradiation demonstrated a significant survival benefit (RR = 0.40, P < 0.001). Disease relapse occurred in 37.1% of all patients, most commonly metastatic disease in the liver or peritoneum. Conclusions: Node-positive patients with resected ampullary adenocarcinoma may benefit from 5-FU based adjuvant chemoradiation. Since a significant proportion of patients develop metastatic disease, there is a need for more effective systemic treatment. Keywords: ampullary, carcinoma, adjuvant, chemoradiation, resectable * Correspondence: jherma15@jhmi.edu Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Full list of author information is available at the end of the article © 2011 Narang et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Narang et al. Radiation Oncology 2011, 6:126 Page 2 of 11 http://www.ro-journal.com/content/6/1/126 Background Methods Although carcinoma of the ampulla of Vater is a rare Study design and participants malignancy with an overall incidence of 6 in 1 million, it The study was approved by the institutional review is the second most common periampullary cancer, com- boards of the Mayo Clinic, Rochester, MN, and the prising 6-20% of malignancies in this region [1-3]. Com- JohnsHopkins Hospital,Baltimore,MD. Thestudy pared to pancreatic adenocarcinoma, ampullary cancer is cohort was drawn from all patients who underwent associated with a higher likelihood of resectability and a curative surgery for ampullary carcinoma at the Johns more favorable prognosis. Whereas patients with resect- Hopkins Hospital between 1992 and 2007 (n = 290, pro- able pancreatic adenocarcinoma show a 5-year survival of spectively collected) and the Mayo Clinic from 1977 to only 20%, most retrospective reviews of ampullary cancer 2005 (n = 130, retrospectively collected). Cancer of the over the past two decades have reported 5-year survival ampulla of Vater was defined as adenocarcinoma between 30-40% [4-11]. The earlier appearance of directly centered on or associated with an in situ carci- obstructive symptoms, more favorable histology, and a noma of the ampulla, papilla, or both, as evidenced by decreased inclination for lymphatic or perineural inva- review of the final pathology report. Patients with can- sion have all been cited as potential explanations for the cers arising from the duodenum, pancreatic head, or better outcomes with ampullary carcinoma [12]. common bile duct were not eligible. Patients who were Pancreaticoduodenectomy (PD) remains the only pos- referred to outside institutions for adjuvant therapy or sible curative treatment for patients with pancreatic or follow-up care were excluded because information ampullarycancer,but theroleofadjuvanttherapy regarding the details of their outcomes or whether they remains controversial. In the United States, postopera- received adjuvant treatment was unavailable (n = 156). tive adjuvant chemoradiation (CRT) has been used for Individuals who died within 60 days of surgery (n = 6), pancreatic cancer based on evidence suggesting had less than 60 days of follow-up (n = 6), or had evi- improved survival [4,13,14]. Whether these results can dence of metastatic disease at surgery (n = 11) were be extrapolated to resected ampullary carcinoma has excluded as well. Those missing information on T-stage, been an area of active debate. A 1999 randomized con- tumor size, margin status, node status, or histologic trolled trial by the European Organization for Research grade (n = 55) were also not analyzed. The final study and Treatment of Cancer (EORTC) examined post- population contained 186 patients (n = 104 JHH, n = 82 operative 5-fluorouracil (5-FU) based CRT in patients Mayo). with pancreatic head or other periampullary malignan- All patients received preoperative staging by one or cies. This study demonstrated no survival benefit in more of the following modalities: abdominal and pelvic- patients with periampullary cancer at 2 or 5 years, but computed tomography (CT), endoscopic retrograde cho- the number of patients with ampullary carcinoma was langiopancreatography (ERCP), endoscopic ultrasonogra- small, most of whom had favorable prognostic factors phy (EUS), and percutaneous transhepatic [14]. More recently, a retrospective review from the MD cholangiography or percutaneous biliary drainage (PTC/ Anderson Cancer Center showed a borderline significant PBD). The majority of patients (77%) received both CT improvement in survival with CRT in a subset of and ERCP. Laboratory tests included a full blood count, patients with advanced tumor stage (T3/T4), while a serum electrolytes, creatinine, urea, liver transaminases, study from the Mayo Clinic found a survival benefit in alkaline phosphatase, total bilirubin, carcinoembryonic patients with pathologic lymph node involvement antigen (CEA), and carbohydrate antigen 19-9 (CA19-9). [15,16]. A third review from the Johns Hopkins Hospital Patient demographic and pathologic data are outlined (JHH) also suggested a potential survival benefit from in Table 1. Of the 186 patients in the study, 109 (59%) CRT in patients with resected ampullary carcinoma who were male. Median age was 68 years (range 29-90 had lymph node involvement, although this finding was years). Pathologic data is limited to those variables not statistically significant (p = 0.092) [17]. While these potentially conferring poor prognosis, including T-stage, studies indicate that certain subsets of patients with tumor size, lymph node status, histologic grade, and ampullary carcinoma may benefit from postoperative margin status. CRT, they are limited by the small number of patients analyzed. In the present study, we combine the experi- Surgery ence of two of the aforementioned institutions, namely Patients underwent either a pylorus-preserving or classic the Johns Hopkins Hospital and the Mayo Clinic, to pancreaticoduodenectomy (PD). A pylorus-preserving compare surgery followed by modern conformal 5-FU PD included resection of the head and uncinate process based adjuvant CRT with surgery alone for patients with of the pancreas, distal bile duct, all but the most proxi- resectable carcinoma of the ampulla of Vater. mal duodenum, and gallbladder, when present. In a Narang et al. Radiation Oncology 2011, 6:126 Page 3 of 11 http://www.ro-journal.com/content/6/1/126 Table 1 Baseline Characteristics between Treatment Groups Observation Only Adjuvant Chemoradiation (CRT) Therapy P-Value N = 120 N= 66 DEMOGRAPHIC Age at Surgery (yr) Mean, (SD*) 68.9 (11.6) 62.0 (10.8) <0.001 Median (Range) 71.3 (28.7-90.3) 63.3 (29.3-81.5) Gender Male, No. (%) 66 (55.0) 43 (65.2) 0.179 Institution Mayo Clinic 63 (52.5) 19 (28.8) 0.002 Johns Hopkins Hospital (JHH) 57 (47.5) 47 (71.2) TUMOR CHARACTERISTCS T Stage 1 37 (30.8) 8 (12.1) 0.002 2 46 (38.3) 20 (30.3) 3 33 (27.5) 34 (51.5) 4 4 (3.3) 4 (6.1) Tumor Diameter < 3 cm 81 (67.5) 39 (59.1) 0.251 ≥ 3 cm 39 (32.5) 27 (40.9) Nodal Status N0 84 (70.0) 18 (27.3) <0.001 N1 36 (30.0) 48 (72.3) Histologic Grading 1 8 (6.7) 0 (0.0) 0.053 2 52 (43.3) 25 (37.9) 3 60 (50.0) 41 (62.1) Surgical Margins Positive 0 (0.0) 3 (4.6) 0.019 Negative 120 (100.0) 63 (95.4) *SD = standard deviation classic PD, the antrum of the stomach was also resected. carcinoma was close to (within 1 mm) or present at At JHH, 82.5% of patients underwent a pylorus-preser- these margins. ving PD, while these data were unavailable for patients treated at the Mayo Clinic. All pathology specimens Chemoradiation regimen were reviewed by either a pathologist at JHH or cen- Of the 186 patients in this study, 120 (64.5%) received trally at the Mayo Clinic, and patients were restaged surgery alone, while 66 (35.5%) were given adjuvant according to American Joint Committee on Cancer CRT. In patients receiving adjuvant therapy, radiation (AJCC) guidelines, sixth edition. Pathologic data regard- treatments were administered with a 3-field coplanar ing T stage, tumor size, histologic grade, lymph node approach (7.6%), 4-field coplanar approach (78.8%), 5- involvement, lymphovascular invasion, perineural inva- field non-coplanar approach (3.0%), or intensity modu- sion, and surgical margins were recorded. Lymph nodes lated radiation therapy (IMRT, 10.6%). A total of 45 Gy were considered positive if the resection specimen con- was generally delivered to the ampullary tumor bed tained metastatic carcinoma in any of the lymph nodes, (based on preoperative images), surgical anastomoses whether they were involved by direct extension or con- (hepatojejunostomy, pancreaticojejunostomy) and adja- tiguous with the primary tumor. At the Mayo Clinic, cent regional lymph nodes (proximal celiac and superior margin status was determined by the presence of carci- mesenteric). Additional radiation (5-15 Gy) was admi- noma at the final pancreatic neck, uncinate process, bile nistered to the tumor bed/area of involved margins and duct, duodenal, or retroperitoneal soft tissue margin. At anastomoses paying careful attention to the dose to the JHH, resection margins were considered positive if the small bowel. The median total dose was 50.4 Gy (range Narang et al. Radiation Oncology 2011, 6:126 Page 4 of 11 http://www.ro-journal.com/content/6/1/126 37.8-50.4 Gy). Radiation was given in consecutive, daily 3). Survival curves were estimated with Kaplan-Meier fractions except for 7 patients (10.6%) who underwent a techniques. two week planned break in therapy as part of a treat- ment protocol investigating split-course chemoradiation. Results In this protocol, patients received two weeks of 5-fluor- At thetimeofanalysis, 82 patients (44.1%) were still ouracil based chemoradiation, a two week treatment alive while 104 patients (55.9%) had died. Progression of break, and two additional weeks of 5-fluorouracil based disease was the cause of death for 58 patients (55.2%), chemoradiation, followed by 5-fluorouracil based main- while the remaining 46 deaths (44.8%) were from tenance chemotherapy. No patient received neoadjuvant unknown or other causes. Median follow-up time for or intraoperative radiation. Concurrent chemotherapy surviving patients was 31.7 months (range 2.0 - 160.1 most commonly consisted of 5-fluorouracil (95.5%), months). although three patients (4.5%) received gemcitabine. As displayed in Table 1, when compared with patients Maintenance chemotherapy was given to 37.9% of who were treated with surgery alone, those patients who patients in the form of single-agent 5-fluorouracil received adjuvant CRT were significantly younger (62.0 (15.2%), single-agent gemcitabine (19.7%), or combina- vs. 68.9, p < 0.001), were more likely from JHH (71.2% tion gemcitabine with either cisplatin/erlotinib (1.5%) or vs. 47.5%, p = 0.002), had more advanced T-stage (T3/ capecitabine (1.5%). All patients who received mainte- T4: 57.6% vs. 30.8%, p = 0.002), and showed more fre- nance chemotherapy were treated at JHH. Note that quent pathologic lymph node involvement (72.3% vs. patients were not excluded from our analysis based on 30.0%, p < 0.001). Patients in the CRT group also more the concurrent or maintenance chemotherapeutic agents frequently had close or positive surgical margins (4.6% that were administered given the lack of clear evidence vs. 0.0%, p = 0.019), although only three patients in the supporting a specific regimen. None of the patients in entire sample had close or positive margins, all of whom this study were treated with adjuvant chemotherapy were given CRT. Histologic grade, while not significantly alone. different between treatment groups, did show a trend towards poorer differentiation amongst patients given Statistical Analysis CRT (grade 3: 62.1% vs. 50.0%, p = 0.053). Neither Statistical analysis was performed using STATA, version tumor size nor gender was associated with the type of 9 (Stata, College Station, TX). Summary statistics for treatment that the patient received. Additionally, when continuous and dichotomous variables are provided. In patient demographics and tumor characteristics were constructing dichotomous variables, thresholds were stratified by institution, there was no significant differ- ence between the JHH and Mayo cohorts for any of defined in accordance with the literature [15-18]. The distribution of prognostic variables between treatment these factors (results not shown). groups was compared using Pearson’s chi-squared test. Median overall survival (mOS) for all patients was The primary outcome variable was overall survival (OS), 39.9 months (95% CI: 29.5 - 54.7 months) with a 2-year defined as the time from surgical resection to death. and 5-year survival of 62.4% and 39.1%, respectively. As Survival time was censored at date of last follow up if displayed in Table 2, on univariate analysis, lymph node death had not occurred. Univariate analysis was con- involvement had the strongest association with ducted using the log-rank test to examine risk factors decreased overall survival (mOS: 23.0 vs. 79.4 months, and associations with mortality. Median OS was esti- RR 2.11 - 4.78, p < 0.001). Advanced T-stage and poor mated within each risk group and by adjuvant treat- histologic differentiation were also significantly asso- ment. The proportion of individuals surviving up to 2 ciated with poor prognosis. Specifically, tumors classified and 5 years was calculated using life tables and stratified as T3/T4 showed significantly worse overall survival by treatment group to assess for a significant difference compared with T1/T2 disease (mOS: 27.0 vs. 55.4 using the log-rank test. Proportional hazards models months, RR 1.26 - 2.75, p = 0.002), as did grade 3 his- were used to examine the association of adjuvant treat- tology when compared with grade 1 or 2 disease (mOS: ment, baseline patient characteristics, and pathologic 32.1 vs. 60.0 months, RR 1.13 - 2.53, p = 0.011). Age, data with mortality. To explore the independent associa- gender, institution, tumor size, and margin status were tion of adjuvant therapy and OS, multivariate analysis not predictive of overall survival. Furthermore, as illu- was performed, adjusting for possible confounders, strated in Figure 1, adjuvant treatment with CRT was namely age, sex, institution, tumor stage, tumor size, not significantly associated with overall survival when lymph node status, and histologic differentiation. Margin compared with surgery alone (median survival 39.9 vs. status was not included in multivariate analysis due to a 40.1 months, RR 0.64 - 1.43, p = 0.839) using univariate analysis. As shown in Table 3, when patients were paucity of patients with close or positive margins (n = Narang et al. Radiation Oncology 2011, 6:126 Page 5 of 11 http://www.ro-journal.com/content/6/1/126 Table 2 Associations of Overall Survival with Patient Tumor and Treatment Characteristics No. (%) 2-Year Survival, % 5-year Survival, % Median Survival, months Univariate RR (95% CI) P-value Age, yrs < 75 137 (73.7) 66.5 41.2 40.6 1.00 0.281 ≥ 75 49 (26.3) 66.7 32.5 35.5 1.27 (0.82 - 1.98) Gender Female 77 (41.4) 67.4 37.4 39.9 1.00 0.954 Male 109 (58.6) 66.0 40.4 36.5 0.99 (0.67 - 1.47) Institution Mayo Clinic 82 (44.1) 68.6 39.9 40.6 1.00 0.350 JHH 104 (55.9) 64.8 38.9 36.9 1.20 (0.81 - 1.78) T stage 1/2 111 (59.7) 75.0 46.3 55.4 1.00 0.002 3/4 75 (40.3) 54.1 28.1 27.0 1.86 (1.26 - 2.75) Tumor Size ≤ 3 cm 120 (64.5) 72.5 39.3 40.1 1.00 0.838 > 3 cm 66 (35.5) 56.5 38.3 35.5 1.04 (0.70 - 1.55) Node Status Negative 102 (54.8) 84.1 58.7 79.4 1.00 <0.001 Positive 84 (45.2) 47.2 18.4 23.0 3.18 (2.11 - 4.78) Histology Grade 1/2 85 (45.7) 75.8 49.9 60.0 1.00 0.011 Grade 3 101 (54.3) 59.1 30.6 32.1 1.69 (1.13 - 2.53) Margin Status Negative 183 (98.4) 66.6 39.3 39.9 1.00 0.493 Positive 3 (1.6) 33.3 0.0 33.3 1.49 (0.47 - 4.72) Adjuvant Treatment None 120 (64.5) 67.3 37.2 40.1 1.00 0.839 CRT* 66 (35.5) 65.3 42.1 39.9 0.96 (0.64 - 1.43) *CRT = chemoradiation stratified into eight risk groups, and survival by treat- overall survival on multivariate analysis, with node posi- ment type was compared within each subgroup, the tive patients experiencing significantly increased risk of only patients who showed a significant difference in death (RR 2.50 - 7.17, p < 0.001). Of the 66 patients who underwent adjuvant CRT, 41 median survival between adjuvant CRT and surgery alone were those with pathologic lymph node involve- (62.1%) experienced some form of toxicity during therapy. ment (mOS: 32.1 vs. 15.7 months, p = 0.004). In node- The most common toxicities reported were nausea positive patients, adjuvant CRT resulted in a 5-year sur- (25.8%), diarrhea (16.7%), weight loss (9.1%), fatigue vival of 27.5%, while surgery alone led to a 5-year rate (9.1%), and epigastric pain (7.6%). While side effects of only 5.9%. Figure 2 compares the survival curves by tended to be mild in nature, treatment-related toxicity did treatment type for node-positive patients. Median survi- lead to an interruption of therapy in 8 patients (12.1%). val was also higher in node negative patients receiving Grade 3 toxicities were reported in two patients from the adjuvant CRT (mOS: 103.2 vs. 61.6 months), but the dif- Mayo Clinic who suffered from myelosuppression and ference was not statistically significant (p = 0.122). sepsis respectively. The grade of toxicity for patients trea- As displayed in Table 4, on multivariate analysis, adju- ted at JHH was unavailable, although no patient from JHH vant CRT was significantly associated with improved was hospitalized for radiation-associated toxicity. There overall survival (RR 0.25 - 0.67, p < 0.001), when were no known treatment related deaths. adjusted for age, gender, institution, T-stage, tumor size, Sixty-nine patients (37.1%) experienced a recurrence node status, and grade. Additionally, lymph node invol- by the end of follow-up. The most common pattern of vement was the only other variable associated with initial recurrence was distant metastasis without local Narang et al. Radiation Oncology 2011, 6:126 Page 6 of 11 http://www.ro-journal.com/content/6/1/126 Pancreaticoduodenectomy is the preferred surgical approach for carcinoma of the ampulla of Vater that is amenable to resection [19]. However, similar to pancrea- tic cancer, the role of post-operative adjuvant therapy remains undefined. While prognosis for resectable ampullary carcinoma is considerably better than for pancreatic cancer, patients with node positive disease have poor survival and appear to benefit from adjuvant therapy [20,21]. A number of reports, mostly consisting of single institution series, have established adverse prognostic factors, including extent of local invasion, status of surgical margins, presence of nodal metastasis, and histologic grade, all of which predict for overall sur- vival as well as local and distant disease [5-9,22-29]. In these cohorts, nodal involvement has been a particularly Figure 1 Survival following pancreaticoduodenectomy strong predictor of poor outcomes, with 5-year survival stratified by type of adjuvant therapy. Kaplan-Meier curves rates following PD ranging from 64-80% in patients with comparing overall survival between patients who received adjuvant node-negative disease and 17-50% in patients with chemoradiation (n = 66) and those treated with surgery alone (n = node-positive disease. A more recent population-based 120). Adjuvant therapy was not significantly associated with improved overall survival (p = 0.839) on univariate analysis. analysis of roughly 4,000 patients with ampullary carci- noma was conducted using the National Cancer Insti- tute’s Surveillance, Epidemiology, and End Results relapse, which was seen in 49 patients (26.3%). Thirteen database [30]. Outcomes were slightly worse than the patients (7.0%) had both local and metastatic disease at aforementioned series from specialized cancer centers initial relapse. Only 7 patients (3.8%) presented with but were highly dependent on nodal metastasis (5 year local recurrence without evidence of metastatic spread, survival: 47.6% vs. 21.0%). of which 6 had not been given adjuvant therapy. The High rates of relapse along with identification of distribution in patterns of initial recurrence between adverse prognostic factors have led to exploration of treatment groups is summarized in Table 5. Overall, the adjuvant chemoradiation for “high risk” ampullary carci- liver was the most common site of metastasis, with noma, although the literature in this area remains sparse. Willett et al. first reported a trend towards 24.7% of all patients and 36.5% of those patients who improved local control with no improvement in overall died harboring disease in the liver. The peritoneum was survival when adjuvant 5-FU based chemoradiation was the second most common site of metastasis, present in given to a small cohort of patients with high risk fea- 5.9% of all patients and 9.5% among those patients who tures, defined as invasion of the pancreas, nodal metas- died. Lung metastases were found in 4.8% of all patients tasis, positive margins, or poor histology [31]. A and 6.7% of patients who died, making it the third most subsequent review by Mehta et al. reported a favorable common site of distant spread. 3-year actuarial survival rate of 44% using adjuvant 5- FU based chemoradiation in patients with large tumor Discussion size, nodal involvement, positive surgical margins, poor This combined series of patients with ampullary carci- histology, or neurovascular invasion [32]. Similarly, Lee noma represents the largest study to date that demon- et al. achieved superior disease-free survival in patients strates an overall survival benefit in patients receiving adjuvant chemoradiation following surgical resection with advanced tumor stage (T3/T4) or positive nodes when controlling for adverse prognostic factors. After receiving adjuvant chemoradiation [33]. On multivariate adjusting for institution, patient demographics such as analysis, adjuvant therapy was also a significantly favor- age and gender, and disease characteristics such as able factor for the entire cohort (HR: 0.16, p = 0.030). tumor stage, tumor size, nodal involvement, and histol- However, less than twenty patients received adjuvant ogy, patients treated with adjuvant CRT experienced therapy in each of these studies, making it difficult to enhanced survival (HR = 0.41, 95% CI: 0.25-0.67, p < derive convincing conclusions. 0.001). This series also confirms improved outcomes in More recently, three retrospective studies from institu- patients with ampullary carcinoma when compared with tions that treat high volumes of periampullary malignan- cies reviewed their experience with adjuvant CRT for pancreatic cancer, with a median survival of 39.9 ampullary carcinoma. Krishnan et al. examined 96 months and two and five-year survival rates of 62.4% patients, 54 of whom had received adjuvant CRT and 39.1% respectively. Narang et al. Radiation Oncology 2011, 6:126 Page 7 of 11 http://www.ro-journal.com/content/6/1/126 Table 3 Survival between Treatment Groups by Patient, Tumor, and Treatment Characteristics No. of Patients, (%) Overall Survival, Median, mo 5-year Survival, Percent Observation Adjuvant CRT Observation Adjuvant CRT P-value Observation Adjuvant CRT ALL PATIENTS 120 (64.5) 66 (35.5) 39.9 40.1 0.839 37.2 42.1 Age, yrs < 75 79 (57.7) 58 (42.3) 41.3 40.6 0.913 37.9 45.9 ≥ 75 41 (83.7) 8 (16.3) 35.5 33.3 0.939 36.0 25.0 Gender Female 54 (70.1) 23 (20.9) 42.7 32.1 0.162 40.8 29.3 Male 66 (60.6) 43 (39.4) 32.2 46.0 0.238 33.9 48.4 Institution Mayo 63 (76.8) 19 (23.2) 38.2 62.4 0.599 35.5 51.3 Hopkins 57 (54.8) 47 (45.2) 41.7 36.5 0.890 40.0 37.0 Histology Grade 1/2 60 (70.6) 25 (29.4) 53.6 62.2 0.328 47.1 56.6 Grade 3 60 (59.4) 41 (40.6) 34.9 27.1 0.985 27.5 34.1 Node Negative 84 (82.4) 18 (17.7) 61.6 103.2 0.122 52.4 87.1 Positive 36 (42.9) 48 (57.1) 15.7 32.1 0.004 5.9 27.5 Tumor Stage T1/T2 83 (74.8) 28 (25.2) 41.3 87.5 0.172 41.7 56.8 T3/T4 37 (49.3) 38 (50.7) 27.0 25.0 0.873 27.5 28.7 Tumor Size ≤ 3 cm 81 (67.5) 39 (32.5) 41.3 36.5 0.797 38.8 40.0 > 3 cm 39 (59.1) 27 (40.9) 27.0 40.6 0.496 33.9 44.0 Margin status Negative 120 (65.6) 63 (34.4) 40.1 39.9 0.754 37.2 42.7 Positive 0 (0.0) 3 (100.0) N/A 33.3 N/A N/A 33.3 *CRT = chemoradiation consisting of either preoperative radiation to a median dose of 45 Gy or postoperative radiation to a median dose of 50.4 Gy, with concurrent 5-FU or capecitabine [15]. Patients with advanced T-stage (T3/T4) who were treated with CRT showed a borderline significant increase in survival (mOS: 35.2 vs. 16.5 months, p = 0.06). Similarly, a JHH review of 111 patients identified a trend towards improved survival with adjuvant CRT among those patients with nodal metastasis (mOS: 30.0 vs. 21.6 months, p = 0.092) [17]. Postoperative therapy in this study consisted of a median radiation dose of 50.4 to the tumor bed and regional nodes with concur- rent 5-FU or capecitabine. Furthermore, a statistically significant difference in survival among patients with lymph node involvement treated with adjuvant CRT was Figure 2 Survival following pancreaticoduodenectomy in node found in a previous study from the Mayo Clinic (mOS: positive patients stratified by type of adjuvant therapy. Kaplan- 3.4 vs. 1.6 years, p = 0.02) [16]. Note, however, that in Meier curves comparing overall survival amongst node-positive patients between patients who received adjuvant chemoradiation (n none of these studies was adjuvant CRT associated with = 48) and those treated with surgery alone (n = 36). In node- increased survival on multivariate analysis. positive patients, adjuvant therapy was significantly associated with In the present series, adjuvant therapy was not found improved overall survival (p = 0.004) on univariate analysis. on univariate analysis to be associated with increased Narang et al. Radiation Oncology 2011, 6:126 Page 8 of 11 http://www.ro-journal.com/content/6/1/126 Table 4 Multivariate Cox Proportional Hazards Survival proportion of patients with advanced T-stage (p = Analysis of Adjuvant Chemoradiation therapy and 0.002), pathologic lymph node involvement (p < 0.001), Overall Survival and positive surgical margins (p = 0.019), and a border- RR (95% CI) P-value line statistically significant trend towards poorer histolo- Age, yrs gic grade (p = 0.053). The fact that survival was comparable between treatment groups despite these dis- < 75 1.00 0.755 crepancies suggests the potential benefit of adjuvant ≥ 75 0.93 (0.57 - 1.50) CRT, particularly amongst high risk populations. Gender Moreover, when baseline demographic and treatment- Female 1.00 0.402 related characteristics were adjusted for on multivariate Male 0.84 (0.56-1.26) analysis, a significant association between adjuvant ther- Institution apy and improved survival appeared. Indeed, this study Mayo 1.00 0.222 represents the second reported survival benefit from Hopkins 1.30 (0.85-1.99) adjuvant CRT found on multivariate analysis, albeit with Tumor Stage a much larger cohort than was analyzed in the afore- mentioned study by Lee et al [33]. Interestingly, when T1/T2 1.00 0.317 patients were stratified by baseline demographic and dis- T3/T4 1.24 (0.81-1.91) ease-related characteristics, no subgroup showed a sig- Tumor Size nificant survival benefit from adjuvant CRT except for ≤ 3 cm 1.00 0.391 patients with nodal metastasis, who experienced a large > 3 cm 1.20 (0.79-1.80) difference in median survival (mOS: 32.1 vs. 17.5 Node months, p = 0.004). As suggested in multiple previous Negative 1.00 <0.001 studies, node-positive patients were found to carry a Positive 4.29 (2.5-7.17) very poor prognosis on both univariate analysis (p < Histology 0.001) and multivariate analysis (p < 0.001), with a med- Grade 1/2 1.00 0.191 ian survival of only 18.4 months. The fact that node- positive patients who were not treated with adjuvant Grade 3 1.35 (0.86-2.41) CRT showed a dismal 5-year survival rate of only 5.9% Adjuvant Treatment indicates that this group may be particularly suited for Observation 1.00 <0.001 post-operative therapy. Moreover, while the effect of Adjuvant CRT* 0.41 (0.25 - 0.67) adjuvant therapy in node negative patients did not reach *CRT = chemoradiation statistical significance, the absolute difference in survival (mOS: 103.2 vs. 61.6 months) is noteworthy and remi- survival when compared to surgery (mOS: 39.9 vs. 40.1 niscent of the CONKO-001 trial in which node negative months, p-0.839), as summarized in Table 2 and illu- pancreatic cancer patients experienced superior survival strated in Figure 1. This lack of survival benefit is likely with adjuvant chemotherapy [34]. a result of the imbalance in adverse prognostic factors While good local control was achieved in this study, between treatment groups. In this series, nodal metasta- nearly a third of patients suffered from distant relapse, sis (p < 0.001), advanced T stage (p = 0.002), and poorly and roughly 90% of recurrences were attributable in differentiated histology (p = 0.011) were all significantly part to metastatic disease. Consistent with the literature, associated with decreased survival. While margin status the most common sites of metastasis were the liver and was not a predictor of survival (p = 0.493), margin sta- peritoneum. Overall, progression of disease led to more tus is widely considered to be a poor prognostic factor, than half of the deaths in the cohort, with nearly one and its lack of association with survival in this study third of patients who died harboring disease in the liver. maybeattributabletothe smallnumberofpatients The prevalence of metastatic disease suggests the need withcloseorpositivemargins (n =3). Regardless,the formoreeffectivesystemictherapy,particularlyin high cohort that received CRT had a significantly higher risk patients. Unfortunately, there is even less Table 5 Initial Sites of First Recurrence by Treatment Group No Recurrence Local Recurrence Distant Recurrence Local & Distant Overall Recurrences Total Patients CRT 31 (47.0%) 1 (1.5%) 23 (34.8%) 11 (16.7%) 35 (53.0%) 66 No CRT 86 (71.7%) 6 (5.0%) 26 (21.7%) 2 (1.7%) 34 (28.3%) 120 Total 118 (63.4%) 7 (3.8%) 49 (26.3%) 12 (6.5%) 68 (36.6%) 186 Narang et al. Radiation Oncology 2011, 6:126 Page 9 of 11 http://www.ro-journal.com/content/6/1/126 information regarding appropriate type and duration of association between institution and survival on univari- chemotherapeutic agents when incorporated with radia- ate or multivariate analysis, and institution did not affect tion for ampullary cancer. Furthermore, the role of adju- outcomes when stratified by treatment type. Another vant chemotherapy alone is an area that has been largely limitation was the number of patients excluded for understudied, a remnant of borrowed U.S. practice pat- either missing data (i.e. stage or nodal status) or because terns supporting adjuvant CRT for resected pancreatic they were lost to follow-up. It is probable that follow-up was not consistent among treatment groups, with cancer. A Japanese study of adjuvant mitomycin C and patients receiving adjuvant therapy likely showing better 5-FU for pancreaticobiliary carcinomas found no overall follow-up. The number of patients lost to follow along or disease-free survival benefit in a subset of 24 patients with ampullary carcinoma when compared to surgery with thenumberofpatientsaliveattimeofanalysis alone [35]. More recent and robust results from the resulted in a low number of documented recurrences. European Study Group for Pancreatic Cancer (ESPAC) - Ideally, we would have been able to examine the asso- 3(v2) trial also showed no difference in survival in 304 ciation between adjuvant therapy and patterns of recur- patients with resected ampullary cancer who were ran- rence, but the low number of recurrences prevented the domized to 5-FU/folinic acid, gemcitabine, or observa- possibility of meaningful analysis. Nevertheless, this tion [36]. Combination chemotherapy may provide study combines the experience of two high volume insti- better results, as a randomized control trial comparing tutions to allow for the largest series to date that has gemcitabine and cisplatin versus gemcitabine alone in examined the role of adjuvant therapy following surgery 410 patients with locally advanced or metastatic biliary for ampullary cancer. or ampullary cancers did show superior survival with the combination regimen (mOS: 11.7 vs. 8.1 months, p Conclusions < 0.001), although it should be acknowledged that only Lymph node involvement, advanced tumor stage, and 5% of tumors in the study had an ampullary origin [37]. poor histology are adverse prognostic factors associated Of note, no study has directly compared adjuvant che- with poor survival in patients with ampullary carcinoma. motherapy alone with adjuvant chemoradiation. The addition of adjuvant chemoradiation likely improves Given the retrospective nature of this study and wide survival in patients with high risk disease, particularly in time period over which this study spanned, our findings those with lymph node involvement. Whether all are limited by the variability in treatment regimens and patients with resectable ampullary carcinoma should be the potentially unequal distribution of confounding fac- treated with adjuvant chemoradiation is subject to tors in patient selection between treatment groups. Cer- debate. Certainly, better systemic therapy is necessary to tainly, patients in our study were subject to different improve the high rate of distant metastasis found in this operative methods, radiation plans, and chemotherapeu- population. ticagents, whichwewere unabletocontrol fordueto incomplete information or insufficient power. Addition- List of abbreviations ally, this study has shown that patients selected for adju- PD: pancreaticoduodenectomy; CRT: chemoradiation therapy; EORTC: vant CRT at the Johns Hopkins Hospital and the Mayo European Organization for Research and Treatment of Cancer; 5-FU: 5- fluorouracil; JHH: Johns Hopkins Hospital; CT: computed tomography; ERCP: Clinic possessed more adverse prognostic factors than endoscopic retrograde cholangiopancreatography; EUS: endoscopic those treated with surgery alone. While several high risk ultrasonography; PTC: percutaneous transhepatic cholangiography; PBD: characteristics were adjusted for in our analysis, other percutaneous biliary drainage; CEA: carcinoembryonic antigen; CA19-9: carbohydrate antigen 19-9; AJCC: American Joint Committee on Cancer; variables that were not taken into account include per- IMRT: intensity modulated radiation therapy. formance status and weight loss, both of which may be correlated with disease outcomes. Since patients who Acknowledgements This work was in part supported by the Claudio X Gonzalez Family received adjuvant CRT were significantly younger, it is Foundation. easy to imagine that healthier patients were more likely offered adjuvant treatment. The retrospective nature of Author details Department of Radiation Oncology, Johns Hopkins University School of our study may have also compromised our ability to Medicine, Baltimore, MD, USA. Department of Radiation Oncology, The accurately capture certain information such as the toxi- 3 Mayo Clinic, Rochester, MN, USA. Department of Radiation Oncology, city data, which was lower when compared to prior University of California, San Francisco, San Francisco, CA, USA. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, experience [14]. Furthermore, variations in institutional USA. The Sol Goldman Pancreatic Research Center, Johns Hopkins protocols regarding treatment delivery can be a source University School of Medicine, Baltimore, MD, USA. Department of of bias in studies analyzing data from multiple sites, but Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Pathology, Johns Hopkins University School of Medicine, it should be noted that while the distribution of treat- Baltimore, MD, USA. Department of Surgery, The Mayo Clinic, Rochester, ment type did in fact vary by institution, there was no MN, USA. Narang et al. Radiation Oncology 2011, 6:126 Page 10 of 11 http://www.ro-journal.com/content/6/1/126 pancreas and periampullary region. Phase III trial of the EORTC Authors’ contributions Gastrointestinal Tract Cancer Cooperative Group. Ann Surg 1999, AKN participated in the analysis and interpretation of data and drafting of 230:776-784. the manuscript. RCM contributed to study design and provided critical 15. Krishnan S, Rana V, Evans DB, Varadhachary G, Das P, Bhatia S, Delclos ME, revisions. CCH was involved in study design, acquisition and analysis of data, Janjan NA, Wolff RA, Crane CH, Pisters PW: Role of adjuvant and critical review of the manuscript. SB helped with acquisition and chemoradiation therapy in adenocarcinomas of the ampulla of vater. Int analysis of data and critical review of the manuscript. TMP contributed to J Radiat Oncol Biol Phys 2008, 70:735-743. interpretation of data and provided critical revisions. DL was involved with 16. Bhatia S, Miller RC, Haddock MG, Donohue JH, Krishnan S: Adjuvant interpretation of data and critical review of the manuscript. RHH provided therapy for ampullary carcinomas: the Mayo Clinic experience. Int J analysis and interpretation of data and critical revisions. JZ contributed to Radiat Oncol Biol Phys 2006, 66:514-519. acquisition and analysis of data and critical review of the manuscript. JMW 17. Zhou J, Hsu CC, Winter JM, Pawlik TM, Laheru D, Hughes MA, was involved in analysis and interpretation of data and critical review of the manuscript. MGH helped with study design and interpretation of data and Donehower R, Wolfgang C, Akbar U, Schulick R, Cameron J, Herman JM: provided critical revisions. JHD participated in interpretation of data and Adjuvant chemoradiation versus surgery alone for adenocarcinoma of critical review of the manuscript. RDS provided interpretation of data and the ampulla of Vater. Radiotherapy and Oncology 2009, 92:244-248. critical revisions. CLW contributed to study design, interpretation of data, 18. Horowitz DP, Hsu CC, Wang J, Makary MA, Winter JM, Robinson R, and critical review of the manuscript. JLC participated in study design, Schulick RD, Cameron JL, Pawlik TM, Herman JM: Adjuvant chemoradiation interpretation of data, and critical revisions. JMH contributed to study therapy after pancreaticoduodenectomy in elderly patients with conception and design, interpretation of data, and drafting of the adenocarcinoma. Int J Radiat Oncol Biol Phys . manuscript. All authors have read and approved the final manuscript. 19. Winter JM, Cameron JL, Olino K, Herman JM, de Jong MC, Hruban RH, Wolfgang CL, Eckhauser F, Edil BH, Choti MA, Schulick RD, Pawlik TM: Competing interests Clinicopathologic analysis for ampullary neoplasms in 450 patients: The authors declare that they have no competing interests. implications for surgical strategy and long-term prognosis. J Gastrointest Surg 2010, 14:379-387. Received: 16 June 2011 Accepted: 28 September 2011 20. Kopelson G: Curative surgery for adenocarcinoma of the pancreas/ Published: 28 September 2011 ampulla of Vater: the role of adjuvant pre or postoperative radiation therapy. Int J Radiat Oncol Biol Phys 1983, 9:911-915. 21. Kopelson G, Galdabini J, Warshaw AL, Gunderson LL: Patterns of failure after References curative surgery for extra-hepatic biliary tract carcinoma: Implications for 1. Yeo CJ, Cameron JL, Sohn TA, Lillemoe KD, Pitt HA, Talamini MA, adjuvant therapy. Int J Radiat Oncol Biol Phys 1981, 7:413-417. Hruban RH, Ord SE, Sauter PK, Coleman J, Zahurak ML, Grochow LB, 22. Allema JH, Reinders ME, van Gulik TM, van Leeuwen DJ, Verbeek PC, de Abrams RA: Six hundred fifty consecutive pancreaticoduodenectomies in Wit LT, Gouma DJ: Results of pancreaticoduodenectomy for ampullary the 1990s. Pathology, complication and outcomes. Ann Surg 1997, carcinoma and analysis of prognostic factors for survival. Surgery 1995, 226:248-260. 117:247-253. 2. Bouvet M, Gamagami RA, Gilpin EA, Romeo O, Sasson A, Easter DW, 23. Neoptolemos JP, Talbot IC, Shaw DC: Long-term survival after resection of Moossa AR: Factors influencing survival after resection for periampullary ampullary carcinoma is associated independently with tumor grade and neoplasms. Am J Surg 2000, 180:13-17. a new staging classification that assesses local invasiveness. Cancer 1988, 3. Stephens J, Kuhn J, O’Brien J, Preskitt J, Derrick H, Fisher T, Fuller R, 61:1403-1407. Lieberman Z: Surgical morbidity, mortality, and long term survival in 24. Beger HG, Treitschke F, Gansauge F, Harada N, Hiki N, Mattfeldt T: Tumor of patients with pancreatic cancer following pancreaticoduodenectomy. the ampulla of Vater: experience with local or radical resection in 171 Am J Surg 1997, 174:600-604. consecutively treated patients. Arch Surg 1999, 134:526-532. 4. Kalser MH, Ellenberg SS: Pancreatic cancer: adjuvant combined radiation 25. Yeo CJ, Sohn TA, Cameron JL, Hruban RH, Lillemoe KD, Pitt HA: and chemotherapy following curative resection. Arch Surg 1985, Periampullary adenocarcinoma: analysis of 5-year survivors. Ann Surg 120:899-903. 1998, 227:821-831. 5. Matory YL, Gaynor J, Brennan M: Carcinoma of the ampulla of Vator. Surg 26. Duffy JP, Hines OJ, Liu JH, Ko CY, Cortina G, Isacoff WH, Nguyen H, Gynecol Obstet 1993, 177:366-370. Leonardi M, Tompkins RK, Reber HA: Improved survival for 6. Monson JR, Donohue JH, McEntee GP, McIlrath DC, van Heerden JA, adenocarcinoma of the ampulla of Vater: fifty-five consecutive Shorter RG, Nagorney DM, Ilstrup DM: Radical resection for carcinoma of resections. Arch Surg 2003, 138:941-948. the ampulla of Vater. Arch Surg 1991, 126:353-357. 27. Hsu HP, Yang TM, Hsieh YH: Predictors for patterns of failure after 7. Talamini MA, Moesinger RC, Pitt HA, Sohn TA, Hruban RH, Lillemoe KD, pancreaticoduodenectomy in ampullary cancer. Ann Surg Oncol 2007, Yeo CJ, Cameron JL: Adenocarcinoma of the ampulla of Vater: a 28-year 14:50-60. experience. Ann Surg 1997, 225:590-600. 28. 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Arch Surg 2001, 136:65-69. ductal cancer of the pancreatic head. Br J Surg 1995, 82:1686-1691. 33. Lee JH, Whittington R, Williams NN, Berry MF, Vaughn DJ, Haller DG, 13. Gastrointestinal Tumor Study Group: Further evidence of effective Rosato EF: Outcome of pancreaticoduodenectomy and impact of adjuvant combined radiation and chemotherapy following curative adjuvant therapy for ampullary carcinomas. Int J Radiat Oncol Biol Phys resection of pancreatic cancer. Cancer 1987, 59:2006-2010. 2000, 47:945-953. 14. Klinkenbijl JH, Jeekel J, Sahmoud T, van Pel R, Couvreur ML, Veenhof CH, 34. Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Arnaud JP, Gonzalez DG, de Wit LT, Hennipman A, Wils J: Adjuvant Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, radiotherapy and 5- Fluorouracil after curative resection of cancer of the Narang et al. Radiation Oncology 2011, 6:126 Page 11 of 11 http://www.ro-journal.com/content/6/1/126 Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H: Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer. JAMA 2007, 297:267-277. 35. Takada T, Amano H, Yasuda H, Nimura Y, Matsushiro T, Kato H, Nagakawa T, Nakayama T: Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer 2002, 95:1685-1695. 36. Neoptolemos JP, Moore MJ, Cox TF, Valle JW, Palmer DH, Mcdonald A, Carter R, Tebbutt NC, Dervenis C, Smith D, Glimelius B, Coxon FY, Lacaine F, Middleton MR, Ghaneh P, Bassi C, Halloran C, Olah A, Rawcliffe CL, Büchler MW: Ampullary cancer ESPAC-3 (v2) trial: A multicenter, international, open-label, randomized controlled phase III trial of adjuvant chemotherapy versus observation in patients with adenocarcinoma of the ampulla of vater [abstract]. J Clin Oncol 2011, 29, abstr LBA4006. 37. Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J: Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010, 14:1273-1281. doi:10.1186/1748-717X-6-126 Cite this article as: Narang et al.: Evaluation of adjuvant chemoradiation therapy for ampullary adenocarcinoma: the Johns Hopkins Hospital - Mayo Clinic collaborative study. Radiation Oncology 2011 6:126. 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Evaluation of adjuvant chemoradiation therapy for ampullary adenocarcinoma: the Johns Hopkins Hospital - Mayo Clinic collaborative study

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Springer Journals
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Copyright © 2011 by Narang et al; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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1748-717X
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10.1186/1748-717X-6-126
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21951377
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Abstract

Background: The role of adjuvant chemoradiation therapy for ampullary carcinoma is unknown. Previous literature suggests that certain populations with high risk factors for recurrence may benefit from adjuvant chemoradiation. We combined the experience of two institutions to better delineate which patients may benefit from adjuvant chemoradiation. Methods: Patients who underwent curative surgery for ampullary carcinoma at the Johns Hopkins Hospital (n = 290; 1992-2007) and at the Mayo Clinic (n = 130; 1977-2005) were reviewed. Patients with <60 days of follow-up, metastatic disease at surgery, or insufficient pathologic data were excluded. The final combined study consisted of 186 patients (n = 104 Johns Hopkins, n = 82 Mayo). Most patients received 5-FU based chemoradiation with conformal radiation. Cox proportional hazards models were used for survival analysis. Results: Median overall-survival was 39.9 months with 2- and 5-year survival rates of 62.4% and 39.1%. On univariate analysis, adverse prognostic factors for overall survival included T3/T4 stage disease (RR = 1.86, p = 0.002), node positive status (RR = 3.18, p < 0.001), and poor histological grade (RR = 1.69, p = 0.011). Patients who received adjuvant chemoradiation (n = 66) vs. surgery alone (n = 120) showed a higher rate of T3/T4 stage disease (57.6% vs. 30.8%, P < 0.001), lymph node involvement (72.7% vs. 30.0%, P < 0.001), and close or positive margins (4.6% vs. 0.0%, P = 0.019). Five year survival rates among node negative and node positive patients were 58.7% and 18.4% respectively. When compared with surgery alone, use of adjuvant chemoradiation improved survival among node positive patients (mOS 32.1 vs. 15.7 mos, 5 yr OS: 27.5% vs. 5.9%; RR = 0.47, P = 0.004). After adjusting for adverse prognostic factors on multivariate analysis, patients treated with adjuvant chemoradiation demonstrated a significant survival benefit (RR = 0.40, P < 0.001). Disease relapse occurred in 37.1% of all patients, most commonly metastatic disease in the liver or peritoneum. Conclusions: Node-positive patients with resected ampullary adenocarcinoma may benefit from 5-FU based adjuvant chemoradiation. Since a significant proportion of patients develop metastatic disease, there is a need for more effective systemic treatment. Keywords: ampullary, carcinoma, adjuvant, chemoradiation, resectable * Correspondence: jherma15@jhmi.edu Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Full list of author information is available at the end of the article © 2011 Narang et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Narang et al. Radiation Oncology 2011, 6:126 Page 2 of 11 http://www.ro-journal.com/content/6/1/126 Background Methods Although carcinoma of the ampulla of Vater is a rare Study design and participants malignancy with an overall incidence of 6 in 1 million, it The study was approved by the institutional review is the second most common periampullary cancer, com- boards of the Mayo Clinic, Rochester, MN, and the prising 6-20% of malignancies in this region [1-3]. Com- JohnsHopkins Hospital,Baltimore,MD. Thestudy pared to pancreatic adenocarcinoma, ampullary cancer is cohort was drawn from all patients who underwent associated with a higher likelihood of resectability and a curative surgery for ampullary carcinoma at the Johns more favorable prognosis. Whereas patients with resect- Hopkins Hospital between 1992 and 2007 (n = 290, pro- able pancreatic adenocarcinoma show a 5-year survival of spectively collected) and the Mayo Clinic from 1977 to only 20%, most retrospective reviews of ampullary cancer 2005 (n = 130, retrospectively collected). Cancer of the over the past two decades have reported 5-year survival ampulla of Vater was defined as adenocarcinoma between 30-40% [4-11]. The earlier appearance of directly centered on or associated with an in situ carci- obstructive symptoms, more favorable histology, and a noma of the ampulla, papilla, or both, as evidenced by decreased inclination for lymphatic or perineural inva- review of the final pathology report. Patients with can- sion have all been cited as potential explanations for the cers arising from the duodenum, pancreatic head, or better outcomes with ampullary carcinoma [12]. common bile duct were not eligible. Patients who were Pancreaticoduodenectomy (PD) remains the only pos- referred to outside institutions for adjuvant therapy or sible curative treatment for patients with pancreatic or follow-up care were excluded because information ampullarycancer,but theroleofadjuvanttherapy regarding the details of their outcomes or whether they remains controversial. In the United States, postopera- received adjuvant treatment was unavailable (n = 156). tive adjuvant chemoradiation (CRT) has been used for Individuals who died within 60 days of surgery (n = 6), pancreatic cancer based on evidence suggesting had less than 60 days of follow-up (n = 6), or had evi- improved survival [4,13,14]. Whether these results can dence of metastatic disease at surgery (n = 11) were be extrapolated to resected ampullary carcinoma has excluded as well. Those missing information on T-stage, been an area of active debate. A 1999 randomized con- tumor size, margin status, node status, or histologic trolled trial by the European Organization for Research grade (n = 55) were also not analyzed. The final study and Treatment of Cancer (EORTC) examined post- population contained 186 patients (n = 104 JHH, n = 82 operative 5-fluorouracil (5-FU) based CRT in patients Mayo). with pancreatic head or other periampullary malignan- All patients received preoperative staging by one or cies. This study demonstrated no survival benefit in more of the following modalities: abdominal and pelvic- patients with periampullary cancer at 2 or 5 years, but computed tomography (CT), endoscopic retrograde cho- the number of patients with ampullary carcinoma was langiopancreatography (ERCP), endoscopic ultrasonogra- small, most of whom had favorable prognostic factors phy (EUS), and percutaneous transhepatic [14]. More recently, a retrospective review from the MD cholangiography or percutaneous biliary drainage (PTC/ Anderson Cancer Center showed a borderline significant PBD). The majority of patients (77%) received both CT improvement in survival with CRT in a subset of and ERCP. Laboratory tests included a full blood count, patients with advanced tumor stage (T3/T4), while a serum electrolytes, creatinine, urea, liver transaminases, study from the Mayo Clinic found a survival benefit in alkaline phosphatase, total bilirubin, carcinoembryonic patients with pathologic lymph node involvement antigen (CEA), and carbohydrate antigen 19-9 (CA19-9). [15,16]. A third review from the Johns Hopkins Hospital Patient demographic and pathologic data are outlined (JHH) also suggested a potential survival benefit from in Table 1. Of the 186 patients in the study, 109 (59%) CRT in patients with resected ampullary carcinoma who were male. Median age was 68 years (range 29-90 had lymph node involvement, although this finding was years). Pathologic data is limited to those variables not statistically significant (p = 0.092) [17]. While these potentially conferring poor prognosis, including T-stage, studies indicate that certain subsets of patients with tumor size, lymph node status, histologic grade, and ampullary carcinoma may benefit from postoperative margin status. CRT, they are limited by the small number of patients analyzed. In the present study, we combine the experi- Surgery ence of two of the aforementioned institutions, namely Patients underwent either a pylorus-preserving or classic the Johns Hopkins Hospital and the Mayo Clinic, to pancreaticoduodenectomy (PD). A pylorus-preserving compare surgery followed by modern conformal 5-FU PD included resection of the head and uncinate process based adjuvant CRT with surgery alone for patients with of the pancreas, distal bile duct, all but the most proxi- resectable carcinoma of the ampulla of Vater. mal duodenum, and gallbladder, when present. In a Narang et al. Radiation Oncology 2011, 6:126 Page 3 of 11 http://www.ro-journal.com/content/6/1/126 Table 1 Baseline Characteristics between Treatment Groups Observation Only Adjuvant Chemoradiation (CRT) Therapy P-Value N = 120 N= 66 DEMOGRAPHIC Age at Surgery (yr) Mean, (SD*) 68.9 (11.6) 62.0 (10.8) <0.001 Median (Range) 71.3 (28.7-90.3) 63.3 (29.3-81.5) Gender Male, No. (%) 66 (55.0) 43 (65.2) 0.179 Institution Mayo Clinic 63 (52.5) 19 (28.8) 0.002 Johns Hopkins Hospital (JHH) 57 (47.5) 47 (71.2) TUMOR CHARACTERISTCS T Stage 1 37 (30.8) 8 (12.1) 0.002 2 46 (38.3) 20 (30.3) 3 33 (27.5) 34 (51.5) 4 4 (3.3) 4 (6.1) Tumor Diameter < 3 cm 81 (67.5) 39 (59.1) 0.251 ≥ 3 cm 39 (32.5) 27 (40.9) Nodal Status N0 84 (70.0) 18 (27.3) <0.001 N1 36 (30.0) 48 (72.3) Histologic Grading 1 8 (6.7) 0 (0.0) 0.053 2 52 (43.3) 25 (37.9) 3 60 (50.0) 41 (62.1) Surgical Margins Positive 0 (0.0) 3 (4.6) 0.019 Negative 120 (100.0) 63 (95.4) *SD = standard deviation classic PD, the antrum of the stomach was also resected. carcinoma was close to (within 1 mm) or present at At JHH, 82.5% of patients underwent a pylorus-preser- these margins. ving PD, while these data were unavailable for patients treated at the Mayo Clinic. All pathology specimens Chemoradiation regimen were reviewed by either a pathologist at JHH or cen- Of the 186 patients in this study, 120 (64.5%) received trally at the Mayo Clinic, and patients were restaged surgery alone, while 66 (35.5%) were given adjuvant according to American Joint Committee on Cancer CRT. In patients receiving adjuvant therapy, radiation (AJCC) guidelines, sixth edition. Pathologic data regard- treatments were administered with a 3-field coplanar ing T stage, tumor size, histologic grade, lymph node approach (7.6%), 4-field coplanar approach (78.8%), 5- involvement, lymphovascular invasion, perineural inva- field non-coplanar approach (3.0%), or intensity modu- sion, and surgical margins were recorded. Lymph nodes lated radiation therapy (IMRT, 10.6%). A total of 45 Gy were considered positive if the resection specimen con- was generally delivered to the ampullary tumor bed tained metastatic carcinoma in any of the lymph nodes, (based on preoperative images), surgical anastomoses whether they were involved by direct extension or con- (hepatojejunostomy, pancreaticojejunostomy) and adja- tiguous with the primary tumor. At the Mayo Clinic, cent regional lymph nodes (proximal celiac and superior margin status was determined by the presence of carci- mesenteric). Additional radiation (5-15 Gy) was admi- noma at the final pancreatic neck, uncinate process, bile nistered to the tumor bed/area of involved margins and duct, duodenal, or retroperitoneal soft tissue margin. At anastomoses paying careful attention to the dose to the JHH, resection margins were considered positive if the small bowel. The median total dose was 50.4 Gy (range Narang et al. Radiation Oncology 2011, 6:126 Page 4 of 11 http://www.ro-journal.com/content/6/1/126 37.8-50.4 Gy). Radiation was given in consecutive, daily 3). Survival curves were estimated with Kaplan-Meier fractions except for 7 patients (10.6%) who underwent a techniques. two week planned break in therapy as part of a treat- ment protocol investigating split-course chemoradiation. Results In this protocol, patients received two weeks of 5-fluor- At thetimeofanalysis, 82 patients (44.1%) were still ouracil based chemoradiation, a two week treatment alive while 104 patients (55.9%) had died. Progression of break, and two additional weeks of 5-fluorouracil based disease was the cause of death for 58 patients (55.2%), chemoradiation, followed by 5-fluorouracil based main- while the remaining 46 deaths (44.8%) were from tenance chemotherapy. No patient received neoadjuvant unknown or other causes. Median follow-up time for or intraoperative radiation. Concurrent chemotherapy surviving patients was 31.7 months (range 2.0 - 160.1 most commonly consisted of 5-fluorouracil (95.5%), months). although three patients (4.5%) received gemcitabine. As displayed in Table 1, when compared with patients Maintenance chemotherapy was given to 37.9% of who were treated with surgery alone, those patients who patients in the form of single-agent 5-fluorouracil received adjuvant CRT were significantly younger (62.0 (15.2%), single-agent gemcitabine (19.7%), or combina- vs. 68.9, p < 0.001), were more likely from JHH (71.2% tion gemcitabine with either cisplatin/erlotinib (1.5%) or vs. 47.5%, p = 0.002), had more advanced T-stage (T3/ capecitabine (1.5%). All patients who received mainte- T4: 57.6% vs. 30.8%, p = 0.002), and showed more fre- nance chemotherapy were treated at JHH. Note that quent pathologic lymph node involvement (72.3% vs. patients were not excluded from our analysis based on 30.0%, p < 0.001). Patients in the CRT group also more the concurrent or maintenance chemotherapeutic agents frequently had close or positive surgical margins (4.6% that were administered given the lack of clear evidence vs. 0.0%, p = 0.019), although only three patients in the supporting a specific regimen. None of the patients in entire sample had close or positive margins, all of whom this study were treated with adjuvant chemotherapy were given CRT. Histologic grade, while not significantly alone. different between treatment groups, did show a trend towards poorer differentiation amongst patients given Statistical Analysis CRT (grade 3: 62.1% vs. 50.0%, p = 0.053). Neither Statistical analysis was performed using STATA, version tumor size nor gender was associated with the type of 9 (Stata, College Station, TX). Summary statistics for treatment that the patient received. Additionally, when continuous and dichotomous variables are provided. In patient demographics and tumor characteristics were constructing dichotomous variables, thresholds were stratified by institution, there was no significant differ- ence between the JHH and Mayo cohorts for any of defined in accordance with the literature [15-18]. The distribution of prognostic variables between treatment these factors (results not shown). groups was compared using Pearson’s chi-squared test. Median overall survival (mOS) for all patients was The primary outcome variable was overall survival (OS), 39.9 months (95% CI: 29.5 - 54.7 months) with a 2-year defined as the time from surgical resection to death. and 5-year survival of 62.4% and 39.1%, respectively. As Survival time was censored at date of last follow up if displayed in Table 2, on univariate analysis, lymph node death had not occurred. Univariate analysis was con- involvement had the strongest association with ducted using the log-rank test to examine risk factors decreased overall survival (mOS: 23.0 vs. 79.4 months, and associations with mortality. Median OS was esti- RR 2.11 - 4.78, p < 0.001). Advanced T-stage and poor mated within each risk group and by adjuvant treat- histologic differentiation were also significantly asso- ment. The proportion of individuals surviving up to 2 ciated with poor prognosis. Specifically, tumors classified and 5 years was calculated using life tables and stratified as T3/T4 showed significantly worse overall survival by treatment group to assess for a significant difference compared with T1/T2 disease (mOS: 27.0 vs. 55.4 using the log-rank test. Proportional hazards models months, RR 1.26 - 2.75, p = 0.002), as did grade 3 his- were used to examine the association of adjuvant treat- tology when compared with grade 1 or 2 disease (mOS: ment, baseline patient characteristics, and pathologic 32.1 vs. 60.0 months, RR 1.13 - 2.53, p = 0.011). Age, data with mortality. To explore the independent associa- gender, institution, tumor size, and margin status were tion of adjuvant therapy and OS, multivariate analysis not predictive of overall survival. Furthermore, as illu- was performed, adjusting for possible confounders, strated in Figure 1, adjuvant treatment with CRT was namely age, sex, institution, tumor stage, tumor size, not significantly associated with overall survival when lymph node status, and histologic differentiation. Margin compared with surgery alone (median survival 39.9 vs. status was not included in multivariate analysis due to a 40.1 months, RR 0.64 - 1.43, p = 0.839) using univariate analysis. As shown in Table 3, when patients were paucity of patients with close or positive margins (n = Narang et al. Radiation Oncology 2011, 6:126 Page 5 of 11 http://www.ro-journal.com/content/6/1/126 Table 2 Associations of Overall Survival with Patient Tumor and Treatment Characteristics No. (%) 2-Year Survival, % 5-year Survival, % Median Survival, months Univariate RR (95% CI) P-value Age, yrs < 75 137 (73.7) 66.5 41.2 40.6 1.00 0.281 ≥ 75 49 (26.3) 66.7 32.5 35.5 1.27 (0.82 - 1.98) Gender Female 77 (41.4) 67.4 37.4 39.9 1.00 0.954 Male 109 (58.6) 66.0 40.4 36.5 0.99 (0.67 - 1.47) Institution Mayo Clinic 82 (44.1) 68.6 39.9 40.6 1.00 0.350 JHH 104 (55.9) 64.8 38.9 36.9 1.20 (0.81 - 1.78) T stage 1/2 111 (59.7) 75.0 46.3 55.4 1.00 0.002 3/4 75 (40.3) 54.1 28.1 27.0 1.86 (1.26 - 2.75) Tumor Size ≤ 3 cm 120 (64.5) 72.5 39.3 40.1 1.00 0.838 > 3 cm 66 (35.5) 56.5 38.3 35.5 1.04 (0.70 - 1.55) Node Status Negative 102 (54.8) 84.1 58.7 79.4 1.00 <0.001 Positive 84 (45.2) 47.2 18.4 23.0 3.18 (2.11 - 4.78) Histology Grade 1/2 85 (45.7) 75.8 49.9 60.0 1.00 0.011 Grade 3 101 (54.3) 59.1 30.6 32.1 1.69 (1.13 - 2.53) Margin Status Negative 183 (98.4) 66.6 39.3 39.9 1.00 0.493 Positive 3 (1.6) 33.3 0.0 33.3 1.49 (0.47 - 4.72) Adjuvant Treatment None 120 (64.5) 67.3 37.2 40.1 1.00 0.839 CRT* 66 (35.5) 65.3 42.1 39.9 0.96 (0.64 - 1.43) *CRT = chemoradiation stratified into eight risk groups, and survival by treat- overall survival on multivariate analysis, with node posi- ment type was compared within each subgroup, the tive patients experiencing significantly increased risk of only patients who showed a significant difference in death (RR 2.50 - 7.17, p < 0.001). Of the 66 patients who underwent adjuvant CRT, 41 median survival between adjuvant CRT and surgery alone were those with pathologic lymph node involve- (62.1%) experienced some form of toxicity during therapy. ment (mOS: 32.1 vs. 15.7 months, p = 0.004). In node- The most common toxicities reported were nausea positive patients, adjuvant CRT resulted in a 5-year sur- (25.8%), diarrhea (16.7%), weight loss (9.1%), fatigue vival of 27.5%, while surgery alone led to a 5-year rate (9.1%), and epigastric pain (7.6%). While side effects of only 5.9%. Figure 2 compares the survival curves by tended to be mild in nature, treatment-related toxicity did treatment type for node-positive patients. Median survi- lead to an interruption of therapy in 8 patients (12.1%). val was also higher in node negative patients receiving Grade 3 toxicities were reported in two patients from the adjuvant CRT (mOS: 103.2 vs. 61.6 months), but the dif- Mayo Clinic who suffered from myelosuppression and ference was not statistically significant (p = 0.122). sepsis respectively. The grade of toxicity for patients trea- As displayed in Table 4, on multivariate analysis, adju- ted at JHH was unavailable, although no patient from JHH vant CRT was significantly associated with improved was hospitalized for radiation-associated toxicity. There overall survival (RR 0.25 - 0.67, p < 0.001), when were no known treatment related deaths. adjusted for age, gender, institution, T-stage, tumor size, Sixty-nine patients (37.1%) experienced a recurrence node status, and grade. Additionally, lymph node invol- by the end of follow-up. The most common pattern of vement was the only other variable associated with initial recurrence was distant metastasis without local Narang et al. Radiation Oncology 2011, 6:126 Page 6 of 11 http://www.ro-journal.com/content/6/1/126 Pancreaticoduodenectomy is the preferred surgical approach for carcinoma of the ampulla of Vater that is amenable to resection [19]. However, similar to pancrea- tic cancer, the role of post-operative adjuvant therapy remains undefined. While prognosis for resectable ampullary carcinoma is considerably better than for pancreatic cancer, patients with node positive disease have poor survival and appear to benefit from adjuvant therapy [20,21]. A number of reports, mostly consisting of single institution series, have established adverse prognostic factors, including extent of local invasion, status of surgical margins, presence of nodal metastasis, and histologic grade, all of which predict for overall sur- vival as well as local and distant disease [5-9,22-29]. In these cohorts, nodal involvement has been a particularly Figure 1 Survival following pancreaticoduodenectomy strong predictor of poor outcomes, with 5-year survival stratified by type of adjuvant therapy. Kaplan-Meier curves rates following PD ranging from 64-80% in patients with comparing overall survival between patients who received adjuvant node-negative disease and 17-50% in patients with chemoradiation (n = 66) and those treated with surgery alone (n = node-positive disease. A more recent population-based 120). Adjuvant therapy was not significantly associated with improved overall survival (p = 0.839) on univariate analysis. analysis of roughly 4,000 patients with ampullary carci- noma was conducted using the National Cancer Insti- tute’s Surveillance, Epidemiology, and End Results relapse, which was seen in 49 patients (26.3%). Thirteen database [30]. Outcomes were slightly worse than the patients (7.0%) had both local and metastatic disease at aforementioned series from specialized cancer centers initial relapse. Only 7 patients (3.8%) presented with but were highly dependent on nodal metastasis (5 year local recurrence without evidence of metastatic spread, survival: 47.6% vs. 21.0%). of which 6 had not been given adjuvant therapy. The High rates of relapse along with identification of distribution in patterns of initial recurrence between adverse prognostic factors have led to exploration of treatment groups is summarized in Table 5. Overall, the adjuvant chemoradiation for “high risk” ampullary carci- liver was the most common site of metastasis, with noma, although the literature in this area remains sparse. Willett et al. first reported a trend towards 24.7% of all patients and 36.5% of those patients who improved local control with no improvement in overall died harboring disease in the liver. The peritoneum was survival when adjuvant 5-FU based chemoradiation was the second most common site of metastasis, present in given to a small cohort of patients with high risk fea- 5.9% of all patients and 9.5% among those patients who tures, defined as invasion of the pancreas, nodal metas- died. Lung metastases were found in 4.8% of all patients tasis, positive margins, or poor histology [31]. A and 6.7% of patients who died, making it the third most subsequent review by Mehta et al. reported a favorable common site of distant spread. 3-year actuarial survival rate of 44% using adjuvant 5- FU based chemoradiation in patients with large tumor Discussion size, nodal involvement, positive surgical margins, poor This combined series of patients with ampullary carci- histology, or neurovascular invasion [32]. Similarly, Lee noma represents the largest study to date that demon- et al. achieved superior disease-free survival in patients strates an overall survival benefit in patients receiving adjuvant chemoradiation following surgical resection with advanced tumor stage (T3/T4) or positive nodes when controlling for adverse prognostic factors. After receiving adjuvant chemoradiation [33]. On multivariate adjusting for institution, patient demographics such as analysis, adjuvant therapy was also a significantly favor- age and gender, and disease characteristics such as able factor for the entire cohort (HR: 0.16, p = 0.030). tumor stage, tumor size, nodal involvement, and histol- However, less than twenty patients received adjuvant ogy, patients treated with adjuvant CRT experienced therapy in each of these studies, making it difficult to enhanced survival (HR = 0.41, 95% CI: 0.25-0.67, p < derive convincing conclusions. 0.001). This series also confirms improved outcomes in More recently, three retrospective studies from institu- patients with ampullary carcinoma when compared with tions that treat high volumes of periampullary malignan- cies reviewed their experience with adjuvant CRT for pancreatic cancer, with a median survival of 39.9 ampullary carcinoma. Krishnan et al. examined 96 months and two and five-year survival rates of 62.4% patients, 54 of whom had received adjuvant CRT and 39.1% respectively. Narang et al. Radiation Oncology 2011, 6:126 Page 7 of 11 http://www.ro-journal.com/content/6/1/126 Table 3 Survival between Treatment Groups by Patient, Tumor, and Treatment Characteristics No. of Patients, (%) Overall Survival, Median, mo 5-year Survival, Percent Observation Adjuvant CRT Observation Adjuvant CRT P-value Observation Adjuvant CRT ALL PATIENTS 120 (64.5) 66 (35.5) 39.9 40.1 0.839 37.2 42.1 Age, yrs < 75 79 (57.7) 58 (42.3) 41.3 40.6 0.913 37.9 45.9 ≥ 75 41 (83.7) 8 (16.3) 35.5 33.3 0.939 36.0 25.0 Gender Female 54 (70.1) 23 (20.9) 42.7 32.1 0.162 40.8 29.3 Male 66 (60.6) 43 (39.4) 32.2 46.0 0.238 33.9 48.4 Institution Mayo 63 (76.8) 19 (23.2) 38.2 62.4 0.599 35.5 51.3 Hopkins 57 (54.8) 47 (45.2) 41.7 36.5 0.890 40.0 37.0 Histology Grade 1/2 60 (70.6) 25 (29.4) 53.6 62.2 0.328 47.1 56.6 Grade 3 60 (59.4) 41 (40.6) 34.9 27.1 0.985 27.5 34.1 Node Negative 84 (82.4) 18 (17.7) 61.6 103.2 0.122 52.4 87.1 Positive 36 (42.9) 48 (57.1) 15.7 32.1 0.004 5.9 27.5 Tumor Stage T1/T2 83 (74.8) 28 (25.2) 41.3 87.5 0.172 41.7 56.8 T3/T4 37 (49.3) 38 (50.7) 27.0 25.0 0.873 27.5 28.7 Tumor Size ≤ 3 cm 81 (67.5) 39 (32.5) 41.3 36.5 0.797 38.8 40.0 > 3 cm 39 (59.1) 27 (40.9) 27.0 40.6 0.496 33.9 44.0 Margin status Negative 120 (65.6) 63 (34.4) 40.1 39.9 0.754 37.2 42.7 Positive 0 (0.0) 3 (100.0) N/A 33.3 N/A N/A 33.3 *CRT = chemoradiation consisting of either preoperative radiation to a median dose of 45 Gy or postoperative radiation to a median dose of 50.4 Gy, with concurrent 5-FU or capecitabine [15]. Patients with advanced T-stage (T3/T4) who were treated with CRT showed a borderline significant increase in survival (mOS: 35.2 vs. 16.5 months, p = 0.06). Similarly, a JHH review of 111 patients identified a trend towards improved survival with adjuvant CRT among those patients with nodal metastasis (mOS: 30.0 vs. 21.6 months, p = 0.092) [17]. Postoperative therapy in this study consisted of a median radiation dose of 50.4 to the tumor bed and regional nodes with concur- rent 5-FU or capecitabine. Furthermore, a statistically significant difference in survival among patients with lymph node involvement treated with adjuvant CRT was Figure 2 Survival following pancreaticoduodenectomy in node found in a previous study from the Mayo Clinic (mOS: positive patients stratified by type of adjuvant therapy. Kaplan- 3.4 vs. 1.6 years, p = 0.02) [16]. Note, however, that in Meier curves comparing overall survival amongst node-positive patients between patients who received adjuvant chemoradiation (n none of these studies was adjuvant CRT associated with = 48) and those treated with surgery alone (n = 36). In node- increased survival on multivariate analysis. positive patients, adjuvant therapy was significantly associated with In the present series, adjuvant therapy was not found improved overall survival (p = 0.004) on univariate analysis. on univariate analysis to be associated with increased Narang et al. Radiation Oncology 2011, 6:126 Page 8 of 11 http://www.ro-journal.com/content/6/1/126 Table 4 Multivariate Cox Proportional Hazards Survival proportion of patients with advanced T-stage (p = Analysis of Adjuvant Chemoradiation therapy and 0.002), pathologic lymph node involvement (p < 0.001), Overall Survival and positive surgical margins (p = 0.019), and a border- RR (95% CI) P-value line statistically significant trend towards poorer histolo- Age, yrs gic grade (p = 0.053). The fact that survival was comparable between treatment groups despite these dis- < 75 1.00 0.755 crepancies suggests the potential benefit of adjuvant ≥ 75 0.93 (0.57 - 1.50) CRT, particularly amongst high risk populations. Gender Moreover, when baseline demographic and treatment- Female 1.00 0.402 related characteristics were adjusted for on multivariate Male 0.84 (0.56-1.26) analysis, a significant association between adjuvant ther- Institution apy and improved survival appeared. Indeed, this study Mayo 1.00 0.222 represents the second reported survival benefit from Hopkins 1.30 (0.85-1.99) adjuvant CRT found on multivariate analysis, albeit with Tumor Stage a much larger cohort than was analyzed in the afore- mentioned study by Lee et al [33]. Interestingly, when T1/T2 1.00 0.317 patients were stratified by baseline demographic and dis- T3/T4 1.24 (0.81-1.91) ease-related characteristics, no subgroup showed a sig- Tumor Size nificant survival benefit from adjuvant CRT except for ≤ 3 cm 1.00 0.391 patients with nodal metastasis, who experienced a large > 3 cm 1.20 (0.79-1.80) difference in median survival (mOS: 32.1 vs. 17.5 Node months, p = 0.004). As suggested in multiple previous Negative 1.00 <0.001 studies, node-positive patients were found to carry a Positive 4.29 (2.5-7.17) very poor prognosis on both univariate analysis (p < Histology 0.001) and multivariate analysis (p < 0.001), with a med- Grade 1/2 1.00 0.191 ian survival of only 18.4 months. The fact that node- positive patients who were not treated with adjuvant Grade 3 1.35 (0.86-2.41) CRT showed a dismal 5-year survival rate of only 5.9% Adjuvant Treatment indicates that this group may be particularly suited for Observation 1.00 <0.001 post-operative therapy. Moreover, while the effect of Adjuvant CRT* 0.41 (0.25 - 0.67) adjuvant therapy in node negative patients did not reach *CRT = chemoradiation statistical significance, the absolute difference in survival (mOS: 103.2 vs. 61.6 months) is noteworthy and remi- survival when compared to surgery (mOS: 39.9 vs. 40.1 niscent of the CONKO-001 trial in which node negative months, p-0.839), as summarized in Table 2 and illu- pancreatic cancer patients experienced superior survival strated in Figure 1. This lack of survival benefit is likely with adjuvant chemotherapy [34]. a result of the imbalance in adverse prognostic factors While good local control was achieved in this study, between treatment groups. In this series, nodal metasta- nearly a third of patients suffered from distant relapse, sis (p < 0.001), advanced T stage (p = 0.002), and poorly and roughly 90% of recurrences were attributable in differentiated histology (p = 0.011) were all significantly part to metastatic disease. Consistent with the literature, associated with decreased survival. While margin status the most common sites of metastasis were the liver and was not a predictor of survival (p = 0.493), margin sta- peritoneum. Overall, progression of disease led to more tus is widely considered to be a poor prognostic factor, than half of the deaths in the cohort, with nearly one and its lack of association with survival in this study third of patients who died harboring disease in the liver. maybeattributabletothe smallnumberofpatients The prevalence of metastatic disease suggests the need withcloseorpositivemargins (n =3). Regardless,the formoreeffectivesystemictherapy,particularlyin high cohort that received CRT had a significantly higher risk patients. Unfortunately, there is even less Table 5 Initial Sites of First Recurrence by Treatment Group No Recurrence Local Recurrence Distant Recurrence Local & Distant Overall Recurrences Total Patients CRT 31 (47.0%) 1 (1.5%) 23 (34.8%) 11 (16.7%) 35 (53.0%) 66 No CRT 86 (71.7%) 6 (5.0%) 26 (21.7%) 2 (1.7%) 34 (28.3%) 120 Total 118 (63.4%) 7 (3.8%) 49 (26.3%) 12 (6.5%) 68 (36.6%) 186 Narang et al. Radiation Oncology 2011, 6:126 Page 9 of 11 http://www.ro-journal.com/content/6/1/126 information regarding appropriate type and duration of association between institution and survival on univari- chemotherapeutic agents when incorporated with radia- ate or multivariate analysis, and institution did not affect tion for ampullary cancer. Furthermore, the role of adju- outcomes when stratified by treatment type. Another vant chemotherapy alone is an area that has been largely limitation was the number of patients excluded for understudied, a remnant of borrowed U.S. practice pat- either missing data (i.e. stage or nodal status) or because terns supporting adjuvant CRT for resected pancreatic they were lost to follow-up. It is probable that follow-up was not consistent among treatment groups, with cancer. A Japanese study of adjuvant mitomycin C and patients receiving adjuvant therapy likely showing better 5-FU for pancreaticobiliary carcinomas found no overall follow-up. The number of patients lost to follow along or disease-free survival benefit in a subset of 24 patients with ampullary carcinoma when compared to surgery with thenumberofpatientsaliveattimeofanalysis alone [35]. More recent and robust results from the resulted in a low number of documented recurrences. European Study Group for Pancreatic Cancer (ESPAC) - Ideally, we would have been able to examine the asso- 3(v2) trial also showed no difference in survival in 304 ciation between adjuvant therapy and patterns of recur- patients with resected ampullary cancer who were ran- rence, but the low number of recurrences prevented the domized to 5-FU/folinic acid, gemcitabine, or observa- possibility of meaningful analysis. Nevertheless, this tion [36]. Combination chemotherapy may provide study combines the experience of two high volume insti- better results, as a randomized control trial comparing tutions to allow for the largest series to date that has gemcitabine and cisplatin versus gemcitabine alone in examined the role of adjuvant therapy following surgery 410 patients with locally advanced or metastatic biliary for ampullary cancer. or ampullary cancers did show superior survival with the combination regimen (mOS: 11.7 vs. 8.1 months, p Conclusions < 0.001), although it should be acknowledged that only Lymph node involvement, advanced tumor stage, and 5% of tumors in the study had an ampullary origin [37]. poor histology are adverse prognostic factors associated Of note, no study has directly compared adjuvant che- with poor survival in patients with ampullary carcinoma. motherapy alone with adjuvant chemoradiation. The addition of adjuvant chemoradiation likely improves Given the retrospective nature of this study and wide survival in patients with high risk disease, particularly in time period over which this study spanned, our findings those with lymph node involvement. Whether all are limited by the variability in treatment regimens and patients with resectable ampullary carcinoma should be the potentially unequal distribution of confounding fac- treated with adjuvant chemoradiation is subject to tors in patient selection between treatment groups. Cer- debate. Certainly, better systemic therapy is necessary to tainly, patients in our study were subject to different improve the high rate of distant metastasis found in this operative methods, radiation plans, and chemotherapeu- population. ticagents, whichwewere unabletocontrol fordueto incomplete information or insufficient power. Addition- List of abbreviations ally, this study has shown that patients selected for adju- PD: pancreaticoduodenectomy; CRT: chemoradiation therapy; EORTC: vant CRT at the Johns Hopkins Hospital and the Mayo European Organization for Research and Treatment of Cancer; 5-FU: 5- fluorouracil; JHH: Johns Hopkins Hospital; CT: computed tomography; ERCP: Clinic possessed more adverse prognostic factors than endoscopic retrograde cholangiopancreatography; EUS: endoscopic those treated with surgery alone. While several high risk ultrasonography; PTC: percutaneous transhepatic cholangiography; PBD: characteristics were adjusted for in our analysis, other percutaneous biliary drainage; CEA: carcinoembryonic antigen; CA19-9: carbohydrate antigen 19-9; AJCC: American Joint Committee on Cancer; variables that were not taken into account include per- IMRT: intensity modulated radiation therapy. formance status and weight loss, both of which may be correlated with disease outcomes. Since patients who Acknowledgements This work was in part supported by the Claudio X Gonzalez Family received adjuvant CRT were significantly younger, it is Foundation. easy to imagine that healthier patients were more likely offered adjuvant treatment. The retrospective nature of Author details Department of Radiation Oncology, Johns Hopkins University School of our study may have also compromised our ability to Medicine, Baltimore, MD, USA. Department of Radiation Oncology, The accurately capture certain information such as the toxi- 3 Mayo Clinic, Rochester, MN, USA. Department of Radiation Oncology, city data, which was lower when compared to prior University of California, San Francisco, San Francisco, CA, USA. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, experience [14]. Furthermore, variations in institutional USA. The Sol Goldman Pancreatic Research Center, Johns Hopkins protocols regarding treatment delivery can be a source University School of Medicine, Baltimore, MD, USA. Department of of bias in studies analyzing data from multiple sites, but Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Pathology, Johns Hopkins University School of Medicine, it should be noted that while the distribution of treat- Baltimore, MD, USA. Department of Surgery, The Mayo Clinic, Rochester, ment type did in fact vary by institution, there was no MN, USA. Narang et al. Radiation Oncology 2011, 6:126 Page 10 of 11 http://www.ro-journal.com/content/6/1/126 pancreas and periampullary region. Phase III trial of the EORTC Authors’ contributions Gastrointestinal Tract Cancer Cooperative Group. Ann Surg 1999, AKN participated in the analysis and interpretation of data and drafting of 230:776-784. the manuscript. RCM contributed to study design and provided critical 15. Krishnan S, Rana V, Evans DB, Varadhachary G, Das P, Bhatia S, Delclos ME, revisions. CCH was involved in study design, acquisition and analysis of data, Janjan NA, Wolff RA, Crane CH, Pisters PW: Role of adjuvant and critical review of the manuscript. SB helped with acquisition and chemoradiation therapy in adenocarcinomas of the ampulla of vater. Int analysis of data and critical review of the manuscript. TMP contributed to J Radiat Oncol Biol Phys 2008, 70:735-743. interpretation of data and provided critical revisions. DL was involved with 16. Bhatia S, Miller RC, Haddock MG, Donohue JH, Krishnan S: Adjuvant interpretation of data and critical review of the manuscript. RHH provided therapy for ampullary carcinomas: the Mayo Clinic experience. Int J analysis and interpretation of data and critical revisions. JZ contributed to Radiat Oncol Biol Phys 2006, 66:514-519. acquisition and analysis of data and critical review of the manuscript. JMW 17. Zhou J, Hsu CC, Winter JM, Pawlik TM, Laheru D, Hughes MA, was involved in analysis and interpretation of data and critical review of the manuscript. MGH helped with study design and interpretation of data and Donehower R, Wolfgang C, Akbar U, Schulick R, Cameron J, Herman JM: provided critical revisions. JHD participated in interpretation of data and Adjuvant chemoradiation versus surgery alone for adenocarcinoma of critical review of the manuscript. RDS provided interpretation of data and the ampulla of Vater. Radiotherapy and Oncology 2009, 92:244-248. critical revisions. CLW contributed to study design, interpretation of data, 18. Horowitz DP, Hsu CC, Wang J, Makary MA, Winter JM, Robinson R, and critical review of the manuscript. JLC participated in study design, Schulick RD, Cameron JL, Pawlik TM, Herman JM: Adjuvant chemoradiation interpretation of data, and critical revisions. JMH contributed to study therapy after pancreaticoduodenectomy in elderly patients with conception and design, interpretation of data, and drafting of the adenocarcinoma. Int J Radiat Oncol Biol Phys . manuscript. All authors have read and approved the final manuscript. 19. Winter JM, Cameron JL, Olino K, Herman JM, de Jong MC, Hruban RH, Wolfgang CL, Eckhauser F, Edil BH, Choti MA, Schulick RD, Pawlik TM: Competing interests Clinicopathologic analysis for ampullary neoplasms in 450 patients: The authors declare that they have no competing interests. implications for surgical strategy and long-term prognosis. J Gastrointest Surg 2010, 14:379-387. Received: 16 June 2011 Accepted: 28 September 2011 20. Kopelson G: Curative surgery for adenocarcinoma of the pancreas/ Published: 28 September 2011 ampulla of Vater: the role of adjuvant pre or postoperative radiation therapy. Int J Radiat Oncol Biol Phys 1983, 9:911-915. 21. 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Radiation OncologySpringer Journals

Published: Sep 28, 2011

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