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Clinical Outcome of Ampullary Carcinoma: Single Cancer Center Experience

Clinical Outcome of Ampullary Carcinoma: Single Cancer Center Experience Hindawi Journal of Oncology Volume 2019, Article ID 3293509, 7 pages https://doi.org/10.1155/2019/3293509 Research Article Clinical Outcome of Ampullary Carcinoma: Single Cancer Center Experience Mohammed Al-Jumayli ,Amna Batool,AkshayMiddiniti, Anwaar Saeed, Weijing Sun, Raed Al-Rajabi, Joaquina Baranda, Sean Kumer, Timothy Schmitt, Anusha Chidharla, and Anup Kasi Division of Medical Oncology, KU Cancer Center, eTh University of Kansas Health System, USA Correspondence should be addressed to Anup Kasi; anupdoc@gmail.com Received 11 November 2018; Revised 20 February 2019; Accepted 21 March 2019; Published 2 May 2019 Academic Editor: Jorg Kleeff Copyright © 2019 Mohammed Al-Jumayli et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction. Ampullary cancers represent a subset of periampullary cancers, comprising only 0.2% all gastrointestinal cancers. Localized disease is primarily managed by a surgical intervention, called pancreaticoduodenectomy (PD), followed in many cases by the administration of adjuvant chemotherapy (CT) or chemoradiation therapy (CRT). However, there are no clear evidence-based guidelines to aid in selecting both the modality and regimen of adjuvant therapy for resected Ampullary carcinoma. Methods. We retrospectively analyzed 54 patients at KU Cancer Center, who had undergone endoscopic resection or pancreaticoduodenectomy (PD) for Ampullary cancer from June 2006 to July 2016. We obtained patients’ baseline characteristics, clinical presentation, pathology, treatment modality, recurrence pattern, and survival outcomes. eTh time-to-events data were compared using Kaplan-Meier methods. A univariate and multivariate Cox proportional hazards regression was performed to evaluate factors associated with overall survival (OS) and generate hazard ratios (HR). Results. em Th ean age of the54 patients was 68 (37-90). 38 (70%) were males and 16 (30%) were females. Most of the patients were Caucasian (76%). Approximately half of all patients had a history of smoking, 20% had alcohol abuse, and 13% had pancreatitis. Among the 54 patients with localized cancers, 9 (16%) were treated definitively with nonoperative therapies, usually due to a prohibitive comorbidity profile, performance status, or unresectable tumor. 45 out of 54 patients (83%) underwent surgery. Of the 45 patients who underwent surgery, 18 patients (40% of the study cohort) received adjuvant therapy due to concerns for advanced disease as determined by the treating physician. 13 patients (24%) received adjuvant CT and 5 patients (9.2%) received CRT. The remaining 27 patients (50%) underwent surgery alone. eTh median OS for the entire study cohort was 30 months. When compared to surgery alone, adjuvant therapy with either CT or CRT had no statistically significant difference in terms of progression-free survival (p=0.56) or overall survival (p=0.80). In univariate Cox proportional hazards regression analysis, high-risk features like peripancreatic extension (16%) and perineural invasion (26%) were found to be associated with poor OS. Lymph node metastasis (29%) did not significantly aeff ct OS (HR 1.42, 95% CI [0.73-1.86]; p=0.84). Lymphovascular invasion (29%) was not associated with poor OS (HR 1.22, 95% CI[0.52, 2.96]; p=0.76). In multivariate Cox regression analysis, only age group>70 years was significantly associated with OS , while other factors, including the receipt of adjuvant therapy, lymph nodes, positive margin, and lymphovascular, perineural, and peripancreatic involvement, were not significantly associated with OS. ese Th results are likely due to small sample size. Conclusions. Despite numerous advances in both cancer care and research, efforts in rare malignancies such as Ampullary cancer remain very challenging with a clear lack of an evidence-based standard of care treatment paradigm. Although adding adjuvant therapies such as chemotherapy or chemoradiotherapy is likely to improve survival in high-risk disease, there is no standardized regimen for the treatment of Ampullary cancer. More research is required to elucidate whether statistically and clinically relevant dieff rences exist that may warrant a change in the current adjuvant treatment strategies. 2 Journal of Oncology 1. Introduction Ampullary carcinoma is a rare malignant tumor originating from the Ampulla of Vater [1, 2] The reported incidence is less than one per 100,000 in an autopsy series and in the general population comprises of 0.2% of all gastrointestinal tumors [1]. In 90% of patient cases, this represents a primary presentation with a predominance of Caucasian males being 40 aec ff ted over other races and gender [3]. In patients with hereditary polyposis syndromes, the incidence of Ampullary cancer is multifold and presents at an earlier age warranting surveillance endoscopy [4]. Previous retrospective studies have assessed the dif- 0 20 40 60 80 100 120 ference in prognosis of Ampullary carcinomas based on Figure 1: Overall survival (OS) of study cohort. immunohistologic subtypes. Pancreaticobiliary subtype ver- sus intestinal subtype showed a significant difference of almost 10-fold in median survival, 16 vs. 116 months, respec- tively [5]. In addition to immunohistochemical subtypes, with a followup of at least 2 years for each patient in order to nodal status was also found to have an impact on survival. obtain data relevant for long-term survival analysis. Patients with node-negative, nonpancreatobiliary type had The Institutional Review Board approved this retro- an excellent prognosis with 5-year survival rate of 88%, spective study. Data collection on eligible patients included while those with node-positive, pancreatobiliary type had patient baseline characteristics, clinical presentation, pathol- apoor prognosis with a5-year survival of 20%. Patients ogy, treatment modality, recurrence, and survival. Statistical with node-positive, nonpancreaticobiliary or node-negative, analysis was performed using SPSS 22.0 with statistical pancreatobiliary type had an intermediate prognosis with significance established at p<0.05. Both the Kaplan-Meier a 5-year survival of 47%. A recent meta-analysis reported method and log-rank were used to compare the time-to that pancreatobiliary type predicted a worse overall survival events. Univariate and multivariate Cox proportional hazards (hazard ratio [HR] 1.84, 95% CI 1.49- 2.27; p< 0.001) and regression model were created to identify factors associated disease-free survival (HR 1.93, 95% CI 1.23-3.01; p=0.004) with OS. Of note, many of the older cases included in the [6]. On the other hand, other studies failed to replicate study had no immunostaining performed by pathologists. similar findings, limiting their utility in diagnostic algo- Hence, we were unable to evaluate prognostic association rithms. Emerging evidence suggests an increased complexity with immunohistologic subtypes. of tumor subtypes such as the existence of a mixed subtypes which warrants further research instead of making treatment 3. Results decisions based on immunohistologic subtypes alone [7]. Patients with localized disease are primarily managed A total of 54 patients with Ampullary adenocarcinoma by pancreaticoduodenectomy (PD), oen ft followed by the were selected for evaluation. The epidemiology, clinical administration of adjuvant chemotherapy (CT) or chemora- presentation, pathologic features, and staging of Ampullary diation therapy (CRT) [2]. However, given the paucity of carcinoma at baseline are presented in Table 1. The mean clinical evidence, current treatment recommendations in the age of our patient cohort was 68 years. There were more adjuvant setting are not included in published consensus like males patients than females, 38 vs. 16 respectively. Most of NCCN or ESMO guidelines [8]. Retrospective and prospec- our patients were Caucasians (76%). Approximately half of tive studies have investigated the role of adjuvant therapy the patients (52%) had a history of smoking, 20% were alcohol in this context; however, the evidence remains inconclusive. abusers, and 13% had a history of pancreatitis. Our retrospective, single-center study was conducted to Nine patients were treated nonoperatively, secondary to evaluate whether any survival advantages exist with either a prohibitive comorbidity profile, performance status, or adjuvant chemotherapy or chemoradiotherapy compared to an unresectable tumor. Adjuvant treatment was adminis- surgery alone in the management of resected Ampullary tered after surgery because of concerns for advanced dis- carcinoma. ease determined by the treating physician in 18 patients: 13 (24%) received chemotherapy and 5 (9.2%) received chemoradiation therapy. The remaining 27 (50%) patients 2. Methods underwent surgery alone. The median OS for the study This was a retrospective study conducted at the Kansas cohort was found to be 30 months (Figure 1). Recurrence was University Cancer Center. Data was collected on patients noted in 40% of patients who underwent surgery. Patients with a diagnosis of Ampullary adenocarcinoma who were treated with adjuvant therapies following PD had a more treated at our institution between 2006 and 2016. Our study locally advanced disease than those who had surgery alone. enrollment was over a period of 10 years from 2006 to 2016 Most patients who received adjuvant therapy after surgical Survival probability (%) Journal of Oncology 3 Table 1: Baseline Characteristics. Table 2: Univariate Analyses. Results Hazard Ratio (95% CI) P-value Characteristics (n=54) Variable Age 1.22 (0.52-2.96) 0.6291 Mean 1.06 (0.70-1.06) 0.8504 Gender (Female vs. Male) (%) 1.24 (0.48-1.78) 0.7920 Age (years) Smoking (Yes vs. No) 0.91 (0.42-1.02) 0.5930 n Diabetes (Yes vs. No) Mean 1.22 (0.52-2.96) 0.769 68 Lymphovascular STD 11.2 invasion (Yes vs. No) Gender Lymph node status 1.42 (0.73-1.86) 0.843 (+ve vs. -ve) Female 16(30%) 0.67 (0.49-3.21) 0.709 Perinodal invasion Male 38(70%) (Yes vs. No) Race 1.78 (1.42-2.65) 0.0459 Peripancreatic Caucasian 41 (76%) extension (Yes vs. No) African American 3(5%) Perineural Other 10(19%) 1.62 (1.33-3.02) 0.0352 extension (Yes vs. No) Comorbidities Smoking 28(52%) Table 3: Multivariate Cox proportional hazards regression for Alcohol Use 11(20%) overall survival. History of Pancreatitis 7(13%) characteristics Hazard Ratio (95% CI) p- Value Diabetes 19(35%) Age Tumor Characteristics 60-70 1.56 (0.49–4.9) 0.45 ECOG Score 0-1 15(28%) >70 3.18 (1.0–10.13) 0.04 Elevated CA-19 (>34) 19(36%) Albumin (>3.5 vs.< 3.5) 1.19 (0.66–2.13) 0.56 Biliary Stenting (pre-OP) 39(74%) Margin(+ve vs. -ve) 1.06 (0.26-4.63) 0.193 Tumor Histology 28(44%) Lvi (yes vs. no) 1.68 (0.55–5.12) 0.36 Ductal Adenocarcinoma 38(72%) Ln (+ vs. -) 1.78 (0.35- 1.32) 0.1382 Adenocarcinoma not otherwise specified 8(15%) Pni (yes vs. no) 1.83 (0.62–5.38) 0.6276 Mucinous Adenocarcinoma 4(9%) Peripancreatic (Y vs. No) 4.55 (1.94, 10.64) 0.783 Tumor Grade P-stage (>2vs.<=2) 1.46 (0.46–4.77) 0.53 G1: Well Differentiated 5(9%) Adjuvant eTh rapy 1.14 (0.56–2.31) 0.72 G3: Moderately Differentiated 33(61%) Unknown 16(29%) On Univariate Cox proportional hazards regression, peri- Tumor stages(TNM) pancreatic extension (16%) and perineural invasion (26%) Stage I 13(24%) were found to be associated with poor OS (Table 2). Lymph Stage II 9(20%) node metastases were present in 29% of the cohort but did not Stage III 25(44%) significantly aec ff t OS (HR 1.42, 95% CI [0.73- 1.86]; p=0.84). Stage IV Lymphovascular invasion was present in 29% but did not 7(12%) aeff ct OS (HR 1.22, 95% CI [0.52, 2.96]; p=0.76). In the multivariate Cox regression analysis, only age group>70 years was significantly associated with OS. The resection had positive prognostic features (50% had positive other general and local prognostic factors including the LN and 40% had T4 disease). When compared to surgery receipt of adjuvant therapy (chemotherapy/radiation), lymph alone, adjuvant chemotherapy or chemoradiation therapy nodes, positive margin status, and lymphovascular, per- failed to demonstrate a statistically significant difference in ineural, and peripancreatic extension were not significantly terms of progression-free survival (PFS) (p=0.56) or OS associated with OS (Table 3). These results were largely (p=0.80) (Figure 2). When patients with TNM stage I or II attributed to the small sample size. diseasewerecompared to patients with TNM stage IIIor IV disease, a median survival difference was noted; however, this difference was not at the statistical significance level 4. Discussion (p=0.7) due to the small number of patients in stage I and II cohort (Figure 3). The 5-year survival rates of patients who Ampullary cancer has a better prognosis when compared underwent surgery alone in our cohort were 53%, which is to pancreatic cancer or cholangiocarcinoma, largely in part within the 30-60% historical range published in the literature. due to the location of the tumor which is associated with 4 Journal of Oncology 0 20 40 60 80 100 120 Time Surgery plus Adjuvant Therapy Surgery Alone Median 10 Group 1 year 3 year 5 year year Survival Surgery + 32 100.0% 42.4% 22.7% 0.0% Adjuvant treatment (n=18) Surgery alone (n=27) 61 92.5% 63.3% 52.9% 0.0% Figure 2: Survival following surgery plus adjuvant therapy vs. surgery alone. OS intervention, it is of paramount importance that features associated with recurrence risk are identified and managed accordingly [10]. This risk is highlighted by the fact that up to 28% of patients with T1 disease have been reported having lymph node metastases [11]. This is the primary reason why PD is preferred over local Ampullectomy as determining benign vs. malignant tumor status is not routinely feasible using only preoperative symptoms or lesion size as predictors. Due to their earlier presentation, resection remains the only curative treatment for patients with Ampullary cancer and is feasible in approximately 50% compared to that of less than 10% in pancreatic adenocarcinoma. The mismatch between tumor size and biliary obstruction explains why, compared to pancreatic cancers, resectability of Ampullary cancer at presentation is significantly higher. As a result, the prognosis is considerably better than that for pancreatic cancer [11] 0 20 40 60 80 100 120 However, despite such an aggressive surgical intervention, Time most patients will have a disease recurrence, hence justifying Number at risk 54 32 20 14 12 8 0 a possible role for adjuvant therapies. The role of postsurgical adjuvant treatment of Ampullary Stage I, II cancer remains to be established, because of limited data Stage III, IV available in this rare disease. Preoperative neoadjuvant radi- Figure 3: OS probability according to TNM staging. ation, chemotherapy, or chemoradiation is the available options and has been studied with a survival benefit evident in certain subset populations: patients with multiple morbidi- ties who need preoperative optimization which may delay an early onset of biliary obstruction-associated jaundice and surgery; patients with poor biologic behavior of neoplasm; thus early disease detection [2, 9]. Since half of all Ampullary patients with the possibility of an interruption in therapy due carcinomas are anticipated to recur following the initial Survival probability (%) Survival probability (%) Journal of Oncology 5 to postoperative surgical complications [12]; or advanced dis- [16]. However, both the multicentered EORTC-40891 trial ease with poor prognostic features. A signicfi ant proportion in patients with periampullary cancers (44%[n=92] had of our cohort consisted of patients with advanced disease as Ampullary cancer) and a single-center study in India (n=104) failed to show a survival benefit with adjuvant chemoradi- indicated by perineural invasion rate (26%), extension into adjacent organs (37%), and peripancreatic soft tissue (16%). ation (with fluorouracil) following PD [18, 19]. Both studies Our study failed to demonstrate a survival benefit with were powered adequately to detect significant differences. On the other hand, at least one recent meta-analysis postoperative adjuvant therapy when compared to those who had no adjuvant therapy. This is likely due to the (n=3361 patients) using a pooled analysis reported a signifi- small number of patients available for comparison at our cant survival benefit of adjuvant chemoradiation (HR=0.75, institution. It is reasonable to assume that patients treated p=0.01) following PD [20]. Furthermore, they also found with adjuvant therapies following PD had a more advanced strong associations between postoperative chemoradiation and survival in patients with positive lymph nodes and T3/T4 disease than those who had surgery alone. In our study, for example, most patients who received adjuvant therapy tumors, although they had a limited number of eligible aer ft surgical resection had positive prognostic features (50% subjects (n=3) for this subgroup analysis [20]. Retrospective studies have supported the selective admin- had positive LN and 40% had T4 disease). The 5-year survival rates of patients who underwent surgery alone in istration of adjuvant or neoadjuvant therapy to patients with our cohort were 53%, which is within the 30-60% historical periampullary cancers with high-risk features. Bhatia et al. found a significant survival benefit of adjuvant chemoradia- range published in the literature albeit towards the upper part of therange [13, 14]. Thismay be dueto the useofa tion for patients with lymph node positive Ampullary cancer standardized dissection at the time of PD [15]. To the best (23%[n=29]) [17]. Other retrospective studies including Lee of our knowledge, resection decisions were not based in et al. (33%[n=13] received adjuvant chemoradiation) and part upon histological subtypes. The limitations of our study Narang et al. (55%[n=66] received adjuvant chemoradiation) found a survival benefit albeit only after multivariate analysis include a single institution analysis, retrospective design, and a small sample size that prohibited analyses with adequate [13, 21]. Interestingly, most recently a retrospective analysis power. Another possible limitation of our study is that, given of patients from the Surveillance, Epidemiology, and End Results (SEER) database found significantly longer cancer- the small sample size, we did not control for chemotherapy regimen or were able to compare the ecffi acy of combination specific survival and OS in patients with N2 nodal status over single-agent chemotherapy, as it was previously reported who underwent adjuvant radiotherapy without concomitant [16] chemotherapy [22]. The poor OS observed in our study was likely due to Most relevant in comparison to our findings were results the high rate of tumor invasion and extension. High-risk from a similar single-center study consisting of 52 patients features such as lymph node metastases, lymphovascular who underwent potentially curative PD [23]. As in our invasion, peripancreatic extension, and perineural invasion study, no survival benefit was observed with adjuvant ther- apy; however, they did observe a trend towards improved have been known to impact OS [17]. Perineural invasion is a predictive factor for lymph node metastases: odds ratio (OR) survival with chemoradiation as opposed to chemotherapy. of 3.0 [11]. Other predictive factors of lymph node metastases Perineural invasion was associated with decreased survival, as observed in our study. Lymphovascular invasion was include tumor size≥1cm(OR 2.1), poorhistological grade (OR 4.8), microscopic vessel invasion (OR 6.6), and depth associated with decreased survival, unlike our study. These of invasion > pT1 (OR 4.3; all p< 0.05). In a recent study differences between study findings are likely due to the small by Zhao and colleagues, the degree of tumor infiltration patient population available for analysis yet are relevant correlated with recurrence (p=0.014). Extraduodenal local findings for prognostication. Findings from our single-center resection (p=0.026) was associated with increased survival study along with evidence from other studies support the [9]. Given the signicfi ant association of survival reported with rationale for more prospective investigations to establish the peripancreatic and perineural tumor extension, which was role of adjuvant therapies in the postsurgical setting especially in also found in our study, this indicates a role for adjuvant higher-risk patients with Ampullary adenocarcinoma. therapy especially in high-risk disease. In accordance to Ampullary adenocarcinoma is a rare cancer and most survival trends published in literature, patients with either series have relatively small numbers. As a result, analysis of stage I or II Ampullary cancer demonstrated a trend toward factors influencing outcome has been limited. The strengths survival benefit over more advanced stages [9]. of the current study include its comprehensive study of the The role of adjuvant postoperative chemotherapy or prognostic factors of such a rare cancer extracted from a chemoradiation for Ampullary Adenocarcinoma has been prospectively maintained database with robust clinical data. investigated previously in a few studies with conflicting However, several limitations should be acknowledged. First, results. The ESPAC-3 trial randomized patients with peri- this analysis suffers from the limitations inherent in its ampullary cancers (69.4%[n=297] with Ampullary adenocar- retrospective, single-institution design. Second, the surgical cinoma) who underwent PD to either observation or adjuvant resectability criteria for patients who underwent surgery and chemotherapy. Although no significant differences were seen those who did not are difficult to determine retrospectively in the primary analysis, adjuvant chemotherapy with uo- fl and therefore introduce physician/patient bias that is not rouracil plus folinic acid or gemcitabine was associated with uncommon in a retrospective study. Third, the adjuvant improved survival after controlling for prognostic variables chemotherapy regimens used may have had variable effects; 6 Journal of Oncology however, no standardized regimen in adjuvant setting exists [5] D. W. Rattner, C. Fernandez-Del Castillo, W. R. Brugge, and A. L. Warshaw, “Defining the criteria for local resection of for Ampullary cancer. Finally, there was no stratification by ampullary neoplasms,” JAMA Surgery, vol.131,no. 4,pp. 366– histological subtype and/or other molecular profiling due 371, 1996. to unavailability of archival tissue. The multivariate analysis [6] Y.Zhou, D. 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Clinical Outcome of Ampullary Carcinoma: Single Cancer Center Experience

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Copyright © 2019 Mohammed Al-Jumayli et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Journal of Oncology Volume 2019, Article ID 3293509, 7 pages https://doi.org/10.1155/2019/3293509 Research Article Clinical Outcome of Ampullary Carcinoma: Single Cancer Center Experience Mohammed Al-Jumayli ,Amna Batool,AkshayMiddiniti, Anwaar Saeed, Weijing Sun, Raed Al-Rajabi, Joaquina Baranda, Sean Kumer, Timothy Schmitt, Anusha Chidharla, and Anup Kasi Division of Medical Oncology, KU Cancer Center, eTh University of Kansas Health System, USA Correspondence should be addressed to Anup Kasi; anupdoc@gmail.com Received 11 November 2018; Revised 20 February 2019; Accepted 21 March 2019; Published 2 May 2019 Academic Editor: Jorg Kleeff Copyright © 2019 Mohammed Al-Jumayli et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction. Ampullary cancers represent a subset of periampullary cancers, comprising only 0.2% all gastrointestinal cancers. Localized disease is primarily managed by a surgical intervention, called pancreaticoduodenectomy (PD), followed in many cases by the administration of adjuvant chemotherapy (CT) or chemoradiation therapy (CRT). However, there are no clear evidence-based guidelines to aid in selecting both the modality and regimen of adjuvant therapy for resected Ampullary carcinoma. Methods. We retrospectively analyzed 54 patients at KU Cancer Center, who had undergone endoscopic resection or pancreaticoduodenectomy (PD) for Ampullary cancer from June 2006 to July 2016. We obtained patients’ baseline characteristics, clinical presentation, pathology, treatment modality, recurrence pattern, and survival outcomes. eTh time-to-events data were compared using Kaplan-Meier methods. A univariate and multivariate Cox proportional hazards regression was performed to evaluate factors associated with overall survival (OS) and generate hazard ratios (HR). Results. em Th ean age of the54 patients was 68 (37-90). 38 (70%) were males and 16 (30%) were females. Most of the patients were Caucasian (76%). Approximately half of all patients had a history of smoking, 20% had alcohol abuse, and 13% had pancreatitis. Among the 54 patients with localized cancers, 9 (16%) were treated definitively with nonoperative therapies, usually due to a prohibitive comorbidity profile, performance status, or unresectable tumor. 45 out of 54 patients (83%) underwent surgery. Of the 45 patients who underwent surgery, 18 patients (40% of the study cohort) received adjuvant therapy due to concerns for advanced disease as determined by the treating physician. 13 patients (24%) received adjuvant CT and 5 patients (9.2%) received CRT. The remaining 27 patients (50%) underwent surgery alone. eTh median OS for the entire study cohort was 30 months. When compared to surgery alone, adjuvant therapy with either CT or CRT had no statistically significant difference in terms of progression-free survival (p=0.56) or overall survival (p=0.80). In univariate Cox proportional hazards regression analysis, high-risk features like peripancreatic extension (16%) and perineural invasion (26%) were found to be associated with poor OS. Lymph node metastasis (29%) did not significantly aeff ct OS (HR 1.42, 95% CI [0.73-1.86]; p=0.84). Lymphovascular invasion (29%) was not associated with poor OS (HR 1.22, 95% CI[0.52, 2.96]; p=0.76). In multivariate Cox regression analysis, only age group>70 years was significantly associated with OS , while other factors, including the receipt of adjuvant therapy, lymph nodes, positive margin, and lymphovascular, perineural, and peripancreatic involvement, were not significantly associated with OS. ese Th results are likely due to small sample size. Conclusions. Despite numerous advances in both cancer care and research, efforts in rare malignancies such as Ampullary cancer remain very challenging with a clear lack of an evidence-based standard of care treatment paradigm. Although adding adjuvant therapies such as chemotherapy or chemoradiotherapy is likely to improve survival in high-risk disease, there is no standardized regimen for the treatment of Ampullary cancer. More research is required to elucidate whether statistically and clinically relevant dieff rences exist that may warrant a change in the current adjuvant treatment strategies. 2 Journal of Oncology 1. Introduction Ampullary carcinoma is a rare malignant tumor originating from the Ampulla of Vater [1, 2] The reported incidence is less than one per 100,000 in an autopsy series and in the general population comprises of 0.2% of all gastrointestinal tumors [1]. In 90% of patient cases, this represents a primary presentation with a predominance of Caucasian males being 40 aec ff ted over other races and gender [3]. In patients with hereditary polyposis syndromes, the incidence of Ampullary cancer is multifold and presents at an earlier age warranting surveillance endoscopy [4]. Previous retrospective studies have assessed the dif- 0 20 40 60 80 100 120 ference in prognosis of Ampullary carcinomas based on Figure 1: Overall survival (OS) of study cohort. immunohistologic subtypes. Pancreaticobiliary subtype ver- sus intestinal subtype showed a significant difference of almost 10-fold in median survival, 16 vs. 116 months, respec- tively [5]. In addition to immunohistochemical subtypes, with a followup of at least 2 years for each patient in order to nodal status was also found to have an impact on survival. obtain data relevant for long-term survival analysis. Patients with node-negative, nonpancreatobiliary type had The Institutional Review Board approved this retro- an excellent prognosis with 5-year survival rate of 88%, spective study. Data collection on eligible patients included while those with node-positive, pancreatobiliary type had patient baseline characteristics, clinical presentation, pathol- apoor prognosis with a5-year survival of 20%. Patients ogy, treatment modality, recurrence, and survival. Statistical with node-positive, nonpancreaticobiliary or node-negative, analysis was performed using SPSS 22.0 with statistical pancreatobiliary type had an intermediate prognosis with significance established at p<0.05. Both the Kaplan-Meier a 5-year survival of 47%. A recent meta-analysis reported method and log-rank were used to compare the time-to that pancreatobiliary type predicted a worse overall survival events. Univariate and multivariate Cox proportional hazards (hazard ratio [HR] 1.84, 95% CI 1.49- 2.27; p< 0.001) and regression model were created to identify factors associated disease-free survival (HR 1.93, 95% CI 1.23-3.01; p=0.004) with OS. Of note, many of the older cases included in the [6]. On the other hand, other studies failed to replicate study had no immunostaining performed by pathologists. similar findings, limiting their utility in diagnostic algo- Hence, we were unable to evaluate prognostic association rithms. Emerging evidence suggests an increased complexity with immunohistologic subtypes. of tumor subtypes such as the existence of a mixed subtypes which warrants further research instead of making treatment 3. Results decisions based on immunohistologic subtypes alone [7]. Patients with localized disease are primarily managed A total of 54 patients with Ampullary adenocarcinoma by pancreaticoduodenectomy (PD), oen ft followed by the were selected for evaluation. The epidemiology, clinical administration of adjuvant chemotherapy (CT) or chemora- presentation, pathologic features, and staging of Ampullary diation therapy (CRT) [2]. However, given the paucity of carcinoma at baseline are presented in Table 1. The mean clinical evidence, current treatment recommendations in the age of our patient cohort was 68 years. There were more adjuvant setting are not included in published consensus like males patients than females, 38 vs. 16 respectively. Most of NCCN or ESMO guidelines [8]. Retrospective and prospec- our patients were Caucasians (76%). Approximately half of tive studies have investigated the role of adjuvant therapy the patients (52%) had a history of smoking, 20% were alcohol in this context; however, the evidence remains inconclusive. abusers, and 13% had a history of pancreatitis. Our retrospective, single-center study was conducted to Nine patients were treated nonoperatively, secondary to evaluate whether any survival advantages exist with either a prohibitive comorbidity profile, performance status, or adjuvant chemotherapy or chemoradiotherapy compared to an unresectable tumor. Adjuvant treatment was adminis- surgery alone in the management of resected Ampullary tered after surgery because of concerns for advanced dis- carcinoma. ease determined by the treating physician in 18 patients: 13 (24%) received chemotherapy and 5 (9.2%) received chemoradiation therapy. The remaining 27 (50%) patients 2. Methods underwent surgery alone. The median OS for the study This was a retrospective study conducted at the Kansas cohort was found to be 30 months (Figure 1). Recurrence was University Cancer Center. Data was collected on patients noted in 40% of patients who underwent surgery. Patients with a diagnosis of Ampullary adenocarcinoma who were treated with adjuvant therapies following PD had a more treated at our institution between 2006 and 2016. Our study locally advanced disease than those who had surgery alone. enrollment was over a period of 10 years from 2006 to 2016 Most patients who received adjuvant therapy after surgical Survival probability (%) Journal of Oncology 3 Table 1: Baseline Characteristics. Table 2: Univariate Analyses. Results Hazard Ratio (95% CI) P-value Characteristics (n=54) Variable Age 1.22 (0.52-2.96) 0.6291 Mean 1.06 (0.70-1.06) 0.8504 Gender (Female vs. Male) (%) 1.24 (0.48-1.78) 0.7920 Age (years) Smoking (Yes vs. No) 0.91 (0.42-1.02) 0.5930 n Diabetes (Yes vs. No) Mean 1.22 (0.52-2.96) 0.769 68 Lymphovascular STD 11.2 invasion (Yes vs. No) Gender Lymph node status 1.42 (0.73-1.86) 0.843 (+ve vs. -ve) Female 16(30%) 0.67 (0.49-3.21) 0.709 Perinodal invasion Male 38(70%) (Yes vs. No) Race 1.78 (1.42-2.65) 0.0459 Peripancreatic Caucasian 41 (76%) extension (Yes vs. No) African American 3(5%) Perineural Other 10(19%) 1.62 (1.33-3.02) 0.0352 extension (Yes vs. No) Comorbidities Smoking 28(52%) Table 3: Multivariate Cox proportional hazards regression for Alcohol Use 11(20%) overall survival. History of Pancreatitis 7(13%) characteristics Hazard Ratio (95% CI) p- Value Diabetes 19(35%) Age Tumor Characteristics 60-70 1.56 (0.49–4.9) 0.45 ECOG Score 0-1 15(28%) >70 3.18 (1.0–10.13) 0.04 Elevated CA-19 (>34) 19(36%) Albumin (>3.5 vs.< 3.5) 1.19 (0.66–2.13) 0.56 Biliary Stenting (pre-OP) 39(74%) Margin(+ve vs. -ve) 1.06 (0.26-4.63) 0.193 Tumor Histology 28(44%) Lvi (yes vs. no) 1.68 (0.55–5.12) 0.36 Ductal Adenocarcinoma 38(72%) Ln (+ vs. -) 1.78 (0.35- 1.32) 0.1382 Adenocarcinoma not otherwise specified 8(15%) Pni (yes vs. no) 1.83 (0.62–5.38) 0.6276 Mucinous Adenocarcinoma 4(9%) Peripancreatic (Y vs. No) 4.55 (1.94, 10.64) 0.783 Tumor Grade P-stage (>2vs.<=2) 1.46 (0.46–4.77) 0.53 G1: Well Differentiated 5(9%) Adjuvant eTh rapy 1.14 (0.56–2.31) 0.72 G3: Moderately Differentiated 33(61%) Unknown 16(29%) On Univariate Cox proportional hazards regression, peri- Tumor stages(TNM) pancreatic extension (16%) and perineural invasion (26%) Stage I 13(24%) were found to be associated with poor OS (Table 2). Lymph Stage II 9(20%) node metastases were present in 29% of the cohort but did not Stage III 25(44%) significantly aec ff t OS (HR 1.42, 95% CI [0.73- 1.86]; p=0.84). Stage IV Lymphovascular invasion was present in 29% but did not 7(12%) aeff ct OS (HR 1.22, 95% CI [0.52, 2.96]; p=0.76). In the multivariate Cox regression analysis, only age group>70 years was significantly associated with OS. The resection had positive prognostic features (50% had positive other general and local prognostic factors including the LN and 40% had T4 disease). When compared to surgery receipt of adjuvant therapy (chemotherapy/radiation), lymph alone, adjuvant chemotherapy or chemoradiation therapy nodes, positive margin status, and lymphovascular, per- failed to demonstrate a statistically significant difference in ineural, and peripancreatic extension were not significantly terms of progression-free survival (PFS) (p=0.56) or OS associated with OS (Table 3). These results were largely (p=0.80) (Figure 2). When patients with TNM stage I or II attributed to the small sample size. diseasewerecompared to patients with TNM stage IIIor IV disease, a median survival difference was noted; however, this difference was not at the statistical significance level 4. Discussion (p=0.7) due to the small number of patients in stage I and II cohort (Figure 3). The 5-year survival rates of patients who Ampullary cancer has a better prognosis when compared underwent surgery alone in our cohort were 53%, which is to pancreatic cancer or cholangiocarcinoma, largely in part within the 30-60% historical range published in the literature. due to the location of the tumor which is associated with 4 Journal of Oncology 0 20 40 60 80 100 120 Time Surgery plus Adjuvant Therapy Surgery Alone Median 10 Group 1 year 3 year 5 year year Survival Surgery + 32 100.0% 42.4% 22.7% 0.0% Adjuvant treatment (n=18) Surgery alone (n=27) 61 92.5% 63.3% 52.9% 0.0% Figure 2: Survival following surgery plus adjuvant therapy vs. surgery alone. OS intervention, it is of paramount importance that features associated with recurrence risk are identified and managed accordingly [10]. This risk is highlighted by the fact that up to 28% of patients with T1 disease have been reported having lymph node metastases [11]. This is the primary reason why PD is preferred over local Ampullectomy as determining benign vs. malignant tumor status is not routinely feasible using only preoperative symptoms or lesion size as predictors. Due to their earlier presentation, resection remains the only curative treatment for patients with Ampullary cancer and is feasible in approximately 50% compared to that of less than 10% in pancreatic adenocarcinoma. The mismatch between tumor size and biliary obstruction explains why, compared to pancreatic cancers, resectability of Ampullary cancer at presentation is significantly higher. As a result, the prognosis is considerably better than that for pancreatic cancer [11] 0 20 40 60 80 100 120 However, despite such an aggressive surgical intervention, Time most patients will have a disease recurrence, hence justifying Number at risk 54 32 20 14 12 8 0 a possible role for adjuvant therapies. The role of postsurgical adjuvant treatment of Ampullary Stage I, II cancer remains to be established, because of limited data Stage III, IV available in this rare disease. Preoperative neoadjuvant radi- Figure 3: OS probability according to TNM staging. ation, chemotherapy, or chemoradiation is the available options and has been studied with a survival benefit evident in certain subset populations: patients with multiple morbidi- ties who need preoperative optimization which may delay an early onset of biliary obstruction-associated jaundice and surgery; patients with poor biologic behavior of neoplasm; thus early disease detection [2, 9]. Since half of all Ampullary patients with the possibility of an interruption in therapy due carcinomas are anticipated to recur following the initial Survival probability (%) Survival probability (%) Journal of Oncology 5 to postoperative surgical complications [12]; or advanced dis- [16]. However, both the multicentered EORTC-40891 trial ease with poor prognostic features. A signicfi ant proportion in patients with periampullary cancers (44%[n=92] had of our cohort consisted of patients with advanced disease as Ampullary cancer) and a single-center study in India (n=104) failed to show a survival benefit with adjuvant chemoradi- indicated by perineural invasion rate (26%), extension into adjacent organs (37%), and peripancreatic soft tissue (16%). ation (with fluorouracil) following PD [18, 19]. Both studies Our study failed to demonstrate a survival benefit with were powered adequately to detect significant differences. On the other hand, at least one recent meta-analysis postoperative adjuvant therapy when compared to those who had no adjuvant therapy. This is likely due to the (n=3361 patients) using a pooled analysis reported a signifi- small number of patients available for comparison at our cant survival benefit of adjuvant chemoradiation (HR=0.75, institution. It is reasonable to assume that patients treated p=0.01) following PD [20]. Furthermore, they also found with adjuvant therapies following PD had a more advanced strong associations between postoperative chemoradiation and survival in patients with positive lymph nodes and T3/T4 disease than those who had surgery alone. In our study, for example, most patients who received adjuvant therapy tumors, although they had a limited number of eligible aer ft surgical resection had positive prognostic features (50% subjects (n=3) for this subgroup analysis [20]. Retrospective studies have supported the selective admin- had positive LN and 40% had T4 disease). The 5-year survival rates of patients who underwent surgery alone in istration of adjuvant or neoadjuvant therapy to patients with our cohort were 53%, which is within the 30-60% historical periampullary cancers with high-risk features. Bhatia et al. found a significant survival benefit of adjuvant chemoradia- range published in the literature albeit towards the upper part of therange [13, 14]. Thismay be dueto the useofa tion for patients with lymph node positive Ampullary cancer standardized dissection at the time of PD [15]. To the best (23%[n=29]) [17]. Other retrospective studies including Lee of our knowledge, resection decisions were not based in et al. (33%[n=13] received adjuvant chemoradiation) and part upon histological subtypes. The limitations of our study Narang et al. (55%[n=66] received adjuvant chemoradiation) found a survival benefit albeit only after multivariate analysis include a single institution analysis, retrospective design, and a small sample size that prohibited analyses with adequate [13, 21]. Interestingly, most recently a retrospective analysis power. Another possible limitation of our study is that, given of patients from the Surveillance, Epidemiology, and End Results (SEER) database found significantly longer cancer- the small sample size, we did not control for chemotherapy regimen or were able to compare the ecffi acy of combination specific survival and OS in patients with N2 nodal status over single-agent chemotherapy, as it was previously reported who underwent adjuvant radiotherapy without concomitant [16] chemotherapy [22]. The poor OS observed in our study was likely due to Most relevant in comparison to our findings were results the high rate of tumor invasion and extension. High-risk from a similar single-center study consisting of 52 patients features such as lymph node metastases, lymphovascular who underwent potentially curative PD [23]. As in our invasion, peripancreatic extension, and perineural invasion study, no survival benefit was observed with adjuvant ther- apy; however, they did observe a trend towards improved have been known to impact OS [17]. Perineural invasion is a predictive factor for lymph node metastases: odds ratio (OR) survival with chemoradiation as opposed to chemotherapy. of 3.0 [11]. Other predictive factors of lymph node metastases Perineural invasion was associated with decreased survival, as observed in our study. Lymphovascular invasion was include tumor size≥1cm(OR 2.1), poorhistological grade (OR 4.8), microscopic vessel invasion (OR 6.6), and depth associated with decreased survival, unlike our study. These of invasion > pT1 (OR 4.3; all p< 0.05). In a recent study differences between study findings are likely due to the small by Zhao and colleagues, the degree of tumor infiltration patient population available for analysis yet are relevant correlated with recurrence (p=0.014). Extraduodenal local findings for prognostication. Findings from our single-center resection (p=0.026) was associated with increased survival study along with evidence from other studies support the [9]. Given the signicfi ant association of survival reported with rationale for more prospective investigations to establish the peripancreatic and perineural tumor extension, which was role of adjuvant therapies in the postsurgical setting especially in also found in our study, this indicates a role for adjuvant higher-risk patients with Ampullary adenocarcinoma. therapy especially in high-risk disease. In accordance to Ampullary adenocarcinoma is a rare cancer and most survival trends published in literature, patients with either series have relatively small numbers. As a result, analysis of stage I or II Ampullary cancer demonstrated a trend toward factors influencing outcome has been limited. The strengths survival benefit over more advanced stages [9]. of the current study include its comprehensive study of the The role of adjuvant postoperative chemotherapy or prognostic factors of such a rare cancer extracted from a chemoradiation for Ampullary Adenocarcinoma has been prospectively maintained database with robust clinical data. investigated previously in a few studies with conflicting However, several limitations should be acknowledged. First, results. The ESPAC-3 trial randomized patients with peri- this analysis suffers from the limitations inherent in its ampullary cancers (69.4%[n=297] with Ampullary adenocar- retrospective, single-institution design. Second, the surgical cinoma) who underwent PD to either observation or adjuvant resectability criteria for patients who underwent surgery and chemotherapy. 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