Non-pancreatic Periampullary Adenocarcinoma Research Articles

The road to tailored adjuvant chemotherapy for all four non-pancreatic periampullary cancers: An international multimethod cohort study.

Despite differences in tumour behaviour and characteristics between duodenal adenocarcinoma (DAC), the intestinal (AmpIT) and pancreatobiliary (AmpPB) subtype of ampullary adenocarcinoma and distal cholangiocarcinoma (dCCA), the effect of adjuvant chemotherapy (ACT) on these cancers, as well as the optimal ACT regimen, has not been comprehensively assessed. This study aims to assess the influence of tailored ACT on DAC, dCCA, AmpIT, and AmpPB. Patients after pancreatoduodenectomy for non-pancreatic periampullary adenocarcinoma were identified and collected from 36 tertiary centres between 2010 - 2021. Per non-pancreatic periampullary tumour type, the effect of adjuvant chemotherapy and the main relevant regimens of adjuvant chemotherapy were compared. The primary outcome was overall survival (OS). The study included a total of 2866 patients with DAC (n = 330), AmpIT (n = 765), AmpPB (n = 819), and dCCA (n = 952). Among them, 1329 received ACT, and 1537 did not. ACT was associated with significant improvement in OS for AmpPB (P = 0.004) and dCCA (P < 0.001). Moreover, for patients with dCCA, capecitabine mono ACT provided the greatest OS benefit compared to gemcitabine (P = 0.004) and gemcitabine - cisplatin (P = 0.001). For patients with AmpPB, no superior ACT regime was found (P > 0.226). ACT was not associated with improved OS for DAC and AmpIT (P = 0.113 and P = 0.445, respectively). Patients with resected AmpPB and dCCA appear to benefit from ACT. While the optimal ACT for AmpPB remains undetermined, it appears that dCCA shows the most favourable response to capecitabine monotherapy. Tailored adjuvant treatments are essential for enhancing prognosis across all four non-pancreatic periampullary adenocarcinomas.

Preoperative diagnostics in periampullary adenocarcinomas

Approximately 30-40% of pancreatoduodenectomies for adenocarcinomas result in nonpancreatic periampullary adenocarcinoma as the final diagnosis. Depending on the origin, adistinction is made between four different carcinomas with histomorphological subtypes. Carcinoma location and subtype are of prognostic and therapeutic relevance; however, the preoperative differentiation is often incorrect despite modern diagnostics. Overview of the current literature on the classification and preoperative diagnostics of periampullary adenocarcinomas. Aprecise knowledge of the papillary anatomy is necessary for the correct classification of diagnostic findings. Current studies demonstrate diagnostically valuable information from the anamnesis, imaging and endoscopy. In ca. 70-80% of cases acorrect diagnosis of the type of periampullary adenocarcinoma is possible on the basis of interdisciplinary diagnostics. This potentially enables acorrespondingly individualized treatment planning in the preoperative phase.

The Expression of Immune Checkpoint Inhibitors PDL-1 and CTLA-4 in Pancreatic Versus Non-Pancreatic Periampullary Adenocarcinoma: An Immunohistochemical Study

Background: Periampullary cancers constitute about 5% of gastrointestinal malignancies. They are comprised of tumors of diverse origins and are generally subdivided into pancreatic and non-pancreatic carcinomas. Immune checkpoint regulators, cytotoxic T-lymphocyte antigen 4 (CTLA-4), and the programmed cell death ligand-1 (PDL-1) have emerged as promising new targets for cancer therapeutics. Aim: This study aims to determine the possible role of immune checkpoint inhibitors PDL-1 and CTLA-4 in periampullary carcinoma of pancreatic and non-pancreatic adenocarcinoma subtypes, in an attempt to investigate the possible introduction of their related immunotherapy in the management of these tumors. Materials and Methods: Expression of immune inhibitory molecules was examined by immunohistochemistry in 40 cases including (20) pancreatic adenocarcinoma and (20) non-pancreatic adenocarcinoma. The association between markers and clinicopathological parameters was evaluated. Results: Statistically significant differences in the immunoexpression of both CTLA-4 and PDL-1 in the two studied groups were noticed with higher expression in non-pancreatic adenocarcinoma in relation to pancreatic adenocarcinoma (P=0.004, P=0.008) respectively. PDL-1 expression was positive in 15% and 55% of pancreatic and non-pancreatic adenocarcinoma cases, respectively with a significant correlation with lymph nodes metastasis in non-pancreatic adenocarcinoma cases. CTLA-4 was positive in 20% of pancreatic carcinoma with a significant correlation with lymph node metastasis, perineural invasion and T stage. In non-pancreatic periampullary adenocarcinoma, CTLA-4 was positive in 65% of cases with a significant association with lymph nodes metastasis and T stage. Conclusions: Immunotherapy using anti-PDL-1 and CTLA-4 are proposed as a novel promising management tool in non-pancreatic periampullary adenocarcinoma not in pancreatic adenocarcinomas.

Comparison of laparoscopic and open pancreaticoduodenectomy for the treatment of nonpancreatic periampullary adenocarcinomas: a propensity score matching analysis

BackgroundUse of laparoscopic pancreaticoduodenectomy (LPD) in place of open pancreaticoduodenectomy (OPD) remains controversial. Our aim was to evaluate the results of LPD versus OPD in non-pancreatic periampullary adenocarcinoma (NPPC), a less aggressive tumor. MethodsHere, 488 NPPC patients who underwent LPD or OPD were analyzed in this study. The propensity score matching was used to balance the patients in two groups. Statistical analysis was conducted to investigate the differences between LPD and OPD in patients with NPPC. ResultsThe LPD group had shorter operative time, less intraoperative bleeding, and less postoperative hospital stay than OPD group. The 30- and 90-day mortality rates were significantly lower in LPD than in OPD group. There was no statistical difference in long-term survival between the two groups. ConclusionsFor NPPC, LPD may be the preferred surgical treatment due to its advantages over OPD in terms of intraoperative blood loss and short-term mortality.

Sarcopenia and myosteatosis are accompanied by distinct biological profiles in patients with pancreatic and periampullary adenocarcinomas.

IntroductionPancreatic and periampullary adenocarcinomas are associated with abnormal body composition visible on CT scans, including low muscle mass (sarcopenia) and low muscle radiodensity due to fat infiltration in muscle (myosteatosis). The biological and clinical correlates to these features are poorly understood.MethodsClinical characteristics and outcomes were studied in 123 patients who underwent pancreaticoduodenectomy for pancreatic or non-pancreatic periampullary adenocarcinoma and who had available preoperative CT scans. In a subgroup of patients with pancreatic cancer (n = 29), rectus abdominus muscle mRNA expression was determined by cDNA microarray and in another subgroup (n = 29) 1H-NMR spectroscopy and gas chromatography-mass spectrometry were used to characterize the serum metabolome.ResultsMuscle mass and radiodensity were not significantly correlated. Distinct groups were identified: sarcopenia (40.7%), myosteatosis (25.2%), both (11.4%). Fat distribution differed in these groups; sarcopenia associated with lower subcutaneous adipose tissue (P<0.0001) and myosteatosis associated with greater visceral adipose tissue (P<0.0001). Sarcopenia, myosteatosis and their combined presence associated with shorter survival, Log Rank P = 0.005, P = 0.06, and P = 0.002, respectively. In muscle, transcriptomic analysis suggested increased inflammation and decreased growth in sarcopenia and disrupted oxidative phosphorylation and lipid accumulation in myosteatosis. In the circulating metabolome, metabolites consistent with muscle catabolism associated with sarcopenia. Metabolites consistent with disordered carbohydrate metabolism were identified in both sarcopenia and myosteatosis.DiscussionMuscle phenotypes differ clinically and biologically. Because these muscle phenotypes are linked to poor survival, it will be imperative to delineate their pathophysiologic mechanisms, including whether they are driven by variable tumor biology or host response.

Adjuvant Chemotherapy for Resected Periampullary Adenocarcinoma

To the Editor: Dr Neoptolemos and colleagues reported results from the large, multicenter European Study Group for Pancreatic Cancer (ESPAC)-3 periampullary randomized controlled trial, which demonstrated no significant overall survival benefit from adjuvant chemotherapy in patients with nonpancreatic periampullary adenocarcinoma. We have 2 comments with regard to the trial data. We believe a central pathological review of the primary sites of origin should have been conducted to provide added clarity and further insight into the study. First, the determination of the primary site of origin (epicenter) of the resected periampullary cancers remains a challenge and is best conducted by a gastrointestinal pathologist. In the European Organization for Research and Treatment of Cancer (EORTC) phase 3 study of adjuvant radiotherapy in patients with pancreatic and periampullary carcinomas, central pathology review changed the diagnosis (pancreatic, periampullary, or unknown) in 5% of the cases. We believe the rate might be higher in this study because central pathology review would be required to solve the additional and more challenging problem of determining the specific sites of nonpancreatic periampullary adenocarcinoma (biliary, duodenal, or ampullary). In the ESPAC-3 study, 2 pancreatic pathologists reviewed each pathology report without reviewing histological slides. This has inherent limitations as demonstrated by the inability to properly classify the histological subtypes (pancreaticobiliary, intestinal, or mixed) of ampullary carcinoma in 162 patients (55%). Second, the low frequency of duodenal adenocarcinoma (2%) in this periampullary cohort contrasts with prior periampullary data sets in which duodenal adenocarcinoma was generally more common and represented 25% to 33% of nonpancreatic periampullary adenocarcinoma cases. We believe this reflects the degree of uncertainty with regard to the ascribed primary sites of periampullary adenocarcinoma. Because the site of nonpancreatic periampullary adenocarcinoma was a significant variable in the multivariate modeling, the uncertainty in determining the primary site of the periampullary adenocarcinoma in this study would limit the interpretation of the secondary multiple regression survival analysis. Could the authors also specify if the initiation of adjuvant therapy was restricted by a maximum time postsurgery and if a restaging imaging study was required prior to initiation of therapy?

Fear of cancer recurrence after curative pancreatectomy: a cross-sectional study in survivors of pancreatic and periampullary tumors.

Fear of disease recurrence is well documented among cancer survivors, but its significance among patients treated for solid pancreatic and periampullary neoplasms is unknown despite the known risk of recurrence associated with these tumors. We hypothesized that fear of cancer recurrence (FCR) represents a common source of psychosocial distress in this population and sought to characterize subgroups for whom FCR might represent a target for intervention to improve quality of life. We conducted a cross-sectional study of FCR in patients who were disease-free after potentially curative pancreatectomy for ductal or periampullary adenocarcinoma or pancreatic neuroendocrine tumor. We assessed seven discrete dimensions of FCR using the Fear of Recurrence Inventory and evaluated quality of life and psychosocial distress using the Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire and the Hospital Anxiety and Depression Scale. Of 354 eligible patients, 240 (68 %) participated in the study a median of 48 months after potentially curative pancreatectomy. An FCR severity score indicative of frequent fearful thoughts, emotional disturbance and functional impairment was identified in 37, 28, and 35 % of patients with pancreatic adenocarcinoma, nonpancreatic periampullary adenocarcinoma, and pancreatic neuroendocrine tumor, respectively. Anxiety (P < 0.001) and low quality of life (P = 0.028) were independently associated with a clinically significant level of FCR, but histopathologic diagnosis and clinicopathologic markers of prognosis were not. FCR represents a significant concern for one-third of patients after curative surgery for a pancreatic or periampullary tumor, regardless of their actual likelihood of recurrence or disease-related death.

Intensified adjuvant combined modality therapy for resected periampullary adenocarcinoma: acceptable toxicity and suggestion of improved 1-year disease-free survival

Purpose: ( 1) To determine the toxicity of an intensified postoperative adjuvant regimen for periampullary adenocarcinoma (pancreatic and nonpancreatic) utilizing concurrent 5-fluorouracil (5-FU), leucovorin (LV), dipyridamole (DPM), and mitomycin-C (MMC) combined with split-course locoregional external beam radiotherapy (EBRT) to 50 Gy. This was followed by 4 cycles of the same chemotherapy as adjuvant therapy. ( 2) To determine preliminary estimates of the overall and disease-free survival associated with the use of this regimen. ( 3) To compare the toxicities and early survival results of patients treated with the current regimen to those of patients who completed our prior trial of concurrent chemoradiation infusion with 5-FU/LV chemotherapy and regional nodal and prophylactic hepatic irradiation. Methods: Postpancreaticoduodenectomy, patients received every 4 weeks bolus administration of 5-FU, (400 mg/m 2), and LV, (20 mg/m 2, Days l–3), DPM (75 mg p.o., 4 times per day, Days 0–3, and every 8 weeks), MMC, (10 mg/m 2; maximum of 20 mg, Day l during EBRT). This was followed by 4 months of the same chemotherapy, beginning 1 month following the completion of EBRT. EBRT consisted of split-course 5000 cGy/20 fractions with a 2-week planned rest after the first 10 fractions (2500 cGy). Results: From 4/96 to 6/99, 45 patients were enrolled and treated. Their experience constitutes the basis of this analysis. There were 29 patients with pancreatic cancer and 16 with nonpancreatic periampullary cancer. Seventeen patients had tumors of 3 cm or more, and 39 patients had at least 1 histologically involved lymph node. Thirteen patients had a histologically positive margin of resection. The mean time to start of treatment was 63 days following surgery. During chemoradiation therapy there were no Grade 3 or worse nonhematologic toxicities and 47% Grade 3 or Grade 4 hematologic toxicities of short duration. Following chemoradiation, during chemotherapy treatment only, there was one Grade 3 hepatic and one Grade 3 pulmonary toxicity which was nondebilitating (2% each case) and 42% Grade 3 or 4 hematologic toxicity. There were 2 episodes of neutropenic fever requiring admission and no treatment-related mortalities. One patient developed a mild case of HUS, which responded to standard management. One patient developed persistent shortness of breath (nondebilitating), and another patient had occasional dyspnea on exertion, both occurring after all therapy. The majority of patients complained of increased fatigue (Grade 1–2), greatest during the combined therapy and improving post all treatment. As of 6/23/99, 20 of 45 patients have relapsed, 13 in the liver. Twelve patients have died. Median follow-up for surviving patients is 14.3 months. Disease-free survival at 12 months following surgery is 66% (as compared to 25% in our prior study), and the median disease-free survival is 17 months (as compared to 8.3 months in our prior study). Median survival has not yet been reached, but will be greater than 17 months. Conclusion: With a 14.3-month median follow-up, acute toxicity has been acceptable and manageable. Observed relapses were seen 9–13 months following surgical resection. Early survival analysis suggests a trend toward increased median disease-free survival (8.3 vs. 17 months), especially for patients with nonpancreatic periampullary adenocarcinoma.

Intensified adjuvant therapy for pancreatic and periampullary adenocarcinoma: survival results and observations regarding patterns of failure, radiotherapy dose and CA19-9 levels

Purpose: Primary endpoints were 1. To determine if, in the context of postoperative adjuvant therapy of pancreatic and nonpancreatic periampullary adenocarcinoma, continuous infusion (C.I.) 5-fluorouracil (5-FU) and leucovorin (Lv), combined with continuous-course external-beam radiotherapy (EBRT) to liver (23.4–27.0 Gy), regional lymph nodes (50.4–54.0 Gy) and tumor bed (50.4–57.6 Gy), followed by 4 months of C.I. 5-FU/Lv without EBRT could be given with acceptable toxicity. 2. To determine an estimate of disease-free and overall survival (DFS, OS) with this treatment in this context. Secondary endpoints were 1. To observe the effects of therapy at two different dose levels of irradiation, and 2. To observe for correlations among DFS, OS and CA 19-9 levels during therapy. Methods: Patients received C.I. 5-FU 200 mg/m 2 and Lv 5 mg/m 2 Monday through Friday during EBRT, and 4 cycles of the same chemotherapy without EBRT were planned for each 2 weeks of 4, beginning 1 month following the completion of EBRT. Therapy was to begin within 10 weeks of surgery and patients were monitored for disease recurrence, toxicity, and CA 19-9 levels before the start of EBRT/5-FU/Lv, before each cycle of C.I. 5-FU/Lv, and periodically after the completion of therapy. There were two EBRT dosage groups: Low EBRT, 23.4 Gy to the whole liver, 50.4 Gy to regional nodes and 50.4 Gy to the tumor bed; High EBRT, 27.0 Gy to the whole liver, 54.0 Gy to regional nodes, and 57.6 Gy to the tumor bed. Results: 29 patients were enrolled and treated (23 with pancreatic cancer, and 6 with nonpancreatic periampullary cancer). Of these, 18 had tumor sizes ≥ 3 cm and 23 had at least one histologically involved lymph node; 6 had histologically positive resection margins. Mean time to start of EBRT/5-FU/Lv was 53 ± 2 days following surgery. The first 18 patients were in the Low EBRT Group and the last 11 in the High EBRT Group. Toxicity was moderate and manageable, including a possible case of late radiation hepatitis. Median DFS was 8.3 months (pancreatic cancer patients 8.5 months) and OS was 14.1 months (pancreatic cancer patients 15.9 months). Among patients with pancreatic cancer, results were similar for the Low and High EBRT Groups (DFS: 8.3 vs. 8.6 months; OS: 14.4 vs. 16.9 months, respectively). With a mean follow up of 2.6 ± 0.3 years for the surviving patients and a minimal follow-up of 2.5 years, 27 of 29 pts have relapsed and 25 pts have died. A rise in CA 19-9 levels preceded clinical relapse by 9.1 ± 1.5 months. Time to first relapse by site showed inverse correlation with dose of radiotherapy to that site: peritoneal (5 ± 1 month), hepatic (7 ± 0.9 months), regional nodes/tumor bed (9.6 ± 1.8 months). Mean postresection CA 19-9 level was 63.3 ± 16.2 U/ml. Postresection CA 19-9 values did not correlate with survival, margin status, or with the identification of metastatic carcinoma in resected lymph nodes. However, among patients with histologically involved nodes in the resected specimen, postresection CA 19-9 values did correlate with the number of positive nodes identified ( p = 0.05). Conclusions: Although toxicity was acceptable, survival results were not improved over those seen with standard adjuvant treatment. Most patients relapsed before the planned chemotherapy cycles were completed, or within 100 days thereof, suggesting disease resistance to C.I. 5-FU/Lv as used in this study. Although this regimen is not recommended for further study, the doses of EBRT utilized may be suitable for evaluation with other chemotherapy combinations. Postoperative CA 19-9 levels did not correlate with survival, but did correlate with the number of histologically involved lymph nodes found in the resected specimen among node-positive patients. Moreover, rising CA 19-9 levels anticipated ultimate clinical failure by 9 months.

Reoperative Surgery for Periampullary Adenocarcinoma

In recent years, the morbidity, mortality, and long-term survival of patients undergoing surgery for periampullary adenocarcinoma have improved. These changes have prompted us to reoperate on patients who have previously undergone pancreatobiliary surgery, many of whom were initially considered to have unresectable lesions. From 1979 to 1990, 38 patients with pancreatic and 17 patients with nonpancreatic periampullary adenocarcinoma underwent reexploratory surgery at The Johns Hopkins Hospital, Baltimore, Md. Thirty-three (60%) of these 55 patients had resection at the time of second laparotomy. Of the 46 patients undergoing reexploratory surgery with an intent to resect, the overall resection rate was 72% (33), 64% (16/25) for pancreatic and 100% for nonpancreatic periampullary adenocarcinoma. Postoperative complications occurred in 21 patients (38%), but only one patient (2%) died following surgery. Mean survivals from reexploratory surgery were 6.9 months for the 22 patients with pancreatic cancer undergoing palliative surgery, 20.5 months for the 16 patients with resectable pancreatic cancer, and 33.0 months for the 17 patients with nonpancreatic periampullary adenocarcinoma undergoing resection. We conclude that in carefully selected patients, reoperative surgery for periampullary cancer (1) provides a significant resection rate, (2) can be performed safely, and (3) offers a chance for long-term survival.