Attila Oláh

Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial

ObjectiveTo assess the influence of resection margins on survival for patients with resected pancreatic cancer treated within the context of the adjuvant European Study Group for Pancreatic Cancer-1 (ESPAC-1) study. Summary Background DataPancreatic cancer is associated with a poor long-term survival rate of only 10% to 15% after resection. Patients with positive microscopic resection margins (R1) have a worse survival, but it is not known how they fare in adjuvant studies. MethodsESPAC-1, the largest randomized adjuvant study of resectable pancreatic cancer ever performed, set out to look at the roles of chemoradiation and chemotherapy. Randomization was stratified prospectively by resection margin status. ResultsOf 541 patients with a median follow-up of 10 months, 101 (19%) had R1 resections. Resection margin status was confirmed as an influential prognostic factor, with a median survival of 10.9 months for R1 versus 16.9 months months for patients with R0 margins. Resection margin status remained an independent factor in a Cox proportional hazards model only in the absence of tumor grade and nodal status. There was a survival benefit for chemotherapy but not chemoradiation, irrespective of R0/R1 status. The median survival was 19.7 months with chemotherapy versus 14.0 months without. For patients with R0 margins, chemotherapy produced longer survival compared with to no chemotherapy. This difference was less apparent for the smaller subgroup of R1 patients, but there was no significant heterogeneity between the R0 and R1 groups. ConclusionsResection margin-positive pancreatic tumors represent a biologically more aggressive cancer; these patients benefit from resection and adjuvant chemotherapy but not chemoradiation. The magnitude of benefit for chemotherapy treatment is reduced for patients with R1 margins versus those with R0 margins. Patients with R1 tumors should be included in future trials of adjuvant treatments and randomization and analysis should be stratified by this significant prognostic factor.

Effect of Adjuvant Chemotherapy With Fluorouracil Plus Folinic Acid or Gemcitabine vs Observation on Survival in Patients With Resected Periampullary Adenocarcinoma: The ESPAC-3 Periampullary Cancer Randomized Trial

CONTEXT Patients with periampullary adenocarcinomas undergo the same resectional surgery as that of patients with pancreatic ductal adenocarcinoma. Although adjuvant chemotherapy has been shown to have a survival benefit for pancreatic cancer, there have been no randomized trials for periampullary adenocarcinomas. OBJECTIVE To determine whether adjuvant chemotherapy (fluorouracil or gemcitabine) provides improved overall survival following resection. DESIGN, SETTING, AND PATIENTS The European Study Group for Pancreatic Cancer (ESPAC)-3 periampullary trial, an open-label, phase 3, randomized controlled trial (July 2000-May 2008) in 100 centers in Europe, Australia, Japan, and Canada. Of the 428 patients included in the primary analysis, 297 had ampullary, 96 had bile duct, and 35 had other cancers. INTERVENTIONS One hundred forty-four patients were assigned to the observation group, 143 patients to receive 20 mg/m2 of folinic acid via intravenous bolus injection followed by 425 mg/m2 of fluorouracil via intravenous bolus injection administered 1 to 5 days every 28 days, and 141 patients to receive 1000 mg/m2 of intravenous infusion of gemcitabine once a week for 3 of every 4 weeks for 6 months. MAIN OUTCOME MEASURES The primary outcome measure was overall survival with chemotherapy vs no chemotherapy; secondary measures were chemotherapy type, toxic effects, progression-free survival, and quality of life. RESULTS Eighty-eight patients (61%) in the observation group, 83 (58%) in the fluorouracil plus folinic acid group, and 73 (52%) in the gemcitabine group died. In the observation group, the median survival was 35.2 months (95%% CI, 27.2-43.0 months) and was 43.1 (95%, CI, 34.0-56.0) in the 2 chemotherapy groups (hazard ratio, 0.86; (95% CI, 0.66-1.11; χ2 = 1.33; P = .25). After adjusting for independent prognostic variables of age, bile duct cancer, poor tumor differentiation, and positive lymph nodes and after conducting multiple regression analysis, the hazard ratio for chemotherapy compared with observation was 0.75 (95% CI, 0.57-0.98; Wald χ2 = 4.53, P = .03). CONCLUSIONS Among patients with resected periampullary adenocarcinoma, adjuvant chemotherapy, compared with observation, was not associated with a significant survival benefit in the primary analysis; however, multivariable analysis adjusting for prognostic variables demonstrated a statistically significant survival benefit associated with adjuvant chemotherapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00058201.

Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial

BACKGROUND Human equilibrative nucleoside transporter 1 (hENT1) levels in pancreatic adenocarcinoma may predict survival in patients who receive adjuvant gemcitabine after resection. METHODS Microarrays from 434 patients randomized to chemotherapy in the ESPAC-3 trial (plus controls from ESPAC-1/3) were stained with the 10D7G2 anti-hENT1 antibody. Patients were classified as having high hENT1 expression if the mean H score for their cores was above the overall median H score (48). High and low hENT1-expressing groups were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. All statistical tests were two-sided. RESULTS Three hundred eighty patients (87.6%) and 1808 cores were suitable and included in the final analysis. Median overall survival for gemcitabine-treated patients (n = 176) was 23.4 (95% confidence interval [CI] = 18.3 to 26.0) months vs 23.5 (95% CI = 19.8 to 27.3) months for 176 patients treated with 5-fluorouracil/folinic acid (χ(2) 1=0.24; P = .62). Median survival for patients treated with gemcitabine was 17.1 (95% CI = 14.3 to 23.8) months for those with low hENT1 expression vs 26.2 (95% CI = 21.2 to 31.4) months for those with high hENT1 expression (χ(2)₁= 9.87; P = .002). For the 5-fluorouracil group, median survival was 25.6 (95% CI = 20.1 to 27.9) and 21.9 (95% CI = 16.0 to 28.3) months for those with low and high hENT1 expression, respectively (χ(2)₁ = 0.83; P = .36). hENT1 levels were not predictive of survival for the 28 patients of the observation group (χ(2)₁ = 0.37; P = .54). Multivariable analysis confirmed hENT1 expression as a predictive marker in gemcitabine-treated (Wald χ(2) = 9.16; P = .003) but not 5-fluorouracil-treated (Wald χ(2) = 1.22; P = .27) patients. CONCLUSIONS Subject to prospective validation, gemcitabine should not be used for patients with low tumor hENT1 expression.

Acute pancreatitis in five European countries: etiology and mortality.

Introduction In recent years, many advances have been made in the diagnosis and treatment of acute pancreatitis that have lead to a significant reduction in both morbidity and mortality; however, knowledge of the etiology and of the relation between etiology and mortality is far from complete. Aim To obtain a more comprehensive view of the etiology and mortality of acute pancreatitis in Europe than has been given by previous single-center studies. Methodology The study comprised 1,068 patients in five European countries who were admitted to hospitals for acute pancreatitis from January 1990 to December 1994. Data for each patient were collected on a standardized form. Results Of the 1,068 patients (692 men, 376 women; mean age, 52.8 years; range, 10–95 years), 589 had edematous pancreatitis, and 479 the necrotic form. Cholelithiasis (37.1%) and alcohol (41.0%) were the most frequent etiologic factors. In Germany, cholelithiasis and alcohol occurred with similar frequency (34.9 and 37.9%, respectively); in Hungary, alcohol predominates over cholelithiasis (60.7 vs. 24.0%); in France, a small predominance of alcohol was seen (38.5 vs. 24.6%); and in Greece and Italy, there was a clear predominance of cholelithiasis over alcohol (71.4 vs. 6.0% and 60.3 vs. 13.2%, respectively). The differences in the frequency of cholelithiasis and alcohol between Greece and Italy and the other countries were statistically significant (p < 0.01). Eighty-three patients (7.8%) died of acute pancreatitis; 77 (16.1%) had necrotic disease and 6 (1.0%) edematous. There was no statistically significant difference in mortality among the etiologic groups, and no relation was found between mortality and age. Conclusion Both cholelithiasis and alcohol were main etiologic factors in the more northern countries studied, whereas cholelithiasis alone predominated in the more southern ones. Mortality was high for necrotic pancreatitis; it was similar among the various etiologic groups, and there was no relationship between mortality and age.

The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease

Background: Mutations in the PRSS1 gene explain most occurrences of hereditary pancreatitis (HP) but many HP families have no PRSS1 mutation. Recently, an association between the mutation N34S in the pancreatic secretory trypsin inhibitor (SPINK1 or PSTI) gene and idiopathic chronic pancreatitis (ICP) was reported. It is unclear whether the N34S mutation is a cause of pancreatitis per se, whether it modifies the disease, or whether it is a marker of the disease. Patients and methods: A total of 327 individuals from 217 families affected by pancreatitis were tested: 152 from families with HP, 108 from families with ICP, and 67 with alcohol related CP (ACP). Seven patients with ICP had a family history of pancreatitis but no evidence of autosomal dominant disease (f-ICP) compared with 87 patients with true ICP (t-ICP). Two hundred controls were also tested for the N34S mutation. The findings were related to clinical outcome. Results: The N34S mutation was carried by five controls (2.5%; allele frequency 1.25%), 11/87 (13%) t-ICP patients (p=0.0013 v controls), and 6/7 (86%) affected (p<0.0001 v controls) and 1/9 (11%) unaffected f-ICP cases. N34S was found in 4/108 affected HP patients (p=0.724 v controls), in 3/27 (11%) with wild-type and in 1/81 (1%) with mutant PRSS1, and 4/67 ACP patients (all p>0.05 v controls). The presence of the N34S mutation was not associated with early disease onset or disease severity. Conclusions: The prevalence of the N34S mutation was increased in patients with ICP and was greatest in f-ICP cases. Segregation of the N34S mutation in families with pancreatitis is unexplained and points to a complex association between N34S and another putative pancreatitis related gene.

The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 Years After

Background. In 2005, the International Study Group of Pancreatic Fistula developed a definition and grading of postoperative pancreatic fistula that has been accepted universally. Eleven years later, because postoperative pancreatic fistula remains one of the most relevant and harmful complications of pancreatic operation, the International Study Group of Pancreatic Fistula classification has become the gold standard in defining postoperative pancreatic fistula in clinical practice. The aim of the present report is to verify the value of the International Study Group of Pancreatic Fistula definition and grading of postoperative pancreatic fistula and to update the International Study Group of Pancreatic Fistula classification in light of recent evidence that has emerged, as well as to address the lingering controversies about the original definition and grading of postoperative pancreatic fistula. Methods. The International Study Group of Pancreatic Fistula reconvened as the International Study Group in Pancreatic Surgery in order to perform a review of the recent literature and consequently to update and revise the grading system of postoperative pancreatic fistula. Results. Based on the literature since 2005 investigating the validity and clinical use of the original International Study Group of Pancreatic Fistula classification, a clinically relevant postoperative pancreatic fistula is now redefined as a drain output of any measurable volume of fluid with an amylase level >3 times the upper limit of institutional normal serum amylase activity, associated with a clinically relevant development/condition related directly to the postoperative pancreatic fistula. Consequently, the former “grade A postoperative pancreatic fistula” is now redefined and called a “biochemical leak,” because it has no clinical importance and is no longer referred to a true pancreatic fistula. Postoperative pancreatic fistula grades B and C are confirmed but defined more strictly. In particular, grade B requires a change in the postoperative management; drains are either left in place >3 weeks or repositioned through endoscopic or percutaneous procedures. Grade C postoperative pancreatic fistula refers to those postoperative pancreatic fistula that require reoperation or lead to single or multiple organ failure and/or mortality attributable to the pancreatic fistula. Conclusion. This new definition and grading system of postoperative pancreatic fistula should lead to a more universally consistent evaluation of operative outcomes after pancreatic operation and will allow for a better comparison of techniques used to mitigate the rate and clinical impact of a pancreatic fistula. Use of this updated classification will also allow for more precise comparisons of surgical quality between surgeons and units who perform pancreatic surgery.

Optimal Duration and Timing of Adjuvant Chemotherapy After Definitive Surgery for Ductal Adenocarcinoma of the Pancreas: Ongoing Lessons From the ESPAC-3 Study

PURPOSE Adjuvant chemotherapy improves patient survival rates after resection for pancreatic adenocarcinoma, but the optimal duration and time to initiate chemotherapy is unknown. PATIENTS AND METHODS Patients with pancreatic ductal adenocarcinoma treated within the international, phase III, European Study Group for Pancreatic Cancer-3 (version 2) study were included if they had been randomly assigned to chemotherapy. Overall survival analysis was performed on an intention-to-treat basis, retaining patients in their randomized groups, and adjusting the overall treatment effect by known prognostic variables as well as the start time of chemotherapy. RESULTS There were 985 patients, of whom 486 (49%) received gemcitabine and 499 (51%) received fluorouracil; 675 patients (68%) completed all six cycles of chemotherapy (full course) and 293 patients (30%) completed one to five cycles. Lymph node involvement, resection margins status, tumor differentiation, and completion of therapy were all shown by multivariable Cox regression to be independent survival factors. Overall survival favored patients who completed the full six courses of treatment versus those who did not (hazard ratio [HR], 0.516; 95% CI, 0.443 to 0.601; P < .001). Time to starting chemotherapy did not influence overall survival rates for the full study population (HR, 0.985; 95% CI, 0.956 to 1.015). Chemotherapy start time was an important survival factor only for the subgroup of patients who did not complete therapy, in favor of later treatment (P < .001). CONCLUSION Completion of all six cycles of planned adjuvant chemotherapy rather than early initiation was an independent prognostic factor after resection for pancreatic adenocarcinoma. There seems to be no difference in outcome if chemotherapy is delayed up to 12 weeks, thus allowing adequate time for postoperative recovery.

An update on recurrent acute pancreatitis: data from five European countries

OBJECTIVE:A great number of studies have been published on acute pancreatitis, but few have focused on the recurrent form. In this study, we have sought to determine the relative frequency and mortality of recurrent acute pancreatitis, and also to update our knowledge of its etiological factors.METHODS:Patients were selected from a total of 1068 persons included in a previous European study of acute pancreatitis. All were admitted to a hospital with an attack of acute pancreatitis between January, 1990 and December, 1994. Data for each patient was recorded on a standardized form.RESULTS:Of the 1068 with acute pancreatitis, 288 (27%) had recurrent pancreatitis; the majority (78.8%) were men, with a mean age of 43 yr (range 16–95 yr). Regarding etiology, alcohol was the most frequent factor (57%), followed by gallstones (25%), other factors (7.6%), and no identified factor (10.4%). Of the 288 patients, 17 (5.9%) died, all of whom had necrotizing pancreatitis; among all of the patients with necrotizing pancreatitis (141 of 288), the mortality was 12.1%. These percentages are lower than those for patients who had a single attack (8.5% and 18.6%, respectively), but not to a statistically significant degree. Mortality was significantly lower among patients with alcoholic pancreatitis (6.9%) than among those with biliary (30%) (p < 0.002) or idiopathic pancreatitis (25%) (p < 0.04). Most of the deaths (82.4%) occurred at the second attack of pancreatitis.CONCLUSION:Acute recurrent pancreatitis remains a frequent disease, with alcohol being the most frequent etiological factor. Mortality is similar to that of a single episode of acute pancreatitis, and it is significantly lower among patients with alcohol as the etiology.

Pancreatic Transection from Blunt Abdominal Trauma: Early versus Delayed Diagnosis and Surgical Management

Background and Aims: Pancreatic trauma is relatively uncommon, but carries high morbidity and mortality rates, especially when diagnosis is delayed or inappropriate surgery is attempted. Patient Material: The clinical course and surgical management of 14 patients with distal pancreatic transection or severe laceration with or without main pancreatic duct (MPD) injury caused by blunt abdominal trauma were analyzed in a university teaching hospital. The average age of the 14 patients (12 male, 2 female) was 28.9 years (range 5–56). Six patients had isolated pancreatic trauma, and intra-abdominal and extra-abdominal (mean 0.8) injuries associated with pancreatic transection were seen in the other 8 patients. Results: Nine patients were diagnosed and operated on within the first 24 h. Eight of them underwent transection of the gland with MPD injury; distal pancreatectomy with splenectomy was performed in 3 and without splenectomy in 2, distal pancreatogastrostomy in 1, and – due to associated duodenal laceration and/or contusion of the pancreatic head – pylorus-preserving pancreatoduodenectomy in 2. In 1 case (grade II laceration) only external drainage was necessary. All the patients with early, correctly diagnosed parenchymal and ductal injury survived. Only 1 patient required reoperation due to haemorrhage after pancreatoduodenectomy. The other 5 cases were referred elsewhere after initial treatment, and all of them underwent some kind of external drainage. Three had undetected MPD injury, and in the other 2 cases the parenchymal lesions were either underestimated or missed. All of these cases required subsequent resection (1), internal drainage due to fistula (2), or drainage of developed abscess (2). Three of them had severe septic and pulmonary complications; 1 patient with MPD injury was lost to follow-up. Conclusion: Patients requiring delayed surgical intervention after an unsuccessful period of observation or a subsequent operation due to undected MPD injury demonstrated a higher rate of pancreas-specific mortality and morbidity.

Solid pseudopapillary neoplasm of the pancreas—proposed algorithms for diagnosis and surgical treatment

PurposeThe incidence of solid pseudopapillary neoplasm (SPN) of the pancreas is rising. Although the evidence for proper management is accumulating, we still lack diagnostic and therapeutic guidelines. In this paper, therefore, we propose an algorithm for diagnosis and treatment of this rare type of tumor.MethodsA literature search was carried out on “Medline” and “Pubmed” databases to identify studies investigating the clinicopathologic features, pathogenesis, diagnostic, and differential diagnostic pathways, and surgical and adjuvant treatment options. Evidence from relevant published literature was completed with data of six patients treated with SPN in our institution.ResultsThis study included case series and retrospective reviews only, since no higher level of evidence exists in the relevant literature. The articles emphasized that preoperative diagnosis is desirable to set up a precise plan for surgical treatment. Further, an R0 organ-sparing resection for primary SPN and an en bloc resection of locally advanced SPN are advised, while resection of synchronous as well as metachronous distant metastases is strongly advocated for this rare type of pancreatic cancer. The role of adjuvant chemo- or radiotherapy still needs to be defined. Finally, a diagnostic and therapeutic algorithm is devised in this paper to aid proper management of SPN.ConclusionCurrent recommendations for treatment of SPN of the pancreas rely mainly on case series as single institutional experiences and retrospective reviews. Although the level of evidence is relatively low, the way of management discussed above is likely to provide an excellent prognosis in typically young patients with SPN.