Ross Carter

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.

Diclofenac Reduces the Incidence of Acute Pancreatitis After Endoscopic Retrograde Cholangiopancreatography

BACKGROUND & AIMS Acute pancreatitis following endoscopic retrograde cholangiopancreatography presents a unique opportunity for prophylaxis and early modification of the disease process because the initial triggering event is temporally well defined and takes place in the hospital. We report a prospective, single-center, randomized, double-blind controlled trial to determine if rectal diclofenac reduces the incidence of pancreatitis following cholangiopancreatography. METHODS Entry to the trial was restricted to patients who underwent endoscopic retrograde pancreatography or had manometrically verified sphincter of Oddi hypertension. Immediately after endoscopy, patients were given a suppository containing either 100 mg diclofenac or placebo. Estimation of serum amylase levels and clinical evaluation were performed in all patients. RESULTS A total of 220 patients entered the trial, and 110 received rectal diclofenac. Twenty-four patients developed pancreatitis (11%), of whom 7 received rectal diclofenac and 17 received placebo (P < 0.05). CONCLUSIONS This trial shows that rectal diclofenac given immediately after endoscopic retrograde cholangiopancreatography can reduce the incidence of acute pancreatitis.

Brush cytology in the assessment of pancreatico–biliary strictures: a review of 406 cases

Aims—To assess the accuracy of brush cytology in patients investigated for pancreatico–biliary strictures. Methods—All pancreatico–biliary brush cytology specimens submitted from two major teaching hospitals over a 6.5 year period were reviewed. Four hundred and forty eight satisfactory specimens from 406 patients with adequate clinical and/or pathological follow up data were examined in the study period. Results—Two hundred and forty six patients (60.6%) were shown to have neoplastic strictures. One hundred and forty seven tumours were identified cytologically, including 87 of 146 pancreatic carcinomas, 29 of 47 cholangiocarcinomas, one of one bile duct adenoma, four of seven carcinomas of the gallbladder, eight of 13 ampullary carcinomas, two of three ampullary adenomas, 10 of 16 malignancies of undetermined origin, none of two islet cell tumours, one of three hepatocellular carcinomas, and five of eight metastatic tumours. The three adenomas identified on brush cytology could not be distinguished from adenocarcinoma morphologically. One hundred and sixty patients (39.4%) had benign strictures, most often as a result of chronic pancreatitis and bile duct stones. There were three false positive cytological diagnoses mainly as a result of the misinterpretation of cases with relatively scant and/or degenerative atypical epithelial cells. Forty one cases were reported as atypical or suspicious of malignancy on brush cytology, of which 29 were ultimately shown to have carcinoma. The overall diagnostic sensitivity and specificity were 59.8% and 98.1%, respectively. The sensitivity increased from 44.3% in the initial third of cases to 70.7% in the final third of cases examined in the series. Conclusions—Brush cytology, in conjunction with other clinical and radiological investigations, is a useful technique in the assessment of patients with suspected pancreatico–biliary neoplasia.

Rab25 and CLIC3 Collaborate to Promote Integrin Recycling from Late Endosomes/Lysosomes and Drive Cancer Progression

Summary Here we show that Rab25 permits the sorting of ligand-occupied, active-conformation α5β1 integrin to late endosomes/lysosomes. Photoactivation and biochemical approaches show that lysosomally targeted integrins are not degraded but are retrogradely transported and recycled to the plasma membrane at the back of invading cells. This requires CLIC3, a protein upregulated in Rab25-expressing cells and tumors, which colocalizes with active α5β1 in late endosomes/lysosomes. CLIC3 is necessary for release of the cell rear during migration on 3D matrices and is required for invasion and maintenance of active Src signaling in organotypic microenvironments. CLIC3 expression predicts lymph node metastasis and poor prognosis in operable cases of pancreatic ductal adenocarcinoma (PDAC). The identification of CLIC3 as a regulator of a recycling pathway and as an independent prognostic indicator in PDAC highlights the importance of active integrin trafficking as a potential drive to cancer progression in vivo.

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.

Evaluation of an inflammation-based prognostic score in patients with inoperable pancreatic cancer.

Background/Aims: Patients with pancreatic cancer have one of the poorest survival rates and selection of patients for active treatment remains problematical. The present study assesses the value of an inflammation-based score (Glasgow Prognostic Score, GPS) in patients with inoperable pancreatic cancer. Methods: The GPS was constructed as follows: patients with both an elevated C-reactive protein (>10 mg/l) and hypoalbuminaemia (<35 g/l) were allocated a score of 2. Patients in whom only 1 or none of these biochemical abnormalities was present were allocated a score of 1 or 0, respectively. Results: One hundred and eighty-seven patients were studied and 49 (26%) underwent an operative palliative bypass procedure. At the end of follow-up, 181 (97%) patients died, 17% of patients were alive at 12 months. On univariate analysis, age (p < 0.01), TNM stage (p < 0.001) and the GPS (p < 0.001) were significant predictors of survival. On multivariate survival analysis, stratified for bypass procedure, age (hazard ratio 1.53, 95%CI 1.12–2.10, p = 0.008), TNM stage (hazard ratio 1.70, 95%CI 1.33–2.18, p < 0.001) and the GPS (hazard ratio 1.72, 95%CI 1.40–2.11, p < 0.001) remained independent significant predictors of survival. Conclusion: At diagnosis, the presence of a systemic inflammatory response (as measured by the GPS) appears to be a useful indicator of poor outcome, independent of TNM stage, in patients with inoperable pancreatic cancer.

Positive Mobilization Margins Alone Do Not Influence Survival Following Pancreatico-Duodenectomy for Pancreatic Ductal Adenocarcinoma

Objective:To determine the prognostic influence of residual tumor at or within 1 mm of the mobilization margins (R1Mobilization) compared with transection margins (R1Transection) following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma (PDAC). Background:The prognostic strength of R1 status increases with frequency of margin positivity and is enhanced by protocol driven pathology reporting. Currently, margins are treated uniformly with tumor at or close to any margin considered of equal prognostic significance. The resection involves a mobilization phase freeing the posterior margin and anterior surface then a transection phase requiring lympho-vascular division forming the medial resection and pancreatic transection margin. The comparative assessment of the relative importance of tumor involvement of these different margins has not previously been investigated. Methods:Retrospective analysis of 148 consecutive resections for PDAC from 1996–2007 was performed. The individual (pancreatic transection, medial, posterior, and anterior surface) margins were separately identified and analyzed by a senior pathologist. An R1 resection was defined as microscopic evidence of tumor ≤1 mm from a resection margin. R1Mobilization tumor extension included both R1Anterior and R1Posterior cases; while R1Transection included pancreatic neck/body transection, R1Medial and adjacent transection margins. Results:R1 status was confirmed in 109 patients (74%). The medial (46%) and posterior (44%) margins were most commonly involved. R1 status was found to an independent predictor of poor outcome (P < 0.001). R1Mobilization involvement only (n = 48) was associated with a significantly longer median survival of 18.9 months (95% CI, 13.7–24.8) versus 11.1 months (95% CI, 7.1–15.0) for those with R1Transection tumor involvement (n = 61) (P < 0.001). There was no significant difference in the survival of the R1Mobilization compared with R0 group (P = 0.52). Conclusions:Following pancreaticoduodenectomy for PDAC, involvement of the transection margins in contrast to mobilization margins defines a group whose outcome is significantly worse. This may impact upon the allocation of adjuvant therapy within the setting of randomized controlled trials.

Nasogastric feeding in severe acute pancreatitis may be practical and safe

SummaryBackground. Severe acute pancreatitis may be protracted and some form of nutritional support is frequently required to maintain the patient’s nutritional status. Recent work has suggested that enteral feeding via a jejunal route of delivery may reduce the magnitude of the inflammatory response. Insertion of nasojejunal (NJ) tubes in the patient with severe acute pancreatitis involves both delay and inconvenience. We undertook a prospective, feasibility study to assess the safety and practicability of nasogastric (NG) feeding in patients with severe acute pancreatitis.Patients and Methods. Twenty-six patients with objective evidence of severe acute pancreatitis received nasogastric feeding within 48 h of admission to our unit.Results. Etiology was identified as cholelithiasis (18 patients), ethanol (5), and miscellaneous (3). The median Glasgow score was 4 (range 2–7), APACHE II score 10 (4–28), and C-reactive protein concentration 286 mg/L (79–469). Fifteen patients had pancreatic and/or peripancreatic necrosis. Eleven patients developed severe organ failure, necessitating ventilatory support. Six developed multiple organ system failure, requiring inotropic support and/or renal dialysis. There were four deaths (15.3%).Nine patients underwent early, and nine late, ERCP, respectively; six necrosectomy (5 proven infected necrosis, 1 continued deterioration despite maximal support) and 4 patients internal drainage of a pseudocyst.The feed was well-tolerated in 22 patients. In 3 patients gastric stasis proved troublesome. There was no evidence of clinical or biochemical deterioration on commencing nasogastric feeding. Conclusion. It would appear that early NG feeding is usually possible in severe acute pancreatitis. In most patients it appears safe, well-tolerated, and worthy of further study.

Systemic inflammatory response predicts outcome in patients undergoing resection for ductal adenocarcinoma head of pancreas.

The aim of the present study was to examine the relationship between the clinicopathological status, the pre- and postoperative systemic inflammatory response and survival in patients undergoing potentially curative resection for ductal adenocarcinoma of the head of the pancreas. Patients (n=65) who underwent resection of ductal adenocarcinoma of the head of pancreas between 1993 and 2001, and had pre- and postoperative measurements of C-reactive protein, were included in the study. The majority of patients had stage III disease (International Union Against Cancer Criteria, IUCC), positive circumferential margin involvement (R1), tumour size greater than 25 mm with perineural and lymph node invasion and died within the follow-up period. On multivariate analysis, tumour size (hazard ratio (HR) 2.10, 95% confidence interval (CI) 1.20–3.68, P=0.009), vascular invasion (HR 2.58, 95% CI 1.48–4.50, P<0.001) and postoperative C-reactive protein (HR 2.00, 95% CI 1.14–3.52, P=0.015) retained independent significance. Those patients with a postoperative C-reactive protein ⩽10 mg l−1 had a median survival of 21.5 months compared with 8.4 months in those patients with a C-reactive protein >10 mg l−1 (P<0.001). The results of the present study indicate that, in patients who have undergone potentially curative resection for ductal adenocarcinoma of the head of pancreas, the presence of a systemic inflammatory response predicts poor outcome.