Adjuvant combination chemotherapy (AMF) following radical resection of carcinoma of the pancreas and papilla of Vater--results of a controlled, prospective, randomised multicentre study.

Between 1984 and 1987, 61 radically resected patients with carcinoma of the pancreas (n = 47) or the papilla of Vater (n = 14) were randomised either into postoperative adjuvant combination chemotherapy (AMF); 5-fluorouracil 500 mg/m2, doxorubicin 40 mg/m2, mitomycin C 6 mg/m2 (n = 30) once every 3 weeks for six cycles, or into a control group (no adjuvant chemotherapy) (n = 31). The median survival in the treatment group was 23 months compared with 11 months (P = 0.02, median test) in the control group, dependent on a survival benefit in the treatment group during the initial 2 years (P = 0.04 generalised Wilcoxon). The long-term prognosis was the same with an identical survival after 2 years (P = 0.10, power = 0.83). The observed 1, 2, 3 and 5-year survivals in the treatment group were 70, 43, 27 and 4% compared with 45, 32, 30 and 8 in the control group. 1 patient succumbed to sepsis probably attributable to chemotherapy. Cardiotoxicity and nephrotoxicity were recorded in 2 patients. These results suggest that adjuvant chemotherapy does postpone the incidence of recurrence in the first 2 years following radical surgery but increased cure rate was not observed.

Long-term survival following radical and palliative treatment of patients with carcinoma of the pancreas and papilla of Vater--the prognostic factors influencing the long-term results. A prospective multicentre study.

Between 1984-1987, 472 Norwegian patients with histologically or cytologically verified adenocarcinoma of the pancreas (n = 442) and papilla of Vater (n = 30) were prospectively accrued. Radical surgery, i.e. Whipple's procedure (n = 80) or total pancreatectomy (n = 28) were performed in 19% and 80% of patients with pancreatic and papilla carcinoma, respectively. The 1- and 5-year survival rate of patients with pancreatic and papilla carcinoma were 15 and 0.2%, median survival 4.5 months; and 66 and 15%, median survival 17 months, respectively. The corresponding results following radical surgery of pancreatic carcinoma were 45 and 1%, median survival 11.4 months; of papilla carcinoma 78 and 20%, median survival 38.1 months. Radical surgery or a palliative bypass of pancreatic carcinoma were followed by a mean survival of 20.1 vs 9.1 months (P = 0.03) in Stage I and 15.1 vs 7.5 months (P = 0.004) in Stage III, respectively. A Whipple's operation and total pancreatectomy were followed by a mean survival of 16.7 and 18.3 months (P = 0.5), respectively. Dismal prognostic factors were: a distal tumour site, high TNM stage grouping and weight loss. Beneficial factors were a high Karnofsky's index and radical surgery.

Palliation of pancreatic cancer. A prospective multicentre study.

The aim of this study was to compare palliation of patients with verified pancreatic carcinoma after radical surgery (n = 84), bypass surgery, i.e. biliary (n = 106), biliary and duodenal (n = 85), and for patients with advanced disease, i.e. laparotomy alone (n = 56), not operated (n = 106), 3 months after discharge from hospital. 128 of 233 patients (55%) still alive were followed up. Radically resected patients had the best palliation and clinical performance; on average they could perform normal activities if helped, 82% were mobile at home and 62% were pain-free. Bypassed patients can on average look after themselves but normal activities are not possible, 31% were in hospital, 26% were pain-free and 39% suffered from nausea and vomiting. Patients with advanced disease were on average incapable and required special help and care, about 70% were in hospital, 8-17% were pain-free. 'Good risk' bypassed patients, i.e. in stage I-III, used stronger analgesics (29 vs 3%) (P = 0.006) and more frequently complained of nausea and vomiting (38 vs 12%) (P = 0.02) than radically resected patients. Palliation was comparable for the two bypassed groups.

Carcinoma of the pancreas and papilla of Vater--assessment of resectability and factors influencing resectability in stage I carcinomas. A prospective multicentre trial in 472 patients.

Between 1984 and 1987, 472 patients with histologically or cytologically verified carcinomas of the pancreas or papilla of Vater, were accrued in the Norwegian Pancreatic Cancer Trial. Surgical assessment revealed resectability in 29% (94 of 330) of the pancreatic tumours and 89% (25 of 28) of the papillar tumours. Tumours of the pancreatic head were resectable in 32% (84 of 259). The sensitivities of the different diagnostic methods in patients with resectable tumours were: FNAC (fine needle aspiration cytology) 80%, ERCP (endoscopic retrograde cholangio-pancreatography) 78%, PTC (percutaneous transhepatic cholangiography) 73%, ERCP with duct cytology 67%, CT (computed tomography) 58%, US (ultrasound) 42% and angiography 22%. The positive predictive values (PV+) in resectable disease were: US 29%, CT 35%, ERCP 43% and angiography 44%. Corresponding figures for unresectable disease were US 95%, CT 97%, ERCP 75% and angiography 88%. Resectable tumours of the pancreas and papilla of Vater had an average macroscopic diameter of 3.2 x 3.4 cm and 2.2 x 2.3 cm, respectively. Tumour size increased with stage. Increasing tumour size and abdominal pain combined with short diagnostic delay both decreased resectability rate, whereas a combination of long diagnostic delay and abdominal pain had a more favorable resectability rate. Radical pancreatic surgery, if effective in the treatment of carcinoma of the pancreas or papilla of Vater, should not be undertaken if any preoperative diagnostic test demonstrates signs of indisputable unresectability. Available methods for the evaluation of resectability in patients lacking such signs are insufficient. This necessitates exploratory laparotomy in many patients.

Meta-analysis of randomised adjuvant therapy trials for pancreatic cancer.

The aim of this study was to investigate the worldwide evidence of the roles of adjuvant chemoradiation and adjuvant chemotherapy on survival in potentially curative resected pancreatic cancer. Five randomised controlled trials of adjuvant treatment in patients with histologically proven pancreatic ductal adenocarcinoma were identified, of which the four most recent trials provided individual patient data (875 patients). This meta-analysis includes previously unpublished follow-up data on 261 patients. The pooled estimate of the hazard ratio (HR) indicated a 25% significant reduction in the risk of death with chemotherapy (H = 0.75, 95% confidence interval (CI): 0.64, 0.90, P-values(stratified) (Pstrat) = 0.001) with median survival estimated at 19.0 (95% CI: 16.4, 21.1) months with chemotherapy and 13.5 (95% CI: 12.2, 15.8) without. The 2- and 5-year survival rates were estimated at 38 and 19%, respectively, with chemotherapy and 28 and 12% without. The pooled estimate of the HR indicated no significant difference in the risk of death with chemoradiation (HR = 1.09, 95% CI: 0.89, 1.32, Pstrat = 0.43) with median survivals estimated at 15.8 (95% CI: 13.9, 18.1) months with chemoradiation and 15.2 (95% CI: 13.1, 18.2) without. The 2- and 5-year survival rates were estimated at 30 and 12%, respectively, with chemoradiation and 34 and 17% without. Subgroup analyses estimated that chemoradiation was more effective and chemotherapy less effective in patients with positive resection margins. These results show that chemotherapy is effective adjuvant treatment in pancreatic cancer but not chemoradiation. Further studies with chemoradiation are warranted in patients with positive resection margins, as chemotherapy appeared relatively ineffective in this patient subgroup.

Nipple valve anastomosis for preventing recurrence of Crohn disease in the neoterminal ileum after ileocolic resection. A prospective pilot study.

BACKGROUND: Crohn disease may recur within months in the neoterminal ileum after ileocolic resection. Coloileal reflux may be a factor contributing to recurrence. This study tests the effect of a nipple valve anastomosis in preventing symptomatic and endoscopic neoileal recurrence. METHODS: Between January 1993 and April 1997, 25 patients with Crohn disease were resected and anastomosed with an ileocolic nipple valve. Postoperatively, the patients were given 5-aminosalicylic acid, 0.75-3 g/daily. Regular follow-up included the Harvey-Bradshaw index, ileocolonoscopy, and hydrocolonic sonography. RESULTS: After 1 year 2 of 25 patients (8%) had a symptomatic and 3 of 23 patients (13%) an endoscopic recurrence. There was no symptomatic neoileal recurrence between 1 and 5 years. After 3 years 6 of 13 patients (46%) had an endoscopic recurrence. After 5 years 4 of 11 patients (36%) had a symptomatic recurrence. CONCLUSIONS: These results may suggest that a nipple valve anstomosis delays and perhaps prevents symptomatic recurrence of Crohn disease in the neoterminal ileum.

Morbidity and mortality after radical and palliative pancreatic cancer surgery. Risk factors influencing the short-term results.

OBJECTIVE: To analyze the morbidity and mortality after radical and palliative pancreatic cancer surgery in Norway, especially the risk factors. SUMMARY BACKGROUND DATA: A prospective multicenter study between 1984-1987 including only histologically or cytologically verified adenocarcinoma of the pancreas (N = 442) or the papilla of Vater (N = 30); 84 patients (19%) with pancreatic carcinoma and 24 patients (80%) with papilla carcinoma underwent radical operations. A palliative procedure was performed in 252 patients (53%). METHODS: Clinical data, surgical procedures and the following morbidity and mortality were recorded on standardized forms. The risk factors were analyzed by a logistic multiple regression model. RESULTS: The morbidity, reoperation, and mortality rates were 43, 18, and 11% after radical surgery and 23, 4, and 14% after palliative surgery. Karnofsky's index was the sole independent risk factor for death after radical surgery. Splenectomy, age, and TNM stage influenced morbidity. Diabetes, Karnofsky's index, and liver metastases were risk factors in palliative surgery. CONCLUSIONS: The morbidity and mortality risks were comparable between total pancreatectomy and a Whipple's procedure and between biliary and a double bypass. Preoperative biliary drainage had no impact on the risks and may be abandoned. High age is a relative and a low Karnofsky's index an absolute contraindication for radical surgery. Nonsurgical palliation of jaundice should be considered according to the presence of independent risk factors.

Staging of carcinoma of the pancreas and ampulla of Vater. Tumor (T), lymph node (N), and distant metastasis (M) as prognostic factors.

Between 1984 and 1987, 472 Norwegian patients with histologically or cytologically verified carcinoma of the pancreas (N = 442) and ampulla of Vater (N = 30) were accrued and TNM staged according to UICC. The influence of the T, N, and M categories on long-term survival was evaluated. The T1a and T1b tumors of stage I pancreatic carcinoma had a comparable survival (p = 0.68-0.95). A higher T category (T1-T3) predicted a more dismal prognosis (p = 0.000). The T1 and T2 carcinomas of the ampulla of Vater had a comparable favorable prognosis, and the T3 and T4 tumors had a comparable unfavorable prognosis. The N1 vs N0 (p = 0.000-0.01) and M1 vs M0 categories (p = 0.00-0.003) predicted a more dismal prognosis for both pancreatic and ampullary carcinoma. By logistic regression analyses, pancreatic tumor extension into peripancreatic fat or nerves and invasion of ampullary carcinomas into duodenal wall, unfavorably influenced the N1 category (p = 0.000-0.04) and tumor diameter influenced the M1 category (p = 0.002-0.04) both for pancreatic and ampullary carcinoma. The T, N, and M categories all independently influenced survival of pancreatic carcinoma (p = 0.000-0.003). Only the N category (p = 0.01) influenced the prognosis of ampullary carcinomas.

Tamoxifen therapy in unresectable adenocarcinoma of the pancreas and the papilla of Vater.

Between 1984 and 1987, 176 Norwegian patients with histologically verified unresectable pancreatic adenocarcinoma were randomized to double-blind treatment with oral tamoxifen (30 mg daily; 48 men and 44 women) or placebo (47 men and 37 women). Analysis of oestrogen receptor activity in the carcinomas was not performed. There were no statistically significant differences between the two groups according to age, Karnofsky performance index, tumour node metastasis (TNM) stage, operative treatment or other patient characteristics. The tamoxifen or placebo treatment continued to death or to 10 months after accrual into the trial was stopped. In the tamoxifen group, the mean and median survivals were 205 and 115 days, respectively. These values did not differ statistically from the 192 and 122 days, respectively, observed in the placebo group. Additional retrospective analyses of sex and stage revealed no beneficial effect of tamoxifen upon survival. For women in stage III (any T N1 M0), mean and median survivals were 255 and 191 days, respectively, compared with values of 84 and 45 days, respectively, in the placebo group (P = 0.011). After 2.5 years, three (7 per cent) women in the tamoxifen group were still alive compared with no survivors in the placebo group. No male patients survived beyond 2.5 years. This therapeutic result in a small subgroup of women is probably incidental and not an effect of tamoxifen.

Carcinoma of the pancreas and papilla of Vater: presenting symptoms, signs, and diagnosis related to stage and tumour site. A prospective multicentre trial in 472 patients. Norwegian Pancreatic Cancer Trial.

During the period 1984-87, 472 patients with histologically or cytologically verified carcinoma of the pancreas (n = 442) or the papilla of Vater (n = 30) were accrued. Diagnostic investigations were performed in accordance with the ordinary routines of 38 Norwegian hospitals. Jaundice at presentation, found in 47% of the patients, indicated a relatively low staging. Abdominal pain or weight loss, present in 72% and 58%, respectively, indicated higher staging. The sensitivities of the diagnostic investigations were 1) endoscopic retrograde cholangiopancreatography (ERCP), 79%, and computed tomography (CT), 75%; 2) ultrasonography (US), 57%; angiography performed in 18% to assess unresectability, sensitivity, 43%; fine-needle aspiration cytology performed in 27%, sensitivity, 86%; and percutaneous transhepatic cholangiography (PTC) performed solely on papillar and head tumours in 16%, sensitivity, 85%. In stage I, PTC and ERCP had a sensitivity of 78%; CT, 52%; and US, 40%. Patient's, physician's, and diagnostic delay averaged 1.8, 2.4, and 4.0 months, respectively. The delays were shortest in stage I and papillar carcinomas.

Pooling of prognostic studies in cancer of the pancreatic head and periampullary region: the Triple-P study. Triple-P study group.

OBJECTIVE: Development of a prognostic tool for patients with unresectable pancreatic cancer to distinguish between with low or high probabilities of survival 3 to 9 months after diagnosis. DESIGN: Data about individual patients from five studies were pooled. A multivariate proportional hazards model with time-dependent covariates was developed, including age, sex, and metastases. An extended model was developed on a subset of patients, including weight loss, pain, and jaundice at diagnosis. SETTING: Multicentre study, The Netherlands, Norway, USA, UK, and Canada. SUBJECTS: 1020 patients with unresectable pancreatic cancer. MAIN OUTCOME MEASURES: Prediction of prognosis. RESULTS: Patients with metastases, pain, or weight loss at diagnosis had a significantly poorer prognosis than the others. Older men had a worse prognosis than younger men, while older women had a better prognosis than younger ones. Patients with jaundice had a relatively good prognosis. Differences in survival among the studies were incorporated in a prognostic score chart. CONCLUSION: The prognostic score chart can be used to select patients with relatively low expectation of survival for endoscopic palliation, and patients with relatively high expectation for surgical palliation.