Hans G. Beger

Glucose homeostasis and endocrine pancreatic function in patients with chronic pancreatitis before and after surgical therapy

In a prospective clinical-experimental study, 15 consecutive patients with chronic pancreatitis, operated on because of severe pain, were examined for the effects of a duodenum-preserving resection of the pancreas head on endocrine pancreas function. This was done by means of oral and intravenous glucose tolerance testing before the operation, on the 10th or 11th day postoperatively, and 3 months after the operation. In addition to glucose levels in the peripheral venous blood, levels of insulin, C-peptide, glucagon, and pancreatic polypeptide were determined. As indicated by the k value, glucose tolerance improved postoperatively in 10 patients (66.6%); three patients (19.9%) showed no change, and one patient (6.6%) was worse. Only one patient (6.6%) developed evident diabetes mellitus immediately postoperatively. Pre- and postoperative levels of insulin and C-peptide showed no significant differences. The fasting levels of glucagon were significantly lower postoperatively than before the operation (p < 0.01). The stimulation of pancreatic polypeptide after oral glucose was significantly lower postoperatively (p < 0.01). Duodenum-preserving pancreas head resection does not lead to an impairment of glucose tolerance in the majority of patients; a deterioration was observed only in few cases (13.3%).

In vitro pharmalogic rationale for intraperitoneal regional chemotherapy

We performed basic in vitro studies on cell lines and individual tumor cell suspensions to support the concept of intraperitoneal regional chemotherapy, and to improve the rationale for drug selection in this regional chemotherapeutic method. We defined the concentration-response behavior and the dependence of drug cytotoxicity on time using the two human colorectal carcinoma cell lines HT29 and NMG 64/84. In addition, the drugs concentration-response behavior and cytotoxic potency for IPRC after a single drug exposure at 10 micrograms/ml (5-FU at 100 micrograms/ml) was preclinically defined with in vitro phase II studies using single cell suspensions of human solid tumor biopsies in the human tumor colony assay (HTCA). The drugs doxorubicin (ADM), cisplatin (CDDP), epidoxorubicin (EPI), 5-fluorouracy (5-FU), 5-fluorodeoxyuridine (5-FUDR), melphalan (LPAM), mitomycin C (MMC), and mitroxantrone were incubated at increasing concentrations up to 1000 micrograms/ml at 10, 30, 60, 360, and 1440 minutes with the cell lines. These drugs, as well as vindesine (VDS) and mafosfamide (MAF) were also tested in the HTCA at increasing concentrations. The HTCA response rates at 10 micrograms/ml (5-FU and MAF at 100 micrograms/ml) were used for in vitro phase II comparisons of potential drug clinical activities. All test drugs showed a time- and concentration-dependent cytotoxic activity against the cell lines. Based on the cytotoxicity test results with HT29 and NMG 64/84, specific times were recommended for clinical therapy with each drug. In the HTCA, the drugs showed different cytotoxic concentration responses. The concentration-response behavior of each drug varied in individual tumor biopsies of the same histology. Comparing the response rates at 1 microgram/ml (5-FU and MAF 10 micrograms/ml) and 10 micrograms/ml (5-FU and MAF 100 micrograms/ml), an overall increase of in vitro response by a factor of 2.1 +/- 0.7 (1.1-3.7) was noted. We were able to prove this principle qualification of various test drugs in our in vitro studies and to suggest the optimal exposure times for their use in intraperitoneal chemotherapy. Based on these results, NOV was successfully used in an IPRC clinical study.

Intraperitoneal regional chemotherapy with mitroxantrone

Pharmacokinetic considerations and tests with cell lines and individual cell suspensions from metastatic human solid tumor biopsies suggested testing the efficacy of mitoxantrone (NOV) in intraperitoneal regional chemotherapy (IPRC). Twenty-seven patients with intraperitoneal metastatic disease of various solid tumors received cyclic IPRC with NOV for treatment of malignant ascites (N = 16) or of peritoneal carcinomatosis (N = 11) at a NOV instillate concentration of 10 micrograms/ml. A total of 125 cycles (1-5 per patient) were applied. Response and toxicity were registered according to WHO criteria. The response rate (CR+PR) was 56 percent in malignant ascites, 45 percent in peritoneal carcinomatosis, and 52 percent overall. There were no systemic toxicities. Regional side effects were bacteriemia (4 of 125 cycles), pain (2 of 125 cycles), small bowel stricture (1 of 27 patients), and small bowel perforation (1 of 27 patients). From these results we can conclude that NOV appears to be effective in IPRC for malignant ascites and peritoneal carcinomatosis at tolerable toxicities.

European Adjuvant Trials

The results of large European randomized studies have been invaluable in determining a safe and standardized treatment protocol for patients with pancreatic cancer. It is clear that standard doses of postoperative adjuvant chemoradiotherapy have no survival advantage and may even be disadvantageous. Adjuvant chemotherapy, on the other hand, looks to be much more promising and warrants detailed evaluation. Further effective therapies can now be assessed within large cooperative organizations to improve the outlook, survival, expectancy, and quality of life for these patients. In this respect, ESPAC has been a major advance in clinical scientific investigation.

Chernotherapie, nicht jedoch Radiotherapie verbessert die Prognose des resezierten Pankreaskarzinoms: Ergebnisse einer prospektiven randomisierten Multizenterstudie (ESPAC-1) / Chemotherapy — Not Radiotherapy — Improves the Prognosis of Resected Pancreatic Cancer: Results of a Prospective Randomized Multicenter Study (ESPAC-1)

Das Pankreaskarzinom hat eine uberaus schlechte Prognose. Ob eine adjuvante Therapie nach Tumorresektion eine Prognoseverbesserung erzielen kann, ist bisher kontrovers diskutiert, insbesondere da keine aussagekraftigen Studien mit ausreichender Patientenzahl vorliegen. Die europaische Study Group for Pancreatic Cancer (ESPAC) hat daher eine prospektive randomisierte Multizenterstudie initiiert, in der 3 adjuvante Therapieschemata mit einer Beobachtungsgruppe verglichen wurden: 6 Zyklen Chemotherapie (5-FU+Leukovorin); Radiotherapie (2×20 Gy); Kombination von Radiotherapie (2×20 Gy) und nachfolgend 6 Zyklen Chemotherapie (5-FU+Leukovorin). In die Studie wurden insgesamt 591 Pat. einbezogen. Bei einer med. Nachbeobachtung von 10 Monaten (Range: 0-62 Monate) sind noch 227 Pat. (42%) am Leben. Die Auswertung zeigt keinen Nutzen einer Radiotherapie (med. Uberleben 15,5 Monate, 175 Pat.) versus keine Radiotherapie (med. Uberleben 16,1 Monate, 178 Pat.). Im Gegensatz hierzu war ein signifikanter Uberlebensvorteil (p<0,005) bei Pat. mit Chemotherapie (med. Uberleben 19,7 Monate, 238 Pat.) versus keine Chemotherapie (med. Uberleben 14,0 Monate, 235 Pat.) zu verzeichnen. Dies ist die grosste kontrollierte randomisierte Therapiestudie, welche bisher beim resezierten Pankreaskarzinom durchgefuhrt wurde. Eine adjuvante Chemotherapie (5-FU+Leukovorin) verbessert die Prognose nach Pankreaskarzinomresektion signifikant, wahrend eine postoperative Radiotherapie nutzlos ist.