| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
NEW APPROACHES TO THE TREATMENT OF HEPATIC MALIGNANCIES |
From the Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kobe University, Kobe, Japan.
Correspondence: Address correspondence and reprint requests to: Yasuyuki Suzuki, MD, Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kobe University, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan; Fax: 81-78-382-5939; E-mail: szk{at}med.kobe-u.ac.jp
ABSTRACT
Background: Recently a few centers reported promising results of regional intra-arterial chemotherapy for pancreatic cancer. However, the detailed pharmacokinetics and the side effects of anticancer agents remain unclear.
Methods: Catheters were introduced into the gastroduodenal artery and the splenic artery of dogs. In group I, arterial infusion of 5-fluorouracil (5-FU) was performed over 10 minutes. In group II, 5-FU was infused systemically. In group III, an intra-arterial infusion was repeated weekly three times. Blood samples and liver and pancreas tissue samples were obtained to determine 5-FU levels. In a subset of each group, the pancreas, duodenum, and liver were excised for histological analyses.
Results: Immediately after the infusion of 5-FU, the portal level in group I was higher than that in group II. However, the mean systemic level in group I was lower than in group II. The mean tissue concentration in the pancreas in group I was significantly higher than that of group II. Histological examination revealed no microscopic alterations after treatment in all groups, including group III.
Conclusions: This fundamental study suggested that intra-arterial chemotherapy of 5-FU for pancreatic cancer allows higher regional drug delivery without adverse effects on normal regions of the pancreas, the duodenum, and the liver.
Key Words: Pancreas cancer • Intra-arterial chemotherapy • Pharmacokinetics • 5-FU
Carcinoma of the pancreas is the fifth leading cause of cancer death in Japan, and the number of patients has increased in recent years. The 5-year survival of even resectable pancreatic ductal cancers has been reported to be approximately 10%. Moreover, the cancer has already spread and is no longer resectable at presentation in many patients. Unresectable pancreatic cancers have an extremely dismal prognosis because systemic chemotherapy is of limited effectiveness for this disease.1–5
Recently a few centers reported promising results of regional intra-arterial chemotherapy as an adjuvant or as a treatment for pancreatic cancer.6–14 This has the theoretical advantage of achieving higher local drug concentrations in the tumor with lower systemic drug toxicity. However, the detailed pharmacokinetics and the side effects of anticancer agents by intra-arterial chemotherapy on the normal pancreas and duodenum remain unclear.
MATERIALS AND METHODS
Animals
Mongrel dogs of both sexes weighing 6 to 15 kg were used in this study. All dogs were maintained in animal care facilities in accordance with National Institutes of Health guidelines. Protocols were reviewed and approved by the Kobe University Animal Care Committee.
Procedures
Animals were anesthetized with intravenous sodium pentobarbital (25 mg/kg body weight) after overnight fasting. An intravenous catheter was introduced into the right external jugular vein for both blood sampling and fluid replacement. After laparotomy through a midline incision, 3F intraarterial catheters (Atom-tube; Terumo Co. Ltd, Tokyo, Japan) were introduced into the gastroduodenal artery and the splenic artery retrogradely. The catheter tip in the splenic artery was positioned as near the celiac axis as possible. For sampling the portal blood, an intravenous catheter was placed into the portal vein from the first jejunal vein. The left gastric artery was clamped near its origin transiently during 5-fluorouracil (5-FU) arterial infusion (Fig. 1).
|
Pharmacokinetic Study
In groups I and II, blood samples were obtained from the right external jugular vein and the portal vein before and 0, 5, 10, 30, and 60 minutes after the infusion to determine plasma 5-FU levels. The liver and pancreas tissue samples were obtained 2 minutes after completion of the infusion of 20 mg/kg of 5-FU for tissue 5-FU determination. Plasma and tissue concentrations of 5-FU were measured by high-performance liquid chromatography and compared among the groups.
Biochemical Study
In group I, blood samples were obtained immediately before and 1 day after 5-FU intra-arterial infusion for biochemical analysis. The serum samples were stored at -80°C until serum amylase, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) determina- tions.
Histological Study
In a subset of each group, the pancreas, duodenum, and liver were excised under laparotomy 24 and 72 hours after the treatments for histological analyses. In group III, the tissue sample was obtained after completion of the final (third) treatment. Specimens were fixed in 10% buffered formalin and embedded in paraffin by automatic tissue processing. Sections were stained with hematoxylin and eosin.
Statistical Analysis
Values are expressed as the mean ± SD. Statistical analyses were performed with Student’s t-test to determine the P values for unpaired data between the groups. Differences were considered significant at P < .05.
RESULTS
All animals given a 10 or 20 mg/kg 5-FU infusion survived throughout the experimental periods. In contrast, no dogs were alive for 24 hours after the infusion of 50 mg/kg of 5-FU. Results from the plasma pharmacokinetic studies are shown in Figs. 2 through 4 
. The portal 5-FU levels in group I were higher than those in group II immediately after infusion and were significantly higher with 5-FU doses of 10 and 20 mg/kg. Thereafter, however, no consistent tendency was observed in this study. In contrast, the peripheral levels were higher in group II than in group I only for a short time after 5-FU infusion with doses of 20 and 50 mg/kg (P < .05 in 0 minutes). This tendency was less prominent after 30 minutes. In both groups, the plasma 5-FU concentration decreased rapidly to very low levels in 20 to 30 minutes in portal and systemic blood samples, presumably because of fast disintegration or tissue incorporation.
|
|
|
|
DISCUSSION
There have been few breakthroughs in the field of unresectable pancreatic cancer treatments in the last century.2 A large number of trials performed with systemic chemotherapy, including combination therapies, have not shown any meaningful improvements.3–5 One possible explanation for the inefficacy of systemic chemotherapy lies in poor tumor perfusion because of the hypovascular nature of pancreatic cancer.
In recent years, regional intra-arterial chemotherapy has been introduced as an alternative treatment to enhance the drug delivery to the tumor.6–11 A few centers stated that regional chemotherapy is a promising treatment modality for locally advanced pancreatic cancers, on the basis of small clinical trials. Ohigashi et al.9 reported that the median survival of 15 patients with locally nonresectable pancreatic cancer was 14 months when treated by regional intra-arterial chemotherapy. Their protocol was weekly or biweekly infusion of methotrexate mixed with angiotensin II via two catheters placed into the splenic artery and the gastroduodenal artery. Link et al.6 treated 32 nonresectable pancreatic cancers with repeated celiac axis intra-arterial infusion of mitoxantrone, folic acid, 5-FU, and cis-platinum. The median survival time was 12 months in Internation Union Against Cancer stage III nonresectable pancreatic cancer patients. These authors demonstrated that this modality was also effective as an adjuvant after resection of pancreatic cancer.6–11
Regional intra-arterial chemotherapy certainly has the theoretical advantages of enhancing anticancer drug delivery into the tumor tissue and reducing the side effects of a comparable level of systemic treatment. However, to our knowledge and from a MEDLINE search, no basic study has focused on the detailed pharmacokinetics of anticancer agents and their side effects on the normal pancreas or duodenum. In this study, we have clarified the pharmacokinetics and whether the therapy causes tissue injury in the normal pancreas, duodenum, and liver in regional intra-arterial chemotherapy.
Plasma 5-FU concentrations in the portal vein immediately after the arterial infusion of 10 and 20 mg/kg of 5-FU were significantly higher than those after the systemic infusion, whereas the concentrations in peripheral blood were significantly lower immediately after the arterial infusion with doses of 20 and 50 mg/kg. In both groups, the plasma 5-FU concentration decreased rapidly to very low levels in 20 to 30 minutes in portal and systemic blood samples. Meanwhile, tissue 5-FU concentrations in the pancreas and the liver were significantly higher 2 minutes after the arterial infusion compared with the systemic infusion. These results suggest that most of the 5-FU delivered to the normal pancreas and duodenum was rapidly washed out after the intra-arterial infusion. Furthermore, it is speculated that 5-FU is extracted, disintegrated, and/or incorporated by the liver immediately on the first pass through the hepatic circulation.
From our results, the risks of systemic toxicity (e.g., leukocytopenia) may be reduced in 5-FU regional chemotherapy. Although a substantial increase of AST was observed 24 hours after a 20-mg 5-FU intra-arterial infusion, no distinct damage of the pancreas or the liver was caused by this treatment with at least 20 mg of 5-FU, on the basis of the histopathologic findings of these organs. In the study of a 50 mg/kg 5-FU intra-arterial infusion, no dogs were alive for the entire period of evaluation. No particular morphological changes of the associated organs were observed, even in these dead animals. Appropriate postoperative general management, including medication, infusion, or both, which seems considerably difficult in canine experiments, might rescue these animals. Otherwise, lethal doses for 5-FU might be <50 mg/kg in dogs.
In the literature, 5-FU dosing methods varied from a 10-minute bolus to continuous-infusion protocols.6–11 Protracted regional infusion of 5-FU likely gives an increased antitumor effect, whereas the modes of 5-FU administration—protracted and bolus—have different toxicities with different mechanisms. We chose a 10-minute infusion of drug in this study because bolus 5-FU is still generally accepted as a standard treatment for locally advanced pancreatic carcinoma and because one purpose of this experimental study was to analyze the toxicities of this treatment to the normal pancreas, duodenum, and liver. Pharmacokinetic and toxicity studies of protracted 5-FU regional chemotherapy should be performed in the future.
When the clinical setting is considered, pancreatic cancers often affect the remnant pancreas in various degrees because of associated outflow block of the exocrine pancreas. Thus, it remains to evaluate the influences of intra-arterial chemotherapy on such pancreases, although an animal model is difficult to set.
In conclusion, this fundamental study suggested that regional intra-arterial chemotherapy with 5-FU (10 and 20 mg/kg) for pancreatic cancer allows higher regional drug delivery without adverse effects on the normal region of the pancreas, duodenum, and liver and may be a modality with reduced systemic toxicity.
Acknowledgments
Supported by a Grant-in-Aid from the Ministry of Education, Science and Culture of Japan.
The acknowledgments are available online at www.annalssurgicaloncology.org.
Footnotes
In regional chemotherapy for pancreatic cancer, the detailed pharmacokinetics and side effects of anticancer agents remain unclear. This fundamental study suggested that fluorouracil intra-arterial chemotherapy allows higher regional drug delivery without adverse effects on normal regions of the pancreas, duodenum, and liver.
Received for publication July 24, 2001. Accepted for publication January 9, 2003.
REFERENCES
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
