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Intraperitoneal 5-Fluorouracil treatment of cancer - clinical and experimental studies
Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background:Pancreas cancer is a most aggressive malignancy. More than 80% of patients diagnosed with pancreas cancer, exhibit such advanced disease, that curative surgery is impossible. Systemic chemotherapy prolongs survival to 5-9 months. High concentrations of chemotherapeutic agents in the abdominal cavity and in the lymphatics draining the area is achieved by intraperitoneal administration. Vasopressin decreases splanchnic blood flow, reducing the intraperitoneal uptake of drugs, thus raising the local and lymphatic dose intensity.

Aim: The aim of the study was to investigate the feasibility and tumour response of intraperitoneal 5-Fluorouracil (5-FU) treatment in non-resectable pancreas cancer, using vasopressin to improve the pharmacokinetic profile. Further, to study the effect of vasopressin on peritoneal blood flow, altered by intraperitoneal 5-FU or the presence of peritoneal carcinomatosis.

Methods: In the animal experiments, the 133Xe-clearance technique and as a comparison Laser doppler flow, were used to identify changes of peritoneal blood flow caused by vasopressin in unmanipulated animals and in animals with peritoneal carcinomatosis or animals given intraperitoneal 5-FU. In the clinical studies, 68 (39 women/29 men) patients, with a non-resectable ductal pancreas cancer and a Karnovsky Index ≥70 were included. Patients were treated with 750-1500 mg/m2 5-FU intraperitoneally through a Port-a-cath and Leucovorin 100 mg/m2 intravenously on two consecutive days every 21 days until progression. Seventeen patients, receiving 750 mg/m2 5-FU, were given concomitant vasopressin 0.1 IU/min during 180 minutes, alternatively day 1 or 2.

Results: In the animal experiments, vasopressin 0.07 IU/kg/min significantly reduced the 133Xe-clearance. Intraperitoneal 5-FU decreased the basal peritoneal blood flow and abrogated the vasopressin effect for 1-2 days. The presence of peritoneal carcinomatosis did not influence the basal peritoneal blood flow, nor the reduction of peritoneal blood flow caused by vasopressin. In the clinical studies, the treatment with intraperitoneal 5-FU was well tolerated, with no WHO Grade 3 or 4 toxicity with doses up to 1250 mg/m2. Thirty patients achieved at least stable disease at three months. The median survival time was 8.0 (range 0.8-54.1) months. There was a significant reduction of 5-FU Cmax on day 2, but no significant reduction of AUC, when vasopressin was given.

Conclusion: Peritoneal blood flow changes caused by vasopressin can be estimated with the 133Xe-clearance technique. Intraperitoneal 5-FU but not peritoneal carcinomatosis decreases the vasopressin induced 133Xe-clearance reduction, 1-2 days after administration. In patients with non-resectable pancreas cancer, intraperitoneal 5-FU up to 1250 mg/m2 for two days every third week can be given without WHO grade 3 and 4 toxicity. The treatment is well tolerated with few and minor side effects. Tumour responses were observed. Addition of vasopressin does not significantly enhance the pharmacokinetics of intraperitoneal 5-Flurorouracil, but adds toxicity.

Place, publisher, year, edition, pages
Umeå: Kirurgisk och perioperativ vetenskap , 2004. , 98 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 935
Keyword [en]
Surgery, intraperitoneal, 5-fluorouracil, pancreas cancer, vasopressin, Xenon-clearance
Keyword [sv]
Kirurgi
National Category
Surgery
Research subject
Surgery
Identifiers
URN: urn:nbn:se:umu:diva-372ISBN: 91-7305-747-9 (print)OAI: oai:DiVA.org:umu-372DiVA: diva2:143292
Public defence
2004-12-10
Opponent
Supervisors
Available from: 2004-11-18 Created: 2004-11-18Bibliographically approved
List of papers
1. Treatment of non-resectable pancreatic cancer with intraperitoneal 5-FU and leucovorin IV
Open this publication in new window or tab >>Treatment of non-resectable pancreatic cancer with intraperitoneal 5-FU and leucovorin IV
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2001 In: European Journal of Surgical Oncology, Vol. 27, no 5, 477-481 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-4270 (URN)
Available from: 2004-11-18 Created: 2004-11-18Bibliographically approved
2. 133Xe clearance estimates the effect of vasopressin on peritoneal blood flow in rats
Open this publication in new window or tab >>133Xe clearance estimates the effect of vasopressin on peritoneal blood flow in rats
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2004 (English)In: Hepato-Gastroenterology, ISSN 0172-6390, Vol. 51, no 58, 1037-1041 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND/AIMS: When assessing the peritoneal microcirculation with invasive methods, interference with the mechanisms of vaso-regulation may occur. The 133Xe clearance technique renders the possibility, by minimal invasiveness, to estimate the influence of a vasoactive agent on the peritoneal microcirculation. METHODOLOGY: Ten to 15MBq of 133Xe were injected in the abdominal cavity in thirty-eight Wistar-FU (W-FU) rats and 35 Lister-Hooded (LH) rats. A NaI (Tl)-scintillation detector registered activity before and during vasopressin infusion. Gamma camera imaging confirmed the washout from the abdominal cavity. The laser Doppler flowmetry technique was used as a comparison. RESULTS: Vasopressin at 0.07 IU/kg/min IV significantly reduced 133Xe-clearance by 37% (p = 0.029) and 52% (p=0.036) and laser Doppler flowmetry by 69% (p=0.0019) and 44% (p=0.0039) in W-FU and LH rats, respectively. A linear correlation between dose of vasopressin and relative decrease in 133Xe clearance was demonstrated in the W-FU rat model (r2=0.98, p=0.023). The 133Xe clearance from the abdominal cavity in rat using a single-compartment model or the slow compartment in a double-compartment model gave reproducible information. CONCLUSIONS: The usefulness of this mini-invasive technique for sequential measurements before and during intervention will render the 133Xe clearance suitable for assessment of blood flow changes in the abdominal cavity.

Keyword
Animals, Blood Pressure/drug effects, Gamma Cameras, Laser-Doppler Flowmetry, Microcirculation/drug effects, Peritoneum/*blood supply/radiography, Rats, Rats; Inbred Strains, Rats; Wistar, Regional Blood Flow/drug effects, Vasoconstrictor Agents/*pharmacology, Vasopressins/*pharmacology, Xenon Radioisotopes/*pharmacokinetics
Identifiers
urn:nbn:se:umu:diva-4271 (URN)15239241 (PubMedID)
Available from: 2004-11-18 Created: 2004-11-18 Last updated: 2010-08-24Bibliographically approved
3. Effect of carcinomatosis and intraperitoneal 5-fluorouracil on peritoneal blood flow modulated by vasopressin in the rat as measured with the 133Xe-clearance technique
Open this publication in new window or tab >>Effect of carcinomatosis and intraperitoneal 5-fluorouracil on peritoneal blood flow modulated by vasopressin in the rat as measured with the 133Xe-clearance technique
2004 (English)In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 54, no 3, 213-218 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: Intraperitoneal administration of 5-fluorouracil for the treatment of gastrointestinal malignancies results in a greater total drug exposure in the peritoneal fluid than in plasma. Drugs are eliminated from the peritoneal cavity mainly by capillaries leading to the portal venous system and to a lesser extent by lymphatics. The drug itself and the presence of peritoneal carcinomatosis may affect elimination of the drug. The 133Xe-clearance technique allows the influence of a vasoactive agent on the peritoneal blood flow to be estimated with minimal invasiveness. The aim of the present study was to explore whether intraperitoneal 5-FU or peritoneal carcinomatosis affects the peritoneal blood flow and its reactivity to intravenous vasopressin, as measured indirectly with the 133Xe-clearance technique. Methods: The animals used in this study were 63 Wistar-Fu (W-Fu) rats and 67 Lister-Hooded (LH) rats. On day 0, either 5-FU at 25 mg/kg body weight in 25 ml/kg isotonic saline was instilled intraperitoneally, or 1·105 syngeneic tumour cells were inoculated intraperitoneally. On days 1, 2 and 3 in the 5-FU-treated rats, and on days 12–16 in rats inoculated with tumour cells, peritoneal blood flow was analysed with the 133Xeclearance technique, before and during intravenous infusion of vasopressin at 0.07 IU/min/kg body weight. Results: The basal 133Xe-clearance before administration of vasopressin was similar in all groups except in the LH rats treated with 5-FU in which it was significantly lower. Infusion of vasopressin induced a significant decrease in 133Xe-clearance of the same magnitude in controls and in tumour-bearing rats. In the rats given intraperitoneal 5-FU, vasopressin did not reduce the 133Xe-clearance the first day after administration of 5-FU. Conclusions: Intravenous vasopressin at 0.07 IU/ min/kg decreased peritoneal blood flow as measured indirectly with the 133Xe-clearance method. Intraperitoneal 5-FU abrogated the reduction in peritoneal blood flow with intravenous vasopressin the first day after treatment. In contrast, the presence of peritoneal carcinomatosis did not influence peritoneal blood flow, nor the effect of vasopressin

Keyword
Vasopressin, Xenon-133, Intraperitoneal, Carcinomatosis, 5-fluorouracil, Peritoneal, blood flow
Identifiers
urn:nbn:se:umu:diva-4272 (URN)10.1007/s00280-004-0812-3 (DOI)15138707 (PubMedID)
Available from: 2004-11-18 Created: 2004-11-18 Last updated: 2010-08-24Bibliographically approved
4. Phase I/II trial of intraperitoneal 5-Fluorouracil with and without intravenous Vasopressin in non-resectable pancreatic cancer
Open this publication in new window or tab >>Phase I/II trial of intraperitoneal 5-Fluorouracil with and without intravenous Vasopressin in non-resectable pancreatic cancer
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2005 (English)In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 56, no 6, 603-609 p.Article in journal (Refereed) Published
Abstract [en]

Background: Systemic palliative treatment with chemotherapy against advanced pancreas cancer has low effectiveness despite considerable toxicity. Aim: To investigate the safety, toxicity and tumour response of intraperitoneal 5-Fluorouracil (5-FU) with intravenous Leucovorin and to monitor 5-FU pharmacokinetics in plasma during intraperitoneal instillation with and without vasopressin in patients with non-resectable pancreas cancer. Patients/methods: Between 1994 and 2003, 68 patients with non-resectable pancreas cancer TNM stage III and IV, were enrolled to receive intraperitoneal 5-FU instillation 750–1500 mg/m2 and intravenous Leucovorin 100 mg/m2 for two days every third week. Tumour response, performance status and toxicity were recorded. Seventeen patients were also treated with intravenous vasopressin 0.1 IU/minute for 180 minutes, during intraperitoneal 5-FU instillation. Area under the curve (AUC) and peak concentration (Cmax) of 5-FU in plasma were analysed. Results: The treatment was well tolerated with minor toxicity. One complete response (54.1+ months) and 2 partial responses were observed. Time to progression was 4.4 months (0.8–54.1+), and median survival was 8.0 months (0.8–54.1+). There was a significant reduction of 5-FU Cmax in plasma the second day of treatment if vasopressin was used (3.4 ± 2.5 and 6.1 ± 5.4 μmol/l, respectively, p<0.05). 5-FU AUC in plasma was not significantly affected by vasopressin either day of treatment. Conclusion: Intraperitoneal 5-FU is a safe treatment with low toxicity to patients with non-resectable pancreas cancer. Tumour response was 4.4% and median survival time 8.0 months. Addition of vasopressin did not significantly decrease plasma 5-FU AUC but reduced Cmax on day 2 of treatment.

Keyword
intraperitoneal chemotherapy, pancreas cancer, 5-fluorouracil, vasopressin, leucovorin, pharmacokinetics, Adenocarcinoma/*drug therapy/mortality/pathology, Adult, Aged, Aged; 80 and over, Antimetabolites; Antineoplastic/*administration & dosage/pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols/*therapeutic use, Area Under Curve, Female, Fluorouracil/*administration & dosage/pharmacokinetics, Hemostatics/*administration & dosage, Humans, Injections; Intraperitoneal, Injections; Intravenous, Leucovorin/administration & dosage, Male, Middle Aged, Palliative Care, Pancreatic Neoplasms/*drug therapy/mortality/pathology, Survival Rate, Vasopressins/*administration & dosage
Identifiers
urn:nbn:se:umu:diva-4273 (URN)10.1007/s00280-005-1012-5 (DOI)16047145 (PubMedID)
Available from: 2004-11-18 Created: 2004-11-18 Last updated: 2010-08-24Bibliographically approved

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