Biomedical subjects

L Hafström

Publications and source records attributed to L Hafström.

At least 19 recordsLinked to original sources

PubMed2003

A comparison between hepatic artery ligation and portal 5-Fu infusion versus 5-Fu intra arterial infusion for colorectal liver metastases.

AIM: A prospective randomized study was executed comparing two regimens of regional therapy for liver metastases from colorectal cancer. METHODS: Eighteen patients were allocated to hepatic artery occlusion for 16 h followed by intraportal 5-fluorouracil (5-Fu) infusion (1000 mg/m(2)) for 5 days every sixth week (HAO). Twenty-one patients received intra-arterial 5-Fu infusion+Leucovorin (100 mg) i.v. for 2 days every second week (HAI). The follow up every third month included CT and CEA. Thirteen patients had limited extrahepatic cancer. At tumor progression regional therapy was stopped and systemic chemotherapy or the best supportive care was administered. RESULTS: The study was discontinued after randomization of 39 patients. No significant difference in survival within patients with and without extrahepatic cancer was present. The mean survival was longer in the HAI group than for the HAO group (19 months versus 13 months, p=0.0147) (median 18 (8-37) versus 12 (2-26). PR and SD were registered in 8/18 in the HAO group and 17/21 patients in HAI group. The median time to progress was 4 (1-22) months versus 7 (1-23) months for the HAO and HAI group, respectively. CONCLUSION: Regional intraarterial infusion with 5-Fu gives significantly better survival than hepatic artery occlusion followed by portal infusion. A limited amount of extrahepatic cancer does not influence survival time. A trial comparing hepatic artery 5-FU infusion and Leucovorin versus the most effective systemic therapy is warranted.

Adult↗

PubMed2001

P53 mutations in primary tumors and subsequent liver metastases are related to survival in patients with colorectal carcinoma who undergo liver resection.

BACKGROUND: The appearance of p53 mutations in colorectal carcinoma was determined, independent of differentiation and tumor stage of the primary tumors, in relation to the survival of patients who were scheduled to undergo liver resection. METHODS: Tumor material was analyzed for p53 mutations in primary colorectal tumors and subsequent liver metastases from 41 consecutive patients who were scheduled to undergo surgical liver resection. DNA sequencing and immunohistochemical staining of p53 protein within tumor nuclei were performed. RESULTS: Primary tumors displayed p53 mutations within exons 5-9 in 41% of patients. No mutations were found in exons 4, 10, or 11. Forty-one percent of metastatic lesions had the same single mutation that was found in the primary tumor, whereas 11% of metastatic lesions had one additional mutation within exons 5-9; 22% had mutations only in their liver metastases, whereas corresponding primary tumors displayed wild-type p53. None of the patients had mutated p53 in their primary tumor and wild type in their metastases. Survival after undergoing liver resection was correlated negatively (P < 0.05-0.01) with Duke Stages A-D classification of the primary tumors, tumor differentiation, and radicality (> 0.7-0.8 mm) of resected liver metastases. CONCLUSIONS: The presence of p53 mutations in patients with metastatic lesions was related significantly (P < 0.003) to better survival after the patients underwent liver resection compared with patients with wild type p53 in their metastatic lesions. This finding was not related to covariates, such as Duke classification, tumor differentiation, type of liver metastasis, or metastatic radicality during resections. Explanations for this unexpected finding remain unclear, although the authors speculate that occult tumor cells with p53 mutations may be less responsive to growth factor(s) exposure during hepatic regeneration after resection.

Adult↗

PubMed2001

CEA, CA 50 and CA 242 in patients surviving colorectal cancer without recurrent disease.

AIMS: To establish a baseline and intraindividual fluctuations of the tumour markers CEA, CA 50 and CA 242 in patients cured from colorectal cancer, and to test the hypothesis that serum concentrations and intraindividual fluctuations do not differ from the concentrations in cancer-free individuals. PATIENTS AND METHODS: Ninety patients with colorectal cancer, who had undergone surgery with curative intent, were still alive at least 5 years after surgery with no signs of recurrent disease. Serum levels of tumour markers CEA, CA 50 and CA 242 before and up to 2 years after surgery were analysed after the prospective study was terminated. RESULTS: The pre-operative serum levels of CEA, CA 50 and CEA 242 were elevated in 36%, 16% and 20% of the patients. They were lowered after curative surgery. A small increase of CEA levels was found after the initial post-operative decrease. The intraindividual fluctuations for CA 50 and CA 242 did not exceed 15% but in 24% of the patients the serum levels of CA 50 were high and oscillating. The patients cured from Dukes >> C cancer had higher serum concentrations of CEA than patients who had a Dukes >> B cancer, which were higher than in patients who had Dukes >> A cancer. Concentrations of CA 242 were higher in patients cured from Dukes >> A than patients cured from Dukes>> B or C cancers. CONCLUSIONS: During the first 2 years after curative surgery for colorectal cancer the serum levels of CEA did not differ from those levels in normal cancer-free subjects. The serum levels of CEA were related to Dukes >> staging whereas the levels of CA 242 were inversely related to Dukes >> staging.

Adult↗

PubMed2001

The Swedish Council on Technology Assessment in Health Care (SBU) systematic overview of chemotherapy effects in some major tumour types--summary and conclusions.

This report by The Swedish Council on Technology Assessment in Health Care (SBU) reviews, classifies, and grades the scientific literature on cancer chemotherapy in some major tumour types, describes the practice of chemotherapy in Sweden, compares practice with scientific knowledge, and analyses the costs and cost-effectiveness of chemotherapy. The report is intended primarily for decision-makers at various levels, both practitioners and administrators. It is also of interest for the medical profession. The extensive body of scientific literature was reviewed according to strict criteria that reflected the scientific weight of the literature. Sixteen experts representing different disciplines (oncology, surgery, internal medicine, health economy and quality of life research) participated in the literature review. Each section was discussed within the project group and was reviewed by at least one, but usually two international researchers. Additional input was provided by national experts representing different scientific disciplines. For the final evaluation to be as close to the objective truth as possible, a concerted effort was made to guarantee objectivity and thorough assessment of current knowledge about the effects of chemotherapy on the selected cancers. The tumour types selected for this assessment include firstly those types where three investigations had shown an increased use of chemotherapy in Sweden during the latest decade. These were non-small cell lung cancer (NSCLC), gastric cancer, pancreatic cancer, colorectal cancer and urinary bladder cancer. Secondly, the two tumour types comprising the greatest number of patients treated with chemotherapy in Sweden, breast cancer and haematological malignancies, were included. Among the haematological malignancies, the most prevalent ones, acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), Hodgkin's disease (HD), aggressive non-Hodgkin's lymphoma (NHL) of the large B-cell type and indolent NHL of follicular type were evaluated. These constitute about 75%, of all haematological malignancies. Thirdly, ovarian cancer was included since chemotherapy has been extensively used and since, at the time of the planning of this overview, a group of very expensive drugs, the taxanes, had preliminarily shown promising results. A wealth of scientific literature has been published on cancer therapy. The review presented in this report is limited to scientific studies judged to be important for evaluating chemotherapy efficacy. Assessments of the content and quality of these studies, and a critical summary of the results in all stages of the selected tumours, have never before been attempted in this way. However, similar comprehensive overviews of certain stages of the tumours have previously been made. These overviews were also critically evaluated. Totally 1,496 studies involving 558,743 patients were reviewed. The survey of practice of chemotherapy use involved all departments of surgery, urology, gynaecology, internal medicine including haematologic units, pulmonary medicine and general and gynaecologic oncology at 16 hospitals in two health care regions in Sweden, covering 39% of the Swedish population. During the 4 weeks of the survey, all patients with the diagnoses concerned who received chemotherapy were registered. The study included 1,590 patients. The working group's general conclusions are summarised in the following points: The literature on the effects of chemotherapy is extensive. Chemotherapy has a well-documented role in the curative and palliative treatment of patients with several types of cancer. The use of chemotherapy is of utmost importance for the possibility of cure in certain tumour types. In other tumours, chemotherapy increases the possibility of cure when added to local and regional treatments, particularly surgery. In the instances of no possibility of cure, chemotherapy may to a variable extent improve both patient survival and well-being. In Sweden chemotherapy is largely used in accordance with that documented in the scientific literature. The extent of both over- and under-treatment seems to be limited but cannot be excluded at the individual patient level. The literature-based knowledge is scientifically of lower quality in the most chemotherapy sensitive tumours than in tumours showing more limited sensitivity. In the more sensitive tumours, positive effects on a symptomatic stage and survival were seen several decades ago. In those days, clinical treatment studies did not fulfil the current high quality requirements. Small life-prolonging effects of chemotherapy are sometimes very well documented in large, high quality scientific studies. Some of these s

Antineoplastic Agents↗

PubMed2001

A systematic overview of chemotherapy effects in colorectal cancer.

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This synthesis of the literature on adjuvant and palliative therapy with cytostatics for colorectal cancer is based on 208 scientific articles, including eight meta-analyses and 162 randomised studies. These studies involve approximately 126,800 patients. The conclusions reached can be summarized into the following points: The benefit of postoperative adjuvant chemotherapy with fluorouracil and levamisole in patients with colon cancer stage Dukes' C was demonstrated more than ten years ago in two phase III trials. There was a reduction of recurrence from 56% to 39% and reduction of death from 51% to 40% after more than five years of follow-up. Although this combination has been widely accepted as standard adjuvant treatments for stage Dukes' C colon cancer, there is still debate on whether adjuvant treatment with fluorouracil alone would be equally efficacious. Several phase III trials with postoperative adjuvant chemotherapy with fluorouracil and leucovorin in patients with colon cancer stage Dukes' C have demonstrated a similar statistically significant improvement in disease-free and overall survival in comparison with a control arm. Six months of treatment with fluorouracil and leucovorin is as efficient as twelve months of fluorouracil and levamisole. This treatment is, thus, recommended for routine use. No convincing benefit from adjuvant chemotherapy is proven in colon cancer stage Dukes' B although some randomised trials have shown the same relative survival gain as seen in stage Dukes' C. There is less knowledge on survival benefits from adjuvant chemotherapy for Dukes' stage B and C rectal cancer. In small randomised trials, postoperative radiochemotherapy has, however, improved survival to the same extent as chemotherapy in colon cancer Dukes' stage C. A meta-analysis of nine randomised trials revealed a small but statistically significant benefit in five-year survival and a reduction in the risk of death for the patients receiving immediate postoperative portal vein infusion compared with controls. At present, however, the use of portal vein infusion or intraperitoneal therapy outside of a research trial cannot be recommended in the light of the limited effects. This conclusion is further supported by similarly limited effects in two recently reported very large European multicentre trials. In advanced colorectal cancer, chemotherapy may prolong survival, decrease tumour-related symptoms, improve general well-being or maintain it at a high level for a longer time period compared with best supportive care. These effects have been seen using systemic chemotherapy and using regional chemotherapy in patients with metastases limited to the liver. Subjective responses and quality of life improvements are seen more frequently than objective tumour remissions. Although the impact on overall survival is modest, i.e. an improvement in median survival of five to six months, treatment is recommended also outside clinical trials. High-dose infusional regimens with modulated fluorouracil may turn out to be superior to conventional bolus regimens, since they result in more tumour regressions, longer times to disease progression and possibly longer survival. A plateau seems, however, to have been reached with fluorouracil, giving objective response rates of up to 30% to 40% with a variety of modulators. Randomised studies of regional therapy, mostly hepatic arterial infusions, of liver metastases in colorectal patients have demonstrated significantly higher response rates than systemic fluorouracil therapy alone without impact on overall survival. The importance of the higher response rates for patient benefit in the predominantly asymptomatic patients with isolated liver metastasis remains to be elucidated. Regional therapy in advanced disease cannot be recommended outside of clinical trials. New cytotoxic agents are emerging with antitumour activity similar to fluorouracil-based chemotherapy. The addition of oxaliplatin or irinotecan to existing fluorouracil regimens improves response rates and duration of response, and possibly overall survival. Based upon the results of two randomised studies, there is a role for irinotecan as second line therapy for selected patients who have failed first-line therapy with fluorouracil plus leucovorin. The role of these agents, alone or in combinations, in clinical routine remains, however, to be determined due to more pronounced toxicity than caused b

Adjuvants, Immunologic↗

PubMed2001

A systematic overview of chemotherapy effects in gastric cancer.

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This overview of the literature on chemotherapy in the treatment of gastric cancer is based on 153 scientific papers including one meta-analysis, 18 reviews, 60 randomised studies and 57 prospective studies. The trials consist of 12,367 patients. The conclusions reached can be summarized into the following points: A meta-analysis of 21 randomised adjuvant studies revealed a statistically significant survival benefit. The Odds Ratio (OR) is 0.84 (95% confidence interval, 95% CI, 0.74-0.96). However, by analysing Western world and Asian studies separately, a statistically significant difference can be noticed; the Western world studies showed an OR of 0.96 (95% CI 0.83-1.12) and the Asian an OR of 0.58 (95% CI 0.44-0.76). The cause of this difference is not apparent. There is not sufficient evidence to recommend adjuvant chemotherapy as routine treatment in the Western world. Preoperative chemotherapy given to patients with non-resectable tumours or locally advanced potentially resectable tumours has achieved resectability rates of 40-100% and potentially curative resections in 37-80%. One out of two randomised studies showed a significant survival benefit, but reported data are not convincing. Experimental data in favour of preoperative therapy has not yet been confirmed in randomised clinical studies. Therapy is only justified in controlled clinical trials. Published studies on the use of intraperitoneal chemotherapy are few and not conclusive regarding the efficiency and safety. This method of drug administration is, accordingly, justified only in controlled clinical trials. In advanced gastric cancer, phase II studies have indicated better response rates using drug combinations than using single drug regimens, differences that have not, however, been convincingly demonstrated in randomised studies. No firm conclusions can be drawn regarding the superiority for any of the studied drug combinations with respect to response or survival gain. A statistically significant survival benefit has been shown in trials comparing drug combinations with a best supportive care arm in the treatment of advanced gastric cancer. However, the number of included patients is small. The median survival benefit in advanced disease is in the range of three to nine months. The use of chemotherapy in advanced gastric cancer is justified in selected patients, e.g. in younger patients in good performance status, low tumour burden and no other serious medical condition after adequate information of potential gains and risks. The influence of chemotherapy on quality of life in advanced gastric cancer has been reported in only a few studies. It appears that about 50% of the patients have a clinically relevant relief of tumour-related symptoms and thereby improved quality of life. In one study, quality-adjusted survival was estimated to a median of six months in the treated patients compared with two months in the controls. The quality of the literature addressing chemotherapy for gastric cancer is frequently poor with few properly designed randomised trials. In a number of randomised multi-centre adjuvant studies the inclusions rates are remarkably low, which reduces the scientific value of the studies.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2001

A systematic overview of chemotherapy effects in pancreatic cancer.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1999

Megestrol acetate in advanced, progressive, hormone-insensitive cancer. Effects on the quality of life: a placebo-controlled, randomised, multicentre trial.

A randomised double-blind placebo-controlled multicentre trial was performed to investigate the effects of megestrol acetate (MA) on the quality of life (QoL), appetite, weight and survival of patients with advanced, incurable, hormone-insensitive cancer. QoL was assessed at the start of treatment and at 4, 8 and 12 weeks, using the EORTC-QLQ-C30 instrument. 255 patients were randomised to 320 mg of MA daily or placebo for 12 weeks. 244 patients were assessable at baseline, 190 at 4 weeks (placebo 94; MA 96), 150 at 8 weeks (placebo 69; MA 81) and 112 at 12 weeks (placebo 55; MA 57). A beneficial effect of MA on appetite loss was observed at week 4 (P < 0.0001) and possibly at week 8 (P = 0.058). Further weight loss during treatment was significant only in the placebo group. In the first 8 weeks, changes in mean global QoL were small and similar in both groups. By 12 weeks the decrease in mean global QoL was more pronounced in the MA group (P = 0.028), which was related to a deterioration in physical function, while psychosocial function was not affected. Survival was not affected by MA, and side-effects were mild. The results show that MA has a beneficial effect on appetite and that it may retard weight loss with no adverse impact on survival and with mild toxicity. However, MA does not appear to improve global QoL as measured by the EORTC QLQ-C30.

Adult↗

PubMed1999

Isolated hepatic perfusion with extracorporeal oxygenation using hyperthermia, tumour necrosis factor alpha and melphalan.

AIMS: To determine the toxicity and efficacy of isolated hepatic perfusion with tumour necrosis factor alpha (TNF-alpha) and melphalan (Alkeran) under mild hyperthermic conditions. METHODS: A phase I trial was performed. Eleven patients with unresectable metastatic malignancies in the liver were pre-treated with 3 x 10(6) U leukocyte IFN daily 2 days before the perfusion. The liver was isolated and inflow catheters inserted in the hepatic artery and the portal vein. The hepatic veins were drained via a catheter in the retrohepatic caval vein. The venous blood flow from the lower extremities and the splanchnic circulation was bypassed to the axillar vein. The liver circuit was perfused with oxygenated blood and 30-200 microg TNF-alpha was added. At 39 degrees C in the liver circuit 0.5 mg/kg melphalan was added and the perfusion was continued for 1 h. RESULTS: Six patients underwent re-operation due to post-operative bleeding. Two patients died of coagulopathy or multiple organ failure within the first post-operative month. Three of six patients with liver metastases from malignant melanoma or leiomyosarcoma showed a partial response while no patients with liver metastases from colorectal cancer showed any response. The mean survival time was 20 months, which is within the same range as seen in previous isolated hepatic perfusion (IHP) studies. CONCLUSIONS: IHP with this drug regimen is a method with a considerable toxicity, though it is hard to distinguish between toxicity from TNF-alpha and that from the perfusion procedure itself. The method was not effective in patients with colorectal liver metastasis, but the results in melanoma and leiomyosarcoma patients warrant further studies.

Adult↗

PubMed1999

Standard serum concentrations and normal fluctuations of CEA, CA 50 and CA 242 during twelve months in men and women aged 60-64 years without malignant disease.

OBJECTIVE: To establish standard serum concentrations of carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 50 and CA 242 in cancer-free subjects in the age group during which cancers are likely to develop. DESIGN: Prospective study. SETTING: University hospital, Sweden. INTERVENTIONS: Blood samples obtained by venepuncture on four occasions during one year. MAIN OUTCOME MEASURES: Consultation with the Regional Cancer Registry to exclude those who had previously had malignant disease diagnosed or developed cancer during and up to two years after the end of the clinical part of the study. Serum concentrations of CEA, CA 50, and CA 242. RESULTS: The 90th centile was 5.6 ng/ml for CEA, 30.1 U/ml for CA 50, and 24.5 U/ml for CA 242. The mean (SD) serum concentrations were 2.6 ng/ml (2.2) for CEA, 13.2 U/ml (11.4) for CA 50, and 10.6 U/ml (9.6) for CA 242. Serum concentrations of CEA were significantly higher (p < 0.001) among smokers. The intraindividual fluctuations were 16%, 16%, and 14%, respectively. CONCLUSIONS: Serum concentrations of CEA, CA 50, and CA 242 were higher in this study than previously reported, probably because the subjects were older than in other reports. The fluctuations were small. Serum concentrations of CEA were higher in smokers than in non-smokers.

Antigens, Tumor-Associated, Carbohydrate↗

PubMed1998

Isolated hepatic perfusion with extracorporeal oxygenation using hyperthermia TNF alpha and melphalan: Swedish experience.

A phase I trial was performed to determine the toxicity and efficacy of isolated hepatic perfusion with tumour necrosis factor alpha (TNF) and melphalan (Alkeran) under mild hyperthermic conditions. Eleven patients with unresectable metastatic malignancies in the liver (malignant melanoma, leiomyosarcoma, colorectal cancer) underwent the procedure. Compared to our earlier experience with melphalan and cis-platinum under hyperthermic conditions (41.7 degrees C), this phase I study with TNF 30-200 micrograms and melphalan ).5 mg/kg body weight under 39 degrees C hyperthermia neither improved the response rate nor decreased the serious adverse effects. Two patients died within the first postoperative month owing to coagulopathy or multiple organ failure. Five patients were reoperated owing to postoperative bleeding. Three of six patients with liver metastases from malignant melanoma or leiomyosarcoma and none of five patients with liver metastases from colorectal cancer showed a partial response.

Antineoplastic Agents, Alkylating↗

PubMed1998

Treatment of primary liver cancer.

OBJECTIVE: To evaluate treatment of patients with primary liver cancer. DESIGN: Prospective protocol including subsets of randomised studies. SETTING: University hospital, Sweden. SUBJECTS: 123 patients with primary liver cancer. INTERVENTIONS: 64 patients underwent hepatic resection, 25 were included in a trial of adjuvant chemotherapy. 24 further patients whose tumours were not resectable were included in a trial of intra-arterial infusion of doxorubicin. MAIN OUTCOME MEASURES: Survival and postoperative morbidity. RESULTS: The median survival time for patients who had had resections was 11 months (range 0-111). Twelve per cent survived more than 5 years. No prognostic factor had any significant effect on outcome. The postoperative mortality was 11% (7/64). The patients allocated to adjuvant chemotherapy survived a median of 10 months (range 1-47) and the controls 29 months (range 8-111) (p=0.04). Patients with unresectable liver cancer treated with intra-arterial doxorubicin lived no longer than untreated controls (median 8 months (range 1-56) compared with 7 months (range 1-28)). CONCLUSIONS: Treatment of patients with primary liver cancer is still an unsolved problem. Adjuvant chemotherapy with doxorubicin had no beneficial effect on survival.

Adult↗

PubMed1996

Resection margins of 2 versus 5 cm for cutaneous malignant melanoma with a tumor thickness of 0.8 to 2.0 mm: randomized study by the Swedish Melanoma Study Group.

BACKGROUND: The traditional surgical treatment for primary malignant melanoma has often been a wide excision with a margin of about 5 cm. Since the risk of local recurrences is dependent on tumor thickness, thin tumors (<1 mm) have routinely been excised with a narrow margin. For thick tumors, the optimal resection margin is controversial, and can be determined only by prospective, randomized trials. METHODS: The Swedish Melanoma Study Group performed a prospective, randomized multicenter study to evaluate an excision margin of 2 versus 5 cm for patients with cutaneous malignant melanoma with tumor thickness > 0.8 and < or = 2.0 mm. The trial includes 769 patients. Patients with melanomas of the skin of the head, neck, hands, feet, or vulva were not included in the trial. In the event of an excision biopsy for diagnosis, radical surgery was completed within 6 weeks. The median follow-up time was 5.8 years for estimation of survival and 4.0 years for diagnosis of recurrent disease. RESULTS: No significant differences have been observed between the treatment groups regarding local or regional recurrences or survival. CONCLUSIONS: We recommend an excision with a margin of 2 cm for cutaneous malignant melanoma with a tumor thickness > 0.8 and < or = 2.0 mm.

Biopsy↗

PubMed1996

Vasopressin modulation of peritoneal, lymphatic, and plasma drug exposure following intraperitoneal administration.

i.p. administration of cytotoxic drugs for the treatment of regionally confined cancers results in a greater total drug exposure [area under the concentration x time curve (AUC)] for the peritoneal fluid and regional lymphatics than for plasma. We sought to augment the relative advantage of i.p. administration further through modulation of peritoneal clearance by reduction in splanchnic blood flow. Pigs were treated with 5-fluorouracil, etoposide (VP-16), and carboplatin (CBDCA) alone by the i.p. route or with the same drugs in combination with i.v. lypressin, a synthetic vasopressin analogue, which reduces splanchnic blood flow. Drug concentrations in peritoneal fluid, plasma, and thoracic duct lymph were monitored over the ensuing 6 h. The pharmacokinetics of 5-fluorouracil were not altered by vasopressin; however, vasopressin increased the peritoneal fluid:plasma AUC ratio for CBDCA from 30.6 +/- 5.6 to 70. 6 +/- 7.4 (P < 0.01) and increased the lymph:plasma AUC ratio from 1.1 +/- 0.4 to 2.6 +/- 0.22 (P < 0.05). In the case of VP-16, vasopressin increased the peritoneal fluid:plasma AUC ratio from 129 +/- 35 to 350 +/- 76 (P < 0.05) and the lymph:plasma AUC ratio from 2.1 +/- 0.6 to 10.6 +/- 3.5 (P < 0.05). Concurrent i.v. administration of vasopressin can increase the pharmacokinetic advantage of the i.p. route of administration of CBDCA and VP-16 markedly in the pig model. These data suggest that the strategy of concurrent i.p. administration of CBDCA or VP-16 plus an agent that reduces splanchnic blood flow may increase the dose intensity in the abdominal cavity and intraabdominal lymphatic tissue substantially without increasing systemic toxicity.

Animals↗

PubMed1995

Influence of hepatic artery occlusion and desferrioxamine on liver-tumour growth.

The mechanisms behind tumour regression during ischaemic therapy of liver malignancy are not thoroughly elucidated. Ischaemia-reperfusion injury and release of free radicals is one mechanism suggested. The aim of the present study was to explore whether inhibition of hydroxyl radicals, by complex binding Fe with desferrioxamine (DFO), counteracted the retardation in tumour growth rate after HAL and whether DFO in itself had an effect on tumour growth in 2 experimental rat liver tumours. Rats with a hepatoma or an adenocarcinoma were subjected to HAL or to a sham procedure with or without additional injections of DFO daily for 2 or 7 days. HAL had an inhibitory effect on tumour growth rate. The effect of HAL was not counteracted by DFO, while DFO alone caused a decrease in tumour volume. There was an additive effect of DFO and HAL on tumour growth rate in both tumour systems. In vitro there was a growth inhibitory effect of DFO in both tumours, more pronounced in the hepatoma than in the adenocarcinoma. Our findings indicate that the effect of HAL is not mediated by release of oxygen free radicals. In the adenocarcinoma system, an additive effect of DFO and HAL was seen. As a rate-limiting enzyme for DNA synthesis is dependent on iron, depletion of iron can decrease mitotic activity, a mechanism that could explain the effect of DFO on tumour growth.

Adenocarcinoma↗

PubMed1995

Insulin sensitivity, hormonal levels and skeletal muscle protein metabolism in tumour-bearing exercising rats.

We have previously shown that spontaneous physical exercise can delay onset of experimental anorexia and cachexia, and retard tumour growth; we now report the effects on insulin sensitivity, hormonal levels and skeletal muscle protein metabolism. Insulin sensitivity determined with a euglycaemic hyperinsulinaemic clamp revealed a normalised glucose disposal rate in tumour-bearing exercising (TBE) versus sedentary (TBS) animals (TBE 15.55 +/- 2.71 versus TBS 2.47 +/- 2.12 mg/kg/min; P < 0.05). Both TBE and TBS animals had decreased levels of corticosterone during the clamp. Serum levels of insulin during tumour progression were unaffected by exercise, but the insulin: glucagon ratio increased and the progressive decrease in rT3 was attenuated. The concentration of glucagon decreased in both tumour-bearing groups during the experiment, while TBE animals showed a relative reduction in corticosterone. Capacity for skeletal muscle protein synthesis, expressed as RNA: protein ratio, was normalised in TBE animals in two tumour protocols (TBE 5.9 +/- 0.6 versus TBS 4.7 +/- 0.3; TBE 2.9 +/- 0.4 versus TBS 1.8 +/- 0.2; P < 0.05, respectively). Incorporation rate of 14C-phenylalanine into skeletal muscle protein was increased in the TBE group in vitro and in vivo. In the postexercise period, protein degradation evaluated by tyrosine release in vitro was increased, but decreased over time. This study has confirmed a positive skeletal muscle protein balance in exercising tumour-bearing animals, partly explained by the increased insulin sensitivity. This conclusion was further supported by the less catabolic pattern indicated by hormonal levels.

Animals↗

PubMed1994

Treatment of liver metastases from colorectal cancer with hepatic artery occlusion, intraportal 5-fluorouracil infusion, and oral allopurinol. A randomized clinical trial.

BACKGROUND: Regional therapy for colorectal liver metastases aimed at prolonging survival has not been tested fully in a randomized trial with untreated control subjects. This study explored the efficacy of temporary hepatic artery occlusion followed by intraportal infusion of 5-fluorouracil (5-FU) and oral allopurinol as biochemical modulators in prolonging the survival of patients with nonresectable liver metastases and no extrahepatic cancer. METHODS: Eighty-four patients were considered for randomization, of whom 24 were excluded at laparotomy because of extrahepatic cancer (n = 17) or resectable lesions (n = 5). In two patients, no cancer was identified in the liver. Thirty-two patients were allocated to receive treatment, and 28 were allocated to receive no regional or systemic treatment. Six patients were excluded after randomization because of major protocol violations. RESULTS: The median survival time for patients was 17 months (range, 0-66), and for control subjects, the median was 8 months (range, 0-31). Log rank analysis demonstrated a significant survival benefit for treatment versus no treatment (P = 0.0039). (In two patients, early death was due to toxicity from the wrong dose of 5-FU and the wrong route of administration, respectively; the mean and median survival were reduced by 1 month). CONCLUSION: This study identified a treatment modality that prolongs survival in patients with nonresectable liver metastases and no extrahepatic metastases from colorectal cancer, suggesting that control subjects receiving no therapy may not be necessary in future randomized trials.

Administration, Oral↗

PubMed1994

Quantitative measurements of collateral arterial blood flow in nonarterialized rat liver grafts.

The early development of arterial blood flow in the grafted liver after orthotopic liver transplantation in the rat without reconstruction of the hepatic artery was studied. Arterial liver blood flow was measured on day 21 after transplantation with NEN-TRAC microspheres (size 15.5 +/- 0.1 microns) and labelled with 103Ru. The arterial liver blood flow in the grafted liver was 0.778 +/- 0.247 ml/min per gram for transplanted rats after 21 days. One day after transplantation, the blood flow was only 0.006 +/- 0.002 ml/min per gram. The results of this study demonstrate that there was no arterial blood flow on day 1 after transplantation, as expected, but that there was a high arterial blood flow in the transplanted liver by day 21. This was also supported by the angiographic findings. The early development of arterial blood flow via collaterals may account for the excellent results that we and others have attained in orthotopic liver transplantation without rearterialization in the rat.

Animals↗