Continuous angiotensin II infusion increases tumour: normal blood flow ratio in colo-rectal liver metastases.

Insufficient blood flow within colo-rectal hepatic metastases is a factor which may limit drug delivery to, and thus the response of, these tumours to regional chemotherapy. Loco-regional flow may be manipulated pharmacologically to enhance the tumour blood flow relative to that of the normal liver. However, as yet, only transient effects have been studied. Patients receiving regional chemotherapy for unresectable hepatic disease were given a 45 min regional infusion of the vasoconstrictor Angiotensin II. Intrahepatic blood flow distribution was assessed serially by Positron Emission Tomography (PET) imaging together with the trapping tracer copper(II) pyruvaldehyde bis(N-4-methylthiosemicarbazone) (Cu-PTSM) labelled using copper-62. Eleven lesions in nine patients were studied, with no adverse effects. Prior to Angiotensin II administration tumour blood flow was generally found to be greater than that of liver (10/11 lesions; 8/9 patients; median TNR 1.3, iqr 0.9-2.5). A significant increase in relative flow to tumour was seen in response to 10 min Angiotensin II infusion in most cases (7/11 lesions; 7/9 patients; median TNR 2.1, iqr 1.4-4.1; P = 0.008), which appeared to be sustained throughout the 45 min infusion period (median TNR 1.85, iqr 1.3-3.8; P = 0.03). These effects were accompanied by transient elevation of mean arterial pressure, but no change in pulse rate. These observations suggest that prolonged regional vasoconstrictor administration could prove useful in the management of unresectable colo-rectal hepatic metastases, and that further development of vascular manipulation to enhance tumour targeting and drug delivery is warranted.

62Cu-PTSM and PET used for the assessment of angiotensin II-induced blood flow changes in patients with colorectal liver metastases.

The aim of this study was to establish a quantitative positron emission tomography (PET) method for investigating angiotensin II (AII)-induced changes in blood flow distribution in the liver. This was in order to evaluate the role of vascular manipulation applied to locoregional chemotherapy treatment in patients with colorectal liver metastases. The tracer selected was copper-62 (II) pyruvaldehyde bis-(N4-methyl)thiosemicarbazone (62Cu-PTSM), which exhibits high first-pass extraction and tissue retention following intra-arterial administration. The short half-life of the tracer and its availability from a 62Zn/62Cu generator enabled short-interval repeat PET scans on patients in a single imaging session. Distribution of tracer within the liver was imaged in a single view using a PET camera with rotating large-area detectors. By optimisation of the acquisition protocol, it was possible to acquire sufficient data to produce good-quality images and to quantify tracer uptake with an accuracy of <10%. Reproducibility of the imaging method was assessed in a single patient in whom three consecutive 62Cu-PTSM PET scans were obtained, and in whom no vascular manipulation was performed. Sets of scans (before, during and immediately after a 45-min AII infusion) were obtained in nine patients to assess blood flow changes associated with prolonged vascular manipulation. Significant individual responses, varying in both the magnitude and the duration of flow change, were observed in the majority of cases (7/11 lesions; 7/9 patients). These findings illustrate the potential of 62Cu-PTSM and PET for pharmacological studies. The wide range of individual patient responses to AII infusion suggests that PET blood flow assessment would be of value for selecting patients in whom this procedure may be effective.

Effect of continuous regional vasoactive agent infusion on liver metastasis blood flow.

Regionally administered vasopressors might increase tumour chemotherapy uptake by differentially constricting normal and tumour blood vessels, leading to a selective increase in blood flow to the tumour. In this study, we compared the effects of the vasopressors angiotensin II, vasopressin and endothelin I and the vasodilator calcitonin gene-related peptide (CGRP) by continuously measuring liver parenchymal and tumour blood flow during a 30-min regional vasoactive infusion in a rat HSN liver metastasis model. Vasopressin and angiotensin II produced a vasoconstriction that decreased despite continued infusion, while endothelin I infusion led to prolonged vasoconstriction with a more gradual onset. CGRP infusion resulted in increased vessel conductance but a reduction in blood flow due to systemic hypotension. The tumour to normal flow ratio (TNR) was transiently increased during infusion of all pressors, but only endothelin I produced sufficient change to result in a rise in average TNR throughout pressor infusion. Continuous liver and tumour blood flow measurement throughout vasoactive infusion demonstrated that the extent and the duration of blood flow change varied with the agents assessed. No vasoactive agent increased tumour blood flow, but endothelin I had the most suitable vasoactive properties for enhancing tumour uptake of continuously infused chemotherapy.

Effect of inferior mesenteric artery ligation on blood flow in the marginal artery-dependent sigmoid colon.

BACKGROUND: Anastomotic leakage after restorative rectal excision may develop from ischemia associated with inadequate blood flow in the marginal artery-dependent colon. STUDY DESIGN: We have used laser Doppler flowmetry to measure blood flow change during mobilization of the sigmoid colon before excision of the sigmoid colon or rectum in 26 patients and proximal to the colorectal anastomosis during the first five postoperative days in five patients. RESULTS: There was a significant (p < 0.005) fall (median, 50 percent interquartile range, 41 to 86 percent) in sigmoid colon serosal flow after ligation of the inferior mesenteric artery (IMA) and distal marginal artery (DMA) that was not influenced by the order of vessel ligation. No increase in perianastomotic colonic perfusion was detected during the first five postoperative days. CONCLUSIONS: The significant blood flow reduction after ligation of the IMA and DMA supports the hypothesis that anastomotic leakage after restorative rectal excision may result from ischemia associated with inadequate blood flow in the marginal artery-dependent sigmoid colon. Improvement in inadequate intraoperative colonic perfusion from increased collateral circulation is unlikely to develop in the marginal artery-dependent colon during the first five postoperative days.

Effect of regional angiotensin II infusion on the relationship between tumour blood flow and fluorouracil uptake in a liver metastasis animal model.

The aim of this study was to assess the relationship between tumour:liver blood flow and 5-fluorouracil (5-FU) uptake ratios in a hypovascular liver metastasis animal model, and examine whether they were similarly affected by a 5 min infusion of angiotension II via the hepatic artery. Tumour:liver blood flow ratio was measured using the isotope tracer 64Copper (II)-pyruvaldehyde bis(n-4 methyl thiosemicarbazone, and 5-FU was tritiated. There was a wide variation in tumour:liver blood flow and 5-FU uptake ratios which could only partly be explained by between animal variation, and was not related either to individual tumour size or overall tumour burden within the liver. There was a close correlation (r = 0.957, P < 0.0001) between tumour:liver blood flow and 5-FU uptake ratios. Angiotensin II infusion significantly increased tumour:liver blood flow (nested analysis of variance, P= 0.05) but not 5-FU uptake (P = 0.29) ratios. There was a poor correlation (r = 0.51, P = 0.13) between tumour:liver blood flow and 5-FU uptake ratios with angiotensin II infusion. Thus, despite an increased 5-FU blood concentration arising from angiotensin-induced reduction in blood flow at constant 5-FU infusion dose, tumour:liver 5-FU uptake ratio did not increase as expected, and there ceased to be a significant correlation between tumour:liver blood flow and 5-FU uptake ratios. We conclude that the vasoactive changes within the hypovascular tumour circulation produced by a 5 min angiotensin II infusion did not significantly increase tumour 5-FU uptake.

Nitric oxide inhibition sustains vasopressin-induced vasoconstriction.

Hepatic parenchymal vasoconstriction increases cytotoxic drug uptake into hepatic metastases by increasing the tumour to liver blood flow ratio. Prolonged infusion of the vasoconstrictor vasopressin does not result in sustained vasoconstriction, and this may limit the benefit of vasopressin in infusional chemotherapy. We have assessed whether loss of vasopressin-induced vasoconstriction is mediated by nitric oxide. Hepatic and tumour blood flow were continuously monitored, in an animal hepatic tumour model, by laser Doppler flowmetry. The response to regionally infused vasopressin and the nitric oxide inhibitor N-nitro-L-arginine methyl ester (L-NAME) were assessed over a 30 min infusion period. The vasopressin-induced vasoconstrictor effect diminished after 15 min despite continued infusion. Vasoconstriction was significantly prolonged when L-NAME was infused in addition to vasopressin. The increase in tumour to normal blood flow ratio was greater over the infusion period when L-NAME was co-administered with vasopressin. Our results suggest that the loss of vasopressin-induced vasoconstriction seen in liver parenchyma after regional infusion is prevented by the nitric oxide synthase inhibitor L-name and may be mediated by nitric oxide.

Measurement of response to treatment in colorectal liver metastases.

Assessment of tumour response to chemotherapy is important when assessing efficacy of treatment and comparing differing therapeutic regimens. Percentage hepatic replacement (PHR) is commonly used to assess response to treatment of colorectal hepatic metastases. PHR is dependent not only on tumour volume, but also on hepatic parenchymal volume. The effect of tumour growth on hepatic parenchymal volume is unclear but is of importance owing to its effect on PHR. We assessed tumour and hepatic parenchymal weights in an animal tumour model using dissection, and tumour and hepatic parenchymal volumes in patients with colorectal hepatic metastases using CT scanning, in order to establish how hepatic parenchyma varied with change in metastasis size. There was no significant correlation between tumour and liver parenchyma in either the animal model (r = -0.03, P > 0.05) or the patient study (r = 0.3, P < 0.05). This suggests that hepatic parenchymal volume was preserved in the presence of increasing tumour volume. In a further study of computerised tomographic (CT) scans before and after treatment in patients whose tumours either responded to chemotherapy or continued to grow, change in PHR (median proportion of PHR change = 0.40) significantly (P = 0.04) underestimated the change in tumour volume (median proportion of tumour volume change = 0.56), particularly at higher (> 400 ml) volumes. There was good correlation between change in tumour volume and WHO criteria in assigning patients to tumour growth, stable disease or tumour response categories. This study suggests that, in clinical trials comparing colorectal liver metastasis treatments, metastasis volume and not PHR should be used to assess extent of disease and the effect of treatment.

Importance of hepatic artery node involvement in patients with colorectal liver metastases.

Hepatic artery lymph node (HALN) involvement is an adverse prognostic factor in patients treated for colorectal liver metastases. The prevalence of HALN positivity for mid-gut and hind-gut derived colonic tumours, for differing amounts of liver involvement, and for Dukes' A and B versus Dukes' C primary tumours was compared in 75 patients with colorectal liver metastases. All patients whose primary tumours did not invade lymph nodes (Dukes' A or B) had liver metastases that did not involve local hepatic nodes, regardless of the extent of the disease within the liver. This suggests that factors controlling metastasis are not identical with those which control lymphatic invasion in colorectal cancer. HALN positive patients may benefit less from treatment because they are significantly more likely to have both a greater burden of disease within the liver and a tumour with greater lymph invasive potential than patients with HALN negative liver metastases.