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We conclude that the FEC2 regimen, in which epirubicin replaced the methotrexate in CMF, is the preferable adjuvant chemotherapy regimen for premenopausal patients with operable axillary node-positive breast cancer.

1323and still be labelled "approximately 141 mmol/l" and comply with the BPC standard. Another variant of Difusor is stated to contain approximately 130 mmol/l of sodium, and a 5% variation would allow a range of 123-5 to 136-5 mmol/l.The BPC limits for sodium content of haemodialysis solutions are ±3%, and the manufacturers of our haemodialysis solutions work to limits of ±3 mmol/l, which is equivalent to 2-16% on a sodium content of 139 mmol/l. We appreciate the difficulties encountered in manufacturing to narrow limits and possible problems with moisture loss on storage but think that a variation of 5% on the sodium content of peritoneal dialysis fluid is too wide. We would suggest that the British Pharmaceutical Codex limits be reduced to ±3 mmol/l.

Summary Conventional imaging techniques are of limited value in identifying small liver metastases. Indirect methods of measuring blood-flow have shown that metastases may be associated with subtle changes in liver blood-flow. Doppler ultrasonography has the ability to measure liver blood-flow directly. In this study, the role of duplex sonography in the detection of hepatic metastases was evaluated. Hepatic arterial and portal venous blood-flows were In 1983, Parkin and colleagues suggested that changes in liver blood-flow occurring in patients with intra-hepatic tumour could be measured indirectly by dynamic scintigraphy. They described an increase in the ratio of hepatic arterial: total liver blood-flow in patients with overt hepatic metastases. However, this technique has not been widely used in clinical practice because of difficulties in interpretation and reproducibility (Laird et al., 1987).In contrast, duplex sonography has the capacity to measure liver blood-flow directly. In this study, the crosssectional area and velocity of blood-flow within the hepatic artery and portal vein were measured and blood-flow calculated. This technique is less invasive, independent of hepatic function and can be more readily standardised.The aim of this study was to assess the value of duplex sonography in the detection of colorectal liver metastases. StatisticsThe data were analysed using a Mann-Whitney test.

SUMMARY The effects of cytotoxic therapy on the structure and function of the proximal jejunum were studied in six patients receiving intravenous cyclophosphamide (300 mg/M2), methotrexate (40 mg/M2), and 5-fluorouracil (600 mg/M2) as adjuvant therapy for breast cancer. Using a steady state, triple lumen tube perfusion system the absorption of water and electrolytes was measured before and 48 h after administration of the cytotoxic agents. Jejunal biopsies were obtained at each perfusion. Median (range) water absorption fell from 126 (40-142) to 84 (46-142) ml/h/30 cm, with parallel changes for electrolytes; none of the changes was significant. Brush border disaccharidases did not change at 48 h after chemotherapy, while mature enterocytes appeared normal by both light and electron microscopy. Crypt cells and immature enterocytes, however, showed focal vacuolation by light microscopy, corresponding to the occurrence of large residual bodies (secondary lysosomes) containing partially degraded fragments of damaged crypt cells. The confinement of ultrastructural changes to the immature cell population may explain the failure of this study to show a consistent change in the absorptive function of the jejunum 48 h after chemotherapy.Cytotoxic therapy can cause structural and functional changes in the human proximal intestine. '-3 This effect may be important in the development of gastrointestinal symptoms such as diarrhoea and may lead to malabsorption of orally administered drugs, including cytotoxic agents.4 5 Smith et a!6 could find no change in xylose absorption and faecal fat estimation in patients with biopsy proved depression of crypt cell mitosis, but most previous studies of cytotoxic damage have examined changes of gastrointestinal function and structure independently.The technique of small intestinal perfusion is a sensitive method for detecting changes in the transport of water and electrolytes across the jejunal mucosa and might therefore show relatively minor abnormalities of enterocyte function more readily than conventional intestinal absorption tests.7 We have used small intestinal perfusion to investigate IPresent address:

Summary Regional chemotherapy is commonly used to treat patients with colorectal liver metastases. However, improvement in survival has still not been demonstrated. Cytotoxic loaded albumin microspheres for arterial administration have been described as a means of improving the therapeutic index, but their distribution depends upon the prevailing pattern of arterial blood-flow at the time of injection. In this study, the ability of the vasoactive drug angiotensin II to target arterially injected microspheres to colorectal liver metastases is assessed in nine patients using scintigraphic planar and tomographic imaging.The median tumour: normal ratio in nine patients with colorectal liver metastases was 3.4:1 before the administration of angiotensin II. The corresponding ratio after administration of angiotensin II was 7.3:1. The median improvement factor was 1.8 (P <0.05).The data suggest that worthwhile tumour targeting can be achieved with angiotensin II in patients with colorectal liver metastases.Post-mortem studies have shown that up to 70% of patients dying after a potentially curative resection for colorectal cancer, die with liver metastases. The prognosis of patients with colorectal liver metastases is generally poor, survival being in the range of 3 to 9 months (Woods, 1984;Nielsen et al., 1971).Surgical resection of colorectal hepatic metastases may be effective in patients with limited disease (Bradpiece et al., 1987), but may not be feasible in the majority of patients where multiple tumours are present. Although some recent studies of combined systemic 5 fluorouracil and folinic acid or interferon show promising results (O'Connell, 1989;Kerr, 1989;Wadler et al., 1989), conventional systemic chemotherapy has been associated with poor response rates. Attention has therefore turned to regional chemotherapy.It is known that established colorectal liver metastases receive their blood supply from the hepatic artery and the administration of anti-cancer drugs via an indwelling hepatic arterial catheter is now widely practised (Ridge et al., 1987). Unfortunately, although the tumour response rates may increase when chemotherapeutic agents are administered intraarterially rather than systemically (Berger, 1981) a significant increase in survival among treated patients has not been demonstrated by randomised controlled trial (Malik & Wrigley, 1988).Novel chemotherapeutic drug delivery systems including cytotoxic loaded or radioactive microspheres for administration by the arterial route, have been developed. We have previously described cytotoxic loaded albumin microspheres (diameter 20-40IAm) which are trapped in the liver when injected into the hepatic artery (McArdle et al., 1988;Willmott et al., 1985), the drug being released as the microsphere degrades. However intra-arterial injection of such particles results in their unselective distribution throughout the liver, microsphere concentration within different regions of the organ being dependent upon the prevailing distribution of arterial blood-flow. How...

Summary By measuring peripheral drug levels in plasma, the effect of combining albumin microspheres with angiotensin II on systemic exposure to 5FU when administered by bolus injection into the hepatic artery in patients with advanced colorectal liver metastases has been assessed. The results suggest that despite hepatic arterial administration of 5FU, there was no reduction in systemic exposure when compared with that associated with intravenous injection of the same dose. Neither albumin microspheres nor angiotensin II appeared to improve the regional advantage. There have been a number of reports relating the plasma levels of cytotoxic agents with pharmacodynamic parameters. We have shown significant direct correlations between 5FU clearance and 1 week post treatment platelet and white cell counts, and an inverse relationship between the area under the 5FU plasma concentration-time curve (AUC) and 1 week post treatment platelet count and white cell count respectively.The failure and toxicity of systemic chemotherapy in the treatment of liver metastases of colorectal origin has led to increasing interest in locoregional therapy (Taylor, 1985). Most antineoplastic agents have steep dose response curves and systemic toxicity can often be related to some aspect of the drug's plasma concentration-time profile (Powis, 1986 the right chest wall and the peritoneal cavity. The reservoir was then sutured into position over a rib within the subcutaneous pocket. The gastroduodenal artery was ligated distally and cannulated so that the catheter tip lay at the junction of the gastroduodenal and hepatic arteries. The catheter and reservoir were then filled with heparinised saline, which was replaced by flushing daily in the immediate post-operative period, and then once weekly.Albumin microspheres were prepared by a technique involving stabilisation with glutaraldehyde of a water in oil emulsion containing protein (Lee et al., 1981). The basic system has been modified by us to produce microspheres of a size suitable for entrapment in terminal capillaries. (Willmott et al., 1985). Human serum albumin (600mg) was dissolved in 1 mM phosphate buffer containing 0.1% SDS (1 ml) and diluted with water (1.8 ml). The albumin solution is emulsified in an oil phase of cotton seed oil and petroleum ether, and the protein cross-linked with 25% gluteraldehyde (150 jil) to stabilise the microspheres. Following consecutive washes in petroleum ether/isopropanol/PBS/0.5% tween, and PBS/0.2% tween to remove particles <7,um in diameter, the microspheres were ready for use. All procedures were carried out in a sterile products unit which maintains a sterile environment to the required British standard. This ensured that the microspheres were sterile, and an aliquot from each dose was formally checked by solubilisation with trypsin prior to sterility testing. The size of the microspheres was measured by Coulter counter or laser diffraction (Malvern Instruments, Malvern, UK) and was found to be 20-40,jm in diameter (50% weight average). Betwee...