The HPI predicts a poor outcome in patients with colorectal cancer and may be useful in patient selection for adjuvant chemotherapy.

The clinical application of ultrasonographic contrast agents in colour Doppler flow imaging of hepatic tumours is receiving increasing attention. Levovist is a suspension of galactose microparticles that provides reproducible concentrations of stabilized air bubbles with transpulmonary stability. Its effect on colour Doppler imaging was assessed in 26 patients with colorectal cancer and histologically proven hepatic metastases. Colour Doppler flow imaging was performed before and after intravenous injection of 10 ml Levovist 300 mg/ml. At 5-10 s after injection there was significant enhancement of the hepatic lesions with colour Doppler signals in 23 patients, lasting for a mean(s.d.) of 180(45) s. A consistent pattern of colour Doppler signal was observed, with increased enhancement predominantly around the tumour periphery and little or no central enhancement. These data suggest that Levovist may increase the sensitivity and specificity of colour Doppler flow imaging of colorectal hepatic metastases.

Background: Statins inhibit proliferative signalling in oesophageal adenocarcinoma (OAC) and their use is associated with better survival in observational studies. The present study was undertaken to examine the feasibility of assessing adjuvant statin therapy in patients with operable OAC in a phase III RCT.Methods: For this multicentre, double-blind, parallel-group, randomized, placebo-controlled feasibility trial, adults with OAC (including Siewert I-II lesions) who had undergone oesophagectomy were centrally allocated (1 : 1) to simvastatin 40 mg or matching placebo by block randomization, stratified by centre. Participants, clinicians and investigators were blinded to treatment allocation. Patients received treatment for up to 1 year. Feasibility outcomes were recruitment, retention, drug absorption, adherence, safety, quality of life, generalizability and survival.Results: A total of 120 patients were assessed for eligibility at four centres, of whom 32 (26⋅7 per cent) were randomized, 16 in each group. Seven patients withdrew. Participants allocated to simvastatin had lower low-density lipoprotein cholesterol levels by 3 months (adjusted mean difference −0⋅83 (95 per cent c.i. −1⋅4 to −0⋅22) mmol/l; P = 0⋅009). Median adherence to medication was greater than 90 per cent between 3 and 12 months' follow-up. Adverse events were similar between the groups. Quality-of-life data were complete for 98⋅3 per cent of questionnaire items. Cardiovascular disease, diabetes and aspirin use were more prevalent in the non-randomized group, whereas tumour site, stage and grade were similar between groups. Survival estimates were imprecise.Conclusion: This RCT supports the conduct and informs the design considerations for a future phase III trial of adjuvant statin therapy in patients with OAC. Registration number: ISRCTN98060456 (www.isrctn/com).

Summary In this review, the rationale of regional chemotherapy for treatment of hepatic metastases in advanced colorectal carcinoma is discussed. Pharmacokinetic principles and early clinical experience of hepatic arterial drug administration are summarised. The regional advantage of fluoropyrimidine compounds in this setting is well established, and recent evidence suggests that 5-fluorouracil (5-FU) is more efficacious than the analogue 5-fluoro-2'-deoxyuridine (FUDR). However, while significantly higher clinical response rates can be achieved with hepatic arterial infusion (HAI) chemotherapy compared with conventional intravenous drug administration, patient survival benefit is not significantly different. Several novel approaches to overcome the limitations of HAI therapy are currently being explored. These include concomitant use of biodegradable microspheres, which both slow tumour blood flow and enhance tumour drug uptake, and use of vasoactive agents to redistribute arterial blood flow towards tumours. In addition, novel chemotherapeutic agents which exploit unique biological characteristics of hepatic tumours are entering clinical trial.The conventional notion of chemotherapy is of a truly systemic treatment designed to combat widely disseminated malignant disease. Colorectal carcinoma is relatively unresponsive to chemotherapy (Mayer, 1992), despite an increasing understanding of drug mechanisms of action at the molecular level. To date, systemic 5-FU plus folinic acid is considered the optimum treatment for metastatic colorectal cancer, yielding response rates of around 25% and median survival of around 12 months (Piedbois et al., 1992). These disappointing results reflect, in part, the narrow therapeutic ratio of 5-FU and the presence of associated severe systemic side-effects limiting dose escalation. Regional chemotherapy affords an alternative method of cytotoxic drug administration which circumvents the constraints of systemic administration, while introducing the concept of targeted drug delivery to metastatic disease localised to specific components of the body.Three levels of tumour targeting have been described (Widder et al., 1979): (1) selective drug delivery to the tumourbearing organ, (2) drug delivery biased to tumour rather than to normal tissue within that organ and (3) enhancement of uptake of cytotoxic drug by malignant cells. In this context, regional chemotherapy constitutes first-order targeting. Currently, the value of this method of drug delivery is being assessed in a number of different malignancies, but experience is greatest in the treatment of hepatic metastases from colorectal carcinoma.Colorectal carcinoma is the second most common malignancy in the UK and the cause of over 19,000 deaths per year. Epidemiological studies show that the incidence of colorectal carcinoma is increasing, with approximately 28,000 new cases now being diagnosed annually. Up to 50% of patients with colorectal carcinoma develop liver metastases, from which as many as 70% of patients will subsequen...

Sunnua" Regional chemotherapy. delivered via the hepatic artery. may significantly increase tumour response rates in patients with colorectal liver metastases. However, survival is limited by extrahepatic disease progression. We have developed a novel therapeutic approach for patients with metastases confined to the liver. In order to achieve high local response rates and also inhibit extrahepatic progression. 5-fluorouracil (5-FU) was infused intra-arterially at a dose previously calculated to achieve both high-dose regional therapy and adequate systemic levels. To enhance efficacy further, 5-FU was combined with high-dose systemic folinic acid (FA). Thirty-one patients were evaluated in a phase II study. 5-FU (1.5 g m2) was infused via a surgically implanted hepatic artery catheter over a 24 h period: FA (total 400 mg m-2) was infused intravenously during the initial and final 2 h. Treatments were given weekly for cycles of 6 weeks' duration. To date, median duration of treatment is 6 months and the median follow-up period is 17 months. 1992a) we initiated a phase II study using high-dose IHA 5-FU so that 'spill-over' into the systemic circulation occurred. To enhance efficacy further. we adopted a schedule using prolonged infusions modulated by high-dose systemic folinic acid. Our aims were not only to maximise tumour response rates but also to delay extrahepatic progression in an attempt to prolong survival. Patients and methodsFrom 1 March 1990 to 31 March 1993. 59 patients with colorectal liver metastases were considered for possible inclusion in the study. which had previously been approved by the local ethical committee. Five of these patients had a WHO performance >2 and were not investigated further. The remaining patients underwent CT scanning of abdomen and pelvis and either thoracic computerised tomography (CT) Thirty-one patients [nine female, 22 male. median age 59 years (range 37-77)] were therefore included. Multiple metastases were detected at the time of primary surgery in 24 patients. Three patients had undergone either wedge resection elsewhere (n = 2) or formal hepatic resection (n = 1) for apparently solitary tumours and were included following tumour recurrence. The remaining four patients had metastases diagnosed at follow-up (range 5-15 months post resection of the primary tumour). Six patients had between 25% and 50% of their livers replaced by tumour (assessed by CT image analysis), while the others had less than 25% hepatic replacement. The median number of metastases was 5 (range 1-30). The patient with a solitary tumour had a catheter placed at the time of primary surgery with a view to treating with regional chemotherapy and hepatic resection at a later (D Macmillan Press Ltd