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protein kinase C inhibition.3 Such a mode of action is consistent with the known mechanism of action of tamoxifen in various oestrogenreceptor-negative malignant disorders in which the therapeutic effect of tamoxifen is mediated by steroidreceptor-independent mechanisms at doses four to eight times that used in breast carcinoma.4 Examples of such steroid-receptorindependent mechanisms are protein kinase C inhibition and interference with the action of calmodulin. Encouraging results have emerged from phase I and II trials of high-dose tamoxifen in oestrogen-receptornegative malignant disorders such as glioblastoma, and pancreatic and renal-cell carcinoma, and from phase III trials of high-dose tamoxifen in combination therapy for melanoma. Partial response in wild-type oestrogen-receptor-positive HCC to tamoxifen at a dose of 80 mg/day has been reported.5 There are, however, no data to suggest that oestrogenreceptor-negative HCC will respond to tamoxifen at doses relevant only to oestrogen-receptor-positive breast carcinoma. Conclusive data on the role of tamoxifen in HCC may, therefore, only be obtained from trials of tamoxifen at doses relevant to its mode of action. In view of evidence, now supported by the CLIP trial itself, we have revised our protocol to include highdose tamoxifen at 120 mg/day. Although we anticipate that any survival advantage may be slight, tamoxifen is well tolerated and easy for the patients to use and may confer quality of life advantages, which we are investigating. *Pierce Chow, Tan Chee Kiat, Tai Bee Choo, David Machin *Department of Surgery, Singapore General Hospital, Singapore 169608, Singapore; Department of Gastroenterology, Singapore General Hospital, Singapore; and Clinical Trials and Epidemiology Research Unit, Ministry of Health, Singapore 1

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CLIP Group (Cancer of the Liver Italian Programme). Tamoxifen in treatment of hepatocellular carcinoma: a randomised controlled trial. Lancet 1998; 352: 17–20. Boix L, Bruix J, Castells A, et al. Sexhormone receptors in hepatocellular carcinoma: is there a rationale for hormonal treatment? J Hepatol 1995; 17: 187–91. Jiang SY, Shyu RY, Yeh MY, Jordan VC. Tamoxifen inhibits hepatoma cell growth through an estrogen receptor independent mechanism. J Hepatol 1995; 23: 712–19. Gelmann EP. Tamoxifen for the treatment of malignancies other than breast and endometrial carcinoma. Semin Oncol 1997; 24: S165–70.

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Villa E, Dugani A, Fantoni E, et al. Type of estrogen receptor determines response to antiestrogen therapy. Cancer Res 1996; 56: 3883–85.

Authors’ reply Sir—The CLIP trial 1 showed that survival of patients with HCC randomly assigned tamoxifen 40 mg/day is the same as that of controls without tamoxifen. The sample size and the power of the trial were large enough to detect an 11% difference in 1-year survival, a much smaller advantage than that reported in some previous underpowered trials. It is unfortunate that tamoxifen did not work because it is a well-tolerated drug at the investigated dose. We believe, however, that the final implication of our paper, that this dose of tamoxifen is not effective in the treatment of HCC, is conceptually correct. As Pierce Chow and colleagues have done, we chose the dose of tamoxifen after a review of the existing conflicting evidence, 2 already discussed elsewhere.3,4 Obviously, the dose chosen in the CLIP trial (40 mg) was similar to the initial dose (60 mg) of the trial of Chow and colleagues. We are pleased that our results helped Chow and colleagues to revise their protocol. Indeed, we agree with them that evidence does suggest that an oestrogen-receptor-independent mechanism of action of tamoxifen may become active at a concentration higher than that required for the receptor-mediated antioestrogenic effect. We believe, however, that current evidence supporting the activity of high-dose tamoxifen in HCC is negligible. Furthermore, it could be inappropriate to extend to HCC patients the weak evidence of activity reported in different kinds of tumours. Finally, as Chow and colleagues are aware, toxic effects of high-dose tamoxifen remains a potential concern for patients who are affected by HCC and liver cirrhosis at the same time (92% of the patients in the CLIP trial). This issue, to our knowledge, has never been investigated. The addition of a study group on high-dose tamoxifen in Chow and colleagues’ placebo-controlled randomised clinical trial might produce some early data on toxicity and activity of high-dose tamoxifen, although early stopping rules should be stated for unacceptable side-effects. Inclusion of quality of life assessment in their randomised study is important. Indeed, in March, 1998, the CLIP Investigators started a

prospective trial of the effect of different locoregional treatment strategies on quality of life of HCC patients, with the same questionnaires of Chow and colleagues. Ciro Gallo, Bruno Daniele, Giovanni Battista Gaeta, *Francesco Perrone, Sandro Pignata, on behalf of the CLIP Group Seconda Università degli Studi di Napoli, Napoli, Italy; and *Istituto Nazionale Tumori di Napoli, Via Marianna Semmola, 80131 Napoli, Italy 1

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CLIP Group (Cancer of the Liver Italian Programme). Tamoxifen in treatment of hepatocellular carcinoma: a randomised controlled trial. Lancet 1998; 352: 17–20. Pignata S, Daniele B, Gallo C, De Vivo R, Monfardini S, Perrone F. Endocrine treatment of hepatocellular carcinoma: any evidence of benefit? Eur J Cancer 1998; 34: 25–32. Farinati F. Tamoxifen treatment in hepatocellular carcinoma. Gastroenterology 1996; 111: 272–73. Bruix J, Castells A, Rodes J, Bru C. Tamoxifen treatment in hepatocellular carcinoma. Gastroenterology 1996; 111: 273–74.

Aortic stenosis and ACE inhibitors Sir—Niall Cox and co-workers (July 11, p 111)1 suggest that “vasodilatation is safe in patients with aortic stenosis”. However this statement is likely to be true only if the left venticle can increase flow adequately in response to a fall in peripheral vascular resistance. In some patinets with severe aortic stenosis and heart failure, leftventricular ejection fraction does not increase during dobutamine infusion.2 Furthermore, transaortic flow increases less in response to dobutamine in patients with severe compared with moderate or mild aortic stenosis, even if left-ventricular systolic function is normal at rest. A proportion of patients with severe aortic stenosis have systemic hypertension,3 whereas in others the blood pressure is low. Vasodilators are unlikely to be safe in the latter group, especially since they tend to reduce the systemic blood pressure more than left-ventricular pressure with a consequent increase in transaortic gradient.4 Each case of aortic stenosis must be characterised not only by the degree of valvar obstruction, but also by leftventricular, systemic, vascular, and clinical adaptations before deciding on therapy with angiotensin-convertingenzyme (ACE) inhibitors. Clinical experience is that ACE inhibitors can

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be harmful and should only be introduced under careful supervision of selected inpatients. We must not forget that the only definitive treatment for severe aortic stenosis is surgery. *Helen Rimington, Scott Takeda, John Chambers Department of Cardiology, St Thomas’ Hospital, Guy’s and St Thomas’ Hospital Trust, London SE1 7EH, UK 1

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Cox NLT, Abdul-Hamid AR, Mulley GP. Why deny ACE inhibitors to patients with aortic stenosis? Lancet 1998; 352: 111–12. De Fillipi, Willet DL, Brickner ME, et al. Usefulness of dobutamine echocardiography in distinguishing severe from nonsevere valvular aortic stenosis in patients with depressed left ventricular function and low transvalvular gradients. Am J Cardiol 1995; 75: 191–94. Wren C, Petch MC. Calcific aortic stenosis. J R Coll Physicians Lond 1983; 17: 192–95. Bruckschlegel G, Holmer S, Jandeleit K, et al. Blockade of the renin-angiotensin system in cardiac pressure-overload hypertrophy in rats. Hypertension 1995; 25: 250–59.

Sir—The report by Niall Cox and colleagues1 is at best misleading, and at worst promotes risky medical practice. The mechanism of first-dose hypotension is due to a sudden decrease in the systemic vascular resistance, via the reduction in circulating angiotensin II. This reduced resistance in turn has two implications. First, coronary blood flow, which is dependent on the diastolic blood pressure for the left ventricle and both systolic and diastolic blood pressure for the right ventricle, decreases. Since three of the studies were in rats with surgically induced supravalvular stenosis, the introduction of angiotensinconverting-enzyme (ACE) inhibitors to these animals would not have reduced coronary blood flow, which contrast with the situation in aortic stenosis. Second, 30 unmatched patients aged 31–85 years with unstated left-ventricular function, do not constitute a realistic intervention group. Left-venticular function determines short-term and long-term survival and the actual transaortic gradient, as measured by echocardiography. A good leftventricular function implies that cardiac decompensation has not yet occurred and a cardiac reserve is still present that could meet the increased demands that ACE inhibitor therapy could place upon the heart via decreased coronary blood flow. Cox and co-workers make no mention of concomitant medical treatment, particularly rate-controlling

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drugs, such as digoxin or ␤-blockers. This omission is important, especially since cardiac output in aortic stenosis is rate dependent. Similarly, no mention is made of concurrent coronary artery disease, and this group is almost certainly a distinct group of patients within the aortic stenosis group, that have an increased risk of death. The presence of heart failure in patients with aortic stenosis needs to be further clarified, because it could be secondary to aortic valve disease or myocardial disease (usually coronary artery disease), which have different characteristics and prognoses. Since only two clinical reports on long-term follow-up are available, we believe it is too early to conclude that ACE inhibitors are safe in the short term; and safety in the short-term could be falsely reassuring, if these drugs are proved harmful in this subgroup of patients in the long-term. Michael Poullis Department of Cardiothoracic Surgery, NHLI, Hammersmith Hospital, East Acton, London W12 0NH, UK (e-mail: [email protected]) 1

Cox NLT , Abdul-Hamid Ahmed R, Mulley GP. Why deny ACE inhibitors to patients with aortic stenosis? Lancet 1998; 352: 111–12.

Metabolic abnormalities and use of HIV-1 protease inhibitors Sir—Insulin has a central role in the management of glucose uptake by different tissues and in the storage of metabolic fuels as glycogen and fat. After binding to its receptor, the receptor-insulin complex is internalised in endocytic vesicles that stimulate various physiological responses. Receptors are then recycled to the cell surface and insulin is degraded inside the cell. Degradation of insulin is important in the termination of signalling and clearance of the circulating hormone. The major site of insulin degradation is the liver, where half of the hormone is removed in a single passage. At least two insulin-degrading enzymes have been identified: glutathioneinsulin transhydrogenase and a protease named insulysin. Insulin resistance has been associated with central and visceral obesity, hyperlipidaemia, type 2 diabetes mellitus, and lipodystrophy. Like Andrew Carr and co-workers (June 20, p 1881),1 we also suggest

that HIV-1 protease inhibitors may inhibit any human protein involved in carbohydrate and lipid metabolism but we offer a simpler alternative hypothesis. The HIV-1 protease is not specific. In addition to the HIV-1 gag polyprotein, other human proteins including insulin may be substrates of the HIV-1 protease.2 The importance of the ability of HIV-1 protease to cleave insulin is unknown, although the effect may be negligible in vivo, since HIV-1 protease and insulin are transported on different compartments (intracellular and plasma, respectively) and act on different cells (HIV-1-infected cells, and liver, muscle, and adipose tissue cells, respectively). If insulindegrading enzymes and the HIV-1 protease share the ability to degrade insulin, we speculate that inhibitors of the HIV-1 protease may also inhibit at least one insulin-degrading enzyme. A reduction of hepatic insulin catabolism on starting protease inhibitor therapy would produce a primary hyperinsulinaemia. Hyperinsulinaemia would lead to an increase of insulin physiological effects since insulin resistance has not yet developed. Insulin would stimulate hepatic lipogenesis. Liver-derived triglycerides would be transported as very low-density lipoproteins for deposition in adipose tissue. Insulininduced stimulation of lipoprotein lipase and inhibition of hormonesensitive lipase would result in a net increase of fat. Glucocorticoids also regulate adipose-tissue metabolism and accumulation of intra-abdominal fat might result from a high density of glucocorticoid receptors stimulating lipoprotein-lipase activity in this region.3 As long as hyperinsulinaemia is maintained, it would finally lead to insulin resistance.4 The net effect at this stage would be inhibition of lipogenesis and stimulation of lipolysis resulting in an inappropriate increase of plasma-free fatty acids. The increased availability of free fatty acids would further increase the hepatic triglyceride synthesis; it would also enhance hepatic glucose output which would induce a compensatory insulin hypersecretion to maintain glucose uptake homoeostasis. In some predisposed individuals, overstimulation of ␤ cells might lead to its failure and give rise to the emergence of type 2 diabetes mellitus. The inhibition of the antilipolytic effect of insulin once insulin resistance has developed 5 might explain the progressive loss of subcutaneous fat resulting in the development of lipodystrophy

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