314

We have investigated the effects of simvastatin treatment for type IIa hypercholesterolaemia on serum Lp(a) concentrations in 30 men and 16 women (mean age 52.5 years, SD 97). Blood samples were taken at baseline (after discontinuing any lipid-lowering therapy for at least one month and while on a low saturated fat, low cholesterol diet) and after three months’ treatment with simvastatin 10-40 mg daily. Serum samples were stored at - 20°C until the end of the study and then assayed in a single batch with an ELISA test (Biopool AB, Sweden). The median serum Lp(a) value after three months’ treatment with simvastatin was 26 mg/dl (range 0-91 mg/dl), slightly less (p 0-08) than the median baseline value of 32 =

mg/dl (range 0-105 mg/dl). Our data confirm that simvastatin does not substantially increase Lp(a). Consequently, the explanation for the failure of others5 to reproduce Gavish and Breslow’s original work6 must lie elsewhere. If, as suggested by Scanu,7Gavish and Breslow’s findings are due merely to an immunoassay artifact, these researchers should repeat their study with an analytical procedure that is independent of Lp(a) immunoreactivity, such as a combination of preparative ultracentrifugation and gel filtration serum

chromatography.8 We thank Prof V. Wynn, Dr D. Patterson, Dr D. Mulcahy, and Dr K. Fox for access to their patients.

DAVID CROOK MANDEEP SIDHU RAYMOND BRUCE

Wynn Institute for Metabolic Research, London NW8 9SQ, UK

1. Kostner GM, Gavish D, Leopold B, Bolzano K, Weintraub MS, Breslow JL. HMG-CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels. Circulation 1988; 80: 1313-19. 2. Thiery J, Armstrong VW, Schleef J, Creutzfeldt C, Creutzfeldt W, Seidel D. Serum lipoprotein Lp(a) concentrations are not influenced by an HMG-CoA reductase inhibitor. Klin Wochenschr 1988; 66: 462-63. 3. Wiklund O, Angelin B, Olofsson S-O, et al. Apolipoprotein(a) and ischaemic heart disease in familial hypercholesterolaemia. Lancet 1990; 335: 1360-63. 4. McDowell IF, Smye M, Trinick T, et al. Simvastatin in severe hypercholesterolaemia: a placebo controlled trial. Br J Clin Pharmacol 1991; 31: 340-43. 5. Stalenhoef AFH, Kroon AA, Demacker PNM. N-acetylcysteine and lipoprotein. Lancet 1991; 337: 491. 6. Gavish D, Breslow JL. Lipoprotein (a) reduction by N-acetylcysteine. Lancet 1991; 337: 203-04. 7. Scanu AM. N-acetylcysteine and immunoreactivity of lipoprotein(a). Lancet 1991; 337: 1159. 8. Gaubatz JW, Heideman C, Gotto AM Jr, Morrisett JD, Dahlen GH. Human plasma lipoprotein(a): structural properties. J Biol Chem 1983; 258: 4582-89.

The

patient’s view of breast cancer trials

SIR,-Mrs Thornton (Jan 4, p 44) rightly recognises some of the dilemmas that trouble doctors in decisions about treatment. However, faced with the diagnosis of ductal carcinoma-in-situ (DCI S) without any evidence of invasion, the doctor must ask, what is the clinical significance of the lesion and how should the patient be advised as to treatment? Most of the evidence comes from uncontrolled studies done before mammographic screening was widespread. Such reports include various types of DCIS, some of which had not been well defined before the introduction of these programmes. In the presence of DCI S, if no further action is taken, an infiltrating ductal carcinoma may develop in 30-50% of cases.1 If a wide excision is done, with confirmation of clearance of DCIS, an invasive lesion later occurs in about 10%, provided that the microcalcification measures no more than 4 cm.Z Mastectomy has been a standard surgical procedure for symptomatic DCIS, and a cure rate of almost 100% has been achieved.3 The UKCCCR DCIS trial protocol accepts that some women may prefer a more extensive operation. However, for those who would prefer limited surgery, as for early invasive cancer, is complete excision enough? In northern Europe and the USA additional radiotherapy is advised and several trials are underway to compare local excision with or without postoperative radiotherapy. These trials are unlikely to be capable of detecting any improvement in survival, but are aimed at reducing the risk of further DCIS and possible development of invasive disease. The only way to determine with any reliability whether radiotherapy reduces these risks is by large randomised trials. If radiotherapy proves useful in trials, many patients worth

may think that the small risk of

balancing against

the risk of

having

to

morbidity is undergo further,

perhaps more aggressive, treatment. The working party, therefore, does not agree that there is any evidence that would persuade it to drop this important arm of the trial. Similarly, the use of tamoxifen as adjuvant treatment for invasive cancer is now well established, especially in the over 50 age group.’ Although there is no direct evidence to support such treatment for DCIS, several studies have shown a substantial reduction in contralateral breast cancer among those with invasive cancer given tamoxifen, as well as a significant fall in the rate of local relapse. In discussing the necessity for continuing treatment trials for DCIS, leading researchers at an international meeting agreed that "the limited data available on DCIS, particularly with regard to the potential promise (and disadvantage) of breast conserving therapy, does not warrant dogmatism concerning the merits of the different treatment options, particularly in relation to patient sub-groups. Hence, it is important to increase the awareness of both physicians and patients as to the value of the data that will be gathered from these trials and to alert them as to how little information there is to " support at present any one treatment option as ’best’ (van Dangen Fentiman Holland et IS, R, al, unpublished results). JA, The fact that Mrs Thomton’s surgeon offered her entry into the 4-arm comparison indicates his ambivalence towards both postoperative radiotherapy and adjuvant tamoxifen in the postexcisional treatment of localised DCIS. Only if he had already decided, on the basis of his belief that one treatment was either essential or unnecessary, would his patients be eligible for a single randomisation. Mrs Thornton feels that the DCIS trial damages the doctor-patient relationship, but is it the trial or the present lack of medical knowledge that does the damage? Doctors have been condemned in the past for acting paternalistically, by taking the decision away from the patientand yet here is a patient in a similar situation in which the doctor has been honest by saying "I do not know which treatment is best for you" and yet expected to be able to advise an individual treatment plan. In such situations, the patient can either take the doctor’s advice and join the trial or make her own decision about treatment. The running of a clinical trial will not prevent a choice being made by an individual patient, if she wishes to make such decisions herself. The paradox is nearer to the truth; unless clinicians are willing to question the treatments they give and to set up protocols, no change will ever happen and choice will not be available since there will be no alternatives. Regrettably, much of modem medicine is the result of uncontrolled studies, and treatments have been introduced merely because a doctor thinks they might be better. Such individuals have no uncertainties and do not require informed consent because treatment is routine practice for them; the patient is happy because she gets advice that induces a positive attitude. Unfortunately, one does not have to look far for examples in which this had not been in patients’ best interests; the introduction of radical and super-radical mastectomy for the treatment of breast cancer has been shown by clinical trials to be unnecessary overtreatment in most patients. The practicalities of obtaining informed consent such as the timing and the amount of information supplied were particularly questioned by Mrs Thornton. The UK DCIS trial protocol, as all should be, was designed to fit with routine clinical practice, and in a non-life-threatening condition such as DCIS there was no need for hurried decisions. Mrs Thornton’s comments reinforce the working party’s view of the need for and value of trained nurse counsellors whether or not the patient is asked to consider trial entry. CRC Clinical Trials Centre, C. A. F. JOSLIN, King’s College School of Medicine and Dentistry, London SE5 9NU, UK 1. Fentiman IS. The treatment of in-situ breast

Chairman, on

behalf of the UKCCCR DCIS

working party

cancer. Acta Oncol 1989; 28: 923-26. Lagios, MD, Margolin FR, Westdahl PR, et al. Mammographically detected duct carcinoma in-situ. Cancer 1989; 63: 618-21. 3. Zafrani B, Fourguet A, Vilcoq J, et al. Conservative management of intraduct carcinoma with tumorectomy and radiation therapy. Cancer 1986; 57: 1299-301 4. Early Breast Cancer Trialist’s Collaborative Group. Systemic treatment of early brest cancer by hormonal, cytotoxic or immune therapy. Lancet 1992; 339: 1-15; 71-85 5. Nayfield SG, Karp JE, Ford LG, Dorr FA, Kramer BS. Potential role of tamoxifen in prevention of breast cancer. J Natl Cancer Inst 1991; 83: 1450-59. 6. Baum M, Zilka K, Houghton J Ethics of clinical research: lessons for the future Br MedJ 1989; 299: 251-53.

2.

315

S]Rf---Mrs Thornton’s article is a salutary reminder to all who ask their patients to take part in clinical trials that the fmal statistical results are made up of individual cases-people who have feelings about the treatment to which they are submitted. The onset of breast cancer screening programmes in several countries draws attention to the difficulty of how best to treat this new group of cases-the 20% of detected cancers that will be ductal carcinomas-in-situ (DCIS). It is important that the detection of this large number of new cases gives statisticians the chance to tell us the most effective treatment for this condition, as they have for early invasive breast cancer (Jan 4 and 11, pp 1 and 71). Breast cancer is complex: surgical treatment has been abhorrent to many women down the generations; it has a poor outlook in some patients; it has multisystem features; it is dependent on a hormonal environment that is bound up with women’s feelings and wellbeing; and now we have this new complexity of treatment. Without the further complication of a trial, any treatment for breast cancer must take a holistic approach to the patient. Attitudes to information given to patients have changed greatly. Patients now expect, and we are bidden to give them, as much accurate knowledge of their disease as we have and as they can understand. With this must come the time and personal support to sit with them and answer their questions, to explain in non-technical language the treatments proposed for them. They hang on to the certainties of time and date, and of results and proposed actions. A trial, by its nature, carries unknowns, and so the level of personal support given must be the greater. I believe that Mrs Thornton’s essay would not have needed writing if she had had the benefit of a good nurse counsellor, possibly backed up by additional time with her surgeon or oncologist. Cancer Relief Macmillan are running an appeal to create more nurse-counsellor posts, by providing so-called pump-priming money to health authorities. This is a splendid initiative, but it is the health service itself that should be recognising this need and providing the impetus and means. It should never happen that a patient with any cancer should be left without support after learning their diagnosis. A sensitive nurse will know when she is not wanted, but the image of a newly diagnosed patient struggling with leaflets for comfort is appalling. I believe the difficulty underscored by Mrs Thornton’s article is more one of the need for counselling than criticism of the DCIS trial. Women everywhere need the results of a well conducted trial of treatment for DCIS, and its frequency requires that this is done on a very widespread multicentre basis. They also require help and support from doctors and nurses. Breast Screening Service, St Margaret’s Hospital, Epping CM16 6TN, UK

RUTH WARREN

Breast cancer found at screening and previous detection by women themselves SIR,-Screening by mammography has reduced mortality from some randomised trials, and non-palpable breast cancer unsuspected by the woman herself can be detected by this breast cancer in

method.’-3 However, there are few data about how many women in such screening programmes have already detected a lump in the breast, and whether breast symptoms and signs are more common among women in whom breast cancer is diagnosed at screening than in those in whom it is not. In a mass mammography screening from 1987 to 1990 for women aged 40-75,204 screen-detected breast cancers were found among 32 557 screened women in the city of Turku, south-western Finland. Breast symptoms and signs present before mammography were recorded with a self-administered questionnaire. For every woman with screen-detected cancer 3 controls, matched for age and year of the diagnosis, were identified by a computer program among the women who had no cancer detected at screening. 23 (11 %) of the 204 women with screen-detected cancer had noticed a lump in the breast before screening, whereas only 12 (2%) of the 512 controls had done so (odds ratio 6-35, 95 % confidence interval [CI], 3-10-13-0). Similarly, 70 (34%) of the women with screen-detected cancer felt that their breasts were not healthy (abnormal sensations, skin changes, nipple discharge, lump, skin dimpling, change in the

breast size or shape), whereas only 124 (20%) of women without screen-detected cancer thought that their breasts were not healthy (odds ratio 21, CI 1-45-2-9). These results show that about 10% of breast cancers detected in mass screening have already been noticed by the woman herself. Some of these women might have waited for screening before consulting their doctor. The results also show that two-thirds of the women with screen-detected cancer had noticed no symptoms or signs in their breasts, and that a fairly large proportion of women (20%) in the general population have some breast symptoms or signs. These findings support screening of the entire population instead of mammography for only women with breast symptoms. Departments of Oncology and Radiotherapy, and Pathology, HEIKKI JOENSUU Turku University Central Hospital, PEKKA J. KLEMI SF-20520 Turku, Finland Turku

Department of Biostatistics, University

JUHANI TUOMINEN

Cancer Society of South-West Finland, Health Center of Turku

OSMO RÄSÄNEN ILMO PARVINEN

1.

2.

Shapiro S, Venet W, Strax P, Venet L, Roeser R. Selection, follow-up, and analysis in the health insurance plan study: a randomized trial with breast cancer screening. Natl Cancer Inst Monogr 1985; 67: 65-74. Verbeek ALM, Holland R, Sturmans F, Hendricks JHCL, Mravunac M, Day NE. Reduction of breast cancer mortality through mass screening with modern mammography. First results of the Nijmegen Project, 1975-1981. Lancet 1984; ii:

1222-24. 3. Tabar L, Fagerberg CJG, Gad A. Baldetorp L, Holmberg LH. Grontoft O. Reduction in mortality from breast cancer after mass screening with mammography. Lancet 1985; i: 829-32.

Protective role for CD8 cells in tuberculosis SIR,-CD4 T cells play an important role in protection against patients with low CD4 counts due to HIV infection are especially susceptible to tuberculosis.1 In mice, both CD4 and CD8 cells contribute to protection against tuberculosis2 but the role tuberculosis:

of CD8 T cells in human tuberculosis is unclear. We report persistent tuberculous infection despite adequate treatment in a man without HIV infection whose CD8 count was significantly below normal. A 58-year-old man, unemployed and with an alcohol problem, presented with pulmonary tuberculosis in 1972. He was treated with streptomycin, p-aminosalicylic acid, and but hypersensitivity to the first two of these drugs developed; he was therefore treated with rifampicin and isoniazid. The first 6 months of treatment were fully supervised in hospital, followed by 2 months’ treatment as an outpatient, during which he lost 3-75 kg in weight. He was readmitted for a further 2 months’ treatment with rifampicin and isoniazid, again followed by 2 months of outpatient treatment. His sputum again became positive on culture for Mycobacterium tuberculosis. He had a further 2 weeks’ treatment in hospital with rifampicin and isoniazid and continued these drugs for 18 months under supervision in a hostel for homeless alcoholics with tuberculosis.3 He then remained well for 4 years with no radiographic evidence of reactivation, although his weight fell by 5 kg. He presented again in February, 1988, with active pulmonary tuberculosis. Despite treatment with rifampicin, isoniazid, and pyrazinamide for 7 months, until the sputum was negative on both smear and culture, followed by rifampicin and isoniazid, he became smear-positive again in November, 1988. Isoniazid-resistant M tuberculosis had been isolated in June, 1988, and was again recovered in December, 1988. Ethambutol was added. In March 1989, organisms resistant to isoniazid, rifampicin, and clofazimine but sensitive to rifabutin, ethambutol, ciprofloxacin, and streptomycin were grown from his sputum. Treatment to date with

isoniazid,

CELL SURFACE MARKERS DURING TREATMENT

*% of total lymphocyte count NT not tested