Complete remission in multiple myeloma

52

Examinations in surgery SIR,-Democracy may be advancing in Eastern Europe, but not within Britain’s surgical Royal Colleges. At the 1988 annual general meeting of the Royal College of Surgeons of England a motion submitted by members of the Association of Surgeons in Training deploring proposals for a new three-part fellowship examination was carried overwhelmingly. A subsequent Lancet editorial’ prompted much further debate. Since then the principle of that motion has been endorsed at many surgical meetings. It was formally endorsed at the AGM of the Association of Surgeons of Great Britain and Ireland in April, 1989.2 It came as something of a surprise therefore to those attending this year’s AGM of the Royal College of Surgeons of England on Dec 13 that this controversy was not mentioned. It would appear that the proposals for the new examination will steamroll ahead without any regard for the wishes of the fellows. The meeting was unusual in that there were no minutes to be read from the previous AGM, so there were no "matters arising"; and there was no "any other business" on the agenda. Open discussion was thereby effectively stifled. Is this democracy? ANDREW J.

MCIRVINE,

Immediate past secretary, Association of Surgeons in Training

35 Elsie Road, London SE22 8DX, UK

that of Gore et al in indicating a relation between the aggressiveness of chemotherapy and the tumour reduction. Our regimen was well tolerated: there were only 3 chemotherapy-related deaths, platelet support was not required, and chemotherapy was administered on an outpatient basis. The high response rate with high-dose melphalan (Gore et al) was associated with serious toxicity and with mortality, whereas VAD (Samson et al) was similar in terms of survival and superior in acceptability and feasibility. Chemotherapy at an intermediate dose, followed by interferon maintenance, represents an alternative to attempts to eradicate multiple myeloma with high-dose regimens followed by bone-marrow support. This approach may be especially useful in older patients who cannot enter intensive chemotherapy programmes and in young patients with good prognostic factors such as low plasma cell proliferative activity and/or low serum &bgr;2-microglobulin levels.2,3 Other members of the study group are M. Boccadoro, G. Awisati, M. Cavo, R. Frieri, M. Liberati, R.Marceno’, F. Marmont, G. Papa, L. Resegotti, M. Tribalto, F. Dammacco, S. Tura, and F. Mandelli.

Department of Medicine and Experimental Oncology, University of Turin, 10126 Turin, Italy

A. PILERI, for the Italian

Multiple Myeloma Study Group

F, Tnbalto M, Avvisati G, et al. Recombinant alfa-2b interferon as post-induction therapy for responding multiple myeloma patients: M84 protocol. Cancer Treat Rev 1988; 15 (suppl A): 43-48. 2. Greipp PR, Katzmann JA, O’Fallon WM, et al. Value of &bgr;2-microglobulin level and plasma cell labeling indices as prognostic factors in patients with newly diagnosed myeloma. Blood 1988; 72: 219-23. 3. Boccadoro M, Marmont F, Tribalto M, et al. Early responder myeloma. kinetic studies identify a patient subgroup characterized by very poor prognosis. J Clin Oncol 1989; 1: 119-25. 1. Mandelli

1. Editorial. Surgical insurrection. Lancet 1988; ii: 884. 2. Jackson B. The examinations leading to the FRCS diploma. Br

J Surg 1989; 76: 1091.

Euthanasia SIR,-Professor Reichel and Professor Dyck (Dec 2,

p

1321)

use

Schweitzer’s "reverence for life" to oppose euthanasia. Schweitzer described Descartes’ dogma cogito ergo sum as "poverty-stricken".l He said it should be replaced with "I am life which wills to live, in the midst of life which wills to live". It is the essence of euthanasia that there is no will to live. Wellside, Livesey Road, Ludlow, Shropshire SY8 1 EZ, UK

IAN A. SLATER

1. Schweitzer A. Civilization and ethics, 2nd ed. London: A & C Black, 1929: 246.

Complete remission in multiple myeloma SIR,-Multiple myeloma is seen as the haematological malignancy with the highest resistance to chemotherapy-indeed, about 50% of patients do not respond to conventional chemotherapy and evidence for complete remission (CR) is no more than anecdotal. Dr Gore, Dr Samson, and their colleagues (Oct 14, pp 879 and 882) have clearly shown that a high rate of CR can be achieved with the high-dose melphalan and a vincristine, doxorubicin, dexamethasone (VAD) regimen. In neither study was survival strikingly different from that seen with conventional chemotherapy, but, as Gore et al say, "cure can only be anticipated if treatments giving high CR rates are developed". In 1988 our group planned a pilot study with an "intermediate" dose of cyclophosphamide (1-2 gfm2 on days 1 and 3) and prednisone (60 mg/m2 on days 1--4). After six cycles, responders received interferon-o2 to maintain remission. 41 patients with multiple myeloma from eight Italian centres took part in this study. CR was defined as the disappearance of the serum and urine M component (on electrophoresis on a cellulose acetate membrane) and a normal bone marrow appearance with less than 1 % of plasma cells, maintained for at least 6 months. Bence-Jones myeloma patients with disappearance of the urine M component were not included in the CR group. 12 CRs (29%) were observed-a proportion well above that obtained with conventional chemotherapy, even though the follow-up is very short (mean 14 months) and it is impossible to forecast long-term survival. The high CR rate must be solely attributed to the intermediate dose of cyclophosphamide because prednisone was used at a conventional dose. Our study confirms

SiR,—Dr Samson and colleagues report excellent results with vincristine, doxorubicin, and dexamethasone (VAD) as first-line therapy for multiple myeloma. From Jan 1, 1985, to May 1, 1989, we treated 38 poor-risk multiple myeloma patients with this regimen as first-line therapy (23 men, 15 women; average age 65, range 44-79, 29 patients over 60). All these patients were in Salinon and Durie stage III and presented with serum paraproteins or urinary light chains. Poor risk was defined as the presence of one or more of the following: serum creatinine above 177 umol/1 (18 patients), Karnofsky index below 50%, bone marrow failure (haemoglobin below 8 g/dl, platelets 80 000/ul, neutrophil polynuclear cells below 1000/1). The VAD regimen’ was administered in 28 day cycles. After the second course, dexamethasone from days 9 to 12 and 17 to 20 was discontinued. After 4 months of treatment 12 patients (32%) responded with a 50% decrease in monoclonal Ig. 13 patients had to be withdrawn before evaluation: 4 because of disease-related deaths, 6 with severe side-effects (2 fatal infective episodes, 2 with heart failure [1 fatal], and 2 digestive tract complications [1 fatal]), and 3 who refused treatment. With a mean follow-up of 30 months average survival is 20 months (65% at 12 months, 45% at 24 months, and 26% at 35 months). Thus in our series of patients with poor-risk stage III multiple myeloma given the VAD regimen as first-line therapy we have obtained much less satisfactory results than those reported by Samson et al, both for response (32% vs 84%)and for mean survival (20 vs 44 months). Differences in patient selection may make the two series non-comparable. Samson’s patients were younger than ours (53 vs 65) and younger than is usual for series of patients with multiple myeloma. The 32 patients in Samson’s series seem to have had a more favourable initial prognosis than ours because only 20 in stage IIII and 10 in stage B. We do not believe it advisable to propose the VAD regimen as first-line therapy for patients presenting with multiple myeloma with myelosuppression or renal impairment. Indeed, in such patients mortality due to treatmentrelated complications appears to be much more frequent and the rate of response much lower than is seen in cases with a less severe prognosis3 or even in refractory and/or relapsing patients. 1 Our were

results

are

part of

a

prospective randomised study,

now

being

53

analysed, comparing the efficacy of the VAD regimen with standard polychemotherapy in patients with poor-risk stage III multiple myeloma. Department of Internal Medicine, Hôpital Sud,

B. GROSBOIS

35056 Rennes, France

Biophysics Laboratory, Hôpital Charles Nicolle, Rouen Rheumatology Service, Hôpital Boisguillaume, Rouen Haematology Service, Hôpital Beaujon, Clichy Haematology Service, UCL Brussels, Belgium Haematology Laboratory, Hôpital Charles Nicolle, Rouen

J.

F. MENARD

X. LELOET

J. F. BERNARD J. L. MICHAUX M. MONCONDUIT, for Groupe d’Etudes et de Recherche sur le Myelome Multiple

Barlogie B, Smith L, Alexanian R. Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med 1984; 310: 1353-56. 2. Karjalainen S, Palva I. Do treatment protocols improve end results? A study of survival of patients with multiple myeloma in Finland. Br Med J 1989; 299: 1.

1069-72. 3. Gore ME, Selby PJ, Viner C, et al. Intensive treatment of multiple myeloma and criteria for complete remission. Lancet 1989; ii: 879-82. 4. Monconduit M, Le Loet X, Bernard JF, Michaux JL. Combination chemotherapy with vincristine, doxorubicin, dexamethasone for refractory or relapsing multiple myeloma. Br JHaematol 1986; 63: 599-608.

Cortisol secretion in patients simvastatin

on

SiR,—Dr French and Dr White (Sept 30, p 807) report transient symptomatic hypotension in 3 hypercholesterolaemic patients treated with the new 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor simvastatin. They explain this finding on the basis that the drug, as well as lowering cholesterol concentration, may interfere with steroid hormone production and hence impair adrenal function. This issue has been addressed in studies with lovastatin.l,22 We have investigated the effects of simvastatin on adrenal function in 7 men and 3 women (mean age 53 years) affected by, or at high risk of, ischaemic heart disease and with heterozygous familial hypercholesterolaemia (FH). After eight weeks on the American Heart Association phase-I diet and placebo treatment, our patients received simvastatin as a single daily bedtime dose of 10 mg for six weeks, 20 mg for a further six weeks, followed by 40 mg for twelve weeks. A rapid adrenocorticotropic hormone (ACTH) test (intravenous tetracosactrin, 0-25 mg), blood being obtained for cortisol assay before and 30 and 60 min after injection, was done at the start, at week twelve, and at the end of simvastatin treatment. All patients completed the study and no important side-effects or changes in routine laboratory tests were noticed. Although the expected lowering of lipid and lipoprotein concentrations was seen, basal and ACTH-stimulated cortisol (table), as well as other steroid hormone and gonadotropin concentrations (data not shown), did not

vary

significantly.

Basal and concentrations

stimulated are

normal in

adrenal and gonadal hormone heterozygous FH, whereas they are

EFFECT OF SIMVASTATIN IN 10 PATIENTS WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLAEMIA

(SEM) shown (Student’s t-test) for differences with baseline values tAfter rapid intravenous ACTH injection Mean

*p < 001

impaired in abetalipoproteinaemia and in homozygous FH.3 Our findings and those for lovastatinl,2,4 suggest that conventional doses of HMG CoA reductase inhibitor do not reduce steroid hormone secretion in heterozygous FH. HMG CoA reductase activity is probably not greatly inhibited in steroid producing cells by clinical doses of such drugs. Alternatively, low-density lipoprotein (LDL) and possibly high-density lipoprotein (HDL) receptor activity may be sufficiently enhanced to provide exogenous cholesterol for steroid synthesis. Whether simvastatin does interfere with the renin-angiotensin-aldosterone system is not known. However, our data and those of others seem to exclude substantial impairment of cortisol secretion.

Department of Medical Pathology, University of Brescia, and Department of Medicine 2a Spedali Civili, 25100 Brescia, Italy 1.

RENATO CANDRINA GIANPAOLO BALESTRIERI ANDREA SALVI OTTAVIO DI STEFANO SARA SPANDRIO GIANNI GIUSTINA

Illingworth DR, Corbin D. The influence of mevinolin on the adrenal cortical response to corticotropin in heterozygous familial hypercholesterolemia. Proc Natl

Acad Sci USA 1985; 82: 6291-94. 2. Laue L, Hoeg JM, Barnes K, Loriaux DL, Chrousos GP. The effect of mevinolin on steroidogenesis in patients with defects in the low density lipoprotein receptor pathway. J Clin Endocrinol Metab 1987; 64: 531-45. 3. Illingworth DR, Alam NA, Lindsey S. Adrenocortical response to adrenocorticotropin in heterozygous familial hypercholesterolemia. J Clin Endocrinol Metab 1984; 58: 206-11. 4. Fansworth WH, Hoeg JM, Maher M, Brittain EH, Sherins RJ, Brewer HB Jr. Testicular function in type II hyperlipoproteinemic patients treated with lovastatin (mevinolin) or neomycin. J Clin Endocrinol Metab 1987; 65: 546-50.

Emollients, salicylic acid, and ultraviolet

erythema SIR,-Dr Kristensen and Dr Kristensen (Nov 4, p 1109) report a photoprotective effect of 2% salicylic acid in an emollient base during ultraviolet (UV) B (280-320 nm) treatment of psoriasis. We have measured the effect of salicylic acid and an emollient base on UVB-induced erythema in five volunteers, as well as the spectral absorption of salicylic acid and the components of the base. Five sites on the flexor aspect of the forearm were irradiated with UVB with a filtered medium-pressure mercury-arc lamp. The irradiance of the lamp at the skin surface was measured with a radiometer that had a UVB sensor (International Light, IL700); the irradiation to all sites was three times the amount expected to cause minimal erythema in individuals. The subjects had no additional treatment, or they had emulsifying ointment alone or 2% salicylic acid in emulsifying ointment applied to the sites immediately before or after irradiation. All sites were then occluded for 2 hours. Erythema was measured before and 24 hours after irradiation with a reflectance instrument,l and the results were recorded as the change in erythema at each site corrected for any change at a non-irradiated control site. In all subjects, the increase in erythema at sites which received emulsifying ointment after UVB was similar to that at the sites which received UBV alone; a site treated with emulsifying ointment after UVB was therefore a positive control and the increase in erythema at other sites was expressed as a percentage of the increase at this control site. Salicylic acid ointment after UVB did not affect the erythema (mean 99% of control, range 75-137%) but application of either ointment before irradiation had a striking effect. The mean increase in erythema at the site pretreated with emulsifying ointment was 17% (range 0-57%), and with salicylic acid ointment it was 29% of the control value (range 0-70%) (p < 0-001 for both, paired t test). The spectral absorption of emulsifying ointment (emulisfying wax 30%, yellow soft paraffin 30%, liquid paraffin 40%) and salicylic acid was measured with a UV-visible recording spectrophotometer (Shimadzu UV 160). Salicylic acid dissolved in ethanol absorbed radiation strongly at wavelengths below 320 nm, with an absorbance coefficient E ( 1 %, 1 cm) of greater than 20 (equivalent to 1 mg/cm2 absorbing greater than 99% of UVB). Emulsifying ointment absorbed 40% of radiation between 310 and 800 nm, probably due to of diffraction of radiation. There was increasing wavelength-specificabsorption at shorter wavelengths,