HIGH-DOSE MELPHALAN AND CYCLOPHOSPHAMIDE PRE-TREATMENT

1313 SERUM-F.S.H.-CONCENTRATIONS

have sufficient numbers of patients remaining in both and control arms for a long period to demonstrate whether such important differences will eventually emerge. We feel that the potential long-term risks and the potential curative effect of adjuvant chemotherapy must be properly assessed before control arms are abandoned and all patients are committed to this expensive and unpleasant treatment. must

treatment

Marsden Hospital, London SW3 6JJ

Royal

however, there is fairly good agreement between the age-specific incidence figures of the low and high risk countries.3 Thus if pineal hypofunction affects international differences in breast-cancer incidence, as Cohen et al. suggest, the implication is that this factor is involved primarily in the oetiology of postmenopausal breast cancer-a concept favoured by the fact that pineal calcification, possibly indicating a hyponunction, is mainly seen in the older ages. However, the postmenopausal ovary loses its capacity to respond to F.S.H. by oestrogen secretion"and postmenopausal oestrogen production is accounted for nearly exclusively by peripheral metabolism of the androgenic precursors,5 mainly derived from the adrenals. We found no correlation between the serum concentrations of F.S.H. and oestrone in postmenopausal women.

HIGH-DOSE MELPHALAN AND CYCLOPHOSPHAMIDE PRE-TREATMENT

women,

Departments of Surgery and Clinical Chemistry, University Hospital, S-750 14 Uppsala, Sweden

HANS-OLOV ADAMI

ÅKE RIMSTEN LEIF WIDE

MULTIMODAL THERAPY FOR STAGE-II BREAST CANCER

IAN E. SMITH TREVOR J. POWLES

SIR,-Dr Hedley and colleagues (Nov. 4, p. 966) imply that pre-treatment with cyclophosphamide might permit increased doses of melphalan to be given more safely. However, it is not clear if they are suggesting that this type of treatment can be given repeatedly and, if so, at what intervals, or whether they are recommending a single treatment cycle. We have demonstrated that the application of certain principles of stem-cell kinetics, based on the work of Bruce et al.,l enables intensive chemotherapy to be given safely.2-6 These principles would predict that the type of therapy advocated by Hedley et al., if repeated too often, might result in cumulative toxicity to normal bone-marrow stem cells. It would therefore be valuable to know the results obtained by successive courses of such treatment since Hedley et al. suggest that this approach might be used in the treatment of breast and ovarian cancers, for which safe protocols already exist. Royal Marsden Hospital, London SW3 6JJ

L. A. PRICE

Department of Cellular Chemotherapy, Imperial Cancer Research Fund, London WC1

BRIDGET T. HILL

SiR,—The latest results reported by Dr Edelstyn and his p. 1092) for patients with stage-ll breast

colleagues (Nov. 18,

carcinoma treated with adjuvant chemo therapy remain encouraging, but comparative survival data are not yet available. We cannot, therefore, agree with their conclusions that it is now unethical to continue with a "no chemotherapy" group. The fundamental aim of adjuvant chemotherapy is not merely to delay tumour recurrence, as they have demonstrated, but to prolong survival, and it is by no means inevitable that the one leads to the other, as experience with adjuvant oophorectomy has shown.1 Adjuvant therapy is not without potential long-term risk. Its use may compromise the efficacy of subsequent palliative treatment in relapsed patients and we note that a 30% relapse-rate is already apparent in Edelstyn’s trial. Furthermore, the longterm incidence of serious complications, including the induction of further malignancies, cannot yet be properly assessed and should not be dismissed as "likely to be insignificant". Conversely, if adjuvant chemotherapy does lead to prolonged survival or cure in some patients, this may not become apparent for many years. Delay in tumour recurrence within the first year or two of treatment, reported in this and in other adjuvant therapy trials, may largely represent short-term regression of clinically undetected but nevertheless advanced metastases. Patients with potentially curable true micrometastases might often be expected to remain in remission during this initial period even if untreated; cure of such patients could therefore only be demonstrated 5-10 years after treatment. It is therefore essential that clinical trials of adjuvant therapy 3. Thomas, D. B., Lilienfeld, A. M. in Risk Factors in Breast Cancer (edited by B. A. Stoll). London, 1976. 4. Barlow, J. J., Emerson, Jr., K., Saxena, B. N. New Engl. J. Med. 1969, 280, 12. 5. Grodin, J. M., Siiteri, P. K., MacDonald, P. C.J. clin. Endocr. Metab. 1973,

Kennedy,

SIR,-Repeated doses of melphalan would cause cumulative toxicity to bone-marrow stem cells, and no melanoma patient treated with cyclophosphamide and high-dose melphalan received more than one course of treatment. Two courses of high-dose melphalan have been given successfully to another series of patients with neuroblastoma and melanoma in whom bone-marrow autografting has been used to enhance haemopoietic recovery, and this will be the subject of a separate report. However, in our Lancet paper, we do not "imply" that cyclophosphamide priming makes the administration of melphalan safer-we show it to be so, just as Bruce has shown that the toxicity of chemotherapy may, in part, be schedule dependent. With reference to breast and ovarian cancers, it seems to us that the problem of chemotherapy is not only that of schedule design but also that of efficacy against the tumours. There is no evidence that any kind of chemotherapy alone permanently eradicates widespread detectable metastatic disease-in breast cancer the median survival for this group of patients is about 8 months-and it therefore seems reasonable to us that the use of very high doses of single agents should be examined eventually, not in isolation but as part of a multimodality approach to the management of these tumours in carefully selected patients. The work we have done with melphalan in melanoma is a first step in this direction. 1. 2.

3. 4.

36, 2. 1.

to Dr McElwain and his colfollows.-ED.L. whose reply leagues,

*** This letter has been shown

B.

118, 524.

J., Mielke, P. W., Fortuny, I. E. Surg. Gynec. Obstet. 1964,

5. 6.

Bruce, W. R., Meeker, B. E., Valeriote, F. A.J.

natn. Cancer Inst. 233. Price, L. A., Goldie, J. H. Br. med. J. 1971, iv, 336. Price, L. A., Hill, B. T., and others. ibid. 1975, iii, 10. Price, L. A., Hill, B. T. Lancet, 1976, ii, 1195. Goldie, J. H., Price, L.A. Br. med. J., 1977, ii, 1064. Price, L. A., Hill, B. T., and others. Oncology, 1978, 35, 26.

1966, 37,

1314 We

are not suggesting that we have an all-embracing philosfor the design of cancer chemotherapy. All that we have shown is that an interesting effect, first observed in animals, occurs also in man and is worth further study.

ophy

T. J. MCELWAIN D. W. HEDLEY J. L. MILLAR

Institute of Cancer Research, Royal Marsden Hospital, Sutton, Surrey SM2 5PT

(unpublished). Finally, bromocriptine may inhibit cord-blood prolactin levels.7 Respiratory distress syndrome (R.D.S.) is asociated with subnormal cord-prolactin concentrations 8 Since it is uncertain whether the bromocriptine-induced suppression of cord blood prolactin may result in R.D.s. caution should be exercised when the drug is used close to delivery. Department of Obstetrics and Gynæcology, University of British Columbia Faculty of Medicine, Vancouver General Hospital, BASIL HO YUEN

Vancouver, V5Z IM9 Canada

BROMOCRIPTINE, PITUITARY TUMOURS, AND NEPHROTOXICITY OF

PREGNANCY

SIR,-Dr Corenblum (Oct. 7, p. 786), describing the

tumour-suppressive properties of bromocriptine, refers to a 2 report by Bergh et al.’ These workers and Hancock et al. favour a conservative approach to the management of infertile and pregnant patients with prolactin-secreting pituitary tumours.

I have treated two women for anovulatory infertility and prolactin-secreting pituitary microadenomas with bromocriptine, maintaining treatment to the third trimester of pregnancy. In case 1 (age 30) the baseline prolactin concentrations ranged between 108 and 160 ng/ml (normal 5-25). She had a subnormal prolactin response to thyrotrophin-releasing hormone (T.R.H.) 200fLg intravenously. Bromocriptine was continued to 35 weeks of gestation in doses varying between 2.55 and 7.5 mg daily. Labour was induced in the 41st week with delivery of a healthy male, 3880 g. In case 2 (age 32) the baseline prolactin was 99 ng/ml. She had subnormal responses to T.R.H. 200fLg i.v. and chlorpromazine 25 mg intramuscularly. Bromocriptine was continued to 33 weeks of pregnancy in doses varying between 2.5 and 5 mg daily. Labour occurred spontaneously with delivery of a healthy female infant, 3090 g, in the 41st week of pregnancy. Initial pituitary polytomography revealed changes consistent with a microadenoma with normal visual-field studies (Goldman technique). Repeat radiological and visual-field examinations 20 months (case 1) and 15 months (case 2) later remained unchanged except in case 2 where there were minimal bitemporal visual-field defects in the latter half of pregnancy. This may have been due to expansion of the pituitary gland or possibly other "functional" effects associated with pregnancy.3 After delivery, we adopted the approach suggested by Corenblum. However, withdrawal of the drug was associated with resumption of galactorrhrea, amenorrhoea, and rising prolactin concentrations. Therefore, we have continued treatment with bromocriptine 7.5 5 mg daily in case 1 and 5 mg daily in case 2. Experience with bromocriptine during pregnancy is increasing. In 360 children born to mothers exposed to the drug after conception (mean 27.4 days), no increased risk of malformations was observed.4 Reports of prolonged use in pregnancy4-7 suggest that it is possible to maintain pregnancy while on bromocriptine therapy. The patient reported by Espersen and Ditzel6 experienced premature rupture of the membranes at 333 weeks. However, in this woman with acromegaly, a dose of 35 mg daily was used during her pregnancy. Although experience is limited, bromocriptine seems to be a promising non-surgical approach to the management of these tumours. However, further study of its effects at various doses on the course of pregnancy and the fetoplacental unit is required to define better its role in the management of prolactin-secreting pituitary tumours complicating pregnancy. Marked suppression of maternal plasma-prolactin to non-pregnant concentrations is possible on low doses of 2.5 mg daily 1. 2. 3.

Hancock, K. W., Scott, J. S., Gibson, R. M., Lamb, J. T. ibid. 1978, i, 1487. Walsh, F. B., Hoyt, W. H. Clinical Neuro-Ophthalmology; p. 2124. Balti-

4. 5.

Griffith, R. W., Turkalj, I., Braun, P. Br. J. clin. Modena, G., Portioli, I. Lancet, 1977, ii, 558.

Bergh, T., Nillius, S. J., Wide, L. Br. med. J. 1978, i, 875. more 1969. Pharmac.

1978, 5, 227.

METHICILLIN/AMINOGLYCOSIDE SIR,-In a prospective randomised study Dr Wade and colleagues (Sept. 16, p. 604) found that methicillin plus an aminoglycoside was less nephrotoxic than cephalothin plus an aminoglycoside. This contradicts our finding’-namely, that the combination methicillin and gentamicin was strongly nephrotoxic. In five patients out of six receiving the combination for more than ten days, acute renal failure developed after 10-20 days (mean 14). In Wade’s study the drugs were given for 7 days; this shorter period of therapy may have prevented drug toxicity from appearing. The increased nephrotoxicity of the combination methicillin/gentamicin is probably due to the potentiation of the allergic mechanism of methicillin nephrotoxicity by the toxic mechanism of gentamicin; 10 days are necessary for this allergic mechanism

to occur.

Wade

et

al. have shown that methicillin/

aminoglycoside combinations are weakly nephrotoxic but only when therapy lasts less than 10 days. I contend that this combination should not be used when therapy has to be long, and particularly for staphylococcal infections. Centre

d’Hémodialyse, Hôpital de Girac, 16470 Saint-Michel, France

L. YVER

CIMETIDINE AND PSORIASIS

SIR,-After reading the letter by Dr Giacosa and colleagues p. 1211) the first patient I saw was a long-standing of severe psoriasis in a woman who had been on cimetidine for a year for duodenal ulcer. Not only had her psoriasis not improved but during that time treatment had been established with methotrexate on a weekly dosage schedule and continued for many months with only moderately good control of her disease. I have several other psoriatic patients who are taking cimetidine for duodenal ulcers whose skin condition remains as difficult to control as before. There must be other dermatologists with similar experience. I feel such comment is pertinent before colleagues embark on trials of this drug in psoriasis or before the popular press herald it as a new cure for

(Dec. 2,

case

psoriasis. Department of Dermatology, Ninewells Hospital, Dundee DD2 1UB

E.

J. RAFFLE

S!R,—Two patients, with long-standing and extensive psoriasis, have recently been in hospital under our care for treatment of relapses of their psoriasis, after treatment with cimetidine in doses of 1 g/day for control of peptic ulceration. This

6. Espersen, T., Ditzel, J. ibid, 1977, ii, 985. 7. del Pozo, E., Hiba, J., Lancranjan, I., Kunzig, H. J. in Prolactin and Reproduction (edited by P. G. Crosignani and C. Robyn); p. 61. London, 1977. 8. Hauth, J. C., Parker, C. R., MacDonald, P. C., Porter, J. C., Johnston J. M. Obstet. Gynecol. 1978, 51, 81. 1. Yver, L., Becq-Giraudon, B., Pourrat, D., Sudre, Y. Sem. Hôp. Paris, 1976,

52,1903.