646 above detection limits, the ratio of adipose to concentrations was 363/1, indicating the high lipid partitioning of the chemical. This ratio fell to 100/1 when only lactating women were studied (fig. 5) showing that fat mobilisation in lactating women seems to alter P.B.B. partitioning. This mobilisation of P.B.B. out of adipose and into milk fat may help explain the nearly equal partitioning of P.B.B. between milk fat and adipose-tissue fat in our small sample of paired speci-

were

serum P.B.B.

AMINOGLUTETHIMIDE IN TREATMENT OF METASTATIC BREAST CARCINOMA I. E. SMITH

J. Royal

Marsden

Hospital, Sutton, Surrey

D. R. FAHMY Tenovus Institute for Cancer Research,

mens.

industrial society we can expect further episodes of environmental contamination with little-studied fat-soluble chemicals. If there is a stable relationship between the concentrations of chemical in various tissues, our experience suggests that breast milk can usefully indicate the extent of population exposure. In

B. M. FITZHARRIS A. MCKINNA

Cardiff

our

A. G. NASH St. Helier Hospital, Carshalton,

A. M. NEVILLE

Ludwig Institute for Cancer Research, Sutton, Surrey

We thank the nursing mothers who provided breast-milk specimens and the county health departments which assisted in collection of specimens ; Dr Philip J. Landrigan of the Bureau of Epidemiology, Center forÐisease Control, and Dr T. S. Jones, Dr Larry Roi, Dr R. Remington, and Ms Susan Maerki, at the University of Michigan, for assistance and critical comments; and the Ford Foundation State Environmental Management Program for financial support. Requests for reprints should be addressed to L.B.B. REFERENCES

Report of the Subcommittee on the Health Effect of Polychlorinated Biphenyls and Polybrominated Biphenyls, Department of Health, Education and Welfare, Washington, D. C., 1976. 2. Jackson, R. F., Halbert, F. L.J. Am. vet. Med. Ass. 1973, 165, 487. 3. Dunckel, A. E. ibid. 1975, 167, 838. 4. Lancet, 1977, il, 19. 5. Isleib, D. R., Whitehead, G. L. in Trace Substances on Environmental Health-IX (edited by D. D. Hemphill); p. 47. Columbia, 1975. 6. Humphrey, H. E. B., et al. ibid. p. 57. 7. U.S. Department of Health, Education and Welfare, Food and Drug Administration: Pesticide Analytic Manual, 1968; vol. I. Washington, D.C., 1968. 8. Gabica, J., et al. J. anal. appl. Chem. 1974, 57, 173. 9. Yobs, A.R. Pestic. Monit. J. 1971, 5, 44. 10. Yobs, A. R. Envir. Hlth Persp. 1972,1, 79. 11. Kutz, F. W., Yobs, A. R., Johnson, W. F., Wiersma, G. B. Paper presented at sixty-third annual meeting of the International Academy of Pathology, San Francisco, March, 1974. 12. Biros, F. J., Enos, H. R. Bull. envir. Contam. Toxicol. 1973, 10, 257. 13. Wasserman, M., Tomatis, L., Wasserman, D., Day, N. E., Djavaherian, M. ibid. 1974, 12, 501. 14. Holdrinet, M. W. H., Braun, H. E., Frank, R., Stopps, G. J., Smout, M. S., McWade, J. W. Can. J. publ. Hlth, 1977, 68, 74. 15. Egan, H., Goulding, R., Roburn, J., Tatton, J. Br. med. J. 1965, ii, 66. 16. Ramachandran, M., Sharma, M. I. D., Sharma, S. C., Mathur, P. S., Aravindakshan, A., Edward, G. J. Bull. Wld Hlth Org. 1973, 49, 637. 17. Warnick, S. L. Pestic. Monit. J. 1972, 6, 9. 18. Wyllie, J., Gabica, J., Benson, W. ibid. p. 84. 19. Edmundson, W. F., Davies, J. E., Hall, W. ibid. 1968, 2, 86. 20. Fiserova-Bergerova, V., Radomski, J. L., Davies, J. E., Davis, J. H. Ind. Med. Surg. 1967, 36, 65. 21. Polishuk, Z. W., Ron, M., Wasserman, M., Cucos, S., Wasserman, D., Lemesch, C. Pestic. Monit. J. 1977, 10, 121. 22. Dyment, P. G., Hebertson, L. M., Decker, W. J., Gomes, E. D., Wiseman, J. S. Bull. envir. Contam. Toxicol. 1971, 6, 449. 23. Watson, M., Benson, W. W., Gabica, J. Pestic. Monit. J. 1970, 4, 47. 24. Dale, W. E., Curley, A., Cueto, C. Life Sci. 1966, 5, 47. 25. Dale, W. E., Curley, A., Hayes, W. J. Ind. Med. Surg. 1967, 36, 275. 26. Doguchi, M., Fukano, S. Bull. envir. Contam. Toxicol. 1975, 13, 57. 27. Hesselberg, R. J., Scherr, D. D. ibid. 1974, 11, 202. 28. McLeod, H. A., Grant, D. L., Phillips, W. E. J. Can. J. publ. Hlth, 1971, 62, 341. 29. Polishuk, Z. W., Wasserman, M., Wasserman, D., Groner, Y., Lazarovici, S., Tomatis, L. Archs envir. Hlth, 1970, 20, 215. 30. Shafik, T. M., Bradway, E. D., Enos, H. R., Yobs, A. R. J. Agric. Fd Chem. 1973, 21, 625. 31. Roan, C. D., Morgan, D. P., Paschal, E. H. Archs envir. Hlth. 1971, 22, 1. Final

309. 32. Davies, J. E., Davis, J. H., Frazier, D. E., Mann, J. B., Welke, J. O. Adv. Chem. Ser. 1966, 60, 67. 33. Gutemann, W. H., Silvin, J. J., Lisk, D. J. Bull. envir. Contam. Toxicol.

1973, 9, 318. Eyl, T. B., Wilcox, K. R., Reizen, M. S. Mich. Med. 1970, 69, 873. Wilcox, K. Paper presented at toxicology forum on Special Problems With Carcinogenicity Protocols, Washington D.C., Feb. 19-22, 1978. 36. Landrigan, P. J., Wilcox, K. R., Silva, J., Humphrey, H. E. B., Kaufman, C., Heath, C. W. Paper presented at New York Academy of Sciences, June 34. 35.

24,1978.

Surrey

J.-C. GAZET

H. T. FORD

T.

J. POWLES

Combined Breast Clinic, St.

George’s Hospital, London SW17, and Royal Marsden Hospital, Sutton

with metastatic breast carcinoma were treated with aminoglutethimide, which inhibits adrenal steroid hormone synthesis. Treatment was stopped in 2 patients before response could be assessed; of the other 40, 15 (37·5%) had an objective response, 1 (2·5%) showed a response in bone but not in soft tissue, and 4 (10%) had complete or very great relief of metastatic bone pain but no radiological evidence of improvement. 19 (53%) of 36 patients with bone metastases responded to treatment (15 had X-ray evidence and 4 had pain relief), as did 5 (45%) of 11 patients with soft tissue metastases, 2 (25%) of 8 with malignant marrow infiltration, 1 (14%) of 7 with lung metastases, and none of 13 with liver metastases. Response was commonest in patients who had previously responded to other forms of endocrine therapy. Sideeffects, usually mild and transient, occurred in a few patients; the most important were an initial period of somnolence in 9 patients and a rash in 5.

Summary

42

patients

Introduction SURGICAL adrenalectomy, first described as a treatfor metastatic breast carcinoma in 1952,1 has proved to be effective; the overall response-rate is around 30-40%,2-7 responses being most likely in patients who have previously responded to oophorec-

ment

tomy.5-7 However, the operation has a significant morbidity8 and a mortality of 4%-15%.36 Another disadvantage is that often the medical condition of patients in whom the operation might be contemplated is poor; and permanent postoperative hormone replacement is required. For these reasons, effective medical inhibition of steroid hormone production would be attractive. Aminoglutethimide, developed as an anticonvulsant in the 1950s, was withdrawn from clinical use after reports that it caused adrenal insufficiency.9 The drug was subsequently shown to suppress synthesis of all adrenal steroid hormones by inhibiting the first step in their metabolic pathway, the enzymic conversion of cholesterol to pregnenolone (fig. 1).’° It was suggested that aminoglutethimide might be used to achieve a "medical

647

discontinued in the other 2 because of toxicity before response could be assessed. 15 (37.5%) of the 40 patients have so far achieved an objective response. 4 others have had complete or very great relief of bone pain as assessed by an independent observer; the relief of pain was associated with arrest of progressive lysis of bone lesions on X-ray, but the lesions have not yet shown radiological evidence of re-sclerosis. 1 patient has had a response in bone, but soft tissue disease has progressed. In all, 20 (50%) of the 40 patients have benefited significantly from aminoglutethimide. treatment was

Response by Site Response by site is shown in the accompanying table. Aminoglutethimide was most effective in the treatment Fig. I-Site of inhibition of andrenal-steroid synthesis by aminoglutethimide. with metastatic breast responses have been reported.12 13 We report here the preliminary findings of a clinical study started 18 months ago to assess the role of aminoglutethimide as an alternative to adrenalectomy in the management of patients with metastatic breast

adrenalectomy"

cancer"

and

in patients encouraging

carcinoma. Patients and Methods 42

evidence of metasincluded in histologically the study. All were post-menopausal or had previously undergone oophorectomy. 28 of the 42 patients had previously received endocrine therapy to which 19 of these had retases

patients with clinical

from

or

radiological

proven breast

cancer were

sponded. A full clinical assessment,

a

peripheral-blood

count,

serum-

chest X-ray, radiological skeletal survey, isotope bone and liver scan, liver ultrasound, and bone-marrow aspirat were carried out before treatment and repeated every 2 months. (These investigations were modified because of age in 3 patients to include only sites of known or suspected metastatic involvement.) Pain was assessed by an independent observer in all patients before the start of treatment and 2-4 weeks later. Aminoglutethimide was given orally, 250 mg four times a day, with cortisone acetate in an oral dose of 25 mg 2-3 times daily, and continued for at least 4 weeks before treatment was assessed. In patients showing a response, treatment was continued until relapse occurred. Overall response to therapy was defined according to the U.I.C.C. criteria for advanced breast cancer.14 Response was also assessed for each affected site, as previously described. 15

biochemistry,

Serum dehydroepiandrosterone-sulphate measured by radioimmunoassay.

(D.H.A.-S.)

was

Results

Responses 40 patients could be assessed for

response

to

RESPONSE TO AMINOGLUTETHIMIDE I

I

I

therapy;

2-Recurrent breast carcinoma (A) before and months after start of treatment by aminoglutethimide.

Fig.

(B) 3

of bone metastases. An example of soft-tissue response is shown in fig. 2. Bone pain associated with metastatic disease was relieved in 19 out of 36 patients, often within 72 h and in 2 patients within 24 h of the start of treatment. 3 patients previously confined to bed or wheelchair because of the severity of their symptoms became ambulant within 2 weeks of the start of treatment.

Duration

of Response Only 3 patients have so far relapsed, 2 after responses lasting 6 months and the third after an 11-month response. The other 17 patients showing a response have continued with the treatment for 3-17 months.

*All had relief of bone pain and 15showed sclerosis on X-ray.

Significance of Previous Endocrine Therapy Response to aminoglutethimide was closely

related

to

648

of 19 paother form of endocrine therapy also showed a radiological response to aminoglutethimide, and 4 others had relief of bone pain (overall 68% response). Of 9 patients who had not responded to previous endocrine therapy only 2 (22%) responded to aminoglutethimide. 3 (25%) of 12 patients who had received no previous endocrine therapy responded to the drug; 7 of the 9 in this group who failed to respond had metastases in the liver. response to previous endocrine tients who had previously

therapy. 9

responded

out

to some

Side-effects Side-effects occurred only in a few patients and were usually mild and transient. 5 patients had an itchy, erythematous, maculopapular rash over the trunk and limbs 8-10 days after the start of treatment. The rash settled spontaneously in 1 patient after 3 days without withdrawal of treatment, and settled in the other 4 within a few days of discontinuation of the drug. In 2 of the latter, aminoglutethimide was given again, with 40 mg of prednisolone per day for the first 4 days of treatment; the rash recurred transiently and then treatment continued uneventfully. 9 patients had a characteristic syndrome of somnolence, dizziness, visual blurring, and a sensation of "walking on air" 24 h after the start of treatment; in all 9 patients this syndrome settled within a few days, either spontaneously or by a reduction in the daily dose to 750 mg. The observation that 6 of the 9 were aged between 60 and 82 years suggests that the side-effect was age-related. 3 patients had clinical features resembling adrenal insufficiency 3, 4, and 12 weeks, respectively, after the start of therapy; each presented with malaise, prostration, hypotension, nausea and vomiting; all responded rapidly to parenteral hydrocortisone and subsequently continued uneventfully on aminoglutethimide with the addition of fludrocortisone 0.1 mg on alternate days. 1 patient had clinical and biochemical features of inappropriate A.D.H. secretion 6 days after the start of treatment; these features settled spontaneously when treatment was stopped. 2 patients had transient nausea initially, and none of the remaining 23 had any side-effects.

Serum D.H.A.-S. Serum-D.H.A.-S. levels fell to very low levels 2-4 weeks after the start of treatment in all 16 patients studied (fig. 3). No correlation was seen between response and fall in D.H.A.-S.

Discussion These results show that oral aminoglutethimide is at least as effective as surgical adrenalectomy in producing responses in patients with metastatic breast cancer. The suppression of serum-D.H.A.-S. during treatment confirms the experience of others 13 and suggests that the drug acts by the inhibition of steroid synthesis in the adrenals and perhaps elsewhere. Patients with bony metastases had the highest response-rate and a striking feature of aminoglutethimide therapy was its rapid and at times dramatic relief of bone-pain. This finding confirms previous experience with adrenalectomy2 6 16 and is of special importance because of the relative ineffectiveness of additive hormone therapy 17 18 and chemotherapy 15 19 against bone metastases.

A

previous response to oophorectomy is a good prognostic factor for surgical adrenalectomy,5-’ and some2 but not a1l6 authors claim that a previous response to oestrogens or androgens is of similar significance. In this study a much higher response rate to aminoglutethimide was seen in patients previously responding to some other form of endocrine therapy than in patients failing to respond to such treatment. Only 25% of patients in whom aminoglutethimide was used as first-line therapy responded, but most of those who failed to respond had liver metastases, and the total number of patients was too few for any conclusions to be drawn regarding the role of this drug as primary en-

docrine therapy. Previous attempts to inhibit adrenal steroid function by medical means, for example, by high doses of glucocorticoid2O or ortho-para-D.D.D./1 have been largely unsuccessful because of the low response-rates and severity of side-effects. The low incidence and moderate nature of side-effects with aminoglutethimide in the dosage used here were therefore encouraging. The somnolence and light-headedness experienced initially by some patients, especially the elderly ones, did not contraindicate further therapy: symptoms either settled spontaneously after a few days or disappeared when the dose was reduced to 750 mg/day, without apparent loss of therapeutic effect. 2 patients had to stop treatment because of a rash but this settled spontaneously in a third and with short-term high-dose steroid cover in 2 others. Similar successful medical management has been reported by others,12 and it would appear that the rash, though not uncommon, need not contraindicate continued amino-

glutethimide therapy. Cortisone acetate is given with aminoglutethimide as steroid replacement, analogous to maintenance therapy after surgical adrenalectomy, and it is very unlikely that it contributes in a significant way to the response to aminoglutethimide. Corticosteroids alone achieve response-rates of less than 15% in the treatment of breast cancer, 20 even when given in dosages much greater than those used here. Nevertheless, because aldosterone secretion falls in patients on aminoglutethimide,22 it is posa

Weeks

Fig. 3-Serum-D.H.A.-S. after start of treatment.

in 16

patients

before and 2-4 weeks

649

sible that the addition of a small replacement dose of the mineralocorticoid fludrocortisone might enable a reduction in the maintenance dose of cortisone acetate; this is now

being investigated.

We thank Prof. K. Griffiths and Dr G. G. Groom, Supraregional Assay Service, Tenovus Institute for Cancer Research, Cardiff, for

carrying out the D.H.A.-S.

the

plasma-25(OH)D into the normal range may be obtained with doses less than those required to produce erythema. The provision of such background irradiation may be a suitable method of preventing vitamin-D deficiency in elderly subjects who receive very little exposure to

sunlight.

assays, Mrs M. Woollard and Sister R. Grabow for technical and nursing assistance, and Dr D. Burley of CIBA Laboratories for the aminoglutethimide.

Introduction

’

Requests for reprints should be addressed to I.E.S., Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 SPT.

REFERENCES 1. 2.

C. B.,

Bergenstal, D. M. Cancer Res. 1952, 12, 134. Hellstrom, J., Franksson, C. in Endocrine Aspects of Breast Cancer (edited

Huggins,

by A. R. Currie and C. F. W. Illingsworth); p. 5. Edinburgh, 1958. Joint Committee on Endocrine Ablative Procedures in Disseminated Mammary Carcinoma. J. Am. med. Ass. 1961, 175, 137, 787. 4. Daicoff, G. R., Harmon, R., Van Prohaska, J. Archs Surg. 1962, 85, 800. 5. McDonald, I. Surg. Gynec. Obstet. 1962, 115, 215. 6. Fracchia, A. A., Randall, H. T., Farrow, J. H. ibid. 1967, 125, 747. 7. Silverstein, M. J., Byron, R. L., Yonemoto, R. H., Riihimaki, D. U., Schuster, G. Surgery, 1975, 77, 825. 8. Nash, A. G., Robbins, G. F. Surg. Gynec. Obstet. 1973, 137, 670. 9. Hughes, S. W. M., Burley, D. M. Postgrad. med. J. 1970, 46, 409. 10. Cash, R., Brough, A. J., Cohen, M. N. P., Satoh, P. S. J. clin. Endocr. Metab. 1967, 27, 1239. 11. Hall, T., Barlow, J., Griffiths, C., Saba, Z. Clin. Res. 1969, 17, 402. 12. Newsome, H. H., Brown, P. W., Terz, J. J., Lawrence, W. Cancer, 1977, 39, 3.

542. 13.

Santen, R. J., Samojlik, E., Lipton, A., Harvey, H., Ruby, E. B., Wells, S. A., Kendall, J. ibid. 2948. 14. Hayward, J. L., Rubens, R. D. Br. J. Cancer, 1977, 35, 292. 15. Russell, J. A., Baker, J. W., Dady, P. J., Ford, H. T., Gazet, J-C., McKinna, J. C., Nash, A. G., Powles, T. J. Br. med. J. 1977, 2, 1390. 16. Stoll, B. A. (editor) Endocrine Therapy in Malignant Disease; p. 199. London and Philadelphia, 1972. 17. A.M.A. Committee on Resarch. J. Am. med. Ass. 1960, 172, 1271. 18. Stoll, B. A. (editor) Hormonal Management in Breast Cancer; p.

38. Lon-

don, 1969. 19. Canellos, G., deVita, V. T., Gold, G. L., Chabner, B. A., Schem, P. S., Young, R. C. Br. med. J., 1974, i, 218. 20. Stoll, B. A. (editor) Endocrine Therapy in Malignant Disease. London and

Philadelphia, 1972. 21. Weisenfield, S., Goldner, M. G. Cancer Chem. Abstr. 1962, 16, 335. 22. Fishman, L. M., Liddle, G. W., Island, D. P., Fleischer, N., Kuchel, O. J. clin. Endocr. Metab. 1967, 27, 481.

RESPONSE OF PLASMA-25-HYDROXYVITAMIN D TO ULTRAVIOLET IRRADIATION IN LONG-STAY GERIATRIC PATIENTS D. CORLESS*

S. P. GUPTA

Department of Geriatric Medicine, Eastern Hospital, London E9

S. SWITALA

J. M. BARRAGRY

B. J. BOUCHER

R. D. COHEN

Unit of Metabolism and Endocrinology, The London Hospital Medical College, London E1 B. L. DIFFEY

Department of Medical Physics, Kent and Canterbury Hospital, Canterbury The response of plasma-25-hydroxyvitamin D (25[OH]D) to different exposures to ultraviolet irradiation has been studied in patients in long-stay geriatric wards. Increases sufficient to bring

Summary

*Present address: Department of Geriatric Medicine, Guy’s Health District.

THE incidence of osteomalacia in the elderly is high, 12and plasma-levels of 25-hydroxylated vitamin D derivatives (25[OH]D) are very low in many patients in long-stay geriatric wards.34 Such levels are due to a combination of negligible exposure to sunlight,7 poor dietary intake of vitamin D, poor absorption of vitamin Dand perhaps to defects in 25-hydroxylation of the vitamin.s6 We have examined the efficacy of artificial ultraviolet radiation (u.v.R.) in restoring plasma-25(OH)D to normal in patients in long-stay geriatric wards. Methods Two separate studies were carried out in female patients from two long-stay geriatric wards. No patient was receiving vitamin-D supplements or affected by any factor, other than age, known to disturb vitamin-D status; none was receiving drugs known to alter vitamin-D metabolism. All patients were informed of the nature of the studies and agreed to participate. Exposure to direct sunlight was virtually non-existent. The first study was carried out in March and April, 1977, and the second in December, 1977, and January, 1978. In the first study 18 patients (mean age 84.1 years, range 74-91 years) were divided into 3 groups of 5, 7, and 6 subjects. The first acted as a control group (A1) and received no U.V.R.; the other groups, B and C, received a higher or lower dose of U.v.R., respectively, as detailed below. When it was found that there was no difference in response between groups B and C, the second study was carried out in 14 patients (mean age 80-4 years, range 70-89 years) with a new control group (A2) consisting of 6 patients, and two u.v.R. treatment groups, D and E, consisting of 4 and 5 patients, respectively. The doses given to groups D and E were lower than those given to groups B and C. In no patient was the dose sufficient to produce erythema; however, conjunctivitis developed in 1 patient in the highest dose group (B) who had an ectropion; she was withdrawn from the trial. Apart from the differences in dosage, both studies were identical. A baseline sample of plasma was obtained before irradiation and further samples were taken, usually weekly, during the 8 weeks of exposure to u.v.R. for measurement of plas-

ma-25(OH)D. U.V.R. was given by a bank of 8 Westinghouse FS20 sun lamp fluorescent tubes suspended from the ceilings of the ward dayrooms at a height of approximately 3 metres. The patients were irradiated for 3 h each day. Different numbers of lamps were used for each group. 8, 4, and 2 lamps were used for groups B, C, and D, respectively; 2 lamps were also used for group E, but the radiation was reflected off the ceiling instead of being given direct. The patients were dressed so that the head and neck, forearms and hands, and legs below the knees were exposed (about 4000 cm2 of skin were exposed). Each patient wore on her lapel a polysulphone ultraviolet dosimeter

badge.7 The badges were changed weekly in groups B and C and monthly in groups D and E. The u.v. dose was expressed in mJ/cm2/week, and refers to incidence of u.v.R. perpendicular to the plane of the badge, which is relatively insensitive to variation of angle of incidence. Because of the incident angle of U.v.R. on the exposed skin varies more on the exposed areas than it does on the badge, the dose received by the patients is