PROBABILITY OF A WOMAN WITH ADVANCED BREAST CANCER RESPONDING TO ADRENALECTOMY OR HYPOPHYSECTOMY

685

patient hyperthyroidism. in

one

in series

A, failed

to

affect the

The Amsterdam and Glasgow patients live in an of borderline iodine abundance in contrast to the overabundance in the New York area; moreover, two patients in series B had nodules within the gland. Thus, the intrinsic variability in resistance of the thyroid to radiation effect from iodine-13 12 may have been further altered by a geographic factor such as iodine deficiency. Possibly also, unknown local factors within the gland may have influenced the gland’s response to radiation, separate from, or in addition to, iodine want. Finally, though unlikely, the effect of random sampling in a small series might be responsible for the discrepancies. In line with the series-A experience is the recent report by Levitus 16 of four patients treated in Israel with iodine-125. Doses were only 2-75 mCi. Three of the four became euthyroid within 14 weeks, but later relapsed. 17 Nevertheless, this experience tends to indicate that the sensitivity of the thyroid to radiation effect was similar to that in New York. Levitus et al.11 now recommend doses of 5’5 mCi. In New York we are now using doses about equal to those which would have been given had iodine-131 been administered (i.e., 3 to 4 mCi). It is possible that an acceptable balance will be found between hypothyroidism and recurrence of thyrotoxicosis after short-term remission. However, the problem is complex, and a solution may not be forthcoming. Moreover, it seems likely that later hypothyroidism may develop in a significant number of patients in view of the prolonged period of time over which changes in thyroid function and size have already been shown to occur. The unusually wide spread of values for effective half-life of the iodine-125 in the thyroids of series A and B, and consequent calculated radiation doses to the gland, plus the biological variability in sensitivity to radiation effect, indicate that it is just as difficult to select an iodine-125 dose as it is to choose one for iodine-131. area

This work was supported by grants AM-00008 (C20-22) from the Division of Arthritis and Metabolic Diseases, National Institutes of Health. Iodine-125 was supplied to the New York workers by E. R. Squibb & Sons. Requests for reprints should be addressed to S. C. W., Department of Medicine, College of Physicians & Surgeons at Columbia University, New York, N.Y. 10032, U.S.A. REFERENCES 1. 2.

Werner, S. C., Coelho, B., Quimby, E. H., Day, M. Mc. Bull. N. Y. Acad. Med., 1957, 33, 783. Werner, S. C., Quimby, E. H., Schmidt, C. Radiology, 1948, 51,

564. 3. Werner, S. C. (editor) in The Thyroid. New York (in the press). 4. Beling, U., Einhorn, J. Acta radiol. 1961, 56, 275. 5. Smith, R. M., Wilson, G. M. Br. med. J. 1967, 1, 129. 6. Dunn, J. T., Chapman, E. M. New Bngl. J. Med. 1964, 271, 1037. 7. Nofal, M. M., Beierwaltes, W. H., Patno, M. E. J. Am. med. Ass. 1966, 197, 605. 8. Smith, R. M., Wilson, G. M. Q. Jl Med. 1964, 33, 529. 9. Hagen, G. A., Oullette, R. P., Chapman, E. M. New Engl. J. Med. 1967, 277, 559. 10. Becker, D. V., McConahey, W. M., Dobyns, B., Tompkins, E.,

Sheline, G., Workman, J. Sixth int. Thyroid Conf. 1970, abstracts, 11.

p. 80. Greig, W. R., Smith, J. F. B., Gillespie, F. C., Thomson, J. A., McGirr. E. M. Lancet 1969, 1, 755.

PROBABILITY OF A WOMAN WITH ADVANCED BREAST CANCER RESPONDING TO ADRENALECTOMY OR HYPOPHYSECTOMY GORDON SARFATY Endocrine Research

Unit, Cancer Institute, Melbourne, Victoria, Australia

MICHAEL TALLIS Division

of Mathematical Statistics, C.S.I.R.O., Newtown, New South Wales, Australia

Data on urinary steroids in women with breast cancer have been used to produce probability curves allowing the chance of success with adrenalectomy or hypophysectomy to be computed for individual patients. Graphs have been drawn for probability of success against size of discriminant (11-deoxy-17-ketosteroids + 17-hydroxycorticosteroids) in 164 cases of breast cancer. In older patients this approach could be made more useful by substituting time to ablation for 17-hydroxycorticosteroids. This probability method may provide the clinician with a useful tool in assessing an individual patient’s likely response to endocrine surgery.

Summary

Introduction THE search for variablesto predict the response

of women with advanced breast cancer to adrenalectomy or hypophysectomy has been triggered off by the low remission-rate achieved by ablative surgery. Quantitative indices, such as the latent period and urinary androgenic steroid metabolites, provide valuable descriptions of group behaviour but are not much help in individual cases because of overlap between responding and non-responding groups. Discriminant function analysis2 of response-related urinary steroid metabolites3 achieves greater precision of classification between responding and non-responding groups especially when combined with the latent period.4 Besides the problem of group overlap, classification of a patient simply as a responder (positive discriminant) or non-responder (negative discriminant) only gives the probability of response of the group (i.e., about 30% probability of success for non-responders and 70% for responders), and results in an unnecessary loss of information in respect of an individual’s potential to respond to ablative surgery. The difficulty can be avoided if the size as well as the sign of the discriminant is used. We have done this with preoperative measurements of urinary total ll-deoxy-17-ketosteroids (11-deoxy-17-K.s.), urinary 17-hydroxycorticosteroids (17-OHc.s.), and the time to ablation (latent period, or free interval), to calculate discriminant values.

PROFESSOR WERNER AND OTHERS:

12. 13. 14. 15.

16. 17.

REFERENCES—Continued

Gillespie, F. C., Orr, J. S., Greig, W. R. Br. J. Radiol. 1970, 43, 40. Dillman, L. T. J. nucl. Med. 1969, suppl. no. 2. Ben-Porath, M., Feige, Y., Lubin, E., Levitus, Z. ibid. 1970, 11, 300. Greig, W. R., Gillespie, F. C., Gray, J. H. W., Smith, J. F. B., Thomson, J. A., McGirr, E. M. Sixth int. Thyroid Conf. 1970, abstracts, p. 82. Levitus, Z. Lancet, 1969, ii, 1368. Levitus, Z., Lubin, E., Rechnic. J., Ben-Porath, M., Feige, Y., Laor, J. Sixth int. Thyroid Conf. 1970, abstracts, p. 83.

686 Material and Methods Dr. R. D. Bulbrook and Mr. J. L. Hayward of the Imperial Cancer Research Fund, London, kindly made available data on 164 of their patients with advanced breast cancer who underwent either total bilateral adrenalectomy or Patients having a hypophysectomy. regression after ablation were classified as responders, the remainder as non-

responders.5 Urinary steroid

metabolites were measured by the methods of Bulbrook et a1.33 Urinary total ll-deoxy-17-K.S. (i.e., Eetiocholanolone, androsterone, and dehydroepiandrosterone) were found to be equivalent to using setiocholanolone alone. Of the clinical data the interval from when the patient was first seen, or when they had had a mastectomy, to the time of ablation was used in preference " to the conventional free " interval since it was not available for all patients. We subsequently found that both intervals gave the same probabilities of remission. We used an extension of the Fisher E discriminant analysis which treats responding and non-responding groups as samples of the true population and an improved account of discriminant analysis by considering errors made by this sampling.7 The consideration of errors also allowed a comparison to be made between estimates of the population probabilities (referred to in the text as the estimate) and those obtained if the sample was regarded as the true population (referred to as the

provides

limit). Fig. 1-Probability of remission after bilateral adrenalectomy or hypophysectomy in advanced breast cancer using a discriminant calculated from urinary steroid metabolite values. Effect of population sampling, mate curve (E) of sample and limit

(a)

population. (b) Probability of remission

showing esti(L) for

curve

true

at

different ages of

ablation.

Fig. 2.-Limited potential for improving probabilities for older patients. Fig. 3-Effect of time to ablation (or free interval) on the probability of remission.

Fig. 4-Role of the patient’s menstrual

status at the time of ablation.

687 Individual probabilities of response were generated by a 11 programme written in Fortran for the CDC 3200 computer. The output was plotted to yield the probability of remission as a function of the discriminant. Figs. 1-4 were redrawn from the computer plots. Results and Discussion

Population Sampling and Age at Ablation The effect of population sampling is seen in fig.

la. associated with the discriminant function statistics are neglected the limit curve is obtained. The difference between the limit (L) and estimated (E) curve is not great, revealing the absence of a major For sampling effect on estimated probabilities. example, a discriminant value of 2 read on the estimate curve results in a probability of remission of approximately 55%, whereas the limit that can be obtained from the true population is approximately 65%. Conversely, a discriminant of -2 gives an estimate probability of 15% and a limit probability of 8%. The patient’s age at ablation is an important variable when determining response (fig. lb). Urinary steroids seem to be of greatest value in determining response when measured in women below the age When

errors

of fifty. What potential is there for improvement in the older age-group with the use of these steroid metabolites ? This can be determined by comparing the estimate and the limit probability curves at ages 30 and 60 (fig. 2). With a discriminant of 1, at age thirty gives a limit probability about 16% higher than the estimate, whereas the same discriminant at age sixty can be expected to be improved by only 8%. It seems that in older women this urinary steroid discriminant is neither useful nor potentially useful in detecting probabilities of remission.

Time to Ablation (or Free Interval) When the latent period of the disease is substituted for urinary 17-OHc.s. as a discriminant variable, we get a substantial improvement in the likelihood of remission in older patients (fig. 3), and a slightly diminished probability of response in the age-groups around thirty years. We do not know why slower tumour growth, as indicated by the latent period, has a more important bearing on the outcome of surgery than does the urinary steroid pattern in older women. Menopausal Status Although the cyclic-functioning ovary is a control mechanism of tumour growth in some patients, it does not necessarily imply that the menopausal status of a woman is a determinant of remission to major ablation. Some workers regard the menopausal state as important, others disagreed Fig. 4 shows the estimate and limit curves for three menstrual groupings; premenopause, up to three years after the menopause, and more than four years postmenopausal. The curves for premenopausal and postmenopausal patients are very similar to the age-probability curves in fig. 2, and the age forty to forty-five curve in fig. lb. These findings suggest that the menstrual be

an important determinant of probability only in so far as it reflects the patient’s age. Clinical application of discriminant analysis has not resulted in the hoped-for improvement in the selection

status may

of response

of women for major endocrine surgery.9 The reason for this is the inability of the discriminant to identify clearly individual responders or non-responders. The probability approach to the use of discriminants for determining the likelihood of patient response can provide the clinician with more useful information when assessing the role of surgery in the individual woman. Whether the objective measurement of probability will be of greater value than clinical judgement of the likelihood of response can only be decided by a prospective study. Requests for reprints should be addressed to G. S. REFERENCES 1. 2. 3.

Fairgrieve, J. Surgery Gynec. Obstet. 1965, 120, 371. Kendall, M. G., Stuart, A. Advanced Theory of Statistics; vol. III. New York, 1966. Bulbrook, R. D., Greenwood, F. C., Hayward, J. L. Lancet, 1960, i, 1154.

Wilson, R. E., Crocker, D. N., Fairgrieve, J., Bartholomay, A. F., Emerson, K., Moore, F. D. J. Am. med. Ass. 1967, 199, 474. 5. Sarfaty, G. A. Med. J. Aust. 1969, i, 398. 6. Fisher, R. A. Ann. Eugen. 1936, 7, 179. 7. Tallis, G. M. Metrika (in the press). 8. Tallis, G. M., Shaw, D. E., Williams, J., Sarfaty, G. A. Aust. Comp. J. 1970, 2, 3. 9. Atkins, H. J. B., Bulbrook, R. D., Falconer, M. A., Hayward, J. L., MacLean, K. S., Schurr, P. H. Lancet, 1968, ii, 1255. 4.

LONG-TERM CONTINUOUS INTRACRANIAL-PRESSURE MONITORING BY MEANS OF A MODIFIED SUBDURAL PRESSURE TRANSDUCER ALAN RICHARDSON T. A. H. HIDE I. D. EVERSDEN

Department of Neurosurgery, St. George’s Hospital, at Atkinson Morley’s Hospital, Wimbledon, London S.W.20 Previous methods for monitoring intracranial pressure have proved unsatisfactory in routine clinical use. Modifications to a miniature subdural pressure transducer are described which allow the accuracy of its calibration or baseline zero to be checked while in situ, and a total of 1500 hours’ recording is reported in patients with cerebral tumours or head injuries. In several patients dangerous falls of cerebral perfusion pressure, both spontaneous and during anæsthesia, occurred without clinical warning. By the use of continuous intracranial-pressure monitoring it is possible to forecast which patients are at risk, and so take measures to prevent such highpressure cerebral ischæmic attacks.

Summary

Introduction

ESTIMATES of intracranial pressure (r.c.P.) by clinical examination or lumbar puncture are unreliable, 1-3 and present methods for continuous direct r.c.P. monitoring have several drawbacks. Techniques requiring ventricular catheterisation can be difficult to set up or maintain, and, when an external strain gauge is used, uninterrupted recording is not possible if the