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HOW DOES DANAZOL WORK?
1401
Letters
to
the Editor
POSTOPERATIVE RADIOTHERAPY AND BREAST CANCER
StR,—Two curiously contrasting papers have been published in the past few weeks from the Cancer Research Campaign Breast Study. 12The first paper,’ on all 2268 evaluable patients, shows very well that X-ray therapy as given has no effect on survival, deleterious or beneficial, in clinical stages I and ii breast cancer, but does have a very clear value in both stages in reduction of local recurrence, and thus on quality of life; when local recurrence did occur only "about half have been successfully treated". The second papersextracts 350 cases those in which histology of lymph-nodes was available. Diagrams are then presented showing that survival-rates are better after X-ray therapy in "lymph-node negative cases" (but "not significantly different") and worse in "lymph-node positive cases" ("significant at p<0.05 at 2 years"). There is consistently higher freedom from local recurrence in both groups--"significant at in the lymph-node positive group". It is then sugp<0-001 gested that X-ray therapy is of no value in node-negative cases and causes a 10% increase in mortality in "the early stages" of breast cancer. Haybittle3has already criticised the statistical analysis—p<0-05 at one survival period is not a magic figure below which everything is accepted and above nothing. Is it correct to pick out retrospectively a small subgroup of a trial which has not been separately stratified from the beginning? Surely if one can do this and produce a group in which one treatment is better, there must also be another group in which the same treatment is worse, if overall there is no difference; inspection of the published figures suggests that this might well be the case with these small groups of node-negative and node-
positive cases. The hypothesis that postoperative radiotherapy for early breast cancer impairs immunological defence mechanisms and consequently causes increased mortality is not proven. Total lymphocyte-counts are reduced, but this is mainly in B and not T cells, which may even be increased, with serum antibody levels against herpes and other infections remaining unim-
paired.45Further evidence is reviewed by Alexander.6 The clinical evidence has been summarised by Stjerns8
who added up the results from several selected papers, of which showed any statistically significant differences, The Manchester to make them purportedly trials’o come first. They have been widely misunderstood. The comparison made was between policies of immediate postoperative X-ray therapy and of close follow-up with X-ray therapy being given as soon as there was any clinical suspicion of recurrence. A slightly higher mortality in the immediately treated group was reported to be of no statistical significance; no further evidence of any statistically significant difference has appeared. Bond" is often cited. He reported results from the Birmingham region showing that certain uncontrolled groups of patients had a higher mortality after X-ray therapy and surgery, but these were reports of selected groups of patients, with bad prognostic factors possibly playing a part in
ward7 none
significant.9
1. Working Party of the Cancer Research Campaign Br. med. J. 1976, ii, 1035. 2. McDonald, A. M., Simpson, J. S., Maclntyre, J. Lancet, 1976, i, 1088. 3. Haybittle, J. L. ibid. p. 1242. 4. McCredie, J. A., Inch, W. R., Sutherland, R. M. Cancer, 1972, 29, 349. 5. Blomgren, H., Berg, R. Wasserman, J., Glas, U. Int, J. Rad. Oncol. biol. Phys. 1976, 1,177. 6. Alexander, P. ibid. p. 369. 7. Stjernswärd, J. Muenz, L. R., von Essen, C. F. Lancet, 1976, i, 749. 8. Stjernswärd, J. ibid. 1974, ii, 1285. 9. Levitt, S. H., McHugh, R. B. ibid. 1975, ii, 1258. 10 Paterson, R., Russell, M. H. J. Fac. Radiol. 1959, 10, 175. 11. Bond W. H. in Treatment of Carcinoma of the Breast (edited by A. J. Jarrett); p. 24. Amsterdam, 1967. 12. Bruce, J. Cancer, 1971, 28, 1443.
the selection of radiotherapy. Edinburgh trials’2 are often also mentioned. There have now been several reports, none giving any statistically significant adverse effects of X-ray therapy. Both Manchester and Edinburgh cases have now been followed up for many more years, and it would be well worthwhile reassessing these trials, using also newer methods of analysis such as the log-rank test. Danish and United States data might be similarly treated, and menopausal and lymphnode status analysed. A final point is that the critics of X-ray therapy in breast cancer usually seem to ignore technique and dose, although it is at least worth considering the possibility that higher dosage from telecobalt or megavoltage therapy may improve results. A randomised controlled clinical trial by P. H0st of Oslo, reported at the Edinburgh European Radiology Conference last summer, has indeed recorded statistically significant improvement in survival from telecobalt postoperative radiotherapy in stage I and stage II breast cancer. The biological rationale for expecting better results from prophylactic or adjuvant treatment of micrometastases or latent metastases
applies to radiotherapy as well as to chemotherapy. There is
present much enthusiasm for the
at
use
of adjuvant
chemotherapy in early breast cancer, as a result of two interim reports, and, of course, we should be undertaking properly controlled and conducted clinical trials, with caution regarding beneficial effects. 13 14 we need much better evidence than has been presented so far before we can ethically give up postoperative radiotherapy for early breast cancer, except in equally cautious clinical trials. harmful
as
well
as
However, surely
Glasgow Institute of Radiotherapeutics Radiotherap utics Glasgow Institute
of
and Oncology,
Western Infirmary, Glasgow G11 6NT
KEITH E. HALNAN
HOW DOES DANAZOL WORK?
SIR,-A new synthetic derivative of ethisterone, danazol (17ot-pregn-4-en-20-yno 2, 3-d-isoxazol-17-ol) is advertised as a drug controlling pituitary gonadotrophin excretion in males" and females.’" Its. use is being advocated in the management of severe endometriosis, 17 18 the suppression of endometrial fu nction being secondary to inhibition of gonadotrophin excretion. Our interest was stimulated by "inheriting" a patient with proven endometriosis who required 1000 mg of danazol daily to achieve symptomatic relief; this amount had been taken every day for a year. Wishing to be reassured that this was a reasonable regimen we contacted Winthrop Laboratories (U.K.) who told us that they were unaware of data for patients on such a dose over this prolonged period of time; it therefore seemed reasonable to determine our patient’s endocrine status. Initially F.S.H., L.H., G.H., A.C.T.H., and T.S.H. were determined (patient A, table)..Our laboratory values for the follicular phase of a normal menstrual cycle are up to 8 V/1 for F.s.H. and up to 6 U/1 for L.H.; the gonadotrophins in this patient were not "suppressed", therefore, at least on this occasion. The other hormone values were all in the normal range. The tests were repeated, and restradiol and prolactin concentrations were determined in addition. In view of the high gonadotrophin, cestradiol, and prolactin.levels recorded on some occasions two other patients taking the drug were investigated. , patient B had been taking 600 mg danazol daily for seven weeks and patient C 600 mg daily, for 3 months. Both have proven endometriosis and had achieved complete symptomatic 13. 14. 15.
Constanza, M. E. New Engl. J. Med. 1975, 293, 1095. Constanza, M. E. ibid. 1976, 294, 549. Sherins, R. J., Gandy, H. M., Thorslund, T. W., Paulsen, C. Alvin. J. clin. Endocr. Metab. 1971, 32, 522. 16. Andrews, M. C., Wentz, Ann C. Am. J. Obstet. Gynec. 1975, 121, 817. 17. Wood, Garry P., Wu, Chung-Hsiu, Flickinger, George, L., Mikhail, George Obstet. Gynec. 1975, 45, 302. 18. Greenblatt, R. B., Dmowski, W. P., Mahesh, V. B., Scholer, H. F. L. Fertil. Steril. 1971, 22, 102.
1402 PLASMA-HORMONE LEVELS IN THREE PATIENTS RECEIVING DANAZOL FOR ENDOMETRIOSIS
A.C.T.H.=corticotrophin. T.S.H, =thyroid-sumulating hormone.
F .S.H .=folhcle-stimulating hormone. L.H,=lUtetnlSlng hormone. G.H.=srowth hormone.
relief on this dose. Their data and the time intervals of testing are also detailed in the table. It seems reasonable to state that an active follicular phase was evident in all three patients. Plasma-oestradiol levels were certainly not suppressed, and prolactin levels were up to or above, the laboratory upper limit of normal (18 jig/1) on occasion in two of them. Plasma-progesterone levels were not determined on every occasion but the values we have are not compatible with a functioning corpus luteum. No endometrium could be obtained at dilatation and curettage, and, as stated, each patient achieved total symptomatic relief. These data are too few to allow specific conclusions to be drawn, but it seems reasonable to question whether the primary effect of this drug is to suppress gonadotrophin production by the pituitary. The oestradiol could be from a nonovarian source but it seems just as likely that actively developing follicles are playing their part. If ovulation does not occur
(hence
no
functioning
corpus
luteum),
true menstrua-
tion would be inhibited; however, unopposed oestrogen activity would lead to endometrial build-up and eventual shedding. This did not happen and suggests that danazol may directly inhibit the effect of oestrogens upon endometrial cells. The mode of action could be at the receptor level with danazol occupying the receptor sites. The prolactin effect is unexplained and requires clarification. We do not suggest that danazol should not be used or imply that it is unsafe in any way; we suggest, however, that more needs to be learned about its mode of action, which may be multifocal. If danazol can directly inhibit the effect of oestrogen at the endometrium it may have new uses in the management of endometrial carcinoma and possibly other
prising for two reasons-firstly because only 50% of their hyperprolactinsemic patients ovulated while taking bromocriptine, and secondly because they have reported the same ovulatory response to bromocriptine in a group of normoprolactinsemic women without galactorrhoea, but Seppala et al. have described neither the cause of the weight loss not whether it was altered during treatment. Our own results’ of treating patients with weight-related amenorrhrea accord with those of others2 in suggesting that the patient’s weight has returned to optimal levels (i.e., the weight at which menstrual cycles were last normal) ovulation cycles rapidly return. Psychological factors are of overriding importance in helping these patients to regain both weight and normal reproductive function. We think, therefore, that in the absence of a double-blind controlled trial it is quite unwarranted to conclude from the results of the uncontrolled study described by Seppala et al. that treatment with bromocriptine has any role whatsoever in inducing ovulation in normoprolactinaemic women with amenorrhoea. Our results of treating women with amenorrhcea associated with a raised serum-prolactin concentration are shown in the table. Prolactin was measured using reagents kindly supplied by the National Pituitary Agency of the U.S.A. Bromocriptine was given in a dose of 5-7.5 mg/day and ovulation was either once
RESPONSE TO BROMOCRIPTINE
oestrogen-dependent tumours. We thank the Supra Regional Assay Service laboratories at the Tenovus Institute, Cardiff, and St. Bartholomew’s Hospital, London,
for oestradiol and prolactin determinations. M.R.C. Reproduction and Growth Princess Mary Maternity Hospital, Newcastle upon Tyne NE2 3BD
Unit, T. LIND
I *
I
Includes 1 patient who has been pregnant twice.
Department of Clinical Biochemistry,
Royal Victoria Infirmary, Newcastle upon Tyne
D. B. COOK
BROMOCRIPTINE AND SECONDARY AMENORRHŒA SiR-We were very interested in the report of Dr Seppata and his colleagues (May 29, p. 1154) that the ovulation-rate in women with secondary amenorrhrea treated with bromocriptine was the same in normoprolactinaemic (9/18) as in hyperprolactinaemic (8/14) women. We found this report very sur-
by pregnancy or inferred from a serum-progesterone concentration that exceeded 25 nmol/1 during the putative luteal phase. 25 of the 28 patients have ovulated and there have been 16 pregnancies. The 3 patients who failed to ovulate were all treated with bromocriptine after a surgical hypophysectomy for chromophobe adenoma: tests with luteinising-hormone proven
Jacobs, H. S., Hull, M. G. R., Murray, M. A. F., Franks, S. Hormone Res. 1975, 6, 268. 2. Crisp, A. H., Stonehill, E. Br. med. J. 1971, iii, 149. 1.
Letters
to
the Editor
POSTOPERATIVE RADIOTHERAPY AND BREAST CANCER
StR,—Two curiously contrasting papers have been published in the past few weeks from the Cancer Research Campaign Breast Study. 12The first paper,’ on all 2268 evaluable patients, shows very well that X-ray therapy as given has no effect on survival, deleterious or beneficial, in clinical stages I and ii breast cancer, but does have a very clear value in both stages in reduction of local recurrence, and thus on quality of life; when local recurrence did occur only "about half have been successfully treated". The second papersextracts 350 cases those in which histology of lymph-nodes was available. Diagrams are then presented showing that survival-rates are better after X-ray therapy in "lymph-node negative cases" (but "not significantly different") and worse in "lymph-node positive cases" ("significant at p<0.05 at 2 years"). There is consistently higher freedom from local recurrence in both groups--"significant at in the lymph-node positive group". It is then sugp<0-001 gested that X-ray therapy is of no value in node-negative cases and causes a 10% increase in mortality in "the early stages" of breast cancer. Haybittle3has already criticised the statistical analysis—p<0-05 at one survival period is not a magic figure below which everything is accepted and above nothing. Is it correct to pick out retrospectively a small subgroup of a trial which has not been separately stratified from the beginning? Surely if one can do this and produce a group in which one treatment is better, there must also be another group in which the same treatment is worse, if overall there is no difference; inspection of the published figures suggests that this might well be the case with these small groups of node-negative and node-
positive cases. The hypothesis that postoperative radiotherapy for early breast cancer impairs immunological defence mechanisms and consequently causes increased mortality is not proven. Total lymphocyte-counts are reduced, but this is mainly in B and not T cells, which may even be increased, with serum antibody levels against herpes and other infections remaining unim-
paired.45Further evidence is reviewed by Alexander.6 The clinical evidence has been summarised by Stjerns8
who added up the results from several selected papers, of which showed any statistically significant differences, The Manchester to make them purportedly trials’o come first. They have been widely misunderstood. The comparison made was between policies of immediate postoperative X-ray therapy and of close follow-up with X-ray therapy being given as soon as there was any clinical suspicion of recurrence. A slightly higher mortality in the immediately treated group was reported to be of no statistical significance; no further evidence of any statistically significant difference has appeared. Bond" is often cited. He reported results from the Birmingham region showing that certain uncontrolled groups of patients had a higher mortality after X-ray therapy and surgery, but these were reports of selected groups of patients, with bad prognostic factors possibly playing a part in
ward7 none
significant.9
1. Working Party of the Cancer Research Campaign Br. med. J. 1976, ii, 1035. 2. McDonald, A. M., Simpson, J. S., Maclntyre, J. Lancet, 1976, i, 1088. 3. Haybittle, J. L. ibid. p. 1242. 4. McCredie, J. A., Inch, W. R., Sutherland, R. M. Cancer, 1972, 29, 349. 5. Blomgren, H., Berg, R. Wasserman, J., Glas, U. Int, J. Rad. Oncol. biol. Phys. 1976, 1,177. 6. Alexander, P. ibid. p. 369. 7. Stjernswärd, J. Muenz, L. R., von Essen, C. F. Lancet, 1976, i, 749. 8. Stjernswärd, J. ibid. 1974, ii, 1285. 9. Levitt, S. H., McHugh, R. B. ibid. 1975, ii, 1258. 10 Paterson, R., Russell, M. H. J. Fac. Radiol. 1959, 10, 175. 11. Bond W. H. in Treatment of Carcinoma of the Breast (edited by A. J. Jarrett); p. 24. Amsterdam, 1967. 12. Bruce, J. Cancer, 1971, 28, 1443.
the selection of radiotherapy. Edinburgh trials’2 are often also mentioned. There have now been several reports, none giving any statistically significant adverse effects of X-ray therapy. Both Manchester and Edinburgh cases have now been followed up for many more years, and it would be well worthwhile reassessing these trials, using also newer methods of analysis such as the log-rank test. Danish and United States data might be similarly treated, and menopausal and lymphnode status analysed. A final point is that the critics of X-ray therapy in breast cancer usually seem to ignore technique and dose, although it is at least worth considering the possibility that higher dosage from telecobalt or megavoltage therapy may improve results. A randomised controlled clinical trial by P. H0st of Oslo, reported at the Edinburgh European Radiology Conference last summer, has indeed recorded statistically significant improvement in survival from telecobalt postoperative radiotherapy in stage I and stage II breast cancer. The biological rationale for expecting better results from prophylactic or adjuvant treatment of micrometastases or latent metastases
applies to radiotherapy as well as to chemotherapy. There is
present much enthusiasm for the
at
use
of adjuvant
chemotherapy in early breast cancer, as a result of two interim reports, and, of course, we should be undertaking properly controlled and conducted clinical trials, with caution regarding beneficial effects. 13 14 we need much better evidence than has been presented so far before we can ethically give up postoperative radiotherapy for early breast cancer, except in equally cautious clinical trials. harmful
as
well
as
However, surely
Glasgow Institute of Radiotherapeutics Radiotherap utics Glasgow Institute
of
and Oncology,
Western Infirmary, Glasgow G11 6NT
KEITH E. HALNAN
HOW DOES DANAZOL WORK?
SIR,-A new synthetic derivative of ethisterone, danazol (17ot-pregn-4-en-20-yno 2, 3-d-isoxazol-17-ol) is advertised as a drug controlling pituitary gonadotrophin excretion in males" and females.’" Its. use is being advocated in the management of severe endometriosis, 17 18 the suppression of endometrial fu nction being secondary to inhibition of gonadotrophin excretion. Our interest was stimulated by "inheriting" a patient with proven endometriosis who required 1000 mg of danazol daily to achieve symptomatic relief; this amount had been taken every day for a year. Wishing to be reassured that this was a reasonable regimen we contacted Winthrop Laboratories (U.K.) who told us that they were unaware of data for patients on such a dose over this prolonged period of time; it therefore seemed reasonable to determine our patient’s endocrine status. Initially F.S.H., L.H., G.H., A.C.T.H., and T.S.H. were determined (patient A, table)..Our laboratory values for the follicular phase of a normal menstrual cycle are up to 8 V/1 for F.s.H. and up to 6 U/1 for L.H.; the gonadotrophins in this patient were not "suppressed", therefore, at least on this occasion. The other hormone values were all in the normal range. The tests were repeated, and restradiol and prolactin concentrations were determined in addition. In view of the high gonadotrophin, cestradiol, and prolactin.levels recorded on some occasions two other patients taking the drug were investigated. , patient B had been taking 600 mg danazol daily for seven weeks and patient C 600 mg daily, for 3 months. Both have proven endometriosis and had achieved complete symptomatic 13. 14. 15.
Constanza, M. E. New Engl. J. Med. 1975, 293, 1095. Constanza, M. E. ibid. 1976, 294, 549. Sherins, R. J., Gandy, H. M., Thorslund, T. W., Paulsen, C. Alvin. J. clin. Endocr. Metab. 1971, 32, 522. 16. Andrews, M. C., Wentz, Ann C. Am. J. Obstet. Gynec. 1975, 121, 817. 17. Wood, Garry P., Wu, Chung-Hsiu, Flickinger, George, L., Mikhail, George Obstet. Gynec. 1975, 45, 302. 18. Greenblatt, R. B., Dmowski, W. P., Mahesh, V. B., Scholer, H. F. L. Fertil. Steril. 1971, 22, 102.
1402 PLASMA-HORMONE LEVELS IN THREE PATIENTS RECEIVING DANAZOL FOR ENDOMETRIOSIS
A.C.T.H.=corticotrophin. T.S.H, =thyroid-sumulating hormone.
F .S.H .=folhcle-stimulating hormone. L.H,=lUtetnlSlng hormone. G.H.=srowth hormone.
relief on this dose. Their data and the time intervals of testing are also detailed in the table. It seems reasonable to state that an active follicular phase was evident in all three patients. Plasma-oestradiol levels were certainly not suppressed, and prolactin levels were up to or above, the laboratory upper limit of normal (18 jig/1) on occasion in two of them. Plasma-progesterone levels were not determined on every occasion but the values we have are not compatible with a functioning corpus luteum. No endometrium could be obtained at dilatation and curettage, and, as stated, each patient achieved total symptomatic relief. These data are too few to allow specific conclusions to be drawn, but it seems reasonable to question whether the primary effect of this drug is to suppress gonadotrophin production by the pituitary. The oestradiol could be from a nonovarian source but it seems just as likely that actively developing follicles are playing their part. If ovulation does not occur
(hence
no
functioning
corpus
luteum),
true menstrua-
tion would be inhibited; however, unopposed oestrogen activity would lead to endometrial build-up and eventual shedding. This did not happen and suggests that danazol may directly inhibit the effect of oestrogens upon endometrial cells. The mode of action could be at the receptor level with danazol occupying the receptor sites. The prolactin effect is unexplained and requires clarification. We do not suggest that danazol should not be used or imply that it is unsafe in any way; we suggest, however, that more needs to be learned about its mode of action, which may be multifocal. If danazol can directly inhibit the effect of oestrogen at the endometrium it may have new uses in the management of endometrial carcinoma and possibly other
prising for two reasons-firstly because only 50% of their hyperprolactinsemic patients ovulated while taking bromocriptine, and secondly because they have reported the same ovulatory response to bromocriptine in a group of normoprolactinsemic women without galactorrhoea, but Seppala et al. have described neither the cause of the weight loss not whether it was altered during treatment. Our own results’ of treating patients with weight-related amenorrhrea accord with those of others2 in suggesting that the patient’s weight has returned to optimal levels (i.e., the weight at which menstrual cycles were last normal) ovulation cycles rapidly return. Psychological factors are of overriding importance in helping these patients to regain both weight and normal reproductive function. We think, therefore, that in the absence of a double-blind controlled trial it is quite unwarranted to conclude from the results of the uncontrolled study described by Seppala et al. that treatment with bromocriptine has any role whatsoever in inducing ovulation in normoprolactinaemic women with amenorrhoea. Our results of treating women with amenorrhcea associated with a raised serum-prolactin concentration are shown in the table. Prolactin was measured using reagents kindly supplied by the National Pituitary Agency of the U.S.A. Bromocriptine was given in a dose of 5-7.5 mg/day and ovulation was either once
RESPONSE TO BROMOCRIPTINE
oestrogen-dependent tumours. We thank the Supra Regional Assay Service laboratories at the Tenovus Institute, Cardiff, and St. Bartholomew’s Hospital, London,
for oestradiol and prolactin determinations. M.R.C. Reproduction and Growth Princess Mary Maternity Hospital, Newcastle upon Tyne NE2 3BD
Unit, T. LIND
I *
I
Includes 1 patient who has been pregnant twice.
Department of Clinical Biochemistry,
Royal Victoria Infirmary, Newcastle upon Tyne
D. B. COOK
BROMOCRIPTINE AND SECONDARY AMENORRHŒA SiR-We were very interested in the report of Dr Seppata and his colleagues (May 29, p. 1154) that the ovulation-rate in women with secondary amenorrhrea treated with bromocriptine was the same in normoprolactinaemic (9/18) as in hyperprolactinaemic (8/14) women. We found this report very sur-
by pregnancy or inferred from a serum-progesterone concentration that exceeded 25 nmol/1 during the putative luteal phase. 25 of the 28 patients have ovulated and there have been 16 pregnancies. The 3 patients who failed to ovulate were all treated with bromocriptine after a surgical hypophysectomy for chromophobe adenoma: tests with luteinising-hormone proven
Jacobs, H. S., Hull, M. G. R., Murray, M. A. F., Franks, S. Hormone Res. 1975, 6, 268. 2. Crisp, A. H., Stonehill, E. Br. med. J. 1971, iii, 149. 1.