1079
MULTIMODAL THERAPY FOR STAGE-II BREAST
IMMUNISATION LEVELS
CANCER
SiR,-Dr Bussey and Mr Holmes (Nov. 5, p. 970) suggest that the high levels of immunisation maintained in West Sussex in the face of a national decline in immunisation-rates must be the result of computerisation. Our experience of computerised recall in Rotherham is different. Rotherham is a single-district area which has a recall system for immunisation that is part computerised and part manual. The computerised part of the area lay in the West Riding of Yorkshire before reorganisation and the manual system operates in what was Rotherham County Borough. The two parts of the area operate different schedules for primary immunisation-4, 6, and 12 months (manual) or 6, 8, and 14 months (computerised). IMMUNISATION IN ROTHERHAM AREA
SIR,-The multicentre study reported in your issue of Aug. 20
(p. 396) involves
an
important
area
of treatment, but the
reporting of the data is unsatisfactory. The group correctly points out that prognosis depends on the number of nodes affected, but from the information presented it is not possible to determine whether the responders were in the one to three nodes positive or more than four nodes positive group, or even whether they were premenopausal or postmenopausal. The multicentre group states that chemotherapy should follow adequate reduction of tumour burden, yet we are told only that the patients had "conventional primary treatment". This is not an adequate description of patient management. "... a minority of contributors wished to include patients in whom nodal histology was either unknown or negative": are we to assume that this happened, and, if it did how many such patients were contributed to each arm of the study? standard of
It is clear from the work of Bonnadonna et a1.1.2 that the greatest effect for their chemotherapy regimen was in the pre-
menopausal group with one to three nodes involved. It is no longer acceptable for data on systemic therapy for breast cancer to be reported unless the primary treatment and the precise status of patients are described. The data from the Multicentre Breast Cancer Chemotherapy Group are very difficult to interpret, but on the basis of what has been reported I cannot agree with the suggestion that allocation to a control untreated group is no longer justifiable. There may have been a group in this study who not only did not benefit but also may have been unduly harmed by chemotherapy. children
completing primary courses of diphtheria, pertussis, or polio immunisation over a period of 27 months from Jan. 1 of year of birth (to allow for slight difference in immunisation schedules). Results expressed as 100 x (no. of courses) = (no. of live births).
Department of Surgery, University of Melbourne, Royal Melbourne Hospital,
JOHN F. FORBES
Victoria 3050, Australia
t And tetanus. The immunisation levels for the 1974 and 1975 cohorts are given in the table. The manual system seems to be associated with a rise in the proportion immunised for all the vaccines shown. Conversely computerised recall seems to be associated with a fall throughout. A possible reason for this is that consent for immunisation under the manual system of recall is obtained much closer to the time that the first doses of vaccine are given. For computerised recall consent is obtained when the child is 10 days old, and unless motivation is reinforced throughout the next 6 months and is timed to coincide with any television programme or newspaper article about immunisation, parents may have turned against the idea of having their child immunised by the time the first postcard arrives. Rotherham Area Health Rotherham S60 2UN
Authority, T. S. ADAMS
COMMUNICATING HYDROCEPHALUS
SIR,-We read with interest your editorial of Nov. 12 (p. 1011), particularly the results of treatment of communicating hydrocephalus by shunting. Such results may be adversely affected by the presence of undetected hypopituitarism, and a case-report illustrating this point will appear elsewhere.’ Had the corticotrophin deficiency in our patient not been detected and treated, total recovery might not have been achieved, even though surgical shunting was successful. We are now trying to assess the frequency of this complication and would be interested have had similar experiences.
to
hear from other groups who
Departments of Medicine and Neurosurgery, Queen Elizabeth Hospital,
Birmingham B15 2TH 1
Barber, S. G., Garvan, N. Br. med. J. (in the press).
SIR,-May
we
reply
to
earlier letters from Mr Baum
(Sept.
10, p. 564) and Mr Leaper and his colleagues (Sept. 24,
p.
660) and the above from Mr Forbes. We have been criticised for
our
decision
to
discontinue
chemotherapy control group in future trials.
a no-
In view of the significant difference in recurrences at 15 months in favour of chemotherapy this criticism is, presumably, based on the absence, so far, of long-term recurrence and survival data in our trials and doubts about toxicity, especially long-term. We believe that the large superiority in favour of chemotherapy in the short-term, together with the poor prognosis of stage-n cases, makes continuation with no-chemotherapy groups the decision that needs to be justified, not the decision to abandon such controls. The no-chemotherapy group in the first trial will eventually provide the long-term comparison with chemotherapy, in respect both of therapeutic efficacy and of longterm toxicity. Thus, the doubts raised will be answered in time by data and not speculation. The strongest argument against chemotherapy such as the regimen we have used is uncertainty about long-term toxicity. Mr Baum’s reference to cyclophosphamide is of doubtful relevance because intermittent cyclical treatment is less suppressive, certainly as far as the haemopoietic system is concerned. A review of potential carcinogenesis as a late complication3indicates that there is little evidence one way or the other. What is important is that our trial, being prospective, randomised, and controlled, will eventually provide hard facts in an area where they are noticeably absent at present. To Mr Baum’s claim that tamoxifen is preferable, in that it is without toxicity, we would simply reply "What is your evidence ?". To our knowledge there has been no long-term study
S. G. BARBER N. GARVAN 1. Bonnadonna, G., and others. New Engl. J. Med. 1976, 2. Bonnadonna, G., and others. Cancer, 1977, 39, 2904. 3. Sieber, S. Cancer Chemother. Rep 1975, 59, 915.
294, 405.
1080 in man with tamoxifen, and Mr Baum should be as sceptical of the absence of such data as he is in the case of chemotherapy. Consider, for example, the sad tale of the use of oestrogenic compounds in pregnant women subsequently causing vaginal cancer in their daughters. Experience should tell us that no drug is immune from the possibility of unexpected adverse effects. Other "preferable" forms of chemotherapy alluded to by Mr Leaper and his colleagues are just as open to criticism on the grounds of lack of evidence. Surely the point is that we have to accept our lack of long-term data, the great efficacy in the short-term of adjuvant chemotherapy, and the poor prognosis of stage n cases without such treatment. (Our updated short-term toxicity data, available on request, fully bear out those already published.) Mr Forbes asks about node-negative patients. Some nodenegative patients were contributed but they were not included in the published report. Analyses of recurrences by menstrual status, primary treatment, and number of nodes affected are important but at the time of publication these would have been based on too few patients to be meaningful. His suggestion that certain patients may be harmed by treatment could be true for many therapeutic approaches, not excluding primary local treatment of cancer, but the large number of node-positive women with recurrences within 5 years without adjuvant chemotherapy must be recalled. Without chemotherapy many patients will not be alive to experience long-term toxicity or its absence. The latest evidence is beginning to suggest that this treatment not only delays recurrence but that it may also reduce mortality, in the early stages at least.4,3 This further supports our arguments. Working Party, Multicentre Breast Cancer
Chemotherapy Group, 127 Marlborough Park South, Belfast BT9 6HW
ERICA MANSBACHER, Trial Co-ordinator
DIURETIC EFFECT OF
1,25-DIHYDROXYCHOLECALCIFEROL SIR,-We have treated several patients with secondary hyperparathyroidism, muscular weakness, and renal bone diswith 1,25-dihydroxycholecalciferol (1,25-D.H.C.C.). One of them had a reproducible diuretic response to this hormonally active vitamin-D metabolite. A 40-year-old man had a slowly progressive interstitial nephritis with papillary necrosis since 1965. From 1967 there was a moderate rise of serum-creatinine to 300 pumol/1 while serum calcium and phosphate were normal. In 1973 serumcreatinine was 400 flmol/1 and serum-calcium was now slightly raised (2-5—2-7mmol/1, normal 2-1—2-6). Daily urinary volumes were only about 100 ml. During the ensuing years he retained water periodically despite taking 40 mg frusemide daily. He was admitted to the nephrological department where he was treated with a variety of diuretics with good effect. However, in 1976 the effect of the therapy was so poor that he had a constant, general oedema. Serum-creatinine was now 600 mol/1. In June, 1976, regular peritoneal dialysis was started. Over the next 3 months he received dialysis 3 days a week and during this period serum-calcium was 3-0-3.22 mmol/1, serum iP.T.H. (immunoreactive parathyroid hormone) 280 ng/1 (normal 160-280), and serum-phosphorus 1.2 mmol/1. However, he had severe pruritus and a pronounced muscle weakness. He could hardly walk. Parathyroidectomy was now discussed, but, first, substitution therapy with 1,25-D.H.c.c. was prescribed. 4 flg 1.25-D.H.c.c. (a gift from Hoffman La Roche Inc., Nutley, New Jersey) was administered intravenously dissolved in 10 ml ’Intralipid’. After about 16 h the patient produced 100-150 ml urine/h with an osmolality ease
4. Bonnadonna, G., and others. Cancer, 5. Fisher, B. and others, ibid. p. 2883.
1977, 39, 2904.
of 200-300 mosmol/kg. About 60 h after the injection urine output had fallen to 10-15 ml/h. 1 ug 1,25-D.H.c.c. intravenously again increased urinary volumes to about 150 ml/h. He was put on 1 pLg 1,25-D.H.c.c. daily for 14 days. During this period his muscle weakness disappeared and he could again climb the stairs, his pruritus improved, and he needed no dialysis. Serum-calcium remained slightly raised but no further rise was caused by administration of 1,25-D.H.c.c. At operation four hyperplastic parathyroid glands were removed. Histological examination showed chief-cell hyperplasia. After operation, the serum-calcium slowly returned to normal or below normal. Because of paraesthesiae of his fingers and lips, 1,25-D.H.C.C. was continued for 10 days after the operation. Diuresis remained good, and so did muscle function. He was then given a maintenance dose of 0.7 g 1,25-D.H.c.c. orally per day for 4 months. Because of hypercalcsemia and a rise of serum-creatinine to about 800 p.mol/1 1,25-D.H.c.c. was withdrawn. However, within 2 days urine output was only 10 ml/h and the patient got general oedema. With an oral dose of only 0.33 [ig 1,25-D.H.c.c. daily the diuresis reappeared and has persisted. The reproducible, diuretic effect of 1,25-D.H.C.C. in this patient with renal oedema is not readily explained and has not been observed in our other patients with more advanced and long-standing renal failure and hyperparathyroidism who were also cured with 1,25-D.H.c.c. Possibly, the effect of 1,25-D.H.C.C. in this one case was mediated via an influence on the antidiuretic-hormone system. 1,25-D.H.c.c., although given intravenously, did not cause any significant rise in serum-calcium before parathyroidectomy, probably due to a rise in intracellular calcium and improved transfer of calcium into bone. We tentatively ascribe his improved muscle function and pruritus to a normal intracellular calcium caused by the substitution theranv with 1.25-n.H.c.c. M. ANDRAE D. E. W. HOLMLUND Departments of General Surgery, S-E. LARSSON Orthopædic Surgery, and Nephrology, B. LINDQVIST University Hospital, S-901 85 Umeå, Sweden R. LORENTZON
D.D.A.V.P. AND LITHIUM-INDUCED
POLYURIA/POLYDIPSIA SIR,-Polyuria and polydipsia are common side-effects of lithium prophylaxis in manic-depression.1.2 In a pilot study eleven women (mean age 40, range 24-71) with unipolar or bipolar manic depressive psychosis who had moderate to severe polyuria and polydipsia while taking lithium were given D.D.A.v.p. (desaminocys1-o-arg8 vasopressin, ’Minirin’, Ferring AB, Malmö) 0.2-0-4 ml two or three times daily by intranasal route for 2-12 days. Daily blood-samples and total urine volumes were collected from 2 to 8 days before the first D.D.A.v.P. administration and during treatment. Besides subjective relief in the intensity of polyuria and polydipsia, nine out of eleven patients had lower urine volumes and reported lower fluid intake during the treatment than during the pretreatment period. The mean daily urine volumes fell
by 0-60% (average 23). No side-effects were reported; there were no changes in renal clearance of sodium or lithium; and the lithium levels in plasma were not affected. D.D.A.V.P. might be of some benefit in relieving symptoms of polyuria and polydipsia in patients on prophylactic lithium. Psychiatric Research Centre, University of Uppsala, S-750 17 Uppsala, Sweden
1. Bech, P., Vendsborg, P. B., Rafaelsen, O. 70. 2 Widerlöv, E ibid 1976, 54, 294.
E. WIDERLÖV R. SJÖSTROM U. SÖDERBERG
J. Acta psychiat. scand. 1976, 53,
MULTIMODAL THERAPY FOR STAGE-II BREAST
IMMUNISATION LEVELS
CANCER
SiR,-Dr Bussey and Mr Holmes (Nov. 5, p. 970) suggest that the high levels of immunisation maintained in West Sussex in the face of a national decline in immunisation-rates must be the result of computerisation. Our experience of computerised recall in Rotherham is different. Rotherham is a single-district area which has a recall system for immunisation that is part computerised and part manual. The computerised part of the area lay in the West Riding of Yorkshire before reorganisation and the manual system operates in what was Rotherham County Borough. The two parts of the area operate different schedules for primary immunisation-4, 6, and 12 months (manual) or 6, 8, and 14 months (computerised). IMMUNISATION IN ROTHERHAM AREA
SIR,-The multicentre study reported in your issue of Aug. 20
(p. 396) involves
an
important
area
of treatment, but the
reporting of the data is unsatisfactory. The group correctly points out that prognosis depends on the number of nodes affected, but from the information presented it is not possible to determine whether the responders were in the one to three nodes positive or more than four nodes positive group, or even whether they were premenopausal or postmenopausal. The multicentre group states that chemotherapy should follow adequate reduction of tumour burden, yet we are told only that the patients had "conventional primary treatment". This is not an adequate description of patient management. "... a minority of contributors wished to include patients in whom nodal histology was either unknown or negative": are we to assume that this happened, and, if it did how many such patients were contributed to each arm of the study? standard of
It is clear from the work of Bonnadonna et a1.1.2 that the greatest effect for their chemotherapy regimen was in the pre-
menopausal group with one to three nodes involved. It is no longer acceptable for data on systemic therapy for breast cancer to be reported unless the primary treatment and the precise status of patients are described. The data from the Multicentre Breast Cancer Chemotherapy Group are very difficult to interpret, but on the basis of what has been reported I cannot agree with the suggestion that allocation to a control untreated group is no longer justifiable. There may have been a group in this study who not only did not benefit but also may have been unduly harmed by chemotherapy. children
completing primary courses of diphtheria, pertussis, or polio immunisation over a period of 27 months from Jan. 1 of year of birth (to allow for slight difference in immunisation schedules). Results expressed as 100 x (no. of courses) = (no. of live births).
Department of Surgery, University of Melbourne, Royal Melbourne Hospital,
JOHN F. FORBES
Victoria 3050, Australia
t And tetanus. The immunisation levels for the 1974 and 1975 cohorts are given in the table. The manual system seems to be associated with a rise in the proportion immunised for all the vaccines shown. Conversely computerised recall seems to be associated with a fall throughout. A possible reason for this is that consent for immunisation under the manual system of recall is obtained much closer to the time that the first doses of vaccine are given. For computerised recall consent is obtained when the child is 10 days old, and unless motivation is reinforced throughout the next 6 months and is timed to coincide with any television programme or newspaper article about immunisation, parents may have turned against the idea of having their child immunised by the time the first postcard arrives. Rotherham Area Health Rotherham S60 2UN
Authority, T. S. ADAMS
COMMUNICATING HYDROCEPHALUS
SIR,-We read with interest your editorial of Nov. 12 (p. 1011), particularly the results of treatment of communicating hydrocephalus by shunting. Such results may be adversely affected by the presence of undetected hypopituitarism, and a case-report illustrating this point will appear elsewhere.’ Had the corticotrophin deficiency in our patient not been detected and treated, total recovery might not have been achieved, even though surgical shunting was successful. We are now trying to assess the frequency of this complication and would be interested have had similar experiences.
to
hear from other groups who
Departments of Medicine and Neurosurgery, Queen Elizabeth Hospital,
Birmingham B15 2TH 1
Barber, S. G., Garvan, N. Br. med. J. (in the press).
SIR,-May
we
reply
to
earlier letters from Mr Baum
(Sept.
10, p. 564) and Mr Leaper and his colleagues (Sept. 24,
p.
660) and the above from Mr Forbes. We have been criticised for
our
decision
to
discontinue
chemotherapy control group in future trials.
a no-
In view of the significant difference in recurrences at 15 months in favour of chemotherapy this criticism is, presumably, based on the absence, so far, of long-term recurrence and survival data in our trials and doubts about toxicity, especially long-term. We believe that the large superiority in favour of chemotherapy in the short-term, together with the poor prognosis of stage-n cases, makes continuation with no-chemotherapy groups the decision that needs to be justified, not the decision to abandon such controls. The no-chemotherapy group in the first trial will eventually provide the long-term comparison with chemotherapy, in respect both of therapeutic efficacy and of longterm toxicity. Thus, the doubts raised will be answered in time by data and not speculation. The strongest argument against chemotherapy such as the regimen we have used is uncertainty about long-term toxicity. Mr Baum’s reference to cyclophosphamide is of doubtful relevance because intermittent cyclical treatment is less suppressive, certainly as far as the haemopoietic system is concerned. A review of potential carcinogenesis as a late complication3indicates that there is little evidence one way or the other. What is important is that our trial, being prospective, randomised, and controlled, will eventually provide hard facts in an area where they are noticeably absent at present. To Mr Baum’s claim that tamoxifen is preferable, in that it is without toxicity, we would simply reply "What is your evidence ?". To our knowledge there has been no long-term study
S. G. BARBER N. GARVAN 1. Bonnadonna, G., and others. New Engl. J. Med. 1976, 2. Bonnadonna, G., and others. Cancer, 1977, 39, 2904. 3. Sieber, S. Cancer Chemother. Rep 1975, 59, 915.
294, 405.
1080 in man with tamoxifen, and Mr Baum should be as sceptical of the absence of such data as he is in the case of chemotherapy. Consider, for example, the sad tale of the use of oestrogenic compounds in pregnant women subsequently causing vaginal cancer in their daughters. Experience should tell us that no drug is immune from the possibility of unexpected adverse effects. Other "preferable" forms of chemotherapy alluded to by Mr Leaper and his colleagues are just as open to criticism on the grounds of lack of evidence. Surely the point is that we have to accept our lack of long-term data, the great efficacy in the short-term of adjuvant chemotherapy, and the poor prognosis of stage n cases without such treatment. (Our updated short-term toxicity data, available on request, fully bear out those already published.) Mr Forbes asks about node-negative patients. Some nodenegative patients were contributed but they were not included in the published report. Analyses of recurrences by menstrual status, primary treatment, and number of nodes affected are important but at the time of publication these would have been based on too few patients to be meaningful. His suggestion that certain patients may be harmed by treatment could be true for many therapeutic approaches, not excluding primary local treatment of cancer, but the large number of node-positive women with recurrences within 5 years without adjuvant chemotherapy must be recalled. Without chemotherapy many patients will not be alive to experience long-term toxicity or its absence. The latest evidence is beginning to suggest that this treatment not only delays recurrence but that it may also reduce mortality, in the early stages at least.4,3 This further supports our arguments. Working Party, Multicentre Breast Cancer
Chemotherapy Group, 127 Marlborough Park South, Belfast BT9 6HW
ERICA MANSBACHER, Trial Co-ordinator
DIURETIC EFFECT OF
1,25-DIHYDROXYCHOLECALCIFEROL SIR,-We have treated several patients with secondary hyperparathyroidism, muscular weakness, and renal bone diswith 1,25-dihydroxycholecalciferol (1,25-D.H.C.C.). One of them had a reproducible diuretic response to this hormonally active vitamin-D metabolite. A 40-year-old man had a slowly progressive interstitial nephritis with papillary necrosis since 1965. From 1967 there was a moderate rise of serum-creatinine to 300 pumol/1 while serum calcium and phosphate were normal. In 1973 serumcreatinine was 400 flmol/1 and serum-calcium was now slightly raised (2-5—2-7mmol/1, normal 2-1—2-6). Daily urinary volumes were only about 100 ml. During the ensuing years he retained water periodically despite taking 40 mg frusemide daily. He was admitted to the nephrological department where he was treated with a variety of diuretics with good effect. However, in 1976 the effect of the therapy was so poor that he had a constant, general oedema. Serum-creatinine was now 600 mol/1. In June, 1976, regular peritoneal dialysis was started. Over the next 3 months he received dialysis 3 days a week and during this period serum-calcium was 3-0-3.22 mmol/1, serum iP.T.H. (immunoreactive parathyroid hormone) 280 ng/1 (normal 160-280), and serum-phosphorus 1.2 mmol/1. However, he had severe pruritus and a pronounced muscle weakness. He could hardly walk. Parathyroidectomy was now discussed, but, first, substitution therapy with 1,25-D.H.c.c. was prescribed. 4 flg 1.25-D.H.c.c. (a gift from Hoffman La Roche Inc., Nutley, New Jersey) was administered intravenously dissolved in 10 ml ’Intralipid’. After about 16 h the patient produced 100-150 ml urine/h with an osmolality ease
4. Bonnadonna, G., and others. Cancer, 5. Fisher, B. and others, ibid. p. 2883.
1977, 39, 2904.
of 200-300 mosmol/kg. About 60 h after the injection urine output had fallen to 10-15 ml/h. 1 ug 1,25-D.H.c.c. intravenously again increased urinary volumes to about 150 ml/h. He was put on 1 pLg 1,25-D.H.c.c. daily for 14 days. During this period his muscle weakness disappeared and he could again climb the stairs, his pruritus improved, and he needed no dialysis. Serum-calcium remained slightly raised but no further rise was caused by administration of 1,25-D.H.c.c. At operation four hyperplastic parathyroid glands were removed. Histological examination showed chief-cell hyperplasia. After operation, the serum-calcium slowly returned to normal or below normal. Because of paraesthesiae of his fingers and lips, 1,25-D.H.C.C. was continued for 10 days after the operation. Diuresis remained good, and so did muscle function. He was then given a maintenance dose of 0.7 g 1,25-D.H.c.c. orally per day for 4 months. Because of hypercalcsemia and a rise of serum-creatinine to about 800 p.mol/1 1,25-D.H.c.c. was withdrawn. However, within 2 days urine output was only 10 ml/h and the patient got general oedema. With an oral dose of only 0.33 [ig 1,25-D.H.c.c. daily the diuresis reappeared and has persisted. The reproducible, diuretic effect of 1,25-D.H.C.C. in this patient with renal oedema is not readily explained and has not been observed in our other patients with more advanced and long-standing renal failure and hyperparathyroidism who were also cured with 1,25-D.H.c.c. Possibly, the effect of 1,25-D.H.C.C. in this one case was mediated via an influence on the antidiuretic-hormone system. 1,25-D.H.c.c., although given intravenously, did not cause any significant rise in serum-calcium before parathyroidectomy, probably due to a rise in intracellular calcium and improved transfer of calcium into bone. We tentatively ascribe his improved muscle function and pruritus to a normal intracellular calcium caused by the substitution theranv with 1.25-n.H.c.c. M. ANDRAE D. E. W. HOLMLUND Departments of General Surgery, S-E. LARSSON Orthopædic Surgery, and Nephrology, B. LINDQVIST University Hospital, S-901 85 Umeå, Sweden R. LORENTZON
D.D.A.V.P. AND LITHIUM-INDUCED
POLYURIA/POLYDIPSIA SIR,-Polyuria and polydipsia are common side-effects of lithium prophylaxis in manic-depression.1.2 In a pilot study eleven women (mean age 40, range 24-71) with unipolar or bipolar manic depressive psychosis who had moderate to severe polyuria and polydipsia while taking lithium were given D.D.A.v.p. (desaminocys1-o-arg8 vasopressin, ’Minirin’, Ferring AB, Malmö) 0.2-0-4 ml two or three times daily by intranasal route for 2-12 days. Daily blood-samples and total urine volumes were collected from 2 to 8 days before the first D.D.A.v.P. administration and during treatment. Besides subjective relief in the intensity of polyuria and polydipsia, nine out of eleven patients had lower urine volumes and reported lower fluid intake during the treatment than during the pretreatment period. The mean daily urine volumes fell
by 0-60% (average 23). No side-effects were reported; there were no changes in renal clearance of sodium or lithium; and the lithium levels in plasma were not affected. D.D.A.V.P. might be of some benefit in relieving symptoms of polyuria and polydipsia in patients on prophylactic lithium. Psychiatric Research Centre, University of Uppsala, S-750 17 Uppsala, Sweden
1. Bech, P., Vendsborg, P. B., Rafaelsen, O. 70. 2 Widerlöv, E ibid 1976, 54, 294.
E. WIDERLÖV R. SJÖSTROM U. SÖDERBERG
J. Acta psychiat. scand. 1976, 53,
