324 RESEARCH INTO LEAD POLLUTION
SIR,-In your Parliamentary correspondent’s report (Dec. 23/30, p. 1388) of the debate on lead pollution it was correctly stated that criticisms had been made in the House of Commons of a "group at Great Ormond Street". As members of that group, we should like to explain the situation. We have, for some years, been involved in work in this area. In the summer of 1978, the Department of Health and Social Security asked us to provide comments on two papers that had recently been delivered by two United States workers, Dr David and Dr Needleman. We prepared a report which was critical, but adequate appraisal was difficult because full details of the work had not been published. Our report was sent to the D.H.S.S. who asked if they could send it out in answer to inquiries made to them. We agreed and, indeed, finally sent it out ourselves in response to a number of further inquiries. We should have sent copies to the workers who had delivered the papers; they do now have copies. In the House of Commons debate it was suggested (Hansard, Dec. 12, pp. 435-444) that we had in some way been unwitting dupes of the D.H.S.S. which was using our report as an excuse for inactivity on the subject. We can only say that, had we thought the information presented in the papers supported a sound case for a major or minor effect of a moderate amount of lead on the intelligence or behaviour of children, we should have said so. We are aware of the possibility of covert influence, but we can only say that we have never consciously felt ourselves to be under the slightest pressure from central Government departments to put forward a particular view. It was further suggested, albeit rather unclearly, that one or more of us had been associated with research sponsored by petrol companies. In 1964 Associated Octel Co. Ltd. donated a flow-through cell (approximate value 10), and a member of the chemical industry donated autoanalyser equipment (approximate value £ 500) to the department of chemical pathology at the Hospital for Sick Children. These donations were received well before the present controversy regarding lead in petrol arose. In fact, none of us has undertaken work sponsored by petrol companies or, indeed, any branch of industry even remotely concerned with the dissemination of lead, nor have we, or our departments, benefited since 1964 financially or in any other way from support from such companies. Department of Chemical Pathology University of Southampton Department of Chemical Pathology,
&
Human Metabolism
Institute of Child Health, London WC1
B. E. CLAYTON
Institute of Child Health
Department of Psychological Medicine, Hospital For Sick Children, London WC1
Belfast and Hume Street Hospital, Dublin
G. A. EDELSTYN
Charing Cross Hospital Medical School, T. DELVES
Department of Child Psychiatry,
between efficacy on the one hand and inconvenience to the patient and toxicity on the other. Unfortunately, only a fraction (perhaps 10-15%) of highrisk patients-i.e., those who are axillary-node positive-are being entered into clinical trials in the U.K., despite the fact that twenty or more trials are in progress. Many of these trials will fail because of lack of numbers, and others will take several years to recruit sufficient patients. Some surgeons and radiotherapists not participating in any trial already "know" the truth of the matter: cytotoxic chemotherapy is unpleasant and expensive, has possible long-term risks, and should be avoided completely; or, in view of the results reported so far, the answer to early breast cancer treatment has been found and all patients can be safely given chemotherapy without further evaluation. Other non-trialists may not know what the truth of the matter is: they are content to rest until the facts emerge and to await a change in fashion before they take action. Finding the facts and leading opinion is for others to do-they are busy enough just treating their patients. For whatever reason, such non-participation in trials has tragic consequences. Answers will take a long time to appear, and every suitable patient not entered into a study adds further to the delay and uncertainty. The problem must not be viewed parochially. We do not suggest that the trial with which we are associated is necessarily the one to join.* Any trial that asks a question whose answer is worth knowing deserves support. Although written in the context of breast cancer, the same point can and should be made about other diseases. Even if a clinician does not have a "special" interest in a certain disease, he should still enter his patients into trials which others organise on a multicentre basis. In the absence of hard data doctors will still form views about the best way to treat patients-the clinical situation demands some action from the clinician even if it is inaction. Whatever our own personal prejudices and doubts, it is only in supporting trials that facts can be substituted for opinion. Non-participation in clinical trials is a decision not to contribute to medical progress and this, surely, is morally, if not professionally, indefensible. Northern Ireland Radiotherapy Centre, Belvoir Park Hospital,
P. J. GRAHAM
London W6
K. D. MACRAE
SIR,—On Nov. 23, 1978, the Cancer Research Campaign a meeting to review the progress of the U.K. multicollaborative trial of adjuvant hormono-chemotherapy in poor-risk patients with early carcinoma of the breast. This meeting provided an opportunity for the steering committee of that study to meet with the organisers of the King’s College Hospital breast cancer trials. Both groups agreed on the fol-
sponsored centre
R. LANSDOWN
TRIALS OF ADJUVANT CHEMOTHERAPY IN BREAST CANCER
SIR,—Death in breast cancer usually results from micrometastatic dissemination to bone, lung, liver, and brain which has settled the outcome before treatment is given. Attempts to deal with such micrometastatic spread by the use of cytotoxic regimens after primary therapy’-3 have improved disease-free intervals, and the indications are that death-rates may also be reduced. Nevertheless, much longer follow-up is needed to see if this early encouraging response is sustained. Further studies are also required to explore the various cytotoxic options to see if, for such therapy, a more favourable balance can be struck 1. Fisher, B. Cancer, 1977, 40, 574. 2. Bonadonna, G., and others. A. Rev. Med. 1978, 29, 149. 3. Edelstyn, G. A., Bates, T., Brinkley, D., Kitchen, G., MacRae, K. N. T., Spittle, M., Wheeler, T. Lancet, 1978, ii, 1092.
D., Nicol,
lowing points: (1) It is justifiable to conduct adjuvant therapy studies in poorrisk early-breast-cancer patients whilst still retaining a control arm.
(2) There is sufficient evidence both on theoretical and on experimental groundsi-3 and in work done in advanced disease 4,5 to study the potential advantages of combining chemotherapy and hormone therapy over either modality alone or as adjuvant treatment. *For information apply to: Co-ordinator, Multicentre Breast Cancer Chemotherapy Group, 127 Marlborough Park South, Belfast BT9 6HW. 1. Lippman, M. E., and others New Engl. J. Med. 1978, 298, 1223. 2. Meakin, J. W., and others in Adjuvant Therapy of Cancer (edited Salmon and S. E. Jones). Amsterdam, 1977. 3. Braunsberg, H., and others Lancet, 1973, i, 163. 4. Tormey, D. C. Proc. Am. Ass. Cancer Res. 1978, abstr. 134. 5. Cavalli, F. 4th int. Congr. Chemother. 1977, abstr. 510, 615.
by S. E.
325
(3) Both groups have launched trials of similar design that will study different aspects of this problem. Their cumulative results will be of great value but will depend on recruiting sufficient numbers of patients to each trial. (4) Despite the overwhelming evidence supporting the need for such studies, most poor-risk early-breast-cancer patients in the U.K. are not entered into any trial where the value of adjuvant therapy can be assessed. We therefore ask clinicians in charge of eligible patients to give serious thought to collaborating
VASCULAR PROSTACYCLIN MAY BE REDUCED IN DIABETES IN MAN
SIR,-Vascular endothelium generates prostacyclin (P.G.I2), potent inhibitor of platelet aggregation.’ We have found that aorta2and renal cortex3 from streptozotocin-diabetic rats produce significantly less P.G.I2 than do tissues from control animals. To assess the clinical relevance of these findings, we have now estimated P.G.I2 release by vessels from diabetics and nondiabetics. a
with one or other of these studies. (5) Centres which enter a substantial number of patients will be provided with secretarial or other assistance to facilitate the conduct of the trial. Further information can be obtained from either of us regarding both trials, so that clinicians can choose which they would feel to be most appropriate for them to join.
Department of Radiotherapy, Royal Free Hospital,
F. SENANAYAKE
London NW3
Department of Surgery, King’s College Hospital Medical School, M. BAUM
London SE5
*,*A
note on
the latest U.I.C.C.
and other cancers appears
on
compendium of trials
in breast
p. 339.-ED. L.
SELF-TREATMENT OF COLD SORES WITH ICE
SIR,—Dr Zimmerman’ draws attention to the absence of a clinical trial of ice as a treatment for cold sores and points out that, in general, clinical trials to test non-pharmaceutical "household" remedies are seldom done. This is a valid criticism and reflects on the usual sources of drug-trial funds and on the low prestige attached to this type of investigation compared with studies with an aura of basic science. Another aspect-perhaps the most important one-is the difficulty in deciding which, if any, of these remedies is really likely to be successful and therefore warrants the major effort required to arrange and monitor a double-blind, controlled trial. If household remedies are extended to include the vast array of purportedly successful "traditional remedies" used in Asian medicine, the task of selecting those worthy of formal testing becomes staggering. I do not entirely envy Zimmerman his access to the medical views of 18 million women, for with such a group-as with any other-the strength of the placebo response must not be underestimated. The vast array of "simple" remedies now discarded but once heralded as successful in the treatment of rheumatoid arthritis2 is testimony to the importance of this factor. Similarly, several treatments thought to be effective against cold sores have, when tested in the correct format, proved of no significant value.3-7 In our own study 60% of patients experienced excellent response from placebo.7 While this may reflect a major role for psychogenic factors in this disorder, it sets a high standard for other potentially active agents to
improve on.
the ice therapy for cold sores, rather to emphasise the likelihood of a low yield after testing remedies of this type. Ice is safe, cheap, and relatively painless, and even though it may still be just a placebo, if Zimmerman’s women readers say "aye", who should say "nay"? I do
not mean to
decry
.
Patients A and B had been diabetic for 14 and 4 years respectively. B had been maintained on chlorpropamide, but this had been replaced by insulin 2 weeks preoperatively, and both patients were insulindependent at the time of surgery. Controls were not on any form of drug therapy. Vessels were removed during routine abdominal surgery (laparotomy for gallstones, inguinal hernia repair, and arteriovenous fistula) and immediately placed in Krebs’ buffer containing 200 mg/dl glucose at 4°C. Specimens were carefully dissected free of connective tissue, and pieces (3-31 mg wet weight) were cut into fine rings and incubated (10 mg in 100 µl) in Krebs’ buffer (22°C) with gentle agitation for 3 min. The incubations were performed within 10 min of biopsy. Supernatant (5-25 µl) was added to citrated human plateletrich plasma,’ 30 s before addition of a submaximal concentration of adenosine diphosphate (2 µmo1/1). The activity of the supernatant in inhibiting platelet aggregation’ was measured in a double-channel aggregometer (Payton). The presence of P.G.I2 was confirmed by complete loss of platelet inhibitory activity, after incubation with a specific antiserum raised in rabbits to 5,6-dihydro p.G.I2.5 The quantity of P.G.I2 was estimated from a standard curve using authentic P.G.I2 (sodium salt) and expressed as ng/mg wet weight of tissue.2 PROSTACYCLIN IN HUMAN VASCULAR TISSUES
by the inferior epigastric artery from three (0-26±003 ng/mg wet weight) was significantly (P
SIR,-In your Parliamentary correspondent’s report (Dec. 23/30, p. 1388) of the debate on lead pollution it was correctly stated that criticisms had been made in the House of Commons of a "group at Great Ormond Street". As members of that group, we should like to explain the situation. We have, for some years, been involved in work in this area. In the summer of 1978, the Department of Health and Social Security asked us to provide comments on two papers that had recently been delivered by two United States workers, Dr David and Dr Needleman. We prepared a report which was critical, but adequate appraisal was difficult because full details of the work had not been published. Our report was sent to the D.H.S.S. who asked if they could send it out in answer to inquiries made to them. We agreed and, indeed, finally sent it out ourselves in response to a number of further inquiries. We should have sent copies to the workers who had delivered the papers; they do now have copies. In the House of Commons debate it was suggested (Hansard, Dec. 12, pp. 435-444) that we had in some way been unwitting dupes of the D.H.S.S. which was using our report as an excuse for inactivity on the subject. We can only say that, had we thought the information presented in the papers supported a sound case for a major or minor effect of a moderate amount of lead on the intelligence or behaviour of children, we should have said so. We are aware of the possibility of covert influence, but we can only say that we have never consciously felt ourselves to be under the slightest pressure from central Government departments to put forward a particular view. It was further suggested, albeit rather unclearly, that one or more of us had been associated with research sponsored by petrol companies. In 1964 Associated Octel Co. Ltd. donated a flow-through cell (approximate value 10), and a member of the chemical industry donated autoanalyser equipment (approximate value £ 500) to the department of chemical pathology at the Hospital for Sick Children. These donations were received well before the present controversy regarding lead in petrol arose. In fact, none of us has undertaken work sponsored by petrol companies or, indeed, any branch of industry even remotely concerned with the dissemination of lead, nor have we, or our departments, benefited since 1964 financially or in any other way from support from such companies. Department of Chemical Pathology University of Southampton Department of Chemical Pathology,
&
Human Metabolism
Institute of Child Health, London WC1
B. E. CLAYTON
Institute of Child Health
Department of Psychological Medicine, Hospital For Sick Children, London WC1
Belfast and Hume Street Hospital, Dublin
G. A. EDELSTYN
Charing Cross Hospital Medical School, T. DELVES
Department of Child Psychiatry,
between efficacy on the one hand and inconvenience to the patient and toxicity on the other. Unfortunately, only a fraction (perhaps 10-15%) of highrisk patients-i.e., those who are axillary-node positive-are being entered into clinical trials in the U.K., despite the fact that twenty or more trials are in progress. Many of these trials will fail because of lack of numbers, and others will take several years to recruit sufficient patients. Some surgeons and radiotherapists not participating in any trial already "know" the truth of the matter: cytotoxic chemotherapy is unpleasant and expensive, has possible long-term risks, and should be avoided completely; or, in view of the results reported so far, the answer to early breast cancer treatment has been found and all patients can be safely given chemotherapy without further evaluation. Other non-trialists may not know what the truth of the matter is: they are content to rest until the facts emerge and to await a change in fashion before they take action. Finding the facts and leading opinion is for others to do-they are busy enough just treating their patients. For whatever reason, such non-participation in trials has tragic consequences. Answers will take a long time to appear, and every suitable patient not entered into a study adds further to the delay and uncertainty. The problem must not be viewed parochially. We do not suggest that the trial with which we are associated is necessarily the one to join.* Any trial that asks a question whose answer is worth knowing deserves support. Although written in the context of breast cancer, the same point can and should be made about other diseases. Even if a clinician does not have a "special" interest in a certain disease, he should still enter his patients into trials which others organise on a multicentre basis. In the absence of hard data doctors will still form views about the best way to treat patients-the clinical situation demands some action from the clinician even if it is inaction. Whatever our own personal prejudices and doubts, it is only in supporting trials that facts can be substituted for opinion. Non-participation in clinical trials is a decision not to contribute to medical progress and this, surely, is morally, if not professionally, indefensible. Northern Ireland Radiotherapy Centre, Belvoir Park Hospital,
P. J. GRAHAM
London W6
K. D. MACRAE
SIR,—On Nov. 23, 1978, the Cancer Research Campaign a meeting to review the progress of the U.K. multicollaborative trial of adjuvant hormono-chemotherapy in poor-risk patients with early carcinoma of the breast. This meeting provided an opportunity for the steering committee of that study to meet with the organisers of the King’s College Hospital breast cancer trials. Both groups agreed on the fol-
sponsored centre
R. LANSDOWN
TRIALS OF ADJUVANT CHEMOTHERAPY IN BREAST CANCER
SIR,—Death in breast cancer usually results from micrometastatic dissemination to bone, lung, liver, and brain which has settled the outcome before treatment is given. Attempts to deal with such micrometastatic spread by the use of cytotoxic regimens after primary therapy’-3 have improved disease-free intervals, and the indications are that death-rates may also be reduced. Nevertheless, much longer follow-up is needed to see if this early encouraging response is sustained. Further studies are also required to explore the various cytotoxic options to see if, for such therapy, a more favourable balance can be struck 1. Fisher, B. Cancer, 1977, 40, 574. 2. Bonadonna, G., and others. A. Rev. Med. 1978, 29, 149. 3. Edelstyn, G. A., Bates, T., Brinkley, D., Kitchen, G., MacRae, K. N. T., Spittle, M., Wheeler, T. Lancet, 1978, ii, 1092.
D., Nicol,
lowing points: (1) It is justifiable to conduct adjuvant therapy studies in poorrisk early-breast-cancer patients whilst still retaining a control arm.
(2) There is sufficient evidence both on theoretical and on experimental groundsi-3 and in work done in advanced disease 4,5 to study the potential advantages of combining chemotherapy and hormone therapy over either modality alone or as adjuvant treatment. *For information apply to: Co-ordinator, Multicentre Breast Cancer Chemotherapy Group, 127 Marlborough Park South, Belfast BT9 6HW. 1. Lippman, M. E., and others New Engl. J. Med. 1978, 298, 1223. 2. Meakin, J. W., and others in Adjuvant Therapy of Cancer (edited Salmon and S. E. Jones). Amsterdam, 1977. 3. Braunsberg, H., and others Lancet, 1973, i, 163. 4. Tormey, D. C. Proc. Am. Ass. Cancer Res. 1978, abstr. 134. 5. Cavalli, F. 4th int. Congr. Chemother. 1977, abstr. 510, 615.
by S. E.
325
(3) Both groups have launched trials of similar design that will study different aspects of this problem. Their cumulative results will be of great value but will depend on recruiting sufficient numbers of patients to each trial. (4) Despite the overwhelming evidence supporting the need for such studies, most poor-risk early-breast-cancer patients in the U.K. are not entered into any trial where the value of adjuvant therapy can be assessed. We therefore ask clinicians in charge of eligible patients to give serious thought to collaborating
VASCULAR PROSTACYCLIN MAY BE REDUCED IN DIABETES IN MAN
SIR,-Vascular endothelium generates prostacyclin (P.G.I2), potent inhibitor of platelet aggregation.’ We have found that aorta2and renal cortex3 from streptozotocin-diabetic rats produce significantly less P.G.I2 than do tissues from control animals. To assess the clinical relevance of these findings, we have now estimated P.G.I2 release by vessels from diabetics and nondiabetics. a
with one or other of these studies. (5) Centres which enter a substantial number of patients will be provided with secretarial or other assistance to facilitate the conduct of the trial. Further information can be obtained from either of us regarding both trials, so that clinicians can choose which they would feel to be most appropriate for them to join.
Department of Radiotherapy, Royal Free Hospital,
F. SENANAYAKE
London NW3
Department of Surgery, King’s College Hospital Medical School, M. BAUM
London SE5
*,*A
note on
the latest U.I.C.C.
and other cancers appears
on
compendium of trials
in breast
p. 339.-ED. L.
SELF-TREATMENT OF COLD SORES WITH ICE
SIR,—Dr Zimmerman’ draws attention to the absence of a clinical trial of ice as a treatment for cold sores and points out that, in general, clinical trials to test non-pharmaceutical "household" remedies are seldom done. This is a valid criticism and reflects on the usual sources of drug-trial funds and on the low prestige attached to this type of investigation compared with studies with an aura of basic science. Another aspect-perhaps the most important one-is the difficulty in deciding which, if any, of these remedies is really likely to be successful and therefore warrants the major effort required to arrange and monitor a double-blind, controlled trial. If household remedies are extended to include the vast array of purportedly successful "traditional remedies" used in Asian medicine, the task of selecting those worthy of formal testing becomes staggering. I do not entirely envy Zimmerman his access to the medical views of 18 million women, for with such a group-as with any other-the strength of the placebo response must not be underestimated. The vast array of "simple" remedies now discarded but once heralded as successful in the treatment of rheumatoid arthritis2 is testimony to the importance of this factor. Similarly, several treatments thought to be effective against cold sores have, when tested in the correct format, proved of no significant value.3-7 In our own study 60% of patients experienced excellent response from placebo.7 While this may reflect a major role for psychogenic factors in this disorder, it sets a high standard for other potentially active agents to
improve on.
the ice therapy for cold sores, rather to emphasise the likelihood of a low yield after testing remedies of this type. Ice is safe, cheap, and relatively painless, and even though it may still be just a placebo, if Zimmerman’s women readers say "aye", who should say "nay"? I do
not mean to
decry
.
Patients A and B had been diabetic for 14 and 4 years respectively. B had been maintained on chlorpropamide, but this had been replaced by insulin 2 weeks preoperatively, and both patients were insulindependent at the time of surgery. Controls were not on any form of drug therapy. Vessels were removed during routine abdominal surgery (laparotomy for gallstones, inguinal hernia repair, and arteriovenous fistula) and immediately placed in Krebs’ buffer containing 200 mg/dl glucose at 4°C. Specimens were carefully dissected free of connective tissue, and pieces (3-31 mg wet weight) were cut into fine rings and incubated (10 mg in 100 µl) in Krebs’ buffer (22°C) with gentle agitation for 3 min. The incubations were performed within 10 min of biopsy. Supernatant (5-25 µl) was added to citrated human plateletrich plasma,’ 30 s before addition of a submaximal concentration of adenosine diphosphate (2 µmo1/1). The activity of the supernatant in inhibiting platelet aggregation’ was measured in a double-channel aggregometer (Payton). The presence of P.G.I2 was confirmed by complete loss of platelet inhibitory activity, after incubation with a specific antiserum raised in rabbits to 5,6-dihydro p.G.I2.5 The quantity of P.G.I2 was estimated from a standard curve using authentic P.G.I2 (sodium salt) and expressed as ng/mg wet weight of tissue.2 PROSTACYCLIN IN HUMAN VASCULAR TISSUES
by the inferior epigastric artery from three (0-26±003 ng/mg wet weight) was significantly (P
