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Treatment of Early Cancer of the Breast
1175 man, including their antibiotic resistance. each In area, a veterinary officer should be responsible for investigating infectious diseases in animals; and he should have powers to limit their spread. Further study is needed of how infectious diseases do in fact spread in herds or flocks; and research is called for into the efficacy, feasibility, and economic consequences of deliberate changes in animal husbandry. Departments of veterinary epidemiology should be established in universities. The advocacy of such measures reflects one of the committee’s chief conclusions-that modification of husbandry methods, planned in the light of epidemiological facts, is likely to be, in the end, more effective and safer than attempts to control disease by antibiotics.
ducts, and
Treatment of Early Cancer of the Breast THE best treatment for a patient with early cancer of the breast is not known. Little information exists about which of the different treatments now in use alter the course of the disease for the good of the patient, which have little or no effect, and which may even be harmful. Only prospective randomised clinical trials on large numbers of patients can provide firm facts on which rational decisions can be based. Four such trials have been proceeding. In Copenhagen1 the effects of extended radical mastectomy have been compared with simple mastectomy and radical radiotherapy. At Guy’s Hospital2 the results of standard radical mastectomy are being compared with wedge excision of the tumour from the breast, both groups receiving radiotherapy. At Cambridge3 simple mastectomy has been compared with standard radical mastectomy, again both groups receiving radiotherapy. In Manchester4 all patients underwent standard radical mastectomy; one group then received routine postoperative radiotherapy, and the other did not. Large numbers of patients were included in each of these trials, but no significant difference emerged in the survival-rates in the groups compared. It was assumed in each trial that treatment of the regional lymph-nodes, by surgery or radiotherapy, was necessary ; and this resulted in a final common pathway of radical treatment which reflects the traditional view of tumour spread. It has been assumed that the tumour spreads progressively through the lymphatic system and, usually at a later date, by the bloodstream to produce distant metastases. Thus, the tumour should be confined for some time to the breast and adjacent lymph-nodes. Radical treatment should eliminate the disease in a certain proportion of patients. Conservative local treatment, on this hypothesis, should result in cure in a smaller pro1.
2. 3. 4.
Kaae, S., Johansen, H. in Prognostic Factors in Breast Cancer: Proceedings of 1st Tenovus Symposium, Cardiff, 1967 (edited by A. P. M. Forrest and P. B. Kunkler); p. 93. Edinburgh, 1968. Atkins, H. J. B., Hayward, J. L. Proc. R. Soc. Med. (in the press). Brinkley, D. M., Haybittle, J. L. Lancet, 1966, ii, 291. Easson, E. C. in Prognostic Factors in Breast Cancer: Proceedings of 1st Tenovus Symposium, Cardiff, 1967 (edited by A. P. M. Forrest and P. B. Kunkler); p. 118. Edinburgh, 1968.
portion. What evidence is there that the treatment of regional lymph-nodes improves the prognosis ? In the Manchester trialthose patients who received no radiotherapy to the internal mammary nodes, even though they had medial-quadrant tumours, fared no worse than those who did receive treatment. Again, CRILE5 reported a series where the axillary nodes were not treated and where the patients fared no worse than those who had their axillae cleared of lymph-nodes. There is indeed some evidence s-8, although in no way conclusive, that routine radiotherapy for regional lymph-nodes may actually reduce the survival-time of patients. How might the ablation of regional lymph-nodes be harmful ? The indications are increasing that immune mechanisms play some part in the resistance of the host to tumour growth. They are seen histologically as sinus histiocytosis in the draining lymph-nodes and as lymphocytic infiltration at the periphery of the tumours; and differences in immediate and delayed hypersensitivity responses have been demonstrated between cancerfree patients and those with early cancer.9,10 Perhaps another approach is necessary. The question centres on the role of regional lymph-nodes. The radical approach suggests that, even in early cancer of the breast, nodes should be treated, because they may contain tumour cells, whether they are palpable or not. On the other hand, these nodes may well be important in the natural defences, even if they do contain residual tumour foci." Moreover, if the regional nodes are enlarged clinically, this does not necessarily mean that they have been invaded by malignant cells. The enlargement may represent a reaction to the tumour growth.ll If the conservative view is held, then nodes should be left undisturbed, whether they are palpable or not. This " watch policy " does not prohibit the eventual treatment of nodes which go on advancing in size or seem likely to result in local complications. In order to determine whether the treatment of regional lymph-nodes is of benefit or is harmful in patients with early cancer of the breast, a multi-centre prospective controlled clinical trial is to be carried out in this country. A meeting was held at Cambridge on Sept. 27 to discuss the form of the trial.* Representatives from most of the major centres heard an outline of the aims and methods of the trial from clinicians of King’s College Hospital, London, and Addenbrooke’s Hospital, Cambridge. Other hospitals were invited * Further details of the trial may be had from the Department of Surgery, King’s College Hospital, London S.E.5. 5. Crile, G. Jr. Ann. Surg. 1968, 168, 330. 6. Bond, W. H. Proceedings of a Symposium in Gonville & Caius College, Cambridge, September, 1967 (edited by A. S. Jarrett). Exerpta Medica Foundation, London. 7. Milnes-Walker, R. Ann. R. Coll. Surg. Engl. 1968, 42, 145. 8. Hamlin, I. M. E. Br. J. Cancer 1968, 22, 383. 9. Mackay, W. D. ibid. 1966, 20, 434. 10. Soloway, A. C., Rapaport, F. T. Surgery Gynec. Obstet. 1965, 121, 756. 11. Black, M. M., Speer, F. P. ibid. 1958, 106, 163.
1176
join the trial. A computer will be used to store and analyse the clinical and histological information about recurrence, morbidity, and survival-times. The computer will allow detection of any significant advantage or disadvantage of any form of treatment at the earliest possible moment, so that the management of patients can be flexible. It is expected that all the patients entering this trial will be found within two years and they will be followed up for at least ten years after that. Among the many clinicians at the Cambridge meeting disquiet about the treatment of early cancer of the breast was evident. As long as the response at the meeting is sustained, then reliable evidence, on a national scale, will now be secured. to
lent amount of cation during its passage through the gut, regardless of the particular cation with which it is given. The purgative action of magnesium, another ion which is poorly absorbed, could be similarly explained. Yet magnesium is an ion of many parts, and the possibility of a direct effect of a high concentration of magnesium on the motility of intestinal muscle cannot be discounted. Other, less scientific, observations have suggested that sulphate has the edge over magnesium as a purgative. Thus it has been said3 of Harrogate spa-water that after two glasses of sulphur-water it was necessary to " belt back to your hotel like hell ", whereas after
magnesia water " you can proceed at a and dignified pace ". Much remains
more
leisurely
be learned about the transport and effects of these and other ions in the colon. to
Annotations RUNNING-WATER
SPRING-WATER has raised spas, founded fortunes, and both caused and cured diarrhoea, cause being commoner than cure. One cure, the Tilbury water, was graced by no less than a laudatory pamphlet1 written by an eminent physician, later physician to the London Hospital. Dr. Andree’s pamphlet contained an analysis of the water performed " at the request of some gentlemen of the Royal Society by Mr. White, Chymist at Apothecaries Hall ". Mr. White was an analyst of broad experience, for we read that clearly " the aforesaid ingenious Mr. White thinks that this salt (obtained by evaporating two pounds of the water to dryness) was nearest of any thing to a salt he formerly got from distilled Crabs-Claws and Oyster shells ". The healing properties of Tilbury water were discovered by a certain Mr. Kellaway, who may have suffered from lactose intolerance, for, although partial " to milk, it seldom fail’d of giving him some loose stools ". One day he took a glass of Tilbury water before a drink of milk and to his astonishment the milk no longer purged him. A paper2 from Saskatchewan reports diarrhoea in infants who drank water from local wells. These waters contained sulphate in a concentration of 6001000 mg. per litre. The water was boiled before use, no microorganisms were found, and diarrhoea could be induced or cured simply by manipulation of the sulphate concentration in the water. On the Canadian prairie many wells yield water which contains such a high concentration of minerals that it is too bitter to drink; water from other wells is palatable yet may cause diarrhoea. Sodium, magnesium, and calcium were the most abundant cations in these waters. Sodium always exceeded magnesium. The high sulphate concentration was sufficient by itself to account for the diarrhoea. Sulphate is poorly absorbed and its purgative action can be explained entirely by its osmotic effect. The absorbability of the cation given with sulphate probably does not affect the purgative potency of the salt, because sulphate retains an equiva1.
2.
Andrée, J. An Account of the Tilbury Water. London, 1737. Chien, L., Robertson, H., Gerrard, J. W. Can. med. Ass. J. 1968, 99, 102.
MINI-EXCHANGE TRANSFUSION IN THROMBOCYTOPENIA
WHEN thrombocytopenia has caused extensive purpura and bleeding from mucous membranes so that the haemoglobin level is much reduced, current practice is to give a transfusion either of fresh blood, usually collected into plastic bags, or of platelet concentrates. The platelet concentrates are expensive in material and their effect tends to be limited, since resistance and diminishing survival of transfused platelets soon appears. The object of transfusion is to stop loss of blood by raising the bleeding-time to normal and to replace the volume lost, thus preventing shock or cardiac failure. But Shaw 4 believes that we are not getting the best effect from blood-transfusion and that better results could be obtained by a technique which he fashionably calls " mini-exchange transfusion ". Shaw maintains that loss of blood-volume is often disregarded in assessing the situation, especially when petechiae are the chief clinical sign. In thrombocytopenic purpura, Shaw estimates bleeding-time, by Duke or Ivy technique, in order to determine the severity of the bleeding abnormality, and he measures the serum-protein level by a copper-sulphate method and uses the result as an indication of the extent of blood-loss. He takes as normal a haemoglobin level of 15-0 g. per 100 ml. (with a diurnal variation of 0-5-1-0 g.) and a serum-protein of 7-0 g. per 100 ml. (0-3-0-6 g.). The critical level of serum-protein, below which signs of shock, liver failure, or oederna are likely to appear, he puts at 5-3 g. per 100 ml. In his patients, in all of whom thrombocytopenia had developed after treatment with drugs such as chloramphenicol or phenylbutazone, serum-protein levels did not fall as low as this as a rule, but some figures were under 6’4 g. per 100 ml., denoting considerable blood-loss. " Replace" ment of this loss ", Shaw says, is not only necessary to prevent the onset of shock, if further losses occur, but is also essential for the preservation of normal vasoconstriction. Without this, haemorrhage will not cease, even in the presence of the normal quantity and quality of platelets and coagulation factors." 3. The Guardian, Aug. 9, 1969. 4. Shaw, A. E. Med. J. Aust. 1969,
ii,
529.
ducts, and
Treatment of Early Cancer of the Breast THE best treatment for a patient with early cancer of the breast is not known. Little information exists about which of the different treatments now in use alter the course of the disease for the good of the patient, which have little or no effect, and which may even be harmful. Only prospective randomised clinical trials on large numbers of patients can provide firm facts on which rational decisions can be based. Four such trials have been proceeding. In Copenhagen1 the effects of extended radical mastectomy have been compared with simple mastectomy and radical radiotherapy. At Guy’s Hospital2 the results of standard radical mastectomy are being compared with wedge excision of the tumour from the breast, both groups receiving radiotherapy. At Cambridge3 simple mastectomy has been compared with standard radical mastectomy, again both groups receiving radiotherapy. In Manchester4 all patients underwent standard radical mastectomy; one group then received routine postoperative radiotherapy, and the other did not. Large numbers of patients were included in each of these trials, but no significant difference emerged in the survival-rates in the groups compared. It was assumed in each trial that treatment of the regional lymph-nodes, by surgery or radiotherapy, was necessary ; and this resulted in a final common pathway of radical treatment which reflects the traditional view of tumour spread. It has been assumed that the tumour spreads progressively through the lymphatic system and, usually at a later date, by the bloodstream to produce distant metastases. Thus, the tumour should be confined for some time to the breast and adjacent lymph-nodes. Radical treatment should eliminate the disease in a certain proportion of patients. Conservative local treatment, on this hypothesis, should result in cure in a smaller pro1.
2. 3. 4.
Kaae, S., Johansen, H. in Prognostic Factors in Breast Cancer: Proceedings of 1st Tenovus Symposium, Cardiff, 1967 (edited by A. P. M. Forrest and P. B. Kunkler); p. 93. Edinburgh, 1968. Atkins, H. J. B., Hayward, J. L. Proc. R. Soc. Med. (in the press). Brinkley, D. M., Haybittle, J. L. Lancet, 1966, ii, 291. Easson, E. C. in Prognostic Factors in Breast Cancer: Proceedings of 1st Tenovus Symposium, Cardiff, 1967 (edited by A. P. M. Forrest and P. B. Kunkler); p. 118. Edinburgh, 1968.
portion. What evidence is there that the treatment of regional lymph-nodes improves the prognosis ? In the Manchester trialthose patients who received no radiotherapy to the internal mammary nodes, even though they had medial-quadrant tumours, fared no worse than those who did receive treatment. Again, CRILE5 reported a series where the axillary nodes were not treated and where the patients fared no worse than those who had their axillae cleared of lymph-nodes. There is indeed some evidence s-8, although in no way conclusive, that routine radiotherapy for regional lymph-nodes may actually reduce the survival-time of patients. How might the ablation of regional lymph-nodes be harmful ? The indications are increasing that immune mechanisms play some part in the resistance of the host to tumour growth. They are seen histologically as sinus histiocytosis in the draining lymph-nodes and as lymphocytic infiltration at the periphery of the tumours; and differences in immediate and delayed hypersensitivity responses have been demonstrated between cancerfree patients and those with early cancer.9,10 Perhaps another approach is necessary. The question centres on the role of regional lymph-nodes. The radical approach suggests that, even in early cancer of the breast, nodes should be treated, because they may contain tumour cells, whether they are palpable or not. On the other hand, these nodes may well be important in the natural defences, even if they do contain residual tumour foci." Moreover, if the regional nodes are enlarged clinically, this does not necessarily mean that they have been invaded by malignant cells. The enlargement may represent a reaction to the tumour growth.ll If the conservative view is held, then nodes should be left undisturbed, whether they are palpable or not. This " watch policy " does not prohibit the eventual treatment of nodes which go on advancing in size or seem likely to result in local complications. In order to determine whether the treatment of regional lymph-nodes is of benefit or is harmful in patients with early cancer of the breast, a multi-centre prospective controlled clinical trial is to be carried out in this country. A meeting was held at Cambridge on Sept. 27 to discuss the form of the trial.* Representatives from most of the major centres heard an outline of the aims and methods of the trial from clinicians of King’s College Hospital, London, and Addenbrooke’s Hospital, Cambridge. Other hospitals were invited * Further details of the trial may be had from the Department of Surgery, King’s College Hospital, London S.E.5. 5. Crile, G. Jr. Ann. Surg. 1968, 168, 330. 6. Bond, W. H. Proceedings of a Symposium in Gonville & Caius College, Cambridge, September, 1967 (edited by A. S. Jarrett). Exerpta Medica Foundation, London. 7. Milnes-Walker, R. Ann. R. Coll. Surg. Engl. 1968, 42, 145. 8. Hamlin, I. M. E. Br. J. Cancer 1968, 22, 383. 9. Mackay, W. D. ibid. 1966, 20, 434. 10. Soloway, A. C., Rapaport, F. T. Surgery Gynec. Obstet. 1965, 121, 756. 11. Black, M. M., Speer, F. P. ibid. 1958, 106, 163.
1176
join the trial. A computer will be used to store and analyse the clinical and histological information about recurrence, morbidity, and survival-times. The computer will allow detection of any significant advantage or disadvantage of any form of treatment at the earliest possible moment, so that the management of patients can be flexible. It is expected that all the patients entering this trial will be found within two years and they will be followed up for at least ten years after that. Among the many clinicians at the Cambridge meeting disquiet about the treatment of early cancer of the breast was evident. As long as the response at the meeting is sustained, then reliable evidence, on a national scale, will now be secured. to
lent amount of cation during its passage through the gut, regardless of the particular cation with which it is given. The purgative action of magnesium, another ion which is poorly absorbed, could be similarly explained. Yet magnesium is an ion of many parts, and the possibility of a direct effect of a high concentration of magnesium on the motility of intestinal muscle cannot be discounted. Other, less scientific, observations have suggested that sulphate has the edge over magnesium as a purgative. Thus it has been said3 of Harrogate spa-water that after two glasses of sulphur-water it was necessary to " belt back to your hotel like hell ", whereas after
magnesia water " you can proceed at a and dignified pace ". Much remains
more
leisurely
be learned about the transport and effects of these and other ions in the colon. to
Annotations RUNNING-WATER
SPRING-WATER has raised spas, founded fortunes, and both caused and cured diarrhoea, cause being commoner than cure. One cure, the Tilbury water, was graced by no less than a laudatory pamphlet1 written by an eminent physician, later physician to the London Hospital. Dr. Andree’s pamphlet contained an analysis of the water performed " at the request of some gentlemen of the Royal Society by Mr. White, Chymist at Apothecaries Hall ". Mr. White was an analyst of broad experience, for we read that clearly " the aforesaid ingenious Mr. White thinks that this salt (obtained by evaporating two pounds of the water to dryness) was nearest of any thing to a salt he formerly got from distilled Crabs-Claws and Oyster shells ". The healing properties of Tilbury water were discovered by a certain Mr. Kellaway, who may have suffered from lactose intolerance, for, although partial " to milk, it seldom fail’d of giving him some loose stools ". One day he took a glass of Tilbury water before a drink of milk and to his astonishment the milk no longer purged him. A paper2 from Saskatchewan reports diarrhoea in infants who drank water from local wells. These waters contained sulphate in a concentration of 6001000 mg. per litre. The water was boiled before use, no microorganisms were found, and diarrhoea could be induced or cured simply by manipulation of the sulphate concentration in the water. On the Canadian prairie many wells yield water which contains such a high concentration of minerals that it is too bitter to drink; water from other wells is palatable yet may cause diarrhoea. Sodium, magnesium, and calcium were the most abundant cations in these waters. Sodium always exceeded magnesium. The high sulphate concentration was sufficient by itself to account for the diarrhoea. Sulphate is poorly absorbed and its purgative action can be explained entirely by its osmotic effect. The absorbability of the cation given with sulphate probably does not affect the purgative potency of the salt, because sulphate retains an equiva1.
2.
Andrée, J. An Account of the Tilbury Water. London, 1737. Chien, L., Robertson, H., Gerrard, J. W. Can. med. Ass. J. 1968, 99, 102.
MINI-EXCHANGE TRANSFUSION IN THROMBOCYTOPENIA
WHEN thrombocytopenia has caused extensive purpura and bleeding from mucous membranes so that the haemoglobin level is much reduced, current practice is to give a transfusion either of fresh blood, usually collected into plastic bags, or of platelet concentrates. The platelet concentrates are expensive in material and their effect tends to be limited, since resistance and diminishing survival of transfused platelets soon appears. The object of transfusion is to stop loss of blood by raising the bleeding-time to normal and to replace the volume lost, thus preventing shock or cardiac failure. But Shaw 4 believes that we are not getting the best effect from blood-transfusion and that better results could be obtained by a technique which he fashionably calls " mini-exchange transfusion ". Shaw maintains that loss of blood-volume is often disregarded in assessing the situation, especially when petechiae are the chief clinical sign. In thrombocytopenic purpura, Shaw estimates bleeding-time, by Duke or Ivy technique, in order to determine the severity of the bleeding abnormality, and he measures the serum-protein level by a copper-sulphate method and uses the result as an indication of the extent of blood-loss. He takes as normal a haemoglobin level of 15-0 g. per 100 ml. (with a diurnal variation of 0-5-1-0 g.) and a serum-protein of 7-0 g. per 100 ml. (0-3-0-6 g.). The critical level of serum-protein, below which signs of shock, liver failure, or oederna are likely to appear, he puts at 5-3 g. per 100 ml. In his patients, in all of whom thrombocytopenia had developed after treatment with drugs such as chloramphenicol or phenylbutazone, serum-protein levels did not fall as low as this as a rule, but some figures were under 6’4 g. per 100 ml., denoting considerable blood-loss. " Replace" ment of this loss ", Shaw says, is not only necessary to prevent the onset of shock, if further losses occur, but is also essential for the preservation of normal vasoconstriction. Without this, haemorrhage will not cease, even in the presence of the normal quantity and quality of platelets and coagulation factors." 3. The Guardian, Aug. 9, 1969. 4. Shaw, A. E. Med. J. Aust. 1969,
ii,
529.