718
ible way of predicting the clinical course of the disease (except the insensitive method of nodecounting), what are the options for local therapy? Some workers judge that, because local treatment has little influence on development of distant metastases and on survival, the actual method is of little consequence in most cases. Nevertheless, local control is important; clinical trials now in progress may soon indicate the most efficient way of achieving this in different clinical states. These trials will not, of course, be the final word, since the results of any local treatment might be greatly modified by adjuvant therapy. (At present, trials of adjuvant systemic treatment are reserved for patients with
stage-II disease.) Accurate staging depends on knowledge of axillary lymph-node status, which in turn demands complete axillary clearance with histopathological examination of the lymph-nodes. Therefore the general view is that, although different surgical procedures may not give different therapeutic results, the most satisfactory surgical for early breast cancer at present is total mastectomy with complete axillary clearance. This achieves local control of the disease and provides a maximum of prognostic information. What of adjuvant systemic treatment? The main thrust here has been in postoperative chemotherapy, because subclinical cancer should in theory be more sensitive than a large tumour load to cytotoxic drugs, and because the tumour cell populations would follow first-order kinetics. Preliminary results of pioneer trials in the United States and Italy engendered some optimism. The National Surgical Adjuvant Breast Project treatment
(N.S.A.B.P.) employed L-phenylalanine mustard,’ and BONADONNA and his colleagues,8 in Milan, used a combination of cyclophosphamide, methotrexate, and 5-fluorouracil. In premenopausal patients, but not postmenopausal patients, adjuvant chemotherapy lengthened the disease-free interval after mastectomy. Actuarial analysis of the Milan trial at four years suggests that a significant benefit in survival may also be achieved. Despite the cautions uttered by FiSHER7 and BONADONNA8 and their colleagues, the results of these trials are now being used by many clinicians as’a basis for routine treatThis may be unwise: corroboration is needed wide variety of trials. The results of the scrupulously conducted N.S.A.B.P. and Milan trials are not in question, but they might not be reproduced in other centres treating different populations. Furthermore, before adjuvant chemotherapy can safely be used routinely it is essential ment.
from
a
Carbone, P., Economu, S. G., Frelick, R., Glass, A., Lerner, H., Redmond, L., Zelen, M., Band, P , Katrych, D. L., Wolmark, N., Fishe, E. R., and other cooperating investigators. New Engl. J. Med. 1975, 292,
7. Fisher, B.,
117. 8.
Bonadonna, G., Brusamolino, E., Valagussa, P., Rossi, A., Brugnatelli, L., Brambilla, C., De Lena, M., Tancini, G., Bajetta, E., Musmeci, R., Veronesi, U. ibid. 1976, 294, 405.
information on long-term survival and For the present, adjuvant chemotherapy is toxicity. experimental and its use should be confined to prospective controlled clinical trials: premature adoption for routine treatment could do patients a great disservice. An encouraging report of the effectiveness of prophylactic ovarian irradiation plus prednisone in premenopausal patients9 similarly needs confirmation, while the combination of endocrine therapy with cytotoxic chemotherapy presents a further possibility to be investigated. Because hormonal procedures could either suppress or stimulate tumour growth, the scheduling of such combined treatment is likely to be important: it might well determine whether combined treatment is additive, synergistic, or antagonistic. Information on this should be derived initially from observations in, advanced disease. Few general recommendations can be made on the "best" treatment for early breast cancer. The only way forward is by well-designed controlled prospective clinical trials in which careful attention is given to prognostic variables. Future trials will have to encompass very large numbers of patients, and the day of the parochial trial with a few patients in each arm is over. to secure
a
MARATHON RUNNERS AND ISCHAEMIC HEARTDISEASE Is exercise an important prophylactic against ischxmic heart-disease? The work of Morris 12 poses many questions. Stamler’s latest review3 of major coronary risk factors and lifestyles concentrates on diet, smoking, and hypertension with no mention of exercise. If exercise protects against ischxmic heart-disease, how much and what sort of exercise is required? Is the effect of lack of exercise independent of the other risk factors or is it mainly mediated by the other risk factors such as serum lipids, the high-density-lipoprotein component of which is high in people who take exercise and is negatively correlated with ischxmic heart-disease?45 How safe is exercise ? In the United States the jogging epidemic has given rise to events such as the Boston marathon, which now attracts more than 3000 runners, and doubtless such spectacles will soon become commonplace. In Britain the Sunday Times National Fun Run already has 11 000 entries. If some exercise is good for you, is one or two hours a day, the marathon runner’s stint, even better? The marathon runner has been regarded as a physiological freak, with his large slow-beating heart, lean wasted 9. Meakin, J W., Allt, W. E. C., Beale, F. A., Brown, T. C., Bush, R. S., Clark, R. M., Fitzpatrick, P. J., Hawkins, N. V., Jenkin, R. D T., Pringle, J. F, Rider, W. D., Hayward, J. L., Bulbrook, R. D. in Adjuvant Therapy of Cancer (edited by S. E. Salmon and S. E. Jones); p. 95. Amsterdam, 1977. 1. Morris, J. N., Heady, A. J., Raffle, P. A., et al. Lancet, 1953, ii, 1053, 1111. 2. Morris, J. N , Chave, S. P. W., Adam, C., et al. ibid. 1973, i, 333. 3. Stamler, J. Circulation, 1978, 58, 3. 4 Martin, R. P., Haskell, W. L., Wood, P. D. Ann. N.Y. Acad. Sci. 1977, 301, 346. 5. Miller, G. J., Miller, N. E., Lancet, 1975, i, 16.
719
appearance, and often abnormal electrocardiogram.6 Since the necropsy report on "Mr Marathon", Clarence DeMar, who was a highly successful runner for over 50 years, and whose heart showed physiological enlargement with widely patent atheroma-free coronary arteriesl-and particularly since Basslerdaringly claimed that there had been no death from atheromatous coronary artery disease in anyone who had completed the full marathon distance of 42 195 m (26 miles, 385 yards)-there has been increasing medical interest in marathon runners. The proceedings of a conference on the marathon have lately been published, and Olivier et al.10 have written on ischxmic heart-disease in marathon runners. The elite marathon runner is lean, under 40 years of age, and unlikely to smoke. Since he produces heat at the rate of over a kilowatt when he is running at his racing speed of 1 mile every five minutes and has a maximum sweat rate of 1-5 1/h at his racing rectal temperature of 39-41 °C, heat-stroke, fluid depletion, traffic accidents, and canine assault are more obvious hazards than myocardial infarction. Olivier et al. have looked at a group of non-elite middle-aged (>40 y) participants in the 1976 Comrades Marathon, a 90 km race in South Africa. They obtained the cooperation of 48 out of 438 of these veteran runners, who were therefore not randomly selected, with the aim of looking for evidence of ischaemic heart-disease. This group averaged 1000 miles a year in training (as opposed to the 5000 miles of elite marathon runners). They had pre-race E.C.G.s, and as soon as possible after the finish a repeat E.c.G. was done and some competitors had blood-samples taken. Although none of the runners had symptoms suggestive of ischaemic heart-disease, Olivier et al. judged that the E.C.G.S of 23 of the 48 runners showed ST segment changes consistent with "early" ischxmic heart-disease. The serum-creatine-kinase was strikingly raised in most runners in whom samples were obtained, and in 11 samples checked for the reputedly specific cardiac component, the Marsh-Bender (MB) fraction, this was also raised. Both E.C.G. and enzyme evidence of ischaemic heart-disease are, however, suspect. The E.c.G.s were all resting traces, and the specificity of the ST-segment abnormalities, in a symptomless athletic population, is very doubtful. The repeatability of the E.c.G.s was poor. A multitude of E.C.G. abnormalities have been reported in athletes with no clinical evidence of heart-disease.6 11 The enzyme changes probably reflected an increase in membrane permeability as a result of the prolonged exertion and heat load. Other workers have obtained similar results.12 For example, blood-samples from five competitors in a 100-mile race showed lactate dehydrogenase and aminotransferare levels that would normally be taken as diagnostic of severe tissue damage. 13I The diagnosis of ischxmic heart-disease in marathon runners by these techniques is therefore difficult, and the
relevance of cardiac events in this selfselected group is anyway hard to assess. The Bassler hypothesis and resulting controversy is fully explored in the publication from the New York Academy of Sciences.8 Enthusiasts such as Kavanagh and Bassler, who regard marathon running as the "logical graduation ceremony" of cardiac rehabilitation, argue the toss with statisticians and devil’s advocates. What emerges is a great deal of suggestive evidence for the benefits of prolonged exercise, not only in improving exercise tolerance and a feeling of wellbeing, but also in preventing coronary atheroma. Scientific proof is still lacking.
epidemiological
-
6. Tunstall Pedoe, D. S., Thomason, H Sports Medicine (edited by J. G. P. Williams and P. N. Spenyn); p. 174. 7. Currens, J., White, P. D., New Engl. J. Med. 1961, 265, 988. 8. Bassler, T.J., Lancet, 1972, ii, 711. 8. Milvy, P. (editor) Ann. N. Y. Acad. Sci. 1977, 301. 10. Olivier, L. R., De Waal, A., Retief, F. J , et al. S. Afr. med. J. 1978, 53, 783. 11. Lichtman, J , O’Rourke, R. A., Klein, A., Karliner, J. S. Archs intern Med.
1973, 132, 763. 12 La Porta M. A., Linde, H. W, Bruce, D. L., Fitzsimons, E.
Ass. 1978, 239, 2685. 13. Brotherhood, J , Tunstall Pedoe, D. S. Unpublished.
J. J.
Am. med.
M.B.LOND. (FAILED) THE Guy’s Hospital Gazette mourns an overall failure-rate of 23% in the final M.B., B.s. examination and highlights a 30% rejection-rate in surgery by comparison with 9% in medicine. The Guy’s experience focuses once again on a perennial question: what are the final examinations all about and do they achieve anything more than stimulation of the sympathetic nervous system and a random failure-rate largely unrelated (as the Guy’s editor claims) to medical competence? The matter is so complex as almost to defy analysis. British examinations-particularly those conducted in London -are almost totally without external standards; are validated only by a long tradition of "good examining" by those (usually senior members of the profession) who believe without evidence that they are maintaining constancy of requirements from one year to the other; and are largely devoid of any defined syllabus about which the candidate can say "here is examinable material". Add to this an alternative examination system (in London and Scotland at least) and, in many places, curious marking systems that apparently allow a candidate to pass if he displays a 50% understanding of his subject but prevents him from achieving more than a 60% total mark (the close system), and the recipe for chaos is com-
plete. We must charitably assume that the final examination is designed to give a limited licence to practise. Though it is largely administered by universities it is thus not a university examination, the essential feature of which is scholarship-which can broadly be defined as the ability to respond to intellectual challenge and to display mastery of a subject in depth. In consequence it tends to be neither a test of intellect nor an assessment of competence. It comes at the end of a period of study and training by young people who have been so highly selected that it is inconceivable that-psychiatric and social reasons
apart-they
can
ultimately fail. Dispassionately
viewed it can be argued that the formal final examination is a waste of time; and some institutions have tacitly accepted this judgment, downgrading the sudden-death final, incorporating continuous assessment (which can create its own tyranny), and generally assuming that, given a minimal standard of achievement, the student is bound to pass. The learning process is thus blended with the examining process in a way that educational theoreticians delight to see, though which they rarely justify by an appeal to experiment. But if the formal final is to 1
Guy’s Hospital Gazette, 1978, 93, 273.
ible way of predicting the clinical course of the disease (except the insensitive method of nodecounting), what are the options for local therapy? Some workers judge that, because local treatment has little influence on development of distant metastases and on survival, the actual method is of little consequence in most cases. Nevertheless, local control is important; clinical trials now in progress may soon indicate the most efficient way of achieving this in different clinical states. These trials will not, of course, be the final word, since the results of any local treatment might be greatly modified by adjuvant therapy. (At present, trials of adjuvant systemic treatment are reserved for patients with
stage-II disease.) Accurate staging depends on knowledge of axillary lymph-node status, which in turn demands complete axillary clearance with histopathological examination of the lymph-nodes. Therefore the general view is that, although different surgical procedures may not give different therapeutic results, the most satisfactory surgical for early breast cancer at present is total mastectomy with complete axillary clearance. This achieves local control of the disease and provides a maximum of prognostic information. What of adjuvant systemic treatment? The main thrust here has been in postoperative chemotherapy, because subclinical cancer should in theory be more sensitive than a large tumour load to cytotoxic drugs, and because the tumour cell populations would follow first-order kinetics. Preliminary results of pioneer trials in the United States and Italy engendered some optimism. The National Surgical Adjuvant Breast Project treatment
(N.S.A.B.P.) employed L-phenylalanine mustard,’ and BONADONNA and his colleagues,8 in Milan, used a combination of cyclophosphamide, methotrexate, and 5-fluorouracil. In premenopausal patients, but not postmenopausal patients, adjuvant chemotherapy lengthened the disease-free interval after mastectomy. Actuarial analysis of the Milan trial at four years suggests that a significant benefit in survival may also be achieved. Despite the cautions uttered by FiSHER7 and BONADONNA8 and their colleagues, the results of these trials are now being used by many clinicians as’a basis for routine treatThis may be unwise: corroboration is needed wide variety of trials. The results of the scrupulously conducted N.S.A.B.P. and Milan trials are not in question, but they might not be reproduced in other centres treating different populations. Furthermore, before adjuvant chemotherapy can safely be used routinely it is essential ment.
from
a
Carbone, P., Economu, S. G., Frelick, R., Glass, A., Lerner, H., Redmond, L., Zelen, M., Band, P , Katrych, D. L., Wolmark, N., Fishe, E. R., and other cooperating investigators. New Engl. J. Med. 1975, 292,
7. Fisher, B.,
117. 8.
Bonadonna, G., Brusamolino, E., Valagussa, P., Rossi, A., Brugnatelli, L., Brambilla, C., De Lena, M., Tancini, G., Bajetta, E., Musmeci, R., Veronesi, U. ibid. 1976, 294, 405.
information on long-term survival and For the present, adjuvant chemotherapy is toxicity. experimental and its use should be confined to prospective controlled clinical trials: premature adoption for routine treatment could do patients a great disservice. An encouraging report of the effectiveness of prophylactic ovarian irradiation plus prednisone in premenopausal patients9 similarly needs confirmation, while the combination of endocrine therapy with cytotoxic chemotherapy presents a further possibility to be investigated. Because hormonal procedures could either suppress or stimulate tumour growth, the scheduling of such combined treatment is likely to be important: it might well determine whether combined treatment is additive, synergistic, or antagonistic. Information on this should be derived initially from observations in, advanced disease. Few general recommendations can be made on the "best" treatment for early breast cancer. The only way forward is by well-designed controlled prospective clinical trials in which careful attention is given to prognostic variables. Future trials will have to encompass very large numbers of patients, and the day of the parochial trial with a few patients in each arm is over. to secure
a
MARATHON RUNNERS AND ISCHAEMIC HEARTDISEASE Is exercise an important prophylactic against ischxmic heart-disease? The work of Morris 12 poses many questions. Stamler’s latest review3 of major coronary risk factors and lifestyles concentrates on diet, smoking, and hypertension with no mention of exercise. If exercise protects against ischxmic heart-disease, how much and what sort of exercise is required? Is the effect of lack of exercise independent of the other risk factors or is it mainly mediated by the other risk factors such as serum lipids, the high-density-lipoprotein component of which is high in people who take exercise and is negatively correlated with ischxmic heart-disease?45 How safe is exercise ? In the United States the jogging epidemic has given rise to events such as the Boston marathon, which now attracts more than 3000 runners, and doubtless such spectacles will soon become commonplace. In Britain the Sunday Times National Fun Run already has 11 000 entries. If some exercise is good for you, is one or two hours a day, the marathon runner’s stint, even better? The marathon runner has been regarded as a physiological freak, with his large slow-beating heart, lean wasted 9. Meakin, J W., Allt, W. E. C., Beale, F. A., Brown, T. C., Bush, R. S., Clark, R. M., Fitzpatrick, P. J., Hawkins, N. V., Jenkin, R. D T., Pringle, J. F, Rider, W. D., Hayward, J. L., Bulbrook, R. D. in Adjuvant Therapy of Cancer (edited by S. E. Salmon and S. E. Jones); p. 95. Amsterdam, 1977. 1. Morris, J. N., Heady, A. J., Raffle, P. A., et al. Lancet, 1953, ii, 1053, 1111. 2. Morris, J. N , Chave, S. P. W., Adam, C., et al. ibid. 1973, i, 333. 3. Stamler, J. Circulation, 1978, 58, 3. 4 Martin, R. P., Haskell, W. L., Wood, P. D. Ann. N.Y. Acad. Sci. 1977, 301, 346. 5. Miller, G. J., Miller, N. E., Lancet, 1975, i, 16.
719
appearance, and often abnormal electrocardiogram.6 Since the necropsy report on "Mr Marathon", Clarence DeMar, who was a highly successful runner for over 50 years, and whose heart showed physiological enlargement with widely patent atheroma-free coronary arteriesl-and particularly since Basslerdaringly claimed that there had been no death from atheromatous coronary artery disease in anyone who had completed the full marathon distance of 42 195 m (26 miles, 385 yards)-there has been increasing medical interest in marathon runners. The proceedings of a conference on the marathon have lately been published, and Olivier et al.10 have written on ischxmic heart-disease in marathon runners. The elite marathon runner is lean, under 40 years of age, and unlikely to smoke. Since he produces heat at the rate of over a kilowatt when he is running at his racing speed of 1 mile every five minutes and has a maximum sweat rate of 1-5 1/h at his racing rectal temperature of 39-41 °C, heat-stroke, fluid depletion, traffic accidents, and canine assault are more obvious hazards than myocardial infarction. Olivier et al. have looked at a group of non-elite middle-aged (>40 y) participants in the 1976 Comrades Marathon, a 90 km race in South Africa. They obtained the cooperation of 48 out of 438 of these veteran runners, who were therefore not randomly selected, with the aim of looking for evidence of ischaemic heart-disease. This group averaged 1000 miles a year in training (as opposed to the 5000 miles of elite marathon runners). They had pre-race E.C.G.s, and as soon as possible after the finish a repeat E.c.G. was done and some competitors had blood-samples taken. Although none of the runners had symptoms suggestive of ischaemic heart-disease, Olivier et al. judged that the E.C.G.S of 23 of the 48 runners showed ST segment changes consistent with "early" ischxmic heart-disease. The serum-creatine-kinase was strikingly raised in most runners in whom samples were obtained, and in 11 samples checked for the reputedly specific cardiac component, the Marsh-Bender (MB) fraction, this was also raised. Both E.C.G. and enzyme evidence of ischaemic heart-disease are, however, suspect. The E.c.G.s were all resting traces, and the specificity of the ST-segment abnormalities, in a symptomless athletic population, is very doubtful. The repeatability of the E.c.G.s was poor. A multitude of E.C.G. abnormalities have been reported in athletes with no clinical evidence of heart-disease.6 11 The enzyme changes probably reflected an increase in membrane permeability as a result of the prolonged exertion and heat load. Other workers have obtained similar results.12 For example, blood-samples from five competitors in a 100-mile race showed lactate dehydrogenase and aminotransferare levels that would normally be taken as diagnostic of severe tissue damage. 13I The diagnosis of ischxmic heart-disease in marathon runners by these techniques is therefore difficult, and the
relevance of cardiac events in this selfselected group is anyway hard to assess. The Bassler hypothesis and resulting controversy is fully explored in the publication from the New York Academy of Sciences.8 Enthusiasts such as Kavanagh and Bassler, who regard marathon running as the "logical graduation ceremony" of cardiac rehabilitation, argue the toss with statisticians and devil’s advocates. What emerges is a great deal of suggestive evidence for the benefits of prolonged exercise, not only in improving exercise tolerance and a feeling of wellbeing, but also in preventing coronary atheroma. Scientific proof is still lacking.
epidemiological
-
6. Tunstall Pedoe, D. S., Thomason, H Sports Medicine (edited by J. G. P. Williams and P. N. Spenyn); p. 174. 7. Currens, J., White, P. D., New Engl. J. Med. 1961, 265, 988. 8. Bassler, T.J., Lancet, 1972, ii, 711. 8. Milvy, P. (editor) Ann. N. Y. Acad. Sci. 1977, 301. 10. Olivier, L. R., De Waal, A., Retief, F. J , et al. S. Afr. med. J. 1978, 53, 783. 11. Lichtman, J , O’Rourke, R. A., Klein, A., Karliner, J. S. Archs intern Med.
1973, 132, 763. 12 La Porta M. A., Linde, H. W, Bruce, D. L., Fitzsimons, E.
Ass. 1978, 239, 2685. 13. Brotherhood, J , Tunstall Pedoe, D. S. Unpublished.
J. J.
Am. med.
M.B.LOND. (FAILED) THE Guy’s Hospital Gazette mourns an overall failure-rate of 23% in the final M.B., B.s. examination and highlights a 30% rejection-rate in surgery by comparison with 9% in medicine. The Guy’s experience focuses once again on a perennial question: what are the final examinations all about and do they achieve anything more than stimulation of the sympathetic nervous system and a random failure-rate largely unrelated (as the Guy’s editor claims) to medical competence? The matter is so complex as almost to defy analysis. British examinations-particularly those conducted in London -are almost totally without external standards; are validated only by a long tradition of "good examining" by those (usually senior members of the profession) who believe without evidence that they are maintaining constancy of requirements from one year to the other; and are largely devoid of any defined syllabus about which the candidate can say "here is examinable material". Add to this an alternative examination system (in London and Scotland at least) and, in many places, curious marking systems that apparently allow a candidate to pass if he displays a 50% understanding of his subject but prevents him from achieving more than a 60% total mark (the close system), and the recipe for chaos is com-
plete. We must charitably assume that the final examination is designed to give a limited licence to practise. Though it is largely administered by universities it is thus not a university examination, the essential feature of which is scholarship-which can broadly be defined as the ability to respond to intellectual challenge and to display mastery of a subject in depth. In consequence it tends to be neither a test of intellect nor an assessment of competence. It comes at the end of a period of study and training by young people who have been so highly selected that it is inconceivable that-psychiatric and social reasons
apart-they
can
ultimately fail. Dispassionately
viewed it can be argued that the formal final examination is a waste of time; and some institutions have tacitly accepted this judgment, downgrading the sudden-death final, incorporating continuous assessment (which can create its own tyranny), and generally assuming that, given a minimal standard of achievement, the student is bound to pass. The learning process is thus blended with the examining process in a way that educational theoreticians delight to see, though which they rarely justify by an appeal to experiment. But if the formal final is to 1
Guy’s Hospital Gazette, 1978, 93, 273.
