- Email: [email protected]
Treatment of Early Breast Cancer
717
other foods, coeliac disease, and schizophrenia.29 Just how absorbed macromolecules affect the brain and the psyche is clearly a subject for further research, and most physicians and psychiatrists will tread with caution the path towards a diagnosis of food allergy as an explanation of vague physical or psychiatric symptoms. The case for food allergy as a cause of psychiatric disease may have beer overstated.3° Nevertheless there can be no doubt that some patients are aware of mood and behaviour changes after they have ingested certain foods,31 32 and food -avoidance or sodium cromoglycate33 may abolish these symptoms.
3 node-positive group, too, will have recurrence of cancer, as will some 25% of the node-negative patients. Without accurate information on risk of recurrence, it is impossible to estimate the cost/ benefit ratio for a treatment (cost being defined as the morbidity associated with a given treatment and benefit as disease-free interval, survival, and quality of life). Probably none of the existing predictive tests is powerful enough to be used as a basis for treatment. Perhaps serial measurements of carcinoembryonic antigen will eventually come into this category,2but we cannot yet be sure even that a greater lead-time gained by such measurements will make a decisive difference to the endresults of therapy. A host of tumour markers have been described, but their use is still One major growth point seems to be the predictive value of measurements of specific oestrogen receptors in the tumour. A correlation between the presence of oestrogen receptors and the hormone responsiveness of advanced breast cancer is well established, although similar claims for a converse association with response to chemotherapy4 have yet to be substantiated. Lately it has been claimed that patients with tumours that are oestrogen-receptor positive have a better prognosis after mastectomy than those with negative tumours, irrespective of age, axillary-node status, size of primary, and location within the breast.55 However, with so many variables, very large numbers of results are required for certainty on this point, especially when some groups report that only 20% of their cases lack receptors. The usefulness of oestrogen-receptor analyses in the advanced disease is enhanced by simultaneous measurement of progesterone receptors,6 but the relevance of progesterone receptors to prognosis in early disease awaits evaluation. Should receptors now be measured in all patients with early breast cancer, in the hope that the results will be helpful not only in prediction of recurrence but also in selection of patients for adjuvant therapy and management of subsequent recurrent disease? At present the analyses can be done in only a few laboratories, most of them in research centres. Yet primary tumour may be the only source of material on which the assay can be carried out, so this measurement must be recorded in as many patients as possible. Perhaps in future it will be possible to determine receptors 1
to
experimental. possible
Treatment of Early Breast Cancer "EARLY breast cancer" is clinical shorthand for breast disease which is apparently localised at presentation and thought to be curable by local therapy alone. It is a misnomer. In most patients with axillary-node involvement, and possibly in a substantial proportion of those with negative axillary nodes, the disease is already widely disseminated. A growing acceptance of the concept of breast cancer as a systemic disease at diagnosis has led to unease concerning the traditional methods of treatment and research has lately focused on three main areas -surgical management; adjuvant therapy (radiotherapy, chemotherapy, endocrine therapy, immunotherapy) ; and prediction of the clinical course of the disease. The results have done little to clarify matters: if anything, clinicians are more confused than ever. With the information we now have, is any form of consensus possible on the best treatment for early breast cancer? And what are the growth points in breast-cancer research? With such questions in mind, a small number of specialists* gathered at Leeds Castle, under the auspices of the Leeds Castle Foundation and the Imperial Cancer Research Fund, to review the early-breast-cancer scene.
In prediction of clinical course, accurate assessment of nodal status is important, and in practice nodes positive the "break-point" of 1 to 3 or >> 4 is useful, since prognosis for the latter group is particularly poor. But in the long term, most of the B. FISHER and J. L. HAYWARD (joint chairmen), M. BAUM, G. BONADONNA, R. D. BULBROOK, P. P. CARBONE, S. K. CARTER, E. ENGELSMAN, E. R. FISHER, A. P. M. FORREST, S. M. HELLMAN, J. ZIEGLER, W. L. MCGUIRE, M. N. MAISEY, J. W. MEAKIN, Rosemary MILLIS, Eleanor MONTAGUE, R. D. RUBENS, U. VERONESI, and M. ZELEN.
*Participants:
29 Dohan, F. C. in Antigen Absorption by the Gut; p. 155. Lancaster, 1978 30. Mackarness, R. Not All in the Mind. London, 1976. 31. Finn, R., Cohen, H. N Lancet, 1978, i, 426. 32. Buisseret, P ibid. p. 304 33 Vaz, G. A , Tan, L K-T., Gerrard, J. W. ibid p. 1066 1. Fisher, B., Slack, N. H., Bross, I. D. J., and cooperating investigators. Cancer, 1969, 24, 1071.
histochemically. Given, then, that there is still
no
incontrovert-
2. Wang, D. Y , Bulbrook, R. D., Hayward, J. L., Hendrick, J. C., Franchimont, P. Europ. J. Cancer, 1975, 11, 615. 3. McGuire, W. L., Carbone, P. P., Vollmer, E. P. Estrogen Receptors in Human Breast Cancer. Amsterdam, 1975. 4. Lippman, M. E., Allegra, J. C., Thompson, E. B., Simon, R., Barlock, A., Green, L., Huff, K K., Do, H. M. T., Aitkens, S. C., Warren, R. New Engl. J. Med. 1978, 298, 1223. 5. McGuire, W. L., Raynaud, J.-P , Baulier, E.-E. Progress in Cancer Research and Therapy, vol. IV. New York, 1977. 6. Knight, W. A., Livingstone, R. B., Gregory, E. J., McGuire, W. L. Cancer
Res. 1977, 37, 4669
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.
other foods, coeliac disease, and schizophrenia.29 Just how absorbed macromolecules affect the brain and the psyche is clearly a subject for further research, and most physicians and psychiatrists will tread with caution the path towards a diagnosis of food allergy as an explanation of vague physical or psychiatric symptoms. The case for food allergy as a cause of psychiatric disease may have beer overstated.3° Nevertheless there can be no doubt that some patients are aware of mood and behaviour changes after they have ingested certain foods,31 32 and food -avoidance or sodium cromoglycate33 may abolish these symptoms.
3 node-positive group, too, will have recurrence of cancer, as will some 25% of the node-negative patients. Without accurate information on risk of recurrence, it is impossible to estimate the cost/ benefit ratio for a treatment (cost being defined as the morbidity associated with a given treatment and benefit as disease-free interval, survival, and quality of life). Probably none of the existing predictive tests is powerful enough to be used as a basis for treatment. Perhaps serial measurements of carcinoembryonic antigen will eventually come into this category,2but we cannot yet be sure even that a greater lead-time gained by such measurements will make a decisive difference to the endresults of therapy. A host of tumour markers have been described, but their use is still One major growth point seems to be the predictive value of measurements of specific oestrogen receptors in the tumour. A correlation between the presence of oestrogen receptors and the hormone responsiveness of advanced breast cancer is well established, although similar claims for a converse association with response to chemotherapy4 have yet to be substantiated. Lately it has been claimed that patients with tumours that are oestrogen-receptor positive have a better prognosis after mastectomy than those with negative tumours, irrespective of age, axillary-node status, size of primary, and location within the breast.55 However, with so many variables, very large numbers of results are required for certainty on this point, especially when some groups report that only 20% of their cases lack receptors. The usefulness of oestrogen-receptor analyses in the advanced disease is enhanced by simultaneous measurement of progesterone receptors,6 but the relevance of progesterone receptors to prognosis in early disease awaits evaluation. Should receptors now be measured in all patients with early breast cancer, in the hope that the results will be helpful not only in prediction of recurrence but also in selection of patients for adjuvant therapy and management of subsequent recurrent disease? At present the analyses can be done in only a few laboratories, most of them in research centres. Yet primary tumour may be the only source of material on which the assay can be carried out, so this measurement must be recorded in as many patients as possible. Perhaps in future it will be possible to determine receptors 1
to
experimental. possible
Treatment of Early Breast Cancer "EARLY breast cancer" is clinical shorthand for breast disease which is apparently localised at presentation and thought to be curable by local therapy alone. It is a misnomer. In most patients with axillary-node involvement, and possibly in a substantial proportion of those with negative axillary nodes, the disease is already widely disseminated. A growing acceptance of the concept of breast cancer as a systemic disease at diagnosis has led to unease concerning the traditional methods of treatment and research has lately focused on three main areas -surgical management; adjuvant therapy (radiotherapy, chemotherapy, endocrine therapy, immunotherapy) ; and prediction of the clinical course of the disease. The results have done little to clarify matters: if anything, clinicians are more confused than ever. With the information we now have, is any form of consensus possible on the best treatment for early breast cancer? And what are the growth points in breast-cancer research? With such questions in mind, a small number of specialists* gathered at Leeds Castle, under the auspices of the Leeds Castle Foundation and the Imperial Cancer Research Fund, to review the early-breast-cancer scene.
In prediction of clinical course, accurate assessment of nodal status is important, and in practice nodes positive the "break-point" of 1 to 3 or >> 4 is useful, since prognosis for the latter group is particularly poor. But in the long term, most of the B. FISHER and J. L. HAYWARD (joint chairmen), M. BAUM, G. BONADONNA, R. D. BULBROOK, P. P. CARBONE, S. K. CARTER, E. ENGELSMAN, E. R. FISHER, A. P. M. FORREST, S. M. HELLMAN, J. ZIEGLER, W. L. MCGUIRE, M. N. MAISEY, J. W. MEAKIN, Rosemary MILLIS, Eleanor MONTAGUE, R. D. RUBENS, U. VERONESI, and M. ZELEN.
*Participants:
29 Dohan, F. C. in Antigen Absorption by the Gut; p. 155. Lancaster, 1978 30. Mackarness, R. Not All in the Mind. London, 1976. 31. Finn, R., Cohen, H. N Lancet, 1978, i, 426. 32. Buisseret, P ibid. p. 304 33 Vaz, G. A , Tan, L K-T., Gerrard, J. W. ibid p. 1066 1. Fisher, B., Slack, N. H., Bross, I. D. J., and cooperating investigators. Cancer, 1969, 24, 1071.
histochemically. Given, then, that there is still
no
incontrovert-
2. Wang, D. Y , Bulbrook, R. D., Hayward, J. L., Hendrick, J. C., Franchimont, P. Europ. J. Cancer, 1975, 11, 615. 3. McGuire, W. L., Carbone, P. P., Vollmer, E. P. Estrogen Receptors in Human Breast Cancer. Amsterdam, 1975. 4. Lippman, M. E., Allegra, J. C., Thompson, E. B., Simon, R., Barlock, A., Green, L., Huff, K K., Do, H. M. T., Aitkens, S. C., Warren, R. New Engl. J. Med. 1978, 298, 1223. 5. McGuire, W. L., Raynaud, J.-P , Baulier, E.-E. Progress in Cancer Research and Therapy, vol. IV. New York, 1977. 6. Knight, W. A., Livingstone, R. B., Gregory, E. J., McGuire, W. L. Cancer
Res. 1977, 37, 4669
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.