1979, British Journal of Radiology, 52, 423-424

MAY

1979

Proceedings of The British Institute of Radiology Principles of clinical trials in cancer Abstracts of papers presented at a meeting of The British Institute of Radiology held on Thursday October 19 1978 at the Institute House, 32 Welbeck Street, London W1M 7PG. Surgical and clinical aspects of some clinical trials, by M. Baum. Comments on the feasibility, practicability and success rate of breast screening, by Audrey Tucker. Comments on the statistical approach and the interpretation of results, by K. D. MacRae.

SURGICAL AND CLINICAL ASPECTS OF SOME CLINICAL TRIALS

By M. Baum Welsh National School of Medicine Prospective randomized clinical trials are in their relative infancy but are an essential technique in the application of the scientific method to the treatment of cancer. By this technique not only is it possible to compare competing hypotheses concerning the disease, but by their scientific design there is inevitably a biological fall-out which teaches us more about the very nature of the disease under study, and hence enables us to evolve even more rational treatment programmes. Clinical trials for cancer can be conducted in a single centre or as a multi-centre collaborative programme. Single centre trials have the advantage of tight control, excellent data collection, and the possibility of complicated protocols. However, multicentre trials have the overwhelming advantage in that they allow the rapid accrual of large numbers of patients, but by their very nature control may be less tight and only simple protocols are appropriate. The most important point to consider when planning a multicentre trial is the number of patients that are required to answer the question posed. For example, in setting up a trial that stands a 90% chance of picking up a significant difference of the order of say 10% (the power of the trial), at least 500 patients will be required in each treatment arm. The recruitment and co-ordination of such enormous studies demands special expertise, and the expense of full-time co-ordinators and administrators. Protocols have to be carefully designed so that the question is clearly defined, the treatment modality carefully described, and the possibility of treatment interaction avoided. Examples were given concerning a variety of multicentre prospective trials investigating the treatment of breast cancer, some of which have influenced current thought and management concerning this disease. Thus local therapy by whatever type of operation and covering a wide range of radiotherapy regimes has not influenced survival but may provide different degrees of local control. New adjuvant trials to investigate chemotherapy or endocrine therapy at the time of mastectomy are under evaluation at the present, but the new problem arises in defining what is an optimum chemotherapy regime when dealing with micrometastases whose very presence and growth rate can only be guessed. Details concerning documentation, randomization procedures and communication techniques were described, followed by discussion on the ethics of informed consent, and the timing of closing a trial. It is felt that in all honesty there is no such thing as true informed consent and that the attitude of the Medical Research Council on this issue is the most humane. American attitudes on this subject are not particularly relevant to British practice. Finally, the expense of running a Reprints of these abstracts may be obtained from the Managing Editor, The British Journal of Radiology, 32 Welbeck Street, London W1M 7PG (01-935 6867).

properly organized prospective trial was described. It has to be considered a very costly business which needs to be funded adequately. However, to keep the subject in perspective, the cost of saving a life of a woman as a result of a wide scale screening programme would pay for at least one large scale multicentre trial, that would be likely to detect an improvement with a new treatment regime of the order of 10%. This improvement extrapolated across the country could then save around 800 lives a year. COMMENTS ON THE FEASIBILITY, PRACTICABILITY AND SUCCESS RATE OF BREAST SCREENING

By Audrey Tucker St. Bartholomew's Hospital, London EC1 It is generally known that the commonest cause of death in women aged 40-65 from malignancy in England is carcinoma of the breast. Methods of breast screening include self palpation, palpation by clinicians, thermography and X-ray mammography. Of these methods, mammography detects a much higher percentage of occult (not clinically overt) carcinomata. Such women have a much lower incidence of axillary node involvement, and detection prior to spread to axillary nodes is the only factor at present known to give a significantly better prognosis. Most of the cancers found are also smaller than those presenting as lumps. In the series from Lundgren (Sweden), 112 out of 129 carcinomata found by X-rays had normal axillary nodes. In a series at present being undertaken in England, 23 out of 30 women had no axillary lymph node involvement. Breast sensitivity to ionizing radiation is known to be much greater below the age of 35, and therefore screening should not start before this age. Any breast X-rays must be taken with the lowest irradiation dose compatible with good diagnostic films; compression helps to reduce the dose. There is no evidence at present, other than extrapolated estimates from very high (radiotherapy) dosages that mammography within the diagnostic range could cause breast cancer; but interval rather than annual mammography is probably advisable for normal women and those not in high risk groups. Mammography is easily performed, and not very expensive. However, with nearly nine million women in Britain between the ages of 40-65, many more radiologists than are available would be needed to interpret the films of a national screening programme. COMMENTS ON THE STATISTICAL APPROACH AND THE INTERPRETATION OF RESULTS

By K. D. MacRae Charing Cross Hospital Medical School, London Only by the use of randomization can a clinical trial be validly said to be a controlled trial; randomization eliminates allocation bias, ensures that the treatment groups

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1979, British Journal of Radiology, 52, 424-427 Proceedings tend to be balanced for predictor factors, and makes the use of statistical tests of significance valid (Byar et ah, 1976). A useful clinical trial must also have an adequate number of patients to ensure that differences between alternative treatments that would be of interest to those in clinical practice are likely to be detected by the trial. Small clinical trials are of very limited value, whether or not they show significant differences between the treatments, because they allow only vague statements about the likely magnitude of the treatment differences to be made. When to stop a clinical trial often poses an ethical and scientific dilemma, and perhaps the only way of dealing with this problem is for the clinicians treating the patients to remain ignorant of the intermediate results and for a close scrutiny to be kept on the data by a suitably constituted group of assessors (Chalmers e* a/., 1972).

It is also necessary that the question being asked in a clinical trial should not be wrongly put; examples of confounded comparisons have occurred in some major trials in the past, and factorial trials are almost unknown in the field of breast cancer. REFERENCES BYAR, D. P., SIMON, R. M., FRIEDEWALD, W. T., SCHLESSELMAN, J. J., DEMETS, D. L., ELLENBERG, J. H., GAIL, M. H., and WARE, J. W., 1976. Randomized

clinical trials. New England Journal of Medicine, 295, 74-80. CHALMERS, T. C , BLOCK, J. B., and LEE, S., 1972.

Con-

trolled studies in clinical cancer research. New England Journal of Medicine, 287, 75-78.

The scientific basis of radiation protection Abstracts of papers presented at a Radiobiology Work-in-Progress meeting of The British Institute of Radiology held on October20,1978 in the Reid-Knox Hall, Institute House, 32 Welbeck Street, London W1M7PG. An introduction to "The Scientific basis of radiation protection", by R. H. Mole. Chromosome damage: the RBE of (d + T) neutrons from two different generators, by Gillian Clare, C. Oxby and B. Dixon. Low doses of neutron radiation and the frequency of satellite association complexes of human acrocentric chromosomes, by M. T. Khokhar, T. Min and J. A. Houghton. Accurate quantification of radiation-induced chromosome damage in human lymphocytes utilizing the harlequin-banding technique: implications for biological dosimetry, by D. Scott, C. Y. Lyons, J. R. Robinson and A. R. Currie. Fast kinetics of radioprotection by sulphydryl compounds in bacteria, by H. A. Harrop and B. D. Michael. Mechanisms of radioprotection by L-cysteine or cytosine arabinoside in mouse marrow, by J. L. Millar. A method for measuring the effects of plutonium 239 on cells in haemopoietic marrow, by E. R. Humphreys and V. A. Stones. An alternative bone model in the calculation of annual limits of intake for plutonium 239 compounds, by N. D. Priest. The initial deposition and redistribution of plutonium 239 in the mouse skeleton: implications for rodent studies in plutonium 239 toxicology, by D. Green, G. R. Howells and C. M. Thorne. Skin and eye irradiations—examples of some problems of implementing international recommendations in radiological protection, by M. W. Charles. The scientific basis for the ICRP's use of linear extrapolation to obtain best estimates of the risk of radiation-induced cancer at low doses, by J. M. Brown. graded reduction in organ function requires much more precise definition than ICRP has given it. Radiobiological experiments are of applied value only if they lead to defensible generalizations which are applicable to the human By R. H. Mole species. A system of radiological protection, because it must Medical Research Council Radiobiology Unit, Harwell, Oxon be simple enough for practical use, must also involve considerable simplification of inevitable biological complexity Chemical agents reducing effects of radiation could well be but simplification is a matter for judgement, not primarily of called radio-resistizers (by analogy and in contrast with science. The increased emphasis on cost-benefit analysis in radio-sensitizers). Radiation protection is a misnomer for ICRP Publ. 26 (1977) demands a considerably increased effort if all the realistic risk estimates which are needed are their action. Radiobiological protection is an activity maintaining con- to be provided. REFERENCE ditions which minimize exposure to ionizing radiation. Its scientific basis is the field of knowledge, both facts and con- ICRP, 1977. Recommendations of the International Commission on Radiological Protection. Annals of the ICRP, cepts, which allows risk to be defined quantitatively for any Publication 26. and every kind of exposure. Since human experience of radiation risk is limited to particular cases, the available information has to be codified before it can be applied to other circumstances, absorbed dose providing the necessary linkCHROMOSOME DAMAGE: THE RBE OF (d + T1) ing concept. The effect of protraction (rather than physical NEUTRONS FROM TWO DIFFERENT GENERATORS dose-rate which is relevant to low LET radiation but not high LET radiation) and of radiation quality are the two By Gillian Clare, C. Oxby and B. Dixon main quantitative problems if the metabolic models in use for assessment of dose from "internal emitters" can be acUniversity Department of Radiotherapy, Cookridge cepted as adequate, but the non-stochastic concept of a Hospital and University Department of Medical Physics The General Infirmary, Leeds Reprints of these abstracts may be obtained from the irradiated in vitro at 22°C with 60Co Managing Editor, British Journal of Radiology, 32 Welbeck Human blood has been y rays at 1.5 Gy min-1 or 0.006 Gy min^1, or with 14 MeV Street, London W1M 7PG (01-935 6867). AN INTRODUCTION TO "THE SCIENTIFIC BASIS OF RADIATION PROTECTION"

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Proceedings of the British Institute of Radiology. Principles of clinical trials in cancer. Abstracts.

1979, British Journal of Radiology, 52, 423-424 MAY 1979 Proceedings of The British Institute of Radiology Principles of clinical trials in cancer...
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