1978, British Journal of Radiology, 51, 401-405
VOLUME 51 NUMBER 606
JUNE 1978
The British Journal of Radiology Review article The sensitivity of the human breast to cancer induction by ionizing radiation By R. H. Mole, B.M., F.R.C.P., F.R.C.Path. MRC Radiobiology Unit, Harwell, Oxon 0X11 ORD {Received December, 197 7 and in revisedform February, 1978)
It is often difficult to accept that cancer induction by small doses of radiation is more than a theoretical possibility but actually happens. Indeed it is only quite recently that confirmatory evidence of considerable weight has become available to support the conclusion that the breast may be more sensitive to cancer induction by ionizing radiation than any other human tissue. EVIDENCE THAT IONIZING RADIATION CAUSES BREAST CANCER IN HUMANS
determine with any accuracy so many years later even if the original equipment is available for calibration of output dose-rate (as it sometimes is): the duration of an individual fluoroscopy is an unknown variable. However, this does not alter the demonstration that breast cancer induction has been linearly proportional to number of fluoroscopies nor does it altogether falsify estimates of breast cancer risk per rad of tissue dose. These estimates have to be based on a decision about the average duration of a fluoroscopy as it was practised in particular institutions several decades ago and over a period of years and the risk estimates quoted below may thus be in error by a factor of perhaps 2 to 5, quite apart from statistical considerations, but they cannot be wholly wrong.
Multiplefluoroscopyas employed in the treatment of pulmonary tuberculosis by artificial pneumothorax Two groups of female patients have been followed up for ten to 44 years (mean follow-up each exceeding 25 years) (in Nova Scotia by Myrden and Hiltz, 1969; BEIR, 1972, and in Massachusetts by Boice and Monson, 1977). In the first series breast cancer incidence was five times, in the other twice, what would be expected in controls (tuberculous patients treated without pneumothorax, or regional population statistics). Other series may fail to show an increase but this is to be expected given the numbers of subjects, the magnitude of the breast doses and/or the use of mortality instead of incidence as the index of effect. In the two surveys mentioned there was an approximately linear relationship between excess breast cancer incidence and number of fluoroscopies. This is as would be predicted from the simple hypothesis that cancer frequency caused by multiple small doses of radiation would be proportional to total accumulated dose. Of course the dose for an individual fluoroscopic examination is impossible to
Radiotherapy of post-partum mastitis and other non-malignant diseases of the breast The tissue doses here are known fairly exactly but, to set against this, the irradiated tissue was not normal and the individual treatment doses were ten to 100 times larger than for individual fluoroscopic examinations. The observations, therefore, cannot be so easily assumed to be relevant to occupational exposure or screening by mammography. Radiotherapy of acute post-partum mastitis in New York led to a doubled increase in breast cancer incidence as compared with non-irradiated cases or sibling controls (Mettler et al., 1969; Shore et ah, 1977). Radiotherapy of a variety of benign breast diseases in Stockholm with considerably larger total doses increased expected breast cancer incidence by four to six times (Baral et al., 1977).
Copies of this article may be obtained from The British Journal of Radiology, 32 Welbeck Street, London W1M 7PG at a cost of 60p; remittance with order please.
Japanese bomb survivors By 1969 the incidence of breast cancer in those exposed to ten or more rad (kerma) was increased by
401
VOL.
51, No. 606 R. H. Mole TABLE I. BREAST CANCER MORTALITY IN JAPANESE BOMB SURVIVORS 1950-1972
discussed below are extracted from one or other of these unless specifically referenced.
(primary data in Tables 2 and 13.2-13.5 of Moriyama and Kato, 1973).
APPLICATION OF THIS EVIDENCE TO PRACTICAL PROBLEMS
The mean absorbed dose to breast tissue for an individual fluoroscopic examination was inferred to be 7.5 or 3.6 rad in the Nova Scotia series, depending 0-9 10-34 35 + Breast cancer deaths on the method of assessment, and 1.5 rad in the 21 20 0 Number observed for all Massachusetts series. At levels of dose from 10 rad exposures of 10 rad (kerma) of low LET radiation downwards there is no known or more Number expected: radiobiological reason for expecting much variation 6.4 0 19.3 (a) from experience of those in frequency of effect per rad according to the who received 0—9 rad, magnitude of an individual exposure or according to 7.8 very 12.6 (b) from Japanese national the number of successive, spaced exposures. It is small statistics. Excess rate per 100000 perhaps remarkable, given all the other problems of person-years in those who analysis, that the overall risk estimate per rad is so received 10 rad or more* 8.8 0 0.7 Base-line (a) similar in the two fluoroscopy series (Table II). It is 7.9 0 7.2 Base-line (b) further remarkable that the risk estimates for the two radiotherapy series agree so well with each other and *(i) Whether there is a striking difference in age-related sensitivity to breast cancer induction or not depends with the fluoroscopy series (Table II). entirely on the choice of the control population. It so These estimates are primarily for young adult happens that bomb survivors receiving 0-9 rad at age 35 + years suffered 41 breast cancer deaths in 1950-1972 as women and, although many fewer older women were compared with an expectation of 26.9 as judged by Japanese serially fluoroscoped, the evidence (Table II) may national statistics. This difference is too great to be at- suggest quite strongly that older women are less tributed to the mean radiation dose received by the 0-9 rad group. It may be attributed to chance, in which case the sensitive. However, the risk estimate for incidence in national statistics would provide the appropriate base-line Japanese bomb survivors appears not to be strikingly for risk evaluation, or to some systematic difference between greater for young than for older adults (in contrast the bomb survivor population and the generality of Japanese (which seems very likely), in which case the 0-9 rad group of with mortality, see Table I). Upton et al (1977) survivors would provide the better base-line, cited an unpublished report of an increase in second (ii) McGregor et al. (1977, Table 3) used base-line (a) when breast cancers in women given radiotherapy for a comparing frequencies of breast cancer diagnoses. The excess rates per 100000 person-years were 0, 18.8 and 7.8 first breast cancer with a risk estimate comparable to for the three age-groups respectively for the period 1950-69. those for the other series: if all the second cancers The ratio between the rates for those irradiated at 10-34 are attributable to the dose received by the iryears and 35+ years was smaller for diagnoses than for mortality by about 1 :4. McGregor et al. (1977) noted that radiated breast it might appear that older women the main contribution of new cases after 1960 was from the cannot be strikingly less radiosensitive than younger 10-34 year age group and also that ascertainment for women. However, it seems clear from the Masdiagnoses in 1965-69 was likely to be incomplete. sachusetts fluoroscopy series and the Japanese bomb survivors (both for incidence up to 1969 and mora factor of 1.5 to 2 over those receiving 0-9 rad tality up to 1972) that the maximum sensitivity to (McGregor et al, 1977). By 1972 mortality from breast cancer induction by radiation is in women at breast cancer was also one and a half times to twice some period between 10 and 20 years of age. There that expected (UNSCEAR 1977) and was largely are case reports of breast cancer following doses confined to those irradiated when less than 35 years exceeding 100 rad in the age range 0 to 10 years but of age (Table I) The incidence of breast cancer per the epidemiological evidence is that sensitivity is rad was closely similar at Hiroshima and Nagasaki, much less before puberty than afterwards. It is for deaths (Mole, 1975) and for diagnoses certainly an attractive working hypothesis to postu(McGregor et al, 1977), showing that the RBE of late that the sensitivity of the human breast to fission neutrons cannot much exceed one for cancer induction by ionizing radiation is correlated with hormonally regulated tissue activity. induction of breast cancer in women. The risk estimate for induced breast cancer freThe full reports of four of these surveys have just been published and substantial citations from all of quency in Japanese bomb survivors is lower than any them can be found in two very recent reviews other value in Table II and some of the difference, (Upton et al, 1977; UNSCEAR 1977). The results but not all, is removed by allowing for the much Age at time of irradiation (years)
402
JUNE 1978
Review article. The sensitivity of the human breast to cancer induction by ionizing radiation TABLE II. RISK ESTIMATES OF INDUCTION OF HUMAN BREAST CANCER BY IONIZING RADIATION WHEN BOTH BREASTS ARE EXPOSED.
Frequency of breast cancer in excess of controls per million subjects per rad mean breast dose UNSCEAR1977 Fluoroscopy Nova Scotia Massachusetts
Acute post-partum mastitis (New York) Benign breast disease (Stockholm) Atom bomb survivors Japan
Upton etal., 1977f
years of follow-up
Notes on inform ation relevant to variation in radic age at ex posure*
range in years 20 cases in excess in 234 subjects up to 29 years old 18 cases in excess in 804 subjects up to 29 years old
No breast cancers in 66 subjects aged 30 years and more No excess cases in 243 subjects aged 30 years and more
30-140 ("perhaps greater")
150J
10-28
113
210
10-44 (mean 27)
200
10-34 (mean 25) 6-42 (mean 32)
20 cases in excess in 560 subjects up to 40 years old About 100 cases in excess in 111 5 subjects. Excess most pronounced in those under age 35 when
5-24
About 33 cases in excess (all ages known doses). Excess rate at 35 + years perhaps 1 /4-1 /2 of rate in young adults
175
60§
—
*The number of cases in excess of expected depends on the control population used for the comparison and, since more than one control population was examined in several of the surveys, the excess noted may be an approximate figure. fUpton et al. reported risks in terms of cases per million per year per rad. These annual rates have been converted to total risks by multiplying by the duration of follow-up as given and recorded above. J320 if mean breast dose = 3.6 rad, not 7.5 rad. §Excluding subjects irradiated at < 10 years. The risk estimate given by Upton et al. was in terms of exposure. The value given above includes an approximate allowance for mean dose in breast tissue which is smaller than kerma.
higher proportion of older women amongst them than among those fluoroscoped or treated for acute post-partum mastitis (who in the nature of the case can rarely be more than 40 years' old when irradiated). Additional factors could be the normally lower natural breast cancer incidence in Japan than in occidental countries or the fact that the Japanese received single exposures all exceeding 10 rad (by definition, cf Table I) and running up to several hundred rad. The observed excess rate per rad appears to be smaller at the large doses both for incidence and mortality (though not significantly so in a statistical sense). Radiobiological reasons for expecting such a phenomenon have been discussed (Mole, 1975) and, if accepted, would bring the Japanese rate for single small exposures to a value quite close to the others in Table II. But, whatever the factors affecting the value of the mean risk estimate in Japanese bomb survivors, the weight of the other evidence seems inescapably to lead to the conclusion that the two adult human breasts are between them several times more sensitive to cancer
induction than is human bone marrow. Risk estimates per rad of tissue dose for human leukaemia as commonly given rarely exceed one-quarter of the values for breast cancer given in Table II. An estimate of 15-25 cases per million per rad for low LET radiation at low dose is given by UNSCEAR (1977) and twice that by Mole (1977). The minimum latent period before any induced breast cancer was seen was 10-15 years for fluoroscopy and radiotherapy but perhaps shorter in Japanese bomb survivors. The observations show that induced cases continue to appear for up to 40 years at least after exposure. Mammography Any risk of inducing breast cancer by mammography must be definitely smaller than the expected benefit if screening of well women by mammography is to be used on a population scale (Bailar, 1977). There seem to be two reasons for limiting such screening to women of 50 years and over. In the United States HIP trial of the value of
403
VOL.
51, No. 606
R. H. Mole mammmography in the early diagnosis of breast cancer (Shapiro, 1977) there has so far been no benefit for those under the age of 50. Secondly, the risk of mammography seems likely to be smaller at older ages because the natural expectation of life is then becoming shorter than the latent period for a proportion of the induced cancers and, in addition, the risk per rad of breast tissue dose may be smaller than for younger women. Further analysis of the Stockholm radiotherapy series and of data from the Japanese bomb survivors (see footnote Table I) may allow firmer conclusions about this latter question. Other diagnostic radiology
If the Adrian Committee in 1956 had known what is known now about the radiation sensitivity of the human breast, it seems highly probable that it would have sponsored estimates of population breast dose from routine diagnostic radiology as well as estimates of bone marrow dose. Even without this information it may seem unlikely that medical radiology contributes significantly to the total of naturally occurring breast cancer. Occupational exposure and radiological protection
Because of the growing evidence about the sensitivity of the human breast to cancer induction by ionizing radiation the recently revised (1977) Recommendations of the International Commission on Radiological Protection (Publication 26) have made exposure of breast tissue more restrictive than exposure of bone marrow. It may be noted that ICRP (1977) cited for protection purposes a single compromise value for the sensitivity of the human breast to be applied regardless of sex and age. Males are much less sensitive than females and the evidence for a progressive decrease in sensitivity of females from young adulthood to middle and old age has been alluded to. The ICRP compromise is appropriate for practical application because its dose limits are limits on annual dose and the associated risk is linked to the assumption of life-long exposure at the limit. Thus any increased risk per year's exposure for younger women is counterbalanced by the decreased risk per year's exposure for older women. Refined calculations could be made by considering only the risk to females and by taking account of what is known about the distribution of latent periods for radiation-induced breast cancer after a brief exposure. Young adult women are highly represented amongst those occupationally exposed in the medical services. This is just another reason for making sure that X-ray departments are well-
run. Specific restrictions on exposure of female staff beyond those already recommended by ICRP may seem unjustified. Biology of breast cancer
Since radiotherapy is commonly part of treatment for breast cancer and since the untreated breast is bound to receive some dose (depending on the technique used), the observations discussed above would lead to the prediction that subsequent frequency of breast cancer would be raised in the untreated breast and that this increase in frequency would be more conspicuous the younger the age at which the treatment had been given. Both predictions appear to be supported by observations. At ten to 15 years after treatment of breast cancer the frequency of cancer in the untreated breast was found to be four-fold greater than that expected from national statistics (Brinkley and Haybittle, 1968). The risk of occurrence of a second primary breast cancer in the other breast was markedly dependent on the age at diagnosis of a first breast cancer, in one survey being 84-fold higher for those aged 20-24 years and four-fold higher for those aged 40-44 years at the time of the first diagnosis (Waterhouse and Prior, 1975). However there is as yet no evidence to tell how much of these observed differences may be attributed to biological factors and how much, if any, to radiotherapy. Known biological factors, such as cystic mastitis and the length of the time interval between the menarche and the first pregnancy, seem responsible for only a three to four-fold difference in risk of breast cancer (MacMahon and Brown, 1973). Now that the high radiation sensitivity of the human breast is established, the effect of radiation dose on the untreated breast must be evaluated before accepting quantitative conclusions about genetic or other influences derived from epidemiological reports on the occurrence of a second cancer in individuals who have already had a first breast cancer. Concluding comment
No attempt is made here to make recommendations about the use of radiotherapy in breast disease or about mammography as a screening procedure aimed at detecting early breast cancer and so improving the results of treatment. In each case the balance of risk and benefit can be established only by careful study of all the factors involved. The purpose of this brief review is merely to provide a short summary of quite recently acquired information about just one of these factors.
404
JUNE 1978
Review article. The sensitivity of the human breast to cancer induction by ionizing radiation REFERENCES BAILER, J. C. Ill, 1977. Screening for early breast cancer: pros and cons. Cancer, 39, Supplement, 2783-2795. BARAL, E., LARSSON, L. E., and MATTSSON, B., 1977.
Breast cancer following irradiation of the breast. Cancer, 40,2905-2910. BEIR, 1972. Advisory Committee on the Biological Effects of Ionizing Radiation: report on the effects on populations of exposure to low levels of ionizing radiation, Washington, D.C. National Academy of Sciences—National Research Council.
MOLE, R. H., 1975. Ionizing radiation as a carcinogen: practical questions and academic pursuits. British Journal of Radiology, 48, 157-169. 1977. Radiation-induced leukaemia in man. Proceedings of the International Symposium on Radiation-induced Leukemogenesis and Related Viruses, held in Bordeaux. December 7-9, 1976, ed. J. F. Duplan INSERM Symposium No. 4, pp. 19-36 (North-Holland Publishing Company). MORIYAMA, I. M., and KATO, M., 1973. Mortality experi-
ence of A-bomb survivors 1970-72, 1950-72. Atomic Bomb Casualty Commission Report ABCC-15-73. women after repeated fluoroscopic examinations of the MYRDEN, J. A., and HILTZ, J. E., 1969. Breast cancer chest. Journal of the National Cancer Institute, 59, 823following multiple fiuoroscopies during artificial pneu832. mothorax treatment of pulmonary tuberculosis. Canadian BRINKLEY, D., and HAYBITTLE, J. L., 1968. A 15-year Medical Association Journal, 100, 1032-34. follow-up study of patients treated for carcinoma of the SHAPIRO, S., 1977. Evidence on screening for breast cancer breast. British Journal of Radiology, 41, 215-221. from a randomised trial. Cancer, 39, Supplement, 2772— INTERNATIONAL COMMISSION ON RADIOLOGICAL PROTEC2782. TION, 1977. ICRP Publication 26. Recommendations of SHORE, R. E., HEMPELMANN, L. H., KOWALUK, E., MANSUR, the International Commission on Radiological Protection P. S., PASTERNAK, B. S., ALBERT, R. E., and HAUGHIE, (Pergamon Press, Oxford). G. E., 1977. Breast neoplasms in women treated with MACMAHON, B., and BROWN, J., 1973. Etiology of human X-rays for acute post-partum mastitis. Journal of the breast cancer: a review. Journal of the National Cancer National Cancer Institute, 59, 813-822. Institute, 50, 21-42. UNSCEAR, 1977. Sources and effects of ionizing radiation. MCGREGOR, D. H., LAND, C. E., CHOI, K., TOKUOKA, S., Annex G Radiation Carcinogenesis in Man (United LUI, P., WAKABAYASHI, T., and BEEBE, G. W., 1977. Nations, New York). Breast cancer incidence among atomic bomb survivors, UPTON, A. C , BEEBE, G. W., BROWN, J. M., QUIMBY, Hiroshima and Nagasaki, 1950-69. Journal of the National E. H., and SHELLABARGER, C , 1977. Report of NCI Ad Cancer Institute, 59, 799-811. Hoc Working Group on the risks associated with mamMETTLER, F. A., HEMPELMANN, L. H., DUTTON, A. M., mography in mass screening for the detection of breast PIFER, J. W., TOYOOKA, E. T., and AMES, W. R., 1969. cancer. Journal of the National Cancer Institute, 59, Breast neoplasms in women treated with X rays for acute 480-493. post partum mastitis. A pilot study. Journal of the National WATERHOUSE, J. A. H., and PRIOR, M. P., 1975. Breast Cancer Institute, 43, 803-811. cancer in young women. British Medical Journal, 2, 434. BOICE, J. D., Jr., and MONSON, R. R., 1977. Breast cancer in
Book review Growth Kinetics of Tumours {Cell population kinetics in rela-ation studies that have been reported for both experimental tion to the growth and treatment of cancer). By G. G. Steel, and human tumours. He stresses the importance and the pp. xi + 351, illus., 1977 (Oxford, Clarendon Press) £1500. inadequacy of data on solid tumours, and perhaps his This book provides us at last with a comprehensive, account will stimulate further work. He analyses the authoritative and very readable account of cell kinetics in relevance of tumour size, of transplantation history and of tumours. It fills a gap that has been glaringly obvious. This the microanatomical structure in experimental tumours and volume must be considered an essential part of any Library highlights the lack of data on spontaneous tumours. on Cancer Research, and at £15-00 for 350 fact-filled pages The chapter on stem cells presents an unbiased account of it also represents excellent value. the evidence for and against their existence, and is a useful The information is clearly presented with plenty of introduction to the clonogenic cell assays available for use on diagrams, and Dr. Steel stresses the evaluation of data rather treated and untreated tumours. This leads into the discusthan simply its accumulation. There are two chapters on the sion of the response of tumours to various cy to toxic agents. overall growth rate of tumours and the theory of growing He emphasizes that to the cell kineticist cytotoxic drugs and populations of cells. These are followed by an account of the radiation would naturally be classed together. This book techniques available to study tumour cell production and may help to encourage interaction between groups whose cell loss. The most commonly used technique (percent of interest at present is restricted to either drugs or radiation. labelled mitoses) is the subject of a whole chapter, including The book ends with a glossary of terms (essential for any a very useful summary and intercomparison of the computer newcomer) and a list of "growing points" which are likely to programmes available for analysing such data. Other less encourage other researchers to include cell kinetic analyses commonly used techniques are comprehensively surveyed, in their future work. Armed with this book they could do so although surprisingly little space is allotted to cytofluoro- with confidence. metry and cell sorters. A most stimulating and rewarding book to read. Dr. Steel provides an excellent summary of the proliferJ. DENEKAMP.
405
VOLUME 51 NUMBER 606
JUNE 1978
The British Journal of Radiology Review article The sensitivity of the human breast to cancer induction by ionizing radiation By R. H. Mole, B.M., F.R.C.P., F.R.C.Path. MRC Radiobiology Unit, Harwell, Oxon 0X11 ORD {Received December, 197 7 and in revisedform February, 1978)
It is often difficult to accept that cancer induction by small doses of radiation is more than a theoretical possibility but actually happens. Indeed it is only quite recently that confirmatory evidence of considerable weight has become available to support the conclusion that the breast may be more sensitive to cancer induction by ionizing radiation than any other human tissue. EVIDENCE THAT IONIZING RADIATION CAUSES BREAST CANCER IN HUMANS
determine with any accuracy so many years later even if the original equipment is available for calibration of output dose-rate (as it sometimes is): the duration of an individual fluoroscopy is an unknown variable. However, this does not alter the demonstration that breast cancer induction has been linearly proportional to number of fluoroscopies nor does it altogether falsify estimates of breast cancer risk per rad of tissue dose. These estimates have to be based on a decision about the average duration of a fluoroscopy as it was practised in particular institutions several decades ago and over a period of years and the risk estimates quoted below may thus be in error by a factor of perhaps 2 to 5, quite apart from statistical considerations, but they cannot be wholly wrong.
Multiplefluoroscopyas employed in the treatment of pulmonary tuberculosis by artificial pneumothorax Two groups of female patients have been followed up for ten to 44 years (mean follow-up each exceeding 25 years) (in Nova Scotia by Myrden and Hiltz, 1969; BEIR, 1972, and in Massachusetts by Boice and Monson, 1977). In the first series breast cancer incidence was five times, in the other twice, what would be expected in controls (tuberculous patients treated without pneumothorax, or regional population statistics). Other series may fail to show an increase but this is to be expected given the numbers of subjects, the magnitude of the breast doses and/or the use of mortality instead of incidence as the index of effect. In the two surveys mentioned there was an approximately linear relationship between excess breast cancer incidence and number of fluoroscopies. This is as would be predicted from the simple hypothesis that cancer frequency caused by multiple small doses of radiation would be proportional to total accumulated dose. Of course the dose for an individual fluoroscopic examination is impossible to
Radiotherapy of post-partum mastitis and other non-malignant diseases of the breast The tissue doses here are known fairly exactly but, to set against this, the irradiated tissue was not normal and the individual treatment doses were ten to 100 times larger than for individual fluoroscopic examinations. The observations, therefore, cannot be so easily assumed to be relevant to occupational exposure or screening by mammography. Radiotherapy of acute post-partum mastitis in New York led to a doubled increase in breast cancer incidence as compared with non-irradiated cases or sibling controls (Mettler et al., 1969; Shore et ah, 1977). Radiotherapy of a variety of benign breast diseases in Stockholm with considerably larger total doses increased expected breast cancer incidence by four to six times (Baral et al., 1977).
Copies of this article may be obtained from The British Journal of Radiology, 32 Welbeck Street, London W1M 7PG at a cost of 60p; remittance with order please.
Japanese bomb survivors By 1969 the incidence of breast cancer in those exposed to ten or more rad (kerma) was increased by
401
VOL.
51, No. 606 R. H. Mole TABLE I. BREAST CANCER MORTALITY IN JAPANESE BOMB SURVIVORS 1950-1972
discussed below are extracted from one or other of these unless specifically referenced.
(primary data in Tables 2 and 13.2-13.5 of Moriyama and Kato, 1973).
APPLICATION OF THIS EVIDENCE TO PRACTICAL PROBLEMS
The mean absorbed dose to breast tissue for an individual fluoroscopic examination was inferred to be 7.5 or 3.6 rad in the Nova Scotia series, depending 0-9 10-34 35 + Breast cancer deaths on the method of assessment, and 1.5 rad in the 21 20 0 Number observed for all Massachusetts series. At levels of dose from 10 rad exposures of 10 rad (kerma) of low LET radiation downwards there is no known or more Number expected: radiobiological reason for expecting much variation 6.4 0 19.3 (a) from experience of those in frequency of effect per rad according to the who received 0—9 rad, magnitude of an individual exposure or according to 7.8 very 12.6 (b) from Japanese national the number of successive, spaced exposures. It is small statistics. Excess rate per 100000 perhaps remarkable, given all the other problems of person-years in those who analysis, that the overall risk estimate per rad is so received 10 rad or more* 8.8 0 0.7 Base-line (a) similar in the two fluoroscopy series (Table II). It is 7.9 0 7.2 Base-line (b) further remarkable that the risk estimates for the two radiotherapy series agree so well with each other and *(i) Whether there is a striking difference in age-related sensitivity to breast cancer induction or not depends with the fluoroscopy series (Table II). entirely on the choice of the control population. It so These estimates are primarily for young adult happens that bomb survivors receiving 0-9 rad at age 35 + years suffered 41 breast cancer deaths in 1950-1972 as women and, although many fewer older women were compared with an expectation of 26.9 as judged by Japanese serially fluoroscoped, the evidence (Table II) may national statistics. This difference is too great to be at- suggest quite strongly that older women are less tributed to the mean radiation dose received by the 0-9 rad group. It may be attributed to chance, in which case the sensitive. However, the risk estimate for incidence in national statistics would provide the appropriate base-line Japanese bomb survivors appears not to be strikingly for risk evaluation, or to some systematic difference between greater for young than for older adults (in contrast the bomb survivor population and the generality of Japanese (which seems very likely), in which case the 0-9 rad group of with mortality, see Table I). Upton et al (1977) survivors would provide the better base-line, cited an unpublished report of an increase in second (ii) McGregor et al. (1977, Table 3) used base-line (a) when breast cancers in women given radiotherapy for a comparing frequencies of breast cancer diagnoses. The excess rates per 100000 person-years were 0, 18.8 and 7.8 first breast cancer with a risk estimate comparable to for the three age-groups respectively for the period 1950-69. those for the other series: if all the second cancers The ratio between the rates for those irradiated at 10-34 are attributable to the dose received by the iryears and 35+ years was smaller for diagnoses than for mortality by about 1 :4. McGregor et al. (1977) noted that radiated breast it might appear that older women the main contribution of new cases after 1960 was from the cannot be strikingly less radiosensitive than younger 10-34 year age group and also that ascertainment for women. However, it seems clear from the Masdiagnoses in 1965-69 was likely to be incomplete. sachusetts fluoroscopy series and the Japanese bomb survivors (both for incidence up to 1969 and mora factor of 1.5 to 2 over those receiving 0-9 rad tality up to 1972) that the maximum sensitivity to (McGregor et al, 1977). By 1972 mortality from breast cancer induction by radiation is in women at breast cancer was also one and a half times to twice some period between 10 and 20 years of age. There that expected (UNSCEAR 1977) and was largely are case reports of breast cancer following doses confined to those irradiated when less than 35 years exceeding 100 rad in the age range 0 to 10 years but of age (Table I) The incidence of breast cancer per the epidemiological evidence is that sensitivity is rad was closely similar at Hiroshima and Nagasaki, much less before puberty than afterwards. It is for deaths (Mole, 1975) and for diagnoses certainly an attractive working hypothesis to postu(McGregor et al, 1977), showing that the RBE of late that the sensitivity of the human breast to fission neutrons cannot much exceed one for cancer induction by ionizing radiation is correlated with hormonally regulated tissue activity. induction of breast cancer in women. The risk estimate for induced breast cancer freThe full reports of four of these surveys have just been published and substantial citations from all of quency in Japanese bomb survivors is lower than any them can be found in two very recent reviews other value in Table II and some of the difference, (Upton et al, 1977; UNSCEAR 1977). The results but not all, is removed by allowing for the much Age at time of irradiation (years)
402
JUNE 1978
Review article. The sensitivity of the human breast to cancer induction by ionizing radiation TABLE II. RISK ESTIMATES OF INDUCTION OF HUMAN BREAST CANCER BY IONIZING RADIATION WHEN BOTH BREASTS ARE EXPOSED.
Frequency of breast cancer in excess of controls per million subjects per rad mean breast dose UNSCEAR1977 Fluoroscopy Nova Scotia Massachusetts
Acute post-partum mastitis (New York) Benign breast disease (Stockholm) Atom bomb survivors Japan
Upton etal., 1977f
years of follow-up
Notes on inform ation relevant to variation in radic age at ex posure*
range in years 20 cases in excess in 234 subjects up to 29 years old 18 cases in excess in 804 subjects up to 29 years old
No breast cancers in 66 subjects aged 30 years and more No excess cases in 243 subjects aged 30 years and more
30-140 ("perhaps greater")
150J
10-28
113
210
10-44 (mean 27)
200
10-34 (mean 25) 6-42 (mean 32)
20 cases in excess in 560 subjects up to 40 years old About 100 cases in excess in 111 5 subjects. Excess most pronounced in those under age 35 when
5-24
About 33 cases in excess (all ages known doses). Excess rate at 35 + years perhaps 1 /4-1 /2 of rate in young adults
175
60§
—
*The number of cases in excess of expected depends on the control population used for the comparison and, since more than one control population was examined in several of the surveys, the excess noted may be an approximate figure. fUpton et al. reported risks in terms of cases per million per year per rad. These annual rates have been converted to total risks by multiplying by the duration of follow-up as given and recorded above. J320 if mean breast dose = 3.6 rad, not 7.5 rad. §Excluding subjects irradiated at < 10 years. The risk estimate given by Upton et al. was in terms of exposure. The value given above includes an approximate allowance for mean dose in breast tissue which is smaller than kerma.
higher proportion of older women amongst them than among those fluoroscoped or treated for acute post-partum mastitis (who in the nature of the case can rarely be more than 40 years' old when irradiated). Additional factors could be the normally lower natural breast cancer incidence in Japan than in occidental countries or the fact that the Japanese received single exposures all exceeding 10 rad (by definition, cf Table I) and running up to several hundred rad. The observed excess rate per rad appears to be smaller at the large doses both for incidence and mortality (though not significantly so in a statistical sense). Radiobiological reasons for expecting such a phenomenon have been discussed (Mole, 1975) and, if accepted, would bring the Japanese rate for single small exposures to a value quite close to the others in Table II. But, whatever the factors affecting the value of the mean risk estimate in Japanese bomb survivors, the weight of the other evidence seems inescapably to lead to the conclusion that the two adult human breasts are between them several times more sensitive to cancer
induction than is human bone marrow. Risk estimates per rad of tissue dose for human leukaemia as commonly given rarely exceed one-quarter of the values for breast cancer given in Table II. An estimate of 15-25 cases per million per rad for low LET radiation at low dose is given by UNSCEAR (1977) and twice that by Mole (1977). The minimum latent period before any induced breast cancer was seen was 10-15 years for fluoroscopy and radiotherapy but perhaps shorter in Japanese bomb survivors. The observations show that induced cases continue to appear for up to 40 years at least after exposure. Mammography Any risk of inducing breast cancer by mammography must be definitely smaller than the expected benefit if screening of well women by mammography is to be used on a population scale (Bailar, 1977). There seem to be two reasons for limiting such screening to women of 50 years and over. In the United States HIP trial of the value of
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R. H. Mole mammmography in the early diagnosis of breast cancer (Shapiro, 1977) there has so far been no benefit for those under the age of 50. Secondly, the risk of mammography seems likely to be smaller at older ages because the natural expectation of life is then becoming shorter than the latent period for a proportion of the induced cancers and, in addition, the risk per rad of breast tissue dose may be smaller than for younger women. Further analysis of the Stockholm radiotherapy series and of data from the Japanese bomb survivors (see footnote Table I) may allow firmer conclusions about this latter question. Other diagnostic radiology
If the Adrian Committee in 1956 had known what is known now about the radiation sensitivity of the human breast, it seems highly probable that it would have sponsored estimates of population breast dose from routine diagnostic radiology as well as estimates of bone marrow dose. Even without this information it may seem unlikely that medical radiology contributes significantly to the total of naturally occurring breast cancer. Occupational exposure and radiological protection
Because of the growing evidence about the sensitivity of the human breast to cancer induction by ionizing radiation the recently revised (1977) Recommendations of the International Commission on Radiological Protection (Publication 26) have made exposure of breast tissue more restrictive than exposure of bone marrow. It may be noted that ICRP (1977) cited for protection purposes a single compromise value for the sensitivity of the human breast to be applied regardless of sex and age. Males are much less sensitive than females and the evidence for a progressive decrease in sensitivity of females from young adulthood to middle and old age has been alluded to. The ICRP compromise is appropriate for practical application because its dose limits are limits on annual dose and the associated risk is linked to the assumption of life-long exposure at the limit. Thus any increased risk per year's exposure for younger women is counterbalanced by the decreased risk per year's exposure for older women. Refined calculations could be made by considering only the risk to females and by taking account of what is known about the distribution of latent periods for radiation-induced breast cancer after a brief exposure. Young adult women are highly represented amongst those occupationally exposed in the medical services. This is just another reason for making sure that X-ray departments are well-
run. Specific restrictions on exposure of female staff beyond those already recommended by ICRP may seem unjustified. Biology of breast cancer
Since radiotherapy is commonly part of treatment for breast cancer and since the untreated breast is bound to receive some dose (depending on the technique used), the observations discussed above would lead to the prediction that subsequent frequency of breast cancer would be raised in the untreated breast and that this increase in frequency would be more conspicuous the younger the age at which the treatment had been given. Both predictions appear to be supported by observations. At ten to 15 years after treatment of breast cancer the frequency of cancer in the untreated breast was found to be four-fold greater than that expected from national statistics (Brinkley and Haybittle, 1968). The risk of occurrence of a second primary breast cancer in the other breast was markedly dependent on the age at diagnosis of a first breast cancer, in one survey being 84-fold higher for those aged 20-24 years and four-fold higher for those aged 40-44 years at the time of the first diagnosis (Waterhouse and Prior, 1975). However there is as yet no evidence to tell how much of these observed differences may be attributed to biological factors and how much, if any, to radiotherapy. Known biological factors, such as cystic mastitis and the length of the time interval between the menarche and the first pregnancy, seem responsible for only a three to four-fold difference in risk of breast cancer (MacMahon and Brown, 1973). Now that the high radiation sensitivity of the human breast is established, the effect of radiation dose on the untreated breast must be evaluated before accepting quantitative conclusions about genetic or other influences derived from epidemiological reports on the occurrence of a second cancer in individuals who have already had a first breast cancer. Concluding comment
No attempt is made here to make recommendations about the use of radiotherapy in breast disease or about mammography as a screening procedure aimed at detecting early breast cancer and so improving the results of treatment. In each case the balance of risk and benefit can be established only by careful study of all the factors involved. The purpose of this brief review is merely to provide a short summary of quite recently acquired information about just one of these factors.
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Review article. The sensitivity of the human breast to cancer induction by ionizing radiation REFERENCES BAILER, J. C. Ill, 1977. Screening for early breast cancer: pros and cons. Cancer, 39, Supplement, 2783-2795. BARAL, E., LARSSON, L. E., and MATTSSON, B., 1977.
Breast cancer following irradiation of the breast. Cancer, 40,2905-2910. BEIR, 1972. Advisory Committee on the Biological Effects of Ionizing Radiation: report on the effects on populations of exposure to low levels of ionizing radiation, Washington, D.C. National Academy of Sciences—National Research Council.
MOLE, R. H., 1975. Ionizing radiation as a carcinogen: practical questions and academic pursuits. British Journal of Radiology, 48, 157-169. 1977. Radiation-induced leukaemia in man. Proceedings of the International Symposium on Radiation-induced Leukemogenesis and Related Viruses, held in Bordeaux. December 7-9, 1976, ed. J. F. Duplan INSERM Symposium No. 4, pp. 19-36 (North-Holland Publishing Company). MORIYAMA, I. M., and KATO, M., 1973. Mortality experi-
ence of A-bomb survivors 1970-72, 1950-72. Atomic Bomb Casualty Commission Report ABCC-15-73. women after repeated fluoroscopic examinations of the MYRDEN, J. A., and HILTZ, J. E., 1969. Breast cancer chest. Journal of the National Cancer Institute, 59, 823following multiple fiuoroscopies during artificial pneu832. mothorax treatment of pulmonary tuberculosis. Canadian BRINKLEY, D., and HAYBITTLE, J. L., 1968. A 15-year Medical Association Journal, 100, 1032-34. follow-up study of patients treated for carcinoma of the SHAPIRO, S., 1977. Evidence on screening for breast cancer breast. British Journal of Radiology, 41, 215-221. from a randomised trial. Cancer, 39, Supplement, 2772— INTERNATIONAL COMMISSION ON RADIOLOGICAL PROTEC2782. TION, 1977. ICRP Publication 26. Recommendations of SHORE, R. E., HEMPELMANN, L. H., KOWALUK, E., MANSUR, the International Commission on Radiological Protection P. S., PASTERNAK, B. S., ALBERT, R. E., and HAUGHIE, (Pergamon Press, Oxford). G. E., 1977. Breast neoplasms in women treated with MACMAHON, B., and BROWN, J., 1973. Etiology of human X-rays for acute post-partum mastitis. Journal of the breast cancer: a review. Journal of the National Cancer National Cancer Institute, 59, 813-822. Institute, 50, 21-42. UNSCEAR, 1977. Sources and effects of ionizing radiation. MCGREGOR, D. H., LAND, C. E., CHOI, K., TOKUOKA, S., Annex G Radiation Carcinogenesis in Man (United LUI, P., WAKABAYASHI, T., and BEEBE, G. W., 1977. Nations, New York). Breast cancer incidence among atomic bomb survivors, UPTON, A. C , BEEBE, G. W., BROWN, J. M., QUIMBY, Hiroshima and Nagasaki, 1950-69. Journal of the National E. H., and SHELLABARGER, C , 1977. Report of NCI Ad Cancer Institute, 59, 799-811. Hoc Working Group on the risks associated with mamMETTLER, F. A., HEMPELMANN, L. H., DUTTON, A. M., mography in mass screening for the detection of breast PIFER, J. W., TOYOOKA, E. T., and AMES, W. R., 1969. cancer. Journal of the National Cancer Institute, 59, Breast neoplasms in women treated with X rays for acute 480-493. post partum mastitis. A pilot study. Journal of the National WATERHOUSE, J. A. H., and PRIOR, M. P., 1975. Breast Cancer Institute, 43, 803-811. cancer in young women. British Medical Journal, 2, 434. BOICE, J. D., Jr., and MONSON, R. R., 1977. Breast cancer in
Book review Growth Kinetics of Tumours {Cell population kinetics in rela-ation studies that have been reported for both experimental tion to the growth and treatment of cancer). By G. G. Steel, and human tumours. He stresses the importance and the pp. xi + 351, illus., 1977 (Oxford, Clarendon Press) £1500. inadequacy of data on solid tumours, and perhaps his This book provides us at last with a comprehensive, account will stimulate further work. He analyses the authoritative and very readable account of cell kinetics in relevance of tumour size, of transplantation history and of tumours. It fills a gap that has been glaringly obvious. This the microanatomical structure in experimental tumours and volume must be considered an essential part of any Library highlights the lack of data on spontaneous tumours. on Cancer Research, and at £15-00 for 350 fact-filled pages The chapter on stem cells presents an unbiased account of it also represents excellent value. the evidence for and against their existence, and is a useful The information is clearly presented with plenty of introduction to the clonogenic cell assays available for use on diagrams, and Dr. Steel stresses the evaluation of data rather treated and untreated tumours. This leads into the discusthan simply its accumulation. There are two chapters on the sion of the response of tumours to various cy to toxic agents. overall growth rate of tumours and the theory of growing He emphasizes that to the cell kineticist cytotoxic drugs and populations of cells. These are followed by an account of the radiation would naturally be classed together. This book techniques available to study tumour cell production and may help to encourage interaction between groups whose cell loss. The most commonly used technique (percent of interest at present is restricted to either drugs or radiation. labelled mitoses) is the subject of a whole chapter, including The book ends with a glossary of terms (essential for any a very useful summary and intercomparison of the computer newcomer) and a list of "growing points" which are likely to programmes available for analysing such data. Other less encourage other researchers to include cell kinetic analyses commonly used techniques are comprehensively surveyed, in their future work. Armed with this book they could do so although surprisingly little space is allotted to cytofluoro- with confidence. metry and cell sorters. A most stimulating and rewarding book to read. Dr. Steel provides an excellent summary of the proliferJ. DENEKAMP.
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