-EDITORIALS
prospective clinical studies to determine benefits and risks as accurately as possible. Such studies, of course, should require informed consent of all participants. The most promising attempt to date has been the joint ACS-NCI project. Mammography is already known to be beneficial for symptomatic patients of all ages and for the screening of asymptomatic women over 50. Let us now find out whether this also applies to the screening of women under 50 by proceeding with the breast cancer detection project without alteration or delay. EDWARD A. SICKLES, MD Chief, Mammography Section Department of Radiology University of California, San Francisco
REFERENCES 1. Strax P, Venet L, Shapiro S: Value of mammography in reduction of mortality from breast cancer in mass screening. Am J Ronetgenol 117:686-689, 1973 2. Stark AM, Way S: The screening of well women for the early detection of breast cancer using clinical examination with thermography and mammography. Cancer 33:1671-1679, 1974 3. Sadowsky NL, Kalisher L, White G, et al: Radiologic detection of breast cancer-Review and recommendations. N Engl J Med 294:370-373, 1976
EDITOR'S NOTE: The above editorial was sent to Lester Breslow, MD, for comment. Dr. Breslow's views are presented below. A reply from Dr. Sickles will appear in the Correspondence section next month.
Radiation Risks of Mammography: Another View IT IS PROBABLY TRUE that recent and unfortunately sometimes misleading publicity has created some undue alarm about the risks of mammography. Matters are not set straight, however, by statements such as that of Sickles. He touches mainly on two points. One point advanced by Sickles can be represented by quoting from his editorial: ". . . potential risks of mammography are not fully known." most radiobiologists construct a doseresponse curve and extrapolate linearly back toward zero, assuming that there is no threshold below which carcinogenic effects are absent." ". . . such analyses are based on assumptions that have never been proved, and about which there is considerable disagreement. Conclusive
4. Wolfe JN: Analysis of 462 breast carcinomas. Am J Roentgenol 121:846-853, 1974 5. Strax P: Control of breast cancer through mass screening. JAMA 235:1600-1602, 1976 6. Preliminary unedited (current) statistics, Breast Cancer Detection Demonstration Project, Bethesda, Md, Jul 19, 1976 7. Margulis AR: The lesions of radiobiology for diagnostic radiology. Caldwell Lecture, 1972. Am J Roentgenol 117:741756, 1973 8. MacKenzie I: Breast cancer following multiple fluoroscopies. Br J Cancer 19:1-8, 1965 9. Wanebo CK, Johnson KG, Sato K, et al: Breast cancer after exposure to the atomic bombings of Hiroshima and Nagasaki. N Engl J Med 279:667-671, 1968 10. Myrden JA, Hiltz JE: Breast cancer following multiple fluoroscopies during artificial pneumothorax treatment of pulmonary tuberculosis. Canad Med Assoc J 100:1032-1034, 1969 11. Mettler FA Jr, Hempelmann LH, Dutton AM, et al: Breast neoplasms in women treated with x-rays for acute postpartum mastititis-A pilot study. J Nat Cancer lnst 43:803-811, 1969 12. Rossi HH, Kellerer AM: Radiation carcinogenesis at low doses. Science 175:200-202, 1972 13. Mole RH: Ionizing radiation as a carcinogen: Practical questions and academic pursuits. Br J Radiol 48:157-169, 1975 14. Morgan KZ: Reducing medical exposure to ionizing radiation. J Am Industr Hyg Assoc 36:358-368, 1975 15. National Council on Radiation Protection and Measurements: Review of the Current State of Radiation Protection Philosophy. NCPR Report No. 43. Washington, National Council on Radiaticn Protection, 1975 16. Bailar JC III: Mammography: A contrary view. Ann Intern Med 84:77-84, 1976 17. Breslow L: Unpublished data, released Jul 15, 1976 18. San Francisco Chronicle: Jul 29, 1976, p 17
evidence does not exist for either a linear doseresponse curve or lack of a threshold dose." In our report to the National Cancer Institute of 15 July 1976,1 we stated: "The basis for believing that mammography may induce breast cancer lies in a series of studies indicating that exposure of the breast to radiation can cause breast cancer. These studies show that women (a) exposed to radiation in the Japan atomic bomb explosion;2-4 (b) treated by radiation for benign breast disease;5 or (c) subjected to repeated x-ray fluoroscopy of the chest in connection with treatment for tuberculosis,6-'0 all suffered a significantly higher incidence of breast cancer in later years than did comparable groups of women considered as controls. Although the amount of radiation exposure in these series of women was many times greater than that encountered in mammography, a National Academy of Sciences review indicated (and we concur) that one must assume a linear dose-response relationship on the basis of present evidence and in the absence of any clear information to the contrary." This means that there is no absolutely safe dose and that, in the case of breast cancer induced by x-rays, the number of cases resulting from the exposure will be simply proportional to THE WESTERN JOURNAL OF MEDICINE
495
EDITORIALS
the number of years lived after exposure to a certain quantity of radiation, with some minimum latent period. The National Academy of Sciences report11 estimated that 6 extra cases of breast cancer are induced per million per year rad after a 10 year minimum latent period." Arthur Upton, speaking for himself and other leading radiation-biologists appointed by the National Cancer Institute to reexamine the matter, reaffirmed on 19 July 1976 at the National Cancer Institute that linear extrapolation (and no "threshold") should continue as the basis for estimating risk.12 Incidentally, at least some of the references cited by Sickles do not deny linear extrapolation but merely question whether it has been "conclusively" proved. The evidence both in the 1972 report" and subsequently assembled by Upton'2 clearly favors linear extrapolation and no "threshold." In view of the above-cited evidence and interpretation of it, is it not prudent to assume mammography will induce some breast cancer rather than wait 10 to 30 years for "conclusive proof" among millions of women? Sickles further expresses a "hope" that the nationwide Breast Cancer Demonstration Detection Project (BCDDP) will result in information as to, among other things, ". . . whether or not there are significant long-term radiation risks." Unfortunately the BCDDP was not designed to discover, and will not yield, this information. Radiation-induced breast cancer, according to all human exposures studied thus far, begins to appear only after about a ten-year latent period. The BCDDP was designed to include five years of periodic mammography (and other) examinations, and an additional five years of observation. Such a design obviously cannot show "whether or not there are significant long-term radiation risks." Even if the design were altered now, simply to extend the period of observation into the time when radiation-induced breast cancer would be expected to occur, there is presently no control group for comparison. The women coming to the BCDDP constitute a unique group of volunteers, all of whom have been receiving mammography. In the absence of any data showing that radiation-induced breast cancers are pathologically or otherwise unique, and in the absence of a control group, it is difficult to see how any conclusion could be drawn about radiation-induced breast cancer from the BCDDP experience presently underway. 496
DECEMBER 1976 * 125 * 6
The second main point advanced by Sickles is that we make "no allowance . . . for improvements in mammographic equipment, technique and knowledge that have accrued in the greater than ten-year interval since the HIP (Health Insurance Plan of Greater New York) study mammograms were taken." He then cites certain data from the BCDDP as evidence of this
improvement. The fact "that a third of the breast cancer so far detected [in the BCDDP] has been in women under age 50, and that 45 percent of this cancer was detected by mammography alone" is irrelevant to the important issue of whether current mammography is finding breast cancer in women whose lives will be saved. The fact that a third of the breast cancer detected has been in women under 50 reflects mainly that about half of the women screened have been under 50; if only a fourth of those screened had been under 50 a smaller proportion of the cases found would have been under 50; and if three fourths of those screened had been under 50, a larger proportion would have been under 50. Conclusions about the benefits of mammography cannot be drawn from such proportions, or from the 45 percent figure mentioned by Sickles. The only scientific approach I can see to ascertaining whether current mammography will disclose breast cancer in women under 50 whose lives can thereby be saved is to conduct a randomized clinical trial which might contradict the HIP data. As medical technology advances and brings greater potential for harm as well as good, the randomized clinical trial will become increasingly important as a means of ascertaining risk/benefit. If mammography technique has advanced to the point where women under 50 who receive mammography routinely do have a substantially better chance of avoiding death from breast cancer than women who do not receive it, that should certainly be established by proper study. The HIP study did not show any such benefit, and that is the only controlled trial to date. I agree with Sickles' suggestions numbered 1, 2 and 4. I would hope he might change his view on 3. With the available evidence and prudent interpretation of it indicating a risk of radiationinduced breast cancer from mammography; with all the available evidence (the HIP study being the only controlled study) showing no measurable mortality benefit to women under 50; with the BCDDP not designed (and not claimed by its
EDITORIALS
sponsors) to yield risk/benefit data-why continue routine mammography screening at present for women under 50? As a long-time and continuing enthusiast for early breast cancer detection, using all appropriate modalities, my preference would be to design and conduct appropriate studies before exposing women under 50 to the risk of radiation-induced breast cancer without clear-cut evidence of benefit. LESTER BRESLOW, MD, MPH Dean, School of Public Health University of California, Los Angeles Center for the Health Sciences
REFERENCES 1. Breslow L, Henderson B, Massey F, Pike M, Winkelstein W: Report to National Cancer Institute. Jul 15, 1976 2. Wanebo CK, Johnson KG, Sato K, et al: Breast cancer after exposure to the atomic bombings of Hiroshima and Nagasaki. N Engl J Med 279:667-671, Sep 26, 1968 3. Jablon S, Kato H: Studies of mortality of A-bomb survivors
-No 5: Radiation dose and mortality, 1950-1970. Radiat Res 50: 649-698, Jun 1972 4. Beebe GW, Kato H: Biological effects E: Cancer other than leukemia, in review of thirty years study of Hiroshima and Nagasaki atomic bomb survivors. J Radiat Res Suppl: 97-107, 1975 5. Mettler FA Jr, Hempelmann LH, Dutton AM, et al: Breast neoplasms in women treated with x-rays for acute postpartum mastitis-A pilot study. J Nat Cancer Inst 43:803-811, Oct 1969 6. Mackenzie I: Breast cancer following multiple fluoroscopies. Br J Cancer 19:1-8, 1965 7. Myrden JA, Hiltz JE: Breast cancer following multiple fluoroscopies during artificial pneumothorax treatment of pulmonary tuberculosis. Can Med Assoc J 100:1032-1034, 1969 8. Cook DC, Dent 0, Hewitt D: Breast cancer following multiple chest fluoroscopy: The Ontario experience. Can Med Assoc J 111:406-409, 412, Sep 7, 1974 9. Delarue NC, Gale G, Ronald A: Multiple fluoroscopy of the chest: Carcinogenicity for the female breast and implications for breast cancer screening programs. Can Med Assoc J 112:14051413, Jun 21, 1975 10. Boice JD, Monson JD: X-ray exposure and breast cancer.
(Personal Communication) 11. Report of the Advisory Committee on the Biological Effects of Ionizing Radiations: The Effects on Population of Exposures to Low Levels of Ionizing Radiation (BEIR Report). Washington, DC, Division of Medical Sciences, National Academy of Sciences
-National Research Council, Nov 1972 12. Upton A: Personal Statement. Meeting at National Cancer Institute, Jul 19, 1976
THE WESTERN JOURNAL OF MEDICINE
497
prospective clinical studies to determine benefits and risks as accurately as possible. Such studies, of course, should require informed consent of all participants. The most promising attempt to date has been the joint ACS-NCI project. Mammography is already known to be beneficial for symptomatic patients of all ages and for the screening of asymptomatic women over 50. Let us now find out whether this also applies to the screening of women under 50 by proceeding with the breast cancer detection project without alteration or delay. EDWARD A. SICKLES, MD Chief, Mammography Section Department of Radiology University of California, San Francisco
REFERENCES 1. Strax P, Venet L, Shapiro S: Value of mammography in reduction of mortality from breast cancer in mass screening. Am J Ronetgenol 117:686-689, 1973 2. Stark AM, Way S: The screening of well women for the early detection of breast cancer using clinical examination with thermography and mammography. Cancer 33:1671-1679, 1974 3. Sadowsky NL, Kalisher L, White G, et al: Radiologic detection of breast cancer-Review and recommendations. N Engl J Med 294:370-373, 1976
EDITOR'S NOTE: The above editorial was sent to Lester Breslow, MD, for comment. Dr. Breslow's views are presented below. A reply from Dr. Sickles will appear in the Correspondence section next month.
Radiation Risks of Mammography: Another View IT IS PROBABLY TRUE that recent and unfortunately sometimes misleading publicity has created some undue alarm about the risks of mammography. Matters are not set straight, however, by statements such as that of Sickles. He touches mainly on two points. One point advanced by Sickles can be represented by quoting from his editorial: ". . . potential risks of mammography are not fully known." most radiobiologists construct a doseresponse curve and extrapolate linearly back toward zero, assuming that there is no threshold below which carcinogenic effects are absent." ". . . such analyses are based on assumptions that have never been proved, and about which there is considerable disagreement. Conclusive
4. Wolfe JN: Analysis of 462 breast carcinomas. Am J Roentgenol 121:846-853, 1974 5. Strax P: Control of breast cancer through mass screening. JAMA 235:1600-1602, 1976 6. Preliminary unedited (current) statistics, Breast Cancer Detection Demonstration Project, Bethesda, Md, Jul 19, 1976 7. Margulis AR: The lesions of radiobiology for diagnostic radiology. Caldwell Lecture, 1972. Am J Roentgenol 117:741756, 1973 8. MacKenzie I: Breast cancer following multiple fluoroscopies. Br J Cancer 19:1-8, 1965 9. Wanebo CK, Johnson KG, Sato K, et al: Breast cancer after exposure to the atomic bombings of Hiroshima and Nagasaki. N Engl J Med 279:667-671, 1968 10. Myrden JA, Hiltz JE: Breast cancer following multiple fluoroscopies during artificial pneumothorax treatment of pulmonary tuberculosis. Canad Med Assoc J 100:1032-1034, 1969 11. Mettler FA Jr, Hempelmann LH, Dutton AM, et al: Breast neoplasms in women treated with x-rays for acute postpartum mastititis-A pilot study. J Nat Cancer lnst 43:803-811, 1969 12. Rossi HH, Kellerer AM: Radiation carcinogenesis at low doses. Science 175:200-202, 1972 13. Mole RH: Ionizing radiation as a carcinogen: Practical questions and academic pursuits. Br J Radiol 48:157-169, 1975 14. Morgan KZ: Reducing medical exposure to ionizing radiation. J Am Industr Hyg Assoc 36:358-368, 1975 15. National Council on Radiation Protection and Measurements: Review of the Current State of Radiation Protection Philosophy. NCPR Report No. 43. Washington, National Council on Radiaticn Protection, 1975 16. Bailar JC III: Mammography: A contrary view. Ann Intern Med 84:77-84, 1976 17. Breslow L: Unpublished data, released Jul 15, 1976 18. San Francisco Chronicle: Jul 29, 1976, p 17
evidence does not exist for either a linear doseresponse curve or lack of a threshold dose." In our report to the National Cancer Institute of 15 July 1976,1 we stated: "The basis for believing that mammography may induce breast cancer lies in a series of studies indicating that exposure of the breast to radiation can cause breast cancer. These studies show that women (a) exposed to radiation in the Japan atomic bomb explosion;2-4 (b) treated by radiation for benign breast disease;5 or (c) subjected to repeated x-ray fluoroscopy of the chest in connection with treatment for tuberculosis,6-'0 all suffered a significantly higher incidence of breast cancer in later years than did comparable groups of women considered as controls. Although the amount of radiation exposure in these series of women was many times greater than that encountered in mammography, a National Academy of Sciences review indicated (and we concur) that one must assume a linear dose-response relationship on the basis of present evidence and in the absence of any clear information to the contrary." This means that there is no absolutely safe dose and that, in the case of breast cancer induced by x-rays, the number of cases resulting from the exposure will be simply proportional to THE WESTERN JOURNAL OF MEDICINE
495
EDITORIALS
the number of years lived after exposure to a certain quantity of radiation, with some minimum latent period. The National Academy of Sciences report11 estimated that 6 extra cases of breast cancer are induced per million per year rad after a 10 year minimum latent period." Arthur Upton, speaking for himself and other leading radiation-biologists appointed by the National Cancer Institute to reexamine the matter, reaffirmed on 19 July 1976 at the National Cancer Institute that linear extrapolation (and no "threshold") should continue as the basis for estimating risk.12 Incidentally, at least some of the references cited by Sickles do not deny linear extrapolation but merely question whether it has been "conclusively" proved. The evidence both in the 1972 report" and subsequently assembled by Upton'2 clearly favors linear extrapolation and no "threshold." In view of the above-cited evidence and interpretation of it, is it not prudent to assume mammography will induce some breast cancer rather than wait 10 to 30 years for "conclusive proof" among millions of women? Sickles further expresses a "hope" that the nationwide Breast Cancer Demonstration Detection Project (BCDDP) will result in information as to, among other things, ". . . whether or not there are significant long-term radiation risks." Unfortunately the BCDDP was not designed to discover, and will not yield, this information. Radiation-induced breast cancer, according to all human exposures studied thus far, begins to appear only after about a ten-year latent period. The BCDDP was designed to include five years of periodic mammography (and other) examinations, and an additional five years of observation. Such a design obviously cannot show "whether or not there are significant long-term radiation risks." Even if the design were altered now, simply to extend the period of observation into the time when radiation-induced breast cancer would be expected to occur, there is presently no control group for comparison. The women coming to the BCDDP constitute a unique group of volunteers, all of whom have been receiving mammography. In the absence of any data showing that radiation-induced breast cancers are pathologically or otherwise unique, and in the absence of a control group, it is difficult to see how any conclusion could be drawn about radiation-induced breast cancer from the BCDDP experience presently underway. 496
DECEMBER 1976 * 125 * 6
The second main point advanced by Sickles is that we make "no allowance . . . for improvements in mammographic equipment, technique and knowledge that have accrued in the greater than ten-year interval since the HIP (Health Insurance Plan of Greater New York) study mammograms were taken." He then cites certain data from the BCDDP as evidence of this
improvement. The fact "that a third of the breast cancer so far detected [in the BCDDP] has been in women under age 50, and that 45 percent of this cancer was detected by mammography alone" is irrelevant to the important issue of whether current mammography is finding breast cancer in women whose lives will be saved. The fact that a third of the breast cancer detected has been in women under 50 reflects mainly that about half of the women screened have been under 50; if only a fourth of those screened had been under 50 a smaller proportion of the cases found would have been under 50; and if three fourths of those screened had been under 50, a larger proportion would have been under 50. Conclusions about the benefits of mammography cannot be drawn from such proportions, or from the 45 percent figure mentioned by Sickles. The only scientific approach I can see to ascertaining whether current mammography will disclose breast cancer in women under 50 whose lives can thereby be saved is to conduct a randomized clinical trial which might contradict the HIP data. As medical technology advances and brings greater potential for harm as well as good, the randomized clinical trial will become increasingly important as a means of ascertaining risk/benefit. If mammography technique has advanced to the point where women under 50 who receive mammography routinely do have a substantially better chance of avoiding death from breast cancer than women who do not receive it, that should certainly be established by proper study. The HIP study did not show any such benefit, and that is the only controlled trial to date. I agree with Sickles' suggestions numbered 1, 2 and 4. I would hope he might change his view on 3. With the available evidence and prudent interpretation of it indicating a risk of radiationinduced breast cancer from mammography; with all the available evidence (the HIP study being the only controlled study) showing no measurable mortality benefit to women under 50; with the BCDDP not designed (and not claimed by its
EDITORIALS
sponsors) to yield risk/benefit data-why continue routine mammography screening at present for women under 50? As a long-time and continuing enthusiast for early breast cancer detection, using all appropriate modalities, my preference would be to design and conduct appropriate studies before exposing women under 50 to the risk of radiation-induced breast cancer without clear-cut evidence of benefit. LESTER BRESLOW, MD, MPH Dean, School of Public Health University of California, Los Angeles Center for the Health Sciences
REFERENCES 1. Breslow L, Henderson B, Massey F, Pike M, Winkelstein W: Report to National Cancer Institute. Jul 15, 1976 2. Wanebo CK, Johnson KG, Sato K, et al: Breast cancer after exposure to the atomic bombings of Hiroshima and Nagasaki. N Engl J Med 279:667-671, Sep 26, 1968 3. Jablon S, Kato H: Studies of mortality of A-bomb survivors
-No 5: Radiation dose and mortality, 1950-1970. Radiat Res 50: 649-698, Jun 1972 4. Beebe GW, Kato H: Biological effects E: Cancer other than leukemia, in review of thirty years study of Hiroshima and Nagasaki atomic bomb survivors. J Radiat Res Suppl: 97-107, 1975 5. Mettler FA Jr, Hempelmann LH, Dutton AM, et al: Breast neoplasms in women treated with x-rays for acute postpartum mastitis-A pilot study. J Nat Cancer Inst 43:803-811, Oct 1969 6. Mackenzie I: Breast cancer following multiple fluoroscopies. Br J Cancer 19:1-8, 1965 7. Myrden JA, Hiltz JE: Breast cancer following multiple fluoroscopies during artificial pneumothorax treatment of pulmonary tuberculosis. Can Med Assoc J 100:1032-1034, 1969 8. Cook DC, Dent 0, Hewitt D: Breast cancer following multiple chest fluoroscopy: The Ontario experience. Can Med Assoc J 111:406-409, 412, Sep 7, 1974 9. Delarue NC, Gale G, Ronald A: Multiple fluoroscopy of the chest: Carcinogenicity for the female breast and implications for breast cancer screening programs. Can Med Assoc J 112:14051413, Jun 21, 1975 10. Boice JD, Monson JD: X-ray exposure and breast cancer.
(Personal Communication) 11. Report of the Advisory Committee on the Biological Effects of Ionizing Radiations: The Effects on Population of Exposures to Low Levels of Ionizing Radiation (BEIR Report). Washington, DC, Division of Medical Sciences, National Academy of Sciences
-National Research Council, Nov 1972 12. Upton A: Personal Statement. Meeting at National Cancer Institute, Jul 19, 1976
THE WESTERN JOURNAL OF MEDICINE
497
