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Posted on: 06.09.2015

Mammography’s Shadows, IV: Hunting Cancer with X-Rays

by Sylvia Kraemer
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Posted in Healthcare, Science and Policy

Crab ImageAll of us come into the world designed by evolution to survive.  Failing some rare mishap, we arrive equipped with immune systems ready to do battle with unfriendly biologic mischief makers.  The wizards within us that enable this microscopic life-preserving enterprise reside in the nuclei of our 75-100 trillion cells.

Just as millions of  ‘0s’ and ‘1s’ arrayed in lines of computer code serve as the language  of a computer’s operations, a sequence  of roughly 100 millions of four different kinds of organic molecules, or nucleotides, arranged in pairs between two identical DNA strands, provide the  instructional language for our cells’ functions.  These lengthy strands (estimates range from about 3 to 5 feet) are wound in a double helix and folded over themselves repeatedly in order to fit within the chromosomes of cell nuclei, thanks to some very clever engineering work by proteins, our bodies’ ‘hard hats.’

DNA molecules  govern our  cells’ functions, their  development and their reproduction.  After a limited number of generations, they ensure cell  death  to make way for new cell growth.[1]   Cell reproduction requires that the two DNA strands separate and unwind (more work for proteins), each strand then directing the synthesis of a new, identical partner.  The new, double stranded DNA in the new “daughter” cell must be an exact replica of its parent.  To make sure that that happens, DNA is capable of detecting and repairing any damage that might have occurred in a microscopic  process of remarkable complexity, mastered by living organisms eons ago.

These complex molecular structures are composed of intricate flotillas of atoms, atoms that have combined—by exchanging or sharing electrons—to form them.   Imagine, then, the consequences for living cells if their smallest subunits—atoms—lose their electronic stability (their balance of positive and negative electric charges).  They become ionized, or electrically charged ions; we know them as chemically unruly ‘free radicals.’  This can occur in a variety of ways, one of which is bombardment with very high frequency electromagnetic radiation (e.g., x-rays and gamma rays), which can break lose one or more electrons.[2]

The effects of ‘ionizing radiation’ can include the destruction of the molecules that form our DNA.  Certain proteins in our cells will enable those molecules to continue growing—but without the regulatory guidance of their finely constructed DNA.  This unregulated cell growth is what we call ‘cancer,’ named for the crab which it often resembles.

Radiation surrounds us and is as common to our lives as the night follows the day.  The sun’s radiance provides energy that turns into matter by powering natural and vital rearrangements of atoms’ electrons into different molecular combinations.  Among plants, for example, photosynthesis uses light energy from the sun to convert carbon dioxide and water into food, which is then consumed by animals—and ourselves.

Thus a certain amount of background or natural radiation is essential to life, and part of the DNA code that guides our cellular functions includes instructions for the repair of molecules damaged by ionizing radiation.  But at some point for each living organism the radiation it receives may exceed the native cellular repair capacity of its organs.  Just what that point is varies from individual to individual. Beyond a certain dose and duration of exposure, ionizing radiation is certain to overwhelm the orderly cell repair capacity of most people.

Medical x-rays represent a significant net increase to our cumulative radiation exposure over any given period of time.  In the 1970s, when annual mammography screening of asymptomatic women at low or normal risk for breast cancer began, medical x-ray exposure already “accounted for approximately 90 percent of . . . total radiation other than natural background [radiation].”[3]

X-rays effect different organs and tissues in different ways.  Variations in “probability and severity of harm” to living things from radiation are described by the International Atomic Energy Agency as “detriment,” which the IAEA calibrates by using a “tissue weighting factor” to determine the actual effective radiation dose for particular organs and tissues.  These tissue weighting factors (WT) range from 0.01 for skin and bone surface tissue, to 0.12 (or a multiple of 12) for bone marrow, breast, colon, lung and stomach tissue.[4]  Thus comparing x-radiation damage to breast tissue to general background radiation risk may understate the risk by as much as a factor of twelve.

Information about medical x-ray dosing in the case of mammography typically relies on ratings given by manufacturers of specific equipment used.  Such ratings assume a standard thickness of the compressed breast, a standard combination of glandular and adipose tissue (breast density), and standard x-ray beam characteristics.  In real life, however, the absorbed glandular dose (measured in Grays[5]) received during a mammogram can vary by nearly 50%, depending upon breast thickness and density.[6]  The newer three dimensional mammogram, or ‘breast tomosynthesis,’ which is similar to a CAT scan of the breast, involves yet more radiation.

Numbers are useful for calibrating machines, but when we discuss medical x-ray risk in terms of numers we imply that there is a number that represents relative safety, and that we know what that number is.  The numbers that represent radiation doses from mammography machines have little to do with our as yet imperfect understanding of the biology of cancer, which cannot be calibrated.  By relying such numbers—whatever the quantity of millisieverts we might agree upon—we are dissembling, pretending that we can adequately predict what will happen to an individual’s organs when struck by ionizing radiation, what results will follow, and most importantly, how and for how long those results will make a difference to the normal functioning of that person’s body.   But we cannot.

Long before the Health Insurance Plan (HIP) of Greater New York began its mammography trial in 1963,  scientists had demonstrated that carcinogenic capacity of ionizing radiation delivered as x-rays.   A major contribution to that research came from the German cytologist Theodor Heinrich Boveri’s studies of the chromosome in cell division and heredity.

In 1902 Boveri concluded from his work that there was a strong link between cancer and chromosomal abnormalities within the cell:

“The tumour problem is a cell problem . . .  The cells of even the most     malignant tumours can be formed from normal tissue cells.  . . . the differences between the cells of different tissues are ultimately determined by differences in the state of the chromosomes. . . . . The primordial tumorigenic cell . . . is a cell that harbours a specific faulty assembly of chromosomes as a consequence of an abnormal event. This is the main cause of the propensity for unrestrained proliferation that the primordial cell passes to its progeny . . . .”[7]

Boveri’s findings were first published in 1914 in his native German.  By 1929 his booklet was available in six English language editions both in the United States and Great Britain.  A half-century after the first appearance of Boveri’s essay on the chromosome and tumorigenesis, Science magazine in 1964 published an appreciation written by his fellow biologist and biographer, Fritz Baltzer.[8]

Meanwhile, the power of x-rays to infiltrate our bodies’ invisible depths has been known to us since Wilhelm Conrad Röntgen, experimenting with cathode ray (vacuum) tubes in 1895, discovered that electric current passing through a cathode ray tube could penetrate various materials and leave marks on photosensitive plates or film.  When such rays fail to penetrate, or are absorbed by, an intervening material such as the calcium in bone, they leave a white shadow on the dark background of a photosensitive surface.

Five years later, in 1901, Röntgen would receive the Nobel Prize in physics for a discovery which, by then, had—in today’s parlance—gone “viral.”  As medical imaging’s historian Bettyann Holzman Kevles describes it,

“Within weeks . . . X-ray Boy’s Clubs sprouted in the United States, and X-ray slot machines were installed in Chicago and Lawrence, Kansas, where, for a coin, you could examine the bones in your own hand. . . . Anybody could cobble together an X-ray machine, and just about anyone did. . . . There was no hint of danger.”[9]  It did not take long for the possible medical and industrial applications of X-ray machines to become apparent.  But danger, there was.

Initially, in the early 20th century, medical and dental exposures lasted for hours at a time, as patients, dentists, physicians, and x-ray tube makers all endured burns and deeper tissue damage, not to mention fatal metastatic carcinomas.  Thomas Edison famously abandoned work on x-ray tubes after his glassblower, Clarence Madison Dally, died in 1904, having suffered from what would later be called radiation sickness, and then finally losing both arms to cancer.[10]

Soon on the heels of Röntgen’s discovery, English physicist Joseph John Thomson, further investigating the properties of electricity as it passed through vacuum tubes, detected individual particles which were a thousand times smaller than atoms.  These he identified as subparticles of atoms, which he named electrons, produced when x-rays struck atoms with sufficient force to disperse one or more of their electrons, leaving behind unstable ions.

By the end of the 1920s biological investigations of genetic mutations had converged with research into the long-term damage from ionizing radiation.   Geneticist Hermann Joseph Muller, experimenting with varying doses of X-rays, discovered a directly proportional connection between radiation exposure and lethal genetic mutations in fruit flies.  His work, reported in 1926 at a scientific conference in Berlin, earned him the 1946 Nobel Prize in Physiology or Medicine.

Thus by World War II scientists had not only connected abnormal disruptions to the molecular structure of the chromosome and aberrant cell growth, but recognized that x-rays could produce those disruptions.  What had been previously only observed—a link between cumulative or prolonged x-ray exposures and cancer—was now understood.  All that remained was to determine the minimum extent of x-ray exposure that might produce oncogenes—or whether there was such a thing as a safe minimum exposure at all.

Within a few months after the U.S. atomic bombings of Hiroshima (August 6, 1945) and Nagasaki (August 9, 1945), Japanese and American scientists collaborated on the Atomic Bomb Casualty Commission to assess the radiation consequences of the bombings.  (Their work was continued, after 1975, by the Radiation Effects Research Foundation.)  Their efforts were handicapped by the difficulty of establishing the precise nature of the radiation emitted in any given location and relating those findings to other than broad-scale epidemiological data.   Added to that was the difficulty of determining the long-term effects of low-level ionizing radiation, because carcinomas can have long latency periods.  For decades after 1945 attributions of cancer cases to radiation from the bombings relied on estimates, and were regularly disputed.[11]

The National Academy of Sciences created in 1955 a committee on the biological effects of atomic radiation, with six subcommittees which investigated radiation’s effects on genetics, pathology, meteorology, oceanography and fisheries, agriculture and food supplies, and the disposal and dispersal of radioactive wastes.    The committee issued an initial assessment in 1956, which was updated for its 1960 report.[12]

The group examining genetic effects confirmed that irradiation of female mice produced genetic damage.  It also confirmed genetic consequences for the “children of survivors of the atomic bombings at Hiroshima and Nagasaki,” as well as “children elsewhere whose parents received radiation for medical or other reasons.”[13]

However, cautioned the report,  “. . . most of the man-made radiation to which the population of the United States is exposed involves dose rates not yet adequately investigated experimentally. For example, we do not know whether the effects of low doses given at high dose rates, as in medical exposures, will be more like the response from acute irradiation or more like that from chronic irradiation.”  Pathologies such as skin cancer and leukemia may result from “relatively low level” exposure “from time to time over a period of years. . . .” and it is “characteristic” of radiation that its “effects may manifest themselves not only immediately, but perhaps only after a long period of intermittent . . .exposure.

“Delayed manifestation of biological effects results from the fact that “all types of induced and spontaneous tumors appear not to arise at once . . . . There is much evidence indicating that malignant change ordinarily develops only after a series of ‘precancerous’ changes or a state of tissue disorder has taken place.”[14]

Given what the subcommittee on pathological effects had learned, and the questions remaining, it recommended against predicting “human tumor incidences from small radiation doses based on extrapolation from the observed incidences following high dosage,” such as those recorded after the atomic bombings of Japan.  Furthermore, prediction ” . . . requires evaluation of the possibility that there is a threshold dose below which there is no probability of inducing leukemia, a concept which implies a factor of safety that would be most reassuring to those who are exposed to radiation in excess of the natural background . . . .  However, no member of the Subcommittee feels that he can estimate the size of the threshold or, for that matter, even prove its existence. Accordingly, the Subcommittee believes it is prudent to assume that there is no threshold.” [15]

Subsequent reports from the National Academy of Sciences’ Committee to Assess Health Risks from Exposure to Low Level Ionizing Radiation have affirmed this conclusion.  For example, “. . . at the level of cancer-associated gene or chromosomal mutation, the presence of a true dose threshold demands totally error-free DNA damage response and repair.  The detailed information available . . . argues strongly against a DNA repair-mediated low-dose threshold for cancer initiation. [16]  James V. Neel, who served on the Academy’s subcommittee on genetic effects of atomic radiation, ensured that the entire medical profession could readily learn of its findings with his article in the February 22, 1958 issue of the Journal of the American Medical Association, titled “The Delayed Effects of Ionizing Radiation.”[17]                

And so, by 1960 the medical as well as scientific communities should have been fully aware that directing x-rays at any portion of the female body could violate the physician’s ethical duty to “do no harm.”  And yet women are still advised by generally trusted sources that screening mammography “is safe; there is only a very tiny amount of radiation exposure,” and “strict guidelines ensure that mammography equipment is safe and uses the lowest dose of radiation possible.” [18]

The National Cancer Institute has always been was somewhat less breezy on the subject, cautioning women to “always let their health care provider and the x-ray technician know if there is any possibility that they are pregnant, because radiation can harm a growing fetus.”[19]  Embedded in this caution is the recognition that it is not only the breast, but a woman’s entire torso, which is exposed (through x-ray scatter) to ionizing radiation.

Advances in all technological fields that contributed to allied victory in World War II included improvements in x-ray technology, first widely used in military hospitals during the previous world war.  By the 1960s breast compression, improvements in film, and the use of high milliamperage-low voltage x-ray technique had led to successful efforts at M.D. Anderson Cancer Hospital in Houston, TX to find possibly cancerous anomalies in the breasts of 1,000 women with no palpable symptoms.   Nearly all of the 245 ultimately confirmed breast cancers found during the experiment —including one that was as small as eight millimeter in diameter–had been detected by newly specialized mammography x-ray equipment.[20]

The availability of x-ray machines designed for breast imaging, along with the successful experiments at M.D. Anderson, inspired the hope that breast cancer deaths generally could be reduced as a result of x-ray screening for such small (“early”) cancers.[21]  Given the interventionist imperative of modern medicine, reinforced by a capitalist economy in which the conquest of disease is marketable, few questioned the necessity for further diagnostic mammography and biopsies for barely visible white (radiopaque) spots in the breast representing calcification–a sign of possible cell death. Fewer still doubted the need to treat all detected “early” cancers.  Few women were likely to appreciate that such irregularities do not in themselves represent cancerous growths.  Cancers are actually identified through diagnostic mammography and biopsies, which require additional and significantly more radiation exposure.

Only later would physicians begin to question the wisdom of attacking cancers that might otherwise never have caused symptoms or death in a woman’s lifetime, while subjecting women to surgical deformities, toxic radiation and chemotherapy.  Then there were the longer term risks— radiation induced lymphedema, new cancers, breast cancer metastasis, recurring breast cancers, and cardiac toxicity.[22]

All that was necessary at the end of the 1960s for the triumph of the new breast x-ray technology, not to mention its remunerative industrial and institutional infrastructure, was universal adoption of the policy, “early detection saved lives.”  That declaration came, without rigorous theoretical and experimental proof, from the Health Insurance Plan of Greater New York.

Meanwhile, the American Cancer Society in 1972, during the nation’s Cold War against the spread of communism, began its own national campaign to promote routine x-ray screening for breast cancer for all women, benefiting from the Nixon administration’s newly launched national “war on cancer.”  The ACS was ready to begin field testing its own version of a costly new weapon. Thousands upon thousands of trusting and unsuspecting women provided the proving grounds. š

(Published June 9, 2015.  Following posts will examine the risks to which women have been subjected as a result of the screening mammography experiment, and the unraveling of “mammography saves lives” as a medical protocol.)

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

[1] RNA or ribonucleic acid, also resident in the human chromosome, has more varied structures thanks to its principal roles, which are to convey DNA instructions to proteins and to assist in the transfer of DNA during cell division.

[2] Higher frequency ultraviolet radiation begins to have enough energy to break chemical bonds. X-ray and gamma ray radiation, which are at the upper end of magnetic radiation, have very high frequency in the range of 100 billion Hertz and very short wavelengths 1 millionth of a meter. Radiation in this range has extremely high energy, enough to strip off electrons or to break up the nucleus of atoms.  See: “Ionizing & Non-Ionizing Radiation,” Environmental Protection Agency, http://www.epa.gov/radiation/understand/ionize_nonionize.html.  Downloaded November 13, 2014.

[3] J. Samuel Walker, Permissible Dose:  A History of Radiation Protection in the Twentieth Century (University of California Press,  2000), p. 80.

[4] International Atomic Energy Agency, Training Material on Radiation Protection in Diagnostic and Interventional Radiology, “Radiation Units and Dose Quantities.” https://rpop.iaea.org./ Downloaded March 3, 2014. [Slide 26].

[5] A gray is a measure of the radiation energy absorbed per a unit of mass. One ‘gray’ = one joule of radiation energy by one kilogram of matter.

[6] V. Patel et al, “Patient Specific Average Glandular Dose in Mammography,” Paper presented at the 55th Annual Meeting of the American Association of Physicists in Medicine, August 4-8, 2013, Indianapolis, Indiana.

[7]  Theodor Boveri, “Concerning the Origin of Malignant Tumours,” Translated and annotated by Henry Harris, Journal of Cell Science (January 1, 2008).  Originally published as Zur Frage der Entstehung maligner Tumoren (Jena, 1914), trans. by Marcella Boveri as The Origin of Malignant Tumors (Baltimore, 1929).

[8] OCLC WorldCat.  “All Editions for ‘The Origin of Malignant Tumors.”  Fritz Baltzer, “Theodor Boveri,” Science, Vol. 144 (15 May 1964), pp. 809-815. See also Samantha Hansford and David G Huntsman, “Boveri at 100: Theodor Boveri and Genetic Predisposition to Cancer,” The Journal of Pathology, Vol. 234 (October 2014), pp. 142-145.

[9] Bettyann Holtzmann Kevles, Naked to The Bone: Medical Imaging in The Twentieth Century  (Rutgers University Press, 1997). Kindle edition, location 390.

[10] Bettyann Holtzmann Kevles, Naked to The Bone: Medical Imaging in The Twentieth Century  (Rutgers University Press, 1997), Chapter 2.  See also K. Sansare, V. Khanna, and F. Karjodkar, “Early Victims of X-rays: A Tribute and Current Perception,” DMFR: Journal of Head & Neck Imaging (February, 2011), pp. 123-125, and Percy Brown, M.D., American Martyrs to Science  through the Roentgen Rays (Springfield, Ill.: Charles C. Thomas, 1936).

[11] For an account of these post-Hiroshima investigations and the resulting disputes see J. Samuel Walker, Permissible Dose: A History of Radiation Protection in the Twentieth Century (University of California Press, 2000), especially Chapter 5.  Also: M.  Susan Lindee, Suffering Made Real: American Science and the Survivors at Hiroshima (University of Chicago Press, 1994), William J. Schull, Effects of Atomic Radiation: A Half-Century of Studies from Hiroshima and Nagasaki (New York: Wiley-Liss, 1005), and U.S. General Accounting Office, Problems in Assessing the Cancer Risks of Low-Level Ionizing Radiation Exposure (EMD-81-1) January 2, 198l.

[12] National Academy of Sciences-National Research Council, The Biological Effects of Radiation:  Summary Reports (Washington, DC: 1960).

[13] National Academy of Sciences-National Research Council, The Biological Effects of Radiation:  Summary Reports (Washington, DC: 1960), p. 3.

[14] National Academy of Sciences-National Research Council, The Biological Effects of Radiation:  Summary Reports (Washington, DC: 1960), pp. 27-29.

[15] National Academy of Sciences-National Research Council, The Biological Effects of Radiation:  Summary Reports (Washington, DC: 1960), pp. 32-35.

[16] National Academy of Sciences, Biological Effects of Ionizing Radiation, V (National Research Council, 1990),  National Academy of Sciences, Biological Effects of Ionizing Radiation, VII, Phase 2 (National Research Council,  2006), p.245.

[17] James V. Neel, M.D., Ph.D., “The Delayed Effects of Ionizing Radiation,” Journal of the American Medical Association, Vol. 166 (February 22, 1958), p. 908.

[18] “Mammography: Benefits, Risks, What You Need to Know,” www.breastcancer.org, downloaded March 20, 2014;

[19] “Mammograms Fact Sheet,” National Cancer Institute, http://www.cancer.gov, downloaded February 19, 2015.

[20] Barron H. Lerner, “’To See Today with the Eyes of Tomorrow’: A History of Screening Mammography,” Canadian Bulletin of Medical History, Vol. 20:2 (2003), pp. 300-302.  Radiographic image quality is a function of kilovoltage, amperage, and time of exposure.

[21] For a more recent critique of the limits of ever advancing breast imaging technology, see C.W. Stevens and E. Glatstein, “Beware the Medical-Industrial Comples,” Oncologist Vol. 1 (1996). http://www.nvbi.nlm.nih.gov/pubmed/10388005. Downloaded January 5, 2015.

[22]National Cancer Institute, “Brest Cancer Institute: Harms of Screening Mammography,” updated February 6, 2015. http://www.cancer.gov/cancertopics/pdq/screening/breast/healthprofessional/page8.  Downloaded February 21, 2015).

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Posted on: 05.26.2015

Mammography’s Shadows, III: The Campaign

by Sylvia Kraemer
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Posted in Healthcare, Science and Policy

Crab ImageScientists at the National Cancer Institute recognized the limitations of the mammography screening trial conducted during 1963-1969 by the Health Insurance Plan of Greater New York (HIP-GNY).  Those limits prevented the trial from supporting a widespread screening protocol for breast cancer among asymptomatic women of average risk. (See previous post, “Mammography’s Shadows, II:  Numbers and the First Large X-Ray Screening Trial.)  But their concerns were overridden by media inflated fears of breast cancer, and the organizations whose members stood to gain from widespread breast cancer screening.

For the careers and institutions committed to the understanding, diagnosis, and treatment of cancer, 1971 was an annus mirabilis.   That year the Journal of the American Medical Association published a report of the HIP-GNY breast cancer screening study that purportedly proved that early detection with mammography screening “saves lives.”

It was also the year that Congress passed, and President Richard Nixon signed, the National Cancer Act of 1971, which had strong bi-partisan support.   Provisions in the legislation ensured that the NCI, established in 1937, would become a virtually autonomous unit of the National Institutes of Health (NIH),  First, the NCI director would be appointed by the president. Then the institute would be able to submit its own budget to the White House, and have its own independent procurement authority, which meant that it could award grants and contracts without NIH review.  These provisions signaled the success of a masterful maneuver for those who lobbied aggressively for the legislation, among them, the American Cancer Society (ACS).

The influence the American Cancer Society could wield over the National Cancer Institute was foretold by President Nixon himself, who nominally originated the legislation with a message to congress earlier in 1971.  During the bill’s White House signing ceremony Nixon invited to the dais only two (non-congressional) dignitaries:  chair of the President’s Cancer Panel Benno Schmidt, a lawyer and wealthy partner in the New York investment firm J.H. Whitney & Co., and Dr. Alva H. Letton, physician and president of the American Cancer Society.  Each man received one of the two pens Nixon used to sign the act.  Nixon invited Letton to speak, which he did, briefly, commending the new War on Cancer as “the greatest thing ever done by the United States.”[1]

Shortly thereafter the American Cancer Society planned its own campaign in the War on Cancer.  The campaign had two leading salients–a national membership campaign, and a marketing campaign for routine screening mammography.  The mammography

screening campaign would be named the national Breast Cancer Detection Demonstration Project (BCDDP), thereby implying that the detection method being used had been proven to be both safe and effective at defeating breast cancer.

Since its lobbying had resulted in a substantial increase in the NCI’s budget, the American Cancer Society turned to the NCI for funding for its project to recruit over a quarter-million women for annual screening mammography.  The society’s objective was to “search out people who have undetected cancer” by convincing the public that “early detection saves lives.”[2]  Like all large screening programs, the campaign would increase revenue streams not only for physicians and clinics, but for x-ray equipment manufacturers and pharmaceutical companies. [3]

The National Cancer Institute’s own civil service scientists undoubtedly knew at the time that the carcinogenic effects of x-rays had been demonstrated before World War II, and confirmed thereafter by the National Academy of Sciences’ panels on the biological effects of exposure to ionizing radiation.   Moreover, the probability that physical compression of, and piercing or cutting into, breast tumor cells might cause metastasis, could have been readily suspected.  In any event, physicians had been warned of that possibility as early as 1958.[4]  Questioning the validity of the HIP-GNY study, which was cited as having proven the value of screening mammography, scientists at the National Cancer Institute opposed NCI support of the American Cancer Society’s screening mammography campaign.

Most vocal among them was NCI’s John C. Bailar, III, a noted epidemiologist who had also trained in medicine at the Yale University of Medicine before turning to statistics.  As NCI’s deputy associate director for cancer control he reviewed the ACS’s proposed program. Bailar was soon troubled not only by the seemingly indiscriminate exposure to x-radiation of thousands of asymptomatic women, but by the fact that there were no controls to ensure consistent compliance with standard mammography procedures or dosages among the 27 screening centers involved.[5]

His concerns were dismissed at NCI by the explanation that the project’s “objectives have been pretty well dictated by the American Cancer Society.  In summary they are ‘Can American Cancer Society volunteers mobilize a large number (100,000 per year) of volunteers for thermography, mammography, and a physical exam?’”[6]

Civil-service scientists do not typically question work sponsored by their own organizations, so one must suspect that Bailar had considerable support from his peers when he submitted a manuscript to the Annals of Internal Medicine in June of 1975 in which he “regretfully” concluded “that there seems to be a possibility that the routine use of mammography in screening asymptomatic women may eventually take almost as many lives as it saves.”  Using ionizing radiation risk estimates developed by the National Academy of Sciences, he cautioned that mammography doses could substantially increase not only the incidence of breast cancer, but “lesser hazards of radiation induction of leukemia, lung cancer, or other conditions.”[7]

Bailar noted that the methodological deficiencies in the HIP-GNY study (e.g., self-selection by participants and lack of clarity about the clinical breast exam techniques used for both study and control groups) rendered useful interpretation of its numbers difficult.  Perhaps the greatest pitfall of attempting to quantify in years survival as a result of mammography, Bailar pointed out, was reflected in two biases evident in the HIP study:  “lead time” and “length time.”  The lead time bias invites the mistaken view that a cancer detected through mammography three years before it would have been detected clinically or through breast self-exam results in the addition of three years’ life—“survival”–to the patient’s prognosis.

The length-time bias results when an asymptomatic and indolent neoplasm, which would likely result in a good prognosis, is detected through mammography and survival is attributed to mammography.[8]  In short, given the complexities of cancer such as wide variations in latency and aggressiveness, attempting to quantify the relationship of early detection to mortality would produce debatable conclusions at best.

Bailar was not alone in his misgivings about a project that would be largely funded by the NCI.[9]  Scientists at the Institute voiced concerns not only about the lack of standardization in x-ray equipment, but “the possible hazards of ionizing radiation and the ability of an uncontrolled study to generate any meaningful conclusions about the value of screening mammography.”[10]  Other statisticians agreed, also noting “the absence of a control group” which would prevent one from comparing results from the BCDDP with “data derivable from other sources.”

One leading radiation scientist questioned whether “mass screenings involving mammograhy is consistent with good radiation protection theory.”[11]   Roswell Park Memorial Institute (cancer research center) biostatistician Irwin D. J. Bross warned, “many more cancers are produced than cured by x-rays …. This exposure to diagnostic x-ray will probably result in the worst iatrogenic epidemic of breast cancer in history.”[12]

In spite of the NCI scientists’ concerns, director Frank J. Rauscher, Jr. approved the joint project.  Rauscher, who had been a scientist at the NCI since 1959, was appointed to the post by the ACS’s friend Richard Nixon, undoubtedly with the organization’s approval, if not at its suggestion.  He was rewarded in 1976 for his support for the ACS project with a new position as Vice-President for Research at the ACS, at nearly double the salary he had been receiving at the NCI.[13]   His new boss at the ACS, R. Lee Clark (Byrd’s successor), had previously served on the President’s Cancer Panel and president of the Cancer Center at the M.D. Anderson Hospital and Tumor Institute,[14] where some of the earliest uses of mammography had occurred.  That institution would be one of the recipients of NCI funds to participate in the BCDDP.

By October 1975 the NCI was under assault for supporting the project.   To respond to its critics the NCI created three expert panels to review the efficacy and safety of screening mammography.  Having reviewed the HIP-GNY study, which the ACS asserted validated the “benefit” of mammography screening through a random controlled trial, the NCI panels’ report concluded that half of the cancers claimed to have been found only by mammography in the HIP study were, in fact, “palpable, in no sense clinically occult.”  Proper review of any uncertain physical exam results might have prevented the resort to mammography at all in those cases.  At the same time, “mammography was negative” for over 40% of the cancers detected through clinical breast exam. [15]

The institute’s review panels’ report, issued in March of 1976, should have brought the project to a halt.  The report concluded that it was “difficult to assess the independent contribution of mammography” to any benefit of screening for women over 50 [italics added].   But rather than suggest that screening be stopped, the report temporized by recommending that “x-ray dosages should be kept as low as possible.”  As for mammography for younger women, NCI support for such screening should “be concentrated on validating its use through appropriately designed randomized trials.”[16]

The Breast Cancer Detection Demonstration Project was completed in 1981.  During that period controversy over the program continued unabated, so the National Institutes of Health, parent department to the NCI, did what many institutions do when faced with serious controversy:  It sought to achieve a negotiated resolution of the issues—relying on process to obtain an outcome that a majority would accept. In 1977 the NIH convened the first of several “consensus conferences” held during the next two decades on the merits of mammography.  Conference topics in 1977 included reviews of pathology specimens from biopsies conducted as a result of BCDDP screening.

One such review found that 66 of 506 pathological specimens taken thus far in the program “contained neither cancer nor carcinoma in situ.” As a result, 58 of the women from whom those specimens had been taken suffered unnecessary mastectomies.[17]  Rather than regard these grievous errors as a serious risk of screening mammography, NCI declined to halt the program and referred the matter to those who made the diagnoses and performed the surgeries.  As for whether to inform the misdiagnosed women of the mistaken results, the NCI side-stepped that moral obligation by leaving notification up to the women’s own physicians.[18]

When women recruited for the BCDDP were asked the source of their information about the campaign, their answers must have pleased the ACS, for which the project had always been essentially a marketing campaign.  Slightly over 90% had heard about it through social contacts, the media, or ACS volunteers.[19]  But what that number also revealed was that less than 10% had been recruited by their physicians on the basis of individual medical assessment.  Thus over 90% of the BCDDP’s research subjects were self-selected for what most likely was a combination of personal reasons, social persuasion, and American Cancer Society assurances that they would benefit.

Slightly over a quarter of a million women participated in the Breast Cancer Detection Demonstration Project, or only .67% of the entire population in the country of women between the ages of 35 and 74. (In 1970 there were 40.4 million women resident in the United States in that age group.)  Since there is no way we could consider the participants in the BCDDP as representative of that larger population, using data from the project as a basis for establishing health policy or medical screening protocols was scientifically unsupportable.  Given the risks these women were subjected to, risks of which they knew little if anything, it was also ethically reprehensible.

Never adequately examined have been the consequences for these women of the radiation exposures they received during their five annual screenings. In the fall of 1976, not long after the NCI’s review panels issued their report, the Health Research Group of Public Citizen called for stronger informed consent requirements for “women undergoing mammographies at … federally sponsored screening centers across the country.”

In its letter to Dr. Theodore Cooper, assistant secretary at the department of Health, Education and Welfare which oversees the National Institutes of Health, the group cited “mammography machines which are emitting enough excessive radiation so that the absorbed dose is more than one rad per exam, a danger even to women over 50.” [20]  (The NCI’s own BCDDP review panels had found “substantially higher [radiation] exposure levels in unmonitored screening clinics.”[21])

While supporters of mammography screening relied exclusively on unreliable quantitative data in an effort to prove its benefits, quantitative data became magically unimportant when considering its risks.   Responding to the Health Research Group’s warnings about excessive radiation exposure, a National Cancer Institute official declared “’that’s uncertain.  There just isn’t enough information to quantify the risk that much.”[22]

Women who entered the program at ages 35-44 had nearly twice as many instances of new breast cancers detected between the first and fifth year of screening as did women who began five years of screening at age 45 and older (which does not support claims that older women are at greater risk of breast cancer than younger women, and thus can benefit from mammography screening).  At the same time, women between the age of 40 and 45 participating in the BCDDP experienced double the number of new cancers detected in the fifth year as were detected in their first year.[23]

Thus the longer women remained in the program, the more likely they were to have new breast cancer detected in the fifth year of their participation.[24]  The possibility that a higher detection rate in the fifth year might be attributable to cumulative x-ray exposure during the previous four years was not mentioned in the BCDDP five-year summary report.

As with virtually all attempts to justify screening mammography by linking it to breast cancer mortality data, BCDDP-reliant articles in medical literature sampled from the 1980s and 1990s overlooked the important role of breast cancer treatment on survival rates.  Disregarding treatment as a critical variable in cancer mortality assumes that the same treatment was provided to all of the women diagnosed with cancer at the same age and stage in their cancers, and that all women responded to that same treatment uniformly.  Such assumptions are clearly untenable.

In any event, in 1997 the National Institutes of Health convened a 12-member panel for a ‘Consensus Development Conference’ with an audience of 1,100 in hopes of resolving the question of whether women in their 40’s should undergo routine screening mammography.  The panel concluded that “the data currently available do not warrant a universal recommendation for mammography for all women in their forties.” That decision belonged to individual women, deciding for themselves, with “access to the best possible relevant information regarding both benefits and risks.”

Such decisions would be “difficult,” because they involved not only “scientific evidence and . . . her individual medical history;” they also involved each woman’s perception of “each potential risk and benefit, the values she places on each, and how she deals with uncertainty.”  Finally, “a woman’s health care provider must be equipped with sufficient information to facilitate her decision making process.”  Unfortunately, information then available to women and their health care providers was inadequate to warrant annual x-ray breast cancer screening for asymptomatic women of average or low risk.

Women over the age of 50 have occupied a curious category in the ongoing effort to market screening mammography for healthy women at normal risk for breast cancer.  Both proponents and a few critics of adopting the practice as a standard medical protocol opined that the women most in danger of x-ray harm were women under 50, while women over 50 had been shown to “benefit.”   Since the problems with the HIP-GNY study applied to the entire study, it could not be said to support mammography screening for older women any more than younger women.  Nor did the BCDDP demonstrate such a benefit.

Was it that older women were more prone to breast cancer?  If so, they did not become more prone to it until after the inception of mammography screening.  Cancer deaths among women over 45 as well as women over 55 declined steadily during the 1950s and 1960s, only to rise after 1970.  Since a majority of breast cancers are estrogen hormone responsive, it would seem natural that post-menopausal women would be less likely to develop breast cancer.  But after three decades of routine mammography screening, the cancer death rate for women over 45 and 55 (as for all women) in 2000 exceeded the rate in 1950.[25]

Absent compelling epidemiological or laboratory evidence that all women over the age of 45 or 50 are more prone to breast cancer, that age threshold begs other explanations.  Was it that older women could be exposed to x-radiation with less concern about its consequences because their instrumental value was diminished, i.e., they were less likely to get pregnant, or to be nursing, or to have the care of young children?  Was it that if they were, indeed, to get x-ray induced cancer, it would not appear until their late 50s or later, at which time they might be just as likely to die of other causes as well as breast cancer?

Detecting and treating breast cancer at any stage was and remains far more profitable for the medical-industrial complex[26] than is cancer prevention.  It is women–not those who gain materially from their treatment–who endure debilitating chemotherapy and radiation therapy, unnatural hair loss, mutilating surgeries, and catastrophic expense for those who are inadequately insured.

A cavalier disregard for this aspect of ‘curing’ breast cancer is reflected in ACS President (in 1976) Dr. Benjamin F. Byrd, Jr.’s response, when queried about the cancer risk of x-ray screening.  “Even if there is a slightly increased risk of her getting the disease in the distant future, there’s also an excellent chance that by that time science will have learned to control the disease.”[27]

In all probability the 45 or 50 year threshold for routine screening mammography appealed because it offered a compromise in a highly contested medical protocol.  Screening mammography’s opponents could ‘hold the line’ for younger women, at least, who supposedly had more to lose from the ravages of breast cancer than older women.  As a compromise, the 50 year threshold enabled physicians to go about their business without being stymied by the dispute.  Meanwhile, millions of asymptomatic women, urged on by powerful and trusted organizations (and sometimes their own physicians) to get their yearly screening mammograms, conscientiously complied.

(Published May 26, 2015.  The next post examines the radiation risk of low-dose x-ray mammography, noting that those risks were known well before the American Cancer Society’s 1970s campaign to market screening mammography.)

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

[1] “Nixon Signing the National Cancer Act of 1971,” National Cancer Institute, News and Public Affairs.  Video uploaded November 8, 2009 to You Tube.  See https://www.youtube.com/watch?v=E2dzEDnGqHY.

[2] Lane E. Adams, “Executive Vice President’s Report,” American Cancer Society Annual Report, 1977. http://tobaccodocuments.org/rjr/502379608-9644.html. Downloaded December 29, 2014.

[3] For example:  “Guttman Institute Reopens with Expanded Screening Services,” Cancer Network (Sept.01, 1996).

[4] J. W. Hendrick, M.D., Results of Treatment of Carcinoma of the Breast, Five to 18 Years,” Annals of Surgery, Vol. 146, pp. 728-750 (November 1957); J.W. Hendrick, M.D., “Aspiration Biopsy in Breast Cancer,” Journal of the American Medical Association, Vol. 166, No. 8 (February 22, 1958), p. 892.

[5] Daniel S. Greenberg and Judith E. Randal, “The Questionable Breast X-ray Program,” Washington Post (May 1, 1977).

[6] Daniel S. Greenberg and Judith E. Randal, “The Questionable Breast X-ray Program,” Washington Post (May 1, 1977).

[7] John C. Bailar, III, “Mammography: A Contrary View,” Annals of Internal Medicine, Vol. 84 (1976), pp. 80-82.

[8] John C. Bailar, III, “Mammography: A Contrary View,” Annals of Internal Medicine, Vol. 84 (1976), pp. 77.

[9] Daniel S. Greenberg and Judith E. Randall, “The Questionable Breast X-ray Program,” Washington Post (May 1, 1977).

[10] Barron H. Lerner, M.D., The Breast Cancer Wars: Fear, Hope, and the Pursuit of a Cure in Twentieth-Century America (Oxford University Press, 2001), Kindle edition, location 213.

[11] Barron H. Lerner, M.D., The Breast Cancer Wars: Fear, Hope, and the Pursuit of a Cure in Twentieth-Century America (Oxford University Press, 2001), Kindle edition, location 212-213.

[12] Daniel S. Greenberg and Judith E. Randal, “The Questionable Breast X-Ray Program,”  and “Waging the Wrong War on Cancer,” The Washington Post (May 1, 1977).

[13] Daniel S. Greenberg, “X-Ray Mammography: Silent Treatment for a Troublesome Report,” New England Journal of Medicine, Vol. 296, No. 17 (April 28, 1977), p. 1015.

[14] Daniel S. Greenberg, “X-Ray Mammography: Silent Treatment for a Troublesome Report,” New England Journal of Medicine, Vol. 296, No. 17 (April 28, 1977), p. 1015.

[15] Daniel S. Greenberg, “X-Ray Mammography: Silent Treatment for a Troublesome Report,” New England Journal of Medicine, Vol. 296, No. 17 (April 28, 1977), p. 1016.

[16] Daniel S. Greenberg, “X-Ray Mammography: Silent Treatment for a Troublesome Report,” New England Journal of Medicine, Vol. 296, No. 17 (April 28, 1977), p. 1016.

[17] Barron H. Lerner, “To See Today With the Eyes of Tomorrow: A History of Screening Mammography.” Canadian Bulletin of Medical History, Vol. 20, No. 2 (2003), p. 311; Daniel S. Greenberg, “A Cancer Controversy:  Did Doctor Know Best?” The Washington Post, April 4, 1978, p. A19.

[18] Barron H. Lerner, “To See Today With the Eyes of Tomorrow: A History of Screening Mammography.” Canadian Bulletin of Medical History, Vol. 20, No. 2 (2003), p. 311-12; “From the Editor,” New York Times, October 8, 1977.

[19]   Based on 10% sample of initial patient history records. Larry H.  Baker, M.D., “Breast Cancer Detection Demonstration Project: Five-Year Summary Report,” CA-Cancer Journal for Clinicians, Vol. 32, No. 4 (July/August, 1982), pp. 195-196.

[20] “Mammography Risky, Ralph Nader Warns,” The Milwaukee Sentinel, (November 3, 1976), p. 4.

[21] Daniel S. Greenberg, “X-Ray Mammography: Silent Treatment for a Troublesome Report,” New England Journal of Medicine, Vol. 296, No. 17 (April 28, 1977), p. 1016.

[22]  “Mammography Risky, Ralph Nader Warns,” The Milwaukee Sentinel, (November 3, 1976), p. 4.

[23] Larry H.  Baker, M.D., “Breast Cancer Detection Demonstration Project: Five-Year Summary Report,” CA-Cancer Journal for Clinicians, Vol. 32, No. 4 (July/August, 1982), p. 208.

[24] Larry H.  Baker, M.D., “Breast Cancer Detection Demonstration Project: Five-Year Summary Report,” CA-Cancer Journal for Clinicians, Vol. 32, No. 4 (July/August, 1982), p. 208.

[25] Source: Centers for Disease Control, National Center for Health Statistics, Health, United States, 2013: With Special Feature on Prescription Drugs, Hyattsville, MD (2014); Centers for Disease Control, National Center for Health Statistics, Health, United States, 2010: With Special Feature on

Death and Dying, Hyattsville, MD (2011).

[26] Stevens, CW, Glatstein, E, “Beware the Medical-Industrial Complex,” Oncologist,Vol.1,No.4(1996), http://www.ncbi.nlm.nih.gov/pubmed/10388005.

[27] Daniel S. Greenberg and Judith E. Randal, “Waging the Wrong War on Cancer,” The Washington Post, (May 1, 1977).

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Posted on: 05.15.2015

Mammography’s Shadows, II: Numbers and the First Large X-ray Screening Trial

by Sylvia Kraemer
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Posted in Healthcare

Crab ImageQuantities, measured and analyzed with numbers and statistics, are the foundation of our ability to communicate the attributes of much of the physical world.   Mathematical formulas and calculus enable us to predict what will happen when we manipulate matter in motion.  Notations measuring differing lengths of vibrating strings can create the exquisite harmonies of the “music of the spheres” or a Bach cantata.  And varied linear dimensions in building construction can be arranged to form the ‘golden section’ of classical architecture, thus yielding harmonious proportions that please the eye.

Small wonder, then, that new models of representative government that emerged from the Atlantic basin at the close of the 18th century would rely on achieving harmony by balancing quantities.  Co-opting human passions and desires with numbers fixes them as universally measureable and thus, we want to believe, manageable.  The belief that what can be measured, can be managed, has carried over into modern economic and social policy, for which statistics have become essential ingredients.

Scientists and statisticians attempt to hold inessential variables constant when comparing quantifiable phenomena.  In the realms of nature and society, however, few important variables can be held constant for more than a moment in time.  The social and natural phenomena that often interest us—e.g., disease and its course—happen over time.   The passage of time, during which nature is in constant flux, is what most often confounds our efforts to measure causes and effects in the realm of biology and medicine.

Medical protocols for the detection and treatment of disease normally rely on efforts to measure either the course of disease in large, defined populations (epidemiology) or to evaluate cause and effect relationships for diagnostic or therapeutic purposes (trials).  Virtually all investigations of diagnostic and treatment options today assume that randomized controlled trials are the ‘gold standard’ for medical research.

Since it is practically impossible to test a treatment option against its alternatives using a nation’s entire population,  test subjects are identified through random sampling, which, as when a dealer shuffles a deck of cards, is intended to eliminate all bias in their selection.

In addition to randomization, the best research trials are blinded.  The purpose of single- and double-blinded trials is to eliminate bias from entering into the identification and measurement of causes and effects.  If a test subject in a single-blind trial is unaware whether she is receiving the medication being tested or a placebo, for example, she will be less likely to stint (or exceed) the instructed dosage.

In double-blind trials both the test subjects and those conducting the experiment are unaware of whether individuals belong to the test subject group or to the randomly chosen control group not using the tested drug or medical device. Double-blinding ensures that researchers as well will not, however unconsciously, allow their own biases to influence how they characterize a cause or an effect.

Thus when evaluating the quality of evidence used to support a medical protocol, physicians and medical researchers normally consider the evidence’s ‘internal’ validity.  Was the supporting trial or study randomized? Was it double blinded?  But they must also consider a study’s ‘external’ validity.  How reliably can a study’s findings can be generalized to the population being sampled?  Are those findings consistent with what epidemiological data tells us about that larger population?

šNewspaper outlets occasionally bring us fresh stories of studies proving or challenging the benefits of mammography screening. [1]   Still influential, however, is the first and purportedly randomized large controlled study of mammography screening performed in the United States, the mammography trial conducted by the Health Insurance Plan (HIP) of Greater New York (GNY) in the 1960s.[2]

Statistician Sam Shapiro; Dr. Philip Strax, a radiologist; and Dr. Louis Venet, a surgeon, led the study which was designed to test “the hypothesis that…periodic beast cancer screening with mammography and clinical examination…leads to earlier detection of breast cancer than ordinarily experienced and that mammography contributes significantly to detection.”[3]   Their results were published in the Journal of the American Medical Association (JMA) in 1966 and 1971. 

Strax, Shapiro, and Venet initiated their study as a randomized control trial of clinical breast cancer screening (i.e., palpation, or CBE), breast x-ray (mammography) screening, and mammography screening in combination with CBE. [4]   Their objective was fortuitously served by being able to take advantage of the availability to them of a defined population of 85,000 women enrolled in 23 of the many group medical practices affiliated with the Health Insurance Plan of Greater New York, where Shapiro was employed as Director of Research and Statistics.[5]

Thirty-one thousand women selected at random from HIP-GNY patients aged 40 to 64 years were designated for the study group, and an identical number in the same age group selected for the control group.  The study-group women were “offered a screening examination in their medical group centers, and 64 percent cooperate [sic].”  Meanwhile, patients “in the control group follow their usual practices in receiving medical care.  No special effort is made to encourage them to have general physical examinations…. Mammography is not routinely included in the general physical examination.”[6]

Clinical breast examination remained a significant diagnostic variable throughout the trial: “Even under the best conditions for applying mammography, certain types of breast cancer that are palpable are missed with this technique.”[7]  Nonetheless, most reports of the HIP-GNY study represented its findings as proof of the value of x-ray mammography alone.  Data for breast self-examination, which had been encouraged by the American Cancer Society and the National Cancer Institute since the 1950s, were not included in the study.[8]

Cautioning that their findings were “preliminary,” the study’s authors acknowledged that their data applied to a “more limited period” (1963 – 1969) than the “minimum of five to ten years experience … necessary to answer the question definitively.” [9]   More than the limited period of time, however, compromised the study.

While the initial total of randomly sampled patients was 62,000, with 31,000 assigned to each group, in the end only “about 20,000 women,” or 65%, “of the study group … appeared for their initial screening examinations,  and of these, 80% participated in the first annual examination, 74% in the second annual examination, and 69% in the third annual examination.”[10]  In other words, of the original 31,000 women assigned to the study group, barely half (52%) underwent their first annual examination, and only a quarter (26.5%, or 8,215 women) appeared for all three annual examinations.

The applicability of the study to all asymptomatic women aged 40 to 64 was further compromised by the fact that the population sampled was more urban and more ethnically and racially diverse than the larger population of the nation’s women.  In 1970 over two-thirds of the U.S. population lived in areas characterized by the Census Bureau as “outside central cities” or “nonmetropolitan areas.”   Members of the HIP also represented only women who, as a result of their income or employment, were able to afford membership.

Such variables matter.  In the epidemiology of breast cancer, higher socioeconomic status, residence in the urban and northern United States, and a first full-term pregnancy after age 30 all increase a woman’s relative risk for breast cancer.[11]  Moreover, while women might be randomly selected for the study and control groups, in practice they could not be forced to undergo screening—whether X-ray or palpation or both.  Nor could women in the control group, for whom general physical exams were included in their HIP coverage, be denied breast palpation by individual physicians who might have chosen to do so as a matter of course, or patient request.  What that number was, and the thoroughness of the palpation or CBE, we don’t know.

We do know that some women declined to be screened (whether they declined X-ray screening or clinical breast exam, or both, is not clear).  And we know that once they declined, those who remained in the study group were not even representative of the women of New York:

…study women who refused screening differed from those examined in several respects: eg, they are slightly older; have lower educational   attainment; are less likely to be Jewish, to have been married, or to be multiparous or premenopausal; and a lower proportion report ever having     had a lump in the breast.  Also, they differ markedly from the others in basic attitudes toward preventive health examinations.  They are more apt to avoid physical examinations in general, to feel that people should wait until they have symptoms before seeing a physician, and to believe that their physicians “know all my health conditions without . . . more special tests. [12]

  The numbers of biopsies recommended as a result of mammographies, mammographies in combination with clinical breast examination (palpation), and clinical breast examination alone—all three of which were part of the study group screening–were combined with the numbers of biopsies performed as a result of “changes in opinion that occurred later on the basis of additional information obtained through reexamination of the patient by her own physician.  About one out of six of the cases classified as biopsy recommendation … were affected by these changes.” [13]

In short, both the study and control groups selected from among HIP-GNY participants lost their randomly chosen composition as the study progressed.  Some women declined to be screened after all, and some failed to participate in the full protocol of three annual screenings.  Physician recommendations to biopsy on the basis of “additional information” served as another confounding variable.

Ultimately x-ray screening alone accounted for the detection of 60% of the 127 confirmed cancers found in the 8,215 women who completed three annual examinations.  Palpation alone accounted for 56 confirmed cancers, and a combination of x-ray and palpation accounted for 29 confirmed cancers.   This is the essence of the first of the two principal claims made for the GNY-HIP study, namely, that mammography is an improvement over palpation for the detection of breast cancer.

The second most-repeated claim for mammography screening attributed to the HIP-GNY trial is that mammography saves lives.  On close inspection, however, one finds more questionable numbers.  According to the study’s authors, after the six-year period of the trial (1963-1969), there were 52 deaths among the control women “in which breast cancer was the underlying cause,” and 31 deaths among the study women, “screened and not screened combined.” [Italics added.]  These numbers, which do not compare breast cancer mortality among women who received screening mammography with women who did not, are the source of claims that screening biography can reduce breast cancer deaths by as much as 40 percent.

Then there were the study’s reported “case fatality rates,” defined as the “probabilities of death among women with breast cancer during specified periods following histologic confirmation of breast cancer.”  While this phrasing invites the inference that the probable deaths would have been from breast cancer, the authors themselves stated otherwise:  These case fatality rates did not necessarily represent breast cancer deaths because they included “all deaths among women with breast cancer regardless of the cause of death [italics added].” [14]  (Autopsy studies have found breast cancer in approximately 10% of women who die of non-cancer causes.[15])

Since an unknown quantity of the deaths had not yet occurred, their causes could not be given.  Therefore, to posit case fatality rates, the nature of the quantitative data the authors presented necessarily changed from data descriptive of actual events to data resulting from the calculation of mathematical probabilities based on statistical projections.  This was a subtle but crucial epistemic shift that may have been lost on readers ready for the study’s “preliminary…optimism.”   Shapiro continued to track and report breast cancer deaths from the HIP-GNY study’s patients until 1985.[16]  Given the serious shortcomings of the study, the usefulness of this information is debatable.

Because the HIP-GNY trial was later used to justify a nation-wide program of x-ray breast cancer screening sponsored, and largely funded, by the federal government, it is important to recognize what it did, and did not, do.   It did not prove that mammography alone substantially improves the detection of clinically significant breast cancers.  It did not prove that mammography “saves lives.”  It was unable to prove those things because trial’s internal and external validity were so compromised that it could not justify a medical screening protocol for the general adult female population.

Not only did the HIP-GNY trial lack both internal and external validity.  It was conducted with women who had every reason to believe that their individual health needs were paramount in their own clinical setting.  Therefore it was conducted in violation of the standards of medical research ethics current at the time.

Tension between the ethical obligation of physicians to consider first and foremost the interests of individual patients, and a desire to advance medical research, is evident throughout the men’s description of the manner in which the study was conducted.  For example:

The patient appears for a screening examination in a familiar setting, the medical group center, and she knows that the group’s surgeon and radiologist are participating directly in the program.  Her responsiveness to the initial invitation to participate is increased …. The surgeon who functions as the examining physician is a member of the medical team in the group responsible for the patient’s care, and the findings of examinations in which he has been a critical participant are more readily translated into action than might ordinarily be true in a screening program.[17]

Meanwhile, in order to

reduce … the amount of time required to screen a patient“  imaging was limited to “a cephalocaudad [vertical] and mediolateral [horizontal] view of each breast and … slightly increasing the kilovoltage. [Thus] it was possible to screen women at the rate of 13 patients per three-hour session.[18]

In the event that a patient whose mammography revealed suspicious white spots or shadows hesitated to proceed with a biopsy, “special measures” were “introduced to increase the likelihood that…the woman will accept hospitalization.”

A team approach has been developed to minimize the likelihood of ‘losing’ the patient.  Responsibility for communicating with the patient is assumed by the medical group surgeon assisted by a regisered nurse on the central staff who has wide experience in the fields of health education and research.[19]

Just what these patients were told to persuade them to proceed with hospitalization was not reported in the JAM articles.  Whether, if a biopsy and histology revealed cancerous cells, the patient was awakened and given a reasonable and informed opportunity to decide what sort of treatment she chose to receive—a lumpectomy, modified mastectomy, radical mastectomy or no surgery at all—was also not reported.  Of the 23 women whose suspicious results were confirmed as cancers during the first two years of the trial, all but 3 underwent radical mastectomies.[20]  Whether the surgeries were performed and billed by HIP-GNY affiliated surgeons, a potential conflict of interest, we do not know.

In the end what the HIP-GNY study did do was subject the breasts of thousands of female patients to ionizing radiation, with unknown consequences. Furthermore, while over 1,800 women suffered the anxieties of biopsy recommendations, over a thousand women were actually subjected to the risks—principally infection and tumor metastasis—of their biopsies.  With the exception of the 212 women whose biopsies confirmed cancers, the rest underwent these risks unnecessarily.[21]

If relying on quantifiable evidence in setting medical protocols has complicated the challenge of proving the value of x-ray breast cancer screeening, it has also impeded efforts to quanitify mammography’s risks. These risks were known even before “over-diagnosis” began to receive general media coverage in the late 1990s, [22] as we shall see in a subsequent post.

The frequency of, and ages at which, breasts are x-rayed are easily counted.  Mortality likewise provides a quantifiable point of comparison.   But, as we age, the biological processes of health and disease are unique to individuals.  Medical efforts to defeat cancer are experienced differently by individuals as well, for whom the miseries of cancer treatment may become just as important as the year in which they expire.  Hence the ‘quality of life’ considerations with which all patients and good physicians must grapple when confronting death.

Finally, just as perilous as the common confusion of statistical correlation and causation is the failure to appreciate the profound moral distinction between description and prescription. This failure is a serious obstacle to those intent on ensuring that competent professional judgment is also ethically defensible.  Deep within the epistemic chasm between description and prescription—between what “is” and what “ought to be”–lies a subjective medical bias toward intervention, whatever its risks.

When the body’s failure to suppress cancerous cell growth demands interference, good medicine must be ready to interfere.  But when screening technologies entail probable and perhaps irreparable harm—as all screening involving x-radiation does—one must ask how many women might be harmed so that one might be saved?  Like most ethical questions, this one does not lend itself to a numerical solution.

(Published May 15, 2015.  The next post takes a hard look at the American Cancer Society’s 1970s campaign to market screening mammography to healthy women.)

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[1] See, for example: Gina Kolata, “New Mammogram Studies Divided on Benefits,” The New York Times (September 3, 2002), “Vast Study Cast Doubts on Value of Mammograms,” The New York Times (February 11, 2014) and other reporting by Kolata and Jane Brody in the Times.

[2] Handel Reynods, M.D. The Big Squeeze: A Social and Political History of the Controversial Mammogram (Cornell University Press, 2012),  Chapter 2 (13%).

[3] Sam Shapiro, Philip Strax, MD, Louis Venet, MD, “Evaluation of Periodic Breast Cancer Screening with Mammography: Methodology and Early Observations,” Journal of the American Medical Association, Vol. 196 (1966).  Reprinted in Cancer Journal for Clinicians, Vol. 40, No. 2 (March-April, 1990), pp. 1990), pp.111-125. A pilot study to determine the feasibility of such a trial had been supported by the National Cancer Institute, the HIP-GNY trial itself was partly funded by a contract with the U.S. Public Health Service.

[4] Sam Shapiro, Philip Strax, and Louis Venet, “Periodic Breast Cancer Screening in Reducing Mortality from Breast Cancer,” Journal of the American Medical Association, Vol. 215, (1971), pp. 1777-1785.

[5] Sam Shapiro, Philip Strax, MD, Louis Venet, MD, “Evaluation of Periodic Breast Cancer Screening . . .,” (1966, 1990), p.113.

[6] Sam Shapiro, Philip Strax, MD, Louis Venet, MD, “Evaluation of Periodic Breast Cancer Screening . . . .” (1966, 1990) p.115.

[7] Sam Shapiro, Philip Strax, and Louis Venet, “Periodic Breast Cancer Screeening . . .,” (1971), p.1788.

[8] Barron H. Learner, The Breast Cancer Wars: Hope, Fear, and the Pursuit of a Cure in Twentieth Century America (Oxford University Press, 2001), p. 55.

[9] Sam Shapiro, Philip Strax, and Louis Venet, “Periodic Breast Cancer Screeening . . .,” (1971), pp. 1777, 1785.

[10] Sam Shapiro, Philip Strax, and Louis Venet, “Periodic Breast Cancer Screeening . . .,” (1971), p. 1780.

[11] Jennifer L. Kelsey and Marillie D. Gammon, “The Epidemiology of Breast Cancer,” CA-A Cancer Journal for Clinicians, Vol. 41, No. 3 (May-June 1991), p. 157.

[12] Sam Shapiro, Philip Strax, and Louis Venet, “Periodic Breast Cancer Screeening . . .,” (1971), p. 1780.

[13] Sam Shapiro, Philip Strax, and Louis Venet, “Periodic Breast Cancer Screeening . . . ,” (1971), p. 1781.

[14] Sam Shapiro, Philip Strax, and Louis Venet, “Periodic Breast Cancer Screeening in Reducing Mortality from Breast Cancer,”  Journal of the American Medical Association, Vol. 215 (1971), p. 1783.

[15] Welch, H.G. and W.C. Black, “Using Autopsy Series to Estimate the Disease ‘Reservoir’ for ductal carcinoma in situ of the Breast: How Much More Cancer Can We Find?” Annals of Internal Medicine, Vol. 127, (1997), pp. 1023-1028; W.C. Black and H.G. Welch, “Advances in Diagnostic Imaging and Overestimations of Disease Prevalence and the Benefits of Therapy,” New England Journal of Medicine, Vol. 328 (1993), pp. 1237-43.

[16] Shapiro S., Venet W. Strax P., Venet L., Roeser “Selection, follow-up and analysis in the Health Insurance Plan Study: A Randomized trial with breast cancer screening,” National Cancer Institute Monographs, Vol. 67 (May 1985), pp. 65-74.

[17] Sam Shapiro, Philip Strax, MD, Louis Venet, MD, “Evaluation of Periodic Breast Cancer Screening . . . “, (1966, 1990), p.116.

[18] Sam Shapiro, Philip Strax, MD, Louis Venet, MD, “Evaluation of Periodic Breast Cancer Screening . . .”, (1966, 1990), pp.116-117.

[19] Sam Shapiro, Philip Strax, MD, Louis Venet, MD, “Evaluation of Periodic Breast Cancer Screening. . .”, (1966,1990) p.116.

[20] Shapiro S., Venet W. Strax P., Venet L., Roeser “Selection, follow-up and analysis in the Health Insurance Plan Study: A Randomized trial with breast cancer screening,” National Cancer Institute Monographs, Vol. 67 (May 1985), pp. 65-74

[21] Of the 1,840 biopsy recommendations arising from all screening, only 1,056 (57%) were actually performed, and of those performed, only 212 biopsies  (11.5%) confirmed cancers.Sam Shapiro, Philip Strax, and Louis Venet, “Periodic Breast Cancer Screeening . . .,” (1971), Table 3, p. 1780.

[22] Johannes P. van Netten,  Stephen A. Cann and James G. Hall, “Mammography Controversies: Time for Informed Consent?” Journal of the National Cancer Institute, Vol. 89, Issue 15 (August 6, 1997); on “overdiagnosis,” see for example H. Gilbert Welch, “Breast Cancer Screenings:  What We Still Don’t Know,” New York Times (December 29, 2013).

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