Screening for breast cancer with mammography

CLINICAL IMAGING 1991;15:253-260 253

SCREENING FOR BREAST CANCER WITH MAMMOGRAPHY

EDWARD A. SICKLES, MD

Edward A. Sickles, M.D., the 16th Annual John A. Evans Lecturer

KEY WORDS:

Mammography screening; Breast calcifications; Breast masses; Indirect signs of malignancy

Mammography can serve two purposes in evaluating the breast for disease: detection and diagnosis (1, 2). Used as a detection device, it is capable of indicating the existence of many breast abnormalities, espe- cially small cancers, months and often years before

Professor of Radiology, Chief, Breast Imaging Section, Univer- sity of California School of Medicine, San Francisco, California.

Address reprint requests to: Dr. Edward A. Sickles, Depart- ment of Radiology, Box 0628, University of California School of Medicine, San Francisco, CA 94143.

Received May 16, 1991; accepted May 17, 1981. 0 1991 by Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 ot?99-7071/911$3.50

they are found by any other method. This involves the screening of asymptomatic women, an uncom- plicated task that has as its primary goal the identifi- cation of all potentially malignant lesions to be found in a population of well women. A streamlined yet highly effective imaging approach can be devised to achieve this limited goal (3, 4). Interpretation can also be simplified, to involve a normal versus abnormal decision, with normal women needing no further attention but with abnormalities usually prompting additional imaging and/or invasive pro- cedures (3, 5, 6).

Mammography also can be used as a diagnostic examination, to help characterize the specific nature of already detected lesions, thereby distinguishing among many differential diagnostic possibilities so that appropriate treatment can be given in a timely manner (2, 3, 7). Streamlining will not work in this situation; rather, a problem-solving type of mammography examination must be tailored to the individual needs of each patient (3, 8). Furthermore, in this case, a wide variety of interpretations are possible, comprising a full spectrum of grays in contrast to the black-and-white normal versus abnormal decisions that are sufficient for screening.

Despite the fact that there are major differences between the goals and operational aspects of screening and problem-solving mammography, most radiologists make no attempt to separate the two types of examination (4, 9). I suspect that this status has developed because mammography was introduced and popularized initially as a problem-solving examination, to be monitored closely by the radiologist, and that only later did screening begin to take hold. In addition, the increased use of screening occurred gradually (lo), so that it was easiest to simply assimi- late these cases into the already established mode of problem-solving operation. Independent of the merits and disadvantages of this traditional practice, the co-mingling of both types of examination makes it more difficult to assess the value of screening alone.

254 SICKLES CLINICAL IMAGING VOL. 15, NO. 4

EVIDENCE OF THE BENEFITS OF SCREENING MAMMOGRAPHY

Breast cancer is the fourth most common cause of death among women in the United States (11). There is no known means of preventing the disease, and available therapy has been unsuccessful in reducing the national mortality rate over the past 60 years. Current attempts at controlling breast cancer concen- trate on early detection by means of mass screening, using periodic mammography and physical examination, because ample evidence is now available to indicate that such screening indeed can be effective in lowering the death rate.

It is well known that routine screening with mammography and physical examination detects breast cancer long before its chance discovery, which usually is made by the woman herself (12, 13). This results in a measurable increase in survival (14). Un- fortunately, evidence based solely on prolonged survival can be criticized on two grounds, lead time bias and length bias (2, 13, 15). The lead time bias argument postulates that some breast cancers are already incurable prior to detection by any means, so that women with screening-detected cancers will still die of their disease at a predetermined time that is independent of stage at detection. Any measured increase in survival therefore reflects only the lead time due to early detection rather than true prolonga- tion of life. The length bias argument postulates that some breast cancers grow so slowly as to have little if any potential for metastasis. Demonstration of lengthy survival due to detection by screening of nonaggressive lesions therefore would falsely indicate a beneficial effect because such indolent cancers would otherwise remain undetected until death from another cause. Clearly, these two very disparate arguments cannot both pertain to the same specific case of cancer, but it is possible that one or both may describe a large enough subset of all cancers that the clinically observed endpoint of increased survival gives false indication that screening truly saves lives.

A much more meaningful clinical endpoint is breast cancer mortality. Results using this endpoint are not subject to criticism by lead time bias and length bias arguments (13, 15). The best method to evaluate the effectiveness of screening is by randomized controlled trials. Such experiments examine two identical populations of women, except that the study group is offered screening while the control group is not. In this manner, one eliminates the pos- sibility that women selected for screening are those who might develop cancers having a better than av- erage prognosis (15). Only randomized controlled

trials can offer incontrovertible proof of benefit from screening (13).

Results of two such trials provide convincing evidence that screening can reduce breast cancer deaths: the HIP (Health Insurance Plan of Greater New York] study of 1963-1969 (16-19) and the Swedish WE study begun in 1977 (20-22). In the HIP study women aged 40-64 were screened with both two-view mammography and physical examination at yearly intervals for 4 years. The WE study involves women screened with single-view mammography alone, every 24 months in women aged 40-49 and every 33 months in women aged 50-74. Each trial clearly indicates that screening produces a statisti- cally significant decrease in mortality from breast cancer in the entire patient population studied. This provides conclusive proof that mass screening for breast cancer among women aged 40-74 can reduce mortality from the disease (13, 15).

Neither trial was designed to evaluate sufficient numbers of women to determine the benefit from screening in specific age subgroups (151. Nonethe- less, attempts have been made to derive such find- ings. In the HIP study, striking reduction in breast cancer mortality due to screening appeared earlier in women aged 50 and older (4 years after entry into the study] than in women aged 40-49 (7 years after entry) (18, 23). These mortality reductions persist after 18 years of follow up, now being essentially equal in extent for both age subgroups (19, 24). Similar results have been reported for the WE study, with observed mortality reduction beginning at year 4 after randomization for women aged 50-74, but not until after year 7 for women under age 50 (15).

An additional Swedish randomized controlled trial has been reported, indicating a somewhat less successful outcome (25). However, the validity of these results has been questioned due to problems in implementing the study protocol: relatively low compliance among study-group women in obtaining screening mammography examinations, relatively high numbers of control-group women obtaining screening examinations on their own, and inade- quate statistical power to produce meaningful results.

RADIATION RISK OF SCREENING MAMMOGRAPHY

A variety of retrospective studies have been conducted to estimate the risk of ionizing radiation to the breast. These involve Japanese atomic bomb survivors (26), North American women receiving multi-

OCTOBER-DECEMBER 1991 MAMMOGRAPHY SCREENINGFORBREASTCANCER 255

ple fluoroscopies during pneumothorax therapy for tuberculosis (27-291, New York women receiving radiation therapy for acute postpartum mastitis (30), and Swedish women given radiation therapy for fi- bradenomatosis and other benign breast diseases (31). All studies indicate an increased incidence of breast cancer following radiation, beginning about 10 years after exposure and continuing with no apparent decline for the remainder of subjects’ life- times (2, 32). The total radiation doses for women in most of the studies exceeds 100 rads, except that in the Japanese study there are considerable data at lower doses. As a result, estimation of radiation risk at the very small doses of modern mammography depends primarily but not entirely on extrapolation from high doses (2, 32). The observed dose-response relationships are consistent with either a linear or linear-quadratic curve. However, because data are insufficient to choose between these possibilities, prudent risk estimates are based on the more conservative linear dose-response curve (2). It is also unclear whether there is any risk-sparing effect of dose fractionation at the very low doses per fraction used in mammography. Again, to be prudent, the conservative assumption is made that the risks from many small doses are additive (2).

Radiation risk varies considerably with age, being highest when the breast is irradiated before the age of 20 (2, 32-35). The absolute-risk for women aged 20- 39 is somewhat lower, estimated to be 6.6 excess cancers per million women per year per rad (36). Risk declines even further in older women (screening mammography usually begins at age 4O), although available studies produce conflicting results as to the magnitude of this decline. The most widely used estimate of absolute risk for women aged 35 and above is 3.5 excess cancers per million women per year per rad (37).

Many comparisons of the benefits and risks of screening mammography have been made. Most complete are the estimates of the National Council on Radiation Protection and Measurements (2). These indicate a steadily increasing ratio of benefit to risk with advancing age. For typical screen-film mammography techniques among women aged 40- 44, benefit appears to be 40 to 80 times greater than risk, with benefit-risk ratios in excess of 100 : 1 for women over age 50. A more current report indicates even more favorable benefit-risk ratios, greater than 100 : 1 for women age 40 and approximately 500 : 1 for women over age 50 (38). Clearly, the radiation risk from periodic screening mammography is negli- gible in comparison with the substantial benefit that it affords (2, 32, 38).

COSTS OF SCREENING MAMMOGRAPHY

Although there no longer is any doubt that the benefit of screening mammography far exceeds radiation risk for women aged 40 and above, analyses of benefit versus cost do not produce similar conclusive results. Such cost-benefit evaluations are inherently unconvincing, primarily because of the great diffi- culty in deciding what assumptions to adopt in con- structing the analysis (39). The vast differences in assumptions that can be made by well-intentioned, informed investigators points clearly to the great uncertainties involved in these exercises. The two most recent and most ambitious analyses, those of Eddy et al. (40) and Moskowitz (al), are based on widely disparate assumptions and not surprisingly arrive at opposite conclusions.

Eddy et al. choose to limit their evaluation to the incremental benefit and costs of screening mammography above those of breast physical examination, while Moskowitz prefers to evaluate screening by mammography and physical examination versus the practice of no screening at all. On this issue Mosko- witz appears to have the more convincing argument, because there is no proved benefit for physical examination apart from its use in combination with mammography, nor is there evidence that large numbers of women currently are being given physical examinations as complete as are required for screening (42).

A second major difference in assumptions between these two analyses concerns inclusion of the costs of not screening. The Moskowitz study takes into account the medical costs of dying from breast cancer for those women whose lives would have been saved by screening, the costs borne by industry for short-term and long-term disability for these women, and the hiring and training costs to replace these women in the workplace. The study of Eddy et al. essentially omits such costs, based on the premise that screened women who survive their breast cancer will eventually contract other diseases and suffer morbidity and mortality at similar cost, so that screening produces no substantial net savings. Moskowitz attacks this basically nihilist argument on the grounds that, if taken to its logical conclusion, such an approach would lead us to abandon all medical care, the ultimate in cost-effective strategies.

If you are interested in a more complete discussion of these and related issues I urge you to criti- cally review the original studies (40, 41) and the letters to the editor generated by them (43). Suffice it to say that depending on the biases with which you choose to operate, a convincing argument can be

256 SICKLES CLFJICAL IMAGING VOL. 15, NO. 4

made that screening either should or should not be done.

Radiologists who wish to strengthen the argument in favor of screening should consider reducing the costs and charges for screening in their own practices. This can be accomplished by segregating screening mammography examinations from those done for problem-solving purposes, and then streamlining the screening operation (3, 4, 44, 45). If prop- erly implemented, this approach will not compro- mise effectiveness, because the two randomized controlled trials that incontrovertibly establish the benefit of screening were each run using just such cost-saving methods. Because my personal biases favor the more widespread acceptance of screening, I am pleased to report a growing trend among radiologists to adopt low-cost screening practices (46, 47). I also find it heartening that the governments of several northern European countries (and some prov- inces/states in Canada and Australia) have carefully considered the costs and benefit of screening for breast cancer and have decided to implement and fund comprehensive screening programs. In the United States, mammography screening now is provided to the subscribers of a wide variety of health maintenance organizations (45), more than half of our state legislatures have mandated medical insurance coverage for mammography screening (48), and the Medicare program now reimburses for mammography screening on a routine basis (49, 50).

STRATEGIES TO IMPLEMENT MAMMOGRA .PHY SCREENING

A successful overall strategy for breast cancer screening must address three issues. 1) Which seg- ment of the population should be screened? 2) With what examination(s) should screening be done? 3) How frequently should screening be done? Answers to these questions must take into account not only the effectiveness of screening but also its costs.

Assuming that cost considerations support the practice of screening in general, currently available data suggests the answer to the first question is that all women aged 40 to 74 should be screened. Breast cancer in men is too uncommon to justify screening, but randomized controlled trials indicate benefit for women within this age group (13, 15, 24). We must screen all such women because there are no known risk factors that select a relatively small subset which contains the majority of cancers. Indeed, it is estimated that 75% of breast cancers develop in women with no significant risk factors for the dis-

ease (51). Both younger and older populations of women might well benefit from screening, but appropriate clinical trials have not been conducted to support such practice. For women under age 40, although there are even more years of life to be saved by screening, this is at least partially offset by relatively low breast cancer incidence and a slightly di- minished capability for screening to detect the disease. The converse applies to screening women aged 75 and above; while the incidence of breast cancer is very high and screening is particularly effective in detecting small lesions, competing causes of death dilute overall screening effectiveness by substantially decreasing life expectancy.

In considering the second question, with what examination(s) should breast cancer screening be done, the only modalities proved effective are mammography and physical examination (13, 15, 41). It is likely that mammography currently provides the major component of screening benefit, not only because the randomized controlled WE trial proved the effectiveness of screening with mammography alone (21) (there is no study using physical examination alone that indicates such a benefit), but also because studies employing both examinations show that mammography detects cancers having a more favorable prognosis (12, 13, 52). However, these same studies also show that screening with physical examination detects some cancers missed by mammography. Be- cause the addition of physical examination to mammography can be accomplished with only a small increment in cost, a strong argument can be con- structed to screen with both modalities (41, 53). On the other hand, the absence of supportive data argues against the use of still other types of breast examination, either as complementary or competitive proce- dures (54).

The third question, how frequently should screening be done, has generated the most controversy because there is no direct evidence supporting the use of any one protocol over another. The American Can- cer Society, the National Cancer Institute, and the American College of Radiology all recommend screening at l-2 year intervals between ages 40-49, with yearly screening thereafter. The rationale be- hind this approach is that the incidence of breast cancer increases with advancing age, so that it makes some sense to screen older women more frequently because they can be expected to harbor more cancers. However, recent screening studies provide compelling evidence for just the opposite strategy, screening women under age 50 at yearly intervals, with older women screened at l-2-year intervals (13, 15, 55). This suggested change is based on the

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observation that the lead time gained by screening appears to be considerably shorter in younger women, only 18-24 months, than it is in women aged 50 and above, for whom lead time is estimated to be 3-4 years. As a basic practice, the screening interval should be somewhat shorter than lead time, to minimize the number of cancers that grow sufficiently large to surface clinically in between screens. This is not just a theoretical concept. It already has been demonstrated, by the randomized controlled WE trial, that screening younger women at Z-year intervals indeed allows large numbers of interval cancers to surface (56). In this study, among younger women, only 38% of the expected number of interval cancers actually became clinically apparent in the first 12 months after screening, whereas 68% of the expected number of interval cancers were detected clinically in the second 12 months between screens. This observation suggests that screening younger women at l-year intervals would have substantially reduced the number of interval cancers by detecting them at a smaller, potentially more curable stage.

PROBLEMS IN IMPLEMENTING MAMMOGRAPHY SCREENING There are many tens of millions of women in the United States of appropriate age to undergo breast cancer screening, but no more than 20%-25% actually are being screened at regular intervals (57-59). Opinion surveys point to the following Catch-22 condition: 75%-93% of women would comply with screening if recommended by their physicians (60), while 80% of physicians would advise screening if requested by their patients (58). A variety of factors contribute to this situation.

First, over the past several years there has been considerable nonuniformity in recommendations for screening among the various national medical organizations in the United States, some suggesting screening at a variety of different intervals, others declining to recommend screening at all (4). This general lack of agreement serves as a source of confusion to both women and their referring physicians. Within the past several years, after major efforts at achieving concordance, there has been some move- ment toward more universal adoption of the guidelines suggesting l-&year screening intervals between ages 40-49 and yearly intervals for older women. However, this uniformity is now threatened if only one national organization adopts what currently appears to be the more sensible strategy of screening younger women at shorter intervals. The likely outcome is that guidelines will not be changed

until a sufficiently strong consensus builds to con- vince most if not all organizations to revise their recommendations at the same time.

Confusion over screening guidelines is only one small part of the general reluctance of most physicians to recommend screening to their women patients. Some are still not convinced that screening indeed saves lives (45, 60-62); it is unfortunate that these physicians simply have not taken the time to read the reports of the randomized controlled trials that conclusively establish the benefit of screening. Others are troubled by uncertainties over radiation carcinogenesis (45, 58, SO-SZ), despite the clear demonstration that benefit far exceeds radiation risk. Some physicians complain that the quality of mammography practiced in their communities is spotty or even substandard, a subject addressed in several paragraphs that follow. However, the majority of physicians appear to ignore screening because of ec- onomic issues (45, 58, 60-62). One must recognize that referring physicians derive no income from rec- ommending screening to their patients yet it often takes a considerable amount of their time to con- vince women to accept screening. The other major barrier is the current high price of screening mammography, averaging approximately $100 (40, 62). Not only do such high prices weaken arguments supporting the cost-effectiveness of screening, but they also discourage compliance among women who are uninsured or whose health care insurance does not cover screening examinations. Here, at least, there is substantial promise of improvement. As stated previously, there is a growing trend among radiologists to offer screening mammography at considerably reduced prices, often for $50 or less (3, 4,44-47). Fur- thermore, 10 additional state legislatures now are considering legislation mandating health insurance coverage for screening mammography (48).

As mentioned previously, there is a common per- ception that a large proportion of mammography equipment currently in service is obsolete or otherwise substandard in quality. While this is true in a small percentage of cases, it certainly represents the exception rather than the rule. The most recent pub- lished nationwide survey on equipment indicates that 99% of mammography practices performing screen-film mammography use dedicated equipment, and that 77% of xeromammography practices do as well (63). Note that dedicated equipment is not necessary for routine xeromammography, although it does produce higher quality radiographs (2). The same survey also shows a clear trend toward im- proved image quality as determined by phantom image scores. The American College of Radiology also


has recently developed a voluntary mammography accreditation program, through which radiologists can have their equipment assessed for image quality and radiation dosage (64, 65). More than half of the practices performing mammography in the United States already have applied for accreditation. This should provide an objective standard by which women and their referring physicians can select a mammography practice that uses up-to-date equipment.

Another common misperception is that we do not have adequate numbers of technologists and radiologists to perform all the screening mammography examinations that would be done were there substantial compliance with current screening guidelines (66). No realistic observer expects dramatically increased utilization of screening mammography to oc- cur overnight; rather, it will take place gradually. In Northern California from 1983 to 1987 there was a five-fold increase in the number of mammography examinations, primarily screening examinations (10). This occurred gradually, and the supply of personnel (and equipment) was always adequate to meet the growing demand. There is no reason to an- ticipate a different scenario in the years to come.

Finally, no discussion of barriers to mammography screening would be complete without considering the competence of the personnel who perform examinations, both the technologists who produce mammograms and the radiologists who in- terpret them. In my opinion, this is one area in which there is need for improvement. I state this not to denigrate the many highly skilled and dedicated men and women who perform the great majority of current examinations with care and expertise. I merely want to point out several major deficiencies in training opportunities.

In general the training of technologists to do mammography is accomplished on the job, usually by another technologist already performing these examinations. Of course, this approach can produce ex- cellent results if the instructor is skillful as both a technologist and a teacher. Unfortunately, this is not always the case, nor does such “inbreeding” encour- age the influx of new ideas or techniques. There are very few opportunities for technologists to visit university centers of mammography learning for the hands-on experience they need, principally because the cost of such one-on-one instruction in a teaching hospital environment usually is prohibitively high. Large-scale postgraduate continuing education courses for technologists are much more affordable and are becoming widely available. However, these provide little if any opportunity to practice position-

ing skills, the most important aspect of technologist training. Equipment manufacturers also provide ap- plication specialists to familiarize technologists with the features of a recently purchased mammography unit, but training often is too superficial and much too short in duration. However, this type of teaching is ideal in several ways. It is done at the work site, using the equipment and patient population with which the technologist ultimately must work. Why not offer such training over sufficiently long periods of time, at least 1 week per technologist, even more when necessary? If provided by equipment manufacturers, the costs of training could be incorporated into purchase agreements. I suspect that the enlight- ened manufacturer that is first to develop and ac- tively promote such a course of instruction might well find itself capturing a larger share of the mammography market because of its comprehensive technologist training program.

There is considerably more opportunity available for postgraduate mammography training of radiologists. Lecture, workshop, and even hands-on film- interpretation courses, varying from l-5 days in length, are now given by the American College of Radiology, many university-based and nonacademic medical centers, and even some individual mammography experts (45, 64). However, the overwhelming popularity of these courses attests to the major gap in radiologist training that currently exists, the relative lack of instruction at the residency and fellowship level (67). Efforts encouraging diagnostic radiology residencies to require rotations devoted exclusively to breast imaging only recently have begun to suc- ceed, principally because of the recent addition of a separate mammography section in the oral certifica- tion examination given by the American Board of Radiology (50). The current system of under-training of radiologists, in which most learning is accomplished on the job, produces results as spotty as those found for mammography technologists. This occurs most often in relatively small group practices, where it is not practical for only one or two radiologists to take responsibility for and therefore gain considerable experience in interpreting mammograms (461.

However, there have been several encouraging developments recently. The rising demand for screening mammography has permitted a growing number of highly skilled radiologists to establish successful practices devoted entirely to breast imaging. In many larger group and University-based practices, the increased number of mammography cases has allowed for much more meaningful subspecialization of selected radiologists, with attendant improvements in

OCTOBER-DECEMBER 1991

quality of care. There even now are several year-long breast imaging fellowships, although these are few and far between (45).

FUTURE DIRECTIONS What does the future hold for mammography screening? The overwhelming likelihood is that its use will continue to grow. As ongoing screening trials ma- ture, we can expect more solid evidence with which we can plan increasingly effective screening strategies. As the mammography case load continues to increase, we can expect more subspecialization in breast imaging, because it will become more feasible for practices to support dedicated mammography experts (46, 47). We also can expect increasingly fre- quent turf battles over screening mammography, as primary care physicians find it an ever more attrac- tive field of endeavor (68). In my opinion the most effective way to counter such incursions, and also to maximize the skills of those actually doing the screening, is to develop programs that provide more and more extensive subspecialty training in breast imaging. Finally, for this indeed is our ultimate goal, once screening becomes sufficiently widespread we may even begin to see breast cancer mortality decrease to the extent that it can be measured on a national scale.

SUMMARY Mammography is generally accepted as a useful problem-solving clinical tool in characterizing known breast lesions, so that appropriate and timely treatment can be given. However, it remains grossly underutilized at what it does best: screening. The major strengths of mammography are a] its ability to detect breast cancer at a smaller, potentially more curable stage than any other examination, and b) its proved efficacy in reducing breast cancer mortality in asymptomatic women aged 40-74. If, as has recently been estimated, screening with mammography and physical examination can be expected to lower breast cancer deaths by 40%50% among those actually examined (13), then the lives of al- most 20,000 U.S. women might be saved each year if screening were to become very widely used. The challenges of the next decade are clear, to mount much more effective campaigns to educate physicians and lay women about the life-saving benefits of breast cancer screening, to devise increasingly effective and lower cost screening strategies, to further improve the current high quality of mammographic imaging despite its increasing proliferation, and to train large numbers of breast imaging specialists to

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guarantee that the growing case load of screening and problem-solving mammograms is interpreted with a very high level of skill.

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Documents

Screening for breast cancer with mammography