Respectful Insolence

Screening for disease, especially cancer, is a real bitch.

I was reminded of this by the publication of a study in BMJ the very day of the Science-Based Medicine Conference a week and a half ago. Unfortunately, between The Amaz!ng Meeting and other activities, I was too busy to give this study the attention it deserved last Monday. Given the media coverage of the study, which in essence tried to paint mammography screening for breast cancer as being either useless or doing more harm than good, I thought it was imperative for me still to write about it. Better late than never, and I was further prodded by an article that was published late last week in the New York Times about screening for cancer.

If there’s one aspect of medicine that causes more confusion among the public and even among physicians, I’d be hard-pressed to come up with one more contentious than screening for disease, be it cancer, heart disease, or whatever. The reason is that any screening test is by definition looking for disease in an asymptomatic population, which is very different from looking for a cause of a patient’s symptoms. In the latter case, the patient is already being troubled by something that is bothering him. There may or may not be a cause in the form of a disease or syndrome that is responsible for the symptoms, but the very existence of the symptoms clues the physician in that there may be something going on that requires treatment. The doctor can then narrow down range of possibilities for what may be the cause of the patient’s symptoms by taking a careful history and physical examination (which will by themselves most often lead to the diagnosis). Diagnostic tests, be they blood tests, X-rays, or other tests, then tend to be more confirmatory of the suspected diagnosis than the main evidence supporting a diagnosis.

In contrast, screening for a disease involves subjecting a population, the vast majority of whom don’t have the disease and nearly all of whom are asymptomatic, to a diagnostic test in order to find disease before it has begun to cause symptoms. This is very different from the vast majority of diagnostic tests used in medicine, the vast majority of which are done for specific indications. Any test to be contemplated for doing this thus has to meet a very stringent set of requirements. First, it must be safe. Remember, we’re subjecting asymptomatic patients to a test, and a risky, invasive tests are rarely going to be worthwhile, except under uncommon circumstances. Second, the disease being screened for must be a disease that is curable or manageable. For instance, it makes little sense to screen for a disease like amyotropic lateral sclerosis (Lou Gehrig’s disease) because there is very little that can be done for it; diagnosing it a few months or a few years before symptoms appear won’t change the ultimate outcome. A corollary to this principle is that acting to treat or manage a disease early, before symptoms appear, should result in a better outcome. I’ve discussed the phenomenon of lead time bias in depth before; it’s a phenomenon in which earlier diagnosis only makes it seem that survival is longer because it was caught earlier when in reality it progressed at the same rate as it would without treatment. Lead time bias is such an important concept that I’m going to republish the diagram I last used to explain it, because in this case a picture is worth a thousand words:

Another requirement for a screening test is that the disease being screened for must be relatively common. Screening for rare diseases is simply not practical from an economic standpoint, as the vast majority of “positive” test results will be false positives. Another way of saying this is that the specificity of the test must be such that, whatever the prevalence of the disease in the population, it does not produce too many false positives. In other words, for less common diseases the specificity and positive predictive value must be very high (i.e., a “positive” test result must have a very high probability of representing a true positive in which the patient actually does have the disease being tested for and there can’t be too high a percentage of false negatives). For more common diseases, less specificity is tolerable. The test must also be sufficiently sensitive that it doesn’t produce too many false negatives. Remember, one potential drawback of a screening program is a false sense of security in patients who have been screened, a drawback that will be increased if a test misses too many patients with disease. Finally, a screening test must also be relatively inexpensive. One of the reasons there is so much controversy over using MRI as a screening test for breast cancer, for example, is because an MRI easily costs over $1,000 per test. In contrast, good, old-fashioned mammography is between 10- and 20-fold less expensive. Consequently, MRI is currently not recommended for breast cancer screening in the general population and is instead reserved for younger women at high risk due to a strong family history or a known mutation in a cancer susceptibility gene, as I discussed last year.

Recently, there has been a bit of a kerfuffle in the literature and in the lay press reporting on the literature regarding the risks and the benefits of various screening tests, including mammography. Prostate cancer, for example, is a particularly difficult disease to screen for because there is such a high incidence of disease that never causes a problem. In autopsy series of men over 80, at least 75% of men have evidence of at least one focus of prostate cancer somewhere in their prostate glands, but obviously it never caused them any problem and they died of something else, including old age. On the other hand, prostate cancer is consistently one of the top cancers in men, resulting in 30,000 deaths a year. Sometimes, it can be quite aggressive. Because we don’t have reliable tests to differentiate prostate cancer that will progress from prostate cancer that will never cause a problem, whenever we find prostate cancer by screening there is always the question of what to do with it, to treat or not to treat.

Indeed, one thing that surprised me was that the NYT article got things mostly right.

Nearly every body part susceptible to cancer now has an advocacy group, politician or athlete with a public awareness campaign to promote routine screening tests — even though it is well established that many of these exams offer little benefit for the general public.

An upshot of the decades-long war on cancer is the popular belief that healthy people should regularly examine their bodies or undergo screening because early detection saves lives. But in fact, except for a few types of cancer, routine screening has not been proven to reduce the death toll from cancer for people without specific symptoms or risk factors — like a breast lump or a family history of cancer — and could even lead to harm, many experts on health say.

That is why the continued rollout of screening campaigns, and even the introduction of a Congressional bill, worries some health experts. And these experts say such efforts add to the large number of expensive and unnecessary treatments each year that help drive up the nation’s health care bill. Rather than heed mass-market calls for screening, these experts urge people without symptoms or special risks to talk to their own doctors about what cancer tests, if any, might be appropriate for them.

Blanket screenings do come with medical risks. A recent European study on prostate cancer screening indicated that saving one man’s life from the disease would require screening about 1,400 men. But among those 1,400, 48 others would undergo treatments like surgery or radiation procedures that would not improve their health because the cancer was not life-threatening to begin with or because it was too far along. And those treatments could lead to complications including impotence, urinary incontinence and bowel problems.

These are the downsides of screening that are not discussed nearly as much as they ought to be. As I emphasize time and time again, no medical intervention is without risk, and all medical interventions boil down to a risk-benefit ratio. When that ratio ends up in favor of the intervention, then it should be considered; when it doesn’t it shouldn’t. Then there’s the issue of cost. Mass screening programs are just that: Mass screening. That means tens or hundreds of thousands must be screened, even millions.

Since my specialty is breast cancer, in the wake of the aforementioned New York Times article In Push for Cancer Screening, Limited Benefits and multiple news stories about a study that purports to show that 1 in 3 breast cancers detected by mammographic screening are overdiagnosed and overtreated, entitled, appropriately enough, Overdiagnosis in publicly organised mammography screening programmes: systematic review of incidence trends. This study was done by Karsten Juhl Jørgensen and Peter C. Gøtzsche at The Nordic Cochrane Centre. Here’s how an AP story described the study:

LONDON - One in three breast cancer patients identified in public screening programs may be treated unnecessarily, a new study says. Karsten Jorgensen and Peter Gotzsche of the Nordic Cochrane Centre in Copenhagen analyzed breast cancer trends at least seven years before and after government-run screening programs for breast cancer started in parts of Australia, Britain, Canada, Norway and Sweden.

The research was published Friday in the BMJ, formerly known as the British Medical Journal. Jorgensen and Gotzsche did not cite any funding for their study.

Once screening programs began, more cases of breast cancer were inevitably picked up, the study showed. If a screening program is working, there should also be a drop in the number of advanced cancer cases detected in older women, since their cancers should theoretically have been caught earlier when they were screened.

However, Jorgensen and Gotzsche found the national breast cancer screening systems, which usually test women aged between 50 and 69, simply reported thousands more cases than previously identified.

Overall, Jorgensen and Gotzsche found that one third of the women identified as having breast cancer didn’t actually need to be treated.

This is more or less a half way decent CliffsNotes version of the study, but let’s look at the study in a bit more detail, because I have–shall we say?–issues about it. First off, it’s important to remember that this is a systematic review. Actually, it is part systematic review, part meta-analysis, which is one reason why I have issues with it. Whether you call it a systematic review or meta-analysis, as a consequence it is highly dependent upon the selection of studies and how the studies are interpreted. I wasn’t encouraged by this statement in the introduction:

It is well known that many cases of carcinoma in situ in the breast do not develop into potentially lethal invasive disease. In contrast, many find it difficult to accept that screening for breast cancer also leads to overdiagnosis of invasive cancer.

While this may be true of certain advocacy groups, the implication seems to be that many physicians also find it “difficult to accept” that screening can lead to overdiagnosis. No evidence is presented to support this little dig, and overall it sets the tone of settling scores. This is not terribly surprising, because these two authors are well known for publishing articles about mammography that absolutely, positively always downplay the benefits of screening mammography and play up the risks, as a couple of quick PubMed searches show (1, 2). They’re also known for writing letters to scientific journals that dispute points of papers that find a benefit from screening mammography. This doesn’t mean that Jørgensen and Gøtzsche are wrong, of course, only that they do appear to have a definite point of view, which should be kept in mind as much as anyone else’s point of view when examining a scientific paper. While I like their work to some extent as a counterweight to too much boosterism for ever earlier screening, I do find that they tend to go a bit too far at times in downplaying the usefulness of mammography, and at times they seem to be on a mission to cast doubt on mammography, as when they led a campaign to change a British leaflet used to encourage women to undergo mammography and making statements like:

But “it has not been proven that screening saves lives,” they insist, and new evidence shows less benefit and substantially more harm from screening than previously thought.

In fact, this balance between risk and benefit has changed so much in recent years that nationwide programs of breast screening would be unacceptable, they say. “We believe that if policy makers had had the knowledge we now have when they decided to introduce screening about 20 years ago . . . we probably would not have had mammography screening.”

Personally, I think that’s a huge overstatement. However, in fairness, I must mention that Michael Baum ChM, FRCS, MD, FRCR hon., a breast surgeon in England and someone I respect, also signed on to this campaign. I don’t entirely agree with everything he said, but I do take him, as well as Jørgensen and Gøtzsche, seriously. In any case, what bothers me about Jørgensen and Gøtzsche’s systematic review the most is the assumption behind it. Let’s look at how Jørgensen and Gøtzsche estimated overdiagnosis. Basically, the assumption is that in a population that begins screening, intitial cancer diagnoses should increase and there should be a compensatory decrease in cancer diagnoses in the population as women get older. The reason, if this model is valid, is that cancers that wouldn’t have been diagnosed until later ages are now being diagnosed when women are younger. So what Jørgensen and Gøtzsche did was to look for compensatory drops in breast cancer diagnoses in older women. One thing that also has to be emphasized is that this study looked only at mammographically detected breast cancers found by screening, not breast cancers detected by the palpation of a lump in the breast or other symptoms. If a woman has a lump in the breast, ruling out cancer is imperative, especially if the woman is over 40.

One thing that needs to be understood is that the countries examined in this study (United Kingdom; Manitoba, Canada; New South Wales, Australia; Sweden; and parts of Norway) have very different screening protocols than we do in the United States. In most of these countries, for women at an average risk for breast cancer, screening with mammography doesn’t begin until age 50, and in some countries mammography is performed only once every two years, rather than every year. In addition, in many of these countries, screening ends after age 70 or so, which is one reason why Jørgensen and Gøtzsche break down the groups they look at into “too young for screening,” “screening age” (50-64 or 50-69, depending on the nation), or too old for screening. In the U.S., screening generally begins at age 40 and continues on a yearly basis in essence forever, a system that is, quite frankly, not well grounded in evidence and designed to maximize overdiagnosis, given that the evidence that screening between ages 40-50 reduces breast cancer mortality is rather weak, that the prospective randomized controlled trials evaluating mammography to date have excluded patients older than 74, and that few studies have rigorously looked at screening in women over 80. It’s also rather fascinating to those of us in the U.S. that mass screening programs in some of these countries didn’t start until the 1990s.

Basically, what Jørgensen and Gøtzsche found was that in these countries there was, as expected, an increase in the rate of diagnosis of both invasive breast cancer and ductal carcinoma in situ (DCIS), a lesion that is considered cancer but has not yet invaded out of the breast ducts. This is one problem that I have with this article, namely that it lumps together invasive cancers and DCIS. The reason is that DCIS is a condition of uncertain significance in that it is known that a significant percentage of DCIS never progresses to full cancer. Consequently, the inclusion of DCIS is guaranteed to inflate the estimate of overdiagnosis; from my perspective, DCIS should be analyzed separately. For one thing, it would give us a better idea of just how much overdiagnosis there might be in invasive breast cancer; more importantly it might provide evidence that “watchful waiting” might be safe in some cases of DCIS. Dumping the two together, however, confuses things. For example, what if 80% of the overdiagnosis is due to DCIS? Then overdiagnosis of invasive cancer would be much less, telling us that we should treat invasive cancers discovered by mammographic screening.

Another problem with the study was pointed out in the rapid responses on BMJ by Dr. Daniel B. Kopans, Professor of Radiology at the Harvard Medical School and the Massachusetts General Hospital. I noticed this problem, too, but couldn’t formulate it as clearly at first. The problem is that this study is not looking at a fixed cohort of women before and after screening began. Consequently, every year, new women turn 50 and begin screening, and screened women “age out” of the screening system. Finally, another huge confounder that I don’t think that Jørgensen and Gøtzsche adequately account for is the use of hormone replacement therapy and the decrease in inherent breast cancer incidence that has begun since the report from the Women’s Health Initiative study that found increased risk of breast cancer, heart disease, stroke and blood clots in women taking hormone replacement therapy (HRT) led to a dramatic decrease in the number of women using HRT.

Don’t get me wrong. There is no doubt that mammographic screening programs produce a rate of overdiagnosis. The question is: What is the rate? Unfortunately, the most accurate way to measure the true rate of overdiagnosis would be a prospective randomized trial, in which one group of women is screened and another is not, that follows both groups for many years, preferably their entire life. Such a study is highly unlikely ever to be done for obvious reasons, namely cost and the fact that there is sufficient evidence to show that mammographic screening reduces breast cancer-specific mortality for women between the ages of 50 and 70 at least, the latter of which would make such a study unethical. Consequently, we’re stuck with retrospective observational studies, such as the ones analyzed in this systematic review. One trial that has a stronger design, as far as I’m concerned, was reported in 2006 by Zackrisson et al entitled Rate of over-diagnosis of breast cancer 15 years after end of Malmö mammographic screening trial: follow-up study, which found a rate of overdiagnosis of between 10% and 18%, depending upon how the data were analyzed. For one thing, the Malmö study has the advantage of looking at individual women over time randomized to screening or no screening, rather than population-level numbers, as well as having a 15 year followup. Its disadvantage is that the Malmö mammographic screening trial was one of the classic ongoing studies, for which the screening occurred between the years 1976 to 1986. In the interim, mammography has become more sensitive, with improved imaging and digital mammography. Consequently, it is quite possible that the rate of overdiagnosis is higher than what was reported in the followup to the Malmö study.

There’s another wrinkle. As I discussed last December, there was recently a study that purported to show that roughly 22% of mammographically detected cancers might actually spontaniously regress. You may recall that I disputed whether the number was that high, but accepted that it’s probable that some percentage of mammographically-detected cancers might regress. (Remember, though, I’m referring to mammographically-detected cancers in asymptomatic women. There is no good evidence that cancers detected by palpation of a mass or other symptoms regress at an appreciable rate; they might do so rarely, but certainly not at anything approaching 20%.)

On an issue like this, I like to try to look for confluences of studies, and I think I’m starting to see one here. Overall, if you look at the literature, there appears to be a convergence of estimates of the rate of overdiagnosis for mammographically detected breast cancers of somewhere around 20-25%. Jørgensen and Gøtzsche’s work tends to represent the high end (and, indeed, seem custom-designed to me to make the estimate of overdiagnosis as high as possible), while the Malmö study representing the low end. Throw in the Norwegian study that estimates that one in five mammographically detected breast cancers spontaneously regress, and science seems to be honing in on a “true” rate of overdiagnosis that is probably in the range of one in five to one in four. The problem then becomes: What do we do with that information.

The aforementioned Michael Baum actually commented on the study under the title Attitudes to screening locked in time warp. He’s right to some extent, but he goes too far in implying that the improvements in our understanding of the biology and natural history of breast cancer are such that we know enough to be highly confident in what to do about the program:

Next, as described in Jørgensen and Gøtzsche’s paper, estimates of harm through over-diagnosis have increased. At the same time our understanding of the biology of breast cancer has improved so that the idea of latent or self limiting pathology that is so counter-intuitive to the screening community, is no longer surprising to those who have bothered to keep up to date.

Finally, whilst the screening programme remains an inviolate bovine deity, treatment regimens have improved by leaps and bounds further narrowing the window of opportunity for screening to demonstrate an impact.

Actually, its a huge overstatement to say that treatment regimens have improved by “leaps and bounds” over the last 20 years. They have definitely improved, but not so dramatically that we can, as Baum appears to do, so blithely discount the potential benefits of detecting breast cancer earlier. Even if earlier detection, because of lead time bias, doesn’t change the overall prognosis, at the very least detecting cancer earlier makes it possible to use less disfiguring surgery in more women and to use less aggressive chemotherapy. This is not a benefit to be sneezed at, but it is one that is frequently completely ignored in discussions of this sort.

Where Baum is more on target is his suggestion for risk-adjusting our recommmendations for mammographic screening. I might quibble with his exact approach (and I do, actually), but it is becoming clear that mass screening programs of the “one-size-fits-all” variety for breast cancer are probably not doing as much good as advertised or are arguably doing more harm than previously expected. The time is coming for a less dogmatic approach than has been the norm. One approach might be an evidence- and science-based discussion of the known risks and benefits of mammographic screening. In an accompanying editorial, H. Gilbert Welch tried to provide a “balance sheet” of the risks and benefits for 1000 women undergoing annual mammography for 10 years starting at the age of 50 years. These include:

Benefits

  • 1 woman will avoid dying from breast cancer

Debits

  • 2-10 women will be overdiagnosed and treated needlessly
  • 10-15 women will be told they have breast cancer earlier than they would otherwise have been told, but this will not affect their prognosis
  • 100-500 women will have at least 1 “false alarm” (about half these women will undergo biopsy)

Unfortunately, the error bars around these estimates are very high. Where Welch is correct is here:

Mammography is one of medicine’s “close calls”–a delicate balance between benefits and harms–where different people in the same situation might reasonably make different choices. Mammography undoubtedly helps some women but hurts others. No right answer exists, instead it is a personal choice.
To inform that choice, women need a simple tabular display of benefit and harms–a balance sheet of credits and debits

And:

Equally important are the estimates themselves. Zackrisson and colleagues reported 62 fewer deaths from breast cancer and 115 women overdiagnosed–a ratio of one death avoided to two women overdiagnosed. Recently, Gøtzsche and colleagues argued in the BMJ that the ratio is one to 10. For many women, the tipping point may be within this range. Careful analyses that explicitly lay out their assumptions and methods, which will improve the precision of these estimates, are sorely needed.

The problem in changing the way that screening programs for breast cancer are done is likely to be convincing women that a more selective approach to mammographic screening is desirable. To people not educated in cancer, it makes intuitive sense that detecting cancer earlier will result in better outcomes, and it is hard to explain the down side, namely over diagnosis, unnecessary biopsies and treatment, and the emotional distress that such false positive diagnoses make. Also, the maintenance of public and therefore political support often depends upon keeping the message as simple as possible. Including a discussion of the risks of mammography will likely be seen by many public health officials as “muddying the waters” and harming their efforts to promote screening. Moreover, great care has to be taken to make sure that the public understands that this discussion is only about the screening of asymptomatic women. Women with breast masses or other symptoms worrisome for cancer should not be led to refuse mammograms because of this discussion.

What I hope for one day, and what may well come out of the emerging sciences of oncogenomics and proteonomics, is a manner of determining with more accuracy exactly which cancers will and will not progress. In that case, one potential harm of overtreatment of breast cancer, for example, would be obviated, namely treating women who don’t need them with aggressive surgery, radiation, and chemotherapy. Indeed, we already have some progress in this area with the Oncotype DX gene assay and related products, which have already changed the way oncologists practice by giving them information about which estrogen receptor-positive breast cancer patients can safely forego adjuvant chemotherapy. The problem with such assays, of course, is that they still require tissue, which means that women with overdiagnosed breast cancers would still have to undergo a biopsy. Much better would be an imaging study that could provide the same risk information. Ten years ago, I would have thought such a system to be science fiction. Now I’m optimistic that by the end of my career we will be doing things that way, although what could scuttle any new technology is likely to be cost, which means that mammography is unlikely to be going anywhere any time soon.

Comments

  1. #1 DPSisler
    July 20, 2009

    What we need to remember is that when we say 1 in X that 1 could represent your daughter, wife or mother. When we through statistics around I feel that we sometimes lose the human element attached to the numbers, or is that just me?

  2. #2 Orac
    July 20, 2009

    I do keep that in mind, but I also ask the question: How much more likely is a screening test to cause harm by subjecting a woman to biopsies and surgery that won’t benefit her than it is to find a cancer at such a point where earlier treatment makes a difference. Remember, screening is a balance between risk and harm not just for the population but at the level of each and every person screened.

    I liken this to adjuvant chemotherapy for breast cancer (or other cancers). For early stage disease, the absolute benefit for chemotherapy can actually be quite small; yet studies have shown that a plurality or even a majority of women would opt for chemotherapy even if told it will only increase their chances of survival by 1%.

  3. #3 jim
    July 20, 2009

    Also, in reply to DPSisler:

    The 10 in x that receive a false positive could equally be a cared for person, and that false positive has impacts. Those impacts range from the emotional shock of possibly having cancer, to the negative impacts of unnecessary treatment.

    My sister in law had a false positive biopsy on a breast lump and the emotional stress was significant for the entire family. No one blames anyone for the false positive (though one doctor exaggerated the likelihood of cancer), but it was a significant stress that, if possible, should be reduced.

  4. #4 Mac donalds
    July 20, 2009

    These points to an interesting article in findrxonline where they talk about this subject it is necessary to inform the community.
    It is ultimately the patient’s responsibility to use narcotics responsibly.

    A few years ago, narcotics were only prescribed after surgery, severe trauma, or for terminal cancer because of a concern over the possibility of addiction. Recently, they have been cautiously prescribed to treat moderate to severe non-malignant chronic pain in conjunction with other modalities such as physical therapy, cortisone and trigger point injections, muscle stretching, meditation, or aqua therapy. Unfortunately, the upsurge of narcotics as medical treatment also increased associated cases of abuse and addiction.

    Derived from either opium (made from poppy plants) or similar synthetic compounds, narcotics not only block pain signals and reduce pain, but they affect other neurotransmitters, which can cause addiction. When taken for short periods, only minor side effects such as nausea, constipation, sedation and unclear thinking are noted.

    However, when narcotics are taken for several weeks to months, these side effects can become more challenging: loss of effectiveness due to built-up tolerance, possible addiction, or overuse for a temporary “high,” not for pain. Because of the potential for addiction, whether physical (anxiety, irritability, nausea, vomiting, abdominal cramps and insomnia) or psychological (compulsive use, craving the drug and needing it to “feel good,” narcotics are considered controlled substances, which means that the FDA and DEA govern their distribution, prescription, and use and classify them into different schedules as per the Controlled Substances Act of 1970.

  5. #5 Mac donalds
    July 20, 2009

    It is ultimately the patient’s responsibility to use narcotics responsibly.
    These points to an interesting article where they talk about this subject it is necessary to inform the community.
    A few years ago, narcotics were only prescribed after surgery, severe trauma, or for terminal cancer because of a concern over the possibility of addiction. Recently, they have been cautiously prescribed to treat moderate to severe non-malignant chronic pain in conjunction with other modalities such as physical therapy, cortisone and trigger point injections, muscle stretching, meditation, or aqua therapy. Unfortunately, the upsurge of narcotics as medical treatment also increased associated cases of abuse and addiction.

    Derived from either opium (made from poppy plants) or similar synthetic compounds, narcotics not only block pain signals and reduce pain, but they affect other neurotransmitters, which can cause addiction. When taken for short periods, only minor side effects such as nausea, constipation, sedation and unclear thinking are noted.

    However, when narcotics are taken for several weeks to months, these side effects can become more challenging: loss of effectiveness due to built-up tolerance, possible addiction, or overuse for a temporary “high,” not for pain. Because of the potential for addiction, whether physical (anxiety, irritability, nausea, vomiting, abdominal cramps and insomnia) or psychological (compulsive use, craving the drug and needing it to “feel good,” narcotics are considered controlled substances, which means that the FDA and DEA govern their distribution, prescription, and use and classify them into different schedules as per the Controlled Substances Act of 1970.

  6. #6 joewilly
    July 20, 2009

    First I must nit pick about sensitivity and specificity. The higher the Specificity says that a negative study rules out disease with higher probability. The higher the Sensitivity the more cases of disease are identified, but it increases the false positives. So optimally we need a cheap sensitive and better confirmatory tests.

    Second, you skirt the issue of a negative test assuring everyone that Cancer is not present. Women with dense breast are prone to underdiagnosis with mammograms. This is likely why mammography on younger women is less revealing. Similarly older women on HRT may be influenced.

    Third, and extremely important, in the US system of health insurance, is the identification of pre-existing conditions. As soon as a breast condition is identified, riders and exclusions are attached. This is not the case in the European countries you cited.

  7. #7 Tye
    July 20, 2009

    Orac, I’d like to get your thoughts on another screening process that is currently being considered on congress, the MOTHERS Act. The plan is to screen birthing mothers for postpartum depression. Wouldn’t the false positive rate from a screening program on a population that hasn’t significantly been shown to be at high risk be a danger as it would include placing new moms on psychotropic drugs? There have been multiple studies showing pervasive side effects of the medications and little is known about the risk factors for PPD other than previous psyhiatric disturbance. Another point would be that expectant mothers have more contact with a physician than most of the population and could easily be screened and assessed by their physician for risk of PPD. It seems that a nationwide screening process is nothing but a boon to the pharma industry simply due to the false positive rate.

  8. #8 Shae
    July 20, 2009

    I’m 41, non-symptomatic, and have not yet had my first mammogram. I’ve been following this public discussion/debate somewhat.

    My question is:

    For a person like me, when do *you* recommend mammograms start and how often should they be done?

    I apologize if you’ve covered that before.

    My gut feeling is that I need one now, for a baseline. Beyond that, I’m not sure. Have one every other year? Start at 50?

    How about digital vs. the “old way” (assuming I can request the old way, somewhere)?

  9. #9 Reality Rounds
    July 20, 2009

    This is in response to Tye. I work in OB and it is always being thrown around that we need to start screening all mothers before discharge for PPD. It is ludicrous and a waste of time. A recent study just came out (sorry I do not have the link), that basically said it is useless to screen for PPD until about 2 months post partum. So the best person to screen for this is the infant’s pediatrician who sees the family the most. There are also issues of prescribing psychotropic drugs for breastfeeding mom’s. Don’t get me wrong, PPD can be a very serious condition, but it has varying degrees of severity (post partum blues, PPD, and post partum psychosis). It does not always require medication.

  10. #10 Shae
    July 20, 2009

    I’m 41, non-symptomatic, and have not yet had my first mammogram. I’ve been following this public discussion/debate somewhat.

    My question is:

    For a person like me, when do *you* recommend mammograms start and how often should they be done?

    I apologize if you’ve covered that before.

    My gut feeling is that I need one now, for a baseline. Beyond that, I’m not sure. Have one every other year? Start at 50?

    How about digital vs. the “old way” (assuming I can request the old way, somewhere)?

  11. #11 LovleAnjel
    July 20, 2009

    I’m pretty much against screening for anyone under 50 (excluding those with strong indicators like family history & genes). I had a ‘cancer scare’ through palpation (the “old way”), and let me tell you, it was the worst medical thing I have been through. Aside from months of going back and forth between my normal doctor and the cancer specialists, worrying the hell out of everyone in my life (I spent a good two hours calming my sister down from a panic when I told her), spending nights unable to sleep trying to not think about my possible future, and an extremely painful biopsy, the insurance issues were enormous. I paid– how much out of pocket?– because I have lumpy boobies. Now every time I see a new doctor (I keep moving, so I have to keep switching), I have to explain that the lumpy boobies are normal for me and I have had biopsies and everything is fine, and one day I know I’m going to be sent for another one and it will turn out OK again.

    It was not worth the time, money, physical & emotional pain to myself and my loved ones to have that false positive. If people go through that because of early screening, and catching real cancers earlier has little to no effect on outcome, than you’re putting people through a form of unnecessary torture by having them screened.

    Sorry about the ranting. Thinking about it gets me upset all over again.

  12. #12 James Sweet
    July 20, 2009

    I have to say, this spam for a particular website hawking prescription drugs is starting to get really annoying. I was under the impression the SciBlogs software could filter comments based on a specific word or phrase…? If so, why aren’t you blocking that crap?

  13. #13 HealthEd
    July 20, 2009

    I have to say that, as someone edits and writes health articles for a living, the potential downside of screenings is one of the toughest issues for me to wrap my head around. I saw Barrett Kramer of the NIH speak on it last fall and only then did the risks of screening start to sink in. For everyone like my mother-in-law, for whom a free osteoporosis screening at K-mart caught a potentially serious condition she didn’t know she had, there are plenty of those like LovleAnjel. The situation seems to me to be worst in prostate cancer, as Orac points out, since in many cases “watchful waiting” is the less-harmful option to intervening. I hope that the scientific community can develop ways of better detecting which cancers will progress so that relatively harmless cases won’t be overtreated.

    Shae, I hope Orac answers your question because I’m interested in hearing what he has to say. FWIW I’m 35 and I don’t have any breast cancer risk factors other than prior, long-term oral contraceptive use and fibrocystic breast disease. (Which is symptomless but misery-inducing because it deprives me of my one true vice, caffeinated coffee) But my doc last year scheduled me for a baseline mammogram, I think mainly because of the FBD which can make it difficult to find lumps through palpation alone. The radiologist saw something weird enough that I had to go back for a sonogram, which came out clean. I didn’t have nearly the level of anxiety that LovleAnjel did, and a sonogram is a lot easier on the pocketbook than an MRI, but it was still a little scary to wait for those results. I think my doc doesn’t want me to have another mammo for five years, so hopefully it’s steady as she goes until then.

  14. #14 joewilly
    July 20, 2009

    HealthEd
    Caffeine and breast cancer appears to be a myth. It helps one think they are doing something I guess. see http://www.webmd.com/breast-cancer/news/20081013/caffeine-breast-cancer-link-minimal

    The association if any seems to be more with breast cysts. These can be aspirated. Better if a woman does breast self exam every time she bathes, she will know where the changes occur. Tenderness and rapid onset of a mass imply benign disease.

  15. #15 Lee
    July 20, 2009

    So, ORAC, what is YOUR opinion? What do you think women should do? I kept reading, looking for your bottom line, and couldn’t figure it out. If I’m 53 and asymptomatic and only one paternal aunt ever diagnosed with breast cancer (one out of 12 total grandmothers, mother and her sisters, and my own sisters), should I or should I not get mammograms? If I should, how frequently?

    My other question is: why are MRIs so expensive?

  16. #16 Kate W.
    July 20, 2009

    I find this fascinating because every time I turn around there seem to be new guidelines for screening.

    I’m 35, with no children, my mother has had breast cancer twice, the first time before she was 50. I’ve been told I have very lumpy breasts. I’ve had one baseline mammogram and on ultrasound after my PCP found what she thought was a lump during an annual exam (it was just a bit of dense tissue). There have been threats of annual mammograms, but I haven’t even managed to organize the extra visit for a professional breast exam on a regular basis.

    I feel a bit like the attitude is that we can do all this so why not? My PCP is part of the practice at a large teaching hospital. I’m a federal employee with very good insurance so my out of pocket costs are minimal. I’m sure no one wants to be the doctor that misses the lump on the 30 something patient. I don’t want that to happen either. However, I find this all kind of nerve wracking.

    The time waiting on the ultrasound was the longest two weeks of my life. Among my close friends and family people either freaked, requiring me to console them or refused to talk about it because after all I was going to be just fine because this was all a silly precaution.

    I’d like some reasonable guidance to go by. Heck, I’d like a reasonable risk assessment. The risk assessments I get seem to vary from pretty high to slightly higher than average.

  17. #17 antipodean
    July 20, 2009

    Now, that is scienceblogging. Nice work Orac.

  18. #18 Chris
    July 20, 2009

    Spam troll, Mike, is obvious spam troll.

  19. #19 Donna B.
    July 20, 2009

    I am 57, 4 pregnancies, 3 healthy children. I had a mammogram at 40 because I was told I should. I haven’t had one since then because dadgummit that HURT.

    There are no ancestors going back a minimum of three generations that had breast cancer, and the youngest age of death of those grandmothers was 65 due to uterus fibroids (what did that mean in the early 1900s? Was it cancer?)

    The closest relative I’ve had die from cancer was a 1st cousin (lung cancer), however her mother has no cancer at age 89. My father, age 86 was diagnosed with Stage I NSCLC a few months ago. He had no symptoms and the cancer was “caught” when he was being screened for the possibility of having back surgery.

    I get letters yearly to come in for a mammogram. I have excellent insurance, cost is not a factor. However, I see no reason to have another until there’s some indication other than a “schedule”.

  20. #20 Tracy W
    July 21, 2009

    Do you have any advice on how to stop your doctors’ practice sending you the screening letters?

  21. #21 RPK
    July 21, 2009

    Thanks for an interesting article. I’m an American living in Australia, about to turn 40. I asked my Australian GP if I needed a mammogram, given that 2 out of 3 of my closest female relatives have had breast cancer. (My mom and aunt, at age 65 and early 60s.) In the US the answer would have been an emphatic yes. The GP plugged the info into some sort of computer calculator and told me I didn’t need one until I turned 50. I’ve decided not to worry about it until I go back to the US at age 41. So your article is somewhat reassuring.

  22. #22 DebinOz
    July 21, 2009

    I think that ‘screening’, if it is to part of our general ‘well-being’ procedures, needs to be presented a little differently. Rather than being touted as something that will diagnose a problem, it should presented as something that can rule out a problem.

    Then again, I am an epidemiologist and am familiar with rates of false positives and negatives, and the psychological problems that screening tests introduce. And the invasiveness (is there such a word) of some screening tests. Many investigators have busted a gut (LOL) to develop a screening test for bowel cancer instead of the dreaded colonoscopy. Voila, we now have the faecal occult blood test.

    Unfortunately, there will always be those cases that don’t have a disease but a positive test (get over it), and those that really do even though the screening test was negative (it sucks).

  23. #23 ChrisC
    July 21, 2009

    I’ve no cancer history in either side of my family but I was recently diagnosed with Stage 0 DCIS. This was picked up in a screening and then diagnostic mammograms. The biopsy results confirmed the DCIS. My lesion was so small it could only have been imaged — it was too small to feel, and it wasn’t seen in the previous year’s visit. I’m 51 years old and have been getting annual mammograms since I turned 40, as part of my annual “well-woman” physicals.

    Because the cancer was detected so early, I had options I would not have had if the cancer had been detected much later. I chose breast-conserving surgery (lumpectomy)followed by radiation (I’m half-way through the radiation treatments now). I haven’t had to take time off from work except the time I needed after surgery.

    Family history seems to play only a small role in one’s overall risk of cancer. I’ve had several doctors comment to me when I said I had no family history: “That doesn’t really matter.” And in my case it certainly didn’t.

  24. #24 Teresa Twomey
    July 21, 2009

    I’m really glad I did not read this three years ago. Instead I went to my routine age 40 baseline without worry as I did not think I had any risk factors and there was no lump. But, indeed, I did have a very aggressive, invasive breast cancer. We believe that I had a surgical cure (physical removal of the tissue through lumpectomy). If I’d waited until age 50 I’d likely not have made it to 50! My cousin’s wife (I think she turns 39 or 40 this year) has Stage 4 and is on her fourth? round of chemo. Three young children and doctors give her NO hope. I’d go through 50 (minimum) biopsies if it meant saving her life. That is I think you may see the physical trauma and worry of a “false positive” in a different light when you consider the alternative of watching a loved one die so young. (Perhaps even more than considering your own mortality.)

    RE: MOTHERS Act: It requires that women in particular practices are OFFERED screening NOT (the common misperception) that they MUST be(so, not every new mother as somem claim – an expectant woman could choose to go someplace that is not required to offer screening). Maybe that is the answer to all of this — be VERY frank about percentages and odds -benefits vs. drawbacks — without spin — and OFFER these screenings to women. (I still do not understand why it is not done this way anyway.)
    BTW: when I went in for a physical after delivering my baby and broke down in tears and sobs when asked “How are you doing?” I WISH I had been offered screening for postpartum mood disorders. But I was just taken into a room and given a physical exam. No follow-up on how I was doing. I trusted my care providers to know best. I was wrong. I had postpartum psychosis which led into postpartum depression. I lost 2 years, my business and my carreer. And I am GRATEFUL that nobody lost their life at my hands. Would it have been so much bother to offer to screen me? (And, BTW, technically would have been “screening” someone who is already symptomatic — which is technically not true “screening”– but even that is often not done with postpartum mood disorders – hence the need for a law requiring that women are offered screening.)

  25. #25 Teresa Twomey
    July 21, 2009

    I’m really glad I did not read this three years ago. Instead I went to my routine age 40 baseline without worry as I did not think I had any risk factors and there was no lump. But, indeed, I did have a very aggressive, invasive breast cancer. We believe that I had a surgical cure (physical removal of the tissue through lumpectomy). If I’d waited until age 50 I’d likely not have made it to 50! My cousin’s wife (I think she turns 39 or 40 this year) has Stage 4 and is on her fourth? round of chemo. Three young children and doctors give her NO hope. I’d go through 50 (minimum) biopsies if it meant saving her life. That is I think you may see the physical trauma and worry of a “false positive” in a different light when you consider the alternative of watching a loved one die so young. (Perhaps even more than considering your own mortality.)

    RE: MOTHERS Act: It requires that women in particular practices are OFFERED screening NOT (the common misperception) that they MUST be(so, not every new mother as somem claim – an expectant woman could choose to go someplace that is not required to offer screening). Maybe that is the answer to all of this — be VERY frank about percentages and odds -benefits vs. drawbacks — without spin — and OFFER these screenings to women. (I still do not understand why it is not done this way anyway.)
    BTW: when I went in for a physical after delivering my baby and broke down in tears and sobs when asked “How are you doing?” I WISH I had been offered screening for postpartum mood disorders. But I was just taken into a room and given a physical exam. No follow-up on how I was doing. I trusted my care providers to know best. I was wrong. I had postpartum psychosis which led into postpartum depression. I lost 2 years, my business and my carreer. And I am GRATEFUL that nobody lost their life at my hands. Would it have been so much bother to offer to screen me? (And, BTW, technically would have been “screening” someone who is already symptomatic — which is technically not true “screening”– but even that is often not done with postpartum mood disorders – hence the need for a law requiring that women are offered screening.)

  26. #26 Teresa Twomey
    July 21, 2009

    I’m really glad I did not read this three years ago. Instead I went to my routine age 40 baseline without worry as I did not think I had any risk factors and there was no lump. But, indeed, I did have a very aggressive, invasive breast cancer. We believe that I had a surgical cure (physical removal of the tissue through lumpectomy). If I’d waited until age 50 I’d likely not have made it to 50! My cousin’s wife (I think she turns 39 or 40 this year) has Stage 4 and is on her fourth? round of chemo. Three young children and doctors give her NO hope. I’d go through 50 (minimum) biopsies if it meant saving her life. That is I think you may see the physical trauma and worry of a “false positive” in a different light when you consider the alternative of watching a loved one die so young. (Perhaps even more than considering your own mortality.)

  27. #27 Chris
    July 21, 2009

    I have been getting annual screenings since I turned 40. There is very little or no family history to go on. My mother was an only child and possibly adopted, and she died young in an accident (and her mother died when I was a toddler). And my dad’s mother was adopted, so there is no real history.

    I have been fortunate to avoid what ChrisC and Teresa Twomey went through (oh, please read the error message, this is a busy blog and your comment did get posted, it is just that the system is too busy to repaint the page).

  28. #28 Biotunes
    July 21, 2009

    It’s nice to have an actual physician analyze these papers so carefully. I am a biologist who has written a bunch on the topic of cancer screening and treatment since my own breast cancer diagnosis over a year ago. A big piece of the overscreening/overtreatment problem is the paradoxical culture we have in which any cancer diagnosis is taken as a death sentence, but aggressive treatments are touted as the only way to achieve a “cure,” which as a doctor you know can never be definitively stated. Here’s my take on the problem:

    http://bioblog.biotunes.org/bioblog/2009/06/10/there-is-no-cure/

    This culture is part of the reason that strong chemotherapy was recommended to me even though I knew at the time that there is as yet no direct evidence that it would be helpful – I am strongly estrogen positive. I ended up doing second generation chemo – taxotere and cytoxan (switching to abraxane and cytoxan after it turned out I was one of the unfortunate 2% who have a bad allergic reaction to taxotere), after first, second and third were all recommended by different oncologists (I saw four). I was especially miffed that the one at a large cancer center in Seattle told me that CMF would be a reasonable treatment, when I later read the literature confirming that CMF adds no value to hormone therapy. And now we hear that anthracyclines are useful only against HER2-positive cancers. How many lives have been made miserable, and how much money wasted by useless chemotherapy? I fully expect to find out within the next decade or so (if I’m still around) that the chemo I did was of minimal benefit as well – it did a good job of knocking my ovaries out of commission, thankfully, but there are much easier ways to do that.

    http://bioblog.biotunes.org/bioblog/2009/02/18/is-the-main-purpose-of-chemotherapy-to-make-you-miserable/

    You are dead on that treatments haven’t progressed as much as claimed. If you use imaging to find more early cases of cancer, and you treat the ones that never would have progressed in a dangerous way, and those people don’t have a recurrence because they would not have anyway, than statistics claiming those people have been “cured” through treatment are wrong. I’ve been in several discussions on the big paper sites about the overscreening problem, and people there still don’t get it. They all say they were “cured” because their cancer was caught early. They all think that in their case it would have been fatal. But actually for the majority of them, especially breast and prostate cancer patients, it would not have been. Yes, we’re still no good at telling which ones are helped, so that is where the bulk of new cancer research money should be going. You have to understand the beast before you know how to kill it properly, and we’re basically throwing darts over our shoulder blindfolded.

    Incidentally, I don’t take the statement “difficult to accept” to mean physicians, but rather pushy patients. This age of patients having to take more control of their care is a double-edged sword. On the one hand, there is massive and often conflicting information that doctors cannot be expected to have all digested and organized in their minds, so patients do need to be their own advocates, and to do this they need to be informed. Unfortunately on the other hand, many get their information from an unfiltered Google search rather than scientific papers (since most don’t have the training to read scientific papers or evaluate the validity of scientific statements). I believe many doctors take the path of least resistance and give the patient what they want, even if it doesn’t make much sense – in fact I know this is the case with at least one doctor friend of mine who has admitted to giving her patients antibiotics for viral infections because they hounded her so much. Another doctor friend points out that the most aggressive patients will just go get another doctor to do what they want if she doesn’t, so she continually walks a fine line of trying to steer them in the right direction, while being responsive to their personal concerns. Clearly it’s not easy. Despite what I have written here, I have a ton of respect for doctors and the incredible work they have and the job they do – especially cancer doctors. I marveled to think of my cheery breast surgeon and the fact that he probably has women crying in his office several times a day. What you do is so important. My experience has led me to think that if I had to do it all again, I would make the sacrifices to be a doctor instead of taking the cushy route to be an ecologist. Thank you for what you do.

  29. #29 Stripbubbles
    July 21, 2009

    Wait, I’m confused. Do we start at 40 or 50? Also, whatever happened with that nurses study? Weren’t they being followed for over a period of 20+ yrs? ORAC, do you have any thoughts/conclusions concerning self-breast exams? Do they really make any difference?

  30. #30 Lee
    July 22, 2009

    You know, this analysis does us no more good than reading a summary of it in the NYT or some other publication — it has left me, for one, just as confused about what I should do.

    This was like a hit-and-run column — a very confusing analysis, no guidelines or suggestions or opinions for us ignorant laypeople to consider, and abandoning all of us who trust what you write, especially as this is your area of specialty.

    And you get annoyed with Dr. Oz showing up on Oprah in his scrubs? What makes you any better, ORAC, if you write such a provocative blog entry and then just abandon it and all the questions you provoked?

  31. #31 Colin
    July 23, 2009

    “…if you write such a provocative blog entry and then just abandon it and all the questions you provoked?”

    Lee, just because you can comment/discuss/criticize other work does not require you to know the “correct” answer.

  32. #32 Natalie
    July 23, 2009

    Yeah, I didn’t get the impression that Orac was trying to hammer out once and for all what women should do. He is discussing a particular paper, and in the course of that musing on the different factors and considerations that go into this issue. The reason there are no guidelines is because he doesn’t intend to give them.

    I also don’t really understand why we would want Orac to give answers to the questions provoked. Isn’t the point of this kind of essay to give us readers something to think about? What would be the point if he followed that with “answers”?

  33. #33 Orac
    July 23, 2009

    Exactly. It says right in the disclaimer that this blog is not meant to give medical advice. If you ask me for advice, I am going to tell you to follow the current guidelines recommended for screening and listen to your doctor. I’m going to tell you that, if you feel a lump, to go and see your doctor. I practice according to the current standard of care.

    The current screening guidelines may leave something to be desired and I have little doubt that they will change in the not-too-distant future, but until that happens they are the best guidelines we have and reasonably science-based (albeit not as much as I would like). My whole post was meant to reflect some of my thoughts on the matter and to point out that in some cases I’m as puzzled as patients. It was also meant to educate that screening is not a completely benign thing to do. Remember, if 1/4 breast cancers detected by mammography are “overdiagnosed” or (as some call them) “pseudotumors,” then that means 1/4 women diagnosed that way are undergoing surgery, possibly radiation, and even chemotherapy unnecessarily. The problem is, we don’t know which women can get away without it.

    Another aspect of overdiagnosis that I should have mentioned is that women who were overdiagnosed and decided to forego conventional therapy in favor of woo make great alt-med testimonials.

  34. #34 Diora
    July 24, 2009

    “One trial that has a stronger design, as far as I’m concerned, was reported in 2006 by Zackrisson et al entitled Rate of over-diagnosis of breast cancer 15 years after end of Malmö mammographic screening trial: follow-up study, which found a rate of overdiagnosis of between 10% and 18%, depending upon how the data were analyzed.”

    If you read the rapid responses after the article you reference:
    http://www.bmj.com/cgi/eletters/332/7543/689
    you’ll notice that the computation method used has a major math flow – quite obvious to anybody with even basic math knowledge. Basically, they included all new cancer diagnosed after the end of the program into the numbers i.e. they added the same number to both nominator and denominator of a ratio making the ratio smaller. When adjusted for this flaw as done by Welch, the actual number came out closer to 25%. Also, if you consider the improvement in technology since that time, it is quite likely that the rate of overdiagnosis is higher today than during Malmo trial. It is likely to be even higher in the US.

    Regarding some personal stories posted above: nobody knows – neither you nor your doctor – how your cancer would’ve behaved had it remained undetected. Especially for someone with DCIS – it is quite possible that the particular cancer would’ve never been found when remained undetected.

    Mind you, I am not against screening. I choose not to have mammograms in my 40s, but now that I just turned 50, I am thinking about it. Whatever I decide will be my personal decision and choosing not to be screened wouldn’t make me ignorant or stupid or irresponsible.

    What I find upsetting is the culture that believes women have to be dragged to be screened regardless of what their personal preference may be. In our society women who choose not to get screened are labeled stupid or irresponsible; some politicians (e.g. in Germany some time ago) even consider penalizing those who choose not to get screened; some employers “encourage” women to have it by including it as condition for healthy rebates. Every time a woman who choose not to get screened goes to a doctor, she has to mentally prepare for a fight. Screening or even some preventive drugs have to be presented as a choice and not an obligation or something “responsible people do”.

  35. #35 Tara L.
    July 24, 2009

    For me it’s simple; no symptoms, no test. I’m only 45 and have no family history, but some people think I should be arrested for something akin to treason for that simple, personal decision. It’s truly astounding to me. Over-diagnosis does more than cause anxiety; how many women have been seriously harmed by aggressive treatment for cancers that were never going to take their lives if they had not been diagnosed? We’ll never know. But I do know that statistics, unlike multi-billion dollar industries, don’t lie. And I, for one, won’t play the game. Let’s focus on real cures – and real prevention. Not this early detection equals prevention nonsense. (seriously, has no one ever noticed that this mantra makes absolutely no sense?)

  36. #36 DRG
    July 25, 2009

    The simple truth is, despite what the American Cancer Society and the mammography industry continue to claim, there is very little chance that regular mammograms will save your life. The 1 in 1000 number above might even be over-stated. But compare it to the other numbers and decide for yourself where the doing harm vs. doing good line is.

    Your doctor won’t likely tell you this, even if he or she knows the truth. If a physician in the U.S. tells his 50 year old patient that a mammogram isn’t necessary, and she later is diagnosed with breast cancer, he’ll likely face a malpractice suit. This is despite the fact that the patient’s outcome will almost certainly be the same regardless of whether she was screened or not. And so doctors will continue to recommend them. Women will continue to get them. And money will continue to be made while real progress towards eliminating this disease will not.

  37. #37 Karsten Juhl Jørgensen
    July 27, 2009

    I would first like to thank Orac for taking the time and effort that his description of my study must have required. I like the sceptical approach very much – this we all should read papers. And it has spurred a lengthy debate, which is very valuable. I would, however, like to correct a few mistakes and explain some difficult issues.

    1: A systematic review is an approach to evaulate the available evidence by using a specific, reproducible search method to locate all the avaialable evidence. This evidence may or may not warrent the use of a statistical method called a meta-analysis, where the individual studies are grouped as if they were one study. These methods are not mutually exclusive and are used together in most Cochrane reviews. Our study is a systematic review of the available evidence where we found it reasonable to combine this evidence in a meta-analysis. So stating that ‘Actually, it is part systematic review, part meta-analysis, which is one reason why I have issues with it’ is somewhat misleading.

    2: Regarding the statement ‘the implication seems to be that many physicians also find it “difficult to accept” that screening can lead to overdiagnosis. No evidence is presented to support this little dig, and overall it sets the tone of settling scores’. I would encourage you to read the Forrest report from 1986, which formed the basis for the implementation of breast screening in the UK. In here, it is specifically stated that it is the expectaion, and a premise, that there would be no overdiagnosis in breast screening and that it should in no way affect breast cancer incidence. This was wrong. Also, see ‘Br J Cancer. 2003 Feb 10;88(3):362-5′ for a more recent example of people responsible for screening programmes actively denying the existance of overdiagnosis in their programmes.

    3: You write that ‘One thing that also has to be emphasized is that this study looked only at mammographically detected breast cancers found by screening, not breast cancers detected by the palpation of a lump in the breast or other symptoms. If a woman has a lump in the breast, ruling out cancer is imperative, especially if the woman is over 40′. You are absolutely right that any symptomatic lump should be checked. But it is simply wrong to state that we only looked at screen-detected tumors – we looked at population statistics of breast cancers diagnosed through any means, screening or otherwise. That is why we conclude that one in three cancers diagnosed in a population OFFERED screening are overdiagnosed.

    4: ‘as when they led a campaign to change a British leaflet used to encourage women to undergo mammography’. We did not lead a ‘campain’. An open letter was sent to the Times by a group of 27 researchers lead by Michael Baum, who you mention, and Hazel Thornton. Their ‘campain’ was initiated by an article in the BMJ about the UK invitation that we had published, but we did not lead a ‘campain’ in the UK – this, if such a term can be used, was done by others.

    5: You write that ‘This is one problem that I have with this article, namely that it lumps together invasive cancers and DCIS.’ We do in fact give estimates of overdiagnosis of invasive cases separately (around 35%) and including DCIS (52%). We include DCIS because the consequence to the woman is the same: she feels she is a cancer patient, fears the return of the disease for her remaining lifetime and has the same treatment (26% of invasive and 29% of DCIS are treated by mastectomy in the UK, the rest being treated by lumpectomy – most have radiotherapy). Thus, differentiating between the two types would be misleading as all have serious consequences.

    6: ‘The problem is that this study is not looking at a fixed cohort of women before and after screening began. Consequently, every year, new women turn 50 and begin screening, and screened women “age out” of the screening system’ Mr. Kopans is tryoing to explain away an important harm. We have sufficient follow-up to evaluate if screening increases the life-time risk of getting a breast cancer diagnosis – it does, and this makes concerns about closed cohorts obsolete.

    7: ‘I don’t think that Jørgensen and Gøtzsche adequately account for is the use of hormone replacement therapy and the decrease in inherent breast cancer incidence that has begun since the report from the Women’s Health Initiative study that found increased risk of breast cancer, heart disease, stroke and blood clots in women taking hormone replacement therapy (HRT) led to a dramatic decrease in the number of women using HRT.’ Contrary to what has been claimed by Stephen Duffy and others, we did take increasing background incidence into accout. The abrupt increase in incidence occurs only in the invited age range, although this varies from one country to another, and only at the time screening is introduced, although this also varies considerably – as you correctly note, some introduced screening as late as the early 90’s. This speaks strongly against confounders, including HRT, as being important. Specifically for the US, decreasing attendance in screening has also been offered as an expalanation for the recent development in incidence. See our extended material on bmj.com where we specifically adress this issue.

    8: ‘Unfortunately, the most accurate way to measure the true rate of overdiagnosis would be a prospective randomized trial, in which one group of women is screened and another is not, that follows both groups for many years, preferably their entire life. Such a study is highly unlikely ever to be done for obvious reasons, namely cost and the fact that there is sufficient evidence to show that mammographic screening reduces breast cancer-specific mortality for women between the ages of 50 and 70 at least’. Please look at the Cochrane review of the 8 randomised screening trials. There were 30% overdiagnosis in these trials – we estimate 52%, somewhat more. But mammography screening equipment today has vastly higher sensitivity than that used in the trials. e.g. the New York trial was performed in the early 60’s.

    9: ‘Actually, its a huge overstatement to say that treatment regimens have improved by “leaps and bounds” over the last 20 years. They have definitely improved, but not so dramatically that we can, as Baum appears to do, so blithely discount the potential benefits of detecting breast cancer earlier’. Please see our letter in the BMJ from May 30th where we show that there has been no decline in breast cancer mortality in the age group that could benefit from screening in the UK relative to other age groups. In fact, women too young to ever have been screened have enjoyed a larger decline in breast cancer mortality than those that could potentially have benefitted, and women who are too old have enjoyed one of equal proportion.

    Lastly, let me complement Diora for taking the effort to check the Rapid Responses to the article by Zackrisson. Such things are always worthwhile.

    Best regards,

    Karsten

  38. #38 Joseph C.
    July 27, 2009

    And money will continue to be made while real progress towards eliminating this disease will not.

    As far as the radiologists are concerned, reading mammograms is not a well-compensated activity.

  39. #39 Orac
    July 27, 2009

    No, reading mammograms is not a well-compensated activity at all. However, doing stereotactic biopsies and ultrasound-guided core biopsies are well-compensated. Indeed, radiologists make more doing an image-guided needle biopsy than I do doing a surgical biopsy, at least as far as the professional fee goes. Reading mammography is a “loss-leader.”

  40. #40 Orac
    July 27, 2009

    I’m surprised and honored that Dr. Jørgensen would comment here. It never ceases to amaze me that anyone actually cares what I write here. In any case, I’m sorry that it’s too late here and I’m in the middle of writing a grant. I will try to respond later this week, as it will take more time than the usual response.

    One problem I have, though, is that there seems to be an all-or-nothing view on mammography, in which boosters of screening overplay its utility while people like Dr. Jørgensen tend to make it sound as though mammography is useless.

    Let’s say, for the sake of argument, that he’s right and detecting a cancer earlier by mammography won’t change the ultimate outcome. Let’s say it’s all lead time bias. Even so, it’s still worth detecting the cancer early because a cancer detected earlier can be treated with less disfiguring surgery, less chemotherapy, and less radiation. In other words, the smaller the tumor and the earlier the woman is treated, the less likely she is to lose her breast and the less likely she is to have to undergo the nastiest chemotherapy. These benefits tend to be overlooked. Moreover, despite what was posted, it’s still very hard to tease out overdiagnosis from lead time bias from tumors that actually benefit from being treated earlier.

  41. #41 Karsten Juhl Jørgensen
    July 28, 2009

    Thanks, Orac, for getting back so soon. I stumbled across this by ‘accident’ but felt I had to reply because it seemed like a serious debate between someone who were genuinely interested in this question, and because many of the comments to your piece were very thoughtful and relevant.

    Regarding your statement about less invasive surgery that screening should lead to, consider this: you look at this from the point of view of an individual patient diagnosed with breast cancer, as any good surgeon would. And for an individual woman, the earlier diagnosis may mean less invasive surgery. But because of overdiagnosis, many more women are treated when you look at the population as a whole. In the randomised trials, both the number of mastectomies and the number of lumpectomies increased, by about 20% and 30%, respectively (see the Cochrane review). So in the population as a whole, screening causes more women to loose their breast, many of them without good reason. This is why it is so misleading to see again and again that ‘before screening xx% were treated by mastectomy, now it is only xx%’. This may be true, but the total number of mastectomies has increased after screening – the total number of lumpectomies has increased even more.

    Here is one more thought for you to consider: you have undoubtedly observed, in your work as a surgeon, that women who are diagnosied with large tumors that have spread have a poorer prognosis than those that are diagnosed as small. Does this mean that we can change the prognosis of large tumors by detecting them earlier? Not necessarily, although it is very tempting to try. But those tumors that are diagnosed when large may be different from the small ones. They may be the the fast-growing, aggressive, dangerous ones. There is no direct evidence for a mechanism of effect as a ‘whatchful waiting’ trial has never been done (for obvious reasons, it would likely be difficult to get volunteers). This doesn’t mean the hypothesis of earlier treatment-better prognosis is wrong, only that we have to be extra careful with the evidence.

    One last thing: I have no economic interest in raising concerns about screening, or in taking a away funds from screening. In fact, it is rather difficult to built a career saying that an intervention isn’t as great as many think it is. My interest is to draw attention to the important psychological and physical harms that screening causes, which has been kept a secret to invited women for too long.

    Once again, thanks for your interest and much needed scepticism.

    Best,

    Karsten

  42. #42 DRG
    July 28, 2009

    Joseph, please understand that I was not speaking about individual radiologists. Or even about just the mammography industry. Cancer treatment in the US – necessary or otherwise – is very, very big business.

    The more we learn, the more it seems to be becoming clear that it may not be the size of a breast tumor that matters most, but it’s nature. A very small tumor may be far worse than a large one. And mammography cannot tell us the nature of a cancer.

    And for those who think overdiagnosis is a small price to pay when one considers a few may be saved by regular screenings, please remember that people can and do have their lives shortened or altered by undergoing cancer treatments. My own brother died from radiation-related heart disease some years after his treatment for Hodgkin’s disease. We must remember that it cuts both ways.

  43. #43 William Wallace
    November 17, 2009

    Let the rationing begin. Macro-analysis guised as the only form of evidence based medicine still harms specific individuals. But the group-thinkers don’t seem too care much that individuals are better served by micro-analysis and marginal risk/reward. Only governments and large corporations care about macro-analysis.

  44. #44 William Wallace
    November 17, 2009

    Having posted at the liberal science blogs before, and knowing on past experience that a typo is the rabbit that leads liberal science bloggers off the point of the argument, please replace my “too” with “to”.

  45. #45 Chris
    November 17, 2009

    Actually, WW, you would be more criticized for posting in a several month old blog posting when there are more relevant and recent ones available.

  46. #46 Karin
    November 19, 2009

    William Wallace, allow me to ask you a hypothetical question:

    Would you have a chest x-ray every year for 20 years if studies showed that one person in 1000 over that 20 year period might have his life saved by having those x-rays? (note, I’m not equating any diseases or tests, this is simply for illustrative purposes. Mammograms are actually potentially much more harmful due to overdiagnosis – which we know is a real problem – and likely pose a greater cumulative radiation risk. But lets move away from emotional topic of breasts for a moment.)

    And if the answer is yes, do you really think insurance companies should pay for that type of mass screening? Would you call it “rationing” if they didn’t? Myself, I’d call it reasonable. If, with those types of odds you are still that fearful of dying from one specific form of cancer, you should be allowed to pay for own screening.

    We need to move away from anecdotal thinking and focus on the benefits of asymptomatic cancer screenings, balancing this with a clear understanding of the risks. Women have a right to know the truth about the value of these tests they’ve been quite literally brainwashed to believe will save their lives. There are many, many questions here and simplistic, knee jerk reactions will not help us arrive at the answers.

  47. #47 KittyKitty7555
    June 18, 2010

    What bothers me about overdiagnosis is not that it occurs, but that information about it is deliberately withheld from women who have been told to get a mammogram. Unless the woman has studied the issue in some depth and is able to sort out the propaganda and BS from the facts she will never know that screening mammography could subject her to the agony of unnecessary cancer treatment.

    I’m at the age when a number of acquaintances (all in their 40’s) been through the breast cancer mill. The treatments they described sound like absolute torture. And I can’t help but wonder if these women, who were very fit and thin were simply overdiagnosed.

    A great commentary was posted in the BMJ about this issue – please see: http://www.bmj.com/cgi/eletters/340/mar23_1/c1241#234667

    It’s time to make sure that everyone considering screening knows all the facts.

  48. #48 Fitzy
    July 23, 2010

    I am 62 years old. I am fit, a good weight, and healthy. I was diagnosed with asymptomatic DCIS (no family history) after a routine yearly mammogram, followed by a second mammogram, ultrasound, and needle biopsy. I had several consultations with medical, surgical, and radiation oncologists,and read extensively, both medical and non-medical literature. I made the decision to have a mastectomy for my own peace of mind, especially since the area involved was large (>3.5 cm), and my breasts are small. I also asked for sentinel node biopsy.
    My nodal biopsy was clear, and the pathology showed clear margins, with no evidence of invasion.
    Having read all of the interesting posts, I agree that increased screening can lead to over-diagnosis. However, and I may be over-simplifying, it seems to me that most of the conclusions are hindsight. Yes, I may not have developed invasive cancer, if I had not had a mammogram, but I did not want to take the risk.
    For me, the yearly mammogram, while uncomfortable, is worth it for my peace of mind. Each woman needs to make her own decision, based on the best advice she can find.
    Until research finds a better method for predicting which DCIS might become invasive, I am content that mine was the best decision for me, at this time.

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