I tell ya, I’m on the light blogging schedule for a mere four days, thanks to the Thanksgiving holiday weekend, the happy invasion of family on Thursday and Friday, and a significant amount of grant writing I’ve had to deal with on Saturday and Sunday, and somehow I missed not only a study relevant to my field of interest, but the reaction of antiscientific quackery apologists to said study. First, let’s look at the reaction, then the study, which reports that as many as 22% of mammographically detected breast cancer may spontaneously regress.
First off the block is Dr. Joel Fuhrman:
It’s easy to understand why this study was so hard to get published and the stranglehold the drug companies and the medical profession has on the status quo in disease-care. It should not even be called health care!
Actually, given the controversial results of the trial and the somewhat questionable assumption that lies at the very heart of the interpretation of its results, it’s no evidence of some grand conspiracy or ideological blindness that leads reviewers and editors to do a knee-jerk rejection of the manuscript deciding the results of the trial. Rather, it’s simply the editorial process at work. Manuscripts that describe a result that is far outside the range of what previous studies have found are generally greeted with a bit more skepticism, and their authors may have to jump through a few extra hoops to convince reviewers that their results are convincing enough to deserve publication. Indeed, that this manuscript ended up being published in the Archives of Internal Medicine, rather than a higher impact journal like the New England Journal of Medicine, JAMA, or The Lancet, or even prominent journals specializing in cancer, such as Clinical Cancer Research or the Journal of Clinical Oncology, makes me wonder a bit. Still, the manuscript has to stand or fall on the quality of its data (more on that later); besides, I’ve occasionally had to “settle” for a journal less prestigious than the one I originally shot for. It happens.
Not surprisingly, the study also leads Dr. Fuhrman to write:
Lastly, one of the reasons why mammograms have such a small, almost worthless impact on reducing deaths from breast cancer in so many medical studies is because, many of the so-called cancers that are then treated with chemotherapy or radiation are conditions that would never have progressed to a metastatic or life threatening condition, so the risks from the treatment were more significant than from the native disease.
This is especially concerning because belief in the success of chemotherapy for estrogen positive post-menopausal breast cancer is so ubiquitous, but the true benefits are miniscule. The point is that this is a confusing and complicated issue that we are only in the infancy of understanding and our present screening and treatment of most cancers is barbaric, ineffective and leaves much to be desired.
Superior nutrition and a healthful lifestyle is still the best way to win the war on cancer in the modern world, but these protective nutritional changes must taken throughout society, including children when the dividing cells are most susceptible to damage.
How Dr. Fuhrman managed to leap from the results of a study that suggests that more tumors may be overdiagnosed on mammography than previously thought to a rant against chemotherapy and how treatment of cancers is “barbaric” and “ineffective,” I don’t know. Then, how he managed to leap from there to a claim that nutritional changes are the best way to fight cancer, well, let’s just say that Dr. Fuhrman is pretty good at–shall we say?–extrapolating a bit farther than the data warrant (to put it kindly). But Dr. Fuhrman is usually a total lightweight compared to that quack of quacks, that crazy of crazies, Mike Adams and his NaturalNews.com. Whether it’s him or his acolytes, no website brings home the crazy like NaturalNews.com, which is why I find it odd that a writer named Sherry Baker totally misrepresents this study in a piece called Breast Cancer Rates Soar after Mammograms and Some Cancers may Heal Naturally but somehow manages to be pretty tame (for NaturalNews.com, anyway):
A report just published in the Journal of the American Medical Association’s Archives of Internal Medicine (Arch Intern Med. 2008;168[21]:2302-2303) reaches a startling conclusion. Breast cancer rates increased significantly in four Norwegian counties after women there began getting mammograms every two years. In fact, according to background information in the study, the start of screening mammography programs throughout Europe has been associated with increased incidence of breast cancer.
This raises some obvious and worrisome questions: Did the x-rays and/or the sometimes torturous compression of breasts during mammography actually spur cancer to develop? Or does this just look like an increase in the disease rate because mammography is simply identifying more cases of breast cancer?
No, no, no, no! First off, the background reading was all about overdiagnosis; it has nothing to do with an increased incidence of breast cancer. Overdiagnosis, as you may recall, is the diagnosis of disease that, if left untreated, would never have progressed to trouble the patient or endanger her life. In other words, it has to do with detecting what is now being referred to as cancer of limited malignant potential. The speculation that mammography somehow resulted in a massive increase in cancer is not an interpretation listed in the study in question or even in the original studies cited. The question is, rather, what proportion of breast cancers detected mammographically constitute overdiagnosis. A helpful reminder of these concepts comes in the form of two posts I’ve written.
Let’s take a look at the study itself.
A study of this sort could only have been accomplished in a nation with a government-run health care system with extensive databases linking information from every hospital in the nation, and that’s true of this study, which was carried out in Norway. Indeed, the numbers of women in each study are staggering: 109,784 in the control group and 119,472 in the “screened” group. So here’s what Drs. Zahl, Maehlen, and his colleagues did.
In essence, they took advantage of a change in the routine screening protocol in Norway. In 1996, the Ministry of Health and Care Services initiated the Norwegian Breast Cancer Screening Program, in which women between the ages of 50 and 64 were invited to undergo a two-view biennial screening program. The women in this study who make up the “screened” group thus underwent a first round of screening mammography in 1996-1997, a second round in 1998-1999, and a third round in 2000-2001. The control group consisted of women (age range 50-69 years) who would have been invited to participate in the screening program between 1992 to 1997, had the Norwegian Breast Cancer Screening Program existed then. (If you’re interested in the details, the study is available free online.) These women only underwent one screening mammogram at the end of their six year period, compared to the three mammograms the women in the screened group underwent. One thing that’s impossible for me not to mention here is that this is thus a retrospective study and therefore prone to all the problems to which retrospective studies are prone. However, in the case of this study, the screened and control groups are about as well matched as can be done, but never forget that there could be biases inherent in the retrospective study design that can be very hard to ferret out.
Having settled on the two groups, Dr. Zahl then looked at how many diagnoses of breast cancer were made in each group, and they excluded non-invasive (or preinvasive) breast cancer, more commonly referred to as ductal carcinoma in situ (DCIS). Instead, they concentrated only on invasive carcinoma. The screened group had 22% more diagnoses of invasive carcinoma than the group that only received one screening test at the end of a six year period. The authors make a fairly strong argument that the additional invasive cancers in the screened group are unlikely to be explained by better cancer ascertainment with time (ascertainment was excellent for the entire time period covered by the study); increasing sensitivity of mammography (estimated sensitivity and specificity were not significantly different at the beginning of the study time period compared to the end); an increase in the actual incidence of breast cancer (highly unlikely over a six year period, and an increase in the underlying incidence of breast cancer could only explain at most 4% of the observed difference); or hormone replacement therapy, which does confer an increased risk of breast cancer.
Instead, the authors’ favored explanation is regression of some tumors. This is where, I believe, their argument is least convincing, at least to me: They disregard the possibility of stable tumors that do not progress. True, they do posit what they call an “extreme” case, where 50% of breast tumors are stable and are picked up with 50% sensitivity on each round of screening and show that such a case can at most account for the 22% excess number of breast cancers in the screened group, the implication being that their case is so “extreme” that it makes an explanation of stable cancers that do not progress seem very unlikely. However, what they neglect is the case where far more than 50% of breast tumors are stable, which may be the case, at least if the autopsy series I reference above is correct. In that case, it would be quite easy to postulate an explanation where stable cancers, coupled with increasing quality of mammography, could result in an apparent 22% excess number of cancers diagnosed in the screened population. However, I’m not so convinced that that “extreme” case is all that extreme. Even so, I am also not dismissing Dr. Zahl’s contention that 22% of mammographically-detected breast cancers spontaneously regress, either. What I am arguing is that it is doubtful that all 22% of tumors detected in the screened group must have regressed.
There are also methodological problems with Dr. Zahl’s trial to contend with, as an accompanying editorial by Drs. Robert Kaplan and Franz Porzsolt points out:
Because the study by Zahl et al2 was not a randomized clinical trial, methodological concerns may lead to other explanations for these findings. One possibility is that the larger number of mammograms in the multiple screen group could account for the differences. We know, for example, that between 20% and 30% of visible lesions are overlooked. Studies suggest that detection rates are higher if films are reviewed by multiple radiologists. One study showed that among 108 radiologists, there was a range of 40% in the sensitively for detecting breast lesions.12 Women who have had 3 consecutive mammograms may be up to 20% more likely to have a positive result on 1 of the 3 tests. However, the study by Zahl et al2 included 1 additional screen in each group. If the multiple vs single screen explanation is correct, we should have seen a narrowing of the difference between the 2 groups following the additional screen. That did not occur. Furthermore, if we assume that tumors missed in early screens continue to progress, they should have showed up in the tumor registry. They did not. The design of the study has many imperfections, but we should not overlook its strengths. It was population based, it had very high participation, and the outcomes were well documented in an independent tumor registry. Considering the strengths and weaknesses of the methodology, the findings should not be dismissed.
Another reason not to disregard the findings of Zahl et al is that they are consistent with several observations that have troubled investigators for years. For example, randomized clinical trials rarely show the benefits of screening, particularly for women younger than 50 years. The Canadian National Breast Screening Trial hinted of spontaneous regression, and the Wisconsin Breast Cancer Epidemiology Simulation Model required a concept like spontaneous regression to account for observational data. Although the findings of Zahl et al seem counterintuitive, the spontaneous regression hypothesis is difficult to rule out.
Indeed it is, although Drs. Kaplan and Porzsolt overstate the difficulty in finding a survival advantage due to mammographic screening, which in women over 50 is pretty clear, less so in women 40-50 years of age. In any case, the only sure-fire way to rule the hypothesis in or out would be a randomized clinical trial because any such trial designed to answer the question of whether some breast cancers undergo spontaneous regression would require that a significant number of women with diagnosed breast cancer go without treatment. Any such trial would clearly be unethical, because even if this study is correct and roughly one in five breast cancers detected on mammography will regress, that still means that four out of five cancers will progress, meaning that withholding treatment from women with breast cancers detected on mammography would have an 80% chance of resulting in harm in terms of delaying therapy. This means that the real question is not whether some percentage of breast cancer patients didn’t actually require therapy. It’s very likely that some small percentage don’t, although I tend to think that Zahn et al overestimate the level of overdiagnosis, given multiple previous studies suggesting it to be considerably lower. The question is what the risk-benefit ratio is. It also has to do with patient choice and what her tolerance for risk is. After all, if we were to come up with a test that could predict which tumors were likely to regress (or at least not to progress), there would still be a chance of the test being wrong and the tumor’s progressing. Watchful waiting as a management strategy for such tumors may not sit well with patients, many of whom are so terrified of breast cancer that they would rather undergo invasive procedures to biopsy mammographic abnormalities, even when the likelihood of cancer is low. Some will even demand bilateral mastectomies for small tumors that could easily be treated with lumpectomy.
Oddly enough, Sherry seems to recognize this implicitly in NaturalNews.com, although I must confess her next sentence has to be the closest I’ve ever seen to sanity on Mike Adams’ woo-fest, something that utterly shocked me when I read it:
This does not mean breast cancer should be ignored or not treated. After all, breast cancer is the second leading cause of death among American women. But the extraordinarily good and hopeful news is that it appears invasive breast cancer sometimes can be destroyed naturally — at least in some people — by the body’s own innate defenses.
I never thought I’d say this, but an article on NaturalNews.com has been out-cranked by Dr. Fuhrman. In any case, it may also be that a significant fraction of the breast cancer that develops, the exact percentage of which is currently unknown, is biologically not very aggressive and simply never progresses. Alternatively, there may be a factor, either in the host or the surrounding tissue in which the tumor is developing, that is required for progression to continue, and without it tumors cannot be sustained and therefore regress. Indeed, it may even have something to do with my area of expertise, angiogenesis. And it is a hopeful sign. If we could understand what makes some minority of cancers remain dormant or regress, we might be able to apply that to treating patients.
One thing about this particular study, though, that woo-meisters may not like very much is that, if true, it may provide an explanation for even more of the ever-ubiquitous “alternative” medicine breast cancer testimonials. Indeed, if Dr. Zahn’s results hold up, though, there is one rather interesting implication, and that is with regards to “alternative” medicine modalities that, it is claimed, treat breast cancer. Very early on in the history of this blog, I wrote a post that described how it can appear that “alternative medicine” that is completely ineffective can nonetheless lead to the appearance of efficacy and thus to “testimonials” by some women about how they were “cured” by “alternative” medicine. In essence, many breast cancers are cured by surgery alone, which can consist of the excisional biopsy that diagnosed the cancer in the first place, if the biopsy completely removed the cancer. The addition of radiation therapy and chemotherapy are “icing on the cake,” so to speak, in that they decrease the risk of recurrence but are not the primary cure. In cases where patients undergo surgical excision of their breast cancers but eschew chemotherapy and/or radiation in favor of “alternative” medicine, they almost always attribute their survival to the alternative medicine rather than the surgery alone. After all, surgery is a nasty and brutally “primitive” and “disfiguring” business, and in the world of alt-med it can’t possibly be of value, can it?
Now add to this a facet of breast cancer biology in which 20% or more of mammographically detected breast cancers spontaneously regress. If true, this observation could explain an additional set of breast cancer “testimonials,” in which the woman giving the testimonial had a needle biopsy but never underwent curative surgery. Indeed, if Dr. Maehlen is correct and one in five mammographically detected breast cancers do actually spontaneously regress, that would be a major addition to the pool of women who gambled with “alternative” medicine to treat their breast cancer and ended up being one of the lucky one in five. Indeed, if Dr. Mahlen’s results hold up, he may well have done skeptical physicians an unwitting service by providing another potential explanation for the ever-ubiquitous breast cancer “alt-med” testimonial, his exceedingly unfortunate choice of the term “pseudocancers” to describe the additional cancers picked up by mammography notwithstanding.
The bottom line is that the matter of screening mammography is far more complex an issue than it is often portrayed to be. It’s a matter of balancing the benefits of detecting cancer at an earlier stage versus the risk of overdiagnosis. Moreover, it is quite possible that a significant proportion of breast cancers detected by mammography (although, I hasten to add, not cancers detected as palpable masses) may indeed regress. The problem is that we do not yet know enough to identify which tumors will progress and which may not. Even under the most optimistic scenario, in which Dr. Mahlen’s study is confirmed, four out of five breast cancers will progress and become life threatening. Those are not odds that I would want to mess with, unless someone can develop a predictive test that allows me to identify cancers that it’s safe to subject to watchful waiting to see if they regress. Unfortunately, there ain’t no such beast, but I’m optimistic that there may well be before my career comes to an end. In the meantime, the complexities involved in determining the efficacy of any mass cancer screening program provide an excellent example of just how difficult getting answers in science-based medicine can be. Between the ethical problems that make a gold standard trial impossible, the variable biology of breast cancer, and the imperfections in screening tests, science-based medicine is hard. It’s always risk/benefit analyses and shades of gray. Perhaps that’s why quackery is so attractive. There isn’t all that messy dealing complicated and sometimes conflicting science and evidence and trying to apply them to patients.
REFERENCE:
Per-Henrik Zahl, MD, PhD, Jan Mæhlen, MD, PhD, H. Gilbert Welch, MD, MPH (2008). The Natural History of Invasive Breast Cancers Detected by Screening Mammography Archives of Internal Medicine, 168 (21), 2311-2316
