When they were introduced over 20 years ago, national breast screening programs were a milestone in public health. They were based on evidence from randomised trials that screening saved lives. But there are now serious doubts about what these programs can and have achieved.

The first major challenge came with the Cochrane Collaboration’s review of the benefits and harms of breast cancer screening in 2001.

At that time, publication was delayed while the Cochrane reviewers and authors sorted out their differences. Meanwhile, The Lancet published the review, triggering a heated debate about the value of breast cancer screening that has continued ever since.

The latest update of the review, however, went quietly by.

In 2001, reviewers Peter Gotzsche and Ole Olsen pronounced mammography screening “unjustified” on the evidence from randomised trials. But an editorial in the same edition of The Lancet challenged their assertion.

It noted that:

Evaluation of the outcome of cancer screening at a national level is very much a long-term proposition.

In the latest update, the summary from all the available randomised trials of mammography screening hasn’t changed much. That’s because, in the intervening decade, the result of only one more trial has been published.

This hasn’t changed the bottom line: taken together, the eight randomised trials found screening reduced breast cancer deaths by about 20%. But the three best-quality trials did not show a significant reduction, even after following up for 13 years.

What is new in this review is a discussion of the evidence about breast screening that’s accumulated from other sources since screening became common practice.

Does breast screening save lives?

First, it’s clear that breast cancer treatment has advanced significantly in the last few decades. A 2012 meta-analysis found that polychemotherapy can reduce breast cancer deaths by about one third, and earlier work demonstrated the benefits of hormone therapy.

A 2012 study assessing the impact of screening in Australia found that advances in treatment (rather than screening) were primarily responsible for the decline in breast cancer deaths seen over the last 20 years.

So it’s plausible that screening isn’t as necessary now as it was back in the 1960s to 1980s, when most of the randomised trials of screening began.

What’s more, there’s a very mixed picture emerging from non-randomised (observational) studies of screening, including screening program evaluations. BreastScreen Australia (established in 1991) reports that the national screening program has reduced breast cancer deaths by between 22% and 30%. It notes that the biggest effects are in areas where participation in screening is greatest.

This is at odds with the Australian study described above. There, researchers found the benefit happened too early (before breast screening was fully implemented) to be attributed to screening, and was greatest among women between the ages of 40 and 49, who have the lowest participation in screening. It was lowest among women aged 60 to 69 years, who have the highest participation in screening.

The Cochrane review outlines a similarly confused picture from international observational studies. Some claim screening has delivered expected declines in breast cancer deaths across Europe, the United Kingdom and the United States.

A US analysis, for instance, estimated that between 28% and 65% of the decline in breast cancer mortality is due to screening with the rest coming from better treatment.

But other studies show that declines in breast cancer death rates have been just as great or greater among women too young for screening, or in areas where screening has been limited or not provided at all. Increased breast cancer awareness – or hyperawareness – may also play a part.

If screening works, it must do so by picking up breast cancers earlier so that there should be a drop in the rates of advanced breast cancer, as well as a drop in deaths. But there has been only an 8% decline in the rate of advanced (late stage, or metastatic) cancer in the United States over the last 30 years. This suggests that screening is having, at best, a small effect.

This something is better than nothing, right? Not quite, because breast screening can also cause harm.

How much harm does breast screening cause?

The randomised trials did not adequately measure the harms of breast screening. For the most part, they didn’t measure them at all. But evidence of harm has been steadily accumulating.

The main harm is through over-diagnosis: harmless breast cancers found by screening are treated when without screening they wouldn’t have been found at all.

In contrast to the small decline in advanced cancer rates, early-stage breast cancer rates have doubled over the last 30 years, strongly suggesting over-diagnosis. An estimated 1.3 million US women are thought to have been over-diagnosed due to screening.

The impact on these women’s lives, on the lives of their families and the social and economic effects of over-diagnosis is worth serious consideration.

While the frequency of over-diagnosis is still contested (estimates range from one-and-a-half to ten over-diagnosed cases for every breast cancer death prevented), its existence has been documented in countries including Canada, France, Australia, Norway and Sweden.

Advocates of screening point out that even if some women are over-diagnosed, the side effects of early breast cancer treatment (surgery, radiotherapy, hormone therapy and chemotherapy) are worth it. Better to be safe than sorry.

But evidence of unexpected side effects is also growing. We know now that radiotherapy increases women’s risk of having and dying from heart attacks five to 20 years after treatment. It also increases the risk of lung cancer.

Late effects of radiotherapy are important as most women with breast cancer have radiotherapy, and live for many years after it. It’s especially important in light of over-diagnosis of screened women in their 50s and 60s.

This uncertain picture of breast screening from 20 years of observational (non-randomised) studies isn’t surprising. Observational studies provide only “silver medal” evidence about the benefit and harms of screening because they are very susceptible to bias.

In particular, they suffer selection bias – comparing groups of screened and unscreened women who are different in key ways, such as their risk of breast cancer, use of hormone replacement therapy, and lifestyle factors including diet, obesity, reproductive lives and alcohol consumption.

This can lead to misleading conclusions about how many lives are saved by screening and how many cases of over-diagnosis are caused.

Observational studies are also liable to length bias (the tendency of screening to find slow-growing cancers that have excellent prognosis, contributing to over-diagnosis) and lead-time bias (screening finds cancers earlier but may just advance the time of diagnosis rather than prevent death, giving people more “disease time” but no extra years of life).

These are prone to make screening look more effective than it really is.

This is why both the UK Independent Breast Screening Review Panel and the Cochrane Review continue to rely on the older randomised trials that date back to the 1960s. They may be old, but these randomised trials at least provide evidence with a much lower risk of bias.

What do we do now?

It’s 50 years since the first breast screening randomised trial began, and ten years since the first Cochrane review spoke strongly of screening’s harms.

Evaluation of national breast screening programs has clearly been a long-term proposition but one that has failed to resolve our most important questions: does screening work today? And how much over-diagnosis does it cause?

It’s time to acknowledge the true depth of our uncertainty about both the benefits and the harms of breast cancer screening as it is practiced today.

To resolve these questions, we need to do new randomised trials of modern breast cancer screening. New trials are needed because the practice (the quality of mammographic imaging has improved) and context (breast cancer treatments are so different now) of screening has changed so much that we can’t reliably apply the results of the old trials any more.

And we need to do randomised trials because more than ever we need “gold medal” evidence – 20 years of observational studies has proved that observational studies are just not good enough to answer our fundamental questions about modern screening.

The forthcoming expansion of screening to women aged between 70 and 74 is a rare opportunity for Australia to do just this. We may manage to find data that will be valued by the rest of the world

Not content with saving lives, doctors are now credited with (accused of?) bringing the dead back to life. But how true are the stories we hear about people “coming back” from being dead and how does it work?

Here’s a definition of death that gets to the heart of why this is all very complicated:

Death: 1. The end of life. The cessation of life. (These common definitions of death ultimately depend upon the definition of life, upon which there is no consensus.)

Cardiopulmonary resuscitation (CPR), first popularised in the 1960s and widely taught to both first responders and the general public, prevents many deaths across the world.

But it doesn’t bring dead people back to life. And the distinction is an important one.

The problem can be easily stated – death is a process, but is forced to be an event. Organisms die in a piecemeal manner, with the most vulnerable bits going quickest.

Some residual function can be found up to several hours past the point where the heart has stopped beating (though, contrary to myth, the fingernails do not continue to grow).

Why “when” is important

But there are cogent medical, legal and philosophical reasons for death to be considered an event.

Medically, there has to be a moment at which attempts to prolong life should cease (organ donation being a rare but important reason). Organ donation puts great pressure on doctors to define a moment of death. This is to honour the “dead donor rule”, which states that only dead people can be donors.

Legally, time of death is important for determining who out-survived whom, and thus how the deceased person’s possessions will be distributed.

Philosophically, it appears, at least to some, that the categories “alive” and “dead” are to have no overlap. Consider this from a research paper about defining death:

If we regard death as a process, then either the process starts when the person is still living, which confuses the “process of death” with the process of dying, for we all regard someone who is dying as not yet dead, or the “process of death” starts when the person is no longer alive, which confuses death with the process of disintegration.

Hmmmm.

Now we have a problem: we need to know what death is, and we need irrefutable tests to prove it. How are we doing?

Kinds of death

Obviously, it all got much harder when laws were introduced that defined two distinct kinds of death – circulatory (traditional) death and the new kid on the block, brain death.

These laws were introduced in Australia in the early 1980s to legitimise brain death as a form of dying. This had the benefits of allowing treatment withdrawal and permitting organ donation without breaking the “dead donor rule”.

Circulatory death is the “irreversible cessation of circulation of blood in the person’s body”, while brain death is the “irreversible cessation of all function of the person’s brain”.

Many researchers are scrambling to unify these two definitions, by asserting that loss of circulation would inevitably cause irreversible cessation of all brain function.

But, given that we don’t know how long the circulation has to stop before we can be confident that all brain function has stopped in all cases, it seems we are stuck with two definitions for now.

The operative word in each definition is irreversible. The reason why CPR, however prolonged and enhanced by new technologies, does not bring people back to life is that clearly the cessation of circulation and brain function are not irreversible.

So people who are “brought back to life” were, in retrospect, not dead in the first place.

Who is responsible?

But seemingly miraculous results from CPR do pose a serious challenge: how are we then to be certain that cessation of function is irreversible?

The law is steering clear of getting involved in Australia, and the decision is delegated to doctors. This was challenged in a legal case but the law, as it stands, was confirmed.

Irreversible loss of brain function does have a set of tests that appear extremely reliable, as long as they are properly conducted. And nobody declared brain dead in Australia has ever lived to tell the tale.

Irreversible loss of circulation is more difficult to certify, and has been brought into sharp focus by the re-introduction of organ donation after circulatory death, which demands both high certainty and an exact time of death.

Organ donation after circulatory death has become widespread in Australia over the past ten years as a response to the very low numbers of donors, and now accounts for about 25% of all donors.

What we know empirically is that a heart that has stopped will not spontaneously start again after quite a short time (so-called autoresuscitation).

So cessation of circulation is permanent, but is it irreversible? It is, but only in one context; a morally and medically defensible decision not to keep trying to reverse it.

Such decisions are commonplace in modern medical practice (the no-CPR or “Do Not Resuscitate” order), and have a history almost as long as CPR itself.

There are people who cannot be, should not be, or do not want to be resuscitated. For them, permanent loss of circulation is irreversible. For the rest – go for it!

There is only one effective treatment for hot flushes – oestrogen. The way we use it now is much safer than in years gone by. Hot flushes are called vasomotor symptoms in medical speak. I don’t know why they cannot call a “hot flush” a hot flush. Doctors like to use fancy sounding words to confuse our patients, and to show how clever we are.

Non-hormonal management of vasomotor symptoms.

Can exercise-related improvements in immunity influence cancer prevention and prognosis in the elderly?

Abstract

Cancer incidence increases with advancing age. Over 60% of new cancers and 70% of cancer deaths occur in individuals aged 65 years or older. One factor that may contribute to this is immunosenescence – a canopy term that is used to describe age-related declines in the normal functioning of the immune system. There are multiple age-related deficits in both the innate and adaptive systems that may play a role in the increased incidence of cancer. These include decreased NK-cell function, impaired antigen uptake and presentation by monocytes and dendritic cells, an increase in ‘inflammaging’, a decline in the number of naïve T-cells able to respond to evolving tumor cells, and an increase in functionally exhausted senescent cells. There is consensus that habitual physical exercise can offer protection against certain types of cancer; however the evidence linking immunological mechanisms, exercise, and reduced cancer risk remain tentative. Multiple studies published over the last two decades suggest that exercise can mitigate the deleterious effects of age on immune function, thus increasing anti-cancer immunity. The potential ameliorative effect of exercise on these mechanisms include evidence that physical activity is able to stimulate greater NK-cell activity, enhance antigen-presentation, reduce inflammation, and prevent senescent cell accumulation in the elderly. Here we discuss the role played by the immune system in preventing and controlling cancer and how aging may retard these anti-cancer mechanisms. We also propose a pathway by which exercise-induced alterations in immunosenescence may decrease the incidence of cancer and help improve prognosis in cancer patients.

Spot the problem in this scenario. Richard* is stressed. While he’s a high-flyer (a Rhodes Scholar no less), he’s under the pump at work and has just moved his family across nations. The job is taking more than it’s giving back. He’s in a dark place – very down, unmotivated, ill-humoured and lacking energy – so oblivion seems enticing. Worryingly, he also has a family history of depression.

Richard visits his family doctor who refers him to a psychiatrist. So far, this is unremarkable – as depression management goes.

With relief, Richard enters the psychiatrist’s plush rooms, sighs, and prepares to unburden himself and submit to wise counsel. But he’s in for a surprise. Within minutes he’s told he has depression, needs medication, and will likely do so for life. He leaves with sample pack of antidepressants in hand, and troubles still firmly packed in kit bag.

If you’re like me, you see the problem quickly. Richard, and around 70% of the people who share his diagnosis, can implicate a psychosocial stressor in the genesis of his depression. But his doctor has failed to identify and address it, even though stressor-focused treatments are available.

Drug-free alternatives

Evidence-based psychotherapy, in particular cognitive behaviour therapy (CBT), is as effective as medication in the common, lesser grades of depression. You read that correctly – CBT is as good as drugs at relieving the lowered mood, hopelessness, fatigue, guilt, and poor concentration that figure in the depressive diagnostic checklist.

And not only does psychotherapy reduce psychic distress, it also tackles stressors. In addition, CBT tutors healthy scepticism about the negative perceptions that pepper the depressive psychological landscape. Such ideas cause undue pessimism and arise, almost always, from biased information processing. Challenging negative thoughts is a critical element in the therapeutic success of CBT.

Incredibly, doctors who fail to unearth and address stressful life events, or guide a stance of scepticism to negative thinking, do nothing untoward. While recent guidelines laudably embrace a broader role for psychotherapy, depression initiative beyondblue still cites a publication that concludes, because drugs and psychotherapy are equally effective, really, either will do fine. As the authors of that paper state, it’s “not so much what you do but that you keep doing it”.

But is it really all right to just give people antidepressants? Does a doctor have a duty to do more, and provide psychotherapy?

For any other illness…

Try this thought experiment. You have abdominal pain and visit your doctor, who diagnoses gallstones and recommends an operation. You become increasingly anxious, agitated, and ultimately morose at the prospect of surgery. But the doctor has a pill for that – take an antidepressant and your fears will fall away so that you can bravely front up to surgery.

This scenario is laughable, of course. A doctor would never recommend antidepressants to foster acceptance of an unpalatable circumstance. Rather, the physician would explore your fears, determine what aspects of surgery concern you, and offer information about the pre- and post-operative processes.

In essence, the doctor would provide you with information that is material to your decision about surgery, enabling you to cope with your new circumstance and to work out which course is best. And in doing so your doctor conforms to an entrenched moral duty – to promote patient autonomy, that is, the ability to self-determine based on information that is critical to interests.

But, despite respect for autonomy being embedded squarely in the moral firmament of informed consent, it seems alien to many physicians that information, not just about treatment but that results from it could also be material.

Richard will, in all likelihood, believe it material to understand which stressor caused his depression, how best to address it, and how to simultaneously deal with his relentless negative thinking. To glean this, he needs psychotherapy, not just information about it.

And doctors know this. They already promote autonomy through a range of treatment regimes. Specialists in drug and alcohol rehabilitation supply crucial facts about limiting substance use, nutrition consultants advise overweight patients to diet and exercise, hypertension specialists provide strategies for reducing salt intake, and so on.

In each case, a treatment is recommended not just because it’s effective, but because it provides information material to crucial life choices.

And this is precisely why evidence-based psychotherapy ought to be provided to people with depression. Drugs may treat symptoms but they do nothing to help people navigate depression, appraise and manage stressors, or critique the validity of their negative thoughts. A prescription for antidepressants might fulfil a physician’s clinical duty of care on current guidelines, but drugs alone fall short in the moral domain.

What Richard did

Richard opted for the DIY solution. Luckily for him, he had a formidable analytical arsenal at his disposal, and his critical faculties had not been fatally routed. He rounded on his job as a noxious influence in his life and bravely resigned, to the amazement of his boss. The depression lifted, sans medication, in less than a month.

Recently, the black dog scratched at his door again. This time he was prepared, and confidently asked his new boss to cut back his workload a little. Most people are not endowed with such self-possession. What people with depression need are doctors prepared to pay more than lip service to autonomy and to provide psychotherapy in those common grades where evidence supports its use.

*Not his real name

Paul Biegler is the author of The Ethical Treatment of Depression: Autonomy through Psychotherapy (MIT Press 2011), which won the Australian Museum Eureka Prize for Research in Ethics.

If you think you may be experiencing depression or another mental health problem, please contact your general practitioner or in Australia, contact Lifeline 13 11 14 for support, beyondblue 1300 22 4636 or SANE Australia for information.

Brain Fog’ of Menopause Confirmed

Treatment of symptomatic uterine fibroids with green tea extract: a pilot randomized controlled clinical study.

Reduced breast cancer incidence in women treated with subcutaneous testosterone, or testosterone with anastrozole: A prospective, observational study.