Phenylketonuria screening: clearly beneficial

Newborn babies are routinely screened for an inherited disease called phenylketonuria (PKU). Babies with PKU are unable to process phenylalanine, a substance which is present in everyday foods such as milk, meat, fish, and eggs. If the condition is left untreated, phenylalanine accumulates in the blood and leads to serious, irreversible, brain damage. PKU testing involves taking a few drops of blood from the baby’s heel, which are analyzed in a laboratory. If this ‘heel prick test’ is positive, and the diagnosis is confirmed by further tests, babies are treated with a special diet to help them develop normally.

Abdominal aortic aneurysm screening: proceed with care

At the other end of the age spectrum, abdominal aortic aneurysm screening can also be beneficial. The aorta is the main blood vessel in the body, running from the heart through the chest and abdomen. In some people the wall of the aorta in the abdomen weakens as they become older and the vessel starts to expand – this is an aneurysm, a condition that seldom gives rise to symptoms and is most common in men aged 65 and over. Large aneurysms can eventually rupture and leak without warning, often causing death.⁸

This evidence concerning the frequency of aneurysms in older men can be used as the basis for introducing a screening programme. In the UK, for example, men (but not women) as they turn 65 are being offered a screening ultrasound scan. The scans can show the large aneurysms so that these men can receive specialist advice and treatment, usually surgery. Men with smaller aneurysms are monitored by further scans, and those whose aorta is not enlarged need not be screened again. The quality of the screening and the surgery is crucially important. Aneurysm surgery is a major procedure and if complication rates are high then more men would be harmed than helped.

Breast cancer screening: well established but remains contentious

Since routine breast screening with mammography is well established in many countries one could well assume that mammographic screening must be based on sound evidence of benefits outweighing harms. As one US public health expert remarked in 2010: ‘No screening test has ever been more carefully studied. In the past 50 years, more than 600,000 women have participated in 10 randomized trials, each involving approximately 10 years of follow-up’. But he went on to say ‘Given this extraordinary research effort, it is ironic that screening mammography continues to be one of the most contentious issues within the medical community’.⁹

Why is mammographic screening so contentious? A fundamental reason is that it has been ‘sold’ to women as a sensible thing to do by those providing screening and by patient groups. The information provided to women who are invited for breast screening emphasizes the benefits while glossing over the harms, limitations, and consequences.¹⁰ Yet mammography not only leads to early diagnosis but also, much as with prostate cancer (see below), to diagnosis of cancers that would never have become apparent in a patient’s lifetime. And inevitably there will be false-positive results too.

The most reliable evidence comes from reviewing, systematically, the results of clinical trials in which women have been randomly allocated to screening or no screening. And the results make for interesting reading. They show that if 2,000 women are screened regularly for ten years, one will benefit from screening, as she will avoid dying from breast cancer. But at the same time, ten healthy women will, as a consequence of screening, become ‘cancer patients’ and will be treated unnecessarily. Mammography in these women has in fact detected lesions that are so slow-growing (or even not growing at all) that they would never have developed into a real cancer. These healthy women will go on to have either part of their breast removed, or even the whole breast, and will often receive radiotherapy and sometimes chemotherapy.¹¹

Furthermore, 200 screened women out of 2,000 will experience a false alarm, and the psychological strain until the woman knows whether it was cancer, and even afterwards, can be severe. And mammography is often promoted to women alongside advice on breast self-examination or breast awareness, when both these methods have also been shown to result in more harm than benefit.¹²

A British public health expert noted that the potential for individual benefit from mammography is very small. He remarked: ‘this is not widely understood. In part this is due to obfuscation from organisers of mammography services assuming that a positive emphasis is needed to ensure reasonable compliance [with screening]’. Assessing the available evidence in 2010, he commented: ‘Mammography does save lives, more effectively among older women, but does cause some harm.’ The harms he is referring to are overdiagnosis and false positives. Critically, he observed that full examination of all the individual results from recent screening studies had yet to be examined dispassionately.¹³ While such an impartial evaluation is awaited, women continue to be invited for mammographic screening. At the very least, they need to be given sufficiently balanced information to enable them to decide (together with their family and their doctor if they wish), whether to attend for screening – or not.

Prostate cancer screening: clear harms with uncertain benefits

Prostate cancer is the second most common cancer in men worldwide,¹⁴ and broadly falls into two types. Some men have an aggressive form of the disease; these dangerous cancers spread rapidly and the death rate is high. But many men have slow-growing cancers that would never progress to cause a danger to health during a man’s lifetime. Ideally, a screening test would detect the dangerous cancers – with the hope that they could be treated – but not the slow-growing ones. The reason is that treatment of any sort of prostate cancer risks distressing side-effects such as incontinence and impotence – a heavy price to pay if the cancer would not have caused problems in the first place.¹⁵

Blood levels of a substance called prostate-specific antigen (PSA) are raised in most men with prostate cancer. However, there is no clear cut-off level that will distinguish between men who have cancer and those who do not,¹⁶ and as many as one in five men with clinically significant cancers will have normal PSA levels. Moreover, despite its name, PSA is anything but ‘specific’ – for example, non-cancerous prostate tumours, infections, and even some over-the-counter pain-killers can cause raised PSA levels. On these grounds alone, PSA clearly has serious limitations as a screening test.

Yet routine PSA testing of healthy men has been enthusiastically promoted for prostate cancer screening by professional and patient groups and by companies selling the tests, and has been widely adopted in many countries. The pro-PSA-screening lobby has been especially vocal in the USA, where it is estimated that, each year, 30 million men are tested, believing that this is the sensible thing to do. So what is the evidence that earlier detection of prostate cancer with PSA screening improves a man’s outcome; and what is known about harms associated with testing?

High-quality evidence about the benefits and harms of PSA screening is now becoming available. In 2010, the results from all relevant trials were systematically reviewed. This assessment showed that, although PSA screening increased the likelihood of being diagnosed with prostate cancer (as would be expected), there was no evidence of an impact on either the rate of death from the cancer or the overall death rate.¹⁷

So, is the tide turning against PSA screening? Richard Ablin, the discoverer of PSA, certainly thinks it should and has been saying as much for years. Writing in 2010, he commented ‘I never dreamed that my discovery four decades ago would lead to such a profit-driven public health disaster. The medical community must confront reality and stop the inappropriate use of PSA screening. Doing so would save billions of dollars and rescue millions of men from unnecessary, debilitating treatments’. At the very least, any man, before undergoing PSA testing, should be informed of the test’s limitations and possible adverse consequences. As one group of experts noted: ‘[men] should be advised that the test cannot tell [them] whether they have a life-threatening cancer but that it could lead them through a thicket of tests and treatments that they might have better avoided’.¹⁸

Lung cancer screening: early but not early enough?

Screening may detect disease earlier, but not always early enough to make a difference (see Figure).

Growth and spread of lung cancer in heavy smokers

Some cancers, for example lung cancer, spread within the body before the patient has any symptoms and before any tests can detect the presence of the cancer. Attempts to detect lung cancer by the use of chest X-rays illustrate this problem (See stage B in Figure). In the 1970s, several large studies in heavy smokers showed that, although the cancers were detected earlier, there was no evidence this led to a decrease in deaths from the disease. The lung cancers detected on the X-rays had already spread beyond the lungs. So, these patients lived longer with their cancer diagnosis and were treated earlier, but there was no evidence that it made any difference to their life expectancy.

More recently, a large randomized trial involving 53,000 current and former heavy smokers compared chest X-ray screening with screening by a special sort of computed tomography (CT) scan called a spiral CT. Both groups were assigned to three annual screening procedures. Spiral CT diagnosed lung cancers at an even earlier stage than did chest X-rays, and in a small proportion of patients this was sufficiently early (stage A in Figure) for treatment to be of benefit (346 deaths from lung cancer in the spiral CT group vs 425 in the chest X-ray group). But this beneficial outcome came at the expense of a large proportion of people wrongly labelled with lung cancer. Overall, for every 1,000 heavy smokers who had three annual X-rays or scans, over eight years of follow-up, three fewer died of lung cancer. But 13 still died of lung cancer despite earlier detection, and 233 received a false-positive result that required further investigation.¹⁹

Genetic tests: sometimes useful, often dodgy

Not so long ago ‘genetic testing’ was more or less confined to generally rare, single-gene disorders – for example, the childhood-onset muscle-wasting disease Duchenne muscular dystrophy, or Huntington’s disease, a progressive nervous system disorder that usually starts to affect people in middle age. Genetic tests are done to diagnose such conditions but can also be used to screen healthy people whose family history indicates that their chances of developing the disorder in question are above average, and to guide their family plans.

However, most diseases cannot be attributed to a single faulty gene. Usually, diseases depend on the way in which risk variants in several genes interact, and on the interaction of these genetic risk variants with environmental factors. Only when there is a ‘critical’ combination of genetic risk variants and environmental factors will a disease become apparent.¹

Despite the complexity of ascribing most conditions to aberrant genes, media and promoters of direct-to-consumer genetic testing extol the supposed virtue and simplicity of genetic risk profiling. All you need to do is send off a saliva sample to a company for DNA analysis and they will take your money and send you your profile. But the information you receive is unlikely to help you – or your clinician – make any sensible predictions about your risk of disease, let alone what might be done about it, if anything. This ‘do-it-yourself ’ approach clearly does not meet the criteria for a useful screening test (see below). However, the result may well make you anxious and decision-making difficult, and may have wider implications too – on members of your family, for example. As one Australian health journalist put it ‘For anyone concerned about the creeping medicalisation of life, the marketplace for genetic testing is surely one of the latest frontiers, where apparently harmless technology can help mutate healthy people into fearful patients, their personhood redefined by multiple genetic predispositions for disease and early death.’²⁰

What screening aims to achieve and why evidence matters

The examples we have already given show that, before rushing headlong into widespread screening, it is worth pausing a moment to consider the key features of screening programmes and to remind ourselves what they aim to achieve. People being offered screening do not have, or have not noticed, the symptoms or signs of the condition being tested for – they have not sought medical attention for the disorder in question. The purpose of screening individuals or populations is to reduce the risk of death or future ill health from a specific condition by offering a test intended to help identify people who could benefit from treatment.^{1, 21} The aim of screening is not simply to diagnose disease earlier – this may not help anyone and it can even do harm.

The basic criteria for assessing the value of screening tests were outlined in a World Health Organization report in 1968.²² These criteria have been further refined to reflect the way in which healthcare is delivered today. People invited for screening need sufficient, balanced information about the test being offered – including possible harms, consequences, and limitations, as well as potential benefits – so that they can make an informed choice. Essentially, the key points can be summed up by saying don’t screen unless:

• The condition being screened for is important in terms of public health – for example, it is serious and/or affects large numbers of people
• There is a recognizable early stage of the condition
• There is an effective and acceptable treatment for the condition, so screening is likely to make a difference to its outcome
• There is a valid and reliable test for the condition that is acceptable to people being offered screening
• The screening programme is of good quality and cost-effective in the setting in which it is to be offered
• The information provided to people is unbiased; based on good evidence; and clear about possible harms (eg, overdiagnosis leading to over-treatment) as well as potential benefits
• The invitation for screening is not coercive – that is, it indicates it is reasonable to decline
• The chance of physical or psychological harm to those offered screening is likely to be less than the chance of benefit
• There are adequate facilities for the diagnosis and treatment of abnormalities detected by screening

These criteria reinforce our message at the beginning of this chapter: that any decision to introduce a screening programme should be based on good-quality evidence not only about its effectiveness but also about its potential for doing harm.

Whole-body CT scans

Among the tests on offer at private clinics are whole-body computed tomography (CT) scans to look at head, neck, chest, abdomen, and pelvis. They are offered directly to the public, and usually done without reference to the person’s general/primary care practitioner. Whole-body scans are often promoted as the way to keep one step ahead of possible illness, with the premise that a ‘normal’ result will be reassuring. Not only are these scans expensive, but also there is no evidence that any overall health benefit is achieved by doing these tests in people without symptoms or signs of disease.

Moreover, the radiation exposure is considerable – as much as 400 times more than a chest X-ray. So much so that in 2007 the UK’s Committee on Medical Aspects of Radiation in the Environment (COMARE) strongly recommended that ‘services’ offering whole-body CT screening of asymptomatic individuals should discontinue to do so.

In 2010, after consultation, the Government announced its intention to introduce tougher rules for using whole-body scans. Similarly, the US Food and Drug Administration has warned the public that these scans have no proven benefits for healthy people, commenting ‘Many people don’t realize that getting a whole body CT screening exam won’t necessarily give them the “peace of mind” that they are hoping for, or the information that would allow them to prevent a health problem. An abnormal finding, for example, may not be a serious one, and a normal finding may be inaccurate.’ ^{23, 24, 25}

Striking a balance

Striking a balance between over-zealous trawling for disease and failing to identify those people who may benefit from early detection is never going to be easy, and will inevitably lead to unpopular decisions. All healthcare systems need to use their resources thriftily if the whole population is to benefit. This fundamental principle surely means that screening programmes must not only be based on sound evidence when they are introduced but also kept under review to check whether they are helpful as more evidence accrues and circumstances change. A serious consideration is whether screening programmes should be offered to large sectors of the population or more targeted towards those at high risk of a condition.