Early detection of cancer

As a principle, the earlier in its natural history that malignancy is diagnosed and treated, the better the prognosis. The ideal would be to detect cancer before invasion or metastasis had occurred, i.e. during the pre-invasive stage. However, many cancers invade and spread before they reach a detectable size or produce tumour markers. Where true early detection is possible, health education can alert the public to early symptoms and warning signs. In skin and testicular tumours, this should include regular self-examination. Self-examination is still promoted for breast cancer but large trials have shown it to be ineffective and that it causes harm with more biopsies.

The common cancer killers are shown in Table 6.1, with bronchus still leading the field. Unfortunately, this disease does not fit criteria for screening, having no detectable early stage; attempts at screening have been uniformly ineffective.

In women, breast cancer is a huge public health problem, followed by carcinoma of the cervix and ovary. In men, prostate cancer is a large and growing problem. Colorectal cancer is common and evenly matched in frequency in both sexes in the UK; 30 000 new cases are detected each year and 16 000 die of it. Gastric and pancreatic cancers are also big killers but screening is of little value except in areas of exceptionally high incidence. In China, high-risk areas for oesophageal cancer have been identified and brush cytology without gastroscopy has proved beneficial.

Several genetic predispositions to cancer have been identified, e.g. polyposis coli for colorectal cancer and BRCA1 and BRCA2 for breast and other cancers. Genetic screening is not covered in this chapter but individual disorders are described in other chapters.

Cervical cancer

Poorly organised screening trials using cervical smears and Papanicolaou staining began in the UK in the mid-1960s and national screening started in 1988. Nearly all reports show early detection and treatment prevents 80–90% of invasive cervical cancers and has greatly reduced cervical cancer mortality. The International Agency for Research on Cancer (IARC) indicated that yearly screening between the ages of 25 and 64 reduces invasive cancer by 94%, 3-yearly screening reduces it by 91%, 5-yearly by 84%, and 10-yearly by 64%. These figures are the basis for the present UK policy—that yearly screening is unnecessarily frequent and 3- or 5-yearly screening is best.

In the UK, 4 million women are screened annually and 82% of the 14 million eligible women have been screened over the previous 5 years. The programme costs £150 million a year, amounting to £37.50 per screen. Both the number of invasive cancer cases and deaths from it halved between 1988 and 2005, taking the disease from sixth most common cancer in women to 13th.

British data show that about a quarter of all cervical cancers occur in each of the four age groups 25–39, 40–54, 55–69 and 70+ years but there are problems with recruiting young women and women from lower socio-economic strata. Both groups have been shown to be at higher risk. In a study from Hawaii in 2003, only 1 in 12 eligible women had not been screened in the preceding 5 years, but this small group accounted for two-thirds of the invasive cancers in the community. Thus there are real concerns that those at greatest risk are not being tested. In addition, those with positive results may not be treated effectively. Recent recommendations in the UK are that women should first be invited for screening at age 25. They should then be screened 3-yearly until 49 and 5-yearly from 50 to 64. Women of 65+ only need screening if they have not been screened since age 50 or a recent abnormality has been found.

A recent cost effectiveness study from Peru, India, Kenya, Thailand and South Africa indicates that a single screen (and treatment if necessary), employing testing for human papillomavirus (HPV) in cervical cells or visual inspection of the cervix after swabbing with acetic acid rather than a cervical smear is a cheap and effective way to reduce a woman’s lifetime risk by 25–36%. Types 16 and 18 HPV cause most cervical cancer worldwide and effective vaccines are now available. Two rounds of screening at 35 and 40 years could reduce lifetime risk by a further 40%. If screening were introduced across the developing world then the global incidence of cervical cancer could fall by about 50%. Ideally, all young women should be vaccinated against HPV with modern effective quadrivalent vaccines; this would virtually eliminate cervical cancer and the need for screening.

Ovarian cancer

Ovarian cancer screening is not yet reliable enough for general use, but a study of 200 000 women aged 50–74 were screened with transvaginal ultrasound (US) alone or with blood testing for the tumour marker CA125. Sensitivity for US + CA125 was 89% and specificity was 99.8%, both better than US alone. Only 84 cancers were detected overall in preliminary screening and 13 interval cancers were detected in the ensuing year.

Breast cancer

Mammographic screening for breast cancer was introduced nationally in the UK in the late 1980s following the Forrest report of 1986. Most developed countries followed suit after results from the HIP study of New York, the Swedish two-county study and the Canadian National Breast Screening Study. These appeared to demonstrate a 30% reduction in mortality from breast cancer in screened women. In the Swedish study, there was also a significant 13% reduction in all-cause mortality.

Mammographic screening detects breast cancers of smaller size than those presenting clinically, with around 30% either carcinoma in situ or invasive cancers less than 0.5 cm in diameter. A high proportion are node negative—only about 20% have axillary spread compared with 40% for symptomatic cancer. By detecting small lesions, screening substantially increases the reported incidence of invasive breast cancer. This might be expected to mean fewer new cases in later years, as prevalent cases would disappear from the population. In Norway and Sweden this has proved untrue, suggesting that screening is not detecting most of the clinically important cases that progress to become invasive or metastasise.

In any population of women with breast cancer, lesions will be at different stages of development and pathological potential. These may be grouped as follows:

Large trials have concluded that as many as one-third of cancers detected by screening would never have presented clinically.

The sensitivity of screening for clinically significant cancers is poor; in particular, lobular or mucinous cancers and some rapidly proliferating, high-grade tumours may not be detectable. This is illustrated by the high proportion of interval cancers presenting clinically between screening visits. In one representative series, 38% of all breast cancers presented as interval cancers. These tended to occur in younger patients with dense breasts and with a higher usage of hormone replacement therapy (HRT) or the oral contraceptive pill. A study in New South Wales estimated that screening over-diagnosed invasive cancer by 30–42% in women aged 50–69 and other studies have confirmed this. A Dutch study showed that false positives adversely affect quality of life for at least a year.

On the basis of tumour doubling times, breast cancers detected clinically have been present for an average of 8 years, whereas mammographically detected lesions have been present for about 6 years—a long period in which to metastasise. This may explain the failure of screening to increase the cure rate for clinically significant cancers, and also calls into question the political pressure for patients with suspected breast cancers to be evaluated within a very short time.

Colorectal cancer

Colorectal cancer is a major health hazard that kills 16 000 people a year in the UK; only about 10% are diagnosed early. Early cancers have survival rates of better than 90% but the all-stage 5-year survival rate of 35% has hardly improved despite treatment advances, because most cases present late. Nine out of 10 cases occur in people over 50.

Screening for colonic cancer has a good chance of being effective. It fulfils many criteria required for a screening programme. In particular there is a clear sequence of adenoma progressing to adenocarcinoma. Also, early cancers are detectable and progress steadily to advanced cancers. About 75% arise sporadically, most likely in pre-existing adenomas. Thus a window of opportunity exists for detecting adenomatous polyps at a premalignant stage or cancers at an early invasive stage (i.e. pathologically less advanced than those with symptoms), where they are potentially curable. The transition phase from benign to malignant is long, shown by the cumulative risk of cancer in polyps 10 mm or larger being only 8% at 10 years.

However, detection methods are the stumbling block. Screening by symptoms alone is very unreliable. The sensitivity of guiac faecal occult blood (FOB) testing is no better than 50% and the specificity is also low. A new quantitative FOB test, faecal immunological testing (FIT) is much more sensitive and specific and is likely to replace the guiac test. With 2-yearly FOB testing alone, there are many interval cancers: 30–60% of cancers and as many as 80% of polyps are missed after three rounds of testing. Sensitivity and interval cancer rates can be improved by adding flexible sigmoidoscopy. A randomised multicentre once-only trial of flexible sigmoidoscopy in 100 000 people found it reduced the rate of colorectal cancer by 33% and deaths from it by 43%. Rectosigmoid cancers were reduced by 50% (Lancet 2010; 375; 1624–1633) but right-sided cancers are not detected. Unfortunately, both faecal occult blood (FOB) testing and flexible endoscopy are distasteful and patient participation is low. Better forms of screening would undoubtedly improve participation.

Despite the drawbacks of FOB testing, meta-analysis of four RCTs has shown that FOB screening can reduce mortality from colorectal cancer by 16% for those allocated to screening and by 23% of those actually screened. On this basis, a 2-yearly FOB screen offered to 10 000 people aged over 40 with two-thirds attending for at least one test would prevent 8.5 deaths (CI: 3.6–13.5) from colorectal cancer over 10 years, a mortality reduction of 23% (RR 0.77, CI: 0.57–0.89); 2800 participants would have a colonoscopy and there would be 3.4 major complications from this, i.e. perforation or haemorrhage (Cochrane). The cost of screening was £5290 per cancer detected and an estimated £1584 per life year gained.

Reports of pilot screening studies suggest screening could improve mortality by 33%, and national screening with FOB testing every 2 years has been approved for implementation in the UK. This started in April 2006 for men and women aged 60–69 (50–74 in Scotland). In addition, large-scale pilots of endoscopic colorectal screening are being trialled in patients in their late 50s.

Prostate cancer

Prostate cancer is the most common cause of cancer deaths in older men and 84% of deaths are in men over 70. Unfortunately, the prospects for prevention remain poor. The problem is not so much in detecting the disease but in avoiding false positives, detecting it early enough and predicting its clinical course. Many cancers remain forever dormant, as shown by post-mortem studies in men who have died of something else: foci of prostate cancer occur in 70% of 70-year-olds, 60% of 60-year-olds and 50% of 50-year-olds. These patients died with the disease rather than from it and offering radical treatment for them is clearly inappropriate. Serum prostate specific antigen (PSA) levels increase with the volume of tumour, so high levels indicate extensive disease. In one study the age-specific median concentration was 40 µg/L in men who died within 3 years, 6 in men who died in 3–6 years and 4 in those who died between 6 and 10 years. In another study, using a cut-off level of 10 µg/L, the false positive rate was 4% (similar to breast screening) but 15/16 men with prostate cancer had extra-prostatic disease. Using the common cut-off of 4, false positive rate was 18% and 22/33 had extra-prostatic disease. Thus PSA is a good test only for cancers that cause death within 3 years; after that the common cut-off of 4 detects only half of those that would cause death or serious morbidity. Unfortunately, histological grade only partly predicts clinical outcome.

In the USA, uncontrolled screening using PSA has spawned an apparent epidemic of prostate cancer. The chairman of the UK National Screening Committee stated that ‘the scientific evidence is that screening for prostate cancer does not reduce mortality, and causes actual harm by exposing people to a procedure which has side effects of incontinence and impotence and where there is no evidence that they will benefit’.

The UK government sponsored a Health Technology Assessment on prostate screening in 1997, which stated that the criteria for a population screening programme had not been met. Their findings were that:

Overall, PSA screening causes harm. Some men receive unnecessary treatment because the cancer is incurable or because it would never have presented clinically, and those treated risk infection (from biopsies), incontinence and impotence.

Lung cancer

A Cochrane review of all randomised controlled trials showed that no screening test had an impact on the treatment or deaths from lung cancer, despite early stage cancers being detected and resected (most likely because these would not have progressed). Tests examined include chest X-ray, sputum tests and CT scanning.

Hypertension

Hypertension is an important cause of myocardial infarction and stroke. Lowering elevated blood pressure substantially lowers the risk. However, blood pressure on its own has proved a poor screening tool; in one large study, the 10% with the highest blood pressures suffered only 21% of the ischaemic cardiac events and only 28% of the ischaemic strokes. Even after adding other risk factors, including low-density lipoprotein (LDL) cholesterol, diabetes and smoking history, the top 5% had only 28% of the deaths from myocardial infarction. Advancing age or a previous cardiovascular event are probably the best predictors of future cardiovascular events, thus all patients with risk factors should receive best advice and appropriate treatment.

Abdominal aortic aneurysm