Screening for Lung Cancer

It has long been established that the best way to control lung cancer is to reduce cigarette smoking in the population, foremost through prevention, and secondarily through smoking cessation. However, even after stopping smoking longterm smokers remain at high risk of lung cancer. Lung cancer when clinically diagnosed has a poor outcome with 10–16% survival at 5 years. If the tumour is small enough to be removed surgically, the outcome is much better, >70% for stage I tumours. This led to speculation in the past as to whether long-term smokers or others at high risk might benefit from earlier detection.

Low-dose spiral CT scanning can detect lung cancer at an early stage. The Early Lung Cancer Action Project (ELCAP) demonstrated that spiral CT was able to identify very small lung cancers in high-risk volunteers, with a resectability rate of 96% and a proportion of stage I >80%. An initial high false-positive rate was reduced by high-resolution CT (HRCT) with a complex algorithm of 3D reconstruction for tumour growth. Randomised trials of spiral CT using a non-intervention control group and with lung cancer mortality as the trial outcome are needed to determine the value of this method of screening.

Screening for Prostate Cancer

At the present time there is pressure to screen for prostate cancer, but implementation of screening programmes for prostate cancer cannot be recommended based on the available evidence. The main reason for this situation is that no results are available from randomised trials assessing screening for prostate cancer. These are the only methods of evaluation which avoid bias and, in consequence, it is not known whether screening by one of the available modalities or in combination is effective in leading to a reduction in the mortality rate from prostate cancer. This is a necessary prerequisite for embarking on population screening.

Any reduction in mortality from prostate cancer due to screening, while uncertain, must be weighed against the harm from screening diagnosis and treatment. Some men who do not need treatment are likely to receive it. These are men destined to die of causes other than prostate cancer. Unfortunately, at diagnosis, men needing treatment for prostate cancer cannot be differentiated from men who do not.

The PSA test is simple, cheap, readily available and acceptable. PSA testing has already achieved a high penetration among men and their physicians. To document the extent of PSA testing in the general population at Getafe (Spain) a total of 5.371 PSA test records (1997–1999) were reviewed and testing rates estimated per 1.000 person-years. The PSA-testing rate in the general population was 21.6/1000 person-years. In the age-group 55–69 years, this rate was 86.8/1000 and increased to 152.6/1000 in men >70 years. In Milan, Italy where there is no campaign publicising or encouraging prostate cancer screening, it has been estimated that 26.9% of men aged 40 and older and without a history of prostate cancer received a PSA test in the 2-year period 1999–2000. In men aged 50 and greater, this rate rose to 34%.

Multiple sources of data show that prostate cancer incidence rates rose following the introduction of PSA testing. The average age at diagnosis has fallen, the proportion of advanced stage tumours has declined, the proportion of moderately differentiated tumours has increased, and patterns of care have changed accordingly. A decline in mortality began in the USA and other countries in 1991. The decline in mortality is well established, but this recent trend may only retrace an increase in mortality that immediately preceded it. The descriptive epidemiology of prostate cancer reveals many effects of the introduction of prostate cancer screening. Although the evidence suggests increased prostate cancer testing has yielded public health benefit, this has not yet been shown conclusively and a decision on the value of screening should await the results of trials. In any event, systems should now be in place to ensure that men and physicians participating in PSA testing participate in a programme in which the effect of the intervention can be evaluated as best can be done given the non-experimental nature of the intervention.

Screening for other forms of Cancer

Screening has been defined as the systematic application of a test or inquiry to identify individuals at sufficient risk of a specific disorder to benefit from further investigation or direct preventive action, among persons who have not sought medical attention on account of symptoms of that disorder. Before a screening test can be introduced it is necessary to be able to demonstrate that the test not only distinguishes people who will develop the disease from those who will not, but that a remedy is available to individuals who are judged to be screen-positive that can significantly improve their health compared with not screening, and treating the disease on clinical presentation in the usual way.

In assessing screening tests for cancer, a large randomised trial is usually necessary. This would compare mortality from the specific cancer in a group that has been screened and treated with the corresponding mortality in an unscreened group that received treatment only after clinical presentation. In screening programmes that aim to detect cancer lesions at an early stage it is impossible to determine the proportion of all of the cancers in question that would have presented clinically over a specified period that are detected by screening, because cancers cannot be detected without then intervening. The outcome of screening trials is therefore expressed as a proportional reduction in mortality from the specific cancer and then a judgment made as to whether this is worthwhile.

Table 11 shows the cancers and screening methods that have been shown to be worthwhile, those that are of unknown value and those that are known to not be worthwhile. Breast cancer screening by mammography in women aged over 50 years can reduce mortality from the disease by about 30%. Screening for colorectal cancer by FOBT can reduce mortality from the disease by about 15%. Both rates were shown using randomised trials. Screening for cancer of the cervix by cervical cytology has been judged to be worthwhile ( about 80% reduction in mortality from this disease), though without evidence from randomised trials.

A difficulty with screening is that some cancer screening programmes have been introduced in the absence of evidence that they are worthwhile, for example, prostate cancer screening, and breast cancer screening in women aged under 50 years. A difficulty with screening is that some cancer screening programmes have been introduced in the absence of evidence that they are worthwhile, for example, prostate cancer screening, and breast cancer screening in women aged under 50 years. It is important that health authorities resist the temptation to introduce population screening programmes until there is firm evidence of efficacy, as judged by a reduction in mortality from the cancer in question. The presumption of benefit should not be sufficient grounds for introducing large scale programmes. Sometimes an effective screening test (e.g. prostate-specific antigen (PSA) for prostate cancer) has led to the introduction of screening programmes in the absence of trial results showing evidence of benefit in terms of disease prevention. Once such services are in place they can be difficult to stop. Then existing data should be used to try to evaluate efficacy, albeit in a less than ideal manner.

There is a general need to continually evaluate screening services to ensure that the performance expected from the results of randomised trials and other relevant research can be achieved in practice. Service provision will depend on available resources and the burden of disease from the cancer in question in the absence of screening.

The following cancer screening programmes should be made generally available:

  • Screening for breast cancer by 3 yearly mammography examinations for women from the age of 50 years
  • Colorectal cancer screening by FOBT every 2 years from the age of 50 years.
  • Cervical cancer screening by 5 yearly cervical smear examinations for women from the age of 25 years.

Others should not be offered as services at all or should be part of research programmes designed to determine their value. There are screening tests available and being evaluated for stomach cancer, oral cancer, nasopharynx cancer and neuroblastoma. Screening for prostate cancer and screening for lung cancer are, however, the subject of much recent research.

Read More about Prostate Cancer Screening

Read More about Lung Cancer Screening

Oral Contraceptives
Over the last decade, several epidemiological studies have been published on the oral contraceptives (OC) and cancer risk issue. These studies were reviewed in June 1998 by an IARC Working Group, and are summarised in the IARC monograph 72 [43].

A collaborative reanalysis of individual data on 53.297 breast cancer cases and 100.239 controls indicated that there is a moderate excess risk for this disease among current or recent OC users, which tends to level off in the few years after stopping use. OC use has also been found to be positively associated with cervical cancer risk in HPV-positive women. Conversely, OC (with the exception of the currently not used sequential type) reduce the risk of endometrial cancer. Further, data on ovarian cancer indicate a long lasting protection from OC use, which may well be evident up to 20 years after cessation. Several studies have suggested an inverse relation between use of OC and risk of colorectal cancer, but no association with duration of use was observed. An increased risk for OC users of hepatocellular carcinoma is considered as established. The main established evidence on the OC and cancer issue can be summarised as follows:

• There is a small increased risk of breast cancer among current users, but not among former users who have ceased for 10 or more years.
• OC lower the risk of endometrial and ovarian cancer, and the protection seems to persist after cessation of use.

• A reduced risk of colorectal cancer among OC users is possible, but this issue is still open to discussion.

• OC are related to increased risk of cervical cancer and liver cancer, but the public health importance of these associations is small in developed countries.

• OC have been used for 40 years, and the formulations have been modified repeatedly. It is therefore difficult to propose further modifications that may appear favourable on the risk of selected diseases without increasing the risk of other side effects.

Beta-carotene

While observational epidemiological studies have consistently shown that beta-carotene is associated with decreased cancer risk, particularly of lung cancer, findings of seven randomised trials testing the effect of beta-carotene supplementation on cancer incidence and mortality generally have not been supportive. Two of these trials even suggested the possibility of harmful effects.

Two large trials of beta-carotene conducted among persons at average risk of cancer found no statistically significant benefit or harm associated with beta-carotene supplementation [16-17].
Two other large trials tested beta-carotene among persons at high risk of cancer [18, 19]. One (The Alpha-Tocopherol, Beta carotene Cancer Prevention Study, 1996) reported a statistically significant 18% increase in lung cancer incidence after 5–8 years of treatment with beta-carotene among male Finnish smokers 
[18]. Another that used a combination of beta- carotene and retinol, reported a statistically significant 28% increase in lung cancer incidence among United States Smokers, former smokers and asbestos workers[19]. Only one large trial, which tested a combination of beta-carotene, vitamin E and selenium in a poorly nourished Chinese population, found that after 5 years, the treated group experienced a statistically significant 9% reduction in total mortality, primarily as a result of a statistically significant 21%lower stomach cancer mortality rate [20].

The indirect evidence that beta-carotene may protect from stomach cancer comes from the randomised, controlled double-blinded chemoprevention trial in subjects with gastric dysplasia in an area with a very high gastric cancer risk in Columbia. Gastric biopsy taken at baseline was compared with those taken at 72 months. Treatment with 30 mg beta-carotene resulted in a statistically significant increase in the frequency of regression of preneoplastic lesions of the stomach [relative risk (RR) = 5.1, 95% CI 1.6–14.2][21]. One small trial of 1805 people with previous non-melanoma skin cancer that tested treatment with beta-carotene (50 mg per day) to reduce the occurrence of new skin cancer did not find any effect of this intervention[22]

It can be concluded that there is evidence at present that beta-carotene supplements have no value as cancer chemoprevention agents and cannot be recommended for use in the general population in this context.

The committees discussed a number of other issues in cancer epidemiology and cancer control and decided that the situation was not so certain that any recommendation could be made with a convincing probability of success in reducing cancer risk. Issues considered included chemoprevention, exogenous hormones and screening for other forms of cancer.

P. Boyle
Department of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.

P. Autier
Centre for Research on Epidemiology and Health Information Systems (CRESIS), Centre de Recherche Public de la Santé, Luxembourg.

H. Bartelink
Professor and Chairman, Radiotherapy Department, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Huis, Amsterdam, The Netherlands.

J. Baselga
Medical Oncology Service, Vall d’Hebron University Hospital, Vall d’Hebron, Barcelona, Spain.

P. Boffett
Chief, Unit of Environmental Cancer Epidemiology, International Agency for Research on Cancer, Lyon, France.

J. Burn
Cancer Family Network, CancerResearchUK, University of
Newcastle, Newcastle, UK
.

H. J. G. Burns
Chief Administrative Medical Officer, Greater Glasgow Health Board, Glasgow, UK.

L. Christensen
President, The Association of European Cancer Leagues, Oslo, Norway.

L. Denis
Oncology Centre Antwerp, Antwerp, Belgium.

M. Dicato
Hematology-Oncology, Centre Hospitalier, Luxembourg.

V. Diehl
Med. Klinic 1, Universitat zuKoln, Koln, Germany.

R. Doll
Clinical Trial Service Unit, Cancer Research UK Cancer Studies Unit, Radcliffe Infirmary, Oxford, UK.

S. Franceschi
Chief, Field and Intervention StudiesUnit, IARC, Lyon, France.

C. R. Gillis
Scientific Coordinator, Department of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.

N. Gray
Department of
Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.

L. Griciute
Lithuanian Oncology Center, Vilnius, Lithuania.

A. Hackshaw
Deputy Director, Cancer ResearchUK & UCL Cancer Trials Centre, Stephenson House, London, UK.

M. Kasler
Director, National Institute of Oncology, Budapest, Hungary.

M. Kogevinas
Department of Epidemiology andPublic Health, Institut Municipal d’Investigacio Mèdica (IMIM), Barcelona, Spain.

S. Kvinnsland
Department of Oncology, Haukaland Hospital, Bergen, Norway.

C. La Vecchia
Istituto diRicerche Farmacologiche Mario Negri, Milan, Italy.

F. Levi
Director, Registre Vaudois des Tumeurs, Institut Universitaire de Médecine Sociale et Préventive, Lausanne,Switzerland.

J. G. McVie
Scientific Coordinator, Department of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.

P. Maisonneuve
Unit of Clinical Epidemiology,Department of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.

J. M. Martin-Moreno
Director-General of Public Health, Ministerio de Sanidad y Consumo,Madrid, Spain.

J. Newton Bishop
Genetic Epidemiology Division, Cancer Research UK, St James’s University Hospital, Leeds, UK.

F. Oleari 
Ministero della Sanita’, Roma, Italy.

P. Perrin
Chairman,Department of Urology, Hopital de l’Antiquaille, Lyon, France.

M. Quinn
Director, National Cancer Intelligence Centre, Office for National Statistics, B6/02, 1 Drummond
Gate, London, UK
.

M. Richards
National Cancer Director, St Thomas’ Hospital, London, UK.

U. Ringborg
Department of Oncology, Radiumhemmet, Karolinska Hospital, Stockholm.

C. Scully
Dean and Director of Studies and Research, Eastman Dental Institute for Oral Health Care Sciences and International Centres for Excellence in Dentistry,University of London, Eastman Dental Institute, London, UK.

E. Siracka
President, Liga proti rakovine SR, Bratislava, Slovakia.

H. Storm
Danish Cancer Society, Director CancerPrevention and Documentation, Copenhagen, Denmark.

M. Tubiana
President du Centre Antoine Beclere, Centre Antoine Beclere, Faculte’ de Medicine, Paris, France.

T. Tursz
Director, Institut Gustave Roussy, Villejuif, France.

U. Veronesi
Scientific Director, European Institute of Oncology, Milan, Italy.

N. Wald
The Medical College of St Bartholomew’s Hospital, Wolfson Institute of Preventive Medicine, Department of Epidemiology, London, UK.

W. Weber
Schweizerische Krebsliga, Berne, Switzerland.

D. G. Zaridze
Director, Institute of Carcinogenesis, Deputy Director, Cancer Research Centre RAMS, Moscow, Russian Federation.

W. Zatonski
Department of Cancer Epidemiology and Prevention, The Marie-Sklodowska Memorial, Cancer Center and Institute of Oncology, Warsaw, Poland.

H. zur Hausen
Director, German Cancer Research Center (DKFZ), Heidelberg, Germany. 

There are Public Health programmes which could prevent cancers developing or increase the probability that a cancer may be cured. Early detection is an important factor in reducing the death rate from cancer, whether it is achieved by personal actions or through participation in organised public health programmes. Awareness of different visual body signs or symptoms that could easily be observed by anyone and that are possibly related to cancer is important. It is unequivocally established that cancer survival is better for early, localised disease than for the later stage, advanced forms of the disease. Thus, the earlier in the process that a cancer can be diagnosed and treated then the better this is for the patient. Potential symptoms of cancer should not be ignored, but should serve as a clear warning for the individual to consult his or her doctor for advice. The signs and symptoms described in Table 10 are not specific for cancer. When any one is present, the individual should see a doctor. Much effort has gone into cancer screening and the development of methods for finding cancers at an earlier stage in their development and increasing the prospects of a cure. It is possible to make recommendations based on the available evidence.

:: Participate in vaccination programmes against Hepatitis B Virus infectionAbout 18% of human cancers worldwide are currently attributable to persistent infections with viruses, bacteria or parasites. In the European Union this fraction is about 10%, and it is chiefly accounted by four cancer sites or types, namely cancer of the cervix uteri, liver, stomach and some haemo-lymphopoietic tumours. Knowledge about the role of infectious agents in the aeti- ology of several cancer types has rapidly expanded in the last 30 years, after major improvements were made in the detection of markers of chronic infection. Contrary to former beliefs, antibacterial and antiviral treatments, as well as vaccination programs, represent an important tool against cancer.
The four major cancer sites or types that have been linked to infectious agents figure 7 will be discussed below, with special reference to current opportunities for prevention in the European Union, EU, countries.

Every year approximately 25.000 women in the European Union develop cervical cancer. A dozen types of human papillomavirus, HPV, have been identified in 99% of biopsy specimens from cervical cancer worldwide, and in Europe HPV 16 has been reported in 56% of over 3.000 cervical cancer specimens. Five HPV types (HPV 16, 18, 31, 33, 45) account for >85% of European cervical cancer specimens. In control women, the prevalence of the indicated HPV types is several dozen-fold lower. There is no effective medical treatment against HPV; however, very sensitive and specific tests for the detection of HPV DNA in cervical cells have become available. There is sufficient evidence for recommending HPV testing among women who show borderline or low-grade cytological abnormalities. Additionally, HPV testing improves the follow-up of women who have been treated for cervical intra-epithelial lesions, CIN, and, pending results of ongoing trials, may offer a more sensitive alternative to cytology in primary cervical cancer screening.

A prophylactic vaccine, based on late (L) 1 HPV 16 proteins, has been shown to be safe, highly immunogenic and efficacious in preventing persistent HPV infections in a trial of 1523 HPV 16- negative young women in the USA. A multivalent vaccine against the most common oncogenic HPV types may thus ultimately represent the most effective way to prevent cervical cancer worldwide, alone or in combination with screening. Vaccination would benefit women who do not attend screening programs in the EU and, if combined with current screening programs, it would allow substantial savings (i.e., less frequent screening tests, fewer treatments, etc.).
Every year approximately 30.000 new cases of liver cancer are recorded in the European Union figure 4. Upward trends in incidence and mortality rates have been seen in the last two decades, in men in France, Germany and Italy. Chronic infection with hepatitis B virus, HBV, and hepatitis C virus, HCV, accounts for the majority of liver cancer cases in Europe. In a large case-series of liver cancer from six European Liver Centres only 29% of 503 liver cancer patients had no marker of either HBV or HCV infection.

An effective vaccine against HBV has been available for 20 years now. Several countries in the European Union (e.g., Denmark, Finland, Ireland, The Netherlands, Sweden and the United Kingdom ) do not perform routine vaccination against HBV in children, on account of the low prevalence of HBV infection in the general population (http://www.who.int/), whereas other countries (e.g. Belgium, France, Germany) report coverage below 50%. There is scope for reconsidering national policies regarding universal vaccination against HBV since selective vaccination of high-risk groups rarely works, and travelling and migration facilitate the mixing of high- and low-risk populations. Although infection with HBV in young adulthood (typically through sexual intercourse or contaminated needles) carries a much lower risk of chronic hepatitis and liver cancer than infection at birth or during childhood, it frequently induces acute hepatitis.

HCV represents an increasing problem in several areas of the European Union (especially Italy, Greece and Spain) and in some population groups, notably intravenous drug users. A vaccine is not yet available, and the effectiveness of treating all HCVRNA positive individuals with pegylated interferon-2a with or without ribavirin is still under evaluation. Hence, the prevention of HCV infection relies for the moment on a strict control of blood and blood derivatives and avoidance of use of non-disposable needles in medical and non-medical procedures (e.g. acupuncture, tattooing, etc).

Helicobacter pylori, Hp, is associated with an approximatley 6-fold increased risk of non-cardia gastric cancer. Out of approximatley 78.000 new cases of gastric cancer every year in the EU, some 65% may be attributable to Hp (assuming an Hp prevalence of about 35% in the general population). The current therapy of Hp infection, based on the use of proton-pump inhibitors and antibiotics, is efficacious but poor patient compliance, antibiotic resistance and recurrence of infection complicate the issue. Furthermore, although treatment of Hp infection can induce regression of gastric lymphoma, it has not yet been shown to reduce gastric cancer risk. Various approaches have been followed in the development of vaccines against Hp, based on the use of selected Hp antigens, notably urease, the vacuolating cytotoxin, VacA, the cytotoxin-associated antigen, CagA, and the neutrophil-activating protein, NAP. Unfortunately, the natural history of Hp infection and the characteristics of an effective anti-Hp immune response are still poorly understood. Pharmaceutical companies seem to be reluctant to invest in the long and uncertain process of developing a vaccine against Hp, an infection perceived as declining and amenable to medical treatment.

The fourth group of cancers where infectious agents are known or suspected to play a major role is haemo-lymphopoietic tumours ( i.e. non-Hodgkin’s lymphomas, NHL; Hodgkin’s disease, HD; and leukaemias]— a total approximately 104.000 new cases per year in the EU). Certain viruses (i.e. Epstein Barr virus, EBV; human immunodeficiency virus, HIV, human-T-cell leukaemia/lymphoma virus 1, Herpes simplex type 8 and HCV) and Hp account for an illdefined proportion of NHL and HD. Childhood leukaemias may also be linked to one or more not yet identified infectious agents. As for Hp and gastric lymphomas, treatment of HCV has led to the regression of some extra-nodal NHL. Highly active antiretroviral therapy (HAART) has had a favourable impact on the occurrence of Kaposi’s sarcoma, but not as yet of NHL, in HIV-infected patients. Recognising and treating infections linked to haemolymphopoietic tumours is a priority in the EU, on account of the steady increase in the number of cases and high-risk individuals (e.g. iatrogenically immuno-suppressed and HIVpositive subjects).

In conclusion, infectious agents account for a substantial fraction of cancers in the European Union. For the moment, priorities are the expansion of immunisation programs against HBV and the inclusion of HPV testing in cervical cancer screening programs. Vaccines against cancer-causing infectious agents are, however, one of the most promising ways to prevent or even cure some important tumours. Because of the enormous cost of vaccine development, public–private partnerships (e.g. the Global Alliance for Vaccines and Immunisation, GAVI for developing countries) should be actively pursued in the EU, especially with respect to the development of vaccines against HCV and Hp.