[Prevention of cancer and the dose-effect relationship: the carcinogenic effects of ionizing radiations]. / La prévention du cancer et la relation dose-effet : l'effet cancérogène des rayonnements ionisants.

Cancer prevention has to be based on robust biological and epidemiological data, therefore its reappraisal becomes mandatory in view of recent progress in the understanding of carcinogenesis. The first phase of the carcinogenic process, that of initiation, is generally associated with mutation; however the role of extrinsic mutagens is less critical than was thought two decades ago. During intracellular oxygen metabolism, reactive oxygen species (ROS) are made which are potent mutagens. Defense mechanisms against these intrinsic mutagens include scavenger and enzymatic systems which destroy them (catalase, superoxide dismutase). When the radiation dose is low, DNA repair is very effective as well as the elimination of cells with unrepaired or misrepaired DNA. Therefore a small increase in the number of ROS, such as that caused by a small dose of radiation has most probably no significant effect on the risk of DNA damage. These conclusions are consistent with the concept of a practical threshold. The second phase, that of promotion, appears to be the key one. During the promotion phase, initiated cells must acquire new properties (immortalization, release of angiogenic factors, resistance to hypoxia, etc.) in order to become precancerous. This evolution is due to the accumulation in the genome of 6 to 10 new alteration defects. In the clone of initiated cells, the occurrence in one cell of a mutation or an epigenetic event gives birth to a subclone. There is a Darwinian type competition between the subclones and those with the more rapid growth because dominant (the acceleration of the growth rate can be due to shorter cell cycles or to an alleviation of cell proliferation exerted by the neighboring cells or the microenvironment). In the dominant subclones new genomic events provoke the appearance of new subclones growing more rapidly and having greater autonomy. The process is very slow because the specific genetic events that favour this evolution seldom occur. Promoting factors are agents that either perturb intercellular signalling or stimulate cell proliferation (e.g. hormones) or increase cell mortality: mechanical or chemical irritation (e.g. alcohol, bacteria, viruses) thereby inducing compensatory cell proliferation. Thus, gradually precancerous cells become able to divide more rapidly with greater autonomy. This phase ends when a subclone of cells has acquired the capacity of autonomous proliferation. The third phase is that of progression during which cells proliferate regularly without any stimulation. In one of the cells of one of the precancerous lesions (e.g. polyps) a cell acquires the capacity of invading surrounding tissue or to metastasize. The whole carcinogenic process is very slow, extending over several decades, because the specific mutations seldom occur and the probability of an accumulation of several specific mutations in the same cell or cell lineage is very small. It can be accelerated by intense stimulation of cell proliferation or genetic instability. Ionizing radiations act firstly as a mutagen, however when the dose is high they also kill a significant proportion of cells and by a homeostatic mechanism they induce cell proliferation and clonal amplification. It has been claimed that even the smallest dose of radiation can induce a cancer. This concept is associated with the LNT model and it is not based on scientific evidence. It has fuelled a fear of radiation which had detrimental consequences. Conversely the high efficacy of defense mechanisms against radiocarcinogenesis, particularly when the tissue is not disorganized, can explain the lack of carcinogenic effect of contamination by small doses of radium or thorium which has been observed on radium dial painters or in patients injected with thorotrast. The study of second cancers in patients treated by radiotherapy could provide important information and should be actively pursued with two aims: reduce the incidence of second cancers; to better understand radiocarcinogenesis and the relation between dose and carcinogenic effect.

The causes of cancer in France.

BACKGROUND: While external factors are responsible for many human cancers, precise estimates of the contribution of known carcinogens to the cancer burden in a given population have been scarce. METHODS: We estimated the proportion of cancer deaths which occurred in France in 2000 attributable to known risk factors, based on data on frequency of exposure around 1985. RESULTS: In 2000, tobacco smoking was responsible for 23.9% of cancer deaths (33.4% in men and 9.6% in women), alcohol drinking for 6.9% (9.4% in men and 3.0% in women) and chronic infections for 3.7%. Occupation is responsible for 3.7% of cancer deaths in men; lack of physical activity, overweight/obesity and use of exogenous hormones are responsible for 2%-3% of cancer deaths in women. Other risk factors, including pollutants, are responsible for <1% of cancer deaths. Thus, known risk factors explain 35.0% of cancer deaths, and 15.0% among never smokers. CONCLUSIONS: While cancer mortality is decreasing in France, known risk factors of cancer explain only a minority of cancers, with a predominant role of tobacco smoking.

The debate on the use of linear no threshold for assessing the effects of low doses.

From December 2004 to July 2005, three reports on the effects of low doses of ionising radiation were released: ICRP (2004), the joint report of the French Academies of Science and Medicine (Tubiana et al 2005), and a report from the American Academy of Sciences (BEIR VII 2005). These reports quote the same recent articles on the biological effects of low doses, yet their conclusions diverge. The French report concludes that recent biological data show that the efficacy of defense mechanisms is modulated by dose and dose rate and that linear no threshold (LNT) is no longer plausible. The ICRP and the BEIR VII reports recognise that there are biologic arguments against LNT but feel that there are not sufficient biological proofs against it to change risk assessment methodology and subsequent regulatory policy based on LNT. They point out the remaining uncertainties and the lack of mechanistic explanations of phenomena such as low dose hyperlethality or the adaptive response. In this context, a critical analysis of the available data is necessary. The epidemiological data and the experimental data challenge the validity of the LNT hypothesis for assessing the carcinogenic effect of low doses, but do not allow its exclusion. Therefore, the main criteria for selecting the most reliable dose-effect relationship from a scientific point of view should be based on biological data. Their analysis should help one to understand the current controversy.

Recent reports on the effect of low doses of ionizing radiation and its dose-effect relationship.

Recently, the risk associated with low doses of ionizing radiation has gained new interest. Here, we analyze and discuss the major differences between two reports recently published on this issue; the report of the French Academy of Sciences and of the French Academy of Medicine published in March 2005, and the BEIR VII-Phase 2 Report of the American National Academy of Sciences published as a preliminary version in July 2005. The conclusion of the French Report is that the linear no-threshold relationship (LNT) may greatly overestimate the carcinogenic effect of low doses (<100 mSv) and even more that of very low doses (<10 mSv), such as those delivered during X-ray examinations. Conversely, the conclusion of the BEIR VII report is that LNT should be used for assessing the detrimental effects of these low and very low doses. The causes of these diverging conclusions should be carefully examined. They seem to be mostly associated with the interpretation of recent biological data. The point of view of the French Report is that these recent data are incompatible with the postulate on which LNT is implicitly based, namely the constancy of the carcinogenic effect per unit dose, irrespective of dose and dose rate.

Measuring progress against cancer in Europe: has the 15% decline targeted for 2000 come about?

BACKGROUND: Against a background of increasing cancer rates in the mid-1980s, Europe Against Cancer launched an ambitious programme aiming to reduce cancer mortality by 15% by the year 2000. A programme of activities and research, focussing on three major themes [prevention (particularly tobacco control), screening, and education and training], was developed together with the European Code Against Cancer. METHODS: To evaluate the outcome of the programme, all cancer mortality data were abstracted for each member state of the European Union (EU) until the most recent year available. For each gender group in each member state, age-specific rates were estimated for 2000. For each country-gender grouping, the standardized mortality rate (SMR) and expected numbers of deaths in 2000 were calculated based on the age-specific rates for 1985 and the population estimates for 2000. The ratio of the SMR in 2000 to that of 1985, was used as the measure to compare mortality rates. RESULTS: In 1985, there were 850 194 cancer deaths in the EU. Based solely on demographic considerations, this number was expected to rise to 1 033 083 in the year 2000. Between 1985 and 2000, the number of cancer deaths increased in both men (+12%) and women (+9%). The target of a 15% reduction in the expected numbers of cancer deaths in the EU was not met, although the 10% reduction in number of deaths expected in men and 8% in women, along with a 11% reduction in risk of cancer death in men and a 10% reduction in women, was noteworthy. Only Austria and Finland achieved the 15% reductions in deaths in both men and women. The UK and Luxembourg (where the small population and annual number of deaths make interpretation difficult) came close to meeting these targets, as did Italy. Portugal and Greece had the poorest performance, with increases in each gender group. CONCLUSIONS: Cancer deaths in the EU were expected to rise from 850 194 in 1985 to 1 033 083 in 2000. It is estimated that there will be 940 510 cancer deaths that year, due to the decline in risk observed since 1985. The Europe Against Cancer programme appears to have been associated with the avoidance of 92 573 cancer deaths in the year 2000. With few exceptions, most countries are experiencing declining trends in cancer death rates, which seem set to continue, at least in the near future. Renewed tobacco control efforts are clearly needed for women, and there is a strong case for the introduction of organized breast and cervix screening programmes in all member states. Continuing to emphasize prevention within cancer control will help to promote the continuing decline in death rates in the future.

[Health and the city: physical health and mental health]. / La santé et la ville: santé physique et santé mentale.

In France, city size has very little bearing on the mortality rate as a function of age and life expectancy and it is in large cities that these indicators are the most favorable. No increase in maternal or infant mortality rates or deaths due to cancers has been observed in large cities. The lower mortality rate linked to respiratory and cardiovascular diseases in large urban areas contradicts the fears concerning the impact of air pollution. Deaths linked to lifestyle are less frequent in big cities, which could be due to social structures (socio-professional level: the proportion of white-collar workers and professionals is higher in bigger cities than in the suburbs or small cities). However, although the overall mortality rate is lower, it should be emphasized that there is in large cities a greater incidence of sexually transmitted diseases, AIDS and certain infectious diseases (because of social diversity and the fact that certain individuals seeking anonymity and marginality are drawn to large cities). In terms of mental health, the breakdown of family structures, instability, unemployment, the lack of parental authority and failing schools render adolescents vulnerable and hinder their social integration. When the proportion of adolescents at risk is high in a neighborhood, individual problems are amplified and social problems result. In order to restore mental and social health to these neighborhoods, ambitious strategies are necessary which take into account family and social factors as well as environmental ones. At the present time, when physical health is constantly improving, the most pressing problems are those related to lifestyle and mental health which depend for a large part on social factors.

[The precautionary principle: advantages and risks]. / Le principe de précaution: ses avantages et ses risques.

The extension of the precautionary principle to the field of healthcare is the social response to two demands of the population: improved health safety and the inclusion of an informed public in the decision-making process. The necessary balance between cost (treatment-induced risk) and benefit (therapeutic effect) underlies all healthcare decisions. An underestimation or an overestimation of cost, i.e. risk, is equally harmful in public healthcare. A vaccination should be prescribed when its beneficial effect outweighs its inevitable risk. Mandatory vaccination, such as in the case of the Hepatitis B virus, is a health policy requiring some courage because those who benefit will never be aware of its positive effect while those who are victims of the risk could resort to litigation. Defense against such accusations requires an accurate assessment of risk and benefit, which underlines the importance of expertise. Even within the framework of the precautionary principle, it is impossible to act without knowledge, or at least a plausible estimation, of expected effects. Recent affairs (blood contamination, transmissible spongiform encephalitis by growth hormone, and new variant of Creutzfeldt-Jacob disease) illustrate that in such cases the precautionary principle would have had limited impact and it is only when enough knowledge was available that effective action could be taken. Likewise, in current debates concerning the possible risks of electromagnetic fields, cellular phones and radon, research efforts must be given priority. The general public understands intuitively the concept of cost and benefit. For example, the possible health risks of oral contraceptives and hormone replacement therapy were not ignored, but the public has judged that their advantages justify the risk. Estimating risk and benefit and finding a balance between risk and preventive measures could help avoid the main drawbacks of the precautionary principle, i.e. inaction and refusal of innovation, highly restrictive administrative procedures, and a waste of funds on the search for the utopian goal of zero risk. Other drawbacks are more insidious. The precautionary principle could contribute to a general feeling of anxiety and unease in the population. It could be used by campaigns to manipulate public opinion in favor of a particular commercial interest or ideology. Furthermore, practitioners and public policy makers could be led to make choices not dictated by a search for the optimal solution but rather a solution that would protect them from future accusations (the so-called umbrella phenomenon). On the international level, the precautionary principle must not be used to mask protectionism. Nevertheless, a clear advantage of the precautionary principle is that it requires decision-makers to explain the rationale behind their decisions, to quantify the risks, and to provide objective information. However, the physician must not be tempted to make patients sign documents certifying that they have been given all relevant information on his or her diagnosis and treatment. This example underlines the role of legal texts and jurisprudence in the application of the precautionary principle. Finally, the precautionary principle implies new obligations for the State. In the field of health and healthcare, the State must undertake actions based on fully open and undisguised decision-making and provide complete information to the public. A pplication of the precautionary principle requires much discernment because the final outcome can be beneficial or harmful, depending on the way it is implemented. The precautionary principle, and its applications, must be precise and detailed within a well-defined framework.

[Conclusions. The precautionary principle: its advantages and risks]. / Conclusions. Le principe de précaution: ses avantages et ses risques.

The proposed extension to health of the precautionary principle is the reaction to two social demands: the desire for greater health safety and for more transparency in the decision making process by associating the public. In medical care, all decisions are based on the balance between cost (dangers induced by the treatment) and benefit (the therapeutic effect). It is as dangerous to overestimate the cost, in other words the risks, as it is to underestimate them. The same problem is encountered in public health. If a vaccination is to be prescribed, the beneficial effects must outweigh the risks; however, these risks are inevitable and have been known to exist since the 18th century, but they have been accepted for the public good. It takes courage to make a vaccination mandatory because those who benefit from it will never know, while those who suffer from its ill effects could take legal action. In order to counter accusations, an evaluation must be made beforehand of the risks and benefits, which underlines the important role of expert opinion. Within the framework of the precautionary principle, actions cannot be taken in ignorance and, at the very least, plausible estimations must be made. The analysis of several recent events (contaminated blood, BSE, growth hormone and Creutzfeldt-Jacob disease) shows that the precautionary principle would have had a very limited impact and that only once there was sufficient knowledge was action made possible. The same is true concerning current debates (the possible risks associated with electromagnetic fields, mobile phones and radon); in these three cases, no country in the world has invoked the precautionary principle, but rather the priority has been given to research. The public understands quite readily the cost/benefit relationship. In the case of oral contraceptives, or hormone replacement therapy the public was aware of their possible health risks but judged that the advantages outweighed the risks. The estimation of risks and benefits, the putting into proper perspective the possible risks that can be incurred from any given action, enables the main pitfalls of the precautionary principle to be avoided: the opposition to progress and the refusal of innovation, ever greater bureaucracy, and the waste of funds in the pursuit of an utopian "zero risk". Other drawbacks are more insidious: increased anxiety in the population, the manipulation of opinion by campaigns fomented by commercial or ideological interests, the influencing of practitioners and decision-makers to choose not the best solution but rather the one that will protect them from any future accusations. At the international level, efforts must be made to avoid that the precautionary principle be used for protectionist reasons. Nevertheless, the precautionary principle can have advantages, such as motivating decision-makers in the public or private sector to explain and quantify their reasoning, and to give objective information. However, the medical practitioner should not be tempted to ask that documents be signed as proof of the information given. This example underlines the possible dangers of the strict application of the law in certain cases and the importance of the role of jurisprudence. The precautionary principle will also impose new obligations on the State, which also must conform to the requirements of proportionality between risk and action, transparency and information in the field of care and health. The application of the precautionary principle will require good judgment because the way it is implemented will determine whether its outcome will be for the better or the worse. That is why it is indispensable that jurists, medical practitioners, and scientists work together so that the precautionary principle will be as precisely defined and codified as possible.

Conformal radiotherapy and intensity-modulated radiotherapy--clinical data.

Conformal radiotherapy (CRT) is based on three hypotheses: (i) a higher rate of local control can improve the survival rate; (ii) dose escalation can increase tumor control; and (iii) CRT allows the delivery of higher doses by decreasing the incidence of late effects. These postulates are now supported by several data. Three-dimensional conformal radiotherapy (3D-CRT) has markedly progressed since its introduction two decades ago. However, there are situations for which 3D-CRT cannot produce a satisfactory treatment plan because of complex target volume shapes or the close proximity of sensitive normal tissues. This is why intensity-modulated radiation therapy (IMRT) was introduced. Its aim is to overcome the limitations of 3D-CRT by adding modulators of beam intensity to beam shaping. IMRT can achieve nearly any dose distribution; however, the role of the planner remains crucial. CRT has been investigated mainly for prostate cancers and head and neck cancers. By and large, the clinical data, although still limited, seem to confirm the advantages of this type of radiotherapy. Dose escalation in prostate cancers improves the local control rate without increasing late effects and for this cancer site IMRT appears to be a significant advance over conventional 3D-CRT. In head and neck cancers the clinical data are still scarce but encouraging. CRT should be investigated in breast cancers with the aim of reducing the incidence of late effects. The available data underline the great potential for major progress in 3D-CRT and IMRT. The techniques are still costly and time consuming, nevertheless they merit investigation since their cost should decrease. Efforts should be concentrated on the specification of robust optimization criteria, taking into account clinical and radiobiological data.