Can we reduce the incidence of second primary malignancies occurring after radiotherapy? A critical review.

Second primary malignancies (SPMs) occurring after oncological treatment have become a major concern during the past decade. Their incidence has long been underestimated because most patients had a short life expectancy after treatment or their follow-up was shorter than 15 years. With major improvement of long-term survival, longer follow-up, cancer registries and end-result programs, it was found that the cumulative incidence of SPM could be as high as 20% of patients treated by radiotherapy. This cumulative proportion varies with several factors, which ought to be studied more accurately. The delay between irradiation and solid tumor emergence is seldom shorter than 10 years and can be as long as half a century. Thus, inclusion in a cohort of patients with a short follow-up leads to an underestimation of the proportion of SPM caused by treatment, unless actuarial cumulative incidence is computed. The incidence varies with the tissue and organs, the age of the patient at treatment, hereditary factors, but also, and probably mainly, with dose distribution, size of the irradiated volume, dose, and dose-rate. An effort toward a reduction in their incidence is mandatory. Preliminary data suggest that SPMs are mainly observed in tissues having absorbed doses above 2 Gy (fractionated irradiation) and that their incidence increases with the dose. However, in children thyroid and breast cancers are observed following doses as low as 100 mGy, and in adults lung cancers have been reported for doses of 500 mGy, possibly due to interaction with tobacco. The dose distribution and the dose per fraction have a major impact. However, the preliminary data regarding these factors need confirmation. Dose-rates appear to be another important factor. Some data suggest that certain patients, who could be identified, have a high susceptibility to radiocancer induction. Efforts should be made to base SPM reduction on solid data and not on speculation or models built on debatable hypotheses regarding the dose-carcinogenic effect relationship. In parallel, radiation therapy philosophy must evolve, and the aim of treatment should be to deliver the minimal effective radiation therapy rather than the maximal tolerable dose.

Long-term results of breast cancer irradiation treatment with low-dose-rate external irradiation.

PURPOSE: The aim of this study was to assess beam therapy with low-dose-rate (LDR) external irradiation in a group of patients with breast cancer. METHODS AND MATERIALS: This trial compared, from 1986 to 1989, patients with advanced breast cancer treated either by conventional fractionation or low-dose-rate (LDR) external radiotherapy (dose-rate 15 mGy/min, 5 sessions of 9 Gy delivered on 5 consecutive days). RESULTS: A total of 21 patients were included in the fractionated therapy arm. At follow-up 15 years after treatment, 7 local recurrences had occurred, 3 patients had died of cancer, 18 patients were alive, 10 were without evidence of disease, and 6 had evidence of disease. A total of 22 patients had been included in the LDR arm of the study. Of these, 11 had received a dose of 45 Gy; thereafter, in view of severe local reactions, the dose was reduced to 35 Gy. There was no local recurrence in patients who had received 45 Gy, although there were 2 local recurrences among the 11 patients after 35 Gy. The sequelae were severe in patients who received 45 Gy but were comparable to those observed in patients treated by fractionated radiotherapy who received 35 Gy. The higher efficacy of tumor control in patients treated by LDR irradiation as well as the lower tolerance of normal tissue are probably related to the lack of repopulation. CONCLUSION: Although the patient numbers in this study are limited, based on our study results we conclude that the data for LDR irradiation are encouraging and that further investigation is warranted.

[Stem cell colloquy: conclusion]. / Colloque cellules souches: conclusion.

The stem cell data presented and discussed during the symposium raise the hope that important medical progress can be made in several fields: neuro-degenerative diseases, those linked to cellular deficit, some aspects of aging linked to cellular degeneration, and the treatment of cancers that may harm normal tissues at risk of being infiltrated by malignant cells. Three main types of stem cells are available. (i) Those present in normal adult tissue: contrary to what was believed, some data suggest that certain adult stem cells have a great plasticity (they can differentiate into cells different from those in tissues from which they were taken) and can proliferate in vitro without losing their properties. Nevertheless, their use faces several obstacles: in ill or elderly subjects, then these cells can be limited in number or not multiply well in vitro. In this case, auto-grafting of the cells cannot be used. They must be sought in another subject, and allo-grafting causes difficult and sometimes insoluble problems of immunological tolerance. (ii) Embryonic stem cells from surplus human embryos, obtained by in vitro fertilisation, which the parents decide not to use: these cells have a great potential for proliferation and differentiation, but can also encounter problems of immunological intolerance. (iii) Cells obtained from cell nuclear transfer in oocytes: these cells are well tolerated, since they are genetically and immunologically identical to those of the host. All types of stem cells can be obtained with them. However, they do present problems. For obtaining them, female oocytes are needed, which could lead to their commercialization. Moreover, the first steps for obtaining these cells are identical to those used in reproductive cloning. It therefore appears that each type of cell raises difficult scientific and practical problems. More research is needed to overcome these obstacles and to determine which type of stem cell constitutes the best solution for each type of disease and each patient. There are three main ethical problems: (a) to avoid the commercialization of stem cells and oocytes (this can be managed through strict regulations and the supervision of authorized laboratories); (b) to avoid that human embryos be considered as a mere means to an end (they should only be used after obtaining the informed consent of the parents; the conditions of their use must be well defined and research programs must be authorized); (c) to avoid that research on stem cell therapy using cell nuclear replacement opens the way to reproductive cloning (not only should reproductive cloning be firmly forbidden but authorization for cell nuclear transfer should be limited to a small number of laboratories). Overall, it appears that solutions can be found for administrative and ethical problems. Harmonisation of international regulations would be desirable in this respect, in allowing at the same time each country to be responsible for its regulations. A last ethical rule should be implemented, not to give patients and their families false hopes. The scientific and medical problems are many, and the solutions will be long and difficult to find. Regenerative medicine opens important avenues for research, but medical progress will be slow.

[The aged: medical and social aspects]. / Le vieillissement: aspects médicaux et sociaux.

Physical health is affected by physiological aging that impacts on all tissues and organs, notably sensorial systems (hearing, sight), the locomotory and the immunological systems (lowering of resistance to infections). There is an increase with age in the incidence of many cancers (particularly breast, prostate, and colon cancers) and cardiovascular diseases. Regular check-ups are useful in order to take appropriate measures in time. It is important that people maintain regular physical activity and a balanced diet even up to an advanced age and the elderly must learn to adapt themselves to the ever-changing abilities of their organism. It is possible to slow down the aging process through good hygiene and often to maintain autonomy until the end of life. Mental health is threatened by impairment of mental functions, depressive tendencies, and the risk of senile dementia that cannot be foreseen or avoided. It appears that keeping intellectually active and having a good level of education impact favorably on mental aging. Social health depends, for a large part, on the way society accepts and treats the elderly. They must be kept integrated into society and allowed to live at home for as long as possible. Any measures of rejection, discrimination, and exclusion should be opposed. The dignity of the elderly must be respected and activities giving them a feeling of usefulness should be encouraged. It is important to help families who care for their parents at home, to develop and evaluate healthcare networks, and encourage medical professionals and social services to work together. The change in the demographic structure of France is a considerable phenomenon requiring a long-term strategy and not only superficial and cosmetic measures.

An estimate of cancers attributable to occupational exposures in France.

OBJECTIVE: To perform a quantitative estimate of the proportion of cancers attributable to occupational exposures in France in 2000. METHODS: Exposure data for established carcinogens were obtained from a 1994 survey and other sources. Relative risks for 23 exposure-cancer combinations were derived from meta-analyses and pooled analyses. RESULTS: A total of 4335 cases of cancer among men (2.7% of all cancers) and 403 cases among women (0.3% of all cancers) were attributed to occupational exposures. Asbestos, polycyclic aromatic hydrocarbons, and chromium VI were the main occupational carcinogens in men, and asbestos and involuntary smoking were the main carcinogens in women. Corresponding proportions for cancer deaths were 4.0% and 0.6% in men and women, respectively. Lung cancer represented 75% of deaths attributable to occupational exposures. CONCLUSION: Our estimates are comparable with those obtained for other countries in studies based on similar methodology.

[Generalities about carcinogenesis]. / Généralités sur la cancérogenèse.

Currently, carcinogenesis appears to be a process much more complex than what was believed a decade ago. The study of the genome of human tumour cells has revealed a number of genetic and epigenetic modifications much greater than suspected. Moreover, the delay between the first initiating event (when its timing is precisely known) and the clinical emergence of a cancer can be very long, up to 60 years. This long delay shows that risk factors during infancy and childhood deserve critical analysis. The epidemiological data emphasize the role of promotion. For example, alcohol, asbestos are not mutagenic, but cause irritation and cell proliferation. Even for tobacco, the role of promotion appears to be more important than that of mutations. In human carcinogenesis, initial mutations do not appear to be a limiting or crucial step. Finally, the biological study of carcinogenesis has shown that the initiating cell is not passively affected by the accumulation of damages by the carcinogenic physical or chemical agents. It reacts through at least three mechanisms: (a) by fighting against reactive oxygen species (ROS) generated by any oxidative stress, such as UV or ionizing radiations, (b) by eliminating injured cells (mutated or unstable), through two ways--(i) apoptosis, which can be initiated by doses as low as a few millisieverts, thus eliminating cells with genomes that have been damaged or ill-repaired, (ii) death of cells during mitosis when lesions have not been repaired--, (c) by stimulating or activating DNA repair systems. Furthermore, intercellular communication systems inform a cell about the presence of an insult in neighbouring cells. A system of intercellular induction of apoptosis exists whereby non-transformed cells can selectively remove transformed cells. Modern transcriptional analysis of cellular genes using microarray technology reveals that many genes are activated by doses of carcinogenic agents much lower than those for which mutagenesis is observed. These methods have been a source of considerable progress. Moreover, it was thought that carcinogenesis was initiated by lesions of the genome affecting at random a few specific targets (proto-oncogenes, suppressor genes, etc.). This relatively simple model has been replaced by a more complex one, in which the relationship between the initiated cells and their microenvironment plays an essential role. Thus, the carcinogenic process is counteracted by effective defence mechanisms in the cell, tissue and the organism. With regard to tissue, the mechanisms that govern embryogenesis and direct tissue repair after injury appear to play also an important role in the control of cell proliferation. This is particularly important when a transformed cell is surrounded by normal cells that appear to be able to inhibit its proliferation. Tissue disorganization by inflammation or by the death of a large proportion of cells is often associated with the escape of the initiated cells and the emergence of a clone of pre-neoplastic-neoplastic cells. The effectiveness of immunosurveillance is also shown by the large increase in the incidence of several types of cancers among immunodepressed people.

Twenty-five years of follow-up in patients with operable breast carcinoma: correlation between clinicopathologic factors and the risk of death in each 5-year period.

BACKGROUND: Some investigators have suggested a decreased prognostic value for conventional prognostic factors over time in patients with breast carcinoma. The objective of this study was to assess the effect of prognostic factors on the risk of death in patients with breast carcinoma over a long follow-up. METHODS: The authors assessed clinicopathologic prognostic factors in patients with early-stage breast carcinoma over a follow-up > 25 years and analyzed the variation of their effect on death in consecutive 5-year follow-up intervals. The study included 2410 women who primarily underwent complete surgical resection. Time-dependent variables were analyzed by using different multivariate models. RESULTS: Four factors were related strongly to the risk of death in the first 5 years: tumor size, histologic grade, the number of involved axillary lymph nodes, and age at diagnosis. After 10-15 years of follow-up, only age at diagnosis was related to the risk of death. The effect of powerful prognostic factors, except age at diagnosis, on the risk of death was time limited, and no effects or very small effects were detectable after 10 years of follow-up. CONCLUSIONS: Conventional and widely accepted prognostic factors may explain a significant portion of early deaths among patients with early-stage breast carcinoma, but they were of limited value to explain late mortality, that also may be influenced by late events, such as new primary malignancies and treatment complications. Cancer 2006. (c) 2006 American Cancer Society.