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EPIDEMIOLOGICAL STUDIES OF RADIATION CARCINOGENESIS

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There are, at present, 133 surviving patients in the study, who were treated with 224Ra at ages up to 20 years, and who are now in the age group up to about 55 years. These patients shall be called in for careful ophthalmological examinations to be performed at the University of Munich. The patients will be contacted by Prof. H. Spiess who will take responsibility for the organization of this extended project. The mathematical evaluation will be performed within project 3 (Prof. Kellerer) of the current research programme.

Within the next two years the majority of the 133 patients will be motivated to participate in the project.

Project 1: Late effects in 224Ra treated ankylosing spondylitis patients GSF - Prof. Gossner.

Project 2: Late effects in 224Ra treated juvenile and adult patients Universitat Munchen - Prof. Spiess.

Project 3: Epidemiology of radiation carcinogenesis Universitat Munchen - Prof. Kellerer.

The three projects of this research programme are aimed at the epidemiological study of radiation effects in patients injected with 224Ra.
Patients who were under 20 years of age when first injected with radium-224 were investigated. Most cataracts recorded among the 58 patients were diagnosed at an advanced stage when the patients had problems with vision and consulted an eye doctor. The cataracts could therefore not be attributed, in individual cases, to radium treatment and especially among the older patients, some were age related. A mathematical analysis of mature cataracts was performed. The dose and time dependencies of the incidence of cataracts were derived. Critical to the analysis was reliable information on the time after treatment of cataract diagnoses. The analysis showed that most cataracts diagnosed before the age of 53 were radiation induced. No difference in sensitivity with age treatment could be detected. In agreement with other studies it was found that the data are consistent with either a linear dose relation with a threshold or a quadratic relation. Another important conclusion was that a substantial part of the radiation induced cataracts were diagnosed 40 years after radium injection or later.

The health of ankylosing spondylitis patients known to have been treated with radium-224 has been followed. The majority of patients were treated in the years 1948 to 1975 and most received 1 series of 10 weekly injections of about 1 MBq of radium-224 each. This dosage leads to a cumulative alpha-dose of 0.56 Gy to the marrow free skeleton of a 70 kg man. The study consists of 1472 patients in the exposure group and of 1342 patients in the control group. Personal and treatment data exposure have been drawn from the hospital records. Information on current status was gained from reexaminations and from questionnaires. Causes of death were determined preferably from hosptial records, reports from family physicians, or death certificates. The underlying causes of death were classified and registered according to the 7th revision of the International Classification of Diseases. Interest was restricted to those diseases which are known or implied from the higher dose study to be associated with a former administration of radium-224. There is, however, in contrast to the findings in the high dose group, no significant difference between observed and expected cases for cancers of stomach, liver, urinary system, or the female breast neither for the exposure nor for the control group.

3 malignant primary bone tumours were observed in the exposure group. For total leukaemias the increase was highly significant for the exposure group and striking also for the controls compared to a standard population. This indicated an effect of the intake of painkilling or other drugs related to the basic disease which was observed not only in the control group but also in the exposure group prior to irradiation with radium- 224. It is well known that phenylbutazone can cause bone marrow depression. Acute leukaemias occurring in association with phenylbutazone treatment have repeatedly been reported in the literature.

Subclassification of the leukaemias showed a certain preference for the chronic myeloid leukaemia in the exposure group the observed cases were in the range of expectancy. This apparent difference seems somewhat parallel to the fact that in this study bone marrow tumours were more dominant than in the higher dose study.

Certain disorders of the haematopoietic system following treatment with radium-224 were observed earlier by other authors even at the same low dose level. An increased rate of leukaemias would also correspond with results from animal experiments with bone seeking alpha emitters given at very low dose rates, lower than those found to cause bone tumours. Also for plutonium-239, a bone surface seeker like radium-224, the induction of myeloid leukaemia has been demonstrated in mice down to dose rates of a few mGy/day or even less.

The health followed of 900 patients (509 men, 173 women, 111 boys, and 107 girls) who received repeated injections of radium-224 after World War II, for treatment of ankylosing spondylitis or bone tuberculosis, and for other noncancerous diseases. At the time of last contact 553 of 900 patients were deceased. 54 patients developed bone sarcomas, 2 patients developed a second bone sarcoma. The last bone tumour appeared 1 year ago, but the risk appears nearly extinct now. There were 107 observed soft tissue malignancies, and this number is close to the expectation based on the distribution in age, the length of the follow up of the cohort, and the age specific population rates for the different malignancies. The age specific rates were taken from the Saarland and the former German Democratic Republic (GDR) tumour registry. For a few cancer types, however, the observed numbers are in excess of the expectation values.

The breast cancer excess came as a surprise, with 16 cases observed versus 4.1 to 6.1 cases expected. Liver cancers have occurred in 7 radium-224 patients, a significantly larger number than the 1.1 to 1.2 cases expected. Kidney cancers have occurred in 6 patients versus 2.4 to 2.5 cases expected.

The tumour appearance times ranged from 12 to 35 years after the start of radium-224 injections. Leukaemias occurred in 6 patients compared to 2 cases expected based on German Cancer Statistics. 5 leukaemia cases were found among the radium-224 spondylitis patients, whereas from German population rates 2.2 cases would be expected. Of the 6 leukaemias among the radium-224 patients in the study, 4 occurred among the 396 spondylitis for which few drugs were available at that time in Germany. Statistical and radiobiological evidence suggests that radium-224 and its decay products can induce bone sarcomas and may induce breast, liver, and kidney cancers in humans. In the continued followed up, the possibility of increased rates of additional types of cancers wil l need to be monitored.

An analysis has been performed of the incidence of soft tissues tumours in the bone turberculosis and Morbus Bechterew patients treated with radium-224. The expected incidences have been computed on the basis of the age distribution and the time at risk of the patients. Suitable statistical methods have been derived and applied to determine excess frequencies and possible correlation with injected activity.

In the collective of patients followed a variety of soft tissue neoplasms has been observed during recent years. In their entirely the tumour frequencies are in line with the increasing incidences expected in the aging collective. For a few tumour types, breast tumours, liver tumours and kidney tumours the expected numbers are substantially smaller than the observed frequencies. The difference is particularly striking for the breast cancers, and there is specific interest in this apparent excess of view of the recent reports on elevated breast cancer risks in the women who have been irradiated against tinea capitis as children.

However, the age specific breast cancer rates for Germany are somewhat uncertain, since data are available only from the registries of Saarland and of the former German Democratic Republic (GDR). Beyond the mere observation of an excess, it is important to examine the correlation of the incident cases with injected activity. For this purpose suitable rank order procedures have been utilized and it has been concluded, that, at this point in the follow up there is no significant trend with injected activity. This underlines the need for a special control group that may still be formed among bone tuberculosis patients. In this planned investigation particular attention will have to be given to X-ray diagnostics that may have been frequent among the patients.
Project 1 is concerned with more than 1500 ankylosing spondylitis patients treated with intravenous injections of 224Ra. The alpha-ray doses to the skeleton of the patients are considerably lower than the doses in the earlier patients who are being studied in project 2. The analysis of the causes of death and of lesions related to the disease in the group of Ra224 patients with a low mean skeletal dose of 0.67 Gy is paralleled by the study of a control group of ankylosing spondylitis patients not treated with radioactive drugs or X-rays.

Project 2 continues the study of patients who were treated in a German clinic shortly after the war as juveniles for bone tuberculosis and as adults for ankylosing spondylitis. The data, particularly for osteosarcomas, are largely complete, but additional recent observations of various other mostly nonstochastic, radiation effects are still being collected. Furthermore dose assignments and modifications of additional parameters will be updated.

Closely related are the epidemiological studies to be carried out in project 3. This project is concerned with the statistical evaluation of the data in projects 1 and 2. Past epidemiological work in the related earlier project BIO-D-461-81-D(B) has been performed for other data, and these studies will continue. However, the work has recently been focused on the analysis of the osteosarcoma data of project 2. The preliminary results have led to unexpected conclusions that will require further analysis by modern statistical techniques, such as the maximum likelihood analysis in terms of the proportional hazards model or related approaches. The essential problems are the presence or absence of differences in the sensitivity of juveniles and adults, and also the confirmation or rejection of a dose-rate effect.

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GSF - FORSCHUNGSZENTRUM FUER UMWELT UND GESUNDHEIT GMBH
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Letzte Aktualisierung: 23 Januar 1994

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Permalink: https://cordis.europa.eu/project/id/BI6*0221/de

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