Increased risk of myeloid leukaemia in patients with ankylosing spondylitis following treatment with radium-224.

OBJECTIVE: To investigate long-term health effects in AS patients treated with (224)Ra. METHODS: A prospective epidemiological study has been carried out on 1471 AS patients treated with repeated intravenous injections of (224)Ra between 1948 and 1975. These patients have been followed together with a control group of 1324 AS patients not treated with radioactive drugs and/or X-rays. Numbers of malignancies expected in a normal population were computed from German and Danish cancer registry data. RESULTS: After a mean follow-up time of 26 yrs in the exposed group or 25 yrs in the control group, causes of death have been ascertained for 1006 exposed patients and 1072 controls. In particular, 19 cases of leukaemia were observed in the exposure group (vs 6.8 cases expected, P < 0.001) compared to 12 cases of leukaemia in the control group (vs 7.5 cases expected). Further subclassification of the leukaemia cases demonstrated a high increase of myeloid leukaemia in the exposure group (11 cases observed vs 2.9 cases expected, P < 0.001), especially a high excess of acute myeloid leukaemias (7 cases observed vs 1.8 cases expected, P = 0.003), whereas in the controls the observed cases are within the expected range (4 myeloid leukaemias vs 3.1 cases expected). CONCLUSIONS: The enhanced leukaemia incidence in the exposed group is in line with results from experiments in mice injected with varying amounts of the bone-seeking alpha-emitter (224)Ra. In these studies, in animals exposed to lower doses of (224)Ra, i.e. at doses lower than those found to induce osteosarcomas, an increased risk of leukaemia was observed.

The European Radiobiology Archives (ERA)--content, structure and use illustrated by an example.

The European Radiobiology Archives (ERA), supported by the European Commission and the European Late Effect Project Group (EULEP), together with the US National Radiobiology Archives (NRA) and the Japanese Radiobiology Archives (JRA) have collected all information still available on long-term animal experiments, including some selected human studies. The archives consist of a database in Microsoft Access, a website, databases of references and information on the use of the database. At present, the archives contain a description of the exposure conditions, animal strains, etc. from approximately 350,000 individuals; data on survival and pathology are available from approximately 200,000 individuals. Care has been taken to render pathological diagnoses compatible among different studies and to allow the lumping of pathological diagnoses into more general classes. 'Forms' in Access with an underlying computer code facilitate the use of the database. This paper describes the structure and content of the archives and illustrates an example for a possible analysis of such data.

The European Radiobiology Archives (ERA), present state and future developments.

The European Radiobiology Archives (ERA) aims to collect most of the information still available in Europe on long-term animal experiments--including some selected human studies suitable for comparison with animal data--and to make them available to the scientific community for further analysis. ERA cooperates with the US (National Radiobiology Archives, NRA) and Japan (Japanese Radiobiology Archives, JRA) in the International Radiobiology Archives (IRA).

Late effects in ankylosing spondylitis patients treated with 224Ra.

This study is comprised of 1577 ankylosing spondylitis patients from 9 German hospitals who have been treated with multiple injections of (224)Ra. The majority of the patients, most of them treated in the years 1948-1975, received one series of 10 weekly intravenous injections of about 1 MBq of (224)Ra each. This dose leads to a mean absorbed dose due to alpha-particle radiation of 0.56 Gy to the marrow-free skeleton of a 70- kg man (mean bone surface dose of about 5 Gy). To provide comparative information on causes of death and on health effects possibly related to the basic disease itself, a control group of 1462 ankylosing spondylitis patients with roughly the same age distribution has been established. By the end of 1998, 649 patients in the exposed group and 762 control patients had died. Among other observations, it is of particular interest that 13 cases of leukemia in the exposed group have been observed. This is a highly significant excess (P < 0.001) compared to a standard population, but only a marginally significant excess in comparison to the seven cases observed in the control group. Subclassification of the leukemias shows a clear preponderance of the myeloid leukemias in the exposed group (8 cases observed compared to 1.7 cases expected, P < 0.001), whereas in the control group the observed cases are within the expected range for myeloid leukemia (3 cases observed compared to 2.2 cases expected, P = 0.3). The (224)Ra cohort of the earlier study (higher-dose group) has provided a risk coefficient that predicts about 8 excess malignant bone tumors for the irradiated cohort in this study. In actuality, 4 cases of malignant tumors in the skeleton have been observed so far. However, excess of breast cancer has not been observed in either the irradiated or the control group, which is in contrast to the findings in the earlier (224)Ra cohort of Study I.

International radiobiology archives of long-term animal studies: structure, possible uses and potential extension.

Animal experiments have contributed a great deal to our information on effects and risks arising from exposure to radionuclides. This applies, in particular, to alpha-emitting radionuclides where information from man is limited to thorotrast, 224Ra and 226Ra. The late C.W. Mays was the first to suggest that animal data in conjunction with epidemiological data could allow estimates of human risks for radionuclides - predominantly from actinides - where information in man is scarce. The 'International Radiobiology Archives of Long-term Animal Studies' were created through the combined efforts of European, American and Japanese scientists and aim to safeguard the large amount of existing data on long-term animal experiments and make them available for, among others, an improved assessment of risks from alpha-emitting radionuclides. This paper summarizes the structure of the archives and reviews their present status and future plans. It also demonstrates the extensive information available in these archives on alpha-emitting radionuclides which is suitable for further analysis. Also, the structure of the animal archives could - in a slightly modified form - accommodate the epidemiological data available on 224Ra and thorotrast and, thus, facilitate a direct comparison of data from man, dogs and rodents.

Follow-up study of late effects in 224Ra treated ankylosing spondylitis patients.

We are following 1531 patients treated with 224Ra from 14 hospitals in the F.R.G. and 267 control patients with ankylosing spondylitis not treated with any form of ionizing radiation. Since 1970 three cases of malignant tumour in the skeleton have been found among 224Ra-treated patients with skeletal doses below 90 rad compared with 0.4-0.6 expected. Two of these three cases were tumours of the bone marrow. An effect of 224Ra on the haematopoietic system cannot be excluded. Also, seven cases of cataract were found among 274 224Ra patients. The mean time since 224Ra treatment was 26 yr. The mean age at diagnosis was 66 yr. The cataract incidence was not unusual for people of this age.

Long-term clinical investigation of patients with ankylosing spondylitis treated with 224Ra.

Between 1952 and 1980 about 250 patients with ankylosing spondylitis were treated with 224Ra at the Orthopaedic University Hospital of Frankfurt/M. In 1970, 119 of them were examined and X-rayed as was another group of 40 patients in 1980. The results of those examined could be compared with a group of patients treated without 224Ra. Patients with 224Ra demonstrated a long-lasting period of subjective improvement after the treatment, with reduced consumption of antirheumatoid and analgesic drugs, on the average. Blood examinations show inflammatory activities. Nevertheless, the ankylosing spondylitis proceeded. In the final stages of the disease, neither the clinical aspects nor the X-rays showed any specific effect due to 224Ra. Blood examinations, especially blood cells and liver, had shown no specific changes. We observed no case of malignant bone tumor. Of the 169 examined patients, 22 had a total of 32 children after the treatment with 224Ra. Among these was a set of twins with cerebral palsy and diabetes insipidus renalis. In conclusion, 224Ra in ankylosing spondylitis is a recommended treatment without higher risk compared to the common therapy with drugs.