Long term investigation of late effects in ankylosing spondylitis patients treated with radium-224

An epidemiological study has been carried out on 1462 ankylosing spondylitis (AS) patients followed since 1971 at the GSF - National Research Center for Environment and Health. The aim of the study was to ascertain the late health effects occurring in these patients who had received repeated intravenous injections of the short lived α-emitter 224radium between 1948 and 1975 (excluding patients treated additionally with X-rays). The then usual therapeutic protocol consisted of a total of 10 to 12 injections of 1.036 MBq (28 μCi) of 224Ra each, given at weekly intervals. This resulted in a cumulative α-dose of 0.56 to 0.67 Gy to the marrow-free skeleton (bone surface dose: ∝ 5.5 Gy) of a 70-kg-man (standard man). These patients have been followed together with a control group of 1324 ankylosing spondylitis patients not treated with radioactive drugs and/or X-rays. Up to August 2004, causes of death have been ascertained for 913 exposed patients and 971 controls (mean follow-up time ∝ 26 yr in the exposed group or ∝ 24 yr in the control group). In the exposed group there has been a total of 251 malignant diseases (vs. 277.0 expected cases) and 233 cases (vs. 302.4 exp.) among the controls. In the exposure group 16 cases of kidney cancer (vs. 8.7 cases expected, p = 0.02), 6 cases of liver cancer (vs. 3.3 exp., p = 0.12), and 4 cases of thyroid cancer (vs. 1.1 exp., p = 0.03) were observed. The most striking observation, however, were the 16 cases of leukaemia in the exposure group (vs. 6.5 cases expected, p = 0.001) compared to only 10 cases of leukaemia in the control group (vs. 7.1 cases expected, p = 0.2). Further subclassification of the leukaemias demonstrated a high increase of myeloid leukaemia in the exposure group (10 cases obs. vs. 2.8 cases exp., p <0.001), and particularly, of myeloid leukaemia (7 cases observed vs. 1.7 expected, p = 0.002), whereas in the control group the number of observed cases is within the expected range (3 myeloid leukaemias vs. 2.9 cases exp.). Out of these 7 cases of acute myeloid leukaemia, 4 cases have been observed at doses comparable to those of the 224Ra treatment practised currently with the pharmaceutical SpondylAT registered (10 injections of 1 MBq each), in one case the 224Ra-dose was the 0.6fold, in another case 1.6fold, whereas in one case the total dose could not be verified exactly. Similar higher incidences of leukaemia have not been found in another group of patients treated with higher doses or dose rates of 224Ra, observed by Spiess and co-workers. However, the enhanced leukaemia incidence in our exposed group is in line with results from animal experiments in mice having been injected with bone seeking alpha-emitters given at low dose rates. (orig.)