thorium-x and Spondylitis--Ankylosing

Up to the end of World War II, there was no effective therapy against bone tuberculosis, and even today there is no treatment for ankylosing spondylitis. However, in the 1940s up to about 1956, radiotherapy with "Peteosthor" - a drug containing Thorium X ((224)Ra) as an effective compound - was introduced in Germany as a presumed cure and it maintained a central place in the treatment of these diseases. In 1948, I was entrusted to assess the new treatment. Animal studies and the clinical evaluation of the patients made me soon realise a number of severe adverse health effects which induced me to pronounce and subsequently repeat warnings against the intravenous administration of high doses of (224)Ra, especially because it was then administered predominantly to children and juveniles. As a consequence, this type of treatment was finally abandoned in 1956. But there remained a need to observe and document the resulting late health effects. Already in 1967, our initial follow-up study provided data for about 800 patients with exact information on the (224)Ra dose levels administered, administration schemes, and the resulting detrimental effects. A large number of bone sarcomas was the most severe consequence, but even today there is a broad spectrum of other grave health effects. A summary of the major scientific insights which have been achieved in the course of the still on-going epidemiological studies is part of this report.

Topics: Aged; Female; Follow-Up Studies; Germany; Humans; Leukemia, Radiation-Induced; Male; Middle Aged; Neoplasms, Radiation-Induced; Radiation Injuries; Radiopharmaceuticals; Radiotherapy Dosage; Radium; Spondylitis, Ankylosing; Thorium; Time Factors; Tuberculosis, Osteoarticular

Topics: Clinical Trials as Topic; Humans; Radium; Spondylitis, Ankylosing; Thorium; Treatment Outcome

Twelve years after receiving radiation therapy with thorium X (280 microCi) for long-standing Bechterew's disease (ankylosing spondylitis) a 52-year-old man was found, by ultrasonography and computed tomography, to have a round mass, 11 x 12 cm, in the left lobe of the liver. Laparoscopy discovered coarse, discoloured nodes on the surface of the right and left lobes of the liver which histologically showed hepatocellular carcinoma. There were no known risk factor for liver carcinoma (like cirrhosis, positive hepatitis B serology, alcohol abuse, haemochromatosis or alpha 1-antitrypsin deficiency). As exploratory laparotomy found the tumour to be inoperable, 15 chemotherapeutic embolizations were performed. An abdominal wall metastasis was resected after 17 months. At the time of this report, 20 months after the diagnosis was first made, the patient is in a poor general condition. Internal radiotherapy with thorium X was used, all else having failed, in the treatment of severe ankylosing spondylitis. Although it is not possible to prove a direct causal relationship between the thorium X radiation and development of a liver carcinoma, the coincidence is remarkable.

Topics: Carcinoma, Hepatocellular; Combined Modality Therapy; Humans; Injections, Intravenous; Liver Neoplasms; Male; Middle Aged; Neoplasms, Radiation-Induced; Radium; Spondylitis, Ankylosing; Thorium; Time Factors

The use of low doses of radium-224 (224Ra) chloride for the treatment of ankylosing spondylitis was stopped following the discovery that patients treated with it had a higher than control incidence of leukaemia and other cancers. This was so even though the treatment resulted in decreased pain and increased mobility-both of which are associated with decreased mortality. It was decided to re-analyze the epidemiological data looking at all causes of death. The risk of leukaemia, solid cancer, death from non-cancer causes and from all causes in a study populations of men that received either the typical dose of 5.6 to 11.1 MBq of 224Ra, any dose of 224Ra or no radium were compared using the Cox proportional hazard model. For patients that received the typical dose of 224Ra agreed with the excess cancer was similar to that reported in previous studies. In contrast, these patients were less likely to die from non-cancer diseases and from all causes of death than the control patients. No excess mortality was also found in the population of all males that received the radionuclide. It is concluded that 224Ra treatment administered at low doses to patients with ankylosing spondylitis did not impact mortality from all causes. The study demonstrates the need to consider all causes of death and longevity when assessing health impacts following irradiation.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Cause of Death; Dose-Response Relationship, Radiation; Follow-Up Studies; Humans; Injections, Intravenous; Leukemia; Male; Middle Aged; Neoplasms, Radiation-Induced; Radiotherapy Dosage; Radium; Safety-Based Drug Withdrawals; Spondylitis, Ankylosing; Thorium; Time Factors

We performed an epidemiological study on 1,471 ankylosing spondylitis patients treated with repeated intravenous injections of the short lived alpha-emitter (224)Ra (excluding radiation therapy with X-rays) between 1948 and 1975. These patients have been followed together with a control group of 1,324 ankylosing spondylitis patients treated neither with radioactive drugs nor with X-rays. The mean follow-up time was 26.3 years in the exposed and 24.6 years in the control group. To date, causes of death have been ascertained for 1,006 exposed patients and 1,072 controls. Special emphasis was placed on the reporting of malignant diseases. Expected numbers of cases were computed for the age, sex and calendar year distribution of both groups using cancer registry incidence rates. In the exposed group 18 cases of kidney cancer (vs. 9.1 cases expected, P < 0.01) and 4 malignant thyroid tumours (vs. 1.2 cases expected, P = 0.03) were observed. In the control group the observed cases for these tumours were not significantly elevated. The most striking observation, however, were the 21 cases of leukaemia in the exposed 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 sub-classification of the leukaemias demonstrated a high increase of myeloid leukaemia in the exposed group (12 cases observed vs. 2.9 cases expected, P < 0.001), and out of these, especially a high excess of acute myeloid leukaemias (7 cases observed vs. 1.8 expected, P = 0.003). In the controls the observed cases are within the expected range (4 myeloid leukaemias vs. 3.1 cases). This increase in total leukaemias as well as particularly in myeloid leukaemias is significant in direct comparison between the exposed and control groups too (P < 0.05). The enhanced leukaemia incidence in the exposed group is in line with the observation of increased leukaemia incidence in mice injected with (224)Ra.

Topics: Aged; Alpha Particles; Female; Follow-Up Studies; Half-Life; Humans; Injections; Leukemia; Male; Middle Aged; Neoplasms, Radiation-Induced; Radiotherapy Dosage; Radium; Retrospective Studies; Spondylitis, Ankylosing; Thorium; Time Factors

In German-speaking countries, the intravenous treatment of ankylosing spondylitis (AS) with radium-224 ((224)Ra) was common between the late 1940s and 2005. In this long-term investigation, the risk of malignant diseases following intravenous (224)Ra treatment for AS was assessed.. In a prospective long-term study, 1,471 patients with AS who were treated with (224)Ra between 1948 and 1975 have been followed together with a control group of 1,324 AS patients treated neither with radioactive drugs nor with X-rays. Standardized questionnaires to evaluate the patients' health status were used. Observed numbers of malignant diseases were compared with those of the control group as well as with expected numbers for a normal population.. After 26 years of follow-up, causes of death have been certified for 1,006 patients of the exposure group (control group: 1,072 patients). Significantly increased rates of myeloid leukemia (12 cases observed vs. 2.9 expected; p < 0.001), kidney cancer (18 vs. 9.1; p < 0.01), thyroid cancer (4 vs. 1.2; p = 0.03) and borderline significantly increased rates of cancer of female genital organs (10 vs. 5.6; p = 0.06) were found in the exposure group in contrast to no significant increases of these diseases in the control group. Rates of pulmonary and gastrointestinal malignancies were not increased. Lymphatic leukemia (exposure group: 8 vs. 2.7; p < 0.01; control group: 7 vs. 3; p = 0.03) was significantly elevated due to a high rate of chronic lymphatic leukemia in both, the exposure as well as the control group.. Treatment of AS with (224)Ra led to increased incidences of myeloid leukemia and malignancies of kidneys, thyroid and female genital organs. Although this kind of therapy is now abandoned, there is a need for close follow-up of patients who received it.

Topics: Female; Genital Neoplasms, Female; Humans; Kidney Neoplasms; Leukemia, Myeloid; Male; Neoplasms, Radiation-Induced; Radium; Spondylitis, Ankylosing; Thorium; Thyroid Neoplasms

To investigate long-term health effects in AS patients treated with (224)Ra.. 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.. 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).. 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.

Topics: Adult; Aged; Aged, 80 and over; Denmark; Epidemiologic Methods; Female; Germany; Humans; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Radiation-Induced; Male; Middle Aged; Radium; Spondylitis, Ankylosing; Thorium

Cost-benefit analyses are helpful in setting priorities for funding health-care programs. The authors studied the cost/benefit of treatment with radium-224 compared to the treatment without radium-224 in patients with ankylosing spondylitis (AS).. The data of a 2-year retrospective observational study were used to estimate cost/benefit of [224Ra] therapy. Twelve patients treated with [224Ra], complete recruit in AOK Saxony, matched (age, gender, employment status) with twelve patients receiving conservative treatment without [224Ra], were compared for lost productivity and direct medical costs, such as doctor visits, medication and hospitalization, 1 year before and after treatment.. 1 year after the first i.v. injection of [224Ra], all cost factors in the case group were reduced compared to 1 year before treatment with [224Ra] (hospitalization 29.4%, doctor visits 23.5%, medication 9.4%, and lost productivity even 82.3%). The total costs decreased by an average of 3,870 Euros. Because of the small sample the differences showed a trend but were not significant.. The use of [224Ra] in patients with AS seems to reduce lost productivity and direct medical costs, but additional studies based on more patients and long-term data are needed.

Topics: Adult; Aged; Cost-Benefit Analysis; Disability Evaluation; Drug Costs; Germany; Health Expenditures; Humans; Male; Matched-Pair Analysis; Middle Aged; Radium; Referral and Consultation; Retrospective Studies; Spondylitis, Ankylosing; Thorium

Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease which reduces the quality of life and leads to disability in approximately one-third of the patients. The spectrum of therapeutic modalities is limited. The renaissance of the use of (224)Ra-radium chloride for AS treatment, however, gives rise to concern which should result in the reconsideration of (224)Ra dosimetry and in the discussion of the risks associated with this treatment. The present study introduces new dosimetric calculations for alpha and beta/gamma rays performed according to the model proposed by the International Commission on Radiological Protection (ICRP). After a treatment schedule of 10 intravenous injections, each with 1 MBq of (224)Ra, the absorbed doses were calculated to be highest on the bone surface of the patient (4.4 Gy) with a resulting effective dose of 2.5 Sv.

Topics: Adult; Alpha Particles; Beta Particles; Computer Simulation; Gamma Rays; Humans; Models, Biological; Organ Specificity; Radiometry; Radiopharmaceuticals; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Radium; Risk Assessment; Spondylitis, Ankylosing; Thorium; Tissue Distribution

Topics: Arthritis, Rheumatoid; Brachytherapy; Follow-Up Studies; Humans; Radiotherapy Dosage; Radium; Spondylitis, Ankylosing; Synovial Membrane; Thorium

Topics: Clinical Trials as Topic; Humans; Radium; Spondylitis, Ankylosing; Thorium; Treatment Outcome

The incidence of lens opacifications that impaired vision (cataract) was analyzed among 831 patients who were injected with known dosages of 224Ra in Germany shortly after World War II. The dependence of the incidence on dosage, i.e., injected activity per unit body weight, and on time after treatment was determined. The observations are equally consistent with proportionality of the incidence of cataract to the square of dosage or with a linear dependence beyond a threshold of 0.5 MBq/kg. The possibility of a linear dependence without threshold was strongly rejected (P less than 0.001). The analysis of temporal dependences yielded a component that was correlated with the injected amount of 224Ra and a component that was uncorrelated. The former was inferred by a maximum likelihood analysis to increase approximately as the square of the time after treatment. The component unrelated to the treatment was found to increase steeply with age and to become dominant within the collective of patients between age 50 and 60. The relative magnitudes of the two components were such that a fraction of 55 to 60% of the total of 58 cataracts had to be ascribed to the dose-related incidence. Impaired vision due to cataract was diagnosed before age 54 in 25 cases. In terms of injected activity per unit body weight no dependence of the sensitivity on age was found; specifically there was no indication of a faster occurrence of the treatment-related cataracts in patients treated at older ages.

Topics: Adult; Age Factors; Body Weight; Cataract; Child; Dose-Response Relationship, Radiation; Female; Follow-Up Studies; Humans; Male; Middle Aged; Models, Biological; Radiation Injuries; Radium; Spondylitis, Ankylosing; Thorium; Time Factors

Topics: Adolescent; Adult; Aged; Bone Neoplasms; Child; Female; Follow-Up Studies; Germany, West; Humans; Male; Neoplasms, Radiation-Induced; Radium; Sarcoma; Spondylitis, Ankylosing; Thorium; Time Factors; Tuberculosis

Topics: Bone Neoplasms; Female; Follow-Up Studies; Germany, West; Humans; Leukemia, Radiation-Induced; Male; Neoplasms, Radiation-Induced; Radiation Dosage; Radium; Risk; Spondylitis, Ankylosing; Thorium; Time Factors

Topics: Adult; Aged; Cataract; Female; Follow-Up Studies; Germany, West; Humans; Male; Middle Aged; Radiation Dosage; Radiation Injuries; Radium; Spondylitis, Ankylosing; Thorium; Time Factors; Tuberculosis

Topics: Humans; Radium; Spondylitis, Ankylosing; Thorium; Time Factors

Topics: Adult; Humans; Leukemia, Radiation-Induced; Neoplasms, Radiation-Induced; Radiation Injuries; Radium; Spondylitis, Ankylosing; Thorium

Topics: Adult; Female; Humans; Male; Middle Aged; Outcome and Process Assessment, Health Care; Radiation Injuries; Radium; Spondylitis, Ankylosing; Thorium

Topics: Cell Nucleus; Hematopoietic System; Humans; Leukopenia; Radiation Injuries; Radium; Spondylitis; Spondylitis, Ankylosing; Thorium

Topics: Ankylosis; Humans; Radium; Spondylitis; Spondylitis, Ankylosing; Thorium

Topics: Ankylosis; Humans; Radioactivity; Radium; Spondylitis; Spondylitis, Ankylosing; Thorium

Topics: Ankylosis; Humans; Radium; Spondylitis; Spondylitis, Ankylosing; Thorium

Topics: Humans; Radium; Spondylitis; Spondylitis, Ankylosing; Thorium

Topics: Ankylosis; Humans; Radium; Spondylitis; Spondylitis, Ankylosing; Thorium

Topics: Ankylosis; Humans; Radium; Spondylitis; Spondylitis, Ankylosing; Thorium

Topics: Follow-Up Studies; Humans; Radium; Spondylitis; Spondylitis, Ankylosing; Thorium

Topics: Humans; Radium; Spondylarthritis; Spondylitis; Spondylitis, Ankylosing; Thorium