Side Effects

Acute side effects from 224RaCl are rare, and allergic reactions are not likely because of the absence of additives, the high purity, and the nonimmunogenic nature of the product itself as an ion. An undesirable but frequent effect is an increase in pain during the first days of therapy. Prior to the beginning of a treatment course, the patient should be informed in detail about this harmless and transient, but inconvenient, side effect, which can be treated with analgesics in nearly all cases.

Occasionally, an iridocyclitis may occur during the treatment with 224RaCl. This may be induced by the underlying disease, and is not proven to be triggered by the radionuclide. Nevertheless, treatment with 224RaCl should be discontinued in these patients until the iridocyclitis, which is usually treated symptomatically by an ophthalmologist, has stopped.

In rare cases, a mild depression of the bone marrow with a slight and transient decrease of blood counts is seen, although no case of agranulocytosis has been documented so far. In individual cases, lesions of the liver and colicky discomforts in pre-existing urolithiasis were reported for former 224RaCl formulations.

As ionizing radiation may cause chromosomal damage, the long-term compatibility and the evaluation of any risk of cancer induction is of great interest. In this respect, it is very important to differentiate between the former high-dose 224RaCl treatment regimen using less purified drug formulations between the 1940s and the 1970s and the "modern" therapy. There are two major studies performed by the Institute of Radiation Hygiene, Federal Office for Radiation Protection (BfS) in Germany on a long-term follow up of patients who had received these two different treatment schedules.

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In the early years of RaCl therapy, an aqueous mixture of Ra with traces of eosin and colloidal platinum, called "Petheostor" was used not only to treat AS, but also tuberculosis. Many patients were younger than 21 years, and received higher cumulative doses over a longer time course than would be used today. In a total of 899 patients treated in Germany from 1945 to 1964 with high activities of at least 15 MBq "Petheostor," malignant bone tumors, mostly osteosarcomas, were seen in 56 cases (6.2%). Seventy-six percent of those tumors were seen in a subgroup of patients aged 21 years and younger (21,22).

In a second study, 1577 patients, treated between 1948 and 1975 with a cumulative activity of 10 MBq of 224RaCl, 1 MBq per week, were followed (23) and compared with a control group of 1462 patients with AS, who had not been treated with 224RaCl. The total percentage of malignant tumors was 9.4% in the treated versus 11.0% in the control group. No osteosarcoma was seen; however, there were four other malignant bone tumors (0.25%) observed after 224RaCl treatment—one fibrous sarcoma, one malignant fibrous histiocy-toma, one malignant lymphoma, and one malignant myeloma. Of these four tumors, only the first two were possibly induced by ionizing radiation (15). There was only one malignant myeloma in the control group. Eight cases of myeloid leukemia were observed in the 224RaCl group versus three cases in the nontreated patients; this additional risk of 0.4% for leukemia is significantly increased compared with the controls (P < 0.01). This is consistent with the data obtained from animal studies (24), which demonstrated an increase in the incidence of leukemia with a decrease in the number of malignant bone tumors, by lowering the cumulative activity of 224RaCl. Other animal experiments showed an increasing risk for the development of an osteosarcoma with an organ dose of at least 9 Gy to the bone surface (25)—a value which is not reached by current treatment regimens with a cumulative activity of 10 MBq 224RaCl. According to the data known today, the risk of leukemia induction seems to be slightly increased after the treatment of AS with 224RaCl. This should be considered if an indication for 224RaCl therapy is discussed. However, this risk must be balanced against the well-known risks of long-term intake of nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate, or even the still unknown risks of the new group of "biological" TNF-a-blockers. An elevated risk for malignant bone tumors, however, has not been proven after low-dose treatment with 10 MBq 224RaCl in adults. A meta-analysis of the available literature, ordered by the German Federal Institute for Drugs and Medical Devices, covered 7064 treatments from 1969 to 1983, and showed a nonsignificant increase of 0.1% of the total mortality rate after therapy with 224RaCl in patients with AS (26).

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