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Departments of Endocrinology (C.F.A.E.-R., J.A.R., M.J.G., E.P.M.C., A.M.P., J.W.A.S.) and Radiology (G.J.V., R.v.d.B.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands
Address all correspondence to: J. A. Romijn, M.D., Ph.D., Department of Endocrinology, C4-R, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: j.a.romijn{at}lumc.nl.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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We explored the role of selective embolization of bone metastases as an alternative palliative treatment option. This approach was initially introduced in the management of arteriovenous malformations and preoperative and therapeutic management of well-vascularized benign and malignant tumors (10, 11, 12). A review of the literature is given (13). Because embolization can give rapid relief of pain and neurological symptoms in the case of bone metastases, we previously decided to treat four patients with vertebral metastases from follicular carcinoma with this technique (13). Because of the initial success, we extended our series and evaluated the long-term effects of embolization in 16 patients with symptomatic bone metastases of thyroid carcinoma. In our opinion, embolization of bone metastases of differentiated thyroid carcinoma is an attractive palliative therapeutic alternative that may offer rapid, but transient, relief of symptoms.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Between March 1994 and June 2002, we performed selective embolization in 16 patients with symptomatic bone metastases of differentiated thyroid carcinoma, in which radical surgery was impossible. The group consisted of eight male and eight female patients with a median age of 61 yr at the time of diagnosis. Additional patient characteristics are given in Tables 1
and 2. All patients were initially treated by total thyroidectomy. In all, but two patients (patients 1 and 8), thyroidectomy was followed by radioiodine ablation therapy with a dose of 2800 MBq, or, when surgery was incomplete or metastases were present, 6000 MBq. In patients 1 and 8, the first radioiodine therapy was given after embolization because the bone metastases were the presenting symptom of thyroid carcinoma. Selective embolization of bone metastases was carried out because all patients had symptomatic bone metastases varying from pain to severe spinal cord compression. In these 16 patients, a total of 41 embolizations were performed (Tables 2 and 3), 31 embolizations for vertebral lesions, 8 for pelvical metastases, and 2 for lesions at other sites (Tables 2 and 3). Embolization was performed with an interval of 6 d to 12.3 yr after total thyroidectomy. Seven patients were embolized at least two times, with a maximum of 13 embolizations in patient 11 (two embolizations were performed on the same day and the results of these are combined in embolization nr. 5 in Table 2). Additional therapies consisting of radioiodine therapy, external irradiation, or laminectomy were performed before embolization in nine procedures (five patients), after embolization in nine procedures (two patients) and both before and after embolization in eight procedures (seven patients, Tables 2 and 3). More specifically, external irradiation on the skeletal metastases embolized in this study was given before embolization in eight procedures (six patients) and after embolization in seven procedures (six patients). Surgery (laminectomy) for vertebral metastases embolized in this study was performed before embolization in two procedures (two patients) and after embolization in six procedures (three patients). Radioiodine was given within a period of 5 months before embolization in 11 procedures (eight patients) and after embolization in nine procedures (seven patients).
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Successful embolization was defined as an improvement in clinical symptoms for at least 1 month without progression of tumor dimensions at radiological examination (CT or MRI, change in tumor dimensions in two dimensions before and after embolization <25% of original dimensions). Thyroglobulin levels were not included in the criteria for success: an increase in thyroglobulin levels cannot be regarded as proof for an unsuccessful procedure because progression of other metastases could have contributed to this rise. A decrease in thyroglobulin levels without an improvement of clinical symptoms cannot be considered successful palliation. When no radiological examination was performed after embolization, clinical symptoms were used as parameter for success.
The duration of success was defined as the time period evolving after a successful embolization until relapse or worsening of the symptoms occurred related to the embolized metastasis. When no relapse occurred, the duration of success was regarded as the time period between the embolization and the date of last follow-up.
Last known follow-up state was classified as regression (decrease in subsequent thyroglobulin levels greater than 10%, decrease in radiological dimensions 
25%), progressive disease or death (Table 1
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Selective embolization technique
In all patients, serum creatinine levels were checked and if found elevated more than 5% of the upper normal limit, the procedure was not performed. Embolization was performed as follows: after localizing the metastatic lesion by MRI or CT, the feeding arteries were visualized by selective catheterization. When a pathological vascular pattern was recognized and verified that no vital structures were supplied by the particular vessel, particles of polyvinyl alcohol (Ivalon, Laboratoires Nycomed S.A., Paris, France) were injected. The technical success of embolization was verified by angiography performed immediately after the embolization. In case of multiple lesions, only those that were symptomatic or threatening were embolized. The maximum number of lesions that could be embolized within one procedure was approximately five. According to Dutch law, approval from each patient was obtained before embolization, after full explanation of the treatment options, procedures, and potential complications. Palliative embolization of symptomatic tumor metastases is included in the routine clinical care in the Leiden University Medical Center and as such is not considered to be an experimental procedure. Therefore, the procedures described in this study did not require institutional review board approval.
Assays
Thyroglobulin was measured with immunoradiometric assay using the Dynotest TG (Brahms, Berlin, Germany), sensitivity 0.05 mg/ liter, interassay variability 0.3 mg/liter.
Statistics
Data are given individually for all patients. Normally distributed values are summarized as mean ± SD, not normally distributed data as median. Categorical data or proportions are expressed as the number of subjects or embolizations. Differences in not normally distributed data were analyzed with the Mann-Whitney test, categorical variables between subgroups were analyzed with the 
2 test. A P value of less than 0.05 was considered significant.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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After embolization, there was a rapid relief of pain and neurological symptoms, sometimes within minutes, usually within 1 d, in 26 of a total of 41 procedures. In 11 procedures, symptoms remained stable, whereas in three procedures, the patient had progressive symptoms. In seven patients neurological symptoms other than pain were present. Successful embolizations improved all neurological symptoms, except embolizations 11 and 12 in patient 11, that relieved pain but not the paraplegia.
Radiological examination was performed after 22 procedures and demonstrated a reduction of tumor size in 11 cases. In seven cases, the tumor was stable and in four tumor size increased. Serum thyroglobulin levels decreased after 20 and increased after 16 embolizations. Overall, there was a median decrease in serum thyroglobulin levels of 6.5 µg/liter.
According to the criteria for success as defined in Patients and Methods, 24 of 41 (59%) embolization procedures were successful (Tables 2 and 3). In two embolizations (patients 4 and 8, second embolization), symptoms improved, whereas tumor dimensions increased. According to the criteria, these were considered unsuccessful.
No differences in success rates were observed between embolization procedures that were or were not preceded or followed by surgery, radioiodine, and/or external irradiation. The results for all additional therapies as well as radioiodine are given in Table 3.
The duration of success showed a considerable intra- and interindividual variation. The median duration of efficacy was 11 months (range, 1–84). There was a significant difference between embolizations without and with additional therapies: the median duration of effectiveness in embolizations combined with other therapies was 15.5 months (3–84 months), in embolizations without additional therapies only 6 months (1–12 months) (Table 3). This difference was not explained by the presence or absence of additional radioiodine therapies. However, when success duration was compared between embolizations with and without radioiodine therapy and/or external irradiation, the difference in success duration was significant (Table 3). Overall, relapses of symptoms recurred within 4–12 months after the preceding embolization.
During follow-up, nine patients died, and five patients have progressive disease. Only two patients are currently in sustained regression.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Curative therapeutic options in patients with bone metastases of differentiated thyroid carcinoma are limited, especially when there is no uptake of radioiodine. Nevertheless, these patients will have a life expectancy that may extend for several years. As a consequence, these patients may be exposed to the burden of symptomatic metastases for a long period of time, necessitating the need for palliative therapy. Surgery, external irradiation, and to a lesser extent radioiodine therapy are the conventional palliative treatment modalities in these patients. Because many bone metastases of thyroid carcinoma do not accumulate iodine and the effect of radioiodine therapy is not rapid, radioiodine therapy is of limited use as a palliative treatment option. Surgery may lead to rapid relief of symptoms but is possible only when the metastasis is approachable, can be technically complicated, and is always burdensome for the patient. External irradiation is the most frequently applied palliative therapy in bone metastases of thyroid carcinoma. Although this therapy can be effective, limiting factors may be the radiosensitivity of the tumor and the site of the tumor: in vertebral metastases, the maximal radiation dose is limited by the proximity of the spinal cord. Selective embolization of tumor metastases is another option, which is especially effective to induce an immediate relief of pain and neurological symptoms. The procedure can be repeated many times, is relatively easy to perform, and is not very burdensome for the patient.
In 10 patients, at least one successful procedure was performed. It can be questioned whether the presence of additional therapies may have contributed to the success of embolizations or even that the success of embolization combined with other therapies may be entirely attributed to these additional therapies. However, subgroup analysis did not reveal a difference in success rate between embolizations combined or not combined with other therapies (Table 3). In embolizations without additional therapies, the success rate was identical. In addition, successful embolizations were mostly accompanied by an acute improvement in symptoms that cannot be explained by the additional therapies. However, we found an indication that additional therapies influenced the median duration of success, which was longer when embolizations were combined with additional therapies, specifically radioiodine therapy and/or external irradiation. From a theoretical point of view, embolization and irradiation may have additive effects: oxygen deprivation after embolization is a major stimulus for tumor-induced neovascularization and tumor relapse (14). Irradiation may prevent this effect. However, because the additional therapies have not been performed in a randomized fashion, the results as observed in this study have to be interpreted with caution.
Obviously, the success of embolization depends on the completeness of the obstruction in the arterial supply of the particular bone metastasis. In 18 of 22 occasions in which a CT scan was performed, there was a reduction in tumor size or stabilization after embolization.
We did not observe any irreversible complications of selective embolization in our series. Only one patient suffered from a so-called postembolization syndrome, characterized by fever and pain caused by tumor necrosis. In another patient, a reaction to contrast occurred during the embolization procedure. Technical complications, like arteriovenous fistula, aneurysm at the puncture site, or cholesterol emboli did not occur in our study.
In conclusion, selective embolization of bone metastases of differentiated thyroid carcinoma is especially effective in inducing a rapid relief of pain and neurological symptoms in about 60% of occasions. Combination with additional therapies does not appear to influence this percentage but may prolong the duration of the effect.
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Footnotes |
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Received February 12, 2003.
Accepted April 4, 2003.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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