Advances in Radionuclide Therapeutics in Orthopaedics

Herrick J. Siegel, MD, James V. Luck, Jr, MD, and Michael E. Siegel, MD

Abstract
Radiopharmaceuticals not only are used for diagnostic purposes but also increasingly in the treatment of many orthopaedic-related disorders. With the development of specic bone-seeking radiopharmaceuticals, the side effects of treatment are minimized, therapeutic effects are sustained, and concomitant use with other modalities may have synergistic effects. These new radiopharmaceuticals, such as strontium 89 and samarium 153-ethylene diamine tetramethylene phosphate, have been used as palliative treatment for patients with bone pain from osseous metastases. Excellent clinical responses with acceptable hematologic toxicity have been observed, and clinical results rival those of external beam radiation therapy. Radiosynovectomy has become a procedure of choice at many institutions to treat recurrent hemarthrosis and chronic synovitis in patients whose hemophilia is poorly controlled with medical management. Radiosynovectomy also remains a viable option to treat chronic synovitis secondary to inammatory arthropathies, particularly rheumatoid arthritis. J Am Acad Orthop Surg 2004;12:55-64 therapy for chronic synovitis and hemarthrosis would consist of a noninvasive outpatient procedure requiring no posttreatment physical therapy and having limited side effects, a high success rate, and low cost. Radiosynovectomy may be such a therapy.

Overview of Radiopharmaceuticals
Biokinetics and Physical Properties The localization of the boneseeking radiopharmaceuticals depends primarily on two factors: bone blood ow and bone production. Increased radiopharmaceutical deposi-

Nonsurgical management of many orthopaedic-related diseases includes therapeutic modalities such as chemotherapy, anti-inammatory medications, external beam radiation, and, most recently, radiopharmaceuticals. While the diagnostic uses of radionuclides, such as the technetium bone scan or indium- or technetiumlabeled white blood cell scan, are generally familiar, the clinical use of neutron-rich, articially produced radionuclides for therapeutic interventions is growing rapidly. Radionuclide therapy has been shown to be effective for bone pain from osseous metastases, inammatory synovitis of joints, and chronic hemarthrosis in hemophilia. The radionuclide phosphorus-32 (P-32) sodium phosphate has been used since 1948 for relief of bone pain associated with metastatic cancer. Response has varied, and even in patients with a good response, there was an unacceptably high radiation dose to the bone marrow, which in some

patients resulted in bone marrow depression. More recent radiopharmaceuticals have selective uptake and high affinity for bone. They are beta emitters, able to deliver high doses of radioactivity selectively to local areas of increased bone metabolism and osteogenesis. Areas of normal bone have a much more rapid rate of washout of the radiopharmaceutical than areas of metastases do; therefore, regions of bone metastases have a longer exposure to radiation. Although both open and arthroscopic synovectomies have been successful in the treatment of recurrent synovitis secondary to inammatory arthritides or hemophilia, they can result in severe joint stiffness, and prolonged rehabilitation may be necessary. Furthermore, for hemophiliac patients, the prohibitive cost associated with surgical synovectomy for prophylactic clotting factor replacement to prevent hemarthrosis perioperatively decreases the cost effectiveness of this approach. The optimal

Dr. H. Siegel is Assistant Professor, Division of Orthopaedic Surgery, Section of Orthopaedic Oncology, University of Alabama at Birmingham, Birmingham, AL. Dr. Luck is Professor, Department of Orthopaedic Surgery, UCLA/Orthopaedic Hospital of Los Angeles, Los Angeles, CA. Dr. M. Siegel is Professor of Radiology, Department of Nuclear Medicine, Orthopaedic Hospital of Los Angeles and Division of Nuclear Medicine, Los Angeles County + University of Southern California Medical Center, Los Angeles. None of the following authors or the departments with which they are affiliated has received anything of value from or owns stock in a commercial company or institution related directly or indirectly to the subject of this article: Dr. H. Siegel, Dr. Luck, and Dr. M. Siegel. Reprint requests: Dr. H. Siegel, University of Alabama, Medical Faculty Office Towers #920, 510 20th Street South, Birmingham, AL 35294. Copyright 2004 by the American Academy of Orthopaedic Surgeons.

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tion accompanying increased bone production is well exemplied by the increased uptake both on technetium Tc-99m (Tc-99m) bone scintigraphy in the physeal growth plate of children and especially in blastic metastatic disease of bone. The radiopharmaceutical agents used for treating skeletal metastatic disease are incorporated into skeletal tissue, either the bone matrix or bone marrow. These agents all decay primarily or exclusively by beta emission. The administration of beta-emitting radiopharmaceuticals that are part of, or attached to, a chemical moiety with an affinity for bone mineral (hydroxyapatite) permits the selective irradiation of osteoblastic metastases with minimal or no irradiation of normal tissues. Thus, cutaneous or gastrointestinal side effects are avoided, and only minimal to moderate hematologic effects are observed. Intravenously administered radiotracers promptly diffuse from the intravascular to the extravascular space and come into contact with newly produced calcium phosphates, including hydroxyapatite. The radiopharmaceuticals react by incorporation into the hydroxyapatite molecule (P32, strontium-89 chloride [Sr-89]) or by chemisorption on the surface of hydroxyapatite (samarium-153 [Sm-153]). Although cytoreduction may play a role in pain reduction, presumably by decreasing intramedullary pressure from the metastases, there is likely to be further analgesic effect from radiation-induced apoptosis of lymphocytes secreting pain-modulating cytokines such as interleukin-1, interleukin-8, and several interferons.1 The radiopharmaceuticals currently approved by the US Food and Drug Administration for therapy of bone pain are Sr-89 and Sm-153 ethylenediamene tetramethylene phosphate (EDTMP). Sodium phosphate enters hydroxyapatite throughout the bone. In addition, unlike Sr-89 and Sm-153, phosphate is incorporated into many intracellular compounds, such as

those responsible for energy storage (eg, adenosine triphosphate, creatine phosphate) and kinases that signal receptor activation. Also, most crucially, phosphate is part of the structural backbone of DNA and RNA. Sr-89 is a pure beta emitter with a maximum energy of 1.4 MeV, a range of radiation <3 mm in bone, and a half-life of 50.6 days. Chemically similar to calcium, Sr-89 is quickly taken up into the mineral matrix of bone. The compound behaves biologically like calcium and localizes in hydroxyapatite crystals by ion exchange. Sr-89 uptake occurs preferentially at sites of active osteogenesis. This allows primary bone tumors and areas of metastatic involvement to accumulate markedly higher concentrations of strontium than the surrounding normal bone. Elimination is through the kidneys, and careful disposal of urine is needed for 7 to 10 days after administration. Sr-153 EDTMP, with primarily beta emission, has a physical half-life of 46.3 hours and can be chelated with phosphonate complexes. The resulting compound is used to deliver radiation to bone mineral. Sm-153 EDTMP has an affinity for bone and concentrates in areas of high bone turnover in association with hydroxyapatite. The portion of the compound that does not accumulate in the skeleton is rapidly excreted, with approximately 50% eliminated in the urine within 8 hours.2 Similar to Tc-

99m (a pure gamma emitter), Sm-153 also decays by gamma ray emission, which permits conventional gammacamera imaging. Although the mechanism of pain relief by Sm-153 is not known, it is believed that the beta emission from this isotope causes cytotoxicity to adjacent cells and inhibition of tumor growth, resulting in an analgesic effect.3 The most commonly used radiopharmaceuticals for intra-articular administration are P-32 chromic phosphate colloid, yttrium-90 (Y-90) citrate, and dysprosium-165 (Dy-165) in the form of particulate Dy-165 ferric hydroxide macroaggregate. Radiosynovectomy entails injecting a beta-emitting radiopharmaceutical directly into the joint space to ablate the synovium. The injected agents are thought to be rapidly phagocytosed by synoviocytes and then distributed within the synovium, primarily at the surface. A vasculitis results from the radiation effect, which occludes the microvascular supply to the synovium, and this, in addition to the cytotoxic effect of the radiation, results in ablation of the synovium.4 The therapeutic difference between these radionuclides is primarily the result of the depth of soft-tissue penetration and rate of energy deposition (Table 1). Each radioisotope is attached to a colloid, and the overall increase in size of the complex apparently helps prevent leakage from the joint space.

Table 1 Radiopharmaceuticals Commonly Used in Radiosynovectomy Half-life (days) 2.7 14 2.7 0.1 Energy (MeV) 0.96 1.7 2.2 1.29 Range in soft tissue (mm) 1.2-3.6 2.6-7.9 3.6-11.0 1.8-5.7 Particle size (m) 20-70 500-2,000 100 3,000-8,000

Radiopharmaceutical Au-198 P-32 chromic phosphate Y-90 citrate Dy-165 FHMA

Au = gold, P = phosphorus, Y = yttrium, Dy = dysprosium, FHMA = ferric hydroxide macroaggregate

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Administration Systemic administration of the therapeutic radiopharmaceutical requires compliance with radiation safety practices, including use of gloves, a shielded syringe pump, and an absorbent pad under the injection area. Care must be taken to avoid inltrating tissue at the intravenous site. Inltration of skin, fat, or muscle with these nuclear compounds is likely to result in local tissue necrosis. Infusion should be slow, over 1 to 2 minutes, because Sr-89 can mimic the cardiovascular effects of calcium if given rapidly, whereas chelates, such as EDTMP, can bind to intravascular free calcium and magnesium, acutely lowering these blood levels. When radioisotope therapy is given to incontinent patients, urinary catheterization is used to limit radioactive contamination of patients clothing and environment. For intra-articular injection, the target joint is draped and prepared according to standard sterile technique. A 20-gauge needle is placed intraarticularly, and an aspiration is performed to conrm needle placement. If there is any question about the location of the needle, uoroscopy may be used to assist in placement. The radiopharmaceutical is injected, and the track is ushed with 3 to 5 mL of corticosteroid on withdrawal of the needle. This diminishes the risk of an acute inammatory response and prevents radiopharmaceutical skin contamination during removal of the needle.4 The joint is brought through a full range of motion to improve distribution of the radiopharmaceutical and then is splinted for comfort. Toxicity The potential toxicity of radionuclide therapy is almost exclusively hematologic. Bone-marrow stem cells are very radiosensitive, and because of their close proximity to red marrow and the beta-emitting radioisotope localized to bone surface, suppression may occur. Many patients

treated for painful metastatic disease have depressed marrow elements because of previous external beam radiation therapy (EBRT), chemotherapy, or bone marrow replacement by metastases. Other complications related to radionuclide treatment have been minor, and even with exceptionally high doses (30-fold dose) of Sm153 EDTMP, Anderson et al5 reported only mild transient hypocalcemia. The are phenomenon, which is a transient increase in bone pain beginning 48 to 72 hours after radiopharmaceutical therapy, usually lasts 2 to 3 days. It has been reported to occur in as many as 60% of treated patients and may be a positive predictor of a therapeutic response.6 Very few instances of side effects have been reported after intraarticular injection of a radiopharmaceutical. Acute inammation has been reported but is self-limited and does not require treatment. The injection may instigate hemorrhaging, either into the joint itself or into the surrounding soft tissues. This generally is treated with clotting factor infusion and infrequently can require hospitalization for treatment and observation.

Specific Applications
Metastatic Bone Pain Metastatic bone lesions are a common source of disabling pain and neurologic morbidity in some patients with cancer. Approximately 50% of patients with breast and prostate cancer who develop bone metastases experience signicant bone pain. Palliative therapy for patients with diffuse bone pain is subject to a variety of clinical limitations. Nonsteroidal anti-inammatory drugs generally provide relief of mild to moderate bone pain initially, but their efficacy is limited by ceiling effects. Opioid analgesics also may provide adequate relief initially, but they are frequently associated with adverse ef-

fects that limit their utility. Patients develop tolerance and require dose escalation. Although chemotherapy or hormonal therapy may relieve pain, ultimately patients become refractory to these treatments. Bisphosphonates, which are analogues of pyrophosphate and inhibit osteoclast function, may be useful in reducing bone destruction in lytic metastasis and in diminishing hypercalcemia secondary to bone resorption. These agents are more helpful for lytic than blastic metastasis, although zolendronic acid has now been approved for blastic lesions. Radiation therapy combined with analgesics remains the mainstay of treatment of limited focal lesions, but the toxic effects on normal tissue limit repeating treatment in patients with multifocal painful disease. Historically, use of P-32 as an orthophosphate or polyphosphate reduced or relieved the pain of osteoblastic metastases but with some hematologic toxicity, even when used as a single injection. Uptake of this beta emitter by osteoblastic-reactive bone and possibly by tumor and other cells can lead to pain reduction and, often, to tumor lysis. Efficacy has been demonstrated in 84% of 322 breast cancer patients and 77% of 444 prostate cancer patients in a review of the literature.3 However, because it has been associated with marked bone marrow suppression, P-32 has largely been replaced by safer, more recent radiopharmaceuticals. The bone-seeking radiopharmaceuticals Sr-89 and Sm-153 EDTMP have been developed as palliative treatments for patients with severe bone pain from osseous metastases. As a group, these radiopharmaceuticals have been shown to relieve pain at multiple sites following a single treatment. Many patients report improved mobility, reduced dependence on narcotic and non-narcotic analgesics, improved performance status and quality of life, and reduced morbidity.2,3

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Radiopharmaceuticals have notable potential advantages over chemotherapy and EBRT. The carrier-free nature of radiopharmaceuticals allows the therapeutic effect to be accomplished without systemic pharmacologic effect. This minimizes side effects and allows the targeting of very low-concentration receptors. Radiopharmaceutical therapy exposes neighboring malignant cells to lethal irradiation even when the nuclide is not bound to them; with chemotherapy, by contrast, the drug molecule must be taken up by the cell to be lethal. Radiopharmaceutical therapy is selective; that is, a high target-to-nontarget ratio can be achieved. External beams irradiate all the tissues in their path, and chemotherapy targets all fast-growing cell populations. Depth of penetration can be selected by using radionuclides with different emissions of energy. Radiopharmaceutical therapy delivers a hyperfractionated dose compared with EBRT. Fractionation (spreading out radiation dosages over time) has been shown to have fewer side effects in normal tissue than a single large dose.6 The combination of potential cost savings and improved quality of life makes primary pain therapy with a radioisotope an appealing option and/or a useful complement to other pain treatment modalities, such as EBRT and analgesic therapy.

Figure 1 Anterior (A) and posterior (B) whole-body Sr-89 chloride scintigraphs of a 62-yearold man with metastatic prostate cancer. Multiple areas of involvement are demonstrated, particularly the ribs and spine. This patient underwent radionuclide therapy with Sr-89 chloride and subsequently had substantial relief of pain until his death 1 year after treatment.

Patient Selection Before implementing radionuclide therapy, the location, extent of metastatic disease, and osteoblastic activity of the lesion should be conrmed by bone scintigraphy (Fig. 1). Lesions that do not show increased uptake on bone scintigraphy are much less likely to respond to radionuclide therapy; other options for treatment therefore should be considered. Hematologic status is important. Because radionuclide therapy is associated with myelotoxic effects, it is recommended that platelet counts be at least 60 109/L and white blood cell counts

above 2.4 109/L before initiation of therapy.7,8 The maximum hematologic suppression is in the range of 4 to 8 weeks, with return to near baseline by 12 weeks.7,8 The absolute contraindication for radionuclide therapy is an oncologic emergency, such as cord compression or impending fracture of a weight-bearing long bone. Relative contraindications for radioisotope therapy include (1) known or suspected allergy to radionuclide material and other phosphonate compounds, (2) chronically low platelet counts, (3) impending spinal cord compression fractures or unstabilized long-bone fractures, (4) compromised renal function, and (5) treatment

within 6 weeks immediately before or immediately after myelosuppressive chemotherapy or radiation therapy. In patients who have received or will receive another phosphonate-based therapy within 2 or 3 days of the radioisotope therapy, radiopharmaceutical use should be avoided because many phosphate-based therapies (such as pamidronate, a bisphosphonate) compete for the same binding sites in bone as do the radioisotopes, and this possibly may reduce the efcacy of both agents.8 Repeated dosing of radionuclides is not recommended at less than 3-month intervals. Only hematologic parameters limit the number of ra-

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dionuclide treatments a patient may receive. Physicians experienced in the use of radionuclide therapy have not set limits on the number of times the dose can be repeated, with some patients receiving up to 10 doses without increased morbidity.8

Strontium-89 In a phase III trial done in eight Canadian centers to evaluate the efficacy of Sr-89 adjuvant in the management of endocrine-resistant metastatic prostate cancer, 126 patients were randomized after receiving EBRT to either placebo or Sr-89.6 Eighty percent of patients with painful osteoblastic bony metastases from prostate cancer experienced some pain relief after Sr-89 administration. The duration of clinical response ranged from 3 to 6 months. Sr-89 treatment produced several statistically signicant and clinically important effects, including reduced analgesic (P = 0.04) and radiotherapy (P = 0.01) requirements. The study demonstrated that besides these palliative responses, Sr-89 can slow metastatic disease progression. In addition, a signicant (P = 0.006) improvement in overall quality-of-life parameters was reported by the Sr-89 group compared with placebo-treated patients.6 In a trial of 137 patients with metastatic cancer at 3 months, a 3-mCi dose of Sr-89 was compared to the standard 4-mCi dose.1 Overall, 80% of patients reported some symptom improvement, and 11% became completely pain free. In the prostate and breast cancer patients, overall response rates were 80% and 89%, respectively, and completely pain-free response rates were 10% and 18%. Response rates were evaluated over a period of approximately 3 months by assessing need for pain medication, sleep patterns, mobility, ability to work, and medication diaries. Symptom improvement was generally noted within 3 weeks of therapy, and only minimal hematologic effects were observed.

In a study of Sr-89 therapy in 83 patients with metastatic prostatic cancer in whom conventional therapies had failed, an overall response rate of 75% was achieved as well as a complete response rate of 22%.9 Symptom improvement was reported to occur within 6 weeks of Sr-89 therapy (average, 6 months). Myelotoxicity was mild and transient. A trial completed in the United Kingdom provided a direct comparison of Sr-89 therapy with external beam therapy in 305 patients with painful prostatic metastatic cancer.10 Patients were randomized to receive either radiotherapy or 5.4 mCi of Sr89. Equivalent pain relief was noted 3 months after treatment. However, comparisons demonstrated that signicantly (P = 0.003) fewer patients developed new painful sites after Sr89 therapy than after radiotherapy. Also, signicantly (P < 0.01) fewer Sr89treated patients needed radiotherapy for new sites of pain than patients in the local radiotherapy group did. Both studies6,10 conrm the high palliative response rates achieved with Sr-89 therapy over a period of 15 years in more than 1,000 patients. An analysis of the cost-effectiveness of Sr-89 therapy in 29 randomized patients originally reported by Porter and McEwan6 showed that average total lifetime costs for palliative drugs and hospitalization were $5,696 (Canadian) less for patients who received Sr-89 than for those who received placebo.11 Furthermore, direct lifetime therapy costs (ie, drug therapy, radiotherapy, transfusion, and outpatient visits) were lower for radionuclide-treated patients than for the placebo group. Similar cost savings also were noted at 3 and 6 months after treatment.11

nously, Sm-153 EDTMP is rapidly taken up in osteoblastic bone metastases. Several studies have shown that a 1-mCi/kg dose is more effective than a 0.5-mCi/kg dose for achieving pain relief without increasing hematologic toxicity, but that doses >1.5 mCi/ kg yielded no additional benet.12,13 Typically, platelet and white blood cell counts fall transiently by about 50%, with lowest levels seen between 3 and 5 weeks and complete or nearly complete recovery in 5 to 8 weeks. Usually the onset of bone pain palliation is within 1 or 2 weeks in approximately 70% to 75% of patients and lasts for several weeks or months after therapeutic administration. Repeat administration of Sm-153 EDTMP is well tolerated and associated with improved pain control in about 87% of patients.13 The mean duration of pain relief with repeat administration of Sm-153 EDTMP was 24 weeks compared with 8 weeks for single administration.13 The platelet and white blood cell counts are not signicantly different in patients receiving single or repeat administration. A number of clinical studies of Sm-153 EDTMP have also shown encouraging results, with pain relief reported in 61% to 90% of patients with bone metastases from a variety of primary tumors.13-15 For a particularly painful site, use of Sm-153 EDTMP does not necessarily preclude sequential use of supplemental pain relief with other approaches, such as analgesics or EBRT. Additional dosing of Sm-153 EDTMP has been described as safe, feasible, and efficacious. Retreatment generally is not recommended at intervals of <90 days. Typically, about 10% to 15% of patients experience a pain are that can persist for up to 4 days.7

Samarium-153 EDTMP Sm-153 EDTMP has a low affinity for nonosseous localization and a very high affinity for metabolically active bone; therefore, it is an excellent radiopharmaceutical for targeting osteoblastic metastases. Given intrave-

Radiosynovectomy in Inflammatory Arthropathy The inammatory process in rheumatoid arthritis is characterized by cellular proliferation, with formation of synovial granulation tissue (pan-

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nus) and increased secretion of synovial uid. Microvascular injury and synovial cell proliferation appear to be the rst lesions. The normal synovium is composed of a layer of mostly broblastlike cells, one to two cells thick, as well as macrophagelike cells. The synovial lining of the arthritic joint becomes hyperplastic and may thicken to 10 to 12 cells in depth, with a large increase in the percentage of macrophagelike cells. These lining cells produce and secrete cytokines and enzymes that are capable of cartilage and matrix degradation. When the synovium becomes hypertrophic, there is a shift in the metabolic balance within the joint and a continuous release of catabolic agents, leading to joint destruction. Surgical synovectomy done as an open or arthroscopic procedure is the typical method of treating intractable rheumatologic joint disease. Disadvantages include the risk of complications from anesthesia, hospitalization of approximately 2 weeks after the procedure, rehabilitation of up to 6 months, and, frequently, loss of motion as the outcome. Although the expense and rehabilitation are reduced when synovectomy is done arthroscopically, commonly there is recurrence 3 to 5 years later, and at each successive surgery, it becomes more difficult to remove the inamed tissue because of scarring from previous attempts. Ogilvie-Harris and Basinski16 noted marked decreases in pain and synovitis in 96 patients during a 4-year surveillance. They concluded that arthroscopic synovectomy may be a valuable palliative procedure for rheumatoid synovitis of the knee. Radiosynovectomy provides an attractive alternative in that cartilage is naturally hypoxic and relatively radioresistant. Thus, a radiopharmaceutical with an appropriately strong beta emission and related soft-tissue penetration can be administered directly into the joint, where it affects the synovial lining and leaves the ad-

jacent cartilage unaffected. The advantages of radiosynovectomy compared with surgery include little or no need for hospitalization, no physical therapy, decreased cost, the ability to repeat the injection, and results equivalent to those for surgery.17 Irradiation of the inamed, hypertrophic synovial lining decreases both uid secretion and intra-articular pressure. The cytokine and enzyme levels within the joint decrease because there are fewer cells capable of releasing these agents, thereby reducing further cell recruitment and proliferation. Ansell et al18 showed that within 1 hour, a dose of colloidal gold Au-198 was well distributed throughout the joint, and most of the colloid was sequestered in the synovial membrane. Redistribution of P-32 chromic phosphate throughout the joint takes as long as 24 hours after the treatment.19 Using Au-198, satisfactory results have been achieved in at least 60% of patients with rheumatoid arthritis.20-22 However, the gamma radiation and leakage of the small Au198 colloid from the joint led to concerns that it could result in whole-body radiation. Additionally, the maximum tissue penetration range is limited to 4 mm, and the average tissue penetration depth is approximately 2 mm. As an alternative to Au-198, the use of Y-90 was initiated in the early 1970s. Y-90 has the advantage of being a pure beta emitter, with higher energy and a greater maximum tissue penetration than Au-198 (11 versus 4 mm). It is thus an attractive agent for radiosynovectomy. Results of clinical trials showed that 60% to 70% of patients with rheumatoid arthritis beneted from the procedure, that Y-90 was equivalent to Au-198 in its effectiveness, and that it was safer in that there was no whole-body gamma radiation, as with Au-198.23 Although not dose-related, cytogenetic studies documented chromosomal aberrations of uncertain signicance in patients 1 month to 10 years after intra-articular injection of the small

colloids of Y-90 and Au-198. However, results of Y-90 treatment of approximately 1,500 rheumatoid joints showed good results in approximately 67% of joints, and no untoward results were noted over a 20-year follow-up.22 At the other end of the radiopharmaceutical spectrum is Dy-165, which has a very short half-life of 2.3 hours (0.1 day), an energetic beta emission with a maximum tissue penetration of 5.7 mm, and a very large particle size. Dy-165 also has gamma emission, permitting gamma-camera imaging for leakage studies. Because the isotope has a short half-life, the ferric hydroxide macroaggregate must be prepared immediately before injection. Clinical efficacy is similar to that of the other isotopes in that 65% to 70% of patients benet from the procedure, with the best results seen in patients whose disease is at an early stage.24,25 Studies determined that, on average, leakage to the regional lymph nodes was 0.12% of the injected dose and to the liver, 0.64%.24 The primary concern is the potential for late radiation-induced neoplasm. Rivard et al26 concluded that perhaps the strongest argument for the safety of intra-articular radiocolloids is the long-term follow-up of more than 5,000 radiosynovectomies performed since 1971, mainly in patients with rheumatoid arthritis, none of whom have been reported to have developed radiation-induced malignancies. Early studies with Au-198, a very small colloid, demonstrated that >10% and as much as 60% of the activity was in the draining lymph nodes,27 and yet, to date, there have been no reports linking the use of this agent to hematogenous malignancies or sarcomas. Rivard et al26 noted that no chromosomal aberrations were observed 1 week or 6 months after P-32 chromic phosphate injection, and they found leakage in only 3 of 71 radiosynovectomies that also used P-32 colloid, with a mean percentage leakage of 0.6% (range, 0.1% to 2%).

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Siegel et al4 recently published a review of 125 radiosynovectomies; maximum leakage of 2.5% of the target dose occurred in only one patient.

Table 2 Radiosynovectomy in Patients With Hemophilia Joints With Signicantly* Decreased Follow-up Incidence of (yrs) Bleeding (%) 13-15 1 1-15 0.5-3 10 1.5-15 14 2-10 89 76 78 78 69 58 100 82

Hemarthrosis in Hemophilia Radiosynovectomy is an effective means to reduce (or ideally cease) recurrent hemarthrosis in patients with coagulation deciencies. Studies have shown results comparable to surgical synovectomy. Between 58% and 100% of joints exhibit decreased bleeding initially, and this decrease appears to be sustained (Table 2). Most patients maintain or improve their range of motion, despite minimal or no physical rehabilitation or physical therapy. Siegel et al19 reported the results of 28 treated joints with a minimum of 6 months follow-up; 22 (78%) of the treated joints had improved range of motion, coincident with diminished frequency of hemarthrosis. In patients with a minimum of 2 years of follow-up, approximately two thirds had preservation of this improved range of motion.19 More recent data of 125 radiosynovectomies in 80 patients with 2- to 10-year follow-up has conrmed the earlier ndings.4 This is in contrast to open and arthroscopic synovectomies, which rely heavily on aggressive physical therapy and factor replacement to maintain effective motion. As with surgical synovectomy, patients with minimal articular surface involvement who undergo the procedure appear to have fewer progressive radiographic changes than do those with advanced disease before radiosynovectomy. Those with advanced disease tend to continue to deteriorate progressively at a more rapid pace, despite decreased joint bleeding. Radiosynovectomy does not appear to increase the rate of degenerative joint changes, however, and there are no reports of growth disturbances in skeletally immature patients as a result of undergoing radiosynovectomy. The procedure is

Study Merchan et al28 Dawson et al29 Rivard et al26 Siegel et al19 FernandezPalazzi et al30 Lofqvist et al31 RodriguezMerchan et al32 Siegel et al4

No. of Treated Joints 38 34 92 44 50 19 67 125

Radiopharmaceutical Au-198 Y-90 P-32 P-32 Au-198 Au-198 Au-198 P-32

Au = gold, Y = yttrium, P = phosphorus * >75% reduction in bleeding

well tolerated, even in patients with inhibitors, and most experience no or mild adverse events. Simple interventions such as concomitant administration of corticosteroids into the joint and adequately ushing the needle on withdrawal help to keep complications to a minimum. Immobilization of the treated joint for 48 hours after the procedure is recommended because that can potentially avoid leakage of the radionuclide material and minimize inammation at the injection site (Fig. 2). Chromosomal aberrations do occur in some patients as a result of radiosynovectomy, but these can be minimized by the choice of isotope and reduction of leakage. These anomalies are transient and return to baseline usually over several months to 1 to 2 years. There is no reported increased rate of malignancy in 40 years of follow-up experience.25 Radiosynovectomy may be the only option for poor surgical candidates, such as those with high inhibitor titer or advanced AIDS, those without access to arthroscopic synovectomy, or those unable to comply with the rigorous postoperative phys-

ical therapy and factor infusion regimen. In addition, replacing surgical synovectomy with radiosynovectomy could garner savings of more than $1 billion.17 This difference in costs is predominantly inuenced by the large amounts of clotting factor concentrate and postoperative physical rehabilitation required for surgical synovectomy.

Pigmented Villonodular Synovitis Studies using Y-90 in combination with surgery for the treatment of recurrent pigmented villonodular synovitis (PVNS) showed improvement in function and no evidence of recurrence in 10 patients, without evidence of radiologic deterioration of the treated joint or complications related to the radiosynovectomy. Each patient was treated with an intra-articular injection of 15 to 25 mCi of Y-90, 6 to 8 weeks after the last surgery.33 In a report of 11 patients with PVNS involving either the hip or knee, patients had signicant (P < 0.005) improvement in terms of effusion, rubor, and range of motion at 1-year follow-up.34 The authors of both studies concluded that

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Figure 2 Lateral (A) and anteroposterior (B) views of right foot and ankle 24 hours after radiosynovectomy for chronic hemarthropathy and synovitis of the right ankle. The scan demonstrates connement of the P-32 chromic phosphate radioisotope to the ankle joint as well as homogenous distribution of activity. Outlines result from radioimaging marking pens. Lateral (C) and anteroposterior (D) views of right elbow, and anteroposterior (E) view of ipsilateral axilla 24 hours after radiosynovectomy for chronic hemarthropathy and synovitis of the right elbow. The scan demonstrates homogenous distribution of the P-32 chromic phosphate radioisotope with the absence of activity in the ipsilateral axillary nodes.

a combination of debulking surgery with intra-articular injection of Y-90 for extensive diffuse PVNS is a reliable and highly efficacious method of treatment. Wiss35 reported the successful treatment of a patient with recurrent PVNS of the knee and concluded that Y-90 is a useful adjuvant in the treatment of recurrent PVNS. In nearly 20 years of clinical use, no cases of malignancy directly attributable to Y-90 therapy have been reported. de Visser et al36 evaluated 38 patients with PVNS who had been divided into three treatment groups: surgery alone, surgery and radiosynovectomy, and radiosynovectomy alone. Fair to excellent results were noted in 36 of 38 patients, with no signicant difference in outcome among the three groups.

Synovitis of Other Origins Favorable results have been demonstrated in 50% of 82 patients treated with Y-90 for ankylosing spondylitis and psoriatic arthritis.37 Kroger et al38 reported on 98 joints treated with radiosynovectomy for severe osteoarthritis (46 joints), ankylosing spondylitis, reactive arthritis, undifferentiated spondyloarthropathy, psoriatic arthritis, PVNS, and recurrent synovitis. Forty percent of patients showed a good or excellent improvement of clinical symptoms; 51% were unchanged; and in 9%, symptoms worsened.38

Metastatic Osteosarcoma Bone-forming tumors, such as osteosarcoma, often have avid uptake of bone-seeking radiopharmaceuticals. To date, no studies have reported on the use of radionuclide therapy for the primary treatment of osteosarcoma in humans, but management of locally relapsing and metastatic osteosarcoma has been effective.39 Anderson et al5 reported on 30 patients with bone metastasis from osteosarcoma who were treated with Sm-153 EDTMP in doses up to 30 mCi/kg, followed by peripheralblood progenitor cell or marrow support. The key ndings were low nonhematologic toxicity and dramatic pain palliation. Also, a reduction or discontinuance of opiate medication was seen in all patients. The administered activity of Sm-153 can be increased up to 30-fold with peripheralblood progenitor cell support, thereby allowing the delivery of substantial radiation doses to osteoblastic lesions.5 Franzius et al40 described a patient with inoperable pelvic osteosarcoma treated with Sm-153 EDTMP, peripheral-blood progenitor cell support, external beam irradiation (60 Gy), and multiagent chemotherapy, according to a modied COSS-96 regimen of the Cooperative Osteosarcoma Study Group.40 This treatment led to immediate pain relief, followed by a marked reduction of tracer uptake on

bone scan and positron emission tomography. The patient was alive and well at 3.3-year follow-up. Franzius et al41 have suggested that aggressive, rst-line therapy combining targeted internal radiotherapy with high-dose Sm-153 EDTMP, external beam irradiation, and multiagent chemotherapy may offer a reasonable treatment option for select patients with inoperable osteosarcoma.

Summary
Radiopharmaceuticals not only are used for diagnostic purposes but also are being used more frequently in the management of many orthopaedicrelated disorders, particularly in the treatment of metastatic bone pain and chronic synovitis. With the development of specic bone-seeking radiopharmaceuticals, side effects are minimized, therapeutic effects are sustained, and concomitant use with other therapy modalities may have synergistic effects. Radiosynovectomy is the initial procedure of choice at many institutions for the treatment of patients with hemophilia whose recurrent hemarthrosis and chronic synovitis are poorly controlled with medical management. Most patients have notable reduction in the incidence of hemarthrosis. When treated at an early stage, the destructive cycle of bleed-

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Herrick J. Siegel, MD, et al

ing with the subsequent development of synovitis may be prevented. Although leakage of radiopharmaceuticals has been reported, no incidences of malignancy have been reported to date. Radiosynovectomy also remains a viable option for the treatment of chronic synovitis secondary to inammatory arthropathies, particularly rheumatoid arthritis. Further studies are needed to better dene the

role of radiosynovectomy in pigmented villonodular synovitis, but favorable results and few side effects have occurred in a limited number of patients. Future trends in the application of radiopharmaceuticals in orthopaedics will be directed toward developing various combinations of radioimmunotherapy with radiolabeled antibodies and/or peptides, not only for en-

hanced diagnostics but also for the treatment of cancer. Radioimmunotherapy can be thought of as a smart bomb because it allows systemic delivery of radiation targeted to areas of disease while essentially sparing normal tissues. It can deliver a very high radiation dose specically to the tumor and a much lower dose to normal tissues by two or more orders of magnitude.

References
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