The Role of Bone-Seeking Radionuclides in the Palliative Treatment of Patients With Painful Osteoblastic Skeletal Metastases

Transcription

1 Several bone-seeking radionuclides can reduce pain caused by diffuse skeletal metastasis. Common-Yellowthroat_ Photograph courtesy of Henry Domke, MD. The Role of Bone-Seeking Radionuclides in the Palliative Treatment of Patients With Painful Osteoblastic Skeletal Metastases Michael Tomblyn, MD, MS Background: Pain from skeletal metastases represents a major burden of advanced disease from solid tumors. Analgesic medications, bisphosphonates, hormonal agents, cytotoxic chemotherapy, and external beam radiotherapy are all effective treatments. However, patients often suffer from diffuse painful metastases and respond poorly to these standard therapies. Bone-seeking radionuclides can specifically target osteoblastic lesions to offer palliation of pain. Methods: This article offers a narrative review of bone-seeking radionuclides, examines the evidence of safety and efficacy for the treatment of painful skeletal metastases, and presents guidelines for their appropriate use in this patient population. Results: Seven bone-seeking radionuclides have shown evidence of both safety and efficacy in reducing pain from diffuse skeletal metastases. 153 Sm-EDTMP and 89 Sr are most commonly used in the United States and have been safely utilized for both repeat dosing as well as concurrent dosing with cytotoxic chemotherapy. Conclusions: Targeted bone-seeking radionuclides are underutilized in the treatment of painful diffuse osteoblastic metastases. Several new agents are in active clinical investigation, and the pending approval of the first alpha-emitting radionuclide ( 223 Ra) may offer a new class of agents that provide greater efficacy and less toxicity than those currently available for routine clinical use. Introduction Bone pain arising from symptomatic skeletal lesions is a common cause of morbidity in patients with metastatic cancer, and a majority of patients with diffuse disease require multiple treatment modalities for pain. The most common primary sites of solid tumors giving From the Department of Radiation Oncology at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida. Submitted May 31, 2011; accepted January 6, Address correspondence to Michael Tomblyn, MD, MS, Department of Radiation Oncology, Moffitt Cancer Center, Magnolia Drive, Tampa, FL Michael.Tomblyn@moffitt.org No significant relationship exists between the author and the companies/organizations whose products or services may be referenced in this article. rise to such lesions are the breasts, prostate, lungs, and kidneys, together representing nearly 80% of all bony metastases. 1 If undiagnosed or inadequately treated, skeletal metastases often lead to profound pain, compression of the spinal cord, hypercalcemia, and pathological fracture of involved bones. Multiple reports suggest a direct correlation between the burden of bony metastases and survival. 2 Most bone metastases are localized to the red marrow, thus the proclivity for the axial skeleton. 3 Bone metastases are generally classified as osteoblastic (increased formation of bony matrix), osteolytic (increased destruction), or mixed. Although some malignancies give rise principally to blastic or lytic lesions (prostate cancer and multiple myeloma, respectively), most ma- April 2012, Vol. 19, No. 2 Cancer Control 137

2 lignancies exhibit a mixed blastic-lytic phenotype. 4 Recently, the interactions between tumor-expressed surface proteins and the bone microenvironment have been better elucidated. Prostate cancer cells often express transforming growth factor beta (TGF-β), which aids in the adhesion to bone matrix and can affect the maturation of osteoclasts. 5,6 Epidermal growth factor (EGF) may also enhance metastasis by facilitating the migration of cancer cells from circulation and into bone. 7 Diagnosis of Bone Metastases The diagnosis of bone metastases can be made using several diagnostic imaging techniques. The most utilized technique is the 99m Tc nuclear medicine bone scan; the radionuclide tracer, attached to an organophosphate (methylene diphosphonate), is specifically incorporated into the skeleton in areas of significant osteoblast activity, preferentially binding to hydroxyapatite within the bone matrix. Although this type of bone scan is useful for osteoblastic metastases (such as from prostate, lung, or breast tumors), primarily osteolytic lesions (myeloma, thyroid, renal cell), generally exhibit poor uptake. Plain films and computed tomography (CT) scans are sensitive for observing the destructive characteristics of such osteolytic metastases. 8 Other imaging modalities, such as magnetic resonance imaging (MRI) and 18 F sodium fluoride (NaF) positron emission tomography (PET), may also have utility in select patients. Treatment Options Pain from bone metastases generally exhibits two distinct components. The first is a chronic, baseline level of pain caused by local effects of bone remodeling and the inflammatory reaction around the metastatic foci. The second component is often elicited by physical activity or with certain positions. It is more acute and severe and is often referred to as breakthrough pain. 9,10 Beyond nonsteroidal and narcotic analgesics, external-beam radiotherapy (EBRT) is the most common form of palliation for pain arising from bone metastases. The American Society for Radiation Oncology recently published comprehensive evidence-based guidelines for the use of palliative EBRT for bone metastases. 11 Although traditional forms of radiotherapy are effective for palliation of symptoms associated with bone metastases, 12 many patients present concurrently with painful lesions in several distinct areas of the skeleton. Large-field radiotherapy such as hemibody radiation therapy is effective, 13 but it has been largely abandoned due to concerns over the toxicity of radiating such large fields, 14 the technical challenges of providing hemibody radiation therapy, and the time-consuming nature of such a technique. For patients with diffuse symptomatic skeletal involvement, a systemic approach is often necessary. Intravenous bisphosphonates play an important role in the reduction of skeletal events in these patients. Radionuclide Therapy Over the past few decades, several radiopharmaceuticals have been developed with bone-seeking properties that provide palliation of pain to multiple areas of the skeleton simultaneously without the significant soft-tissue toxicity and technical complications of large-field EBRT. These agents are generally delivered intravenously and quickly localize specifically to sites of active bone reaction and remodeling. Excess radionuclides not deposited in these areas of remodeling are typically eliminated quickly from the body, either through the genitourinary or gastrointestinal system. Specific indications and contraindications to bone-seeking radionuclide therapy are summarized in Table 1. To date, seven bone-seeking radiopharmaceutical agents have shown evidence of safety and efficacy in the medical literature (Table 2). Most are beta-emitters, releasing highly energetic electrons that deposit their energy over up to several millimeters in the surrounding tissues. The energies of emitted beta particles are generally not sufficient to elicit a significant cytotoxic response. Radium-223 ( 223 Ra), a recently developed alphaemitter, releases a large helium nucleus, causing more biologic damage but over a much shorter path length and with the possibility of killing tumor cells and reducing tumor burden. Other beta-emitting radionuclides have been proposed for the treatment of bone metastases, with preclinical animal evidence of targeting to the stroma surrounding these lesions. Following is a review of the evidence for their use in patients with diffuse skeletal metastases. Table 1. Indications and Contraindications to the Use of Bone-Seeking Radiopharmaceuticals Indications Diffuse skeletal metastases visualized on nuclear medicine bone scan Painful skeletal metastases inadequately treated by analgesics Intolerance to prescribed analgesics Hormone-insensitive disease (for metastatic prostate cancer) Relative Contraindications Uncontrolled extraskeletal disease burden Asymptomatic skeletal metastases Skeletal lesions limited to fewer than three sites Purely osteolytic lesions (no uptake on bone scan) Poor bone marrow reserve Life expectancy less than 60 days Absolute Contraindications Presence of epidural spinal cord compression Pending or active pathological fracture of weight-bearing bone Renal failure Pregnancy Breast-feeding 138 Cancer Control April 2012, Vol. 19, No. 2

3 Table 2. Properties of Bone-Seeking Radiopharmaceuticals Radionuclide Half-life (days) Emission Average Energy (kev) Average Path Length (mm) Gamma Emission Phosphorus β No Strontium β No Samarium β Yes Rhenium β Yes Rhenium β Yes Tin-117m 13.6 CE 127 < 0.1 No Radium α 5850 < 0.1 Yes β = beta particle, CE = conversion electron, α = alpha particle Mechanism of Uptake Into Bone Radiopharmaceuticals intended for the treatment of bone metastases are incorporated into bone by one of two major mechanisms. Radionuclides residing in family IIA of the periodic table carry the same divalent charge as elemental calcium and are incorporated into bone matrix directly. Most other radionuclides are not efficiently targeted to bone naturally and instead are chelated to organic phosphates, which are incorporated into the matrix. Several of the therapeutic agents emit small amounts of gamma radiation, allowing for a scintigraphic visualization of uptake, and the patterns of skeletal uptake of the therapeutic agents are congruent with those seen with the diagnostic bone scan. Approved Radionuclides Phosphorus-32 ( 32 P): Although no longer in common use, the beta-emitter 32 P, in the form of a sodium orthophosphate, was the first systemic radionuclide to be used for the treatment of bone metastases. It exhibits a physical half-life of 14.3 days, with an average beta particle energy of 695 kev, a mean path length of 3 mm, and a mean range in bone of 1.7 mm P is incorporated into hydroxyapatite and decays to sulfur-32 ( 32 S), the isotope likely responsible for the agent s efficacy. Significant myelosuppression 16 led to the abandonment of 32 P, as newer radionuclides were developed. Strontium-89 ( 89 Sr): Strontium is a member of family IIA of the periodic table and carries the same divalent charge as calcium. The body is unable to distinguish between the two elements, so the clinically utilized isotope 89 Sr is provided as a simple chloride salt and is directly incorporated into bone. 89 Sr is a beta-emitter, with a half-life of 50.5 days. The mean energy of the beta particles is 580 kev, with an average range in soft tissue of 2.4 mm and an effective range of 5 to 6 mm. 17 Less than 0.01% of the emissions are gamma rays, 18 so postinjection imaging is not performed. Osteoblastic bone metastases take up 89 Sr specifically in areas of osteoblastic bone metastases, with approximately 5-fold greater uptake compared to normal bone Sr not incorporated into bone is eliminated from the body through both the genitourinary (80%) and gastrointestinal (20%) systems. The standard prescribed dose for 89 Sr is 4 mci for all patients. 89 Sr can be effective at palliating pain from bone metastases, particularly for metastatic prostate or breast cancer, with pain relief reported in 60% to 92% of patients Relief typically begins by the second or third week following the injection, with a median duration of approximately 6 months. One study showed a significant improvement in quality of life in patients with prostate cancer due to a reduction in skeletal pain following administration of 89 Sr. 25 A brief but self-limited flare of bone pain lasting 24 to 48 hours is not uncommon following treatment with 89 Sr. However, patients experiencing this complication may have a superior long-term palliative response compared with those who do not have a pain flare. A dose-response relationship for relief of pain exists for 89 Sr for patients with metastatic prostate cancer. 26 However, dose escalation up to 10.8 mci does not affect overall survival. 27 Combining 89 Sr with chemotherapy appears to improve pain response 28,29 and may affect survival in patients with metastatic prostate cancer. 30 Two randomized trials of 89 Sr vs EBRT alone showed similar responses for pain relief in patients with androgen-independent prostate cancer metastases, but there seemed to be a greater freedom from developing new painful sites with 89 Sr, and the US Food and Drug Administration (FDA) approval of 89 Sr was granted for this reason. 31,32 However, overall survival was superior in the EBRT arm of a randomized trial by the European Organisation for Research and Treatment of Cancer (EORTC), and radiotherapy was less costly to deliver. Samarium-153 ( 153 Sm): Samarium is a member of the lanthanide family of the periodic table, with several dozen isotopes described. The clinically utilized iso- April 2012, Vol. 19, No. 2 Cancer Control 139

4 tope is 153 Sm, a beta-emitter with a half-life of 1.9 days. Since 153 Sm has no inherent bone-seeking properties, the isotope is chelated to ethylene diamine tetramethylene phosphonate (EDTMP), which targets the bone matrix as a polyphosphonate. The mean energy of released beta particles is 233 kev, with an average range in soft tissue of 0.5 mm and an effective range of 2 to 3 mm Sm also releases gamma radiation (29%, 103 kev), which allows for direct scintigraphy of the administered radionuclide. 34 In fact, scintigraphic studies of patients with metastatic prostate cancer have shown identical patterns of skeletal uptake after administration of technetium-99m-methylene diphosphonate ( 99m Tc- MDP) and 153 Sm-EDTMP. 35 Approximately two-thirds of the injected dose is incorporated into the skeleton, and urinary excretion of unincorporated tracer is essentially complete within 6 hours. 36 The standard specific activity of 153 Sm prescribed for patients with bone metastases is 1 mci/kg to a maximum of 150 mci. Several studies have shown the radionuclide to be effective at palliating pain from bone metastases Palliation of pain occurs in approximately 60% to 80% of patients within 1 week of administration of 53 Sm, with a clear dose response in dose escalation studies. 42 A randomized trial using 0.5 mci/kg vs 1.0 mci/kg of 153 Sm in patients with bone metastases from a variety of primary tumors showed significant pain improvement with the higher dose as well as superior survival in the patients with breast cancer treated with the higher dose. 43 Serafini et al 44 performed a double-blind, randomized controlled trial of 153 Sm-EDTMP (at 0.5 and 1.0 mci/ kg) vs placebo in patients with skeletal metastases from solid primary tumors. Efficacy was measured using a standard subjective visual analog scale (VAS), a blinded physician s global assessment of pain (PGA), and a record of daily use of opioids. Patients receiving the higher dose of 153 Sm reported significant pain responses based on VAS at all time points (weeks 1 4) compared with placebo, whereas patients given the lower dose had improved VAS scores only at week 1. Two-thirds of patients treated at the higher dose with significant pain relief at week 4 were judged by the PGA to be responders at week 16. Significant reduction in opioid use was seen at the higher dose level only, compared with placebo. Sartor et al 45 completed a double-blind (2:1), randomized controlled trial of 1.0 mci/kg of 153 Sm-EDTMP vs placebo in patients with metastatic prostate cancer. Patients randomized to receive 153 Sm reported significant improvement in subjective pain response compared with those receiving placebo in weeks 2 to 4 following injection. They also used significantly fewer opioids than patients who were given placebo. Repeat dosing with 153 Sm is both safe and effective. Two reports of patients with symptomatic bone metastases receiving multiple doses of 153 Sm showed no significant differences in pain reduction or in myelosuppression after a second or third treatment. 46,47 Several early-phase clinical trials combining 153 Sm with cytotoxic chemotherapy for patients with metastatic prostate carcinoma have been reported. Morris et al 48 performed a phase I study of escalating doses of docetaxel (65 75 mg/m 2 ) and 153 Sm ( mci/ kg) in 28 men with androgen-independent disease. No maximum tolerated doses were reached, and 15 patients exhibited a decline in prostate-specific antigen (PSA) level of more than 50%. Tu et al 49 performed a dose-escalation study of two 28-day cycles of low-dose weekly docetaxel (25 35 mg/ m 2 ) on days 1, 8, and 15 with 153 Sm (1.0 mci/kg) on day 1 of each cycle. The maximum tolerated dose was not reached in this study of 18 patients. Five patients (28%) had a decline in PSA level of at least 50%. Fizazi et al 50 reported a phase II trial of 43 patients with androgen-independent metastatic prostate cancer who exhibited a clinical response to 4 cycles of docetaxel and estramustine chemotherapy. Patients received weekly docetaxel (20 mg/m 2 ) for 6 weeks with 153 Sm (1.0 mci/kg) at week 1. A further reduction in PSA level was seen in 77% of patients, with a reduction in pain in 69%. The regimen was well tolerated, with 81% receiving at least 5 of the 6 planned cycles of docetaxel. Grade 3 hematologic toxicity (thrombocytopenia) occurred in 2 patients. The median survival was 29 months, with 1- and 2-year survival rates of 77% and 56%, respectively. Investigational Radionuclides Rhenium-186 ( 186 Re) and Rhenium-188 ( 188 Re): Rhenium is a transition metal with two clinically important isotopes: 186 Re and 188 Re. Both are radionuclides attached to hydroxyethylidene diphosphonate (HEDP) for bone targeting. 186 Re has a half-life of 3.7 days. Its beta emission exhibits a mean energy of 349 kev and an average range in soft tissue of 1.1 mm (maximum range, 4.5 mm) Re also emits a small gamma component (9%, 137 kev), allowing for postadministration imaging of biodistribution. 52 The short half-life and path length of 186 Re could potentially be useful in patients with poor bone marrow reserve. One study of bone metastases from breast cancer showed palliation of bone pain in more than 90% of patients treated with 186 Re-HEDP. 53 Similar efficacy has been seen with this agent in patients with metastatic prostate cancer. 54 The maximum tolerated dose of 186 Re- HEDP appears to be 65 mci. 55 The PLACORHEN randomized controlled trial of 186 Re-HEDP vs placebo showed a significantly higher rate of pain responders (65% vs 36%, respectively). 56 The number of patients in this study requesting palliative EBRT was higher in the placebo group than in the treatment group (67% vs 44%). Repeat administration of 186 Re-HEDP appears to be both safe and effective in select patients Cancer Control April 2012, Vol. 19, No. 2

5 Since 188 Re is easily produced using an inexpensive generator, it has primarily been investigated in the developing world. 188 Re has a half-life of 0.7 days, a mean beta particle energy of 2120 kev, and an average range of 3 mm in soft tissue (maximum, 11 mm). 51 The higher beta energy for this isotope offers the potential for lethal insults to tumor cells in the region of decay. Relatively high doses (up to 70 mci) have been given to patients with metastatic prostate cancer, with good efficacy of pain relief. 58 The safety and efficacy of repeat dosing of 188 Re-(Sn)HEDP have also been described. 59 Tin-117m ( 117m Sn): Tin is a main group metal on the periodic table and has the greatest number of stable isotopes of all the elements. The metastable isotope 117m Sn, chelated to diethylenetriamine pentaacetic acid (DTPA), is under investigation as a possible therapeutic radionuclide for the treatment of bone metastases. 117m Sn has a half-life of 13.6 days and emits low-energy conversion electrons, with an effective path length measured in micrometers. 60 Tin is a natural bone-seeker, but its highest specificity for bone occurs when the element is in its quatravalent state (4+). DTPA stabilizes tin in this preferred 4+ state, protecting it from competing redox reactions in vivo. 61 A comparison of dosimetric models of potential bone-seeking radionuclides performed by Bouchet et al 62 suggests that the low energy and short range of the emitted conversion electron may provide an optimal therapeutic window. In clinical studies, pain relief with 117m Sn in patients with metastatic prostate cancer has been promising, with a low risk of myelosuppression. 63,64 Radium-223 ( 223 Ra): Radium is also a member of family IIA and may be best known for its discovery in 1898 by Marie and Pierre Curie. The propensity for ingested radium to be deposited directly into bone has been recognized for nearly a century, first appreciated when workers using luminous radium-based paint began to exhibit cancers of bone and leukemias. 223 Ra (provided as a radium chloride salt solution) is an alpha-emitting isotope, with a half-life of 11.4 days and a mean path length of less than 0.1 mm in soft tissue. Its mean alpha particle energy is 5850 kev. This limited range and high linear energy transfer of the emitted alpha particle allow for potentially lethal insults to surrounding tumor cells, with minimal exposure to the nearby bone marrow. Early experience with this investigational agent suggests a low incidence of clinically significant myelosuppression, even with repeated dosing. 65 A phase II clinical trial of 223 Ra in patients with symptomatic, hormone-refractory prostate cancer showed an improvement in survival, PSA levels, and alkaline phosphatase levels compared with placebo, with no differences in hematologic toxicity. 66 Based on these early encouraging data, an international double-blind, placebo-controlled randomized trial (alpharadin in symptomatic prostate cancer [ALSYMP- CA]) was performed to compare 223 Ra with placebo (2:1 randomization) in patients with symptomatic, androgenindependent prostate cancer with skeletal metastases. 67 Patients had received docetaxel, were ineligible for the chemotherapy, or refused it. The study was stratified based on alkaline phosphatase levels at registration, bisphosphonate use, and prior treatment with docetaxel. A total of 922 patients from 19 countries were enrolled in this trial, with the primary endpoint of overall survival. At the time of the planned interim analysis, the improvement in overall survival exceeded the predetermined boundary, and the independent data monitoring committee stopped the trial. The data were presented in part at the 2011 European Multidisciplinary Cancer Congress meeting, and the authors reported a significant reduction in the risk of death for patients randomized to the 223 Ra arm (hazard ratio [HR], 0.695; P =.00185), with a median overall survival of 14 vs 11.2 months. The overall survival benefit was seen across all subgroups. The time to a skeletal-related event was also significantly longer for patients in the 223 Ra arm (13.6 vs 8.4 months; P =.00046). The time to disease progression based on PSA and alkaline phosphatase levels was significantly superior in the 223 Ra arm. The patients randomized to 223 Ra tolerated treatment well, with no grade 3 or 4 side effects that occurred more often with 223 Ra than with placebo. Based on the results of this pivotal trial, regulatory approval of this novel agent is expected in late In the interim, an expanded-access protocol is currently open for enrollment of patients with symptomatic metastatic androgen-independent prostate cancer. Additionally, a 60-patient phase I/II protocol examining the combination of 223 Ra with docetaxel chemotherapy for this patient population is currently open for accrual in the United States. A phase II study of 223 Ra in patients with metastatic breast cancer recently closed to accrual in Europe. Potential Future Radionuclides Lutetium-177 ( 177 Lu): A beta-emitter, 177 Lu is currently used for radioimmunotherapy and peptide receptor radionuclide therapy. Due to its 6.7-day half-life, maximum beta energy of 497 kev, and reliable gamma emission for imaging, 177 Lu has been considered for a number of therapeutic roles. Preclinical studies of 177 Lu- EDTMP have shown specific accumulation within the bones of rats. 68, Lu-EDTMP use has been reported in humans for imaging purposes. 70 Results of clinical trials have yet to be reported. Thulium-170 ( 170 Tm): This beta-emitter is produced by thermal neutron bombardment of thulium oxide and has recently been proposed as a potential therapeutic radionuclide. 170 Tm has a long half-life (128 days), a high maximum beta energy (968 kev), and sufficient gamma emission for imaging. Investigators April 2012, Vol. 19, No. 2 Cancer Control 141

6 from India prepared 170 Tm-EDTMP, which was shown to specifically accumulate in bone and reside for at least 60 days following administration in rats. 71 No human use has been reported to date. Potential Uses of Radionuclides Metastatic Breast Cancer Most of the published evidence supporting the use of bone-seeking radionuclides in patients with skeletal metastases has focused on androgen-independent adenocarcinoma of the prostate, especially given its typical osteoblastic bone lesions, the usual absence of extraosseous metastases, and the paucity of effective cytotoxic chemotherapeutic options for these patients. However, many patients with widespread bone metastases from breast cancer harbor painful lesions exhibiting uptake on bone scans. Three major randomized controlled trials of bone-seeking radionuclides allowed for inclusion of 126 patients with breast cancer. Baczyk et al 72 reported the results of a randomized controlled trial comparing 89 Sr and 153 Sm in patients with metastatic prostate cancer (n = 60) and breast cancer (n = 40). There was no difference in pain relief between the radionuclides, but patients with a mixed blastic/lytic pattern of metastases experienced less pain relief than did patients with purely blastic disease. All patients tolerated the radionuclide treatments well. Resche et al 43 compared 0.5 and 1.0 mci/kg of 153 Sm- EDTMP for patients with painful bone metastases. A total of 36 of the 114 patients had breast cancer. A clear dose response was described for pain relief, and the patients with the best pain relief and overall survival were those with breast cancer receiving the higher dose. The only published randomized controlled trial of radionuclides for metastatic breast cancer was performed by Sciuto et al. 53 Patients were randomized to receive either 89 Sr or 186 Re-HEDP. Pain response and duration were similar between the groups. However, patients receiving 186 Re-HEDP obtained pain relief more quickly and recovered from transient myelosuppression significantly faster than did patients treated with 89 Sr. Christensen and Petersen 73 recently performed a systematic review of the evidence for the use of radionuclides for patients with breast cancer and painful bone metastases. In addition to the three randomized controlled trials previously mentioned, they found 16 case series that included patients with metastatic breast cancer and used 89 Sr, 153 Sm, or 186 Re with palliative intent. They concluded that there is a significant lack of high-level evidence supporting the use of bone-seeking radionuclides in this patient population and that randomized controlled trials are needed. Prior to EBRT Although most studies have evaluated either modality alone, investigators have examined the role of combining focal radiotherapy to large symptomatic sites with subsequent systemic radionuclides to address the more diffuse skeletal disease. Investigators from Turkey examined this therapeutic combination in 33 patients with diffuse, symptomatic bone metastases from a variety of solid tumors. In this nonrandomized study, the addition of either 153 Sm-EDTMP or 186 Re-HEDP provided additional pain relief beyond that reported after focal radiotherapy alone. 74 Two placebo-controlled randomized trials examining adjuvant 89 Sr following EBRT reported the opposite conclusions as to the additional pain relief provided by the radionuclide. 75,76 However, the study by Smeland et al 76 closed early due to poor accrual, lacking the power to determine a significant difference between the arms. Administration and Side Effects of Radionuclides In the United States, bone-seeking radionuclides are generally administered in the outpatient setting, as the lack of significant gamma emission makes radiation precaution isolation procedures unnecessary. In other countries, regulatory authorities may require patients to remain in the hospital for hydration and observation for several hours or overnight after the administration. Following informed consent, the patient is identified through two or more identifiers. Intravenous access is obtained and flushed prior to the procedure. Patients often are hydrated prior to the injection, either orally or with up to 500 ml of normal saline, to allow for an efficient elimination of radionuclide not incorporated into bone. The authorized user administers the radionuclide injection through the intravenous access over approximately 1 minute. The line is flushed with 20 to 30 ml of normal saline, and the access is removed by the procedure nurse. The patient is then given discharge instructions as well as recommendations to drink and urinate frequently for the first several hours. Typically, the injection is followed with weekly blood counts for up to 8 weeks to monitor the predictable transient decline and recovery of platelet and leukocyte counts. The principal side effect of bone-seeking radiopharmaceuticals is transient myelosuppression. Thrombocytopenia is the most common form, with platelet counts generally exhibiting a nadir at 40% to 60% from baseline. In most patients, this event will lead to only grade 1 or 2 toxicity. Significant problems with neutropenia and anemia are even less common. Approximately 5% to 10% of patients will experience a flare reaction, with a transient and self-limited increase in bone pain. This event is more common in patients with a significant burden of bone metastases visualized on bone scan. Other uncommon side effects may include nausea, loose stools, asymptomatic hematuria, and heart palpitations. 142 Cancer Control April 2012, Vol. 19, No. 2

7 Bone-Seeking Radionuclides and Bisphosphonates Given the deposition of most agents in this class of radionuclides, many physicians may express concern over patients receiving both bone-seeking radionuclides and bisphosphonate therapy. A European group has reported the results of a prospective study of combined 153 Sm-EDTMP and zoledronic acid in 20 patients with metastatic, hormone-refractory prostate cancer. 77 They found no effect of zoledronic acid on the uptake of 153 Sm- EDTMP, considering combined treatment to be both safe and effective. Conclusions Bone-seeking radionuclides are safe and effective agents to relieve pain in patients with osteoblastic bone metastases from solid tumors, and a recent update of a Cochrane systematic review 78 supports the use of these agents for palliation of bone pain in this population, albeit with the risk of transient myelosuppression. Good candidates are those with multiple sites of symptomatic disease visualized on a nuclear medicine bone scan, with adequate baseline blood counts and pain not well controlled with analgesics. 153 Sm-EDTMP and 89 Sr are two FDA-approved agents in general clinical use in the United States. Both have been shown to be safe and effective with repeat dosing. In early-phase clinical trials, both were shown to offer additional promise when used together with cytotoxic chemotherapy, without adding significant additional hematologic toxicity. Other agents in this class are under active clinical investigation and have shown similar efficacy in early-phase clinical trials. The most promising investigational agent is 223 Ra, an alpha-emitting bone-seeking radionuclide, which led to superior overall survival in a recently reported placebo-controlled randomized clinical trial. References 1. Paes FM, Serafi ni AN. Systemic metabolic radiopharmaceutical therapy in the treatment of metastatic bone pain. Semin Nucl Med. 2010;40(2): Soloway MS, Hardeman SW, Hickey D, et al. Stratifi cation of patients with metastatic prostate cancer based on extent of disease on initial bone scan. Cancer. 1988;61(1): Cleeland CS. Cancer-related symptoms. Semin Radiat Oncol. 2000;10(3): Stoll BA. Natural history, prognosis, and staging of bone metastases. In: Szoll BA, Parboo S, eds. Bone Metastases: Monitoring and Treatment. New York, NY: Raven; 1983: Muir GH, Butta A, Shearer RJ, et al. Induction of transforming growth factor beta in hormonally treated human prostate cancer. Br J Cancer. 1994;69(1): Kostenuik PJ, Singh G, Orr FW. Transforming growth factor beta upregulates the integrin-mediated adhesion of human prostatic carcinoma cells to type I collagen. Clin Exp Metastasis. 1997;15(1): Rajan R, Vanderslice R, Kapur S, et al. Epidermal growth factor (EGF) promotes chemomigration of a human prostatic tumor cell line, and EGF immunoreactive proteins are present at sites of metastasis in the stroma of lymph nodes and medullary bone. Prostate. 1996;28(1): Ludwig H, Kumpan W, Sinzinger H. Radiography and bone scintigraphy in multiple myeloma: a comparative analysis. Br J Radiol. 1982;55(651): Horvat AG, Kovač V, Strojan P. Radiotherapy in palliative treatment of painful bone metastases. Radiol Oncol. 2009;43(4): Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteristics and impact in patients with cancer pain. Pain. 1999;81(1-2): Lutz S, Berk L, Chang E, et al. Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline. Int J Radiat Oncol Biol Phys. 2011;79(4): Tong D, Gillick L, Hendrickson FR. The palliation of symptomatic osseous metastases: fi nal results of the Study by the Radiation Therapy Oncology Group. Cancer. 1982;50(5): Poulter CA, Cosmatos D, Rubin P, et al. A report of RTOG 8206: a phase III study of whether the addition of single dose hemibody irradiation to standard fractionated local fi eld irradiation is more effective than local fi eld irradiation alone in the treatment of symptomatic osseous metastases. Int J Radiat Oncol Biol Phys. 1992;23(1): Kuban DA, Delbridge T, el-mahdi AM, et al. Half-body irradiation for treatment of widely metastatic adenocarcinoma of the prostate. J Urol. 1989;141(3): International Commission on Radiation Units and Measurements. Stopping powers for electrons and positrons. ICRU Report 37. Bethesda, MD: International Commission on Radiation Units and Measurements; Silberstein EB. The treatment of painful osseous metastases with phosphorus-32-labeled phosphates. Semin Oncol. 1993;20(3 suppl 2): Henriksen G, Fisher DR, Roeske JC, et al. Targeting of osseous sites with alpha-emitting 223Ra: comparison with the beta-emitter 89Sr in mice. J Nucl Med. 2003;44(2): Taylor AJ Jr. Strontium-89 for the palliation of bone pain due to metastatic disease. J Nucl Med. 1994;35(12): Blake GM, Zivanovic MA, Blaquiere RM, et al. Strontium-89 therapy: measurement of absorbed dose to skeletal metastases. J Nucl Med. 1988; 29(4): Fuster D, Herranz D, Vidal-Sicart S, et al. Usefulness of strontium-89 for bone pain palliation in metastatic breast cancer patients. Nucl Med Commun. 2000;21(7): Kraeber-Bodéré F, Campion L, Rousseau C, et al. Treatment of bone metastases of prostate cancer with strontium-89 chloride: effi cacy in relation to the degree of bone involvement. Eur J Nucl Med. 2000;27(10): Ashayeri E, Omogbehin A, Sridhar R, et al. Strontium 89 in the treatment of pain due to diffuse osseous metastases: a university hospital experience. J Natl Med Assoc. 2002;94(8): Gunawardana DH, Lichtenstein M, Better N, et al. Results of strontium-89 therapy in patients with prostate cancer resistant to chemotherapy. Clin Nucl Med. 2004;29(2): Liepe K, Kotzerke J. A comparative study of 188Re-HEDP, 186Re- HEDP, 153Sm-EDTMP and 89Sr in the treatment of painful skeletal metastases. Nucl Med Commun. 2007;28(8): Turner SL, Gruenewald S, Spry N, et al; Metastron Users Group. Less pain does equal better quality of life following strontium-89 therapy for metastatic prostate cancer. Br J Cancer. 2001;84(3): Mertens WC, Stitt L, Porter AT. Strontium 89 therapy and relief of pain in patients with prostatic carcinoma metastatic to bone: a dose response relationship? Am J Clin Oncol. 1993;16(3): Porter AT, McEwan AJ, Powe JE, et al. Results of a randomized phase III trial to evaluate the effi cacy of strontium-89 adjuvant to local fi eld external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys. 1993;25(5): Sciuto R, Maini CL, Tofani A, et al. Radiosensitization with lowdose carboplatin enhances pain palliation in radioisotope therapy with strontium-89. Nucl Med Commun. 1996;17(9): Sciuto R, Festa A, Rea S, et al. Effects of low-dose cisplatin on 89Sr therapy for painful bone metastases from prostate cancer: a randomized clinical trial. J Nucl Med. 2002;43(1): Tu SM, Millikan RE, Mengistu B, et al. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial. Lancet. 2001;357(9253): Oosterhof GO, Roberts JT, de Reijke TM, et al. Strontium(89) chloride versus palliative local fi eld radiotherapy in patients with hormonal escaped prostate cancer: a phase III study of the European Organisation for Research and Treatment of Cancer, Genitourinary Group. Eur Urol. 2003;44(5): Quilty PM, Kirk D, Bolger JJ, et al. A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol. 1994;31(1): Goeckeler WF, Troutner DE, Volkert WA, et al. 153Sm radiotherapeutic bone agents. Int J Rad Appl Instrum B. 1986;13(4): Paes FM, Ernani V, Hosein P, et al. Radiopharmaceuticals: when and how to use them to treat metastatic bone pain. J Support Oncol. 2011;9(6): Singh A, Holmes RA, Farhangi M, et al. Human pharmacokinetics of samarium-153 EDTMP in metastatic cancer. J Nucl Med. 1989;30(11): Eary JF, Collins C, Stabin M, et al. Samarium-153-EDTMP biodistribution and dosimetry estimation. J Nucl Med. 1993;34(7): April 2012, Vol. 19, No. 2 Cancer Control 143

8 37. Dolezal J. Systemic radionuclide therapy with samarium-153- EDTMP for painful bone metastases. Nucl Med Rev Cent East Eur. 2000; 3(2): Dolezal J, Vizda J, Odrazka K. Prospective evaluation of samarium-153-edtmp radionuclide treatment for bone metastases in patients with hormone-refractory prostate cancer. Urol Int. 2007;78(1): Tian JH, Zhang JM, Hou QT, et al. Multicentre trial on the effi cacy and toxicity of single-dose samarium-153-ethylene diamine tetramethylene phosphonate as a palliative treatment for painful skeletal metastases in China. Eur J Nucl Med. 1999;26(1): Etchebehere EC, Pereira Neto CA, Lima MC, et al. Treatment of bone pain secondary to metastases using samarium-153-edtmp. Sao Paulo Med J. 2004;122(5): Sapienza MT, Ono CR, Guimarães MI, et al. Retrospective evaluation of bone pain palliation after samarium-153-edtmp therapy. Rev Hosp Clin Fac Med Sao Paulo. 2004;59(6): Collins C, Eary JF, Donaldson G, et al. Samarium-153-EDTMP in bone metastases of hormone refractory prostate carcinoma: a phase I/II trial. J Nucl Med. 1993;34(11): Resche I, Chatal JF, Pecking A, et al. A dose-controlled study of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) in the treatment of patients with painful bone metastases. Eur J Cancer. 1997;33(10): Serafi ni AN, Houston SJ, Resche I, et al. Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial. J Clin Oncol. 1998;16(4): Sartor O, Reid RH, Hoskin PJ, et al. Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology. 2004;63(5): Sartor O, Reid RH, Bushnell DL, et al. Safety and effi cacy of repeat administration of samarium Sm-153 lexidronam to patients with metastatic bone pain. Cancer. 2007;109(3): Menda Y, Bushnell DL, Williams RD, et al. Effi cacy and safety of repeated samarium-153 lexidronam treatment in a patient with prostate cancer and metastatic bone pain. Clin Nucl Med. 2000;25(9): Morris MJ, Pandit-Taskar N, Carrasquillo J, et al. Phase I study of samarium-153 lexidronam with docetaxel in castration-resistant metastatic prostate cancer. J Clin Oncol. 2009;27(15): Tu SM, Mathew P, Wong FC, et al. Phase I study of concurrent weekly docetaxel and repeated samarium-153 lexidronam in patients with castration-resistant metastatic prostate cancer. J Clin Oncol. 2009;27(20): Fizazi K, Beuzeboc P, Lumbroso J, et al. Phase II trial of consolidation docetaxel and samarium-153 in patients with bone metastases from castration-resistant prostate cancer. J Clin Oncol. 2009;27(15): Finlay IG, Mason MD, Shelley M. Radioisotopes for the palliation of metastatic bone cancer: a systematic review. Lancet Oncol. 2005;6(6): De Klerk JM, Zonnenberg BA, Blijham GH, et al. Treatment of metastatic bone pain using the bone seeking radiopharmaceutical Re-186- HEDP. Anticancer Res. 1997;17(3B): Sciuto R, Festa A, Pasqualoni R, et al. Metastatic bone pain palliation with 89-Sr and 186-Re-HEDP in breast cancer patients. Breast Cancer Res Treat. 2001;66(2): Dafermou A, Colamussi P, Giganti M, et al. A multicentre observational study of radionuclide therapy in patients with painful bone metastases of prostate cancer. Eur J Nucl Med. 2001;28(7): de Klerk JM, van het Schip AD, Zonnenberg BA, et al. Phase 1 study of rhenium-186-hedp in patients with bone metastases originating from breast cancer. J Nucl Med. 1996;37(2): Han SH, de Klerk JM, Tan S, et al. The PLACORHEN study: a double-blind, placebo-controlled, randomized radionuclide study with (186) Re-etidronate in hormone-resistant prostate cancer patients with painful bone metastases. Placebo Controlled Rhenium Study. J Nucl Med. 2002;43(9): Englaro EE, Schroder LE, Thomas SR, et al. Safety and effi cacy of repeated sequential administrations of Re-186(Sn)HEDP as palliative therapy for painful skeletal metastases: initial case reports of two patients. Clin Nucl Med. 1992;17(1): Palmedo H, Guhlke S, Bender H, et al. Dose escalation study with rhenium-188 hydroxyethylidene diphosphonate in prostate cancer patients with osseous metastases. Eur J Nucl Med. 2000;27(2): Palmedo H, Manka-Waluch A, Albers P, et al. Repeated bonetargeted therapy for hormone-refractory prostate carcinoma: randomized phase II trial with the new, high-energy radiopharmaceutical rhenium-188 hydroxyethylidenediphosphonate. J Clin Oncol. 2003;21(15): Lewington VJ. Bone-seeking radionuclides for therapy. J Nucl Med. 2005;46(suppl 1):38S-47S. 61. Krishnamurthy GT, Swailem FM, Srivastava SC, et al. Tin-117m(4+) DTPA: pharmacokinetics and imaging characteristics in patients with metastatic bone pain. J Nucl Med. 1997;38(2): Bouchet LG, Bolch WE, Goddu SM, et al. Considerations in the selection of radiopharmaceuticals for palliation of bone pain from metastatic osseous lesions. J Nucl Med. 2000;41(4): Srivastava SC, Atkins HL, Krishnamurthy GT, et al. Treatment of metastatic bone pain with tin-117m stannic diethylenetriaminepentaacetic acid: a phase I/II clinical study. Clin Cancer Res. 1998;4(1): Atkins HL, Mausner LF, Srivastava SC, et al. Tin-117m(4+)-DTPA for palliation of pain from osseous metastases: a pilot study. J Nucl Med. 1995;36(5): Nilsson S, Larsen RH, Fosså SD, et al. First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res. 2005;11(12): Nilsson S, Franzén L, Parker C, et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007;8(7): Parker C, Heinrich D, O Sullivan JM, et al. Overall survival benefi t of radium-223 chloride (Alpharadin) in the treatment of patients with symptomatic bone metastases in castration-resistant prostate cancer (CRPC): a phase III randomised trial (ALSYMPCA). Presented at the European Multidisciplinary Cancer Congress; September 23-27, 2011; Stockholm, Sweden. Abstract 1LBA. 68. Chakraborty S, Das T, Banerjee S, et al. 177Lu-EDTMP: a viable bone pain palliative in skeletal metastasis. Cancer Biother Radiopharm. 2008;23(2): Máthé D, Balogh L, Polyák A, et al. Multispecies animal investigation on biodistribution, pharmacokinetics and toxicity of 177Lu-EDTMP, a potential bone pain palliation agent. Nucl Med Biol. 2010;37(2): Liu C, Brasic JR, Liu X, et al. Timing and optimized acquisition parameters for the whole-body imaging of 177 Lu-EDTMP toward performing bone palliation treatment. Nucl Med Commun. 2012;33(1): Das T, Chakraborty S, Sarma HD, et al. (170)Tm-EDTMP: a potential cost-effective alternative to (89)SrCl(2) for bone pain palliation. Nucl Med Biol. 2009;36(5): Baczyk M, Czepczyński R, Milecki P, et al. 89Sr versus 153Sm- EDTMP: comparison of treatment effi cacy of painful bone metastases in prostate and breast carcinoma. Nucl Med Commun. 2007;28(4): Christensen MH, Petersen LJ. Radionuclide treatment of painful bone metastases in patients with breast cancer: a systematic review. Cancer Treat Rev. 2012;38(2): Hicsonmez A, Kucuk ON, Andrieu MN, et al. Role of radionuclide therapy as adjuvant to palliative external beam radiotherapy for painful multiple skeletal metastasis. World J Oncol. 2010;1(4): Porter AT, McEwan AJ. Strontium-89 as an adjuvant to external beam radiation improves pain relief and delays disease progression in advanced prostate cancer: results of a randomized controlled trial. Semin Oncol. 1993;20(3 suppl 2): Smeland S, Erikstein B, Aas M, et al. Role of strontium-89 as adjuvant to palliative external beam radiotherapy is questionable: results of a double-blind randomized study. Int J Radiat Oncol Biol Phys. 2003;56(5): Lam MG, Dahmane A, Stevens WH, et al. Combined use of zoledronic acid and 153Sm-EDTMP in hormone-refractory prostate cancer patients with bone metastases. Eur J Nucl Med Mol Imaging. 2008;35(4): Roqué I Figuls M, Martinez-Zapata MJ, et al. Radioisotopes for metastatic bone pain. Cochrane Database Syst Rev. 2011;(7):CD Cancer Control April 2012, Vol. 19, No. 2