Use of radionuclides for the palliation of bone metastases

Use of Radionuclides for the Palliation of Bone Metastases A.J. B. McEwan Pain palliation with bone-seeking radiopharmaceuticals is an effective and cost-effective management tool in patients with advanced cancer metastatic to bone. Strontium-89 (89Sr) (Metastron) and samarium-153 (153Sm) EDTMP (Lexidronam) are licensed for use in patients in the United States. Patients with a positive bone scan using technetium 99m methylene diphosphonate (gSmTcMDP) are eligible for treatment, and indications and contraindications for use are now well defined. The evidence in the literature now suggests that the radiopharmaceuticals can significantly reduce pain and analgesic requirements, can improve quality of life, can reduce lifetime radiotherapy requirements and man-

agement costs, and may slow the progression of painful metastatic lesions. Retreatment is safe and effective. Rhenium-186 (18SRe) HEDP and ~n-117m diethylenetriaminepenta-acetic acid (DTPA) are in phase II/111trials to evaluate efficacy and compare efficacy with the licensed agents. Phosphorus-32 (32p) has been reassessed in two trials evaluating efficacy in comparison with 89Sr and safety. Toxicity is reversible myelosuppression, which may be significant, and the treatments should not be given to patients with suspected disseminated intravascular coagulation. Copyright 9 2000 by W.B. Saunders Company

he incidence of painful bone metastases in

nates in modifying disease progression and complication rate. 9,~~

T patients with advanced cancer is high I and may reach 85% in cancers arising from prostate, lung, and breast. Although pain is now more aggressively managed than in the past, poorly controlled pain syndromes, associated with significant reductions in quality of life, remain an ongoing clinical dilemma. 2,:~ A major role of any department of radiation oncology is the management of pain. An increasing recognition of the importance of the management of pain syndromes has led to the development of muhidisciplinary clinics to provide long-term strategies tbr the management of this large number of patients. 4 Although external-beam radiotherapy and the graduated use of narcotic analgesics remain the key elements of pain control," the available treatment options are wide (Table l)J ~In patients with muhiple sites of pain, systemic therapy has increasingly been recognized as an important contributor to improvements in quality of life. The two most recent additions to this armamentarium of systemic therapies are the bisphosphonates 7 and systemic radionuclide therapy, a The response rate seen in bisphosphonate treatment may approach that reported for externalbeam radiotherapy; phase III trials are underway in patients with breast and prostate cancer metastatic to bone, evaluating a wider role for novel bisphospho-

From the Department of Oncology, Faculty of Medicine, University of Alberta," and Department of Omvlogic Imaging, Cross Cancer Institute, Edmonton, Alberta, Canada. Address reprint requests to A. J. B. McEwan, MBBS, Department of OncologicImaging, Cross CancerInstitute, 11560 UniversityAve, Edmonton, Alberta T6G 1Z2, Canada. Cbpyright 9 2000 by W.B. Saunders Company 1053-4296/00/1002-0004510.00/0

Radiopharmaceuticals for Pain Management Despite an initial report of effective palliative treatment in 1942 I] using agSr and a considerable body of literature up to the 1970s on the effectiveness of :~2p,12it is only in the last decade that radiopharmaceutical therapy (RPT) has entered widespread use as an effective and cost-effective management strategy. ]:~ The interest in this form of treatment is reflected in the number of radiopharmaceuticals that are in use, or under development. Table 2 I~ summarizes the physical characteristics of the five most commonly used and discussed agents. Tin-ll7m diethylenetriaminepenta-acetic acid (ll7mSn DTPA) is currently in phase II trials, and rhenium-186 HEDP (latiUe HEDP) is in phase Ill trials in Europe. 89Sr, 32p, and samarium-153 EDTMP (153Sm EDTMP) are now available for routine use in most jurisdictions. Absorbed-dose calculations for the required five compounds are comparable (Table 3).14 The characteristics of the live compounds have been reviewed by McEwan, 6,1:~ Lewington, 15 and Silberstein et al. 12

Phosphorus-32 32p decays by beta emission with a half-life of 14.3 days. Within bone, phosphorus is bound, as inorganic phosphorus, to the hydroxyapatite matrix with slow turnover. Within soft tissue and in the bone marrow, phosphorus distribution is predominantly intracellular. Excretion is mainly renal. 12,16Uptake is increased

Seminars in Radiation Oncology, Vo110, No 2 (April), 2000: pp 103-114

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A.J. B. McEwan

Table 1. Interventions in Pain Palliation

Samarium-153 EDTMP

Non-narcotic analgesics Nonsteroidal anti-inflammatory drugs Narcotic analgesics Local field external-beam radiotherapy Wide-field radiotherapy Unsealed source therapy with bone-seeking radiopharmaceuticals Hormone therapy Chemotherapy Interventional anesthetic techniques Bisphosphonates Reprinted with permission.6 at sites of bone metastases relative to normal bone, reflecting increased metabolic turnover in sites of active remodeling. Strontium-89 89Sr is a pure beta-emitting radioisotope of strontium with a maximum beta-particle energy of 1.46 MeV. S5Sr has been used as a tracer for 89Sr metabolism in dosimetry studies. 17,18 Biological handling of strontium mimics that of calcium in vivo; strontium is incorporated into the inorganic matrix, with uptake being in proportion to the degree of osteoblastic activity. Uptake and retention of agSr at sites of metastatic tumor are increased relative to normal bone. 85Sr images were identical to those obtained with technetium 99m methylene diphosphonate (99mTc MDP). Whole-body retention of 898r has been shown to be proportional to metastatic burden. Calculated doses are to individual metastases, varying from 3.8 to 22.62 Gy/mCi, with marrow doses typically being 1/10 of the doses to the metastatic sites. Excretion is almost entirely by the renal route. The rate of excretion is a complex relationship between metastatic burden and renal plasma clearance of strontium, described by Blake et al.1o This relationship may have implications for the use of 89Sr in patients with significant renal impairment.

1538m is a reactor-produced radioisotope by neutron irradiation of 152Sm. ~53Sm has a complex decay scheme with a principal beta maximum energy of 0.81 MeV. There is a gamma photon of 103 keV, which can be used for correlative imaging. The synthesis of 153Sm complexes was first reported by Goeckeler et a12~ EDTMP showed the optimal combination of high bone uptake and rapid blood clearance and a labeling efficiency of greater than 90%. Most of the administered dose is localized in the skeleton within 3 hours of injection, and less than 2% is seen in soft tissue. Excretion is almost exclusively renal, and distribution correlates with 99roTe MDP imaging. 2~Comparable therapeutic ratios have been demonstrated for 153SmEDTMP as are seen for 89Sr, with bone-to-soft tissue ratios of 10:1 being seen. 21,22 The whole-body dose from an injection of 1538m EDTMP has been calculated at 0.44 mGy/mCi. Metastatic lesion-to-normal bone ratios and metastatic lesion-to-soft tissue ratios have been calculated by Singh et a123 to be 4.04 and 5.98. These values imply a safe therapeutic ratio for the radiopharmaceutical. Rhenium-186 I-IF.Dp la6Re is a group VII metal that decays with the emission of a beta particle of maximum energy 1.07 MeV. A low-abundance gamma ray is also produced in the decay process, enabling correlative imaging to be performed. 186Re HEDP was reported in 1986, and subsequently a clinical formulation of the product entered clinical trials. 24,25Animal biodistribution studies confirmed high uptake in bone with 14% of the injected dose remaining in the skeleton 96 hours postinjection. Of the injected dose, 43% is excreted in the urine in the first hour. A correlation of uptake and retention with metastatic burden is also seen, and 38% of the injected dose may be retained in the skeleton 3 hours after injection.

Table 2. Radiopharmaceuticals for Palliative Therapy Radionuclide

Pharmaceutical

Half-Life (days)

Maximum [3EnergyMeV

89Sr 32p la6Re HEDP 153SmEDTMP lI7mSnDTPA

Chloride Orthophosphate HEDP EDTMP DTPA

50.5 14.3 3.8 1.95 13.6

1.46 1.71 1.07 0.8 (conversionelectrons)

Reprinted with permission.14

Mean Maximum [3Energ7 MeV Rangein Tissue (mm)

0.583 0.695 0.349 0.224 0.129 0.153

6.7 8 4.7 3.4 0.3

y Photon keV (%)

--137 (9) 103 (28) 159 (86)

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Radionuclide Pain Palliation

Table 3. Comparative Absorbed Radiation Doses (Rad/mCi [mGy/MBq]) Radiopharmaceutical

Bone

Marrow

Bladder

Tumor

:~2p 89Sr ~5:~SmEDTMP ~86Re HEDP 117mSn DTPA

41-63 (11.1-17) 50-60 (13.5-16.2) 8.6-25 (2.3-6.8) 3.2 (0.9) 200-300 (54-81)

20-40 (5.4-10.8) 40-200 (10.8-54) 3.8-6.9 (1.1-1.9) 2.8 (0.76) 12-27 (3.2-7.3)

2.7 (0.74) 4.8 ( 1 . 3 ) 3.6-4.6 (1-1.2) 1.8 (0.5) 0.6 (0.16)

400-2,200(108-594) 42 (11.3) 41 (11.1)

Reprintedwithpermission)4

The pharmacokinetics of 186Re HEDP have been described by de Klerk et al,26 and preliminary dosimetry calculations showed a safe therapeutic ratio. Samaratunga et a127 have developed an elegant dosimetry model that may have wider applications in the assessment of local dosimetry for unsealed sources. This is a Monte Carlo simulation of the microdosimetric environment addressing the questions of heterogeneity of the bone-tumor interface, nonuniform distribution of radiopharmaceutical on bone spicules, and differential energy deposition. This model suggests that for osteoblastic lesions, standard dosimetric calculations significantly underestimate tumor dose as well as, perhaps, marrow dose. laaRe has been evaluated as an alternative isotope. It has the advantage of convenience--it is generator produced--but half-life may be a limiting factor in its radiobiological effectiveness.2a

Tin- 117m DTPA ll7mSn (4+) DTPA is a bone-seeking chelate that shows high bone uptake and low soft tissue activity, with rapid renal clearance of the radiopharmaceutical. l l7mSn is reactor produced by irradiation of 117Sn. It decays with the emission of low-energy conversion electrons; the short path length of the conversion electron is anticipated to reduce myelotoxicity by reducing the absorbed dose to marrow. A 159-keV photon is emitted with low abundance, enabling correlative imaging. 29 The mechanism of incorporation is believed to be precipitation of Tin onto the inorganic bone matrix. This compound is just entering phase III trials. In preclinical studies, lesion-to-normal tissue ratios were calculated at 15:1. The physical characteristics of this radiopharmaceutical are slightly different from the other compounds discussed in this section, but the preliminary clinical data suggest that it may have comparable efficacy with theoretical reduction in toxicity.3~

Characteristics of Radiopharmaceutical Pain Palliation The theoretical advantages of all targeted RPT lie in the specific localization of the radionuclide at the site of tumor to be treated and the relatively limited distribution of radionuclide at sites of potential limiting toxicity, such as bone marrow, central nervous system, and kidney. Most currently available radiopharmaceuticals achieve a therapeutic ratio of approximately 10:1. Because the radiopharmaceutical is administered systemically, all metastatic sites are treated simultaneously, and it has been postulated that microscopic deposits can be prevented from progressing31 by achieving a significant dose delivery from the short-range radiation. The characteristics required for radiopharmaceuticals to be effective in palliative treatment have been extensively discussed with respect to half-life, particle energy, stability of binding, percent uptake by tumor of the administered dose, and specific activity. 15,32,3:~These characteristics are summarized in Table 4.6 The mechanism of uptake for each of the boneseeking radiopharmaceuticals is related to the degree ofosteoblastic activity at the site of the metastasis; the selectivity of uptake is related to incorporation within bone rather than within tumor. The complex anatomic relationship between tumor and new bone

Table 4. Characteristics of an Ideal Radiopharmaeeutical for Palliative Therapy in Patients With Bone Metastases Selective uptake in metastases relative to normal bone Rapid clearance from soft tissue and normal bone Distribution predicted by 99myc-MOPbone images Physical half-life greater than or equal to biological half-life Simple production process [3 particle emissions: E max >0.8 MeV and <2.0 MeV Stable and easy to transport Cost-effective and readily available Reprintedwith permission.6

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formation means that the irradiation is delivered to the tumor and the peritumor environment from radionuclide deposited at the bone-tumor interface. As the radionuclide is effectively fLxed within the bone matrix, yielding a long biological half-life, the physical half-life should be longer rather than shorter to give as high a radiation absorbed dose as possible. This model also implies that more energetic beta particles should be more effective as a larger volume of tumor can be irradiated. The clinical effectiveness of ll7mSn DTPA, with a short track length, however, appears comparable to that of 89Sr, which emits an energetic beta particle. The implication is that irradiation of the tumor cell is not the only or even the primary factor in clinical effectiveness. This palliative effect of bone-seeking radiopharmaceuticals is presumably related to the absorbed dose deposited in tumor, in bone, and in the peritumor environment by the beta particle emissions. At most administered doses and for most calculated absorbed doses, there is no clear evidence of a dose response. The absorbed dose to bone metastases is a function of the energy deposited within the tumor. This dose reflects the concentration of radiopharmaceutical within the tumor (at the bone-tumor interface), the retention time at the interface (biological halflife), the physical half-life, and the beta particle energy. 34 The longer the biological retention is at the bone-tumor interface, the more important it becomes that the physical half-life of the radionuclide is also long, to ensure maximum energy deposition within the tumor. Dose rate may also be a factor, but the importance of dose rate in palliative treatment at the ranges of very-low-dose-rate (VLDR) therapy have not been tested clinically or in animal models. 35 Calculations of dose administered with any of the five radiopharmaceuticals are less than would be predicted to be effective using the high-dose-rate model of externalbeam radiotherapy. This discrepancy reflects a limited understanding ofVLDR radiobiology, the imprecision of dosimetry calculations, and the uncertainty about optimal dosage schedules. 36 It has been postulated that the primary palliative effect may be related to the dose administered to the peritumor environment, with subsequent reduction in cytokine production 37 and modulation of humoral pain mediatorsY In addition, mechanical symptom relief, reduction in hypoxia and periosteal compression, and direct tumor cell cytotoxicity have all been shown to be important factors in response to external-

beam radiation and may be important considerations in VLDR therapy. 39 RPT are comparable in cost to other forms of cancer treatment such as newer hormone therapies for prostate cancer or subcutaneous octreotide used for the palliative management of patients with carcinoid syndrome. Two articles have evaluated the cost-effectiveness of 89Sr in the management of patients with prostate cancer; both have shown savings in lifetime management costs when compared with standard patterns of care in patients with advanced and progressive disease. 4~ Cost-effectiveness studies have been performed only for 89Sr, although trials are underway for 1538mEDTMP and 186ReHEDP. Three of the radiopharmaceuticals have an imageable gamma photon, and 85Sr may be used as a tracer for the distribution of agSr. For all compounds, however, the distribution and patterns of abnormal uptake are accurately and consistently predicted by the 99mTcMDP bone scan. This is the most important screening study that can be performed in considering a patient for treatment. The gamma photon also allows individual patient dosimetry calculations to be performed, although administered dose calculations are usually empirically based on a standard dose or are based on a weight or body surface area calculation. It has been suggested that complex individual dose calculations, specifically for the administration of 186Re HEDP, may enhance efficacy and reduce toxicity. 42 This situation has not been validated for the other radiopharmaceuticals.

Clinical Experience The current indications for use of radiopharmaceuticals in pain palliation are largely based on data accumulated in phase II and phase m trials of a9Sr and 153Sm EDTMP over the past 10 to 15 years. A large literature exists for 32p and 89Sr dating back to the 1950s. The early strontium literature has been reviewed by McEwan 43 and is not discussed further. The use of 32p has been extensively reviewed by Silberstein et al. 12Although 32p is an effective treatment, which certainly could be cost-effective, it fell out of routine widespread use because of perceived significantly increased toxicity and morbidity when compared with the other radiopharmaceuticals. Two publications, however, report response rates that are comparable to 898r44'45in terms of analgesic efficacy and duration of response. In addition, although

Radionuclide Pain Palliation

toxicity was significantly greater in the patients treated with 32p, no clinical sequelae to this increased toxicity were reported. 44 Both studies included relatively small populations of patients, but the authors make a case for the resuscitation of this treatment option. These data support the historical review by Montebello and Hartson-Eaton, 46 showing similar efficacy but greater toxicity for 32p when compared with 898r. The results of key preliminary clinical trials and of phase III studies are reviewed for the radiopharmaceuticals in routine use. 6,13 Placebo-Controlled Trials Two double-blind, crossover, placebo-controlled trials ofradiopharmaceuticals for pain palliation have been reported. Maxon et a147 published the results of a double-blind, crossover, placebo-controlled trial of efficacy of 186Re HEDP. Thirteen evaluable patients with bone metastases were randomized to receive either 186Re HEDP or placebo (99mTc MDP). After injection, they were followed for 4 weeks and evaluated at that time point. A crossover injection at 4 weeks was allowed if the patient failed to respond to the first injection. A second trial, reported by Lewington et al,48 evaluated 40/~Ci/kg ~gSr compared with the same molar concentration of stable strontium as placebo. Thirty-two patients were evaluated, and there was also a crossover option at 6 weeks if no response was seen to the first injection. Patients were evaluated at 12 weeks. For both of these studies, there was a statistically significant advantage to the active arm, and both sets of authors argued that the palliative effect of the two radiopharmaceuticals is real. Dose Escalation Studies The first dose escalation study of 89Sr was reported by Silberstein and Williams, 49 who treated 38 patients with multiple primaries; 45 doses were administered, ranging from 10/zCi/kg (0.4 MBq/kg) to 70/xCi/kg (2.6 MBq/kg). For each decile of dose, no difference was seen in the numbers of patients responding, and no significant myclosuppression was seen. The mean duration of response after therapy was 1.6 months, and the median survival was 4 months. Overall the response rate was 51%. Laing et al 5~ also published an open-label dose escalation study in 83 patients with prostate cancer using doses of 20, 40, 60, and 80 txCi/kg (0.74, 1.48, 2.22, and 2.96 MBq/kg). An overall response rate of 75% was seen. There was no evidence of a dose response, although the patient group treated at 20

107

~Ci/kg (0.74 MBq/kg) had a lower overall response rate than those at the other doses. No clinically significant toxicity was observed, although patients at the highest dose level did show the most reversible myelosuppression. Patients with the highest metastatic burden were believed to be those who had the most limited palliation. 153Sin EDTMP has been evaluated by several groups looking at dose response and incremental toxicity. Eary et a151 and Turner et a152have reported incrementally increasing doses to 4.5 mCi/kg, resulting in total administered doses of 300 mCi. There was no convincing evidence of a dose response, but reversible myelotoxicity was dose related and at the highest doses severe. Turner and Claringbold 53 reported safe administration with absorbed dose to marrow of 2 Gy. Farhanghi et a154 have also confirmed lack of a dose response, associated with dose-related toxicity in a dose escalation study to 1.0 mCi/kg. They believed that maximum tolerated dose had not been achieved and noted a direct correlation between metastatic burden and retained activity. Dose escalation studies for 186Re HEDP have also been reported by de Klerk et aP 5 and by Quirijnen et al, 56 who have compared incrementally escalating doses from 35 to 95 mCi. In both of these studies, there is evidence of a dose response, with significantly more patients at the higher dose level showing improvements in quality of life and reduction in pain than at the lower dose levels. A phase I dose escalation study of 1~6Re HEDP in breast cancer 57 has shown that there is increasing toxicity with higher doses and that the maximal tolerable dose is 65 mCi, with dose-limiting toxicity being thrombocytopenia. Much of the preliminary data evaluating all radiopharmaceuticals discussed in this article was pertbrmed initially in patients with prostate cancer. Han et a158 have performed an open-label dose escalation study in 30 patients with breast cancer metastatic to bone. Administered doses ranged from 35 to 80 mCi 1~6Re HEDP. No dose-response relationship was observed, and overall response rates were comparable to those seen in patients with prostate cancer. Doserelated myelosuppression was seen, which apparently recovered more rapidly than with 89Sr. A single dose escalation study of l l7mSn DTPA has been performed. 59 No toxicity was observed at any level, perhaps reflecting the more limited tissue penetration than is seen with the beta-emitting radionuclides.

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Studies to Define Clinical Use The current role of RPT in pain palliation is based on key literature reports of studies evaluating efficacy and definition of patient population.

Strontium-89 The potential ofa9Sr as a palliative radiopharmaceutical was developed by Robinson et al, 6~who obtained the first U.S. IND at the University of Kansas. The experience of this group was reviewed in 1995. A total of 622 patients had been treated more than 450 with prostate cancer. Patients were treated at two dose levels---40 and 55/xCi/kg--and some patients were retreated with doses of 30/xCi/kg. An overall response rate of 81% was reported with 15% achieving a complete resolution of symptoms. A second important trial of the efficacy of 89Sr was reported by Porter et alp 1 In this study, patients with pain requiring local field radiation therapy were randomized to receive either 89Sr or placebo in addition to the standard dose of external-beam radiation. A total of 126 patients were randomized equally between the two arms of the study. The patients in the arm that received 898r in addition to radiation therapy showed significant improvements at 3 months postinjection in requirements for analgesic support and in improved quality of life as measured by a visual analogue scale. In addition, reduced lifetime requirements for radiation therapy were seen in the active group, and there was a reduced rate in the development of new painful bone metastases. Hematological toxicity was greater in the active arm, but no clinically significant events were recorded. No differences in cord compression or pathological fracture were seen between the two arms. In a second multicenter trial, Quilty et a161 compared 5.4 mCi of SgSr with either local field radiation therapy (148 patients) or wide-field radiation therapy (157 patients). No significant differences in analgesic efficacy were seen in either arm of the two studies. Comparable numbers in all arms of the study showed complete or greater than 50% reductions in pain scores at the index site. In addition, there were significant delays to requirement for additional radiotherapy or other interventions in the 89Sr group in comparison to the local field radiotherapy group, and there were also significant delays in the development of new pain sites in the 89Sr arm. Several key elements appear evident from these two trials: (1) Analgesic efficacy of 898r appears

comparable to that of external radiotherapy; (2) significant improvements in quality of life are seen with 898r; (3) there is a delay in progression of painful metastases; and (4) there is a reduction in lifetime radiation therapy requirements. McEwan et al 4~ reviewed the data from a single site from the "Trans Canada" trial with respect to lifetime management costs. This cost was $5,800 lower in the group receiving 89Sr when compared with the placebo group. Cancer Care Ontario have developed a practice guideline for the use of 89Sr in patients with prostate cancer metastatic to bone, which contributes to an enhanced understanding of the most cost-effective practice. 62 The American College of Radiology has published guidelines for cost-effective use 6a of radiotherapy, including unsealed sources, and defining a need for further research. Baziotis et a164 reported a study in which 64 patients with breast cancer were followed after administration of a standard 4-mCi dose of a radiopharmaceutical for a period of 6 months. O f patients, 81% responded, with 35% appearing to become pain-free. Toxicity was moderate and in five patients severe enough to require granulocyte-colony-stimulating factor support. These results are comparable to those seen in patients with prostate cancer. Kasalicky and Krajska 65have confirmed the safety and efficacy of multiple administrations of89Sr in 118 patients with primary cancers of the prostate, breast, and lung, with a maximum number of repeat administrations of five. This important study shows comparable efficacy between the primary sites and shows no significant increase in toxicity with succeeding administrations. Patient selection for administration of 898r has been addressed by Schmeler and Bastin. 66 Response and survival were correlated with Karnofsky performance score (KPS). Limited survival and poor response was observed in the group with a KPS of--<50. Patients with a KPS ---70 had a response rate of approximately 75%. A KPS of 60 gave intermediate responses, and patient selection in this group should be made on an individual basis. This study should become part of a wider discussion of the most appropriate use of bone-seeking radiopharmaceuticals in the therapeutic armamentarium. An unexpected finding in the study reported by Porter et a131was a significant fall in prostate-specific antigen (PSA) values in the group treated with 89Sr. This finding should be treated with caution; it was not a secondary endpoint of the study, and data

RadionuclidePain Palliation

collection was incomplete. The finding may be important, however, in that it implies that treatment of these patients with bone-seeking radiopharmaceuticals may exert a tumoricidal effect, particularly with a radiopharmaceutical with an energetic beta particle. The concept of a tumoricidal effect has been tested by Sciuto et a167who compared 4 mCi 89Sr with 4 mCi 89Sr and low-dose carboplatin infusion. Fifteen patients were treated in each arm. Not only were the palliative responses significantly better in the arm receiving adjuvant carboplatin as a radiosensitizer, but also there appeared to be significant falls in PSA, implying cytoreduction. Samarium-153 EDTMP

153Sm EDTMP is now licensed for routine use in the United States. There is unequivocal evidence of a therapeutic benefit that is comparable to 89Sr in patients with osteoblastic bone metastases as defined by bone scanning with 99mTc MDP, although no comparative trials have been reported. Resche et a168 have compared two doses of 153Sm EDTMP in 1 14 patients; 55 received 0.5 mCi/kg, and 59 received 1.0 mCi/kg, as single administrations. A significant palliative response was seen at the higher dose level, with patients with breast cancer showing a greater response than patients with prostate cancer and lung cancer. No significant differences in toxicity were noted between the two groups, and no significant toxicities were seen. In a second trial, these two dose levels of 0.5 and 1.0 mCi/kg were compared with placebo in a double-blind designJ i9 A total of 118 patients were randomized equally to the three arms. Patients in both active arms fared significantly better than those in the placebo arm, and those at the higher dose had better pain palliation than those treated with 0.5 mCi/kg. Toxicity was greater in the active arms than in the placebo but was not significantly different between the two active arms. As with the previous study, patients with breast cancer responded better than those with prostate and lung cancer.

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A large multicenter trial has been reported by Tian et al, 7~who treated 105 patients with a variety of primary malignancies with 0.5 mCi/kg or 1.0 mCi/kg. Effective palliation was observed in 85% of patients, with those in the high-dose group achieving better responses. No clinically significant myelosuppression was observed. Patients with breast cancer tended to do better. Rhenium-186 ]-IEDp

186Re HEDP is not yet approved in the United States, and large-scale trials have not been reported. The efficacy of the radiopharmaceutical, however, has consistently been reported as comparable to that of 89Sr and 153SmEDTMP at higher administered doses, albeit with a shorter duration of response. Doses of 95 mCi have been shown to be effective and safe, with reversible myelosuppression being seen in a small percentage of patients at the higher doses, de Klerk et a155have shown a response relationship with metastatic burden and devised an algorithm to calculate administered doses using baseline platelet count and metastatic burden. Responses of 75% have been seen in patients with breast cancer. 71,72About one fifth of patients became pain-free, but the series are small. Schoeneich et a173 have reported responses of 60% in 44 patients with prostate cancer treated with 35 mCi 186Re HEDP with a median duration of response of 6 weeks. Guidelines for dose calculation have been prepared by Graham et al, 74 recommending doses of 80 mCi and suggesting individual dose calculations be performed. They propose a repetitive dosing schedule to attain maximum efficacy. The question of radiosensitization has been addressed by Geldof et a175 using 186Re HEDP and cisplatin in vitro. Synergy was observed, and a proposal for ongoing clinical trials was developed.

Clinical Summary Table 5 summarizes response rates that have been described in the literature for the five radiopharma-

Table 5. Summary of Responses

I~Re HEDP 153SmEDTMP :~2p 89Sr 117mSnDTPA

Response Rate (%)

ResponseDuration/ Median(months)

ResponseDuration/ Range (months)

Time to Response(days)

60-75 70-75 70 60-80 70

1-2 2-3 2-3 3-4 2-4

1-4 2-6 2-6 2-12 2-6

5-10 5-10 10-20 10-20 5-15

Thrombocytopenia

Flare (%

Mild-moderate Mild-moderate Moderate-severe Moderate Nil-mild

10 10 10-20 5-10 <5

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A. J. B. McEwan

ceuticals. Overall response rates in terms of efficacy are comparable; conventionally, it is said that approximately 20% become pain-free, and the balance of patients have more or less significant pain relief with reduction in analgesic requirements. It is interesting to compare response rates with RPT with those reported for external-beam radiation therapy. Price et a176 report a complete response rate of 27% and overall response rate of 85% for patients treated with both single fractions and 10-fraction radiotherapy; Tong et a177 report 53% and 89% for 613 patients treated with 5 to 10 fractions.Janjan TMreports overall response rates of 70% to 80% in patients with multiple metastases 4 to 12 weeks after, and 40% to 70% 2 to 4 weeks after radiation therapy. The duration of response appears to be longest with 89Sr and shortest with lS6Re HEDP. Overall response rates of 50% to 100% and complete response rates of 5% to 50% are reported in trials of hemibody radiotherapy. 79 This population of patients is presumably similar to that referred for RPT. Although care in treatment planning can reduce toxicity pneumonitis, thrombocytopenia andgastrointestinal symptoms may be severe and are seen in 2% to 32% of patients in different series. 39 These results are comparable to those seen in appropriately selected patient populations after palliative RPT. The key difference in the two modalities is time to response, which tends to be significantly more rapid with external-beam radiation therapy, although asJanjan 78reports there is a temporal association with response. Duration of response and quality of response may be longer with 89Sr in this population. 60 A flare response, associated with a short-lived increase in pain 24 to 48 hours after administration, may be commoner than originally believed and may be seen in i0% of patients. The impression gleaned from the literature is that it may be commoner in patients with breast cancer and that it may predict a good response. There is a delay to response, typically of about 10 days, although this appears to be related to half-life and is shortest with 186Re H E D P and longer with 89Sr. An increase in the quality of response is often seen for 4 weeks after injection. The reported efficacy data taken with the results of the studies reported by Porter et a131 and Quilty et a161 provide a rationale for the routine clinical use of these agents. Comparative trial data need to be developed to evaluate efficacy in comparison with that seen in bisphosphonate therapy and to evaluate

enhancements of response that may be obtained by the use of cisplatin as a radiosensitizer or possibly in combination with bisphosphonates. Toxicity is limited to reversible myelosuppression, most markedly thrombocytopenia. The nadir is seen 4 to 6 weeks after injection, and recovery is usually complete by 6 to 10 weeks. The severity of the myelosuppression is related to metastatic burden and may be more severe in the longer-lived radiopharmaceuticals and those with more energetic beta particles.

Clinical Use of Bone-Seeking Radiopharmaceuticals Indications Patients with cancer metastatic to bone and significant pain may benefit from treatment with 89Sr or 153Sm EDTMP. Patient selection is key to the successful effective use of these radiopharmaceuticals. Currently available data support their use in any patient with a positive bone scan with progressive pain, pain requiring increasing levels of analgesics, and recurrent pain in a site previously irradiated (Table 6). Patients with multiple transient sites of pain may achieve the best palliative response. The data from the "Trans-Canada" trial reported by Porter et a131 suggest that progression of painful metastases might be significantly reduced in patients with multiple metastases requiring radiotherapy to a single painful site. Hospitals that perform large numbers of RPT are tending to move to the model of joint management clinics to ensure appropriate referral and selection. There are, as yet, no convincing data to support the use of RPT in patients with multiple painless metastases or in those with no bone scan evidence of metastases but evidence of treatment failure based on a rising PSA. Clinical trials are underway to test Table 6. Indications for Treatment of Bone Metastases With Bone-Seeking Radiopharmaceuticals Patient has cancer metastatic to bone Positive 99roTeMDP bone scan (regardless of x-ray appearance) Karnofsky performance score ~60 Pain requiring narcotic analgesic support Multiple sites Diffuse pain Recurrent pain in a radiotherapy field Multiple transient pains Pain requiring radiotherapy to single site with multiple metastases

Radionuclide Pain Palliation

this role for both radiopharmaceuticals. Trials are also under consideration to compare the efficacy of bone-seeking radiopharmaceuticals with that of bisphosphonates and to explore the enhancement of efficacy by adjuvant treatment with radiosensitizing chemotherapeutics, such as low-dose cisplatin. The literature suggests that patients with a low burden of soft tissue disease do better and that patients with a superscan may respond less well. The best discriminator may be the KPS, however. ~6 All the radiopharmaceuticals discussed in this article may be safely used to retreat patients on multiple occasions--the greatest number of retreatments reported is nine. 6~ Requirements for acceptance of patients for subsequent therapies are the same as those for the initial treatment. Most authors, however, indicate that a nonresponder to the first administration is likely to be a nonresponder for subsequent administrations. The minimal time between retreatments is 10 to 12 weeks for 89Sr and 32p and 6 to 10 weeks for the other three radiopharmaceuticals.

Contraindications Although the radiopharmaceuticals are safe and effective, the practitioner needs to be aware of exclusion criteria beforc accepting a patient for therapy (Table 7). Although an absolute platelet count of 60,000 • l06 is the most widely quoted lower level in the literature, the kcy to the safe use ofthesc radiopharmaceuticals is the relative stability of the counts over the previous weeks; a stable lower count is more acccptable than a higher count that has fallen rapidly. There are two case reports in the literature 8~ in which profound thrombocytopenia has occurred in patients with clinical and subclinical disseminated intravascular coagulation after administration of 89Sr. Disseminated intravascular coagulation is a wellrecognized complication of advanced prostate can-

Table 7. Contraindications for Treatment of Bone Metastases With Bone-Seeking Radiopharmaceuticals Karnofsky performance -<50 Extensive soft tissue metastases Platelet count <60,000 • 10~ Recent rapid fall in platelet count even if >60,000 • 106 White count <2.5 X l0ci Disseminated intravascular coagulation Within 1 month of myelosuppressive chemotherapy <2 months projected survival Within 2 months of hernibody radiotherapy

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cer, 82,~3 occurring in 16% of patients, and may often be the terminal event. In patients with counts in the normal range, this condition is probably not an issue. In patients with platelet counts at the lower end of the range, however, or cases in which there has been a sudden fall in counts, the rate of change of counts is probably more important than the absolute value, and in these patients it is prudent to screen for disseminated intravascular coagulation before beginning therapy. The author's practice is to exclude subclinical disseminated intravascular coagulation in patients with advanced prostate cancer as judged using bone scan, PSA measurements, and sequential blood counts. The data reported by Schmeler and Bastin 66 are persuasive on the importance of KPS in patient selection. It is now the author's routine practice not to consider patients for treatment if the KPS is 50 or less. Impending or actual pathologic fractures and cord compression are contraindications to the immediate use of RPT. Those patients require referral for surgical or radiation oncology opinion. Once the acute emergency has been appropriately managed, radiopharmaceuticals may, if otherwise indicated, be safely administered. There is no indication in the literature that RlrF leads to a greater incidence of these complications if the patient is appropriately selected. Unsealed source therapy should not be given before myelosuppressive chemotherapy because there is anecdotal evidence that myelotoxicity is additive under these conditions. Once recovery from chemotherapy-induced myelosuppression has occurred, treatment may cautiously be administered, possibly at a reduced dose. RPT may safely and effectively be given to patients who have previously received hemibody radiotherapy, a4 It is the author's practice to wait for 2 months after completion of the radiation therapy to avoid enhanced toxicity. Treatment with boneseeking radiopharmaceuticals is not contraindicated in patients currently receiving local field radiation therapy.

Radiation Safety The major advantage of treatment of bone-seeking radiopharmaceuticals is that it can be given as a single administration on an outpatient basis in most jurisdictions. In some European jurisdictions, overnight admission may be required for the gamma emitting radiopharmaceuticals.

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For all the compounds, but especially those with long half-lives, precautions should be taken with respect to urine spills, and it is the author's practice to provide all patients with information sheets regarding appropriate hygiene practices. There have also been concerns regarding exposure to mortuary and crematorium staff should the patient die shortly after treatment. The manufacturers have assessed this and shown no significant risk; however, this institution now follows the practice of Amdur et al85 of placing a bracelet on the wrist of each patient receiving 89Sr with a label that states "A Nuclear Medicine Therapy (Strontium-89) Given: / / , Questions? Call . Keep on for 1 week." Summary Pain palliation with bone-seeking radiopharmaceuticals is a safe, effective, and cost-effective management tool in patients with cancer metastatic to bone. Patient selection is the key to the successful use of these agents. Ongoing clinical trials are comparing their effectiveness with that of bisphosphonates, and there is an ongoing effort to determine if adjuvant treatment with cisplatin as a radiosensitizer would enhance the ability of these compounds to slow disease progression and reduce tumor burden. References 1. Daut RL, Cleeland CS: The prevalence and severity of pain in cancer. Cancer 50:1913-1918, 1982 2. Inturrisi CE, Hanks G: Opioid analgesic therapy, in Doyle D, Hans GWC, MacDonald N (eds): Oxford Textbook of Palliative Medicine. Oxford, Oxford Medical, 1993, pp 166-182 3. Bonica J[]-: Treatment of cancer pain: Current status and future needs. Adv Pain Res Ther 9:589-616, 1985 4. Janjan NA, Payne R, Gillis T, et al: Presenting symptoms in patients referred to a multidisciplinary clinic for bone metastases.J Pain Symptom Manage 16:17 I- 178, 1998 5. Nielsen OS, Munro AJ, Tannock IF: Bone metastases: Pathophysiology and management policy. J Clin Oncol 9:509-524, 1991 6. McEwan AJB: Palliative therapywith bone seeking radiopharmaceuticals. Cancer Biother Radiopharmaceut 13:413-426, 1998 7. Fulfaro F, Casuccio A, Ticozzi C, et al: The role ofbisphosphonates in the treatment of painful metastatic bone disease: A review of phase lII trials. Pain 78:157-169, 1998 8. Kim SI, Chen DCP, Muggia FM: A new look at radionuclide therapy in metastatic disease of bone (review and prospects). Anticancer Res 8:681-684, 1988 9. BodyJJ, Bartl R, Burckhardt P, et al: Current use of bisphosphonates in oncology. International Bone and Cancer Study Group.J Clin Oncol 16:3890-3899, 1998

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