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Repeated Bone-Targeted Therapy for Hormone-Refractory Prostate Carcinoma: Randomized Phase II Trial With the New, High-Energy Radiopharmaceutical Rhenium-188 Hydroxyethylidenediphosphonate

From the Departments of Nuclear Medicine, Urology, Internal Medicine/Oncology, and Biostatistics, University of Bonn, Bonn, Germany; and the Nuclear Medicine Group, Oak Ridge National Laboratory, Oak Ridge, TN.

Address reprint requests to Holger Palmedo, MD, Priv Doz, Department of Nuclear Medicine, University of Bonn, Sigmund-Freud-Str 25, 53127 Bonn, Germany; email: holger.palmedo{at}ukb.uni-bonn.de.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: We investigated the effect of repeated bone-targeted therapy with rhenium-188 hydroxyethylidenediphosphonate (HEDP) in patients with progressive, hormone-resistant prostate carcinoma and bone pain. The aim of this study was to determine the pain palliation and the antitumor effect of rhenium-188 HEDP treatments.

Patients and Methods: Sixty-four patients were randomly assigned to one of two groups for radionuclide therapy with rhenium-188 HEDP; patients of group A received a single injection, patients of group B received two injections (interval, 8 weeks). After therapy, patients were followed-up by assessment of pain palliation and clinical outcome until death.

Results: In both groups, toxicity was low, with moderate thrombopenia and leukopenia (maximum common toxicity criteria grade of 2). The effectiveness of rhenium-188 HEDP for pain palliation was better in the repeated treatment group (group B), with a response rate and time of response of 92% and 5.66 months, respectively (P = .006 and P = .001). In group B, 11 (39%) of 28 patients had a prostate-specific antigen decrease of more than 50% for at least 8 weeks, compared with two (7%) of 30 patients in the single-injection group (group A). The median times to progression of group A and group B were 2.3 months (range, 0 to 12.2 months) and 7.0 months (range, 0 to 24.1 months), respectively (P = .0013), and the median overall survival times were 7.0 months (range, 1.3 to 36.7 months) and 12.7 months (range, 4.1 to 32.2 months), respectively (P = .043).

Conclusion: Compared with single-injection therapy, repeated bone-targeted therapy with rhenium-188 HEDP administered to patients with advanced progressive hormone-refractory prostate carcinoma enhanced pain palliation and improved progression-free and overall survival. Larger studies are justified to further evaluate the use of rhenium-188 HEDP.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PATIENTS WITH hormone-refractory prostate carcinoma have a 90% to 95% probability of developing metastatic bone disease, which leads to bone pain, pathologic fractures, thrombocytopenia, anemia, weight loss, and neurologic symptoms.¹ In most patients, bone is the only site of disease progression.² The extent of bone metastases is of prognostic relevance and correlates with patient survival.³ The median survival of androgen-independent prostate cancer patients with progressive osseous metastases is 9 months or less.^4,5

Because of the important role of bone metastases in the progression of prostate cancer, bone-targeted therapy is an appropriate approach for therapy. Treatment with bone-seeking radiopharmaceuticals, such as strontium-89 chloride, rhenium-186 hydroxyethylidenediphosphonate (HEDP), and samarium-153 ethylenediaminetetramethylene phosphonate (EDTMP), is well tolerated and effective for pain palliation in prostate cancer patients with disseminated osseous metastases and hormone-refractory disease.^6–14 Some studies have shown that bone-targeted therapy also has the potential to delay progression of osseous metastases.^7,15,16 Strategies including the administration of high doses of radioactivity, combined treatment of radionuclides and chemotherapy, and repeated radionuclide therapy are currently being discussed as methods of anticancer therapy in prostate cancer patients.¹⁷

Rhenium-188 HEDP is a new radiopharmaceutical that we have previously investigated for pain palliation of bone metastases.¹⁸ We have shown that application of rhenium-188 HEDP in humans is safe and that pain palliation can be achieved in approximately 70% of patients.¹⁸ A major advantage is that rhenium-188 is inexpensively available on demand from a W-188/rhenium-188 generator, and a kit is available for easy radiolabeling of the bone-seeking HEDP.^19,20 The most important physical characteristics of rhenium-188 are its emission of high-energy beta particles, with a maximal energy of 2.1 MeV, and its relatively short physical half-life of 17 hours. Because rhenium-188 is readily available and because of its high-dose constant, it offers the possibility of repeated therapy without additional costs; therefore, the cost of repeated therapy is comparable with the cost of a single injection.^21,22

We designed this phase II trial to evaluate whether repeated treatment with the bone-seeking radionuclide rhenium-188 HEDP would benefit late-stage, hormone-refractory prostate cancer patients. The objectives of this study were to evaluate the pain palliation effect of bone-targeted therapy and to estimate the time to progression in the two study arms.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Preparation of Rhenium-188 HEDP
We have described the preparation of rhenium-188 HEDP in a previous study.¹⁸

Patients
Patients with disseminated osseous metastases generating from prostate cancer received an intravenous injection of 70 to 90 mCi of rhenium-188 HEDP. Patients suffering from multifocal pain and with at least five different sites of bone metastases, as proven by technetium-99m methylenediphosphonate scintigraphy and x-ray, were entered onto the study. Patients had to show progression of disease despite hormonal therapy and despite subsequent antiandrogen withdrawal. Progression of disease was defined as progression of measurable lesions or increasing prostate-specific antigen (PSA) values (three consecutive increasing PSA values). Life expectancy had to be at least 3 months. Patients with leukocyte and thrombocyte counts below 4.0 x 10⁹/L and 100 x 10⁹/L, respectively, or with impaired renal function (creatinine > 1.4 mg/dL) were excluded from the study. None of the patients received hemibody irradiation before rhenium-188 HEDP treatment. However, local external-beam radiation and one previous treatment with chemotherapy were allowed (time interval to rhenium-188 HEDP treatment at least 4 weeks). Patients with pain caused by pathologic fracture, infiltration of a nerval plexus, or peripheral nerves were excluded. Also, patients with visceral metastases (confirmed by x-ray and computed tomography) or serious illness and organ dysfunction not related to prostate cancer were excluded from the study. All patients were informed about the experimental character of the study and the possible side effects, and all had given written consent according to the Declaration of Helsinki. Approval was given by the ethical committee and the radiation safety committee.

Study Design and Protocol
This study was a prospective, clinical phase II trial. Patients were randomly assigned to two groups with different treatment strategies; group A received a single rhenium-188 HEDP injection, and group B received two injections of rhenium-188 HEDP. The time interval between the two rhenium-188 HEDP injections was 8 weeks. Considering a single radionuclide injection as the standard way of bone treatment with radiopharmaceuticals, we decided to perform randomization 7 weeks after the first injection. If baseline thrombocyte or leukocyte counts were not reached after the first treatment, the patient had to be excluded from the study. Patients who did not experience pain relief at week 6 or who reported marked progression of symptoms were considered nonresponders for pain palliation and received further pain medication. Each patient received 1.1 mCi (40.7 MBq) per kilogram of body weight per single injection. Follow-up ended with the death of the patient.

After the injection, patients were hospitalized for 48 hours in the nuclear medicine ward. Rhenium-188 HEDP was administered as a bolus injection via a running intravenous saline drip. Subsequently, whole-body scintigraphy was performed.

For the assessment of toxicity, the National Cancer Institute common toxicity criteria (NCI CTC) was used.²³ The maximal decrease was calculated by comparison of the pretreatment level of thrombocytes and leukocytes (baseline) with the lowest level during the follow-up period.

Blood samples were drawn before treatment and monthly after treatment for the determination of blood counts and clinical chemistry parameters (for at least 9 months after the last rhenium-188 HEDP injection). For analysis of toxicity, the thrombocyte, leukocyte, and erythrocyte counts, hemoglobin, hematokrit, creatinine, liver enzymes, electrolytes, serum proteins, and serum glucose levels were determined.

For the assessment of pain palliation, the patients completed a pain diary during the baseline period and throughout the study. The week before the injection of rhenium-188 HEDP was considered as the baseline period. During this time, no new analgesics were initiated. The consumption of analgesics was noted daily by the patient. The diary was controlled by a physician before therapy and on a monthly basis thereafter.

To determine the extent of disease, the bone scan index was calculated as described by Blake et al.²⁴ Using this method, the skeleton is divided into four anatomic regions, and each region is scored visually on a scale between 0 and 10.

The visual analog scale (VAS) served as a basis for pain documentation.¹⁰ On this scale, zero means no pain, and 10 means intolerable pain. A multisite VAS was used that recorded the patients’ pain intensity for each of several body regions (head, upper spine, lower spine, arms, legs, ribs, sternum and claviculae, and pelvis). The average values of an overall daily pain score (according to the method of Donaldson²⁵) were calculated for the 7-day period before treatment and for a 7-day period monthly thereafter. Referring to the medication index system of Foley,²⁶ a daily pain medication index was calculated. For primary assessment of pain relief, the change of the mean baseline VAS in comparison with the mean VAS at 1 month after injection was used. A VAS decrease of 90% or more, of 50% or more, of 33% or more, and of 20% or more was considered as a complete (++++), marked (+++), moderate (++), and slight (+) treatment response, respectively, if pain medication was stable or reduced. If VAS showed a decrease of less than 20% or an increase, or if the pain medication was increased (> 10% from baseline), the patient was considered a nonresponder.

PSA values were measured monthly to assess the cytostatic effects of rhenium-188 HEDP therapy.²⁷ An antitumor effect was considered evident if a decrease of PSA by at least 50% from baseline was maintained for at least 8 weeks. In both groups, time to progression was measured from the date of the last rhenium-188 HEDP injection (or date of randomization to no further injection) until the time of disease progression, death from any cause, or last follow-up visit. Progression was defined as an increase of PSA of more than 25% over baseline or as an extension of measurable lesions judged by the treating physician. Overall survival was defined as the time period between the last rhenium-188 HEDP injection (or date of randomization) and the date of death from any cause or the last follow-up visit.

Statistical Tests
The primary end point of the study was the pain palliation effect of therapy as measured by VAS. The values were compared between treatment groups with the two-sided t test on the level of 5%. To estimate the power of the study, a mean VAS value of 6 and an SD of 2 within each group were assumed. On the basis of these assumptions, we initially calculated a number of 30 patients for each group to detect a VAS difference of 1.7 with a power of 90%. Secondary end points of the study (time to progression and survival times) were evaluated descriptively. Statistical tests were used to calculate P values as descriptive means. Differences in pre- and posttherapy variables between the two arms were assessed by the Student’s t test for independent samples or by the Fisher’s exact test. Differences between pre- and posttherapy variables within one study arm were assessed by the two-sided Student’s t test for dependent samples. Time-to-event analysis was performed using the Kaplan-Meier method. Survival and time-to-progression curves were compared using the log-rank test.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
We enrolled a total of 64 patients from January 1998 to February 2000 (Fig 1). Two patients in group A (single injection) and four patients in group B (repeated injections) had to be excluded from the study because of incomplete follow-up.

View larger version (7K): [in this window] [in a new window]   Fig 1. Flow chart of included patients.

Overall, pain palliation was achieved in 41 (74%) of 55 patients. Over 50% of patients reported pain relief 3 months after rhenium-188 HEDP injection. In the 41 responding patients, the mean (± SD) VAS value decreased from 4.9 (± 1.7) to 2.8 (± 1.5, P = .0001). The medication index diminished from 54 (± 53) to 43 (± 52, P = .05).

The data for response in both groups at the time of randomization are listed in Table 3. There was no significant difference for the parameters between group A and B.

View larger version (20K): [in this window] [in a new window]   Fig 2. (A) Intensity of response for pain palliation. Number of patients with complete (++++), marked (+++), moderate (++), slight (+), and no pain (0) relief in groups A and B. (B) Pain relief depending on the time after injection of rhenium-188 HEDP in responding patients of group A (18 responders) and group B (23 responders).

View larger version (25K): [in this window] [in a new window]   Fig 3. Average values and SDs of (A) the overall visual analog scale (VAS) and (B) the medication index in the responding patients of group A and group B measured before and 4 weeks after injection of rhenium-188 HEDP.

View larger version (26K): [in this window] [in a new window]   Fig 4. Kaplan-Meier curves of (A) progression-free survival and (B) overall survival.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

During an earlier dose-escalation study with rhenium-188 HEDP,¹⁸ we found that the maximum-tolerated dose for pain palliation treatment in prostate cancer patients was a single injection of 90 mCi if the baseline thrombocyte count was below 200 x 10⁹/L. We observed a pain palliation effect in patients receiving 70 mCi or more of rhenium-188 HEDP. Thrombopenia and leukopenia were the most important side effects. In patients with thrombocyte counts markedly above 200 x 10⁹/L, a higher dose, up to 120 mCi (single injection), seemed to be tolerable. On the basis of these data, we decided to choose a dose between 70 and 90 mCi of rhenium-188 HEDP per injection for this trial.

Generally, radionuclide therapy of bone metastases consists of a single injection that sometimes is repeated in case of a successful treatment. However, it is not clear to date whether repeated administration performed systematically benefits the patient. We supposed that a potential antitumor effect of rhenium-188 HEDP therapy, which was one end point of this study, would be enhanced by a repeat injection. For this reason, we designed a two-arm study comparing prospectively a one-injection group with a two-injection group. The data of our previous dose-escalation study indicated that the nadir of thrombocytopenia is at week 4 after injection, reaching baseline values at week 8, and that the decrease of leukocytes is less marked. Therefore, we decided to administer the second injection 8 weeks after the first one to lower the risk of significant side effects.

In comparison with the literature,^6–14 our results indicate that rhenium-188 HEDP has a good palliative effect in androgen-independent prostate cancer patients with bone disease. After a single injection of radiopharmaceuticals like strontium-89, samarium-153 EDTMP, and rhenium-186 HEDP, pain relief has been reported in 70% to 80% of patients.^6–14 Also, in this study, we found an overall response rate of 74% that lasted an average of 3.7 months. The effect of pain palliation after a single injection of rhenium-188 HEDP, which produced a response rate of 60%, could be increased to 92% after repeated injection; the duration of pain relief was also prolonged from 2.55 after a single injection to 5.66 months after repeated injection. There are reports on successful application of repeated radionuclide therapy in the literature,³⁰ but no systematic studies have yet been performed to evaluate the effect of repeated injections. Moreover, strontium-89 chloride does not seem suitable for repetitive treatments because of its long physical half-life. We observed that a second treatment with rhenium-188 HEDP can lead to effective pain therapy, even if the first injection did not induce pain relief. These data provide evidence that repeated bone-targeted therapy is of clear benefit for the successful management of bone pain.

The mechanism of pain reduction after radiation therapy is not fully understood. One important factor could be that radiation-sensitive cells, such as lymphocytes and macrophages, are deactivated by rhenium-188 HEDP therapy and that these cells discontinue to produce pain-mediating substances like interleukin and tumor growth factor.³¹ Advantages of rhenium-188 HEDP include availability on demand and low cost per injection depending on the number of patients treated per generator.

One aim of our trial was to calculate the time to progression after rhenium-188 HEDP therapy. We found that the PSA progression-free interval was significantly longer after repeated treatments. In this group, approximately 40% of patients demonstrated a PSA decrease of more than 50% for 8 weeks or longer, but this occurred in only 7% of patients in the group that received a single injection. Also, scintigraphic regression of bone metastases was more often seen in the repeated-injection group. Furthermore, the overall survival of patients who were treated twice was significantly longer. These data confirm that bone-targeted therapy with high-energy rhenium-188 HEDP has an antitumor effect in prostate cancer patients, resulting in a better clinical outcome. With regard to the currently used radiopharmaceuticals like strontium-89 and samarium-153 EDTMP, mainly palliative effects have been observed to date.^6–14 However, Porter et al,⁷ who administered high-dose therapy with 370 MBq of strontium-89 chloride to prostate cancer patients adjuvant to local-beam irradiation, reported a PSA decrease greater than 50% in some patients, but they did not find an improvement of overall survival. To date, no studies have been performed to investigate the effect of repeated radionuclide therapy with strontium-89 chloride or different radionuclides on tumor progression.

Our approach for bone-targeted therapy is the repeated administration of a high-energy beta emitter with a short physical half-life. Rhenium-188 HEDP is accumulated in high concentration in the area of osteoblastic bone metastases, has a short, effective half-life between 12 and 14 hours, and is mainly cleared by the kidneys within the first 6 hours after the injection.³² In comparison with rhenium-188 HEDP, radiopharmaceuticals like samarium-153 EDTMP and rhenium-186 HEDP have a longer half-life of 47 hours and 89 hours, respectively, and a significantly lower maximal beta-energy of 0.81 keV and 1.07 keV, respectively. Also, these agents are renally cleared within the first hours after injection, and activity is retained at the metastatic sites mediated by the phosphonate group of the radiopharmaceutical. Data from previous studies indicate that the ratio of the maximum-tolerated dose of rhenium-186 HEDP (80 mCi) and rhenium-188 HEDP (120 mCi) is approximately 0.6.^18,32 Previously reported, absorbed doses in bone metastases delivered by radionuclide therapy vary between 10 and 140 Gy, depending on the intensity of radionuclide accumulation in metastatic areas.^33–35 However, for strontium-89, these doses are delivered over a time period of 60 to 90 days, resulting in a low-dose rate and irradiating tumor cells with a relatively low dose per cell cycle. In contrast, radiopharmaceuticals with a shorter, effective half-life like rhenium-186 HEDP, samarium-153 EDTMP, or rhenium-188 HEDP deliver a high-dose rate. However, we think that the high-electron energy (2.1 MeV) of rhenium-188 HEDP is one important advantage over samarium-153 EDTMP and rhenium-186 HEDP. This results in an increase of the range of electrons from approximately 1 to 2 mm for rhenium-186 HEDP to 3 to 5 mm for rhenium-188 HEDP in osseous tissue. We suppose that only the high-energy radiation of rhenium-188 HEDP reaches the tumor tissue, which is surrounded by bone trabecula. This would lead to cytotoxic effects in the outer layers of the tumor. By repeating treatment with rhenium-188 HEDP within an interval short enough to avoid new tumor growth, the following tumor layer could be eradicated (onion peeling). We believe that a time interval even shorter than 6 to 8 weeks would be more effective and that therapy might be repeated several times to enhance the cytostatic effect. This seems to be possible because toxicity, which was limited to the bone marrow, was very moderate after repeated treatment with rhenium-188 HEDP.

The patient groups of this study were small, and the study was not designed to look at the effect of treatments on survival of patients. In the single-dose group, there were higher PSA and alkaline phosphatase baseline values (though not statistically significant), which may have influenced the survival results. However, all of our patients had progressive, osseous disease with high PSA levels and multifocal pain symptoms. Survival of patients treated by single rhenium-188 HEDP injection was similar to the survival of patients with the same disease status in previous studies.^3–5 The results of this preliminary study are promising and indicate that repeat injection of rhenium-188 HEDP is an effective approach to improve progression-free survival in patients with advanced, progressive, hormone-refractory prostate carcinoma. Our data justify further investigations to draw definitive conclusions on the role of rhenium-188 HEDP therapy.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Vogelzang NJ, Crawford ED, Zietman A: Current clinical trial design issues in hormone-refractory prostate carcinoma. Cancer 82:2093–2101, 1998[CrossRef][Medline]

2. Mc Rea LE, Karafin L: Carcinoma of the prostate: Metastases, therapy and survival—A statistical analysis of 500 cases. Int Coll Surg J 29:723–728, 1958

3. Sabbatini P, Larson SM, Kremer A, et al: Prognostic significance of extent of disease in bone in patients with androgen-independent prostate cancer. J Clin Oncol 17:948–957, 1999[Abstract/Free Full Text]

4. Newling DW, Denis L, Vermeylen K: Orchiectomy versus goserelin and flutamide in the treatment of newly diagnosed metastatic prostate cancer: Analysis of the criteria of evaluation used in the European Organization for Research and Treatment of Cancer-Genitourinary Group Study 30853. Cancer 72:3793–3798, 1993[CrossRef][Medline]

5. Tannock IF, Osoba D, Stockler MR, et al: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-refractory prostate carcinoma: A Canadian randomized trial with palliative end points. J Clin Oncol 14:1756–1764, 1996[Abstract/Free Full Text]

6. Lewington VJ, McEwan AJ, Ackery DM, et al: A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone. Eur J Cancer 27:954–958, 1991[Medline]

7. Porter AT, McEwan AJB, Powe JE, et al: Results of a randomized phase III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys 25:805–813, 1993[Medline]

8. Quilty PM, Kirk D, Bolger JJ, et al: A comparison of the palliative effect of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol 31:33–40, 1994[CrossRef][Medline]

9. Robinson RG: Strontium-89-precursor targeted therapy for pain relief of blastic metastatic disease. Cancer 72:3433–3435, 1993[CrossRef][Medline]

10. Serafini AN, Houston SJ, Resche I, et al: Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: A double-blind placebo-controlled trial. J Clin Oncol 16:1574–1581, 1998[Abstract/Free Full Text]

11. Tian J, Zhang J, Hou Q, et al: Multicentre trial on the efficacy and toxicity of single dose samarium-153 EDTMP as a palliative treatment for painful skeletal metastases in China. Eur J Nucl Med 26:2–7, 1999[CrossRef][Medline]

12. Schoeneich G, Palmedo H, Dierke-Dzierzon C, et al: Palliative radionuclide therapy of painful bone metastases. Scand J Urol Nephrol 31:445–448, 1997[Medline]

13. Quirijnen JMSP, Han SH, Zonnenberg BA, et al: Efficacy of rhenium-186-HEDP in prostate cancer patients with metastatic bone pain. J Nucl Med 37:1511–1515, 1996[Abstract/Free Full Text]

14. Maxon HR, Schroder LE, Hertzberg VS, et al: Rhenium-186(Sn)-HEDP for treatment of painful osseous metastases: Results of a double blind crossover comparison with placebo. J Nucl Med 32:1877–1881, 1991[Abstract/Free Full Text]

15. Tu S, Millikan RE, Mengistu B, et al: Bone targeted therapy for advanced androgen-independent carcinoma of the prostate: A randomised phase II trial. Lancet 357:336–341, 2001[CrossRef][Medline]

16. Sciuto R, Festa A, Rea S, et al: Effects of low-dose cisplatin on strontium-89 therapy for painful bone metastases from prostate cancer: A randomized clinical trial. J Nucl Med 43:79–86, 2002[Abstract/Free Full Text]

17. McCready VR, O’Sullivan JM: Future directions for unsealed source radionuclide therapy for bone metastases. Eur J Nucl Med Mol Imaging 29:1271–1275, 2002[CrossRef][Medline]

18. Palmedo H, Guhlke S, Bender H, et al: Dose escalation study with rhenium-188 HEDP in prostate cancer patients with osseous metastases. Eur J Nucl Med 27:123–130, 2000[CrossRef][Medline]

19. Knapp FF, Mirzadeh S, Beets AL, et al: Reactor-produced radioisotopes from ORNL for bone pain palliation. Appl Radiat Isot 49:309–315, 1998[CrossRef][Medline]

20. Knapp FF, Beets AL, Guhlke S, et al: Availability of rhenium-188 from alumina-based tungsten-188/rhenium-188 generator for preparation of rhenium-188-labeled radiopharmaceuticals for cancer treatment. Anticancer Res 17:1783–1796, 1997[Medline]

21. Elder RC, Yuan J, Helmer B, at al: Studies on the structure of rhenium-1, 1-hydoxyethylidendiphophonate (HEDP) analogues of the radiotherapeutic agent ¹⁸⁶Re-HEDP. Inorg Chem 36:3055–3063, 1997[CrossRef][Medline]

22. Guhlke S, Beets AL, Oetjen K, et al: Convenient concentration of Re-188-perrhenate or Tc-99m-pertechnetate eluates from tungsten-188/rhenium-188 generators or (n, ) produced molybdenum-99/technetium-99m generators to high specific volumes. J Label Compds 40:624–626, 1997

23. Green S, Weiss GR: Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 10:239–253, 1992[CrossRef][Medline]

24. Blake GM, Zivanovic MA, Mc Ewan AJ, et al: Strontium-89 therapy: Strontium kinetics in disseminated carcinoma of the prostate. Eur J Nucl Med 12:447–454, 1986[Medline]

25. Donaldson G: A new approach to calculating pain measurements for cancer patients. Sci Comput Automat 1:45–48, 1992

26. Foley KM: The treatment of cancer pain. N Engl J Med 313:84–95, 1985[Abstract]

27. Kelly WK, Scher HI, Mazumdar M, et al: Prostate specific antigen as a measure of disease outcome in hormone-refractory prostatic cancer. J Clin Oncol 11:607–615, 1993[Abstract]

28. Epstein JI: The diagnosis and reporting of adenocarcinoma of the prostate in core needle biopsy specimens. Cancer 78:350–356, 1996[CrossRef][Medline]

29. Gleason DF, Mellinger GT: Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J Urol 111:58–64, 1974[Medline]

30. 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 28:788–798, 2001[CrossRef][Medline]

31. Mundy GR, Martin TJ: Pathophysiology of skeletal complications of cancer, in Mundy GR, Martin TJ (eds): Physiology and Pharmacology of Bone. New York, NY, Springer, 1989, pp 641–644

32. Maxon HR, Schroder LE, Washburn LC, et al: Rhenium-188 (Sn)-HEDP for treatment of osseous metastases. J Nucl Med 39:659–663, 1998[Abstract/Free Full Text]

33. Blake GM, Zivanovic MA, Blaquiere RM, et al: Strontium-89 therapy: Measurement of absorbed dose to skeletal metastases. J Nucl Med 29:549–557, 1988[Abstract/Free Full Text]

34. Eary JF, Collins C, Stabin M, et al: Samarium-153-EDTMP biodistribution and dosimetry estimation. J Nucl Med 34:1031–1036, 1993[Abstract/Free Full Text]

35. Maxon HR, Deutsch EA, Thomas SR: Re-186 (Sn)HEDP for treatment of multiple metastatic foci in bone: human biodistribution and dosimetric studies. Radiology 166:501–507, 1988[Abstract/Free Full Text]

Submitted December 10, 2002; accepted May 5, 2003.

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