____________________________________________ Radiopharmaceutical (Sm-153-EDTMP) therapy of skeletal metastases: clinical application in 350 patients

Houfu Deng, Tianzhi Tan, Shuenzhong Luo, Changlin Hou, Zhigang Liao, Yuenzhou Hu, Manfu Pu, Zhenglu Liang, Anren Kuang, Xiying Zhang, Lin Li, Tingshu Mo, Changtian Guan, Jian Qiao, Quanlin Wang, Zhonglin Liou, Luyi Zhou, Shubing Jiang, Xiaochuan Yang, Li Cai, Rong Tian, Nan Yu, Mingzhi Pan, Shu Hu, Yong Lei, Guoping Liou. Changying Zhang, Pongji Zhao, Yibei Fu. Departments of Nuclear Medicine, Radiology, Pathology, and Orthopedics First University Teaching Hospital, West China University of Medical Sciences, Chengdu, 610041; Institute of Southwest Nuclear Physics and Chemistry, Chengdu, 610003, P.R. China
*The Project Supported by National Natural Science Foundation of China (38970273, 39470791).

_____________________________________
We have treated 350 patients with Sm-153-EDTMP and had adequate follow-up. Patients with bone metastases were administered a single intravenous injection of 18.5 MBq (0.5mCi) ~37MBq (1.0mCi) /kg Sm-153-EDTMP. None of the patients demonstrated significant clinical problems from the treatment. The skeletal images obtained with Sm-153-EDTMP were similar to the 99mTc-MDP SPECT images performed the previously week. The uptake ratio of tumor to bone was 14.0 to1.0. Complete pain resolution was noted in 102 cases (29.1%, 102/350) and pain partial response in 201 cases (57.4%, 201/350). Thus, 86.5% of the treatment resulted in a definite decrease in pain of our group. Pain relief occurred within 10 days (means.d) of administration Sm-153-EDTMP, the time to initial response was 3 hours, and time to maximum response was 4 to 6 weeks. Duration of pain relief from a single injection ranged from 2 to 26 weeks (average 2.7). Improvement in Karnofsky score averaged 12 (range 5~30). Uninterrupted sleep time in 132 patients increased between 2~7 hours (average 2.5hrs). Analgesic use was discontinued in 102 patients. With a one month administration =29.8MBq/kg 153-Sm -EDYMP, there were no significant changes in blood cell counts, liver or kidney function (P>0.05). There were transient decreases of WBC and platelet counts with doses of 37 MBq/kg . The drop in white blood cell numbers began in 1 ~2 weeks post-injection in patients who received Sm -153-EDTMP, but in 3~4 weeks, the WBC count generally returned to baseline levels. The severity of the drop in platelet count appears dose related. However, none of these patients manifested any of the expected clinical signs of decreased homeostatic capability of the blood. The number and size of metastases decreased in 95 patients. The metastatic foci of 36 patients completely disappeared.

Conclusion: Our data indicated that Sm -153-EDTMP at a dose =29.6MBq/kg is safe; 153-Sm-EDYMP at a dose of 37 MBq/kg may be used without significant clinical problems. Sm-153-EDTMP may be effective in reducing the pain of disseminated skeletal metastasis. It may result in complete resolution of metastases in some patients. KEY WORDS: Radiopharmaceutical Sm -153-EDTMP bone tumor pain relief metastasis focus shrunk focus disappeared

200 2 The Journal of Radiology _____________________________________ with disseminated skeletal metastasis often experience severe and refractory pain. There is little evidence that chemotherapy is useful for palliation in these patients. Although external beam radiation therapy can provide significant palliation in up to three-fourths of patients with osseous metastases, the amount of radiation the body that can be subjected to such therapy is limited, even with regional fields. Furthermore, even when one site of pain is being treated, other areas outside the radiation field may become symptomatic. There is a high incidence of skeletal metastasis in many malignancies [1]. There are more than 2 million new cases of cancer each year in China. Among them, there are more than 1 million new cases of osseous metastases each year. These skeletal metastases often cause excruciating and debilitating pain. More than 50% of patients with multiple skeletal metastases have ineffective

Patients

Copyright The Journal of Radiology www.jradiology.org August 2002

chemotherapy. External beam radiotherapy is only useful to ameliorate localmetastasis [2]. We reported the development of a purified Sm-153-EDTMP compound which localizes in osteoblastic skeletal metastases [3,4],. It emits beta particles with sufficient energy to be therapeutically useful. Initial human studies suggested that 544~1111 MBq (12~30 mCi) administration of this compound would result in relief of pain without significant bone morrow toxicity [5]. This report details the results of a study on the effect of Sm153-EDTMP in the treatment of bone metastases.

hours and 1, 3, 5, 7 and 16 days. Simultaneously, the vital organs, including brain, heart, lung, liver, bone, and bone marrow, of each Wistar rat were removed, stained [HE chromatin] for histopathological study. Clinical studies 1. Patient selection 350 patients were included in the study. All patients gave informed consent. Our institute approved the study protocol. 192 patients were male and 158 female. Their ages ranged from 20~85 yr. There were 130 patients with lung cancer, 50 with breast cancer, 30 with nasopharyngeal carcinoma, 40 with prostate cancer. 50 with other cancers, and 50 with unknown primary lesions. The criteria were as follows: (1) Biopsy proven carcinoma with standard 99m-Tc-MDP bone imaging and radiograph, CT, MRI evidence of osseous metastases. (2). Major protocol violation were considered, failure of prior traditional therapy, for example Any patients who died at any time during the 1 month follow -up period were excluded. (3). A total white blood cell count of at least 3.5109/L, platelet count of at least 8.0109/L and a serum creatinine concentration of 1.5 mg/dl. 2. Preparation of patients For at least 1 week before the therapeutic administration, the patient also kept a daily record that indicated the hours of sleep, analgesic intake and level of pain both at rest and during activity. At the end of each week, the daily records were collected, and average weekly pain and analgesic indices were calculated by using methods previously developed by the National Radiation Therapy Oncology Group for the evaluation of efficacy of external radiation therapy. In all patients, bone metastases were the overwhelming cause of their pain. Finally, each patient was assigned a Karnofsky performance score. These data served as the baseline values against which the therapeutic results were judged. 3. Uptake of Sm-153-EDTMP in metastasis Whole bone imaging of patients was performed after administration of Sm-153-EDTMP, and then, quantitative gamma camera imaging with region of interest (ROI) counts per pixel were used to provide metastasis to normal bone uptake ratio. 4. The blood clearance and urine output The blood clearances of Sm-153-EDTMP of 5 patients were determined at 5, 10, 30, 45, 60, 180,

METHODS
Preparation of Sm-153 -EDTMP Sm-153-EDTMP was prepared by our laboratory [3,4]. Sm-153-EDTMP with high radionuclide purity and specific activity [5.18GBq (140mCi)/mg Sm203] was prepared by irradiating natural Sm2O3 (Sm-152, 26.7%), replacing costly enriched Sm2O 3 target, at a flux of 4 1013 n. Cm 2. s -1 for period up to 110 hours. The yield of Sm-153EDTMP complex is a beta particle -emitting (Emax=0.80 MeV, T 1/2 =46.8 hrs) radionuclide which also emits a 28% abundant 0.103 MeV gamma photon. Sm-153-EDTMP was formulated with a 1:1 molar concentration ratio to ensure complete chelation of Sm-153 [4,6,7]. Animal studies 1. Biodistribution of Sm-1 53-EDTMP in mice 50 White mice [Kuenming race of China] with weights of approximately 18~20g were individually housed in cages. Five mice were killed at each time interval of 5, 15, 30 minutes and 1, 2, 3, 5, 24, 72 and 96 hours following intravenous administration of 100 ul Sm-153-EDTMP solution containing 18.5 KBq. The activity of each organ was determined by gamma counting and was expressed as a percentage of administered activity. 2. Myelotoxicity studies in rats 35 Wistar rats of matched weights of approximately 150g were individually housed in metabolic cages. 5 of 35 rats served as controls. After intravenous administration of 0.5mL of Sm153-EDTMP solution (containing 884 MBq/kg in Wistar rats, equal to 24 times the human dose ), blood cell counts (WBC, RBC and platelet) were obtained in all animals at each time interval of 4

Copyright The Journal of Radiology www.jradiology.org August 2002

300 and 480 minutes. The urine output of Sm-153EDTMP of 5 patients were determined at 0.5, 1, 2, 4, 5, 6, 8, 10 and 24 hours. 5. Clinicopathology of patients with bone metastasis One, 3 and 7 days post administration of Sm-153-EDTMP, the biopsy of metastases of 5 patients (male 3, female 2. among of them, lung cancer 2, breast cancer 2, adenoma cancer 1) were performed and examined by microscope. 6. Radioactive dose of Sm-153-EDTMP Our schedule was as follows [6]: (1). All patients were injected with a tracer dose(Dtr): Injected 185 MBq(5mCi) Sm-153EDTMP. (2). The urine was collected from all patients for 8 hours and total urinary activity was measured (correct decay to time of injection). (3). Calculate skeletal uptake (Upsk): Upsk = Dtr - total urinary activity. (4). Calculate cumulated skeletal activity (Cumsk): Cumsk =(Upsk42.67)/0.693. (5). Calculate absorbed does to red marrow (Drm): Drm=0.5CumskS(rm? cortical) +0.5CumskS(rm? trabecular bone). Where, S=(rm? cortical)+ (rm? trabecular bone)=0.0353mGy/(MBqh) [8] So, Drm=0.5Cumsk0.0353 Apply correction for body weight of patient. (6). Administer appropriate Sm-153EDTMP activity for therapy to limit of nominal marrow dose (Dnom, 150~200 cGy). Therapy activity =( Dnom/Drm) Dtr So, the radioactive dose of Sm-153EDTMP were administered to each patient ranged from 18.5~37.0 MBq(0.5~1.0mCi)/kg. Sm-153EDTMP was administe red intravenously. The blood pressure and pulse rate was monitored before and after therapy. Patients were observed for any acute side effects. 105 patients were administered a single intravenous injection, and 245 patients received 2 to 10 injections. Treatment was repeated at intervals of 2 to 5 weeks. Blood tests were repeated at an interval of 1 week for all patients. 7. Criteria for response to Sm-153-EDTMP therapy

The pain criteria were regarded as the most important points of the study. Most investigators have employed limited verbal descriptors of pain intensity and degree of relief. There are a lot of criteria for scaling clinical pain, such as: no pain, just noticeable, week, wild, moderate, strong and excruciating[2,9,10]. We adopted a pain score to calculate pain response with complete response(CR, pain score > 75), partial response(PR, < 75% pain score >25%), and no change(NC, pain score < 25 %). The analgesic intake was reduced to 25% over a 24 hr period. The average number of hours of sleep before awakening, and Karnofsky performance score were also recorded. 8. Statistical analysis The data were analyzed with the Chisquare(x2)test.

RESULTS
Analysis of Sm-153-EDTMP complex The Sm-153-EDYMP agent is a colorless, tasteless, sterile, pyrogen-free and clear solution. The complex yield was more than 99%. Before the complex was injected, the pH was lowered to 7 with undetectable complex dissociation. The complex preparation can be stored in the formulation vial at room temperature and retains its stability for more than 170 hours. Biodistribution of Sm-153-EDTMP The tissue distribution determined in mice over 96 hours is shown in table 1. From table 1 , we can see that the blood clearance was essentially complete at 3 hours and bone uptake had peaked at 26.44% injected dose. At 3 hours, the concentration of muscle is 0.03% injected dose. The blood and urine clearances of Sm-153 EDTMP in patients The blood clearance of 5 patients was very rapid. There were 3.980.08, 1.130.04, 0.450.07%, 0.060.02 % I.D/organ at 5, 30, 60 and 480 minutes, respectively. The unitary discharge of 5 patients was essential complete within 8 hours. The total activity discharge in urine varied relatively with skeletal uptake [3], being much lower in patients with heavy skeletal metastases and high bone uptake for example in those with a "superscan" appearance on bone imaging. The

Copyright The Journal of Radiology www.jradiology.org August 2002

retained activity of 100 patients were assumed to be within bone and this skeletal uptake varied between 10~95% of the total injected dose [6]. Myelotoxocity of Sm-153 -EDTMP After 4h, 1, 3 and 5 days injection Sm-153EDTMP (888 MBq/kg in Wistar rats, equal to 24 times the human dose ), we found that there were significant decreases in blood cell counts of all the animal which received the radioactivity (p<0.05, WHO in stage? ~? and no animal in stage ? ). At 7days there was no significant difference between RBC and Hb from baseline(P>0.05). The severity of the drop in circulating WBC and platelets occur from 4h to 7 days. After 16 days, the white blood cell and platelet counts have increased (Table 2). After performing a series of blood tests, histopathological examination of vital organs were finished. The results showed no evidence of cell destruction and/or death of vital organs. Using =29.6MBq/kg Sm-153-EDTMP, 93 patients(male 51, female 42, age ranges from 21~76) with bone metastases and primary from lung(31 pts), breast(14 pts), nasopharynx(9 pts), prostate(13 pts), other cancers (14 pts) or unknown(12 pts)were evaluated. The blood cell counts, serum biochemical parameters of 93 patients were measured serially over a period of 1 month following injection. Myelotoxicity was observed in cases (WHO stage 0 in 10%, stage? in 90%). The drop in white blood cell counts began in the first two weeks postinjection in patients who received Sm-153-EDTMP, but in 3 ~4 weeks, WBC counts generally returned to normal levels. The results demonstrated that although the blood cell counts have decreased after 1 week and 1 month, there were no significant differences(Table 3). We found that there were decreases of WBC and platelet counts in patients at absorbed doses of Sm153-EDTMP in excess 200 cGy(that is over >37~74MBq/kg)[6]. WHO stage? in 50%, WHO stage? in 40%, WHO stage? in 10% and no patient in stage? ). Platelets were the most affected series and neutrophils the least affected, but the counts returned to normal between the sixth and eighth week. There were no significant differences between liver and kidney function (p>0.05)(Table 4).

At the same time, there were no significant differences in enzymes and electrolytes(p>0.05)(Table 5). Uptake of Sm-153-EDTMP in bone metastasis The results demonstrated that there is relatively high uptake of Sm-153-EDTMP in metastatic foci. The concentration in metastases is 14 times as large as normal bone after 1 day administered Sm-153-EDTMP. 3 days later, the ratio of metastases to normal bone is 11 to 1, after 7 days the activity in metastases in still 8 times as high as normal bone. 24-72 hours after administration of Sm-153EDTMP, at microscopy there was edema and distension of capillaries of the biopsy samples of patients with metastases. The contour of the metastatic cells is irregular and the nucleoli are indistinct. There are also inflammatory cells. After 168 hours, the contour of the cancer cells is irregular and their cytoplasm contains distinct honeycomb vacuoles. The cancer cells show necrosis and fibrosis, many appear dead under the microscope (Fig.1). Fig 1 pathology variety of patient with metastasis a. Pretreatment The pathologic picture of bone metastasis of patient with adenoma cancer. The contour of cells is very clear (HE chromatin, enlargement 100 times). Picture a and b are same patient. b. After treatment using Sm-153-EDTMP. The contour of cancer cells is irregular. There is marked cellular edema and indistinct or swollen nucleoli . Cancer cells show rupture and death.

Clinical Response of Sm-153-EDTMP Therapy A comparison between Sm-153-EDTMP and 99m-Tc-MDP imaging in the same patient with bone metastases was carried out. The Sm-153-EDTMP scintigram clearly displayed the abnormal findings and pathologic change. 105 patients of 350 received a single injection. 245 patients were received 2~10 injections. Response to treatment was as follows. Pain, complete response(CR) was noted

Copyright The Journal of Radiology www.jradiology.org August 2002

in 102 cases (29.1%, 102/350) and partial response(PR) in 201 cases(57.4%, 201/350). Thus, 86.5% of the treatment resulted in a definite decrease in pain of our group. Pain relief occurred within 10 days (means.d) of administration Sm153-EDTMP, the time to most rapid response was 3 hours, and time to maximum response was 4 to 6 weeks. Duration of pain relief from a single injection ranged from 2 to 26 weeks (average 2.7). Improvement in Karnofsky score average12 (range 5~30). Uninterrupted sleep time in 132 patients increased between 2~7 hours(average 2.5hrs). Analgesics were discontinued in 102 patients. Using optimal mean relief time(days), there was no significant difference with single or multiple doses. With the optimal mean relief time (days), there was no significant difference between single and repeat doses ( Table 6). Recurrences of pain in 245 patients, after remissions lasting 8 to 35 weeks following initial injection of Sm-153-EDTMP, were retreated. The follow -up studies were performed with radiogram or 99m-Tc-MDP 6 months after Sm-153EDTMP therapy. The metastatic foci of 36 patients completely disappeared (focus ranged from 2 to 6)(Fig.2~3). Fig. 2 Male, 68 yr., lung cancer, bone imaging after 20 months of Sm-153-EDTMP (total doses, 11110 MBq) treatment, demonstrated metastases disappeared. a. Pretherapy scintigram of 99m-Tc-MDP. b. 12 months following therapy, with regression of metastatic lesions. He has now survived over 27 months. Fig. 3 This is 61 yo male with prostate cancer. a. There are multiple metastatic foci in the pelvis with 99m-Tc-MDP bone imaging. b. After 16 months using 11840 MBq Sm-153-EDTMP, all

The numbers and size of metastases in 95 patients were decreased (Fig 4~5).

Fig. 4 This is a female, 21 yr. with nasopharynx cancer. a. There are metastases of the left and right mid thighbone (in posterior projections). b. 28 weeks later post administration of 11100 MBq Sm-153-EDTMP, shows the marked reduction in avidity, diminution in tumor size and clearer delineation of the upper margin of the

disease. Fig. 5. Male, 35 years, with breast cancer. (a). Radiograph of the left femur before therapy shows a primarily lytic lesions. (b). Radiograph 11 months later after administration of 7400 MBq 153Sm-EDTMP confirms response by sclerosis of the lytic disease. The cortical bone was thickened . There is marked repairing of the destroyed bone. foci have regressed.

Copyright The Journal of Radiology www.jradiology.org August 2002

50 patients of 350 were found to have significant decreases in WBC and platelet counts due to simultaneous chemotherapy. 25 patients were found to have new foci or local abnormalities after 32 weeks. There are 164 patients surviving for 6 months, 130 patients surviving over 12 months and 56 patients surviving over 24 months.

DISCUSSION
Shortly after radium was discovered, it was used as a radiation source in the therapy of several diseases. But in the past 60 years, most interest in radionuclides has centered on clinical diagnostic uses. Sm-153-EDTMP has several distinct advantages as a radiopharmaceutical for the treatment of patients with bone pain due to skeletal metastasis [10]. (1). Sm-153-EDTMP shows high skeletal uptake and rapid blood and nonosseous tissue clearance. (2). The beta emission (average E =225 KeV) from Sm-153-EDTMP is sufficient to give a high radiation dose to tumor tissues and less damage to bone marrow due to its short range in tissues [11,12]. (3). The gamma photoemission (r= 103Kev) from Sm-153 gives the added advantages of allowing one to monitor Sm-153- EDTMP skeletal uptake by scintillation imaging and quantitating its uptake in specific lesions. (4). The physical half life of Sm-153( 46.8h) is relatively short and should permit it to be administered in either a single or multiple dose. It is also present as a single chemical entity that exhibits excellent in vitro and in vivo stability. Preliminary clinical reports of the efficacy of Sm-153-EDTMP for

amelioration of pain in disseminated skeletal metastasis (Turner et al, 1988; Holmes and Farhangi 1988) have been encouraging and we have attempted to prospectively determine the optimal therapy for each patient to minimize myelotoxicity and to minimize the number of metastases. We have been evaluating Sm-153-EDTMP at the First University Hospital as a palliative therapy for the pain associated with metastatic cancer in bone for the past 9 years. Our goal is pain relief and an improved quality of life. Complete pain response(CR) was noted in 102 cases (29.1%, 102/350) and partial response(PR) in 201 cases(57.4%, 201/350), Thus, 86.5% of the treatment resulted in a definite decrease in pain of our group. The response rate in our study has been as impressive as reported by others [6,13]. The Karnofsky performance score demonstrated more variability over time than the other variables. When improvement occurred, one-third of the time it did so within 2 weeks after injection. Two-thirds of the time, improvement occurred between 2 and 4 weeks after injection. For the group as whole, improvement persisted for 8-9 weeks following injection. After increase in administered activity of Sm-153-EDTMP, the cases of pain elimination did not significant increase (Table 6). These phenomena showed that there is not a clear relationship between dose and relief of pain. It is not clear by what mechanism energetic electrons such as betaparticles cause relief . Perhaps there they affect the depolarization rate of involved nerve endings, inhibit resorption of osteolytic bone metastases, or interrupt biosynthesis of prostaglandin. So further study is clearly necessary. After administering =29.6MBq/kg 153-SmEDYMP, although the blood cell counts have decreased after 1 week and 1 month, there were no persistent significant difference(P>0.05). There were transient decreases of WBC and platelet counts observed at absorbed doses of Sm-153EDTMP in excess 200 cGy [6] , but in 3~4 weeks later, the WBC count generally returned to baseline levels. However, inter-group comparisons indicated that WBC and platelet response differences were not detected between =29.6MBq/kg and 37 MBq/kg (P>0.05). There is no significant difference in comparison with baseline value after 1 month. WBC and platelet counts did not fall below the lower limits of normal baseline value until 270 cGy radiation doses to bone

Copyright The Journal of Radiology www.jradiology.org August 2002

marrow were administered. The severity of the drop in platelets appears dose related. However, none of these patients manifested any of the expected clinical signs of decreased homeostatic capability of the blood. We found that patients with pretreatment low platelet count (albeit within normal range) tended to have a drop in platelet counts [4,5]. We also found that there were no significant changes in liver function. The other results (renal function, enzymes, electrolytes, etc.) showed there were no significant differences before and after treatment with 153-Sm-ETMP. Toxicities were more marked in those who suffered from extensive bone marrow replacement by tumor and received chemotherapy at the same time, and in these patients the effects were prolonged. Our data indicated that Sm-153-EDTMP dose of =29.6MBq/kg is safe and when 153-Sm-EDYMP dose of 37 MBq/kg was used, there were not significant clinical problems Objective evidence of response such as disappearance of focal abnormalities on serial bone scintigraphy was demonstrated in those few patients surviving long term. Results of bone scans within 6 months of treatment were difficult to interpret because longer follow up is generally are required to differentiate the flare phenomena, which may be associated with response of skeletal metastases to therapy (Rossleigh et al, 1982), from increased focal bone uptake due to progression of disease[14]. Our data indicated that the foci most likely to have responded to therapy are those where the cortex of bone is intact, and the metastatic focus is small (diameter in 2.0 ~3.0cm), and those tumors involving the axial skeleton. Our results correspond to the Lattimer et al's data [13]. Sm-153EDTMP is effective in reducing the pain of disseminated skeletal metastases. It has appeared to be curative for some patients with bone metastases( Fig 2~3). We suggest that multiple doses(total dose more than 5000MBq) of Sm-153-EDTMP seems to be effective for regression of disseminated bone metastases. For some patients, multicenter therapy including combination of high doses of Sm-153EDTMP therapy, external radiation, polychemotherapy is useful in order to improve their quality of life[15,16].

REFERENCES
1. Maxon III HR, Schtoder LE, Hertzberg VS, et al. Rhenium 186 (Sn)-HEDP for treatment of painful osseous metas tases: Results of a double-blind crossover comparison with placebo. J Nucl Med. 1991; 32: 1877-1881 2. Trocella L, Auxili CG, Turiziani A, et al. Pain in osseous metastases: Results of radiotherapy. Pain, 1984; 387-396 3. Luo SZ, Pu MF, Li YQ, et al. Studies on bone tumor therapeutic radiopharmaceutical.1. Preparation of 153-Sm and 153-Sm-EDTMP. J of Nucl and Radiachemi, 1991; 13: 233240 4. Luo SZ, PU MF, Qiao J, et al. A potential bone tumor therapeutic agent Sm-153-EDTMP. Its synthesis and preliminary structure analysis. J Radioanaly and Nucl Chemi, 1992; 160: 443-448 5. Holmes RA. Farhangi M. Dose tolerance of 1 53-SmEDTMP in metastatic bone cancer. J Nucl Med, 1988; 29: 775 6. Turner JH, Matyindale AA, Sorhy P, et al. 153-Sm-EDTMP therapy of disseminated skeletal metastasis. Eur J Nucl Med, 1989; 1 5:784-795 7. Goeckler WF, Edwaro B, Vollcelrt WA, et al. Skeletal localization Samarium-153-chelates: Potential therapeutic bone agents. J Nucl Med, 1987; 28: 495-504 8. John C.P. Heggie. Radiation absorbed dose calculations for Samarium-153-EDTMP localized in bone. J Nucl Med, 1991;32:840-844 9. Robinson RG, Spicer JA, Peston DF, et al. Treatment of metastatic bone pain with Strontium-89. Nucl Med Biol, 1987;14: 219-222 10. Stanleg L, Wallenstein MS. Measurement of pain and analgesia in cancer patients. Cancer, 1984; 53: 2260-2226 11. Singh A, Holmes RA, J Farhungi M, et al. Human pharmacokinetics of Samarium-153-EDTMP in metastatic bone cancer. J Nucl Med, 1989; 30: 1814-1818 12. Robinson RG. Editorial: Systemic bone cancer. Systemic radioisotopic therapy of primary and metastatic bone cancer. J Nucl Med, 1990; 31: 1326-1327 13. Farhanghi M, Holmes RA, Volkert WA, et al. Samarium 153-EDTMP. Pharmacokinetic, toxicity and pain response using an escalating dose schedule in treatment of metastatic bone cancer. J Nucl Med, 1992; 33: 1451-1458 14. Lattimer JC, Corwin LA, Slapleton JrJ, et al. Clinical and clinicopathologic responsive canine bone tumor patients with Sm-153-EDTMP, J Nucl Med, 1990; 31: 1316-1325 15. Franzius C, Bielack S, Sciuk J, et al. High -activity samarium-153-EDTMP therapy in unresectable osteosarcoma. Nuklearmedizin, 1999; 38(8): 337-40 16. McEwan AJ. Use of radionuclides for the palliation of bone metastases. Semin Radiat Oncol, 2000; 10(2): 103-14

Copyright The Journal of Radiology www.jradiology.org August 2002

Table 1. Biodistribution of Sm-153-EDTMP in mice(% I.D/organ, means.d, for 5 mice) time 5min 15min 30min 1h 2h 3h 5h 24h 72h 96h blood 4.030.08 2.080.05 1.130.04 0.460.08 0.150.05 0.080.02 0.070.02 0.060.01 0.040.01 0.010.00 heart 1.970.13 1.390.11 1.090.21 0.840.29 0.280.14 0.150.01 0.120.01 0.090.01 0.030.01 0.010.00 lung 1.880.63 1.520.35 1.470.25 0.850.12 0.430.06 0.260.05 0.190.03 0.150.02 0.040.01 0.010.00 liver 1.530.03 1.400.05 0.910.07 0.740.20 0.520.09 0.650.09 0.480.13 0.230.09 0.110.02 0.030.01 kidney 5.140.09 4.830.87 3.730.67 3.090.69 1.100.07 0.750.18 0.330.09 0.080.01 0.030.02 0.010.00 muscle 1.120.06 0.890.07 0.670.08 0.270.06 0.120.01 0.030.01 0.030.01 0.020.01 0.020.01 0.010.00 bone 8.151.89 13.890.67 18.410.51 20.321.18 21.482.07 26.442.53 24.533.15 23.922.87 23.661.94 22.802.31

Table 2 Myelotoxicity of Sm-153-EDTMP in 5 Wistar rats (88MBq/kg) (means.d) RBC(109 /L) Contr. Exp. 4h 1d 3d 5d 7d 16d 5.61.2 P 4.31.4 <0.05 4.21.5 <0.05 4.60.4 <0.05 4.71.3 <0.05 5.70.9 >0.05 5.81.2 >0.05 Hb(g/L) 145.0 28.1 P 139.3 22.3 <0.05 136.7 25.3 <0.05 125.0 11.1 <0.05 145.3 17.1 >0.05 153.3 10.2 >0.05 149.0 25.2 >0.05 WBC(109 /L) 11.62.9 P 7.92.4 <0.05 8.50.4 <0.05 6.20.9 <0.05 8.51.7 <0.05 8.81.0 <0.05 9.01.4 <0.05 Platelet(109 /L) 320.0 30.5 P 238.6 40.1 <0.05 229.3 14.9 <0.05 240.7 18.5 <0.05 233.0 20.7 <0.05 237.0 14.1 <0.05 259.0 19.1 <0.05

Table 3 Sm-153-EDTMP(=29.6MBq/kg )effect on blood cells counts (means.d) n hemoglobin(g/L) platelet( 109/L) WBC(109 /L) granulocyte(%) lymph cell(%) 93 93 93 93 93 before treatment 110.820.3 138.320.1 5.91.4 70.35.3 25.61.4 1 week after treatment 104.521.2 132.718.8 5.71.7 70.91.8 24.61.8 1 month after treatment 104.019.8 130.120.9 5.62.1 68.57.5 25.92.4 P >0.05 >0.05 >0.05 >0.05 >0.05

Table 4 Sm -153-EDTMP effect on the function of liver and kidneys (means.d, mMol/L) n before treatment 1 month after administration P

Copyright The Journal of Radiology www.jradiology.org August 2002

blood urea nitrogen creatinine total bilirubin direct bilrubin SGPT Albumin Globulin

93 93 93 93 93 93 93

4.61.3 75.7 23.5 13.98.0 36.9 21.4 27.0 24.6 40.4 11.4 30.97.5

4.51.6 82.019.0 12.06.3 34.417.1 26.524.7 39.413.8 29.67.1

>0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05

Table 5 Sm-153-EDTMP effect on serum enzymes and electrolytes (means.d) n SGOT(u/L) AKP(u/L) CK(u/L) r-GT(u/L) LDH(u/L) K(mMol/L) Na(mMol/L) Cl(nMol/L) Ca(nMol/L) P(mMol/L) 93 93 93 93 93 93 93 93 93 93 before treatment 37.612.5 136.226.6 73.254.2 47.76.3 228.8101.4 2.51.1 136.13.8 102.42.3 2.10.3 1.30.5 1 month after administration 43.1 10.8 114.9 88.4 70.1 52.7 49.97.1 227.1 102.5 2.30.9 137.32.8 104.80.8 2.10.4 1.20.6 P >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05

Table 6 The r elation between the analgesic effect of Sm-153-EDTMP and dose dose single Repeat(2~10) n 105 245 350 no response 15 32 47 partial response 56 145 201 complete response 34 68 102 day (means.d) 9.66.2 9.97.0

Copyright The Journal of Radiology www.jradiology.org August 2002