Dose escalation study with rhenium-188 hydroxyethylidene diphosphonate in prostate cancer patients with osseous metastases

The aim of this study was to determine the maximum tolerated dose of rhenium-188 hydroxyethylidene diphosphonate (HEDP) in prostate cancer patients with osseous metastases who are suffering from bone pain. Twenty-two patients received a single injection of escalating doses of carrier-added 188Re-HEDP [1.3 GBq (35 mCi), 2.6 GBq (70 mCi), 3.3 GBq (90 mCi) and 4.4 GBq (120 mCi)]. Blood counts and biochemical parameters were measured weekly over a period of 8 weeks. Haematological toxicity (WHO grading) of grade 3 or 4 was considered unacceptable. Clinical follow-up studies including methods of pain documentation (medication, pain diary) were performed for 6 months after treatment. In the 1.3-GBq group, no haematological toxicity was observed. First haematotoxic results were noted in those patients with a dose of 2.6 GBq 188Re-HEDP. In the 3.3-GBq group, one patient showed a reversible thrombopenia of grade 1, one a reversible thrombopenia of grade 2 and three a reversible leukopenia of grade 1. In the 4.4-GBq group, thrombopenia of grades 3 and 4 was observed in one and two patients (baseline thrombocyte count <200x10(9)/l), respectively, and leukopenia of grade 3 was documented in one patient. The overall nadir of thrombopenia was at week 4. The individual, maximum percentage decrease in thrombocytes in the 1.3-, 2.6-, 3.3- and 4.4-GBq groups was 17%, 40%, 60% and 86%, respectively. In two patients, a transient increase in serum creatinine was observed (max. 1.6 mg/dl). Pain palliation was reported by 64% of patients, with a mean duration of 7.5 weeks. The response rate seemed to increase with higher doses, reaching 75% in the 4.4-GBq group. It is concluded that in prostate cancer patients, the maximum tolerated dose of 188Re-HEDP is 3.3 GBq if the baseline thrombocyte count is below 200x10(9)/l. In patients with thrombocyte counts significantly above 200x10(9)/l, a dose of 4.4 GBq might be tolerable. Thrombo- and leukopenia are the most important side-effects. Pain palliation can be achieved in 60%-75% of patients receiving a dose of 2.6 GBq or more of 188Re-HEDP. Studies in a larger patient population are warranted to evaluate further the palliative effect of 188Re-HEDP.     

Dose escalation study with rhenium-188 hydroxyethylidene diphosphonate in prostate cancer patients with osseous metastases

The aim of this study was to determine the maximum tolerated dose of rhenium-188 hydroxyethylidene diphosphonate (HEDP) in prostate cancer patients with osseous metastases who are suffering from bone pain. Twenty-two patients received a single injection of escalating doses of carrier-added ¹⁸⁸Re-HEDP [1.3 GBq (35 mCi), 2.6 GBq (70 mCi), 3.3 GBq (90 mCi) and 4.4 GBq (120 mCi)]. Blood counts and biochemical parameters were measured weekly over a period of 8 weeks. Haematological toxicity (WHO grading) of grade 3 or 4 was considered unacceptable. Clinical follow-up studies including methods of pain documentation (medication, pain diary) were performed for 6 months after treatment. In the 1.3-GBq group, no haematological toxicity was observed. First haematotoxic results were noted in those patients with a dose of 2.6 GBq ¹⁸⁸Re-HEDP. In the 3.3-GBq group, one patient showed a reversible thrombopenia of grade 1, one a reversible thrombopenia of grade 2 and three a reversible leukopenia of grade 1. In the 4.4-GBq group, thrombopenia of grades 3 and 4 was observed in one and two patients (baseline thrombocyte count <200×10⁹/l), respectively, and leukopenia of grade 3 was documented in one patient. The overall nadir of thrombopenia was at week 4. The individual, maximum percentage decrease in thrombocytes in the 1.3-, 2.6-, 3.3- and 4.4-GBq groups was 17%, 40%, 60% and 86%, respectively. In two patients, a transient increase in serum creatinine was observed (max. 1.6 mg/dl). Pain palliation was reported by 64% of patients, with a mean duration of 7.5 weeks. The response rate seemed to increase with higher doses, reaching 75% in the 4.4-GBq group. It is concluded that in prostate cancer patients, the maximum tolerated dose of ¹⁸⁸Re-HEDP is 3.3 GBq if the baseline thrombocyte count is below 200×10⁹/l. In patients with thrombocyte counts significantly above 200×10⁹/l, a dose of 4.4 GBq might be tolerable. Thrombo- and leukopenia are the most important side-effects. Pain palliation can be achieved in 60%–75% of patients receiving a dose of 2.6 GBq or more of ¹⁸⁸Re-HEDP. Studies in a larger patient population are warranted to evaluate further the palliative effect of ¹⁸⁸Re-HEDP. Received 7 July and in revised form 6 October 1999     

A comparative study of 188Re-HEDP, 186Re-HEDP, 153Sm-EDTMP and 89Sr in the treatment of painful skeletal metastases

AIM: The surface bone-seeking radiopharmaceuticals 188Re-HEDP, 186Re-HEDP and 153Sm-EDTMP, and the volume seeker 89Sr were investigated to determine the efficacy and toxicity in pain palliation of bone metastases. METHOD: The effect of treatment with 188Re-HEDP, 186Re-HEDP, 153Sm-EDTMP and 89Sr on pain symptoms, quality of life, and bone marrow function were studied. In total, 79 patients (18 with breast cancer and 61 with prostate cancer) were treated (31 patients with 188Re-HEDP, 15 patients each with 186Re-HEDP and 153Sm-EDTMP, and 18 patients with 89Sr). All patients were interviewed using standardized sets of questions before and after therapy weekly for 12 weeks. Blood counts were taken weekly for 6 weeks and after 12 weeks. RESULTS: In total, 73% of patients reported pain relief (77% after 188Re-HEDP, 67% after 186Re-HEDP 73% after 153Sm-EDTMP, and 72% after 89Sr). Fifteen percent of patients could discontinue their analgesics and were pain-free. Pain showed a decrease from 3.6+/-1.7 to a maximum of 2.2+/-1.8 at visual analogue scale in 10 steps (P<0.01). Patients described an improvement on the Karnofsky performance scale from 70+/-10% to 78+/-14% 12 weeks after treatment (P=0.15). There were eight patients with a thrombocytopenia grade I, two patients with grade II and one with grade III. The maximum nadir of platelet and leukocyte counts were observed between the 2nd to 5th week after treatment and was reversible within 12 weeks. There were no significant differences in pain palliation, Karnofsky performance status (KPS) and bone marrow toxicity between the different radionuclides (P=0.087-0.449). CONCLUSION: All radiopharmaceuticals were effective in pain palliation, without induction of severe side effects or significant differences in therapeutic efficacy or toxicity.     

Labelling of Re-ABP with 188Re for bone pain palliation.

Etidronate and medronate have been labelled with technetium-99m (99mTc-HEDP, 99mTc-MDP) for bone scanning and, with rhenium-188 (188Re-HEDP) to palliate the pain resulting from bone metastases. The objective of this study was to label alendronate, ABP, a new bisphosphonate, with SnF2-reduced-188Re. The reagents for the 5 mg ABP kit were SnF2, KReO4 and gentisic acid at acid pH. The chemical, spectroscopic and microscopic characteristics, quality control, rat bone uptake of [188Re]Re-ABP and similarities with 99mTc-ABP are presented. We conclude that this is a promising new radiopharmaceutical for bone metastases pain palliation.     

Preparation and evaluation of the rhenium-188-labelled anti-NCA antigen monoclonal antibody BW 250/183 for radioimmunotherapy of leukaemia.

Anti-NCA antigen antibody BW 250/183 (Anti-Granulocyte) localizes more than 50% of injected antibody dose to the bone marrow. Therefore, this antibody is promising for adjuvant conditioning radioimmunotherapy of bone marrow before bone marrow transplantation. To examine its potential use for radioimmunotherapy, we developed an efficient and reproducible technical protocol for labelling anti-NCA antigen antibody BW 250/183 with generator-produced rhenium-188, aiming at both high radiochemical yield and high specific activity. (188)Re-labelled BW 250/183 antibody was used in 12 patients with advanced leukaemia. Labelling of BW 250/183 with (188)Re was accomplished by the direct radiolabelling method using tris-(2-carboxyethyl) phosphine (TCEP) as the reducing agent. Twelve patients with recurrent acute or chronic leukaemia were treated with activities of 6.5-12.4 GBq of (188)Re-labelled BW 250/183. Standard gamma camera scintigraphy was used to evaluate the biodistribution, and a region of interest analysis together with the MIRDOSE 3.1 software was applied to determine the radiation doses to relevant tissues. The (188)Re-BW 250/183 antibody was labelled in high radiochemical yield, with high radiochemical purity (94%+/-3%) and specific activity (5.55-7.4 GBq/mg) within 1 h. The preliminary biodistribution studies showed persistent uptake of (188)Re-BW 250/183 in bone marrow. The radiation absorbed doses (mGy/MBq) delivered to the total body, red marrow, liver, spleen and kidneys were 0.13+/-0.02, 1.45+/-0.71, 0.43+/-0.21, 1.32+/-0.99 and 0.71+/-0. 17, respectively. TCEP reduction enabled the direct, fast and effective labelling of the monoclonal antibody BW 250/183 with (188)Re. Preliminary clinical results suggest delivery of a significant radiation dose to bone marrow and thus the potential for adjuvant conditioning therapy before BMT.     

Dosimetry of 188Re-hydroxyethylidene diphosphonate in human prostate cancer skeletal metastases.

188Re-Hydroxyethylidene diphosphonate ((188)Re-HEDP) was used in previous studies for the palliative treatment of metastatic bone pain. However, the kinetic and radiation-absorbed doses have not been well documented. Therefore, the aim of this study was to gather dosimetric data for (188)Re-HEDP. METHODS: Thirteen prostate cancer patients with skeletal involvement were treated with 2,700-3,459 MBq (mean dose, 3,120 MBq) (188)Re-HEDP. Patients underwent whole-body scans 3, 20, and 28 h after therapy. The effective half-life, residence time, and radiation-absorbed dose values were calculated for the whole body, bone marrow, kidneys, and bladder as well as for 29 bone metastases. The urinary excretion rate was determined in 6 urine samples of each patient collected over 48 h at 8-h intervals beginning immediately after the administration of (188)Re-HEDP. After injection of (188)Re-HEDP, blood samples were taken weekly for 6 wk, and platelet and leukocyte counts were performed. RESULTS: The mean effective half-life was 15.9 +/- 3.5 h in bone metastases, 10.9 +/- 2.1 h in the bone marrow, 11.6 +/- 2.1 h in the whole body, 12.7 +/- 2.2 h in the kidneys, and 7.7 +/- 3.4 h in the bladder. The following radiation-absorbed doses were calculated: 3.83 +/- 2.01 mGy/MBq for bone metastases, 0.61 +/- 0.21 mGy/MBq for the bone marrow, 0.07 +/- 0.02 mGy/MBq for the whole body, 0.71 +/- 0.22 mGy/MBq for the kidneys, and 0.99 +/- 0.18 mGy/MBq for the bladder. (188)Re-HEDP showed a rapid urinary excretion within the first 8 h after therapy, with 41% of the (188)Re-HEDP administered being excreted. Forty-eight hours after therapy, the excretion rate was 60% +/- 12%. Only 1 patient showed a decrease of platelet count below 100 x 10(9) counts/L. None of the patients presented with a decrease of leukocyte count below 3.0 x 10(9) counts/L. CONCLUSION: (188)Re-HEDP is an effective radiopharmaceutical used in the palliative treatment of metastatic bone pain. The radiation-absorbed dose is acceptable for bone pain palliation with low doses for the normal bone marrow and the whole body.     

Preparation of (188Re) Re-AEDP and its biodistribution studies.

The synthesis of the Re (V) complex and preparation of 188Re-AEDP are described using 188Re which was obtained from the alumina-based 188W/188Re generator. Dependence of the radiolabeling yields of 188Re-AEDP on reducing agent concentration, AEDP concentration, pH and addition of carrier was examined. In the case of optimum conditions, the radiolabeling yields of 188Re-AEDP were 92-93% for carrier-free 188Re and 95-98% for carrier-added 188Re. The stability of 188Re-AEDP at pH approximately 6 was studied and it is found that the carrier has a significant effect on the stability of 188Re-AEDP. The biodistribution of carrier-free and carrier-added 188Re-labelled compounds in rats was also measured. The results show that 188Re (carrier-added)-AEDP is a potential bone palliation radiopharmaceutical due to its high skeletal uptake, rapid blood clearance and relatively low soft tissue absorption.     

Preparation and evaluation of the rhenium-188-labelled anti-NCA antigen monoclonal antibody BW 250/183 for radioimmunotherapy of leukaemia

Anti-NCA antigen antibody BW 250/183 (Anti-Granulocyte) localizes more than 50% of injected antibody dose to the bone marrow. Therefore, this antibody is promising for adjuvant conditioning radioimmunotherapy of bone marrow before bone marrow transplantation. To examine its potential use for radioimmunotherapy, we developed an efficient and reproducible technical protocol for labelling anti-NCA antigen antibody BW 250/183 with generator-produced rhenium-188, aiming at both high radiochemical yield and high specific activity. ¹⁸⁸Re-labelled BW 250/183 antibody was used in 12 patients with advanced leukaemia. Labelling of BW 250/183 with ¹⁸⁸Re was accomplished by the direct radiolabelling method using tris-(2-carboxyethyl) phosphine (TCEP) as the reducing agent. Twelve patients with recurrent acute or chronic leukaemia were treated with activities of 6.5–12.4 GBq of ¹⁸⁸Re-labelled BW 250/183. Standard gamma camera scintigraphy was used to evaluate the biodistribution, and a region of interest analysis together with the MIRDOSE 3.1 software was applied to determine the radiation doses to relevant tissues. The ¹⁸⁸Re-BW 250/183 antibody was labelled in high radiochemical yield, with high radiochemical purity (94%±3%) and specific activity (5.55–7.4 GBq/mg) within 1 h. The preliminary biodistribution studies showed persistent uptake of ¹⁸⁸Re-BW 250/183 in bone marrow. The radiation absorbed doses (mGy/MBq) delivered to the total body, red marrow, liver, spleen and kidneys were 0.13±0.02, 1.45±0.71, 0.43±0.21, 1.32±0.99 and 0.71±0.17, respectively. TCEP reduction enabled the direct, fast and effective labelling of the monoclonal antibody BW 250/183 with ¹⁸⁸Re. Preliminary clinical results suggest delivery of a significant radiation dose to bone marrow and thus the potential for adjuvant conditioning therapy before BMT. Received 6 January and in revised form 10 May 1999     

Preparation, stability studies and pharmacological behavior of [186Re]Re-HEDP.

99mTc-HEDP is widely used as a bone imaging agent and its Re analog [186Re]Re-HEDP is now well established as a therapeutic radiopharmaceutical for palliation of pain due to bone metastases. In the present paper, we report the work carried out for the preparation of stable 186Re-HEDP which retains RC purity up to 5 days when stored at 4 degrees C. 186Re was prepared by irradiation of natural Re metal at a flux of 3 x 10(13) neutrons/cm2/s for seven days and processed after a cooling period of four days. The specific activity of 186Re formed was approximately 35 mCi/mg. A complex with RC purity > 98% could be prepared by varying the reaction conditions. By carefully optimizing the reaction and storage conditions, a complex which was stable for over 4 days could be synthesized. Bio-distribution studies carried out in rats revealed approximately 30% bone uptake of 186Re-HEDP at 3 h postinjection which remained almost constant for 48 h, at which time there was negligible activity in other organs.     

186Re-etidronate. Efficacy of palliative radionuclide therapy for painful bone metastases.

Pain palliation with bone-seeking radiopharmaceuticals is an effective treatment modality in patients with advanced metastatic bone cancer. Several studies have shown encouraging clinical results of palliative therapy using 186Re-HEDP, with an overall reported response rate of +/-71% for painful osseous metastasized prostate and breast cancer patients. 186Re-HEDP is a very potential isotope with numerous advantageous characteristics for this purpose. Myelosuppressive toxicity is limited and reversible, which makes repetitive treatment safe. However, individual studies are difficult to compare, and are hampered by the numerous and different methods used to assess clinical response. Standardized clinical response assessment using the objective multi-dimensional pain evaluation model should therefore be implemented.     

Biodistribution studies of the 186Re complex of 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid in mice.

Preliminary studies of 186Re-labelled 3-amino-1-hydroxypropylidene-1, 1-bisphosphonic acid (APD) were performed to determine its potential for bone pain palliation, and as a treatment for increased bone resorption. The synthesis of 186Re-APD was carried out by reduction of 186Re-perrhenate in the presence of SnCl2. The APD kit, comprising 2.5 mg of APD, 2.5 mg of gentisic acid and 1 mg of Sn++ as SnCl2 2H2O, was prepared in-house. The APD was labelled with 186Re and injected intravenously into normal mice. Mice were subsequently sacrificed at 1, 3, 24, 48, 72, 168 and 240 h post-injection. The greatest accumulation of 186Re-labelled APD was found in bone, resulting in bone-to-blood ratios of 25, 35, 65, 100, 151, 181 and 189, respectively. 186Re-APD showed high uptake in bone, and relatively low uptake in soft tissue, suggesting that 186Re-APD is a potential agent for bone therapy.     

Rhenium-188 HEDP to treat painful bone metastases

PURPOSE: Rhenium-188 hydroxyethylidine diphosphonate (HEDP) is a new and attractive radiopharmaceutical that localizes in skeletal metastases and emits beta particles that may be therapeutically beneficial. In this study, the therapeutic efficacy of Re-188 HEDP was investigated in an uncontrolled initial trial of 61 patients with different types of advanced cancer for the palliation of painful bone metastases. MATERIALS AND METHODS: Sixty-one patients with painful bone metastases of lung, prostate, breast, renal, rhinopharyngeal, and bladder cancers were treated with 1.1 GBq (31 mCi) to 6.9 GBq (188 mCi) Re-188 HEDP. After treatment, the patients were followed at weekly intervals for the first 2 months and monthly thereafter for as long as 1 year. Hematologic function tests were also performed before and after treatment for 6 weeks. Pain responses were scored according to a three-point pain-rating scale as complete, significant, and minimal. RESULTS: Prompt and significant relief of bone pain occurred in 80% of patients overall. Of the specific tumor types, pain relief was achieved in 77% of patients with lung cancer, in 80% with prostate cancer, in 83% with breast cancer, in 100% with bladder cancer, in 50% with renal cancer, in 50% with rhinopharyngeal cancer, and in 87% of patients with other tumor types, with no severe side effects or hematopoietic toxicity. CONCLUSION: This large clinical trial verified that Re-188 HEDP is a useful radiopharmaceutical agent to treat painful bone metastases from various tumor types.     

Short- and long-term effects of 186Re-1,1-hydroxyethylidene diphosphonate in the treatment of painful bone metastases.

This study evaluates the short- and long-term therapeutic efficacy of 186Re-1,1-hydroxyethylidene diphosphonate (HEDP) in the palliation of painful bone metastases and the influence of variables before therapy in determining the characteristics of pain palliation. METHODS: Sixty patients with painful bone metastases from different tumor types were treated with 1406 MBq 186Re-HEDP. After treatment, the patients were followed up clinically at weekly intervals for the first month and monthly thereafter up to 1 y, until death or pain relapse. Pain response was graded as complete, partial, minimal, or absent using the Wisconsin test scoring system. Duration of pain relief, performance status, tumor markers, serum alkaline phosphatase levels, hematologic toxicity, and metastatic bone progression were also evaluated. RESULTS: Overall, 80% of individuals experienced prompt relief of pain, with 31% complete, 34% partial, and 15% minimal responses. Transient World Health Organization grade 1-2 hematologic toxicity was apparent, with a decrease in the mean platelet (32%) and mean leukocyte (18%) counts at 3 and 4 wk, respectively. The degree of pain response did not correlate with any pretreatment variable. The duration of pain relief ranged from 3 wk to 12 mo and correlated positively with the degree of response (P = 0.02) and negatively with pretreatment scintigraphic scores and alkaline phosphatase levels (P = 0.02). CONCLUSION: 186Re-HEDP is effective for fast palliation of painful bone metastases from various tumors. The effect tends to last longer if patients are treated early in the course of their disease.     

Targeted bone marrow irradiation in the conditioning of high-risk leukaemia prior to stem cell transplantation

Disease recurrence following stem cell transplantation (SCT) remains a major problem. Despite the sensitivity of leukaemias to chemotherapy and irradiation, conventional conditioning before SCT is limited by significant organ toxicity. Targeted irradiation of bone marrow and spleen by radioimmunotherapy may provide considerable dose escalation, with limited toxicity to non-target organs. In this study, 27 patients with high-risk or relapsing leukaemia were treated with rhenium-188-labelled CD66a,b,c,e radioimmunoconjugates (188Re-mAb) specific for normal bone marrow in addition to conventional conditioning with high-dose chemotherapy and 12 Gy total body irradiation prior to SCT. A mean activity of 10.2+/-2.1 (range 6.9-15.8) GBq 188Re-mAb was administered intravenously. Acute side-effects were assessed according to the CTC classification and patient outcome was determined. Mean radiation doses (Gy; range in parentheses) to relevant organs and whole body were as follows: 13.1 (6.5-22) to bone marrow, 11.6 (1.7-31.1) to spleen, 5.0 (2.0-11.7) to liver, 7.0 (2.3-11.6) to kidneys, 0.7 (0.3-1.3) to lungs and 1.4 (0.8-2.1) to the whole body. Stem cells engrafted in all patients within 9-18 days post SCT. Acute organ toxicity of grade II or less was observed. During follow-up for 25.4+/-5.3 (range 18-34) months, 4/27 (15%) patients died from relapse, and 9/27 (33%) from transplantation-related complications. Fourteen patients (52%) are still alive and in ongoing complete clinical remission. Radioimmunotherapy with the bone marrow-seeking 188Re-labelled CD66 mAb can double the dose to bone marrow and spleen without undue extramedullary acute organ toxicity, when given in addition to high-dose chemotherapy and 12 Gy TBI before allogeneic SCT. This intensified conditioning regimen may reduce the relapse rate of high-risk leukaemia.     

用于骨痛治疗的放射性核素

介绍了用于骨疼痛治疗的放射性核素89Sr、153Sm、186Re、188Re和117Snm,评述了这些核素的生产以及在骨疼痛治疗中的应用,并对每个核素的优缺点进行了讨论。     

Preparation of (Re) Re-AEDP and its biodistribution studies

The synthesis of the Re (V) complex and preparation of ¹⁸⁸Re-AEDP are described using ¹⁸⁸Re which was obtained from the alumina-based ¹⁸⁸W/¹⁸⁸Re generator. Dependence of the radiolabeling yields of ¹⁸⁸Re-AEDP on reducing agent concentration, AEDP concentration, pH and addition of carrier was examined. In the case of optimum conditions, the radiolabeling yields of ¹⁸⁸Re-AEDP were 92–93% for carrier-free ¹⁸⁸Re and 95–98% for carrier-added ¹⁸⁸Re. The stability of ¹⁸⁸Re-AEDP at pH≈6 was studied and it is found that the carrier has a significant effect on the stability of ¹⁸⁸Re-AEDP. The biodistribution of carrier-free and carrier-added ¹⁸⁸Re-labelled compounds in rats was also measured. The results show that ¹⁸⁸Re (carrier-added)-AEDP is a potential bone palliation radiopharmaceutical due to its high skeletal uptake, rapid blood clearance and relatively low soft tissue absorption.     

188Re—HEDP治疗肿瘤骨转移痛药代动力学研究

目的研究188Re标记的1-羟基-1,1-二膦酸钠乙烷（即依替膦酸盐,HEDP）在肿瘤骨转移患者体内的分布和排泄,分析不同剂量188Re—HEDP在患者体内的药代动力学特点。方法将40例肿瘤骨转移患者分为4组,每组10例,4组分别按体质量“弹丸”式经肘静脉注射188Re—HEDP20,30,40和50MBq／kg,给药时及给药后1,2,4,5,12,24,36,48,60和72h分别用SPECT仪采集胸前区和前后位、后前位全身图像,并收集患者尿液,测量放射性。利用感兴趣区（ROI）技术在左心室区测得经本底校正的放射性,作为血液放射性。将1h全身前位、后位放射性总计数率经死时间和时间衰减校正后的几何平均值设定为100％注射剂量（ID）,据此估算上述各时间点全身和各器官的百分注射剂量率（％ID）。各组间的计量资料采用元、中位数、范围等表示,组间比较采用方差分析或t检验。结果20～50MBq／kg范围内,188Re—HEDP在体内的时间-放射性曲线下面积（AUC）与其剂量呈线性关系,r^2=0．9376。4组均符合静脉给药二室模型,AUC值中位数分别为3．32×10^5,3．97×10^5,7．83×10^5,8．58×10^5;分布速度常数（α值）中位数分别为0．06,0．05,0．04,0．06;消除速度常数（B值）中位数分别为1．16×10^-3,1．16×10^-3,1．03×10^-3,1．15×10^-3;指数项系数A值中位数分别为3591．21,4858．23,5642．48,4167．05;指数项系数B值中位数分别为293．97,352．95,614．41,1063．82;药物分布相半衰期T1/2值中位数分别为12．51,12．83,15．41,12．02min;药物消除相半衰期T1／2（β）中位数分别为595．47,596．50,673．09,600．93min。骨组织是摄取188Re—HEDP的主要组织,给药后4h放射性摄取高,约为40％ID,其他组织未见明显摄取188Re—HEDP0188Re．HEDP主要通过泌尿系统排泄,给药后24h排出66．79％ID,其中74％在给药后5h内排出。结论20～50MBq／kg范围内,188Re—HEDP在机体内的药代动力学符合血管给药二室模型。188Re—HEDP T1/2（β）平均为616．50min。188Re—HEDP主要通过泌尿系统排泄;骨组织是摄取188Re—HEDP的主要组织。     

Targeted bone marrow irradiation in the conditioning of high-risk leukaemia prior to stem cell transplantation

Disease recurrence following stem cell transplantation (SCT) remains a major problem. Despite the sensitivity of leukaemias to chemotherapy and irradiation, conventional conditioning before SCT is limited by significant organ toxicity. Targeted irradiation of bone marrow and spleen by radioimmunotherapy may provide considerable dose escalation, with limited toxicity to non-target organs. In this study, 27 patients with high-risk or relapsing leukaemia were treated with rhenium-188-labelled CD66a,b,c,e radioimmunoconjugates (¹⁸⁸Re-mAb) specific for normal bone marrow in addition to conventional conditioning with high-dose chemotherapy and 12 Gy total body irradiation prior to SCT. A mean activity of 10.2DŽ.1 (range 6.9-15.8) GBq ¹⁸⁸Re-mAb was administered intravenously. Acute side-effects were assessed according to the CTC classification and patient outcome was determined. Mean radiation doses (Gy; range in parentheses) to relevant organs and whole body were as follows: 13.1 (6.5-22) to bone marrow, 11.6 (1.7-31.1) to spleen, 5.0 (2.0-11.7) to liver, 7.0 (2.3-11.6) to kidneys, 0.7 (0.3-1.3) to lungs and 1.4 (0.8-2.1) to the whole body. Stem cells engrafted in all patients within 9-18 days post SCT. Acute organ toxicity of grade II or less was observed. During follow-up for 25.4LJ.3 (range 18-34) months, 4/27 (15%) patients died from relapse, and 9/27 (33%) from transplantation-related complications. Fourteen patients (52%) are still alive and in ongoing complete clinical remission. Radioimmunotherapy with the bone marrow-seeking ¹⁸⁸Re-labelled CD66 mAb can double the dose to bone marrow and spleen without undue extramedullary acute organ toxicity, when given in addition to high-dose chemotherapy and 12 Gy TBI before allogeneic SCT. This intensified conditioning regimen may reduce the relapse rate of high-risk leukaemia.     

Simple new method for effective concentration of 188Re solutions from alumina-based 188W-188Re generator.

(188)Re is a useful generator-produced radioisotope currently under evaluation for a variety of therapeutic applications, including bone pain palliation and intravascular radiation therapy. Because the (188)W parent is available only in a relatively low specific activity (<0.15-0.19 GBq/mg) from reactor irradiation of enriched (186)W, relatively large volumes of 0.9% saline (>15 mL) are required for elution of the (188)Re daughter from traditional alumina-based (188)W-(188)Re generators. Because these large bolus volumes result in solutions with a relatively low specific volume activity of (188)Re (<1 GBq/mL for the 18.5-GBq generator), the availability of effective methods for eluent concentration is important. Our new approach is based on the use of 0.3 mol/L ammonium acetate as a representative salt of a weak acid instead of saline for generator elution. METHODS: After generator elution, the ammonium acetate generator eluent (15-20 mL) is passed through a tandem IC-H Plus cation (Dowex-H)-anion (QMA Light) column system. Exchange of ammonium cations with hydrogen ions on the cation column forms an acetic acid solution containing perrhenate anions from which the macroscopic levels of the acetate anion of the eluent have been effectively removed. Because perrhenic acid is fully dissociated at this pH, the QMA Light column specifically traps the (188)Re-perrhenate, which is subsequently eluted with a low volume (<1 mL) of saline. Concentration ratios greater than 20:1 are readily achieved with this method. RESULTS: A typical clinical-scale generator loaded with 19.2 GBq (188)W was used to validate the approach. Saline elution provided (188)Re in a 75%-80% yield. Although elution with 0.15 mol/L NH4OAc gave lower yields (55%-60%), use of 0.3 mol/L NH4OAc provided yields comparable with those of saline (70%-75%). (188)W parent breakthrough was not detected after passage of the bolus through the tandem concentration system. Bolus volumes of 15-20 mL, which initially contained as much as 11.1-14.8 GBq (188)Re, were readily concentrated to less than 1 mL saline using QMA Light cartridges. The generator was evaluated for more than 3 mo with no decrease in performance. CONCLUSION: This approach represents a simple, rapid, and effective method using inexpensive disposable components of concentrating solutions of (188)Re for preparation of therapeutic agents.     

186Re-HEDP for metastatic bone pain in breast cancer patients

Two-thirds of patients with metastatic cancer suffer from pain. Pain originating from skeletal metastases is the most common form of cancer-related pain. Bone pain, often exacerbated by pressure or movement, limits the patient's autonomy and social life. Pain palliation with bone-seeking radiopharmaceuticals has proven to be an effective treatment modality in patients with metastatic bone pain. These bone-seeking radiopharmaceuticals are extremely powerful in treating scattered painful bone metastases, for which external beam radiotherapy is impossible because of the large field of irradiation. (186)Re-hydroxyethylidene diphosphonate (HEDP) is a potentially useful radiopharmaceutical for this purpose, having numerous advantageous characteristics. Bone marrow toxicity is limited and reversible, which makes repetitive treatment safe. Studies have shown encouraging clinical results of palliative therapy using (186)Re-HEDP, with an overall response rate of ca. 70% in painful bone metastases. It is effective for fast palliation of painful bone metastases from various tumours and the effect tends to last longer if patients are treated early in the course of their disease. (186)Re-HEDP is at least as effective in breast cancer patients with painful bone metastases as in patients with metastatic prostate cancer. It is to be preferred to radiopharmaceuticals with a long physical half-life in this group of patients, who tend to have more extensive haematological toxicity since they have frequently been pretreated with bone marrow suppressive chemotherapy. This systemic form of radionuclide therapy is simple to administer and complements other treatment options. It has been associated with marked pain reduction, improved mobility in many patients, reduced dependence on analgesics, and improved performance status and quality of life.