Clinical and clinicopathologic response of canine bone tumor patients to treatment with samarium-153-EDTMP

Forty dogs with spontaneous skeletal neoplasia were treated with 153Sm-EDTMP (ethylenediaminetetramethylene phosphonic acid). Both primary and metastatic lesions were treated. Two treatment regimes, a single (37 MBq (1.0 mCi)/kg dose or two 37 MBq (1.0 mCi)/kg doses separated by 1 wk) were tested. Response to treatment was varied. Large lesions with minimal tumor bone formation responded poorly, while primary lesions with substantial ossification usually exhibited a transient response. Small lesions with minimal lysis, metastatic lesions, and axial skeleton lesions generally responded well. The major adverse side effects of treatment were platelet and white blood cell count depression below baseline values for up to 4 wk (p less than 0.05). Minor depression of packed cell volume and transient elevation of serum alkaline phosphatase were also noted (p less than 0.05). No significant differences (p greater than 0.05) between the two treatment groups, either in treatment effect or undesirable side effects, were detected.     

Efficacy and safety of repeated samarium-153 lexidronam treatment in a patient with prostate cancer and metastatic bone pain

A patient with stage D3 prostate cancer was given 11 separate doses of samarium-153 lexidronam (Sm-153 ethylenediaminetetramethylene phosphonate) of 1 mCi/kg (37 MBq/kg) in a period of 28 months for bone pain from metastases. With the first five doses, Sm-153 lexidronam clearly reduced his bone pain and improved his quality of life, as determined by pain-assessment scores and the patient's self-assessment of its effect on his ability to perform activities of daily living. With doses 6 through 11, pain at baseline was on average less, and as a result beneficial effects after treatment were not as apparent. Samarium-153 lexidronam produced transient decreases in the leukocyte and platelet counts, but these never became low enough to cause clinical concern. This case shows both the efficacy and the safety of Sm-153 lexidronam in repeated treatments for metastatic bone pain in patients with prostate cancer.     

153Sm]EDTMP: a potential therapy for bone cancer pain.

Reactor-produced samarium-153 (153Sm) is both a beta and gamma emitter with a physical half-life of 46.3 hours. When complexed with EDTMP, more than 50% of the administered dose localizes in bone. A therapeutic trial on patients with painful bone metastases performed at the University of Missouri produced relief in 65.4% of the patients who were evaluable. Myelotoxicity was mild and transient. For [153Sm]EDTMP to attain clinical utility, studies demonstrating its efficacy as an analgesic must be performed to exclude a "ligand analgesic effect".     

Outcome and toxicity associated with maximum safe dose radioiodine treatment of metastatic thyroid cancer

PURPOSE: This study was designed to determine the outcomes of patients referred to the authors' nuclear medicine service for dosimetric evaluation and treatment of metastatic thyroid cancer with radioiodine I-131. In addition, the incidence and severity of hematologic toxicity associated with treatment were determined. METHODS: A retrospective review of patients referred for dosimetric evaluation was undertaken for the years 1984 to 2000. Chart reviews were performed for 20 patients treated with at least 80% of the calculated maximum safe dose. Outcomes were evaluated for 15 patients for whom sufficient follow-up information was available. The incidence and severity of hematologic toxicity were determined for 12 of the 20 patients. RESULTS: Outcomes were defined as good, fair, or poor. One third of the patients had good, one third had fair, and one third had poor outcomes. Three patients experienced anemia, but no life-threatening hematologic toxicity was observed in any of the patients. Serum thyroglobulin measurements proved to be an efficacious way to predict outcome. The use of recombinant human thyrotropin appears to have increased the sensitivity of the thyroglobulin measurements. CONCLUSIONS: Radioiodine I-131 treatments produce variable outcomes in patients with advanced disease. Hematologic toxicity is well controlled in patients if dosimetric guidelines are followed. I-131 treatment appeared to retard the progression of metastatic thyroid cancer in 50% of the patients who were not cured. Radioiodine doses may be increased to improve efficacy without associated irreversible toxicity.     

186Re-etidronate in breast cancer patients with metastatic bone pain.

The aim of this study was to evaluate the efficacy of 186Re-1,1-hydroxyethylidene diphosphonate (etidronate) in breast cancer patients with painful bone metastases. METHODS: Thirty patients with advanced breast cancer who had metastatic bone pain were treated with 186Re-etidronate using different dosages in a noncomparative, open-label study. Twenty-four patients were evaluated for efficacy (6 patients had incomplete datasets). Dosages varied from 1295 to 2960 MBq (35 to 80 mCi). Efficacy was evaluated according to the multidimensional pain model using a paper-and-pencil diary. The diary was kept twice daily for 8-10 wk (2 wk before through 6-8 wk after 186Re-etidronate treatment). Response was determined with a strict criteria, in which pain intensity (PI), medication index (MI) and daily activities (DA) were core determinants. Response was defined as: (a) Reduced PI > or = 5% while MI and DA were at least constant; or (b) Reduced PI <25% in combination with improvement of MI or DA > or = 25%, without worsening of either factor. Duration of response should always exceed a minimum of 2 wk. RESULTS: Fifty-eight percent (n = 14) of all patients reported a response. The maximum follow-up period was 8 wk. Duration of response ranged from 2 to 8 wk (mean 4 wk). Patients (14/24) not only experienced considerable pain reduction, but in 12 patients this was also accompanied by noteworthy reduction in MI (> or = 25%). No clear dose-response relationship was found. CONCLUSION: With strict pain assessment criteria, 186Re-etidronate showed a response of 58% in the palliative treatment of metastatic bone pain originating from breast cancer.     

Phase I pharmacokinetic and biodistribution study with escalating doses of 223Ra-dichloride in men with castration-resistant metastatic prostate cancer

Purpose

²²³Ra-Dichloride (²²³Ra) is a novel bone-seeking alpha-emitter that prolongs survival in patients with castration-resistant metastatic prostate cancer. We conducted a study to better profile the pharmacokinetics, pharmacodynamics, and biodistribution of this agent.

Methods

Ten patients received either 50, 100, or 200 kBq of ²²³Ra per kilogram of body weight. Subsequently, six of these ten patients received a second dose of 50 kBq/kg. Pharmacokinetics and biodistribution were assessed by serial blood sampling, planar imaging, and whole-body counting. Pharmacodynamic assessment was based on measurements of prostate-specific antigen, bone alkaline phosphatase, and serum N-telopeptide. Safety was also assessed.

Results

Pharmacokinetic studies showed rapid clearance of ²²³Ra from the vasculature, with a median of 14 % (range 9–34 %), 2 % (range 1.6–3.9 %), and 0.5 % (range 0.4–1.0 %) remaining in plasma at the end of infusion, after 4 h, and after 24 h, respectively. Biodistribution studies showed early passage into the small bowel and subsequent fecal excretion with a median of 52 % of administered ²²³Ra in the bowel at 24 h. Urinary excretion was relatively minor (median of 4 % of administered ²²³Ra). Bone retention was prolonged. No dose-limiting toxicity was observed. Pharmacodynamic effects were observed (alkaline phosphatase and serum N-telopeptides) in a significant fraction of patients.

Conclusion

²²³Ra cleared rapidly from plasma and rapidly transited into small bowel, with fecal excretion the major route of elimination. Administered activities up to 200 kBq/kg were associated with few side effects and appeared to induce a decline in serum indicators of bone turnover.     

Clinical role of Sm-153 EDTMP in the treatment of painful bone metastatic disease

PURPOSE: Sm-153 EDTMP is an effective treatment of painful bone metastases from different neoplasms. However, there are few studies describing clinical experience with this therapeutic modality. The aim of this clinical study was to evaluate the efficacy of Sm-153 EDTMP in a group of patients with skeletal metastases and poor pain control with conventional therapies. MATERIALS AND METHODS: Sixty-four patients with painful bone metastases treated with Sm-153 EDTMP were retrospectively evaluated. Nine patients were treated twice. The most common primaries were breast in 28 cases (44%) and prostate in 27 (41%). Treatment efficacy was assessed by a visual analog scale, analgesic consumption, and performance status before and after treatment. Response was graded as complete, moderate, or minor. Toxicity evaluation included analytic parameters (blood counts, renal function) and clinical follow up. RESULTS: Efficacy and toxicity were evaluated separately for each dose (total doses: 73), and complete follow up was only possible in 62 of 73 administrations. The response rate was 85% (21% complete, 40% moderate, and 24% minor). Onset of improvement took place a median of 7 days after Sm-153 EDTMP administration, and pain relief persisted for a mean of 3 months. No relevant toxicity was found in the early phase. Myelotoxicity appeared in 29% of the administrations and was mild in most cases (there was one case of grade 4 leukopenia). CONCLUSIONS: Sm-153 EDTMP is a good therapeutic option for patients with painful bone metastases. It is an effective treatment of pain relief without major secondary effects.     

89SrCl2与153Sm-乙二胺四亚甲基膦酸治疗骨转移癌的对比研究

目的 对比研究89SrCl2和153Sm-乙二胺四亚甲基膦酸(153Sm-EDTMP)治疗骨转移癌疗效.方法 120例骨转移患者随机分为89SrCl2治疗组和153Sm-EDTMP治疗组,分别为69例和51例,89SrCl2剂量为1.11～2.22 MBq/Kg,153Sm-EDTMP剂量为25.9～37.0 MBq/kg,3～6月复查SPECT,对止痛效果、转移灶变化及不良反应进行比较分析.结果 89SrCl2组总有效率、显效、有效、无效分别为92.8%、69.6%、23.3%、7.2%;153Sm-EDTMP组的总有效率、显效、有效、无效分别为94.2%、66.7%、27.5%、5.8%,两组比较的差异无统计学意义(X2=4.98,P>0.05);89SrCl2治疗组骨转移病灶Ⅰ级(变淡,缩小或消失,无新增病灶出现)为56.5%,153Sm-EDTMP组为54.9%,两组比较的差异无统计学意义(X2=4.81,P>0.05);骨髓抑制情况(白细胞和血小板中任一项降低)分别为40.8%和59.2%,两组比较的差异有统计学意义(X2=7.45,P<0.05).结论 153Sm-EDTMP和89SrCl2控制乳腺癌、前列腺癌及大多数肺癌骨转移疼痛有效,可根据经济条件选择相应药物.89SrCl2疗效持久,相对骨髓抑制较小,更安全可靠,可作为早期骨转移患者的首选药物.     

放射性药物治疗肿瘤骨转移性骨痛的作用

恶性肿瘤会发生骨转移,早期发现骨转移可以预防骨相关事件的发生,改善预后.用于治疗转移性骨痛的放射性核素有5大类:89Sr、153Sm、186Re/188Re、117Sn、31P.放射性药物治疗转移性骨痛的效果较好,尤其适用于成骨性或混合型骨转移.放射性药物联合双磷酸盐药物治疗广泛转移性骨痛效果显著,优于两者的单独使用,明显改善患者生存质量.     

Dosimetry-guided radioactive iodine treatment in patients with metastatic differentiated thyroid cancer: largest safe dose using a risk-adapted approach.

This study is a retrospective analysis of 124 differentiated thyroid cancer patients who underwent dosimetric evaluation using MIRD methodology over a period of 15 y. The objectives of the study were to demonstrate the clinical use of dosimetry-guided radioactive iodine ([RAI] (131)I) treatment and the safe and effective application of a 3-Gy bone marrow (BM) dose in patients with differentiated thyroid cancer. METHODS: Tumor and BM dose estimates were obtained. The administered activity that would deliver a maximum safe dose to the organ at risk (red BM or lungs) was determined as well as the resulting doses to the metastases. The clinical benefit of an individual RAI treatment was predicted on the basis of the dose estimates and the expected therapeutic response. Each patient's response to treatment was assessed clinically and by monitoring the hematologic profile. RESULTS: One hundred twenty-four patients underwent 187 dosimetric evaluations. One hundred four RAI treatments were performed. A complete response at metastatic deposits was attained with absorbed doses of >100 Gy. No permanent BM suppression was observed in patients who received absorbed doses of <3 Gy to BM. The maximum administered dose was 38.5 GBq (1,040 mCi) with the BM dose limitation. CONCLUSION: Dosimetry-guided RAI treatment allows administration of the maximum possible RAI dose to achieve the maximum therapeutic benefit. Estimation of tumor dose rates helps to determine the curative versus the palliative intent of the therapy.     

90Y radioembolization of metastatic breast cancer to the liver: toxicity, imaging response, survival

PURPOSE: To present data from patients with breast cancer liver metastases who underwent radioembolization with yttrium (90Y) microspheres. MATERIALS AND METHODS: Using standard 90Y lobar treatment protocol, 27 female patients with progressing liver metastases on standard of care polychemotherapy were treated under an open-label phase 2 protocol. After treatment, we assessed (a) tumor response using computed tomography and/or positron emission tomography, (b) biochemical toxicity, and (c) survival. RESULTS: The mean age of the patients was 52. Seventeen (63%) patients received 20 left lobe treatments (median radiation dose, 123 Gy; mean, 119 Gy), and 20 (74%) patients received 22 right lobe treatments (median radiation dose, 121 Gy; mean, 109 Gy) to the treatment site. No significant dose-difference was noted between the two lobes (P=.69). Tumor response on 90-day follow-up computed tomography showed (a) complete and partial response in nine (39.1%) patients, (b) stable disease in 12 (52.1%) patients, and (c) progressive disease in 2 (8.8%) patients. Positive tumor response on positron emission tomography was noted in 17 (63%) patients. Three of 27 (11%) patients (Eastern Cooperation Oncology Group 1, 2, or 3) showed bilirubin toxicity of grade 3, all of which were attributed to disease progression. Median survival for Eastern Cooperation Oncology Group 0 versus 1, 2, or 3 patients was 6.8 months and 2.6 months, respectively (P=.24) and for patients with tumor burden<25% versus >25% was 9.4 and 2.0 months, respectively (P=.46). CONCLUSIONS: Radioembolization with 90Y brachytherapy device may be a viable therapeutic option for the treatment of breast cancer liver metastases in patients who have progressed or failed on standard of care polychemotherapy.     

Radioprotection and environmental pollution by the use of the radionuclides 89Sr, 186Re, and 153Sm for pain palliation in metastatic bone diseases. Related calculations

Due to the fact that the existing commercial analgesic drugs are not able to reduce effectively the pain caused by the metastatic bone disease, the use of radiopharmaceuticals with avidity to selectively localize in the metastatic skeletal sites, such as strondium-89 chloride (89Sr-Cl2), rhenium-186-hydroxy ethylene diphosphonate (186Re-HEDP), and samarium-153-ethylene diamine tetramethylene (153Sm-EDTMP), is widely accepted. However this medical application may be dangerous for the occupied personnel and more for general public, if radioactive waste is not properly disposed. In the following article we try to estimate the degree and the significance of that risk. For that reason we discuss the physical properties of these radionuclides and their distribution in the body of the patient. We conclude that 89Sr is not harmful for the physician, the attending personnel or those who live with the patient, because it radiates beta-radiation, while its gamma-radiation is negligeable. The radionuclides 186Re and 153Sm besides beta-radiation, also emit a perceptible amount of gamma-radiation. It has been shown that the exposure to gamma-radiation from these radionuclides of the physician, the attending personnel or those who live with the patient is very low as compared to the internationally accepted radioprotection limits. However the environmental contamination per treatment by either of these three radionuclides is not negligeable in comparison to the national and international accepted limits. Patients that are not in good clinical condition may pose an additional contamination danger to those attending them. For limiting radiocontamination, the annual number of treatments by the above three previous radionuclides, should be considered according to the ALARA principle in relation with the correct handling of these patients, and also considering the fundamentals of radioprotection.     

^89SrCl2与^153Sm-乙二胺四亚甲基膦酸治疗骨转移癌的对比研究

目的对比研究^89SrCl2和^153Sm-乙二胺四亚甲基膦酸（^153Sm-EDTMP）治疗骨转移癌疗效。方法120例骨转移患者随机分为SOSrCl2治疗组和^153Sm-EDTMP治疗组,分别为69例和51例,^89SrCl2剂量为1．11-2．22MBq／kg,^153Sm-EDTMP剂量为25．9～37．0MBq／kg,3-6月复查SPECT,对止痛效果、转移灶变化及不良反应进行比较分析。结果^89SrCl2组总有效率、显效、有效、无效分别为92．8％、69．6％、23．3％、7．2％;^153Sm-EDTMP组的总有效率、显效、有效、无效分别为94．2％、66．7％、27．5％、5．8％,两组比较的差异无统计学意义（χ^2=4．98,P〉0．05）;^89SrCl2治疗组骨转移病灶Ⅰ级（变淡,缩小或消失,无新增病灶出现）为56．5％,^153Sm-EDTMP组为54．9％,两组比较的差异无统计学意义（χ^2=4．81,P〉0．05）;骨髓抑制情况（白细胞和血小板中任一项降低）分别为40．8％和59．2％,两组比较的差异有统计学意义（r=7．45,P〈0．05）。结论^153sm-EDTMP和^89SrCl2控制乳腺癌、前列腺癌及大多数肺癌骨转移疼痛有效,可根据经济条件选择相应药物。^89SrCl2疗效持久,相对骨髓抑制较小,更安全可靠,可作为早期骨转移患者的首选药物。     

Osteoblastic response to successful treatment of metastatic cancer of the prostate.

Increasing sclerosis of bone in patients with prostatic cancer most commonly is associated with disease progression. In a study of serial radiographs in a group of 18 patients who experienced objective clinical remission after treatment of metastatic cancer of the prostate, eight (44%) showed an osteoblastic response as part of their healing reaction to successful therapy. The importance of a blastic response as a possible sign of clinical improvement is emphasized. Clinical, biochemical, and bone scan correlations are discussed as they apply to patients who respond favorably to treatment of metastatic cancer of the prostate.     

Usefulness of strontium-89 for bone pain palliation in metastatic breast cancer patients

Most studies of prostate cancer have shown that strontium-89 chloride (89Sr) is effective in the palliation of metastatic bone pain, refractory to conventional analgesia. The aim of this study was to evaluate the usefulness of 89Sr for bone pain palliation in breast cancer patients. Forty women were treated with 148 MBq of 89Sr. Six patients were retreated, receiving two or more doses. The Karnofsky performance status was assessed and pain and analgesia were scored on scales of 9 and 5 points, respectively. The efficacy of 89Sr was evaluated at 3 months of treatment. The response was good in 60% of the patients and partial in 32%; there was no response in the remaining 8% (pre-treatment Karnofsky < or = 60). The duration of the response was 120+/-143 days. In the patients retreated, the response was good in 83% and partial in 17%, without significant differences compared with the first dose, but the pre-treatment Karnofsky and the duration of the efficacy were lower (P < 0.05). A transient and slight decrease of leukocyte and platelet counts after the first month of treatment with 59Sr was observed. In conclusion, breast cancer patients with metastatic bone pain can benefit from therapy with 89Sr. If necessary, the treatment may be repeated safely and with the same efficacy as is achieved after the first dose. A low functional performance status could be a cause of the lower effectiveness of 89Sr.     

Skeletal uptake and soft-tissue retention of 186Re-HEDP and 153Sm-EDTMP in patients with metastatic bone disease.

The aim of this study was to introduce a new quantification method for 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) and 186Re-(tin)1,1-hydroxyethylidene diphosphonate (HEDP) to separately measure bone uptake and soft-tissue retention of these radiopharmaceuticals. METHODS: Studies were performed on 23 men and 6 women undergoing radionuclide therapy for palliation of bone pain. Whole-body images were acquired at 3 min, 3-4 h, and 24-72 h after injection of 1,295 MBq 186Re-HEDP and 37 MBq 153Sm-EDTMP per kilogram of body weight. The activities for whole body, urinary bladder, and both thighs, as representative of soft tissue, were measured by region-of-interest technique. A background region of interest adjacent to the head was used to correct for bremsstrahlung. Bone uptake was calculated as initial whole-body activity minus urinary excretion and remaining soft-tissue activity. RESULTS: For 186Re-HEDP (n = 11) the mean bone uptake at 3 h after injection was 13.7% +/- 8.6% of initial whole-body activity. The remaining soft-tissue activity was 49.4% +/- 16.9%, and urinary excretion was 36.9% +/- 14.4%. At 24 h after injection, bone uptake reached a value of 21.8% +/- 9.0%. Urinary excretion increased to 65.3% +/- 12.8% according to a decreasing soft-tissue remainder activity of 12.8% +/- 5.4%. The corresponding results for 153Sm-EDTMP (n = 18) at 3 h after injection were 29.2% +/- 15.5% for bone uptake, 32.3% +/- 12.9% for urinary excretion, and 38.4% +/- 14.5% for soft tissue. At 24 h after injection, we calculated values of 47.7% +/- 11.2% for bone uptake, 39.5% +/- 13.8% for urinary excretion, and 12.7% +/- 4.7% for soft tissue. CONCLUSION: Bone uptake and soft-tissue retention for both 186Re-HEDP and 153Sm-EDTMP as obtained in this study agree well with the conventional 24-h whole-body retention measurements for these tracers. However, by this new scintigraphic quantification method, bone uptake and soft-tissue retention can be calculated separately, thus providing more detailed kinetic data and potentially improving the dosimetry of these radiopharmaceuticals in, for example, assessment of radiation dosage to bone and bone marrow.     

Marrow toxicity of 33P-versus 32P-orthophosphate: implications for therapy of bone pain and bone metastases.

Several bone-seeking radiopharmaceuticals, such as 32P-orthophosphate, 89Sr-chloride, 186Re-1,1 hydroxyethylidene diphosphonate (HEDP), and 153Sm-ethylene diamine tetramethylene phosphonic acid (EDTMP), have been used to treat bone pain. The major limiting factor with this modality is bone marrow toxicity, which arises from the penetrating nature of the high-energy beta particles emitted by the radionuclides. It has been hypothesized that marrow toxicity can be reduced while maintaining therapeutic efficacy by using radionuclides that emit short-range beta particles or conversion electrons. In view of the significant clinical experience with 32P-orthophosphate, and the similarity in pain relief afforded by 32P-orthophosphate and 89Sr-chloride, this hypothesis is examined in this study using 32P- and 33P-orthophosphate in a mouse femur model. METHODS: Survival of granulocyte macrophage colony-forming cells (GM-CFCs) in femoral marrow was used as a biologic dosimeter for bone marrow. 32P- and 33P-orthophosphate were administered intravenously, and GM-CFC survival was determined as a function of time after injection and, at the nadir, as a function of injected activity. The kinetics of radioactivity in the marrow, muscle, and femoral bone were also determined. The biologic dosimeter was calibrated by assessing GM-CFC survival at its nadir after chronic irradiation of Swiss Webster mice with exponentially decreasing dose rates of gamma rays (relative biologic effectiveness equivalent to that of beta particles) from a low-dose rate 137Cs irradiator. Dose-rate decrease half-times (Td) (time required for 137Cs gamma ray dose rate to decrease by one half) of 62, 255, and 425 h and infinity were used to simulate the dose rate patterns delivered by the radiopharmaceuticals as dictated by their effective clearance half-times from the mouse femurs. These data were used to experimentally determine the mean absorbed dose to the femoral marrow per unit injected activity. Finally, a theoretical dosimetry model of the mouse femur was developed, and the absorbed doses to the femoral marrow, bone, and endosteum were calculated using the EGS4 Monte Carlo code. RESULTS: When the animals were irradiated with exponentially decreasing dose rates of 137Cs gamma rays, initial dose rates required to achieve 37% survival were 1.9, 0.98, 0.88, and 0.79 cGy/h for dose rate decrease half-times of 62, 255, and 425 h and infinity, respectively. The D37 values were 144 +/- 15, 132 +/- 12, 129 +/- 3, and 133 +/- 10 cGy, respectively, compared with a value of 103 cGy for acute irradiation. When 32P and 33P were administered, the injected activities required to achieve 37% survival were 313 and 2,820 kBq, respectively. Theoretical dosimetry calculations show that 33P offers a 3- to 6-fold therapeutic advantage over 32P, depending on the source and target regions assumed. CONCLUSION: The low-energy beta-particle emitter 33P appears to offer a substantial dosimetric advantage over energetic beta-particle emitters (e.g., 32p, 89Sr, 186Re) for irradiating bone and minimizing marrow toxicity. This suggests that low-energy beta or conversion electron emitters may offer a substantial advantage for alleviation of bone pain as well as for specifically irradiating metastatic disease in bone.