Clinical And Foundation Research Of ¹⁸⁸Re-HEDP In Patients For Palliation Of Bone Pain From Osseous Metastases

The incidence of cancer continues to increase.The combination of strong advances in therapeutics and the earlier diagnosis of the primary cancers have led to increasing median survival times for patients with metastatic disease.Bone pain is a common symptom in advancing malignancy and often determines quality of life in the later stages of disease.The long-term management of refractory bone pain requires a multidisciplinary approach and close cross-specialty liaisons.The aim of the studies is to research anthropometric safety,clinical pharmacology,dosimetry,effect of alleviation,and radiation hazards to surrounding people and environment of ¹⁸⁸Re-HEDP in palliation of bone pain from osseous metastases,and the impacts of ¹⁸⁸Re-HEDP on osteoblasts in vitro,to supply theoretical evidences for clinical applications of ¹⁸⁸Re-HEDP,such as dose regimens,optimal dose of ¹⁸⁸Re-HEDP and announcements,radioprotection after therapy et al.Partâ… Tolerance of ¹⁸⁸Re-HEDP in patients with bone pain from osseous metastasesPurpose To study the toleration of ¹⁸⁸Re-HEDP in different type of advanced cancer patients with osseous metastases who are suffering form bone pain.Methods Thirty-one patients(prostate cancer in 10 patients,breast cancer in 9 patients, lung cancer in 3 patients,liver cancer in 5 patients,rectal cancer in 2 patients, esophageal cancer in 1 patient,and renal carcinoma in 1 patient) received a single injection of escalating doses of ¹⁸⁸Re-HEDP.Dose was divided into four groups from 20MBq/kg(6 patients),30MBq/kg(6 patients),40MBq/kg(9 patients),to 50MBq/kg (10 patients).Haematological toxicity(WHO grading) of grade 3 or 4 was considered unacceptable.Vital sign and adverse effects after injection were recorded closely within 8 weeks.Blood counts were measured weekly over a period of 8 weeks. Biochemical parameters and electrocardiogram were detected at week 4 and 8. Statistical analysis was performed only with Per-Protocol population.Results Twenty seven patients belonged to Per-Protocol population.The group of 20MBq/kg included 5 patients;the group of 30MBq/kg included 5 patients;the group of 40MBq/kg 8 patients,and 50MBq/kg 9 patients.Adverse effect and clinically significant change in vital sign,electrocardiogram,liver and renal function weren't observed in different groups aftertherapy.Alkaline phosphataes(ALP) slightly rised aftertherapy at week 4 and 8(compared with baseline),but no statistical significance was found.In the 20MBq/kg group,a reversible leucopenia of grade 1 was noted only in one patient.In the 30MBq/kg group,two patients showed a reversible leucopenia of grade 1 and one of them combining a reversible thrombopenia of grade 3 again.In the 40MBq/kg group,a reversible leucopenia and thrombopenia of grade 1 were observed in one patient,a reversible leucopenia and thrombopenia of grade 2 in another patient.In the 50MBq/kg group,three patients showed a reversible leucopenia of grade 2.The overall nadir of thrombopenia was at week 4,leucopenia at week 6 and anaemia at week 8.At week 8,the level of mean platelet and leucocyte returned to baseline."Bone flare phenomenon"was found in two of 27 patients with a incidence of 7%.Conclusions There were not significant side effects in patients with painful osseous metastases,who received a single injection of ¹⁸⁸Re-HEDP with dose from 20MBq/kg, to 50MBq/kg.Bone marrow depression was temperate and temporal.Partâ…¡Parmacokinetics of ¹⁸⁸Re-HEDP in patients with osseous metastasesPurpose To investigate the biodistribution,excretion and pharmacokinetic parameters, of ¹⁸⁸Re-HEDP in different type of advanced cancer patients with osseous metastases who are suffering form bone pain.Methods All patients were hospitalized for 72 h.A single dose(20MBq/kg, 30MBq/kg,40MBq/kg and 50MBq/kg,10 patients in every group) of ¹⁸⁸Re-HEDP was administered as a bolus injection,meanwile dynamic images were collected for 30 min (matrix:256×256;15s/frame),placing the dectecer on patient's chest including heart, lung,liver,sleep and kidney,using a tri-head,large-field-of-view SPECT.Anterior and posterior whole-body images(185cm/min) and static images(15s/frame) on chest were obtained at 1h,2h,4h,5h,12h,24h,36h,48h,60h and 72h after injection of ¹⁸⁸Re-HEDP.A 20%window was centered around a peak of 155 keV.A high-energy collimator was used to reduce the effect of the bremsstrahlung to the image quality.Dynamic and static images were used to draw left cardiac ventricle ROIs. From the ROIs,the curve of time-background corrected counts of left cardiac ventricle can be generated,which was regarded as curve of time-blood drug concentration. Pharmacokinetics parameters were analyzied by Pkanalyst soft.Whole-body scintigraphy was used to draw ROIs to determine counts over total wholebody and varios organs at 1h,2h,4h,5h,12h,24h,36h,48h,60h and 72h.The corrected counts of varios organs and total wholebody,which was calculated as a geometric mean using the anterior and posterior scans,were transformed to the percentage injected dose (%ID).Urine was collected at 1h,2h,4h,5h,12h,24h,36h,48h,60h and 72h after injection of ¹⁸⁸Re-HEDP.Counts of urine were measured byγcounter.The curve of time-%ID of accumulated urine was drawed.Only Per-Protocol population underwent statistical analysis.Results thirty-three patients belonged to Per-Protocol population with prostate cancer in 3 patients,breast cancer in 10 patients,lung cancer in 7 patients,liver cancer in 9 patients,other cancer in 4 patients.Linear relationship of metabolism of ¹⁸⁸Re-HEDP was observed in the dose from 20 MBq/kg to 50MBq/kg,with correlation coefficient R²=0.9376.A two compartment model was the best fit for metabolism of ¹⁸⁸Re-HEDP with the parameters median AUC 3.32E+05,3.97E+05,7.83E+05,8.58E+05 respectivly;medianα0.06,0.05,0.04,0.06 respectivly;medianβ1.16E-03, 1.16E-03,1.03E-03,1.15E-03 respectivly;median A 3591.21,4858.23,5642.48, 4167.05 respectivly;median B 293.97,352.95,614.41,1063.82 respectivly;median T_1/2(α)12.55,12.83,15.41,12.02 respectivly;median T_1/2(β)595.47,596.50,673.09, 600.93(min) respectivly in the dose of 20MBq/kg,30MBq/kg,40MBq/kg,and 50MBq/kg.Gamma camera images and calculated%ID of various organs showed that ¹⁸⁸Re-HEDP was taked up mainly by bone up to 40%at hour 4,and excreted mainly by uropoietic system.The urinary excretion of ¹⁸⁸Re-HEDP was rapid.Urine profile showed that 66.79%of ID was eliminated within 24 hours,being its 74% collected along the first 5 hours after-administration.Conclusions In the dose of 20 MBq/kg,30 MBq/kg,40 MBq/kg and 50MBq/kg, metabolism of ¹⁸⁸Re-HEDP present linear model.Pharmacokinetics of ¹⁸⁸Re-HEDP follows a two-compartment model administrated by blood vessel.Following injection, ¹⁸⁸Re-HEDP was taked up mainly by bone and excreted by uropoietic system,Partâ…¢Dosimetry of ¹⁸⁸Re-HEDPPurpose To investigate dosimetry of ¹⁸⁸Re-HEDP in patients with different type of advanced cancer for the palliation of painful bone metastases.Methods Nine patients,with prostate cancer in 1 patient,breast cancer in 4 patients, lung cancer in 2 patients,liver cancer 1 patient,laryngeal cancer 1 patient,were studied. All patients were hospitalized for 72 h.A single dose of ¹⁸⁸Re-HEDP of 50MBq/kg was administered as a bolus injection.Anterior and posterior whole-body images (185cm/min) were obtained using a tri-head,large-field-of-view SPECT at 1h,2h,4h, 5h,12h,24h,36h,48h,60h and 72h after injection of ¹⁸⁸Re-HEDP.A 20%window was centered around a peak of 155 keV.A high-energy collimator was used to reduce the effect of the bremsstrahlung to the image quality.The corrected counts of varios organs and total wholebody at different time from ROIs,which was calculated as a geometric mean using the anterior and posterior scans,were transformed to the percentage injected dose(%ID).Retention time in total wholebody as well as varios organs was calculated.The MIRD formulation was applied to calculate the absorbed radiation dose for various organs.Results The highest absorbed dose was received by the bladder(8.2E-01±1.3E-01) mGy/MBq followed by the bone(7.1E-01±3.5E-01) mGy/MBq,the rad bone marrow (6.2E-01±3.2E-01) mGy/MBq,the kidneys(2.5E-01±1.1E-01) mGy/MBq,the total body(7.0E-02±4.0E-02) mGy/MBq,the testis(3.4E-02±1.8E-02) mGy/MBq,the ovary(2.7E-02±1.8E-02) mGy/MBq,the liver(2.4E-02±1.8E-02) mGy/MBq and the lung(2.3E-02±1.2E-02) mGy/MBq.Total marrow absorbed dose in patient with 60 kg weight was 0.74Gy,1.12Gy,1.49Gy,and 1.86 Gy after a single administration of ¹⁸⁸Re-HEDP with the dose of 20 MBq/kg,30 MBq/kg,40 MBq/kg and 50MBq/kg respectively.Maximum total absorbed dose to testis and ovary was 0.09Gy and 0.06Gy,which were far less than 0.15Gy(testis) and 2.5Gy(ovary) that can result in infertility.Conclusions The absorbed dose of target organ bone was greater than that of radiation sensitive organ such as bone marrow,testis and ovary.The obsorbed dose to bone marrow,ovary and testis was similar to congener literatures.Partâ…£Pain Palliation Effect of ¹⁸⁸Re-HEDP and impact on the general status in patients with painful bone metastasesPurpose To investigate pain palliation effect of ¹⁸⁸Re-HEDP in patients with painful bone metastases form various tumor types,and impact of ¹⁸⁸Re-HEDP on the general status in all these patients.Methods Thirty-one patients(prostate cancer in 10 patients,breast cancer in 9 patients, lung cancer in 3 patients,liver cancer in 5 patients,rectal cancer in 2 patients, esophageal cancer in 1 patients,and renal carcinoma in 1 patients) received a single injection of escalating doses of ¹⁸⁸Re-HEDP.Dose was divided into four groups including 20MBq/kg(6 patients),30MBq/kg(6 patients),40MBq/kg(9 patients),and 50MBq/kg(10 patients).The pain scores were recorded before therapy(baseline level) and 1d,2d,3d,1w,2w,3w,4w,6w,and 8w after injection.Karnofsky performance scores were recorded before therapy(baseline level) and1w,2w,3w,4w,6w,and 8w after injection.Paired t test was applied to analyze the change of score.Pain response was scored by a four-point pain-rating scale as complete,marked,mild and no response.Results The pain score descended from baseline level of 8.11 to 7.74 at the same day of therapy,the nadir of 4.89 at week 4,and up to 6.67 at week 8 after therapy(p＜0.05, between scores before and after therapy).Karnofsky performance scores continued increasing from baseline level of 74.81 to 82.31 at week 8(p＜0.05,between scores before and after therapy).An overall response rate of 74.08%,mean last time of 6.85w and mean start time of 4.05 d were observed after a single injection.Response rate included complete response rate of 7.41%,marked response rate of 25.93%,mild response rate of 40.74%.Of the specific tumor types,pain relief was achived in 89.89%of patients with prostate cancer,in 75.50%with breast cancer,in 66.67%with lung cancer and liver cancer respectively.Of the different groups,overall respons rate of 40.00%in 20MBq/kg group,of 60.00%in 30MBq/kg group,of 87.50%in 40MBq/kg group,of 89.89%in 50MBq/kg group,were observed after a single injection.Conclusions ¹⁸⁸Re-HEDP is a useful radiopharmaceutical agent to improve bone pain and general status of patients with painful bone metastases from various tumor types.Partâ…¤Radiation hazards of ¹⁸⁸Re-HEDP to surrounding staff and environment during Clinical applicationPurpose To assess the external radiation dose equivalent and dose equivalent rate to surrounding staff and environment exposed to ¹⁸⁸Re-HEDP clinical application. Methods Dose was divided four groups including 20MBq/kg,30MBq/kg,40MBq/kg, and 50MBq/kg of ¹⁸⁸Re-HEDP,with 5 patients in every group.During 20 clinical applications,a directly readable digital dosimeter and formulas recommended by ICRP were used to measure and calculate radiation dose equivalent rate and dose equivalent to operator who was oprating in different shielding conditions.The shielding conditions consisted of no lead glass and no lead clothes shielding,no lead clothes only shielding by lead galss,and shielding by both lead glass and lead clothes.A directly readable digital dosimeter was used to measure radiation dose equivalent rate on surrounding environment in 1h,2h,4h,5h,12h,24h,36h,48h,60h and 72h after therapy at part of 0m,0.5m,1m,1.5m,2m,2.5m and 3m from patients.Formulas recommended by ICRP were used to estimate radiation dose equivalent to accompanier after therapy.Results In one clinical application of ¹⁸⁸Re-HEDP(in group of 20MBq/kg,30MBq/kg, 40MBq/kg,and 50MBq/kg),the external radiation doses of 0.50±0.26μSv, 0.62±0.31μSv,0.84±0.50μSv and 1.35±0.50μSv respectively were detected to operator who was in shielding conditions by both lead glass and lead clothes;0.75±0.32μSv, 0.96±0.43μSv,1.38±0.56μSv and 1.70±1.14μSv to operator who was in shielding conditions only by lead glass;1.68±0.57μSv,2.22±0.83μSv,2.92±1.16μSv and 3.82±1.51μSv to operator who was not in shielding conditions.The time that external radiation dose equivalent rates to surrounding environment in the part of 1m from patients after injection of different does were less than standard limit of 2.5μSv/h,were at 4h,5h,12h,24h,with 2.3μSv/h,2.35μSv/h,2.06μSv/h,1.95μSv/h respectively.The external radiation dose equivalent of 58.51μSv,89.34μSv, 106.88μSv,and 158.62μSv respectively were estimated to accompanier who accompanied one patient f in different group for three days.Conclusions Both lead glass and lead clothes can shield more half of radiation dose. Small external radiation dose equivalent to operator who was shieled by both lead glass and lead clothes,and accompanier were detected during ¹⁸⁸Re-HEDP clinical applications.We recommended that the patient after therapy with ¹⁸⁸Re-HEDP should be radiationly isolated for one day. Partâ…¥Impacts of ¹⁸⁸Re-HEDP on proliferation and cell cycle of osteoblasts in vitroRadionuclide therapy for bone pain palliation has been used successfully for more than 30y.However,the effect of radionuclide on osteoblasts is unclear.This study is to examine the growth,proliferation and the cell cycle distribution of osteoblasts irradiated by¹⁸⁸Re-HEDP in different activity.Methods Osteoblasts from SD rat were cultured in vitro.The growing osteoblasts from the fifth generation were cultured with ¹⁸⁸Re-HEDP in different activity(0.00,1.85, 9.61,48.00,240.50,462.50,832.50,1110.00 kBq/ml) at the same condition.Then the capability of osteoblasts to intake the ¹⁸⁸Re-HEDP were examined by detectingγcounts of osteoblasts;the growth of osteoblasts were detected by method of MTT; differentiation by ALP.The cell cycle distribution of osteoblasts irradiated by¹⁸⁸Re-HEDP in different activity(0.00,1110.00,5550.00,33300.00,44400.00 kBq/ml) were examined by flow cytometry.Results The ability of osteoblasts to intake ¹⁸⁸Re-HEDP(0～1110 kBq/ml) is strong. The growth and differentiation of osteoblasts were encouraged by ¹⁸⁸Re-HEDP in the range of 0～1110 kBq/ml.Irradiated by ¹⁸⁸Re-HEDP the cells of S period augmented. More than 33,300 kBq/ml,¹⁸⁸Re-HEDP may provoke apoptosis of osteoblasts and the apoptosis rate increased with the activity.Conclusion Under 1,110 kBq/ml,¹⁸⁸Re-HEDP may enhance the growth,proliferation, differentiation of osteoblasts;only over 33,300 kBq/ml,appeared the apoptosis of osteoblasts.