Rhenium-188 radiosynovectomy for chronic haemophilic synovitis: Evaluation of its safety and efficacy in haemophilic patients.

INTRODUCTION: Radiocolloids labelled with less costly and more accessible radionuclides such as rhenium-188 are of interest to developing countries compared with those labelled with rhenium-186 and yttrium-90. AIM: This study was aimed to evaluate the efficacy and safety of radiosynovectomy using rhenium-188 in patients with chronic haemophilic synovitis and recurrent hemarthrosis. METHODS: In this quasi-experimental prospective study, 20 haemophilic patients were evaluated at preinjection, and at 1, 3, 6 and 12 months after injection. Magnetic resonance imaging (MRI) was done to measure synovial thickness and to calculate Denver score. Joint radiographs were taken to measure the Pettersson score. The Gilbert questionnaire, Functional Independence Score in Hemophilia (FISH) and visual analogue scale (VAS) for pain were completed, and the number of bleeding episodes and factor consumption were recorded at each follow-up visit. RESULTS: The number of bleeding episodes, the amount of factor consumption per month, VAS pain scores and synovial thickness decreased significantly over time (P < .05). Gilbert and FISH scores showed significant improvement (P < .001). However, Pettersson score and Denver score showed no significant changes after injection. Minor complications including temporary pain and swelling occurred in 20% of patients, and no major complication was observed after rhenium-188 injection. CONCLUSION: Our results indicated high clinical impact, efficacy, safety and low invasion of rhenium-188 in radiosynovectomy of haemophilic patients. Considering the availability and relatively low cost of rhenium-188 in developing countries, this can be a good treatment option for haemophilic patients with recurrent hemarthrosis, particularly when the synovial hypertrophy is not massive yet.

The cluster [Re6Se8I6]3- induces low hemolysis of human erythrocytes in vitro: protective effect of albumin.

The cluster Re6Se8I63- has been shown to induce preferential cell death of a hepatic carcinoma cell line, thus becoming a promising anti-cancer drug. Whether this cluster induces acute hemolysis or if it interacts with albumin remains unclear. The effect of acute exposure of human red blood cells to different concentrations of the cluster with and without albumin is described. Red blood cells from healthy donors were isolated, diluted at 1% hematocrit and exposed to the cluster (25-150 µM) at 37 °C, under agitation. Hemolysis and morphology were analyzed at 1 and 24 h. The potential protection of 0.1% albumin was also evaluated. Exposition to therapeutic doses of the cluster did not induce acute hemolysis. Similar results were observed following 24 h of exposition, and albumin slightly reduced hemolysis levels. Furthermore, the cluster induced alteration in the morphology of red blood cells, and this was prevented by albumin. Together, these results indicate that the cluster Re6Se8I63- is not a hemolytic component and induces moderate morphological alterations of red blood cells at high doses, which are prevented by co-incubation with albumin. In conclusion, the cluster Re6Se8I63- could be intravenously administered in animals at therapeutic doses for in vivo studies.

Endovascular brachytherapy using liquid Beta-emitting rhenium-188 for the treatment of long-segment femoropopliteal in-stent stenosis.

PURPOSE: To evaluate the efficacy and safety of endovascular brachytherapy with liquid beta-emitting rhenium-188 (Re-188) in patients with long-segment in-stent stenosis in the femoropopliteal segment. METHODS: From July 2009 to April 2011, 90 consecutive patients (59 men; mean age 68.3±10.3 years, range 43-86) with symptomatic in-stent stenosis/occlusion (24.6-cm mean lesion length) of the femoropopliteal segment underwent angioplasty and subsequent endovascular brachytherapy. The liquid beta-emitting Re-188 was applied to the target lesion within an angioplasty balloon using a dose of 13 Gy at a depth of 2 mm into the vessel wall. Clinical and angiographic follow-up data were collected up to 2 years. The main study endpoints were the 6- and 12-month primary patency rates defined as <50% in-stent stenosis as detected by duplex ultrasound. Clinical endpoints were the cumulative rates of death, amputation, and bypass surgery, as well as improvement in the Rutherford category and the ankle-brachial index. Results were correlated with patient and lesion characteristics. RESULTS: Primary technical success was achieved in all patients, with 1 early stent thrombosis, but no other complications related to the irradiation. Eighty-eight patients reached the 6-month and 82 the 12-month examinations; the primary patency was 95.2% and 79.8%, respectively. In-stent stenosis occurred in 9 patients, while 10 patients had reocclusion of the treated segment. During follow-up, there were 2 late acute thrombotic occlusions, both after discontinuation of clopidogrel. The clinical status improved in 67.0% and 62.2% of the patients after 6 and 12 months, respectively. No patient, lesion, or procedure variables were predictive of restenosis after EVBT. CONCLUSION: EVBT with liquid beta-emitting Re-188 was safe and effective in preventing restenosis in long-segment femoropopliteal ISS.

Efficacy of radiosynovectomy in rheumatoid arthritis.

In this retrospective study, we evaluated the effect of radiosynovectomy of patients with rheumatoid arthritis. Radiosynovectomy was performed in 577 joints of 137 rheumatoid patients. We applied 185 MBq yttrium-90 in knees (n = 58), 74-111 MBq rhenium-186 colloids in ankle (n = 50), wrists (n = 43) and shoulders (n = 35), and 15 to 37 MBq in finger (n = 298) and toe joints (n = 46). The effect of radiosynovectomy was scored in 4 subjective categories: excellent response (no symptoms); good response (significant reduction of symptoms); moderate response (slight decrease); and bad response (no change or worsening), of pain and/or swelling in treated joint 3 months after the procedure. Excellent or good response was observed in 57% of treated knees, 63% of shoulders, 60% of wrists, 64% of ankles, 54% of thumb bases, 55% of MCP's, 54% of PIP's, 53% of DIP's, and 54% of MTP's. Side effects associated to the RSO, i.e., swelling or transient increase of pain, were recorded in 7% of the patients that resolved within 1 month. No patient had any non-reversible skin alteration after treatment, only slight erythema was observed in 5 patients. Radiosynovectomy is effective and safe in the treatment of rheumatoid arthritis.

Long-term evaluation of chromosomal breakages after radioisotope synovectomy for treatment of target joints in patients with haemophilia.

Radioisotope synovectomy (RS) is defined as the intra-articular injection of radioisotopic agents with the aim of fibrosis on hypertrophic synovium in the target joint. The aim of this study was to investigate genotoxic effects on lymphocytes and malign transformation induced by Yttrium(90) (Y(90)) and Rhenium(186) (Re(186)) in children with haemophilia undergone RS. Forty haemophilia patients were enrolled. The mean age was 16.4 +/- 6.2 years (range: 8-40). Y(90) was used for knees, Re(186) was used for other joints. For safety, cytogenetic analysis was performed to determine potential chromosomal changes after RS procedure at three different time points as prior to procedure, 3rd day and 90th day. For the stimulation of chromosomal breakages, diepoxybutane was used (DEB test). Chromosomal breakages (CBs) were found in 23 patients (67.6%) prior to RS. We have found CBs additionally in nine of 11 patients who had no CBs prior to RS after 3 days of radioisotope exposure. At that time, the patients who had CBs were 29 (85.2%). At day 90, only 21 patients revealed (61.7%) CBs. The mean frequency of CBs slightly but not significantly increased in the 3rd day. However, there was a significant decreasing trend between 3rd and 90th days. Radioisotope synovectomy with Y(90) and Re(186) does not seem to induce the genotoxic effects significantly on peripheral blood lymphocytes. However, CBs even after one year in the re-evaluation of four patients, significant decrease in the number of CBs between the 3rd and 90th days and de novo CBs after exposure may be accepted as warning signals for young population. It should also be pointed out that families and patients be informed properly related with historical and potential dangers of radioisotopic agents.

[Cellular damage in vitro]. / Einfluss der mittleren Betaengergie und der intrazellulären Radionuklidaufnahme auf die Zellschädigung in vitro.

AIM: The cellular damage of ionising radiation depends on dose, physical radiation quality (e. g. LET) and intracellular radionuclide uptake. The influence of two beta emitters (188Re and 131I) on the thyroid cell line PCCl3 was studied. Furthermore, we analysed the effect of intracellular accumulation. METHODS: The thyroid cell line PCCl3 was irradiated with 188Re-perrhenate or 131I-sodium iodide in presence or absence of perchlorate. The initial DNA-damage was measured in the comet assay as olive tail moment (OTM). The colony forming assay detects the clonogenic cell survival as surviving fraction. Additional the intracellular radionuclide uptake was quantified. RESULTS: Dose response curves were established for irradiation with 188Re-perrhenate or 131I-iodine under various extra- and intracellular activity distribution conditions. In the presence of perchlorate DNA-damage and clonogenic cell survival for both radionuclides were comparable. In the absence of perchlorate radionuclide uptake of 1.39% (131I) and 4.14% (188Re) were measured causing twofold higher radiotoxicity. Although 131I uptake was lower than 188Re uptake the OTM values were higher und surviving fractions were lower. CONCLUSIONS: 131I, compared to 188Re, has lower mean beta energy and a higher LET, and therefore, it induced a higher DNA-damage even at lower intracellular uptake. An additional explanation for the higher radiotoxicity of 131I could be the higher dose exposition caused by cross-fire through neighborhood cells.

Radiation safety considerations for the bone seeking radiopharmaceuticals. 89SrCl2, 186Re-HEDP and 153Sm-EDTMP.

UNLABELLED: The radiation exposure to bystanders from 89SrCl2, 186Re-HEDP and 153Sm-EDTMP, is generally thought to be caused by "bremsstrahlung" and gamma-radiation, with negligible contribution from beta-radiation. The latter assumption may be erroneous. The aim of this prospective study was the investigation of radiation safety after treatment with these radiopharmaceuticals. The radiation field around treated patients was characterized and the magnitude estimated. PATIENTS, METHODS: 33 patients (30 prostate carcinoma, 3 breast carcinoma) were treated with 150 MBq 89SrCl2 (9 patients), 1295 MBq 186Re-HEDP (12 patients) or 37 MBq/kg 153Sm-EDTMP (12 patients). External exposure rates at 30 cm from the patient were measured at times 0 to 72 h post-injection. To evaluate the respective contribution of Bremsstrahlung, beta- and gamma-radiation, a calibrated survey meter was used, equipped with a shutter. For each patient, the measured exposure rate-versus-time data were fit to a curve and the curve integrated (area under the curve) to estimate the total exposure. RESULTS: For 29/33 patients the total ambient equivalent doses (mean+/-1 standard deviation [SD]) based on the integral of the fitted curve were 2.1+/-1.2 mSv for 89SrCl2, 3.3+/-0.6 mSv for 186Re-HEDP and 2.8+/-0.6 mSv for 153Sm-EDTMP. Beta-radiation contributes significantly to these doses (>99% for 89SrCl2, 87% for 186Re-HEDP and 27% for 153Sm-EDTMP). The effective doses (at 30 cm) are <0.1 mSv for 89SrCl2, 0.3 mSv for 186Re-HEDP and 1.6 mSv for 153Sm-EDTMP. CONCLUSION: Patients treated with 89SrCl2, 186Re-HEDP or 153Sm-EDTMP emit a spectrum of radiation, including non-negligible beta-radiation. With specific instructions effective doses to bystanders are acceptable.

[Radiation exposure of staff during endovascular brachytherapy with Re-188 after PTA in the peripheral blood stream]. / Strahlenexposition des Personals bei der endovaskulären Brachytherapie (EVBT) mit Re-188 nach PTA im peripheren Stromgebiet.

Endovascular brachytherapy using a balloon catheter filled with Re-188 solution is a promising method for the prophylaxis of restenosis in peripheral blood circulation after percutaneous transluminal angioplasty (PTA) treatments. Thereby about 20 GBq Re-188 with a specific activity of about 5 GBq/ml are used. The high ionisation density of the beta radiation with high energy leads to selective irradiation of the blood vessel wall near the catheter, whereas the surrounding tissue remains almost unaffected. However the hospital staff has to carry out some work steps within close range to the high activity during preparation and therapy, causing a high risk of skin exposure, in particular at the hands. Estimations and measurements of the maximal local skin dose were made with thin-layered thermoluminescence dosimeters. It was assessed that the annual dose limit for skin of 500 mSv may be exceeded considerably when using conventional procedures and considering the expected number of 75 treatments per annum. By using the newly developed rhenium-188 application device "FlowMedical Application System" the exposure risk for the staff could be reduced drastically. The maximum skin dose of 76 mSv for the radiologist and of 50 mSv for the physicist was decreased to 2 mSv per treatment for both of them. Consequently, from the radiation protection point of view, the itm Rhenium-PTA is a safe method. Any exceeding of the dose limit can be prevented.

Two Cases of 188Re Microspheres for Inoperable Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies. Often, patients present with inoperable and advanced disease. Selective internal radionuclide therapy offers prolonged survival and improved quality of life by delivering high radiation dose to the tumor with minimal complications. We report 2 inoperable cases of HCC treated with therapeutic dose of indigenously developed Re microspheres delivered to the hepatic lesions by transarterial catheterization. Follow-up CT revealed necrosis within the lesion, suggesting response to selective internal radionuclide therapy. Re microspheres may be a potential treatment option for inoperable HCC with or without portal vein thrombosis.

Intra-arterial rhenium-188 lipiodol in the treatment of inoperable hepatocellular carcinoma: results of an IAEA-sponsored multination study.

PURPOSE: Intra-arterial injections (IAI) of 131I-lipiodol is effective in treating hepatocellular carcinoma patients, but is expensive and requires a 7-day hospitalization in a radioprotection room. 188Re is inexpensive, requires no patient isolation, and can be used with lipiodol. METHODS AND MATERIALS: This International Atomic Energy Agency-sponsored phase II trial aimed to assess the safety and the efficacy of a radioconjugate 188Re + lipiodol (188Re-Lip) in a large cohort of hepatocellular carcinoma patients from developing countries. A scout dose is used to determine the maximal tolerated dose (lungs <12 Gy, normal liver <30 Gy, bone marrow <1.5 Gy) and then the delivery of the calculated activity. Efficacy was assessed using response evaluation criteria in solid tumor (RECIST) and alpha-feto-protein (alpha FP) levels and severe adverse events were graded using the Common Toxicity Criteria of the National Cancer Institute scale v2.0. RESULTS: The trial included 185 patients from eight countries. The procedure was feasible in all participating centers. One treatment was given to 134 patients; 42, 8, and 1 received two, three, and four injections, respectively. The injected activity during the first treatment was 100 mCi. Tolerance was excellent. We observed three complete responses and 19 partial responses (22% of evaluable patients, 95% confidence interval 16-35%); 1- and 2-year survivals were 46% and 23%. Some factors affected survival: country of origin, existence of a cirrhosis, Cancer of the Liver Italian Program score, tumor dose, absence of progression, and posttreatment decrease in alpha FP level. CONCLUSIONS: IAI of 188Re-Lip in developing countries is feasible, safe, cost-effective, and deserves a phase III trial.

Feasibility of high activity rhenium-188-microsphere in hepatic radioembolization.

BACKGROUND: This paper describes the feasibility of intra-arterial high-activity administration of (188)Re-microspheres. METHODS: Patients with unresectable colorectal liver metastases or hepatocellular cancer (HCC) received single treatments with (188)Re-microspheres. The administered activity was calculated to give a liver dose of 100 Gy. From post-therapeutic scans and urine sampling, the dose to the liver, metastases and bladder was calculated. Toxicity was assessed up to 3 months after administration by means of the Common Terminology Criteria for Adverse Events v3.0 (Trotti et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13(3):176-81). Response was evaluated on CT. RESULTS: 13.6 +/- 4.7 GBq (188)Re-microspheres was administered selective in the feeding artery of the tumour to 10 patients (3 x HCC and 7 x colorectal liver metastases). There was a low urinary excretion rate of 8.9 +/- 3.8% of administered activity within 96 h. The absorbed dose to the tumour, normal liver (excluding the tumour) and bladder was 10.24 +/- 5.02 Gy/GBq (128 +/- 47 Gy), 3.94 +/- 2.52 Gy/GBq (50 +/- 33 Gy) and 0.27 +/- 0.20 Gy/GBq (2.4 +/- 1.9 Gy), respectively. There was an acceptable rate of toxicity in 30% of grades I and II, respectively, and 10% with grade III. There was reversible in the most patients within 14 days after treatment. The response was assessed on CT: two patients had a partial response (PR), five patients had stable disease and three patients had disease progression. CONCLUSION: Treatment of colorectal liver metastases or HCC using high activities of (188)Re-microspheres was well tolerated and a PR was seen in 2 of 10 patients. The treatment represents a therapeutic option in these patients.

Characterization of Re-188-Sn microparticles used for synovitis treatment.

Rhenium-188 labeled tin (Sn) microparticles were developed for pain palliation therapy in the patients suffering from synovitis with acute pain. The rhenium tin microparticles were prepared using stannous chloride and freshly eluted (188)ReO(4)(-) from (188)W/(188)Re generator. The aggregated colloidal particles, packed in a spherical form after boiling for 90-120min were analyzed using electron microscope. The size, surface morphology and stability of microparticles were analyzed by changing temperature and volume conditions. The small colloidal particles clustered and formed spherical microparticles. The 90% of microparticles were in 5-10microm range, after 90min and 120min of boiling. The radiolabeling efficiency was improved to 98% after centrifugation for 10min at 3500rpm. The formulations were stable but the increase in volume had inverse effect on labeling efficiency. No leak was observed from knee area up to 24h with 15-20mCi injection of (188)Re-Sn microparticles. The relief in treated patients, from the pain and inflammation, was observed clinically and by (99m)Tc-MDP perfusion scan.

Radiation synovectomy of the upper extremity joints: does leakage from the joint to non-target organs impair its therapeutic effect?

Does leakage impair the therapeutic effect of radiosynoviorthesis (RSO)? Are there differences in leakage between (169)Erbium and (186)Rhenium? At baseline and at 6 and 12 months after RSO, six clinical parameters were scored. Changes in clinical variables over time were summed to a change composite index (CCI), ranging from 0 (no effect) to 12 (maximal effect). CCI >or= 6 was considered successful treatment. Differences in leakage between responders and non-responders, and between (169)Erbium and (186)Rhenium were examined. Regression analyses were performed to explore whether baseline variables predicted leakage. Both at 6 and 12 months response rates were 25 of 36 (69%). Five of 11 (45%) non-responders showed leakage versus 20 of 25 (80%) responders (P=0.06). Mean leakage to lymph nodes was 0.4+/-0.7% versus 2.4+/-0.8% (P=0.04). Median leakage to liver/spleen was 0% versus 0.3% (P=0.4). Only age at the time of injection correlated significantly with leakage to lymph nodes. The (169)Erbium group showed leakage in 1 of 7 (14%) versus 24 of 30 (80%) for the (186)Rhenium group (P=0.002). Mean leakage to lymph nodes was 0.11+/-0.3% versus 2.1+/-2.8% (P=0.001). Median leakage to liver/spleen was 0% versus 0.5% (P=0.006). Leakage to non-target organs does not impair the clinical effect of RSO. Only age predicted leakage to lymph nodes significantly. Other baseline characteristics did not predict leakage. (169)Erbium shows significantly lower leakage to non-target organs than (186)Rhenium in RSO.

Comparison of clonogenic cell survival and DNA damage induced by 188Re and X-rays in rat thyroid cells.

AIM: Ionizing radiation produces DNA lesions among which DNA double strand breaks (DSB) are the most critical events. Radiation of various energy types might differ in their biological effectiveness. Here, we compared cell survival and DNA damage induced by 188Re and X-rays using γH2AX foci as a measure of DSB. The correlation between survival and residual foci was also analyzed. METHODS: PCCl3 cells were irradiated with 200 kV X-rays (1.2 Gy/min) or 0.5-25 MBq/ml 188Re (1 h irradiation) achieving doses up to 10 Gy. By blocking of sodium iodide symporter (NIS) essentially extracellular activity could be guaranteed. Survival fractions (SF) were detected by colony forming assay. Initial and residual γH2AX foci (15 min and 24 h after irradiation) were assessed by immunostaining. The relationship between SF and residual radiation induced γH2AX foci (RIF) was evaluated by Spearman and Pearson correlation tests. RESULTS: We did not find significant differences between the survival curves in terms of the radiation quality. The D37 values were 4.6 Gy and 4.2 Gy for 188Re or X-ray, respectively. The initial foci numbers were in the same range for 188Re and X-ray, but higher levels of residual foci persisted after X-rays in comparison to 188Re (1 GyX-ray 6.5 ± 0.2; 1 GyRe-188 4.8 ± 0.2 RIF). Accordingly, for 188Re a higher extent of DSB repair was found. The Spearman test revealed a significant (p < 0.01) correlation between SF and residual RIF for both radiation modalities. CONCLUSION: No differences in terms of radiation were found for SF and initial foci. However, residual foci were lower for 188Re than for X-rays. A prediction of SF by residual foci should consider the properties of the radiation qualities that influence foci removal and DSB repair.

Radioisotope synoviorthesis in paediatric and adolescent patients with haemophilia.

OBJECTIVE: To assess the outcome and adverse-effects of the radioisotope synoviorthesis in paediatric and adolescent patients with haemophilia. MATERIAL AND METHODS: Prospective study of historical cohort was conducted. A total of 20 consecutive haemophiliacs with a mean age of 13.1 years (range 4-17) were included with a mean follow-up of 64.9 months (range 18-109). The diagnosis of synovitis was established on the basis of clinical follow-up including radiological images (radiography and/or MRI). For evaluation, the classification proposed by Fernandez-Palazzi was used. INCLUSION CRITERIA: Patients aged less than 18 years old with haemophilia and more than one haemarthrosis in less than 3 months remaining a chronic synovitis despite prophylactic therapy intensification. EXCLUSION CRITERIA: Any contraindication for radionuclide synoviorthesis. Twenty-seven radioisotope synoviorthesis with (90)Y-citrate-colloid and/or (186)Re-sulphide-colloid were done. The effectiveness of the procedure was assessed through pre and posttreatment clinical comparison at 6 months after radioisotope synoviorthesis. RESULTS: Nineteen of the 27 synoviorthesis (70.3%) had a good or excellent response and 8 joints (29.7%) had partial response. It was necessary to repeat the procedure in 3 joints in 3 different patients, obtaining in all cases a good or excellent response. We appreciated inflammatory reaction after procedure in 4 cases (14.8%), which improved with analgesics and nonsteroidal anti-inflamatory drugs. None of the patients presented malignant or premalignant lesions during the follow-up. CONCLUSION: The radionuclide synoviorthesis is a very effective procedure in paediatric and adolescent patients with hemophilia, being a minimally invasive procedure, easy to perform, safe and with minimal side effects.

Mobilized endothelial progenitor cells by granulocyte-macrophage colony-stimulating factor accelerate reendothelialization and reduce vascular inflammation after intravascular radiation.

BACKGROUND: Endothelial progenitor cells (EPCs) play a pivotal role in repair and regeneration of damaged vessels. We investigated the role of mobilized EPCs in the healing process after intravascular radiation therapy. METHODS AND RESULTS: One iliac artery of hypercholesterolemic rabbits was subjected to balloon injury and intravascular radiation with a Re-188 balloon and the contralateral iliac artery to balloon injury only. Rabbits received granulocyte-macrophage colony-stimulating factor (recombinant human GM-CSF) (60 microg/d subcutaneously) daily for 1 week, either 7 days before the angioplasty or at the time of angioplasty. Control rabbits received human albumin. GM-CSF significantly increased the double-positive (CD31+ and KDR+) fraction in peripheral blood monocytes and showed a higher number of EPCs than albumin after culture and, furthermore, enhanced migration and incorporation of EPCs. In the albumin group, intravascular radiation therapy reduced neointimal hyperplasia but delayed reendothelialization and aggravated monocyte infiltration. GM-CSF treatment significantly accelerated the reendothelialization and inhibited monocyte infiltration (reendothelialization index, 81+/-13% in the GM-CSF radiation [n=7] versus 30+/-11% in the control radiation [n=9] at 2 weeks, P<0.01). GM-CSF treatment produced an additional significant reduction in neointimal formation at 14 and 28 days after injury in the intravascular radiation groups (intima to media ratio, 0.14+/-0.11 in the GM-CSF radiation [n=5] versus 0.36+/-0.07 in the control radiation [n=5] at 4 weeks, P<0.01). CONCLUSIONS: GM-CSF treatment mobilizes EPCs, accelerates reendothelialization, and reduces monocytes infiltration after intravascular radiation therapy, suggesting that stem cell mobilization is a promising strategy for enhancing the vascular healing process after cytotoxic angioplasty.

Marrow toxicity and radiation absorbed dose estimates from rhenium-186-labeled monoclonal antibody.

UNLABELLED: Estimates of radiation absorbed dose to the red marrow (RM) would be valuable in treatment planning for radioimmunotherapy if they could show a correlation with clinical toxicity. In this study, a correlation analysis was performed to determine whether estimates of radiation absorbed dose to the bone marrow could accurately predict marrow toxicity in patients who had received 186Re-labeled monoclonal antibody. METHODS: White blood cell and platelet count data from 25 patients who received 186Re-NR-LU-10 during Phase I radioimmunotherapy trials were analyzed, and the toxicity grade, the fraction of the baseline counts at the nadir (percentage baseline) and the actual nadir were used as the indicators of marrow toxicity. Toxicity was correlated with various predictors of toxicity. These predictors included the absorbed dose to RM, the absorbed dose to whole body (WB) and the total radioactivity administered. RESULTS: Percentage baseline and grade of white blood cells and platelets all showed a moderate correlation with absorbed dose and radioactivity administered (normalized for body size). The percentage baseline platelet count was the indicator of toxicity that achieved the highest correlation with the various predictors of toxicity (r = 0.73-0.79). The estimated RM absorbed dose was not a better predictor of toxicity than either the WB dose or the total radioactivity administered. There was substantial variation in the blood count response of the patients who were administered similar radioactivity doses and who had similar absorbed dose estimates. CONCLUSION: Although there was a moderately good correlation of toxicity with dose, the value of the dose estimates in predicting toxicity is limited by the patient-to-patient variability in response to internally administered radioactivity. In this analysis of patients receiving 186Re-labeled monoclonal antibody, a moderate correlation of toxicity with dose was observed but marrow dose was of limited use in predicting toxicity for individual patients.

Evaluation of thrombocytopenia in patients treated with rhenium-186-HEDP: guidelines for individual dosage recommendations.

UNLABELLED: A potential limitation of rhenium-186-1,1-hydroxyethylidene diphosphonate (186Re-HEDP) therapy in patients with painful bone metastases is thrombocytopenia. Given the palliative character of this therapy, it is essential to be able to predict the degree of thrombocytopenia before therapy. METHODS: Thus far, 39 prostatic cancer patients with multiple painful bone metastases were treated. Twenty-one patients underwent the therapy twice, resulting in 60 therapies. From the pre-therapy 99mTc-HDP scintigram, the bone scan index (BSI) was determined as an index of the extent of bone involvement. RESULTS: The administered activity ranged from 1104 to 3479 MBq 186Re-HEDP. The platelet count was lowest 4 wk following therapy. From this value and the pretreatment level, the percentage decrease in the platelet count was determined (47% +/- 19%, range 14%-89%). The BSI ranged from 8 to 93. Regression analysis showed a functional relation (R = 0.78; p < 0.001) of the percentage of platelet decrease with BSI and administered activity normalized to standard body surface area. CONCLUSION: Using this relation, it is possible to predict thrombocytopenia by pretreatment bone scintigraphy and to adjust the dosage to each patient to avoid unacceptable toxicity.

Pharmacokinetics, dosimetry and toxicity of rhenium-188-labeled anti-carcinoembryonic antigen monoclonal antibody, MN-14, in gastrointestinal cancer.

UNLABELLED: The biodistribution, pharmacokinetics and dosimetry of 188Re-labeled MN-14, an IgG anti-carcinoembryonic antigen monoclonal antibody (MAb), were assessed in patients in advanced gastrointestinal cancer. In addition, the dose-limiting toxicity (DLT) and maximum tolerated dose of fractionated doses of this agent were determined. METHODS: Eleven patients were administered radioactive doses of directly labeled 188Re-MN-14 IgG, ranging from 20.5 mCi to 161.0 mCi (2.0 mg-4.9 mg). Ten of these patients received two or three MAb infusions, given 3-4 days apart, delivering total doses of 30 mCi/m2-80 mCi/m2. External scintigraphy was used to evaluate the MAb biodistribution, and quantitative external scintigraphic methods were used to determine the organ and tumor radiation doses. RESULTS: The biodistribution studies showed enhanced 188Re-MN-14 uptake in the liver, spleen and kidneys, compared to that of 131I-MN-14. The biological T(1/2) values for 188Re-MN-14 in the blood and whole body (in hours) were 8.2 +/- 4.1 (n = 7) and 107.8 +/- 104.2 (n = 9), respectively (mean +/- s.d.). The radiation absorbed doses (cGy/mCi) delivered to the total body, red marrow, lungs, liver, spleen and kidneys were 0.5 +/- 0.05, 3.6 +/- 1.6, 2.0 +/- 0.8, 5.9 +/- 2.5, 7.1 +/- 1.9 and 8.5 +/- 2.8, respectively. Red marrow suppression was the only DLT observed. The maximum tolerated dose of fractionated doses of 188Re-MN-14 was estimated to be 60 mCi/m2. CONCLUSION: Despite its relatively increased renal and hepatic uptake, red marrow suppression is the only DLT of 188Re-MN-14. The feasibility of administering relatively high doses of 188Re on a completely outpatient basis may make this agent a preferred candidate for radioimmunotherapy.

Evaluation of limited blood sampling in a preceding 99mTc-labeled diagnostic study to predict the pharmacokinetics and myelotoxicity of 186Re-cMAb U36 radioimmunotherapy.

UNLABELLED: 186Re-labeled chimeric monoclonal antibody U36 (cMAb U36) was recently evaluated in a phase I dose escalation study in head and neck cancer patients. All 13 patients received 99mTc-labeled cMAb U36 before 186Re-cMAb U36 radioimmunotherapy. The aim of this study was to evaluate the suitability of multiple or limited blood sampling to predict clearance, red marrow absorbed dose, and myelotoxicity of 186Re-cMAb U36. METHODS: Population pharmacokinetics of 186Re-cMAb U36 were analyzed with a nonparametric expectation algorithm (NPEM 2) and used for Bayesian analysis of individual patient data to predict cMAb U36 clearance. RESULTS: 186Re-cMAb U36 clearance was most accurately predicted (r = 0.91, P < 0.001) with limited sampling for sample points 4 and 72 h after administration of 186Re-cMAb U36. These predictions were less accurate with 99mTc-cMAb U36 (r = 0.51, P = 0.078 for multiple sampling; r = 0.47, P = 0.104 for sampling at 4 and 21 h after administration). Thrombocytopenia was found to be correlated with the red marrow absorbed dose and was equally well predicted by limited blood sampling after administration of 99mTc-cMAb U36 (r = 0.81, P < 0.01) or 186Re-cMAb U36 (r = 0.79, P < 0.01). CONCLUSION: Limited sampling seems useful to predict pharmacokinetics and myelotoxicity of 186Re-cMAb U36.