Comparison of various rhenium-188-labeled diphosphonates for the treatment of bone metastases

In the past, many diphosphonates were introduced as bone scan radiopharmaceuticals. In addition, diphosphonates have been labeled with beta-emitted isotopes and developed into useful therapeutic drugs for bone metastases. However, it is not clear which diphosphonate is the best choice when labeling with Re-188. In this study, we labeled methylene diphosphonate (MDP), hydroxyethylidene diphosphonate (HEDP), and hydroxymethane diphosphonate (HDP) with Re-188. Each radiopharmaceutical was further evaluated in two conditions (with and without carrier). Twenty-four rabbits were used (four in each group) for the analysis of the biodistributions and bone uptakes of these radiopharmaceuticals to assess their potential for clinical applicability. Four hours after intravenous injection of approximately 37 MBq (1 mCi) Re-188-labeled diphosphonate preparations, whole body scans were performed using a large-field gamma camera equipped with a high resolution collimator. Bone-to-soft tissue ratios (B/S ratio) were calculated using a computer program. Our data showed that Re-188 HEDP with carrier (10⁻⁴ M carrier) could accumulate in the skeletal system whereas very little absorption by bone was observed in the rabbits that were injected with carrier-free Re-188 HEDP. In addition, no significant bone uptake was demonstrated for Re-188 MDP or Re-188 HDP, with or without carrier. The B/S ratio was 25.06 in the Re-188 HEDP with carrier group but less than 3 in the other groups. In conclusion, HEDP is the best choice among these three bone-seeking drugs when labeled with Re-188. But, it is necessary to add carrier when preparing Re-188 HEDP for the treatment of bone metastases.     

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     

Dose escalation study of rhenium-186 hydroxyethylidene diphosphonate in patients with metastatic prostate cancer

Rhenium-186 hydroxyethylidene diphosphonate (¹⁸⁶Re-HEDP) has been used for the palliative treatment of metastatic bone pain. A phase 1 dose escalation study was performed using ¹⁸⁶Re-HEDP Twenty-four patients with hormone-resistant prostate cancer entered the study. Each patient had at least four bone metastases and adequate haematological function. Groups of at least three consecutive patients were treated with doses starting at 1295 MBq and increasing to 3515 MBq (escalated in increments of 555 MBq). Thrombocytopenia proved to be the dose-limiting toxicity, while leucopenia played a minor role. Early death occurred in one patient (10 days after administration) without clear relationship to the ¹⁸⁶Re-HEDP therapy. Transient neurological dysfunction was seen in two cases. Two patients who received 3515 MBq ¹⁸⁶Re-HEDP showed grade 3 toxicity (thrombocytes 25–50 × 10⁹/1), defined as unacceptable toxicity. After treatment alkaline phosphatase levels showed a transient decrease in all patients (mean: 26% ± 10% IUA; range: 11%–44%). Prostate-specific antigen values showed a decline in eight patients, preceded by a temporary increase in three patients. From this study we conclude that the maximally tolerated dose of ¹⁸⁶Re-HEDP is 2960 MBq. A placebo-controlled comparative study on the efficacy of ¹⁸⁶Re-HEDP has been initiated.     

Rhenium-188 labelled meso-tetrakis[3,4-bis(carboxymethyleneoxy)phenyl] porphyrin for targeted radiotherapy: preliminary biological evaluation in mice

Purpose This study focusses on a promising carrier system for therapeutic and imaging purposes using meso-tetrakis[3,4-bis(carboxymethyleneoxy)phenyl] porphyrin (T_3,4CPP). To assess its potential for clinical use, we labelled T_3,4CPP with ¹⁸⁸Re and analysed some kinetic biodistribution parameters after intravenous injection in mice. Materials and methods T_3,4CPP was synthesized and labelled with ¹⁸⁸Re. Normal Kunming (KM) mice and melanoma- or hepatoma-bearing BALB/c nude mice were injected intravenously with 5.55 MBq ¹⁸⁸Re-labelled T_3,4CPP and sacrificed at 0.5, 2, 4, and 24 h and 8, and 24 h, respectively. Results The ¹⁸⁸Re-T_3,4CPP yield was more than 95% with specific activity 16.9 GBq (mol)⁻¹, and Vitamin C (VC) could increase its stability in vitro. In normal KM mice, ¹⁸⁸Re-T_3,4CPP had fast blood clearance (~99%, 24 h postinjection), low retention in the vital organs and hepatotropic characteristics. In nude mice, more than 4.4 and 6.1% uptake per gram of tumour (%ID g⁻¹) at 8 h postinjection was in melanoma and hepatoma, respectively; this remained as high levels after 24 h as 4.6 and 6.5%, respectively. At 8 h, the tumour/blood and tumour/muscle (T/M) ratios in melanomas and hepatoma bearing mice were 7.3, 13,and 7.0, 20, respectively. Twenty-four hours later, these high ratios still continued in existence which were 9.6, 19 and 10, 25, respectively. Conclusion The results obtained in this study indicate that ¹⁸⁸Re-T_3,4CPP has better tumour affinity and retainable accumulation characteristics in carcinoma which can potentially be used for tumour-targeted radiotherapy.     

Rhenium-186 hydroxyethylidene diphosphonate for the treatment of painful osseous metastases.

Rhenium-186 (tin)hydroxyethylidene diphosphonate (HEDP) is a new radiopharmaceutical that localizes in skeletal metastases in patients with advanced cancer. A single intravenous administration of approximately 34 mCi (1,258 MBq) resulted in significant improvement in pain in 33 of 43 evaluable patients (77%) following the initial injection, and in 7 of 14 evaluable patients (50%) following a second treatment. Patients responding to treatment experienced an average decrease in pain of about 60%, with one in five treatments resulting in a complete resolution of pain. The only adverse clinical reaction was the occurrence after about 10% of the administered doses of a mild, transient increase in pain within a few days following injection. Statistically significant but clinically unimportant decreases in total white blood cell counts and total platelet counts were observed within the first 8 weeks following the injection; no other toxicity was apparent. Rhenium-186(Sn)HEDP is a useful new compound for the palliation of painful skeletal metastases.     

Pentavalent rhenium-188 dimercaptosuccinic acid for targeted radiotherapy: synthesis and preliminary animal and human studies

Pentavalent rhenium-188 dimercaptosuccinic acid [¹⁸⁸Re(V)DMSA] is a β-emitting analogue of ^99mTc(V)DMSA, a tracer that is taken up in a variety of tumours and bone metastases. The aim of this study was to develop the kit-based synthesis of the agent on a therapeutic scale, to assess its stability in vivo, and to obtain preliminary biodistribution and dosimetry estimates, prior to evaluation of its potential as a targeted radiotherapy agent. The organ distribution of ¹⁸⁸Re in mice was determined 2 h after injection of 3 MBq ¹⁸⁸Re(V)DMSA prepared from eluate from a ¹⁸⁸W/¹⁸⁸Re generator. Three patients with cancer of the prostate and three with cancer of the bronchus, all with bone metastases confirmed with a standard ^99mTc-hydroxymethylene diphosphonate (^99mTc-HDP) scan, were given 370 MBq ¹⁸⁸Re(V)DMSA and imaged at 3 h and 24 h using the 155-keV γ-photon (15%). Blood and urine samples were collected to determine clearance and to analyse the speciation of ¹⁸⁸Re. Organ residence times were estimated from the scans, and used to estimate radiation doses using MIRDOSE 3. In mice, ¹⁸⁸Re(V)DMSA was selective for bone and kidney. In patients, it showed selectivity for bone metastases (particularly those from prostate carcinoma) and kidney, but uptake in normal bone was not significantly greater than in surrounding soft tissues. Of the normal tissues the kidneys received the highest radiation dose (0.5–1.3 mGy/MBq). The images were strongly reminiscent of ^99mTc(V)DMSA scans in similar patients. High-performance liquid chromatography analysis of blood and urine showed no evidence of ¹⁸⁸Re in any chemical form other than ¹⁸⁸Re(V)DMSA up to 24 h. In conclusion, ¹⁸⁸Re(V)DMSA and its ¹⁸⁶Re analogue warrant further clinical assessment as generator/kit-derived agents for treatment of painful bone metastases. These agents should also be assessed in medullary thyroid carcinoma and other soft tissue tumours which have been shown to accumulate ^99mTc(V)DMSA. Received 8 January and in revised form 28 February 1998     

Rhenium-188-Labeled DTPA: a new radiopharmaceutical for intravascular radiation therapy

Balloon angioplasty is a standard treatment for artherosclerotic coronary artery disease. However, its clinical value is reduced by a high restenosis rate. A new concept in preventing restenosis is the use of a liquid-filled balloon containing a beta-emitting radioisotope. In this study, we performed biodistribution studies of Re-188 perrhenate and Re-188 diethylenetriaminopentaacetate (DTPA) to assess the resulting organ dose values in the event of balloon rupture if these agents are used for the clinical inhibition of restenosis after percutaneous transluminal coronary angioplasty (PTCA). After injecting Re-188 preparations intravenously, rats were killed at 10 min, 30 min, 60 min, 2 h, and 6 h ( n =5 per group). Tissue concentrations were calculated and expressed as percent injected dose per gram or per milliliter (%ID/g or %ID/mL). In addition, urine excretion and thyroid gland uptake were evaluated in rats ( n=5 per group) with a gamma camera after administration of 37 MBq (1 mCi) of each agent. Our data showed that both agents were excreted primarily via urine. However, the excretion of Re-188 DTPA was much faster than that of Re-188 perrhenate via the urinary system. The biodistribution data revealed that radioactivity levels in the stomach and the thyroid gland were high in the perrhenate group but low in the Re-188 DTPA group. The concentration levels in other tissues including lung, liver, testis, muscle, and blood were low throughout this study for both agents. The thyroid radiation value in the Re-188 perrhenate group was 0.163 mGy/MBq, which was much higher than that of the Re-188 DTPA group (0.0167 mGy/MBq). The stomach radiation value was as high as 0.127 mGy/MBq for Re-188 perrhenate, compared with 0.013 mGy/MBq for Re-188 DTPA. In conclusion, in the event of balloon rupture, the release of Re-188 DTPA results in lower radiation doses than Re-188 perrhenate, especially to the thyroid gland and the stomach. Our data suggest that Re-188 DTPA is a useful radiopharmaceutical for endovascular irradiation.     

Usefulness of technetium-99m hydroxymethylene diphosphonate scans in localizing bone metastases of differentiated thyroid carcinoma

Iodine-131 is uniquely able to demonstrate iodine uptake of differentiated thyroid carcinoma (DTC), but precise localization may be difficult, especially in the thorax, due to the quality of image resolution with 1311 and the lack of anatomical landmarks. When bone metastases do not show radioiodine uptake, bone scintigraphy can be used to detect them. We studied two groups of patients. In group 1, 15 patients with known bone metastases of DTC were treated with 3.7 GBq ¹³¹I. After 4 or 5 days, technetium-99m hydroxymethylene diphosphonate (HMDP; 740 MBq) was injected and a whole-body scan with simultaneous acquisition of ¹³¹I and ^99mTc-HMDP images was carried out using a large field of view gamma camera fitted with a high-energy collimator. Technetium uptake was abnormal in 47 of 63 localizations, being increased in 29 foci, decreased in 7 and heterogeneous in 11. The superimposition of ¹³¹I and ^99mTc-HMDP scans permitted an accurate localization in 80% of spine metastases and in 46% of osseous thoracic localizations, even in the presence of lung metastases. In group 2, 9 patients, who had bone pain, neurological signs or elevated serum thyroglobulin, had DTC bone metastases without iodine uptake. They received a diagnostic dose of ^99mTc-HMDP 3h prior to scintigraphy with a large field of view gamma camera fitted with a low-energy collimator. Technetium uptake was abnormal in 37 of 38 localizations, being increased in 34 foci and decreased in 3. One false-negative was found in a skull metastasis. In both groups of patients, ^99mTc-HMDP scans were useful. The procedure allows accurate localization of bone metastases and can be used as a guide for subsequent radiological investigations.     

188Re标记物治疗肝细胞性肝癌的研究进展

近年来,¹⁸⁸Re标记的放射性药物成为治疗肝细胞性肝癌的讨论热点之一。逐渐增多的研究表明其治疗肝细胞性肝癌具有安全性和有效性,是一种有前景治疗用放射性核素。本文就¹⁸⁸Re物理特性及其标记物在治疗肝细胞性肝癌的动物实验研究、临床研究及放射性防护等方面的新进展进行总结。     

PEGylated N-methyl-S-methyl dithiocarbazate as a new reagent for the high-yield preparation of nitrido Tc-99m and Re-188 radiopharmaceuticals

A novel nitrido nitrogen atom donor for the preparation of ^99mTc and ¹⁸⁸Re radiopharmaceuticals containing a metal-nitrogen multiple bond is presented. HO₂C-PEG₆₀₀-DTCZ was obtained by conjugation of N-methyl-S-methyl dithiocarbazate [H₂N–N(CH₃)–C(S)SCH₃, HDTCZ] with polyethylene glycol 600 (PEG₆₀₀). Asymmetrical heterocomplexes of the type [M(N)(PNP)(B)]^0/+ (M=^99mTc, ¹⁸⁸Re; PNP=diphosphine ligands, B=DBODC, DEDC, NSH, H₂OS, CysNAc, HDTCZ) and symmetrical nitride compounds of the type [M(N)(L)₂] (L=DEDC, DPDC) have been prepared in high yield by using the newly designed nitride nitrogen atom donor HO₂C-PEG₆₀₀-DTCZ. A two-step procedure was applied for preparing the above symmetrical and asymmetrical complexes. The first step involved the preliminary formation of a mixture of nitride Tc-99m or Re-188 precursors, which contained the [MN]²⁺ core, through reduction of generator-eluted ^99mTc-pertechnetate or ¹⁸⁸Re-perrhenate with thin (II) chloride in the presence of HO₂C-PEG₆₀₀-DTCZ. In the second step, the intermediate mixture was converted either in the final mixed asymmetrical complex by the simultaneous addition of diphosphine ligand and the suitable bidentate ligand B, or in the final symmetrical complex by the only addition of the bidentate ligand L. It was also demonstrated that the novel water-soluble nitride nitrogen atom donor HO₂C-PEG₆₀₀-DTCZ did not show coordinating properties toward the MN (^99mTc, ¹⁸⁸Re) core. Biodistribution studies in rats of the hitherto unreported [^99mTc(N)(PNP₃)DTCZ]⁺ and [^99mTc(N)(PNP₅)DTCZ]⁺ complexes showed that they selectively localize in the myocardium of rats with a favourable heart-to-lung and heart-to-liver uptake ratios. In particular, the heart-to-lung and heart-to-liver uptake ratios dramatically increased in the interval between 60 and 120 min postinjection. Hence, the combination of the favourable chemical and biological properties of HO₂C-PEG₆₀₀-DTCZ might confer to this novel compound an important role for the development of new ^99mTc and ¹⁸⁸Re-nitrido radiopharmaceuticals.     

放射性核素骨显像在前列腺癌骨转移中的研究价值

目的:探讨放射性核素骨显像与血清前列腺特异性抗原(PSA)联合检测在前列腺癌骨转移诊断中的临床意义。方法:对130例前列腺癌患者的PSA检测结果及SPECT骨显像进行回顾性分析。结果:130例前列腺癌患者,骨显像诊断骨转移86例,阳性率为66.2%。在86例骨转移的患者中,发生脊椎转移77例,占77.9%,骨盆转移65例,占75.6%,肋骨转移42例,占48.8%,肩胛骨转移11例,占12.8%,胸骨转移7例,占8.1%,颅骨转移6例,占7%。脊椎和骨盆是前列腺癌骨转移主要涉及的部位。骨显像阳性组和骨显像阴性组PSA均值差异有显著性(P<0.01),PSA<20μg/L的前列腺癌患者发生骨转移的可能性小,PSA≥20μg/L的患者发生骨转移的可能性大。结论:PSA≥20μg/L的前列腺患者应行放射性核素骨显像检查。放射性核素全身骨显像与血清PSA浓度联合检测对于前列腺癌骨转移的临床诊断具有重要的指导意义。     

Biokinetic and dosimetric studies of Re-hyaluronic acid: a new radiopharmaceutical for treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and has very limited therapeutic options. Recently, it has been found that hyaluronic acid (HA) shows selective binding to CD44 receptors expressed in most cancer histotypes. Since the trend in cancer treatment is the use of targeted radionuclide therapy, the aim of this research was to label HA with rhenium-188 and to evaluate its potential use as a hepatocarcinoma therapeutic radiopharmaceutical.

Methods

¹⁸⁸Re-HA was prepared by a direct labelling method to produce a ReO(O-COO)₂-type coordination complex. ¹⁸⁸Re-HA protein binding and its stability in saline, phosphate buffer, human serum and cysteine solutions were determined. Biokinetic and dosimetric data were estimated in healthy mice (n=60) using the Medical Internal Radiation Dose methodology and mouse model beta-absorbed fractions. To evaluate liver toxicity, alanine aminotranferase (AST) and aspartate aminotranferase (ALT) levels in mice were assessed and the liver maximum tolerated dose (MTD) of ¹⁸⁸Re-HA was determined.

Results

A stable complex of ¹⁸⁸Re-HA was obtained with high radiochemical purity (>90%) and low serum protein binding (2%). Biokinetic studies showed a rapid blood clearance (T_1/2α=21 min). Four hours after administration, ¹⁸⁸Re-HA was almost totally removed from the blood by the liver due to the selective uptake via HA-specific receptors (73.47±5.11% of the injected dose). The liver MTD in mice was 40 Gy after 7.4 MBq of ¹⁸⁸Re-HA injection.

Conclusions

¹⁸⁸Re-HA complex showed good stability, pharmacokinetic and dosimetric characteristics that confirm its potential as a new agent for HCC radiation therapy.     

Whole-body MRI using a rolling table platform for the detection of bone metastases

The aim of this study was to compare the results of whole-body MRI using a recently developed rolling table platform with findings of nuclear scintigraphy in patients with bone metastases. Twenty-six patients with known or suspected bone metastases who had undergone radionuclide scintigraphy were examined by MRI. Patients were placed on a rolling table platform with integrated phased-array surface coils [BodySURF (system for unlimited field of view)] capable of pulling the patient through the isocenter of the magnet. Using a five-station approach three different image sets (T1-weighted gradient recalled echo, half-Fourier acquired single-shot turbo spin echo, and short tau inversion recovery) were collected in the coronal plane. In addition, the spine was imaged in the sagittal plane. The MRI findings were compared with the results obtained by scintigraphy. The whole-body MR examination lasting merely 40 min was feasible in all 26 patients. The MRI revealed excellent correlation with scintigraphy regarding metastatic lesions. A total of 60 regions with metastatic lesions were identified on bone scintigraphy. Fifty-three regions were detected on identical locations by MRI. The regions missed by MRI were located mainly in ribs and skull. The MRI could identify additional bone metastases in spine, pelvis, and femur. The MRI screening for bone metastases correlated well with bone scintigraphy. Use of the rolling table platform permits rapid imaging based on three different contrast mechanisms of the entire skeletal system.     

The appearance of breast cancer metastases on dry bone: Implications for forensic anthropology

Breast carcinoma is a major cause of morbidity and mortality in women. The study of bone pathologies presents considerable potential in anthropology, paleopathology, forensic science and medicine. In this paper, we present and discuss metastatic lesions found in the skeletons of known individuals from the CAL Milano Cemetery Skeletal Collection, clinically diagnosed with breast cancer during life. Fourteen skeletons from a contemporary and identified collection were macroscopically studied and metastases were identified by comparison with clinical literature. As a result, bone metastases were observed in 43% of the study sample. They were located most commonly on the ribs (28.1%), pelvic girdle (19.8%), vertebrae (15.6%), skull (15.6%), scapulae (10.2%) as well as proximal segment of the femora (8.4%) and humeri (2.4%) respectively, favoring sites of high vascularization. The majority of the lesions were osteolytic, although osteoblastic and mixed metastases did occur. Osteolytic metastases appear as coalescent porosity or round to oval perforating lesions on bones with denticulated margins and pitted surrounding bone, whereas osteoblastic metastases thickened the existing trabecula (spongiosclerosis). Mixed metastases were perforating lytic lesions exposing the osteoblastic activity in the underlying trabecular bone. These results, consistent with the data from the literature, strengthen the diagnostic criteria for metastases and illustrate the aspect of bone metastases in breast carcinoma.     

骨靶向放射性核素治疗肺癌骨转移疼痛的研究进展

肺癌骨转移是肿瘤晚期的常见并发症,患者由于严重的疼痛往往导致生活质量下降,且易出现与骨骼相关的不良事件,如病理性骨折、脊髓压迫和高钙血症等。针对轻、中度骨转移引起的疼痛可以采用常规止痛、镇痛和外部照射放疗。但在全身多处转移和疼痛严重的情况下,以上3种方法的疗效都不好,且不良反应严重。而某些放射性核素能够特异性地被活性增高的成骨细胞摄取,并且能较长时间滞留于骨组织中。因此,使用一些新型骨靶向放射性核素,如89Sr、153Sm和186Re等进行系统性的治疗成为新型方式,为肺癌骨转移疼痛的治疗提供了更多的靶点和安全有效的手段。     

Pitfalls of FDG-PET for the diagnosis of osteoblastic bone metastases in patients with breast cancer

Purpose The purpose of this study was to investigate the pitfalls of using 2-[¹⁸F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for the evaluation of osteoblastic bone metastases in patients with breast cancer by comparing it with ^99mTc-hydroxymethylene diphosphonate bone scintigraphy.Methods Among the 89 breast cancer patients (mean age 59±15 years) who had undergone both FDG-PET and bone scintigraphy within 1 month between September 2003 and December 2004, 55 with bone metastases were studied. The bone metastases were visually classified by multi-slice CT into four types according to their degree of osteosclerosis and osteolysis—osteoblastic, osteolytic, mixed and invisible—and compared in terms of tracer uptake on FDG-PET or bone scintigraphy and SUV_mean on FDG-PET. Differences in the rate of detection on bone scintigraphy and FDG-PET were analysed for significance by the McNemar test.Results The sensitivity, specificity and accuracy of bone scintigraphy were 78.2%, 82.4% and 79.8% respectively, and those of FDG-PET were 80.0%, 88.2% and 83.1%, respectively, revealing no significant differences. According to the CT image type, the visualisation rate of bone scintigraphy/FDG-PET was 100%/55.6% for the blastic type, 70.0%/100.0% for the lytic type, 84.2%/94.7% for the mixed type and 25.0%/87.5% for the invisible type. The visualisation rates of bone scintigraphy for the blastic type and FDG-PET for the invisible type were significantly higher. The SUV_mean of the blastic, lytic, mixed and invisible types were 1.72±0.28, 4.14±2.20, 2.97±1.98 and 2.25±0.80, respectively, showing that the SUV_mean tended to be higher for the lytic type than for the blastic type.Conclusion FDG-PET showed a low visualisation rate in respect of osteoblastic bone metastases. Although FDG-PET is useful for detection of bone metastases from breast cancer, it is apparent that it suffers from some limitations in depicting metastases of the osteoblastic type.An editorial commentary on this paper is available at     

<Superscript>188</Superscript>Re-HEDP combined with capecitabine in hormone-refractory prostate cancer patients with bone metastases: a phase I safety and toxicity study

Purpose

¹⁸⁸Re-HEDP is indicated for the treatment of pain in patients with painful osteoblastic bone metastases, including hormone-refractory prostate cancer patients. Efficacy may be improved by adding chemotherapy to the treatment regimen as a radiation sensitizer. The combination of ¹⁸⁸Re-HEDP and capecitabine (Xeloda®) was tested in a clinical phase I study.

Methods

Patients with hormone-refractory prostate cancer were treated with capecitabine for 14 days (oral twice daily in a dose escalation regimen with steps of 1/3 of 2,500 mg/m² per day in cohorts of three to six patients, depending on toxicity). Two days later patients were treated with 37 MBq/kg ¹⁸⁸Re-HEDP as an intravenous injection. Six hours after treatment post-therapy scintigraphy was performed. Urine was collected for 8 h post-injection. Follow-up was at least 8 weeks. The primary end-point was to establish the maximum tolerable dose (MTD) of capecitabine when combined with ¹⁸⁸Re-HEDP. Secondary end-points included the effect of capecitabine on the biodistribution and pharmacokinetics of ¹⁸⁸Re-HEDP.

Results

Three patients were treated in the first and second cohorts, each without unacceptable toxicity. One of six patients in the highest cohort experienced unacceptable toxicity (grade 4 thrombopaenia). The MTD proved to be the maximum dose of 2,500 mg/m² per day capecitabine. No unexpected toxicity occurred. Capecitabine had no effect on uptake or excretion of ¹⁸⁸Re-HEDP.

Conclusion

Capecitabine may be safely used in combination with ¹⁸⁸Re-HEDP in a dose of 2,500 mg/m² per day and 37 MBq/kg, respectively. Efficacy will be further studied in a phase II study using these dosages.

     

An investigation into the incidence of pain flare in patients undergoing radiotherapy for symptomatic bone metastases

IntroductionExternal Beam Radiotherapy (EBRT) is a recognised intervention for symptomatic pain relief from bone metastases. Pain flare is a reported EBRT toxicity, described in 16–41% of steroid-naïve patients. This study aimed to determine incidence and duration of pain flare amongst patients within one Oncology Centre.MethodsPatients receiving EBRT for bone metastases were recruited to a prospective cohort study. Baseline pain scores and a daily pain/analgesia diary were recorded during EBRT and for 14 days thereafter. Pain flare was defined as a two-point increase on a pain scale or 25% increase in analgesia intake, with a return to baseline.ResultsOf the thirty-two participants, 69% (n = 22) completed the diary. 41% (n = 9) patients experienced pain flare, the median duration being 3 days. Of the evaluable patients, 55% (n = 12) were male, 45% (n = 9) female. The median age was 73 years (range 40–83). The common primary sites of disease were Breast (32%) and Prostate (32%), with other sites making up the remaining 36%. The most frequent EBRT site was the spine (63%), with other treatment sites including pelvis (23%) and extremities (14%). EBRT regimes were restricted to 20 Gy in 5 treatments, received by 32% (n = 7) of patients and 8 Gy in 1 treatment (68% (n = 14)). Of these two regimes, pain flare was reported by 29% and 47% respectively.ConclusionPain flare is a common toxicity of EBRT for bone metastases. Taking the small sample size into consideration, the incidence and duration of pain flare in patients within this single-centre study are comparable with those found in international studies.     

<Superscript>188</Superscript>Re-labelled gemcitabine/bisphosphonate (Gem/BP): a multi-functional,bone-specific agent as a potential treatment for bone metastases

PURPOSE: This study investigated the bone-binding affinity and biodistribution of a (188)Re-labelled gemcitabine/bisphosphonate (Gem/BP) conjugate, a multi-functional drug designed to deliver tumour-specific combined radiotherapy and chemotherapy to the bone using the high bone-binding affinity of the bisphosphonate group. METHODS: The Gem/BP conjugate was labelled at high radiochemical purity with (188)Re. The bone-binding affinity of the (188)Re-Gem/BP was studied in vitro in purified hydroxyapatite emulsion and powdered bovine bone. In vivo biodistribution studies were carried out in normal BALB/c mice. RESULTS: (188)Re-Gem/BP demonstrated strong and stable binding in both in vitro systems. In vivo (188)Re-Gem/BP showed bone uptake, rapid blood clearance and rapid elimination of unbound activity. The bone tissue demonstrated the highest concentration of bound radioactivity exempting the kidneys. Approximately 67% of retained whole-body activity was bound to the bone at 8 h after (188)Re-Gem/BP administration. CONCLUSIONS: (188)Re-Gem/BP demonstrated high, selective and persistent bone binding and can be considered as a model compound for multi-functional bone-specific therapy for bone metastases.     

Whole-body iodine-131 metaiodobenzylguanidine imaging for detection of bone metastases in patients with paraganglioma: comparison with bone scintigraphy

Iodine-131 metaiodobenzylguanidine (¹³¹I-MIBG) therapy is an effective treatment for patients with malignant paraganglioma for which surgical resection is not indicated. We performed high-dose ¹³¹I-MIBG therapy on two patients with malignant paraganglioma and multiple bone metastases. The bone metastases were diagnosed by magnetic resonance imaging (MRI). Metastatic bone lesions were evaluated by whole-body ¹³¹I-MIBG imaging and bone scintigraphy. Whole-body ¹³¹I-MIBG imaging showed extensive metastatic bone lesions, whereas conventional bone scintigraphy did not. There was a remarkable discrepancy between ¹³¹I-MIBG imaging and bone scintigraphy in the diagnosis of metastatic bone lesions of malignant paraganglioma in our two patients. High-dose ¹³¹I-MIBG imaging may detect early stages of bone metastases, compared with bone scintigraphy, in patients with malignant paraganglioma.