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.     

Clinical benefit of bone-targeted radiometabolic therapy with 153Sm-EDTMP combined with chemotherapy in patients with metastatic hormone-refractory prostate cancer

Background Bone metastases are responsible for most of the morbidity associated with hormone-refractory prostate cancer (HRPC). ¹⁵³Sm-ethylenediaminetetramethylene phosphonate (¹⁵³Sm-EDTMP) has been approved for palliation of painful skeletal metastases. We retrospectively investigated the possible synergistic effect on survival of ¹⁵³Sm-EDTMP (given to HRPC patients for bone pain palliation) and chemotherapy. Methods Forty-five HRPC patients were evaluated, with a median age of 71 years. The number of metastatic bone sites was ≤10 in 25 patients and >10 in 20 patients. Median serum PSA was 224 ng/ml. Bone pain was mild in 6 patients, moderate in 16, severe in 22 and intolerable in 1. Fifteen patients were only treated with ¹⁵³Sm-EDTMP (group A), while 30 patients also received chemotherapy (estramustine phosphate or mitoxantrone plus prednisone) at variable times: between 3 and 5 months after ¹⁵³Sm-EDTMP (14 patients, group B) or within 1 month after ¹⁵³Sm-EDTMP (16 patients, group C). Results Haematological toxicities observed after either regimen were in general mild, consistent with common observations after either ¹⁵³Sm-EDTMP or chemotherapy, and without any additive adverse effects in the patients receiving both ¹⁵³Sm-EDTMP and chemotherapy. Bone pain palliation to some degree was induced by ¹⁵³Sm-EDTMP in 32/45 patients (71.1%), the proportion of patients with a favourable clinical response being significantly higher in group C than in group A (87.5% vs 53.3%, p = 0.0388). Also in terms of biochemical response (serum PSA levels), patients of group C performed significantly better than patients of group A (p = 0.0235). Overall median survival from the time of administration of ¹⁵³Sm-EDTMP was 15 months in the total cohort of 45 patients, and was significantly longer in group C than in either group B (30 months vs 11 months, p = 0.023) or group A (30 months vs 10 months, p = 0.008). Conclusion The results of this study confirm that ¹⁵³Sm-EDTMP is effective in terms of pain relief and PSA response, with minimal toxicity. When it was administered in combination with chemotherapy, prolonged survival indicated actual clinical benefit, while there were no additive toxicities. These results provide the rationale for future prospective evaluation of combined therapeutic strategies.     

<Superscript>131</Superscript>I-MIBG Therapy in metastatic phaeochromocytoma and paraganglioma

Purpose ¹³¹Iodine metaiodobenzylguanidine (¹³¹I-MIBG) is a radiopharmaceutical used for scintigraphic localisation of phaeochromocytomas and paragangliomas. The experience with its therapeutic use is limited. We report our experience for the treatment of malignant phaeochromocytoma and paraganglioma. Materials and methods The charts of 19 patients with malignant phaeochromocytoma (n = 12) or paraganglioma (n = 7), who were treated with ¹³¹I-MIBG, were retrospectively reviewed. Four patients (21%) received radiotherapy, three (16%) chemotherapy, and in one patient (5%), both chemotherapy and radiotherapy was given before ¹³¹I-MIBG therapy. Response to ¹³¹I-MIBG treatment was evaluated by objective as tumour response, biochemical and subjective response. Results Of the 19 patients, 13 (68%) were men, 6 (32%) were women. Ages ranged from 22 to 68 years (median, 47). The median initial dose was 7.4 GBq (200 mCi; range, 6.7 GBq–25.9 GBq, 180–700 mCi); median cumulative dose was 22.2 GBq (600 mCi; range, 6.8 GBq–81.4 GBq, 183–2200 mCi). Objective tumour response was achieved in 47% of the patients. Biochemical response rate was 67%, and symptomatic response was seen in 89% of the patients. Overall median follow-up was 29 months, with a range of 3–93 months. Haematologic complications were the most common side effects and were observed in 26% of the patients. Conclusion Our data support that symptomatic and biochemical response can be reached with ¹³¹I-MIBG therapy in patients with metastatic phaeochromocytoma and paraganglioma. Although complete tumour response was not observed, the palliation and control of tumour function by ¹³¹I-MIBG therapy may be valuable for the patients.     

186Re-HEDP in the treatment of patients with inoperable osteosarcoma.

The aim of this study was to examine the safety and efficacy of (186)Re-hydroxyethylidene diphosphonate (HEDP) as an adjuvant to external-beam radiotherapy (EBRT) in the treatment of patients with osteosarcoma. METHODS: Thirteen patients (9 male, 4 female; age range, 12-42 y) were treated with combination chemotherapy (standard U.K. protocol) and (186)Re-HEDP therapy (18.5 MBq/kg, intravenously), followed by EBRT. A full blood count; liver function test; and measurements of urea and electrolytes, glomerular filtration rate, and left ventricular function were performed on all patients before and after therapy. Tumor volume and composition were obtained from CT or MRI data. Dosimetric calculations were performed using the MIRD formalism. RESULTS: Of the 13 patients, 1 is still under follow-up. The median survival time was 36 mo (range, 12-216 mo) from diagnosis and 5 mo (range, 1-60 mo) from the last (186)Re-HEDP treatment. The mean tumor dose delivered with (186)Re-HEDP was calculated to be 5.8 Gy (range, 0.5-16 Gy). CT and MRI revealed the tumors to have a complex structure, comprising "ossified," "partially calcified," and "soft-tissue" components. Posttherapy scans showed a heterogeneous distribution of (186)Re-HEDP in the tumor mass: Although the "soft-tissue" component showed minimal uptake of the therapeutic dose, the "ossified component" showed intense uptake. The 3 long-term survivors in whom tumor sterilization was achieved received calculated mean tumor doses in the range of 2.0-3.1 Gy, which was believed to be an underestimate of the actual tumor doses delivered. CONCLUSION: This study indicates that a simple approach to tumor dosimetry based on mean tumor dose is inappropriate because it may underestimate the dose delivered to these heterogeneous tumors. The data also indicate that EBRT combined with a standard dose of 18.5 MBq/kg of (186)Re-HEDP does not provide a sufficient dose to achieve tumor sterilization. A dose estimation technique is required that is based on the determination of tumor dose at the individual voxel level and that is able to represent the heterogeneous uptake observed in these complex tumor structures with highly nonuniform composition. This, coupled with individualized dose escalation, may then achieve the goal of tumor sterilization.     

Inadequacy of manual measurements compared to automated CT volumetry in assessment of treatment response of pulmonary metastases using RECIST criteria

The purpose of this study was to compare relative values of manual unidimensional measurements (MD) and automated volumetry (AV) for longitudinal treatment response assessment in patients with pulmonary metastases. Fifty consecutive patients with pulmonary metastases and repeat chest multidetector-row CT (median interval=2 months) were independently assessed by two radiologists for treatment response using Response Evaluation Criteria In Solid Tumours (RECIST). Statistics included relative measurement errors (RME), intra-/interobserver correlations, limits of agreement (95% LoA), and kappa. A total of 202 metastases (median volume=182.22 mm³; range=3.16–5,195.13 mm³) were evaluated. RMEs were significantly higher for MD than for AV (intraobserver RME=2.34–3.73% and 0.15–0.22% for MD and AV respectively; P<0.05. Interobserver RME=3.53–3.76% and 0.22–0.29% for MD and AV respectively; P<0.05). Overall correlation was significantly better for AV than for MD (P<0.05). Intraobserver 95% LoAs were −1.85 to 1.75 mm for MD and −11.28 to 9.84 mm³ for AV. The interobserver 95% LoA were −1.46 to 1.92 mm for MD and −11.17 to 9.33 mm³ for AV. There was total intra-/interobserver agreement on response using AV (κ=1). MD intra- and interobserver agreements were 0.73–0.84 and 0.77–0.80 respectively. Of the 200 MD response ratings, 28 (14/50 patients) were discordant. Agreement using MD dropped significantly from total remission to progressive disease (P<0.05). We therefore conclude that AV allows for better reproducibility of response evaluation in pulmonary metastases and should be preferred to MD in these patients.     

Internal radiotherapy using 32P colloid or microsphere for refractory solid tumors

Objective  The aim of this work was to study the effectiveness of ³²P colloids or microspheres, by arterial interventional administration or stromal injection in the treatment of refractory solid tumors. Methods  By arterial intervention, under the guidance of computerized tomography, X-ray, ultrasonogram, or under direct vision of the surgical field, ³²P microspheres (259–685 MBq) or radioactive colloid (281–666 MBq) was administered to 60 cases with refractory solid tumors. Tumor inhibition rate, side effects, survival period, and so on were observed. Results  The tumor growth was obviously inhibited after the intratumoral injection of ³²P colloid. The average survival time in the 60 cases was 35 months with a high tumor inhibition rate (93.4%). Thirty-one cases were completely relieved (51.7%), and 25 cases achieved partial remission (PR, 41.7%). One case with right lobe hepatocellular carcinoma has survived 90 months. The drug was ineffective only in four cases, including one patient who died of gastrointestinal hemorrhage and three of hepatic failure. No other obvious side effects were observed. Intratumoral necrosis, intense fibrosis in the tumor mass, and an integrated capsule encompassing the tumor were revealed by histological examination. Conclusions  Arterial interventional administration or stromal injection with ³²P microspheres or colloid revealed a very fair clinical effectiveness in the treatment of refractory solid tumors. The range of safe effective dosage for ³²P glass microspheres and ³²P chromic phosphate in one treatment course is 555–740 MBq and 185–370 MBq, respectively.     

Transarterial Radioembolization Treatment of Pancreatic Cancer Patients with Liver-Dominant Metastatic Disease Using Yttrium-90 Glass Microspheres: A Single-Institution Retrospective Study

PurposeTo retrospectively evaluate the safety and efficacy of transarterial radioembolization (TARE) with yttrium-90 (⁹⁰Y)-labeled glass microspheres in pancreatic adenocarcinoma patients with liver-dominant metastatic disease.Materials and MethodsThis retrospective, single-center study evaluated 26 patients (12 men and 14 women; mean age, 65.5 ± 11.2 years) with liver-dominant metastatic pancreatic cancer who were treated with TARE from April 2010 to September 2017. All patients received systemic chemotherapy before TARE, and 19 received systemic therapy after embolization. Nineteen patients had extrahepatic disease at the time of TARE. Response to treatment was determined by Response Evaluation Criteria in Solid Tumors at 3 months.ResultsMedian overall survival (OS) from pancreatic cancer diagnosis was 33.0 months (range, 8.5–87.5 months); median OS from diagnosis of liver metastasis was 21.8 months (range, 2.0–86.2 months); and median OS from TARE treatment was 7.0 months (range, 1.0–84.1 months). Grade 1–2 clinical toxicities were noted in 21 patients (80.8%), and 24 patients (92.3%) had grade 1–2 biochemical toxicities. Four patients (15.4%) had grade 3 clinical toxicities, and 6 patients (23.1%) had grade 3 biochemical toxicities. Imaging was available in 22 patients (84.6%) and demonstrated partial response in 1 patient, stable disease in 9 patients, and progressive disease in 12 patients. Improved hepatic progression-free survival was associated in patients younger than 65 years and in those whose carbohydrate antigen 19-9 level decreased or remained stable after treatment.ConclusionsTARE with ⁹⁰Y-labeled glass microspheres is safe and led to promising OS in liver-dominant metastatic pancreatic cancer.     

A randomised,phase II study of repeated rhenium-188-HEDP combined with docetaxel and prednisone versus docetaxel and prednisone alone in castration-resistant prostate cancer (CRPC) metastatic to bone; the Taxium II trial

Background

Rhenium-188-HEDP is a beta-emitting radiopharmaceutical used for palliation of metastatic bone pain. We investigated whether the addition of rhenium-188-HEDP to docetaxel/prednisone improved efficacy of chemotherapy in patients with CRPC.

Methods

Patients with progressive CRPC and osteoblastic bone metastases were randomised for first-line docetaxel 75 mg/m² 3-weekly plus prednisone with or without 2 injections of rhenium-188-HEDP after the third (40 MBq/kg) and after the sixth (20 MBq/kg) cycle of docetaxel. Primary endpoint was progression-free survival (PFS), defined as either PSA, radiographic or clinical progression. Patients were stratified by extent of bone metastases and hospital.

Results

Forty-two patients were randomised for standard treatment and 46 patients for combination therapy. Median number of cycles of docetaxel was 9 in the control group and 8 in the experimental group. Median follow-up was 18.4 months. Two patients from the experimental group did not start treatment after randomisation. In the intention to treat analysis no differences in PFS, survival and PSA became apparent between the two groups. In an exploratory per-protocol analysis median overall survival was significantly longer in the experimental group (33.8 months (95%CI 31.75–35.85)) than in the control group (21.0 months (95%CI 13.61–28.39); p 0.012). Also median PFS in patients with a baseline phosphatase >220U/L was significantly better with combination treatment (9.0 months (95%CI 3.92–14.08) versus 6.2 months (95%CI 3.08–9.32); log rank p 0.005). As expected, thrombocytopenia (grade I/II) was reported more frequently in the experimental group (25% versus 0%).

Conclusion

Combined treatment with rhenium-188-HEDP and docetaxel did not prolong PFS in patients with CRPC. The observed survival benefit in the per-protocol analysis warrants further studies in the combined treatment of chemotherapy and radiopharmaceuticals.

     

The effect of androgen deprivation therapy on 68 Ga-PSMA tracer uptake in non-metastatic prostate cancer patients

To evaluate the effect of neoadjuvant androgen deprivation treatment (ADT) on prostate-specific membrane antigen (PSMA) tracer uptake demonstrated in 68Ga-PSMA-positron emission tomography (PET/CT) in non-metastatic hormone-naïve prostate cancer (PC) patients. The clinical data of 108 PC patients who received neoadjuvant ADT were retrospectively analyzed. All patients had a baseline 68Ga-PSMA-PET/CT scan, and a second scan was delivered median of 2.9 months after the initiation of ADT. The maximum standardized uptake value (SUVmax) of primary tumor (SUVp) and metastatic lymph nodes (SUVln) as well as PSA response were assessed between pre- and post-ADT 68Ga-PSMA-PET/CT scans. There were significant decreases in posttreatment serum PSA, SUVp, and SUVln. A decrease in SUVp was seen in 91 patients (84%) with a median value of 66% (range, 5–100%), while 17 patients (16%) had no change in or an increase in PSMA tracer uptake with a median value of 24% (range, 0–198%). Patients with Gleason score (GS) of 7 had significantly higher metabolic response rates compared to other patients. The disease progression was significantly higher only in patients with GS > 7 disease compared to GS 7 disease. The PSA response to ADT was the lowest in patients with ISUP high-grade tumors. A total of 16 patients (15%) had progressive disease, and in 9 patients (8%), radiotherapy decisions were modified according to posttreatment 68Ga-PSMA-PET/CT scans. The current study includes the largest number of patients analyzed to date and demonstrates that ADT causes a significant decrease in serum PSA values and SUVp and SUVln. The authors demonstrate that 68Ga-PSMA-PET/CT may be used as a quantitative imaging modality after neoadjuvant ADT in hormone-naïve non-metastatic PC patients.     

Strontium-89 for palliation of pain from bone metastases in patients with prostate and breast cancer

We have used strontium-89 chloride (⁸⁹Sr) for the palliative treatment of metastatic bone pain. Seventy-six patients (50 males with prostate carcinoma and 26 females with breast cancer) were treated with 148 MBq of ⁸⁹Sr. Sixteen patients were retreated, receiving two or three doses; the total number of injected doses was consequently 95. 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 treament. Three levels of response were considered: good – when there was an increase in the Karnofsky status and a decrease in the pain score (equal to or higher than 4) or analgesic score (equal to or higher than 1); partial – when there was an increase in the Karnofsky status and a decrease in the pain score (2 or 3 points) without significant changes in the analgesic score; no response – if no variation or deterioration in these parameters was observed. In prostate cancer patients, the response was good in 64% of cases and partial in 25%, and there was no response in the remaining 11%. In breast cancer patients, the response was good in 62% of cases and partial in 31%, and there was no response in the remaining 8%. Duration of the response ranged from 3 to 12 months (mean 6 months). In the patients who were retreated the effectiveness was as good as after the first dose of ⁸⁹Sr. A decrease in the initial leucocyte and platelet counts was observed after the 1st month of treatment, with a gradual partial to complete recovery within 6 months. It is concluded that ⁸⁹Sr is an effective agent in palliative therapy for metastatic bone pain in patients with prostate or breast carcinoma. If required, retreatment can be administered safely and with the same efficacy as is achieved by the first dose. Received 13 March and in revised form 6 June 1997     

Therapeutic effects of a 186Re-complex-conjugated bisphosphonate for the palliation of metastatic bone pain in an animal model.

Previously, based on the concept of bifunctional radiopharmaceuticals, we developed a highly stable (186)Re-mercaptoacetylglycylglycylglycine (MAG3) complex-conjugated bisphosphonate, [[[[(4-hydroxy-4,4-diphosphonobutyl)carbamoylmethyl]carbamoylmethyl]carbamoylmethyl]carbamoylmethanethiolate] oxorhenium(V) ((186)Re-MAG3-HBP), for the treatment of painful bone metastases. This agent showed a superior biodistribution as a bone-seeking agent in normal mice when compared with (186)Re-1-hydroxyethylidene-1,1-diphosphonate ((186)Re-HEDP). In this study, we evaluated the therapeutic effects of (186)Re-MAG3-HBP using an animal model of bone metastasis. METHODS: The model was prepared by injecting syngeneic MRMT-1 mammary tumor cells into the left tibia of female Sprague-Dawley rats. (186)Re-MAG3-HBP (55.5, 111, or 222 MBq/kg) or (186)Re-HEDP (55.5 MBq/kg) was then administered intravenously 21 d later. To evaluate the therapeutic effects and side effects, tumor size and peripheral blood cell counts were determined. Palliation of bone pain was evaluated by a von Frey filament test. RESULTS: In the rats treated with (186)Re-HEDP, tumor growth was comparable with that in untreated rats. In contrast, when (186)Re-MAG3-HBP was administered, tumor growth was significantly inhibited. Allodynia induced by bone metastasis was attenuated by treatment with (186)Re-MAG3-HBP or (186)Re-HEDP, but (186)Re-MAG3-HBP tended to be more effective. CONCLUSION: These results indicate that (186)Re-MAG3-HBP could be useful as a therapeutic agent for the palliation of metastatic bone pain.     

Transacatheter arterial embolization for malignant osseous and soft tissue sarcomas. II. Clinical results

Purpose: To evaluate the clinical effects of transcatheter arterial embolization (TAE) on malignant bone and soft tissue tumors. Methods: TAE was performed in 10 patients with primary bone and soft tissue sarcomas and in 31 patients with metastatic bone tumors. The embolized arteries were the internal iliac artery in 30 cases, the intercostal artery in six cases, the lumbar artery in five cases, the suprascapular artery in three cases, and the iliolumbar artery, the internal pudendal artery, and the lateral sacral artery in one case each. The embolized material was gelatin sponge particles. The chemotherapeutic drugs were usually 20–40 mg of doxorubicin for primary and metastatic tumors and 50–100 mg of cisplatin only for primary tumors. In addition, 50–60 Gy of 10-MV radiotherapy with or without radiofrequency (RF)-capacitive hyperthermia in four sessions was administered before TAE for primary tumors only. Results: Even though the pain score increased immediately after TAE, 30 of 38 (79%) patients with pain (8 of 9 with primary tumors, and 22 of 29 with metastases) achieved pain control after TAE. A necrotic low-density area shown by computed tomography (CT) after TAE was found in 31 of 41 (76%) tumors [8 of 10 (80%) with primary tumors, and 23 of 31 (74%) with metastatic tumors]. The tumor size decreased in 14 of 25 (56%) primary and metastatic tumors after 3 months. Osteosclerotic changes appeared in two cases of metastatic tumors after 6 months. In five tumors resected after TAE, large areas of necrosis within the tumor were confirmed histologically. Transient local pain and numbness appeared after TAE, but were relieved by drug treatment within 1 week. No severe complications except a case of gluteal muscle necrosis were encountered after TAE. The 1-year survival rate of the patients with primary tumors was 38.1%, and the median survival was 18 months. The longest survival was 84 months. The 1-year survival rate of the patients with metastatic bone tumors was 38.9%; the median survival was 12 months. The longest survival was 24 months. Conclusion: TAE could be an effective treatment for pain control and local control of malignant bone and soft-tissue tumors.     

Bland Embolization of Hepatocellular Carcinoma Using Superabsorbent Polymer Microspheres

The purpose of this study was to investigate the clinical outcomes of bland embolization using superabsorbent polymer microspheres (SAP-TAE) as an initial therapeutic option for previously untreated hepatocellular carcinoma (HCC) ineligible for resection or ablation. Fifty-nine patients with previously untreated HCC unamenable to surgery or ablation underwent bland embolization using 100- to 200-μm reconstituted SAP particles (SAP-TAE) as the initial treatment. SAP-TAE was repeated as needed based on tumor response but was switched to chemoembolization when necessary to control residual or progressive tumor. Early tumor response was assessed by contrast-enhanced CT according to RECIST and EASL criteria 1 month after the initial SAP-TAE. The overall survival was calculated using the Kaplan–Meier method. The overall mean follow-up period was 30.6 months (range, 7–59 months). A total of 121 sessions of SAP-TAE were performed, with 1–5 sessions per patient (mean, 2.1 sessions). The mean period of repeated SAP-TAE was 15.6 months (range, 1–51 months), and it exceeded 1 and 2 years in 32 (54%) and 15 (25%) patients, respectively. Thirteen (22%) patients underwent repeated SAP-TAE alone, and the remaining 46 (78%) patients underwent subsequent chemoembolization. No major complication was observed and postembolization syndrome was minimal after SAP-TAE in all patients. Response rate was 14% and 66% by RECIST and EASL criteria, respectively. Overall survival rates were 100% and 83% at 1 and 2 years, respectively, and median survival time was 30 months. In conclusion, SAP-TAE was a safe and repeatable option as the induction therapy for HCC unamenable to surgery or ablation, despite the high incidence of converting to TACE during the total course.     

Use of carbon-11 methionine positron emission tomography to assess malignancy grade and predict survival in patients with lymphomas

The aim of this study was to investigate whether uptake of carbon-11 methionine (MET) is associated with histological grade of malignancy and survival in patients with newly diagnosed or recurrent lymphoma. Thirty-two patients with histologically confirmed lymphoma participated in the study. Twenty-six (81%) were studied before any therapy and six before treatment for recurrent disease. Twenty-eight patients had non-Hodgkin’s lymphoma and four had Hodgkin’s disease. An ECAT 931/08-12 positron emission tomography (PET) scanner was used for PET imaging. After the transmission scan, a median dose of 293 MBq of MET was injected intravenously and dynamic images were acquired for 40 min. The uptake of MET in tumour was measured as the standardized uptake value (SUV) and influx constant (K _i). The SUV formula was also adjusted to the predicted value of lean body mass (SUV_lean) and body surface area (SUV_BSA). The PET results were correlated with the clinical follow-up data. The median SUV in 32 malignant lesions was 6.6 (range, 1.9–12.4) and the median K _i was 0.116 min⁻¹ (range, 0.025–0.201, n=23). The median SUV was 7.0 (range, 5.4–12.4, n=9) in high, 6.2 (range, 1.9–10.4, n=11) in intermediate and 5.7 (range, 3.8–8.3, n=8) in low grade lymphomas. One intermediate grade lymphoma of the skin was visually negative (SUV 1.9). In Hodgkin’s disease the median SUV was 7.0 (range, 3.2–7.9, n=4). The median K _i value was 0.162 min⁻¹ (range, 0.147–0.197, n=7) in high, 0.099 (range, 0.025–0.152, n=10) in intermediate, and 0.078 (range, 0.056–0.152, n=4) in low grade lymphomas and 0.149 (range, 0.096–0.201, n=2) in Hodgkin’s disease. The difference between high and other grade non-Hodgkin’s lymphomas was significant when using K _i (P<0.001), but not with SUV, SUV_lean or SUV_BSA. The final outcome of the patients was not related to MET uptake. Lymphomas with a high K _i value tended to have a high S-phase fraction (r ²=0.46, P=0.043). It is concluded that MET PET is highly sensitive for the detection of untreated and recurrent lymphomas. Differentation of high grade lymphomas from lower malignancy grades seems to be possible if graphical analysis is applied to calculate K _i for MET. However, prediction of survival is not possible with MET PET. Received 5 March and in revised form 25 April 1998     

Evaluation of toxicity and efficacy of 186Re-hydroxyethylidene diphosphonate in patients with painful bone metastases of prostate or breast cancer.

Twenty-eight patients (12 men with prostate cancer, 16 women with breast cancer) were included in a phase II trial to evaluate the efficacy of 186Re-hydroxyethylidene diphosphonate (HEDP) on pain from bone metastasis and the toxicity of this agent. METHODS: After intravenous administration of 1295 MBq 186Re-HEDP, the efficacy was evaluated by means of a daily log. RESULTS: We observed an objective response in 67% of prostate cancer patients and in 36% of breast cancer patients. The mean duration of response was 45 d for prostate cancer patients and 24 d for breast cancer patients. No major adverse effects were observed. Marrow toxicity did not exceed grade 2 for white blood cells and grade 3 for platelets using National Cancer Institute criteria. CONCLUSION: 186Re-HEDP provides safe symptomatic relief of pain in prostate cancer patients. The benefit of this treatment is less clear in breast cancer patients. Further studies should be conducted to evaluate treatment by 186Re-HEDP at an earlier stage of the disease.     

[18F]fluorocholine PET/CT imaging for the detection of recurrent prostate cancer at PSA relapse: experience in 100 consecutive patients

Purpose We evaluated the potential of PET/CT and [¹⁸F]fluoromethylcholine (FCH) in the assessment of suspected recurrence of prostate cancer after treatment. Methods One hundred consecutive prostate cancer patients with a persistent increase in serum PSA (>0.1 ng/ml) after radical prostatectomy (58 cases), radiotherapy (21 cases) or hormonal therapy alone (21 cases) were investigated. After injection of 3.7–4.07 MBq/kg of FCH, both early (at <15 min) and delayed (at >60 min) PET/CT scans were performed in 43 patients, delayed PET/CT scans in 53 patients and early PET/CT scans in four patients. Results Of the 100 patients, 54 (PSA 0.22–511.79 ng/ml) showed positive FCH PET/CT scans. Thirty-seven patients had bone and/or abdominal lymph node uptake, while 17 showed pelvic activity. Malignant disease was confirmed in all but one. Delayed SUV_max of bone metastases was significantly higher (p<0.0001 by paired t test) than that measured at <15 min, whereas no differences were observed between early and delayed SUVs of malignant lymph nodes or pelvic disease. Forty-six patients (PSA 0.12–14.3 ng/ml) showed negative FCH PET/CT scans. Of the negative PET/CT scans, 89% were obtained in patients with serum PSA <4 ng/ml and 87% in patients with a Gleason score <8. In none of these cases could recurrent tumour be proven clinically during a follow-up of 6 months. Conclusion FCH PET/CT is not likely to have a significant impact on the care of prostate cancer patients with biochemical recurrence until PSA increases to above 4 ng/ml. However, in selected patients, FCH PET/CT helps to exclude distant metastases when salvage local treatment is intended.     

Is bracing after anterior cruciate ligament reconstruction necessary? A 2-year follow-up of 78 consecutive patients rehabilitated with or without a brace

The aim of this study was to evaluate the effect of a standard postoperative rehabilitation knee brace on function, stability and postoperative complications at the 2-year follow-up after anterior cruciate ligament (ACL) reconstructive surgery. Seventy-eight consecutive patients with a unilateral chronic ACL rupture reconstructed by the same surgeon using the endoscopic “all-inside” technique, patellar tendon autograft and interference screw fixation were included in the study. The rehabilitation followed a standard protocol. Group A included 39 patients who were supplied postoperatively with a knee brace for 4 (range 3–6) weeks. Group B included 39 patients for whom a brace was not used. The median age was 27 (range 16–48) years in group A and 26 (range 14–51) years in group B. The median time period between the injury and the index operation was 24 (range 3–150) months in group A and 18 (range 3–360) months in group B. All 78 patients were re-examined by two independent observers after a median follow-up period of 25 (range 23–28) months in group A and 24 (range 22– 27) months in group B. The median KT-1000 total side-to-side difference between the reconstructed and the uninjured knees at 89 N was 3 (range –5.5–11) mm in group A and 3 (range –7–10) mm in group B (NS). When the anterior translation was tested separately at 89 N, the corresponding values were 3 (range –4–13) mm in group A and 3 (range –5–10) mm in group B (NS). The median one-leg hop quotient was 95% (range 50%–167%) of the uninjured leg in group A and 92% (range 64%–119%) in group B (NS). The median Lysholm score was 89 (range 39–100) points in group A and 85 (range 37–100) points in group B (NS). In group A, 27/39 (69%) patients and in group B 21/39 (54%) patients were classified as excellent or good (NS). The median Tegner activity level was 7 (range 3–9) in group A and 6 (range 3–9) in group B (NS). Using the IKDC scale, 27/39 (69%) in group A and 24/39 (62%) in group B were classified as normal or nearly normal (NS). The median sick leave in group A was 62 (range 0–357) days and 59 (range 0–243) days in group B (NS). No serious complications occurred during the first 6 postoperative weeks. Two serious complications were, however, registered after the 6th postoperative week. One patient in group A sustained a rupture of the reconstructed ACL 8 weeks postoperatively (3 weeks after removing the brace), and one patient in group B sustained an undislocated patellar fracture during the 7th postoperative week after a fall. This study indicates that the use of a postoperative rehabilitation brace after an arthroscopic ACL reconstruction did not appear to influence either objective stability or subjective function by the 2-year follow-up. Received: 23 December 1996 Accepted: 15 April 1997     

188Re—HEDP治疗肿瘤骨转移痛药代动力学研究

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

Pharmacokinetics of rhenium-186 after administration of rhenium-186-HEDP to patients with bone metastases.

The pharmacokinetics of 186Re-HEDP, a radiopharmaceutical for palliative treatment of metastatic bone pain, was investigated in 11 patients (17 studies) who suffered from metastatic breast or prostate cancer. Half-life times of 186Re in three blood fractions (whole blood, plasma and plasma water) were 40.1 +/- 5.0, 41.0 +/- 6.0 and 29.5 +/- 6.4 hr, respectively. Time-dependent increase in plasma-protein binding was observed, probably caused by in vivo decomposition of 186Re-HEDP. Total urinary 186Re excretion was 69% +/- 15%, of which 71% +/- 6% was excreted in the first 24 hr after injection. The BSI (i.e., fraction of the skeleton showing scintigraphic evidence of metastatic disease) closely correlated with the fraction of dose non-renally cleared (r = 0.98). This implies that the amount of radioactivity taken up by the skeleton and hence the bone marrow absorbed dose can be predicted from a diagnostic pre-therapy 99mTc-HDP scintigram. The pharmacokinetic behavior indicates that 186Re-HEDP has suitable properties to justify its application.     

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

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