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PSMA PET/CT is a diagnostic technique for patients with prostate cancer. It makes use of a radioligand that specifically binds to 'prostate specific membrane antigen' (PSMA), expressed by the prostate cancer cells. PSMA PET has proven to be highly effective in prostate cancer diagnostics in both primary staging and re-staging. PSMA PET/CT has a much higher accuracy than traditional CT and skeletal scintigraphy for the detection of metastases, allowing metastases to be detected in an earlier stage. The clinical relevance of the improved detection is now under investigation. Staging with PSMA PET/CT sometimes leads to avoiding surgery because distant metastases are found that were not detected with conventional imaging. In the Netherlands, PSMA PET/CT is now indicated both in primary prostate cancer diagnostics for the detection of metastases and for the detection of biochemical recurrence after prostatectomy or after radiotherapy.

Purpose: Prospective validation of 68 Ga prostate specific membrane antigen positron emission tomography/computerized tomography is lacking in initial staging of prostate cancer. In this study we evaluated the diagnostic accuracy of 68 Ga prostate specific membrane antigen positron emission tomography/computerized tomography for detecting lymph node metastasis in patients with intermediate-high risk prostate cancer., Materials and Methods: Patients with newly diagnosed prostate cancer and negative bone scan findings at greater than 10% MSKCC (Memorial Sloan Kettering Cancer Center) risk for lymph node metastasis were prospectively included in study from October 2017 to October 2018. In candidates for extended pelvic lymph node dissection 68 Ga prostate specific membrane antigen positron emission tomography/computerized tomography was performed prior to planned surgery. Scan results were evaluated in a second tumor board meeting to assess a potential change of management. Sensitivity, specificity, and positive and negative predictive value for detecting lymph node metastasis were calculated per patient and per resection template using histopathology as the reference. A positron emission tomography based change of management was also reported., Results: A total of 103 patients were eligible for analysis and 97 extended pelvic lymph node dissections were performed. In 41 patients (42.3%) there was a total of 85 lymph node metastases. Positron emission tomography was positive in 17 patients, resulting in 41.5% patient based sensitivity (95% CI 26.7-57.8) for detecting lymph node metastasis. The patient based specificity rate was 90.9% (95% CI 79.3-96.6), and positive and negative predictive values were 77.3% (95% CI 54.2-91.3) and 67.6% (95% CI 55.6-77.7), respectively. A positron emission tomography based change of treatment was observed in 13 patients (12.6%)., Conclusions: In patients with newly diagnosed prostate cancer at greater than 10% MSKCC risk for lymph node involvement 68 Ga prostate specific membrane antigen positron emission tomography/computerized tomography detected lymph node metastasis with high specificity and moderate sensitivity. This led to a treatment change in 12.6% of patients.

Biochemically recurrent prostate cancer (BCR) is the main indication to perform prostate-specific membrane antigen PET/CT. However, localizing BCR with prostate-specific membrane antigen PET/CT remains challenging in patients with low prostate-specific antigen (PSA) values. Here, we studied the impact of advanced PET image reconstruction methods on BCR localization and interobserver agreement with 18 F-DCFPyL PET/CT scans in patients with BCR and low PSA values. Methods: Twenty-four patients with BCR and a PSA level of less than 2.0 ng/mL were included. PET images were reconstructed with 4-mm voxels and 2-mm voxels, both with and without point-spread function. All scans were interpreted by 4 nuclear medicine physicians. Additionally, PET examinations of 5 patients with primary prostate cancer and confirmed absence of lymph node metastases (after lymph node dissection) were included, to assess the risk of introducing false-positive findings when using advanced reconstruction. Calculation of BCR localization rates (scan positivity) was based on consensus among our readers (≥3 readers regarding a scan positive for BCR), as well as the individual scan interpretations of the readers. Results: In the consensus analysis, BCR localization rates were not higher using advanced reconstruction (62.5%-66.7%) than using 4-mm reconstruction (62.5%). On the basis of individual readings, however, more scans were positive using 2-mm reconstruction (74.0%; 95% confidence interval [CI], 65.0%-82.9%) ( P = 0.027) and 2-mm reconstruction with point-spread function (75.0%; 95% CI, 66.2%-83.8%) ( P = 0.014) than 4-mm reconstruction (65.6%; 95% CI, 56.0%-75.3%). A higher number of lesions was detected on the 2-mm scans (median, 2 lesions; interquartile range, 1-3) than the 4-mm scans (median, 1; interquartile range, 0-3; P = 0.008). The advanced reconstruction methods did not increase interobserver agreement (80.6%-84.7%), compared with the 4-mm scans (75.7%, P = 0.08-0.25). In the patients with primary prostate cancer, an equal number of false-positive lesions was observed among the different reconstruction methods (overall, n = 13). Conclusion: Applying advanced image reconstruction for 18 F-DCFPyL PET/CT scans did not increase BCR localization in patients with BCR and low PSA values (reader consensus). Yet, the increased number of positive individual readings may imply that further development of image reconstruction methods holds potential to improve BCR localization. No improved interobserver agreement was observed with advanced reconstruction compared with standard 4-mm reconstruction., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective: Rhenium-188-HEDP is an effective radiopharmaceutical for the treatment of painful bone metastases from prostate cancer. The effectiveness of the β-radiation emitted by 188 Re might be enhanced by combination with chemotherapy, using the radiosensitization concept. Therefore, the authors investigated the combined treatment of the taxanes, docetaxel and cabazitaxel, with 188 Re in prostate carcinoma cell lines., Materials and Methods: The cytotoxic effects of single and combined treatment with taxanes and 188 Re were investigated in three human prostate carcinoma cell lines (PC-3, DU 145, and LNCaP), using the colony-forming assay. The half maximal effective concentration (EC50) of all individual agents was determined. The combined treatment was studied at 0.25, 0.5, 1, 2, and 4 times the EC50 of each agent. The interaction was investigated with a regression model., Results: The survival curves showed dose-dependent cell growth inhibition for both the taxanes and 188 Re. The regression model showed a good capability of explaining the data. It proved additivity in all combination experiments and confirmed a general trend to a slight subadditive effect., Conclusions: This proof-of-mechanism study exploring radiosensitization by combining 188 Re and taxanes showed no synergism, but significant additivity. This encourages the design of in vivo studies. Future research should explore the potential added value of concomitant treatment of bone metastases with chemotherapy and 188 Re-HEDP.

Aim: Rhenium-188-HEDP ((188)Re-HEDP) is an effective radiopharmaceutical for the palliative treatment of osteoblastic bone metastases. However, only limited data on its routine use are available and its effect on quality of life (QoL) has not been studied. Therefore, we evaluated the clinical benefit of (188)Re-HEDP in routine clinical care., Patients and Methods: Prostate or breast cancer patients with painful bone metastases receiving (188)Re-HEDP as a routine clinical procedure were eligible for evaluation. Clinical benefit was assessed in terms of efficacy and toxicity. Pain palliation and QoL were monitored using the visual analogue scale (VAS), corrected for opioid intake, and the EORTC QLQ-C30 Global health status/QoL-scale. Thrombocyte and leukocyte nadirs were used to assess haematological toxicity., Results: 45 and 47 patients were evaluable for pain palliation and QoL, respectively. After a single injection of (188)Re-HEDP, the overall pain response rate was 69% and mean VAS-scores decreased relevantly and significantly (p < 0.05). Repeated treatment resulted in similar pain response. The overall QoL response rate was 68% and mean Global health status/QoL-scores increased relevantly and significantly. Haematological side effects were mild and transient., Conclusion: The clinically relevant response on pain and quality of life and the limited adverse events prove clinical benefit of treatment with (188)Re-HEDP and support its use in routine clinical care. Its effectiveness appears comparable to that of external beam radiotherapy.

Systemic treatment of men with metastatic prostate cancer is rapidly evolving. Androgen deprivation therapy remains the first-line treatment for advanced disease and the backbone of sequential strategies. For patients with extensive metastatic disease the addition of docetaxel markedly improves survival. In case patients develop castration-resistant prostate cancer, several new therapeutic strategies are available. Large trials have shown a survival benefit for patients treated with sipuleucel-T, docetaxel, cabazitaxel, abiraterone, enzalutamide, or radium-223. Along with these new available treatment options, the sequence of applying them has become a serious matter of debate. In this review we provide an overview of current systemic treatment options for metastatic prostate cancer and propose considerations to optimally sequence registered new therapies. In addition, we hypothesize on improvement of outcome with potential combination strategies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Bone-targeting therapeutic radiopharmaceuticals are effective agents for treatment of painful bone metastases. Rhenium-188-HEDP is such a therapeutic radiopharmaceutical and has advantages over commercially available alternatives in terms of efficacy, safety and the ability to be produced on-site, allowing rapid treatment upon presentation of patients with pain. Unlike many other radiopharmaceuticals, there are no standardized preparation methods for Rhenium-188-HEDP. It is known, however, that drug composition may not only affect stability of the final drug product, but it may also influence bone affinity and, thus, efficacy. Furthermore, for support of clinical studies with Rhenium-188-HEDP as an investigational medicinal product, preparation of this radiopharmaceutical has to be performed under GMP conditions. To our knowledge, no group has reported on the preparation of Rhenium-188-HEDP under GMP conditions or on stock production of sterile non-radioactive starting materials. We present the production of GMP grade Rhenium-188-HEDP for application of this therapeutic radiopharmaceutical in routine clinical practice and for support of clinical studies. In addition, bio-distribution data of Rhenium-188-HEDP in mice and in patients with bone metastases originating from prostate cancer are presented., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose: Bone-seeking radiopharmaceuticals have palliative benefit in castration-resistant prostate cancer (CRPC) metastatic to bone. Recent studies have shown improvement of survival and quality of life when radiopharmaceuticals were given repeatedly or in combination with chemotherapy. We designed a phase I study combining docetaxel and (186)Re-labelled hydroxyethylidene diphosphonate (HEDP) in men with CRPC and bone metastases to evaluate toxicity., Methods: A dose escalation schedule was designed consisting of four dose levels with a standard dosage of docetaxel (75 mg/m(2) 3-weekly). (186)Re-HEDP was given in increasing activities (1,250 MBq up to 2,500 MBq) after the third and sixth cycle of docetaxel. Dose limiting toxicity (DLT) was defined as any grade 4 toxicity lasting more than 7 days or any grade 3 toxicity that did not recover within 10 days. Three patients were planned for each dose level expanding to six if a DLT occurred., Results: Fourteen patients were recruited with a median age of 64.6 years. One DLT, grade 3 thrombocytopenia lasting >10 days, occurred at dose level 3 leading to expansion of this group to six. One of these patients had an episode of acute renal failure which resolved. Because of production problems of (186)Re-HEDP dose level 4 was not started., Conclusion: Combined therapy with docetaxel and (186)Re-HEDP is generally well tolerated in patients with CRPC metastatic to bone. We will conduct a randomized phase II study using three cycles of docetaxel 75 mg/m(2) 3-weekly followed by (188)Re-HEDP 40 MBq/kg body weight, followed by another three cycles of docetaxel 75 mg/m(2), followed by (188)Re-HEDP 20 MBq/kg body weight.

Abstract Bone-seeking radiopharmaceuticals and bisphosphonates may be indicated in patients with cancer with painful osseous metastases to palliate pain symptoms or to prevent skeletal-related events. Both pharmaceuticals may have an additive or even synergistic palliative effect. The combined use of bone-seeking radiopharmaceuticals and bisphosphonates is, however, controversial because of assumed competition between both phosphonate-compounds at the bone level. We report a case of hormone-refractory prostate cancer (HRPC) with multiple painful osseous metastases. The patient was treated with samarium-153-ethylenediaminetetramethylphosphonic acid ((153)Sm-EDTMP; Quadramet, CIS bio International, Saclay, France) in combination with zoledronic acid (Zometa, Novartis, Stein, Switzerland). He was treated for 6 months with 4 weekly intervals of zoledronic acid in combination with 3 monthly intervals of (153)Sm-EDTMP. No negative interaction was found, toxicity was low, and efficacy high. He experienced a total relief of pain, a significant decrease of prostate-specific antigen (PSA) and, surprisingly, a significant decrease of tumor burden.

Purpose: (153)Sm-ethylenediaminetetramethylenephosphonic acid (EDTMP; Quadramet) is indicated for the treatment of painful bone metastases, whereas zoledronic acid (Zometa) is indicated for the prevention of skeletal complications. Because of the different therapeutic effects, combining the treatments may be beneficial. Both, however, accumulate in areas with increased osteoblastic activity. Possible drug interactions were investigated., Methods: Patients with hormone-refractory prostate cancer were treated with 18.5 MBq/kg (153)Sm-EDTMP in weeks 1 and 3 and with 37 MBq/kg in week 15. Treatment with 4 mg zoledronic acid began in week 3 and continued every 4 weeks through week 23. In weeks 3 and 15, zoledronic acid was administered 2 days before (153)Sm-EDTMP treatment. Urine was collected 48 h after injection of (153)Sm-EDTMP, and whole-body images were obtained 6, 24 and 48 h post-injection. The effect of zoledronic acid on total bone uptake of (153)Sm-EDTMP was measured indirectly by the cumulative activity excreted in the urine in weeks 1, 3 and 15. Biodistribution, safety, tolerability and effect on prostate-specific antigen level were also studied., Results: The urinary excretion in week 3 divided by the urinary excretion in week 1 (baseline) times 100% was mean 98.4 +/- 11.6% (median 96.2%). From week 1 to 15, after four zoledronic acid treatments, the mean ratio was 101.9 +/- 10.7% (median 101.8%). Bioequivalence could be concluded by using a two-sample t test for both per-protocol (n = 13) and full-analysis sets (n = 18). Toxicity was comparable to of monotherapy with (153)Sm-EDTMP., Conclusion: Zoledronic acid treatment does not influence (153)Sm-EDTMP skeletal uptake. Combined treatment is feasible and safe.

Unlabelled: (186)Re-1,1-hydroxyethylidene diphosphonate (etidronate) can be used for the palliative treatment of metastatic bone pain. A randomized, placebo-controlled study using (186)Re-etidronate was conducted on end-stage prostate cancer patients with metastatic bone pain., Methods: Pain relief was assessed using an electronic diary containing questions reflecting the multidimensional character of chronic pain. The diary was marked twice daily for a maximum of 14 wk (2 wk before and 12 wk after the injection). Pain response was determined using a specific decision rule in which pain intensity, medication index, and daily activities were the core determinants. A positive response day was defined as a day on which pain intensity was reduced > or = 25% compared with baseline values, while medication index and daily activities were at least constant, or on which pain intensity was reduced < 25% and medication index or daily activities improved > or = 25%, without worsening of the remaining factor. The total response (%) was defined as the number of positive response days divided by the number of days of follow-up., Results: Of the 111 included patients, 79 were evaluable (43 (186)Re-etidronate, 36 placebo). Thirty-two patients were excluded from the analysis because of incomplete datasets. The total response of the patients treated with (186)Re-etidronate varied from 0% to 96% (mean, 27%, or 23/84 d). In the placebo group, the total response varied from 0% to 80% (mean, 13%, or 11/84 d; Mann-Whitney U test, P < 0.05). The number of patients who requested radiotherapy was higher in the placebo group (67%) than in the (186)Re-etidronate group (44%) (relative risk, 1.51; Fisher's exact test, P = 0.069)., Conclusion: This randomized controlled trial confirmed that, compared with placebo, (186)Re-etidronate resulted in a significantly longer pain response in the treatment of bone pain from metastasized prostate cancer.