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      Radium-223 in metastatic castration-resistant prostate cancer: whole-body diffusion-weighted magnetic resonance imaging scanning to assess response

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          Abstract

          Background

          Radium-223 is a bone-seeking, ɑ-emitting radionuclide used to treat men with bone metastases from castration-resistant prostate cancer. Sclerotic bone lesions cannot be evaluated using Response Evaluation Criteria in Solid Tumors. Therefore, imaging response biomarkers are needed.

          Methods

          We conducted a phase 2 randomized trial to assess disease response to radium-223. Men with metastatic castration-resistant prostate cancer and bone metastases were randomly allocated to 55 or 88 kBq/kg radium-223 every 4 weeks for 6 cycles. Whole-body diffusion-weighted magnetic resonance imaging (DWI) was performed at baseline, at cycles 2 and 4, and after treatment. The primary endpoint was defined as a 30% increase in global median apparent diffusion coefficient.

          Results

          Disease response on DWI was seen in 14 of 36 evaluable patients (39%; 95% confidence interval = 23% to 56%), with marked interpatient and intrapatient heterogeneity of response. There was an association between prostate-specific antigen response and MRI response (odds ratio = 18.5, 95% confidence interval = 1.32 to 258, P = .013). Mean administered activity of radium-223 per cycle was not associated with global MRI response ( P = .216) but was associated with DWI response using a 5-target-lesion evaluation ( P = .007). In 26 of 36 (72%) patients, new bone metastases, not present at baseline, were seen on DWI scans during radium-223 treatment.

          Conclusions

          DWI is useful for assessment of disease response in bone. Response to radium-223 is heterogeneous, both between patients and between different metastases in the same patient. New bone metastases appear during radium-223 treatment.

          The REASURE trial is registered under ISRCTN17805587.

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          Most cited references10

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          Alpha emitter radium-223 and survival in metastatic prostate cancer.

          Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases. In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223. At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).
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            Diffusion-weighted magnetic resonance imaging as a cancer biomarker: consensus and recommendations.

            On May 3, 2008, a National Cancer Institute (NCI)-sponsored open consensus conference was held in Toronto, Ontario, Canada, during the 2008 International Society for Magnetic Resonance in Medicine Meeting. Approximately 100 experts and stakeholders summarized the current understanding of diffusion-weighted magnetic resonance imaging (DW-MRI) and reached consensus on the use of DW-MRI as a cancer imaging biomarker. DW-MRI should be tested as an imaging biomarker in the context of well-defined clinical trials, by adding DW-MRI to existing NCI-sponsored trials, particularly those with tissue sampling or survival indicators. Where possible, DW-MRI measurements should be compared with histologic indices including cellularity and tissue response. There is a need for tissue equivalent diffusivity phantoms; meanwhile, simple fluid-filled phantoms should be used. Monoexponential assessments of apparent diffusion coefficient values should use two b values (>100 and between 500 and 1000 mm2/sec depending on the application). Free breathing with multiple acquisitions is superior to complex gating techniques. Baseline patient reproducibility studies should be part of study designs. Both region of interest and histogram analysis of apparent diffusion coefficient measurements should be obtained. Standards for measurement, analysis, and display are needed. Annotated data from validation studies (along with outcome measures) should be made publicly available. Magnetic resonance imaging vendors should be engaged in this process. The NCI should establish a task force of experts (physicists, radiologists, and oncologists) to plan, organize technical aspects, and conduct pilot trials. The American College of Radiology Imaging Network infrastructure may be suitable for these purposes. There is an extraordinary opportunity for DW-MRI to evolve into a clinically valuable imaging tool, potentially important for drug development.
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              Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group.

              To update eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone. A committee of investigators experienced in conducting trials for prostate cancer defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in Solid Tumors (RECIST), and emerging trial data. The Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory. Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen (PSA), imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. In most trials, early changes in PSA and/or pain are not acted on without other evidence of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate drug exposure. Bone scans are reported as "new lesions" or "no new lesions," changes in soft-tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for prevent/delay end points requires attention to estimated event frequency and/or random assignment to a control group. PCWG2 recommends increasing emphasis on time-to-event end points (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Writing - original draft
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing - review & editing
                Role: Data curationRole: Formal analysisRole: Writing - review & editing
                Role: InvestigationRole: Writing - review & editing
                Role: InvestigationRole: Writing - review & editing
                Role: InvestigationRole: MethodologyRole: Writing - review & editing
                Role: InvestigationRole: MethodologyRole: Writing - review & editing
                Role: InvestigationRole: MethodologyRole: Writing - review & editing
                Role: InvestigationRole: Writing - review & editing
                Role: InvestigationRole: Writing - review & editing
                Role: InvestigationRole: MethodologyRole: Writing - review & editing
                Role: InvestigationRole: Writing - review & editing
                Role: InvestigationRole: Writing - review & editing
                Role: InvestigationRole: Writing - review & editing
                Role: InvestigationRole: Writing - review & editing
                Role: InvestigationRole: Writing - review & editing
                Role: Data curationRole: Project administrationRole: Writing - review & editing
                Role: Data curationRole: Project administrationRole: Writing - review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing - review & editing
                Role: Funding acquisitionRole: MethodologyRole: Writing - review & editing
                Journal
                JNCI Cancer Spectr
                JNCI Cancer Spectr
                jncics
                JNCI Cancer Spectrum
                Oxford University Press
                2515-5091
                December 2023
                03 October 2023
                03 October 2023
                : 7
                : 6
                : pkad077
                Affiliations
                The Royal Marsden NHS Foundation Trust , London, UK
                The Institute of Cancer Research , London, UK
                The Royal Marsden NHS Foundation Trust , London, UK
                The Institute of Cancer Research , London, UK
                The Institute of Cancer Research , London, UK
                Mount Vernon Cancer Centre , Northwood, UK
                The Institute of Cancer Research , London, UK
                Cancer Imaging Department and King’s College London and Guy’s and St Thomas’ PET Centre, King’s College London , London, UK
                The Royal Marsden NHS Foundation Trust , London, UK
                The Royal Marsden NHS Foundation Trust , London, UK
                The Royal Marsden NHS Foundation Trust , London, UK
                The Institute of Cancer Research , London, UK
                The Royal Marsden NHS Foundation Trust , London, UK
                Paul Strickland Scanner Centre, Mount Vernon Cancer Centre , Northwood, UK
                Velindre Cancer Centre , Cardiff, UK
                The Royal Marsden NHS Foundation Trust , London, UK
                The Institute of Cancer Research , London, UK
                The Royal Marsden NHS Foundation Trust , London, UK
                Mount Vernon Cancer Centre , Northwood, UK
                The Royal Marsden NHS Foundation Trust , London, UK
                The Institute of Cancer Research , London, UK
                The Institute of Cancer Research , London, UK
                The Institute of Cancer Research , London, UK
                The Royal Marsden NHS Foundation Trust , London, UK
                The Institute of Cancer Research , London, UK
                The Institute of Cancer Research , London, UK
                Author notes
                Correspondence to: Chris Parker, MD, Department of Academic Urology, The Royal Marsden Hospital, Downs Rd, Sutton, UK SM2 5PT (e-mail: chris.parker@ 123456icr.ac.uk ).
                Author information
                https://orcid.org/0000-0001-6512-124X
                Article
                pkad077
                10.1093/jncics/pkad077
                10640884
                37788117
                1f835cbc-c1ef-4db0-8267-0ab12c6dc83c
                © The Author(s) 2023. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 13 April 2023
                : 10 July 2023
                : 17 July 2023
                : 11 November 2023
                Page count
                Pages: 8
                Funding
                Funded by: Bayer, DOI 10.13039/100004326;
                Funded by: Cancer Research UK, DOI 10.13039/501100000289;
                Award ID: C1491/A15955
                Award ID: C1491/A25351
                Funded by: National Institute for Health Research, DOI 10.13039/501100000272;
                Funded by: National Cancer Research Network;
                Categories
                Article
                AcademicSubjects/MED00010

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