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Uptake of Radium-223 Dichloride and Early [18F]NaF PET Response Are Driven by Baseline [18F]NaF Parameters: a Pilot Study in Castration-Resistant Prostate Cancer Patients

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Abstract

Purpose

The purpose of this study is to identify predictive factors on baseline [18F]NaF positron emission tomography (PET)/computed tomography (CT) of early response to radium-223 dichloride after 3 cycles of treatment in metastatic castration-resistant prostate cancer patients.

Procedures

Analysis of 152 metastases was performed in six consecutive patients who underwent [18F]NaF PET/CT at baseline and for early monitoring after 3 cycles of radium-223 dichloride. All metastases depicted on whole-body [18F]NaF PET/CT were contoured and CT (density in Hounsfield units, sclerotic, mixed, or lytic appearance) as well as [18F]NaF [maximum standardized uptake value (SUVmax), SUVmean, and lesion volume (V18F-NaF)] patterns were recorded. Tumor response was defined as percentage change in SUVmax and SUVmean between baseline and post-treatment PET. Bone lesions were defined as stable, responsive, or progressive, according to thresholds derived from a recent multicentre test-retest study in [18F]NaF PET/CT. Total [18F]NaF uptake in metastases, defined as MATV × SUVmean, was correlated to uptake of radium-223 on biodistribution scintigraphy performed 7 days after the first cycle of treatment.

Results

Among metastases, 116 involved the axial skeleton and 36 the appendicular skeleton. Lesions were sclerotic in 126 cases and mixed in 26 cases. No lytic lesion was depicted. ROC analysis showed that SUVmax and SUVmean were better predictors of lesion response than V18F-NaF and density on CT (P < 0.0001 and P = 0.001, respectively). SUVmax and SUVmean were predictors of individual tumor response in separate multivariate models (P = 0.01 and P = 0.02, respectively). CT pattern (mixed versus sclerotic) and lesion density were independent predictors only when assessing response with delta SUVmax (P = 0.002 and 0.007, respectively). A good correlation between total [18F]NaF uptake within metastases and their relative radium-223 uptake assessed by two observers 7 days after treatment (r = 0.72 and 0.77, P < 0.0001) was found.

Conclusions

SUVmax and SUVmean on baseline [18F]NaF PET/CT are independent predictors of bone lesions’ response to 3 cycles of radium-223 dichloride, supporting the use of NaF to select patients more likely to respond to treatment.

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References

  1. Rohren EM, Etchebehere EC, Araujo JC et al (2015) Determination of skeletal tumor burden on 18F-fluoride PET/CT. J Nucl Med 56:1507–1512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Etchebehere EC, Milton DR, Araujo JC et al (2016) Factors affecting 223Ra therapy: clinical experience after 532 cycles from a single institution. Eur J Nucl Med Mol Imaging 43:8–20

    Article  CAS  PubMed  Google Scholar 

  3. Nilsson S, Cislo P, Sartor O et al (2016) Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study. Ann Oncol 27:868–874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sartor O, Coleman R, Nilsson S et al (2014) Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol 15:738–746

    Article  CAS  PubMed  Google Scholar 

  5. Hobbs RF, Song H, Watchman CJ et al (2012) A bone marrow toxicity model for (2)(2)(3)Ra alpha-emitter radiopharmaceutical therapy. Phys Med Biol 57:3207–3222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Piert M, Zittel TT, Becker GA et al (2001) Assessment of porcine bone metabolism by dynamic (F-18)fluoride ion PET: correlation with bone histomorphometry. J Nucl Med 42:1091–1100

    CAS  PubMed  Google Scholar 

  7. Bortot DC, Amorim BJ, Oki GC et al (2012) 18F-fluoride PET/CT is highly effective for excluding bone metastases even in patients with equivocal bone scintigraphy. Eur J Nucl Med Mol Imaging 39:1730–1736

    Article  PubMed  Google Scholar 

  8. Even-Sapir E, Metser U, Mishani E et al (2006) The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP planar bone scintigraphy, single- and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT. J Nucl Med 47:287–297

    PubMed  Google Scholar 

  9. Iagaru A, Mittra E, Dick DW, Gambhir SS (2012) Prospective evaluation of (99m)Tc MDP scintigraphy, 18F NaF PET/CT, and 18F FDG PET/CT for detection of skeletal metastases. Mol Imaging Biol 14:252–259

    Article  PubMed  Google Scholar 

  10. Minamimoto R, Loening A, Jamali M et al (2015) Prospective comparison of 99mTc-MDP scintigraphy, combined 18F-NaF and 18F-FDG PET/CT, and whole-body MRI in patients with breast and prostate cancer. J Nucl Med 56:1862–1868

    Article  PubMed  Google Scholar 

  11. Parker C, Nilsson S, Heinrich D et al (2013) Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 369:213–223

    Article  CAS  PubMed  Google Scholar 

  12. Lin C, Bradshaw T, Perk T et al (2016) Repeatability of quantitative 18F-NaF PET: a multicenter study. J Nucl Med 57:1872–1879

    Article  CAS  PubMed  Google Scholar 

  13. Hindorf C, Chittenden S, Aksnes AK et al (2012) Quantitative imaging of 223Ra-chloride (Alpharadin) for targeted alpha-emitting radionuclide therapy of bone metastases. Nucl Med Commun 33:726–732

    Article  CAS  PubMed  Google Scholar 

  14. Siegel JA, Thomas SR, Stubbs JB et al (1999) MIRD pamphlet no. 16: techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates. J Nucl Med 40:37s–61s

    CAS  PubMed  Google Scholar 

  15. Beheshti M, Mottaghy FM, Payche F et al (2015) 18F-NaF PET/CT: EANM procedure guidelines for bone imaging. Eur J Nucl Med Mol Imaging 42:1767–1777

    Article  CAS  PubMed  Google Scholar 

  16. DeLong ER, DeLong DM, Clarke-Pearson DL (1988) Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 44:837–845

    Article  CAS  PubMed  Google Scholar 

  17. Gonen M, Panageas KS, Larson SM (2001) Statistical issues in analysis of diagnostic imaging experiments with multiple observations per patient. Radiology 221:763–767

    Article  CAS  PubMed  Google Scholar 

  18. Pinker K, Riedl C, Weber WA (2017) Evaluating tumor response with FDG PET: updates on PERCIST, comparison with EORTC criteria and clues to future developments. Eur J Nucl Med Mol Imaging 44:55–66

    Article  PubMed  Google Scholar 

  19. de Langen AJ, Vincent A, Velasquez LM et al (2012) Repeatability of 18F-FDG uptake measurements in tumors: a metaanalysis. J Nucl Med 53:701–708

    Article  PubMed  Google Scholar 

  20. Lodge MA (2017) Repeatability of SUV in oncologic 18F-FDG PET. J Nucl Med 58:523–532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cook G Jr, Parker C, Chua S et al (2011) 18F-fluoride PET: changes in uptake as a method to assess response in bone metastases from castrate-resistant prostate cancer patients treated with 223Ra-chloride (Alpharadin). Eur J Nucl Med Mol Imaging Res 1:4

    Google Scholar 

  22. Garcia-Vicente AM, Perez-Beteta J, Perez-Garcia VM et al (2017) Metabolic tumor burden assessed by dual time point [18F]FDG PET/CT in locally advanced breast cancer: relation with tumor biology. Mol Imaging Biol 19:636–644

    Article  CAS  PubMed  Google Scholar 

  23. Wu X, Bhattarai A, Korkola P et al (2017) The association between liver and tumor [18F]FDG uptake in patients with diffuse large B cell lymphoma during chemotherapy. In: Mol Imaging Biol

    Google Scholar 

  24. Pacilio M, Ventroni G, De Vincentis G et al (2016) Dosimetry of bone metastases in targeted radionuclide therapy with alpha-emitting 223Ra-dichloride. Eur J Nucl Med Mol Imaging 43:21–33

    Article  CAS  PubMed  Google Scholar 

  25. Murray I, Chittenden SJ, Denis-Bacelar AM et al (2017) The potential of 223Ra and 18F-fluoride imaging to predict bone lesion response to treatment with 223Ra-dichloride in castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging 44:1832–1844

    Article  CAS  PubMed  Google Scholar 

  26. Etchebehere EC, Araujo JC, Fox PS et al (2015) Prognostic factors in patients treated with 223Ra: the role of skeletal tumor burden on baseline 18F-fluoride PET/CT in predicting overall survival. J Nucl Med 56:1177–1184

    Article  CAS  PubMed  Google Scholar 

  27. Lindgren Belal S, Sadik M, Kaboteh R et al (2017) 3D skeletal uptake of 18F sodium fluoride in PET/CT images is associated with overall survival in patients with prostate cancer. EJNMMI Res 7:15

    Article  PubMed  PubMed Central  Google Scholar 

  28. Anand A, Morris MJ, Kaboteh R et al (2016) Analytic validation of the automated bone scan index as an imaging biomarker to standardize quantitative changes in bone scans of patients with metastatic prostate cancer. J Nucl Med 57:41–45

    Article  CAS  PubMed  Google Scholar 

  29. Anand A, Morris MJ, Larson SM et al (2016) Automated bone scan index as a quantitative imaging biomarker in metastatic castration-resistant prostate cancer patients being treated with enzalutamide. Eur J Nuc Med Mol Imaging Res 6:23

    Google Scholar 

  30. Dennis ER, Jia X, Mezheritskiy IS et al (2012) Bone scan index: a quantitative treatment response biomarker for castration-resistant metastatic prostate cancer. J Clin Oncol 30:519–524

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ceci F, Herrmann K, Hadaschik B, Castellucci P, Fanti S (2017) Therapy assessment in prostate cancer using choline and PSMA PET/CT. Eur J Nucl Med Mol Imaging 44:78–83

    Article  CAS  PubMed  Google Scholar 

  32. Etchebehere E, Brito AE, Rezaee A et al (2017) Therapy assessment of bone metastatic disease in the era of 223radium. Eur J Nucl Med Mol Imaging 44:84–96

    Article  CAS  PubMed  Google Scholar 

  33. Janssen JC, Woythal N, Meissner S et al (2017) [68Ga]PSMA-HBED-CC uptake in osteolytic, osteoblastic, and bone marrow metastases of prostate cancer patients. Mol Imaging Biol. https://doi.org/10.1007/s11307-017-1101-y

  34. Rowe SP, Macura KJ, Mena E et al (2016) PSMA-based [18F]DCFPyL PET/CT is superior to conventional imaging for lesion detection in patients with metastatic prostate cancer. Mol Imaging Biol 18:411–419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Prof. Aide is grateful to the technologists and the secretaries from the François Baclesse Cancer Centre who cared for the patients treated with radium-223 dichloride. The authors thank the medical and radiation oncologists from the François Baclesse Cancer Centre multidisciplinary urological tumors board who referred patients for radium-223 treatment.

Author information

Authors and Affiliations

  1. Nuclear Medicine Department, Caen University Hospital, 14000, Caen, France

    Arthur Letellier, Nicolas How Kit & Nicolas Aide

  2. Radiology Department, University Hospital, Caen, France

    Arthur Letellier & Nicolas How Kit

  3. Medical Oncology, François Baclesse Cancer Centre, Caen, France

    Alison C. Johnson

  4. Nuclear Medicine Department, François Baclesse Cancer Centre, Caen, France

    Jean-François Savigny

  5. Medical Physics, François Baclesse Cancer Centre, Caen, France

    Alain Batalla

  6. Clinical Research Unit, University Hospital, Caen, France

    Jean-Jacques Parienti

  7. EA2656 (GRAM 2.0), Normandie University, Caen, France

    Jean-Jacques Parienti

  8. INSERM 1199 ANTICIPE, Normandie University, Caen, France

    Nicolas Aide

Authors
  1. Arthur Letellier
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  2. Alison C. Johnson
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  3. Nicolas How Kit
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  4. Jean-François Savigny
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  5. Alain Batalla
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  6. Jean-Jacques Parienti
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  7. Nicolas Aide
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Contributions

Study design and coordination: NA

Data gathering: AL, NHK, AJ, JFS, AB

PET Data analysis: Al, AJ, NA

Statistical analysis: JJP

Manuscript writing: AL, AJ, JJP, JFS, AB, NA

All authors checked and approved the final version of the manuscript.

Corresponding author

Correspondence to Nicolas Aide.

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Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed Consent

No written consent was required for this retrospective study, as radium-223 dichloride is an authorized drug in Europe, and NaF PET/CT is used in clinical routine at our institution for therapy monitoring of bone metastatic disease in prostate cancer patients receiving such treatment.

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Letellier, A., Johnson, A.C., Kit, N.H. et al. Uptake of Radium-223 Dichloride and Early [18F]NaF PET Response Are Driven by Baseline [18F]NaF Parameters: a Pilot Study in Castration-Resistant Prostate Cancer Patients. Mol Imaging Biol 20, 482–491 (2018). https://doi.org/10.1007/s11307-017-1132-4

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  • DOI: https://doi.org/10.1007/s11307-017-1132-4

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