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[18F]-Fluciclovine PET/CT for preoperative nodal staging in high-risk primary prostate cancer: final results of a prospective trial

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Abstract

Purpose

The conventional imaging flowchart for prostate cancer (PCa) staging may fail in correctly detecting lymph node metastases (LNM). Pelvic lymph node dissection (PLND) represents the only reliable method, although invasive. A new amino acid PET compound, [18F]-fluciclovine, was recently authorized in suspected PCa recurrence but not yet included in the standard staging work-up of primary PCa. A prospective monocentric study was designed to evaluate [18F]-fluciclovine PET/CT diagnostic performance for preoperative LN staging in primary high-risk PCa.

Methods

Consecutive patients (pts) with biopsy-proven PCa, standard staging (including [11C]choline PET/CT), eligible for PLND, were enrolled to undergo an investigational [18F]-fluciclovine PET/CT. Nodal uptake higher than surrounding background was reported by at least two readers (blinded to [11C]choline) using a visual 5-point scale (1–2 probably negative; 4–5 probably positive; 3 equivocal); SUVmax, target-to-background (aorta—A; bone marrow—BM) ratios (TBRs), were also calculated. PET results were validated with PLND. [18F]-fluciclovine PET/CT performance using visual score and semi-quantitative indexes was analyzed both per patient and per LN anatomical region, compared to conventional [11C]choline and clinical predictive factors (to note that diagnostic performance of [18F]-fluciclovine was explored for LNM but not examined for intrapelvic or extrapelvic M1 lesions).

Results

Overall, 94 pts underwent [18F]-fluciclovine PET/CT; 72/94 (77%) high-risk pts were included in the final analyses (22 pts excluded: 8 limited PLND; 3 intermediate-risk; 2 treated with radiotherapy; 4 found to be M1; 5 neoadjuvant hormonal therapy). Median LNM risk by Briganti nomogram was 19%. LNM confirmed on histology was 25% (18/72 pts). Overall, 1671 LN were retrieved; 45/1671 (3%) LNM detected. Per pt, median no. of removed LN was 22 (mean 23 ± 10; range 8–51), of LNM was 2 (mean 3 ± 2; range 1–10). Median LNM size was 5 mm (mean 5 ± 2.5; range 2–10). On patient-based analyses (n = 72), diagnostic performance for LNM resulted significant with [18F]-fluciclovine (AUC 0.66, p 0.04; 50% sensitivity, 81% specificity, 47% PPV, 83% NPV, 74% accuracy), but not with [11C]choline (AUC 0.60, p 0.2; 50%, 70%, 36%, 81%, and 65% respectively). Briganti nomogram (OR = 1.03, p = 0.04) and [18F]-fluciclovine visual score (≥ 4) (OR = 4.27, p = 0.02) resulted independent predictors of LNM at multivariable analyses. On region-based semi-quantitative analyses (n = 576), PET/CT performed better using TBR parameters (TBR-A similar to TBR-BM; TBR-A fluciclovine AUC 0.61, p 0.35, vs choline AUC 0.57 p 0.54; TBR-BM fluciclovine AUC 0.61, p 0.36, vs choline AUC 0.58, p 0.52) rather than using absolute LN SUVmax (fluciclovine AUC 0.51, p 0.91, vs choline AUC 0.51, p 0.94). However, in all cases, diagnostic performance was not statistically significant for LNM detection, although slightly in favor of the experimental tracer [18F]-fluciclovine for each parameter. On the contrary, visual interpretation significantly outperformed PET semi-quantitative parameters (choline and fluciclovine: AUC 0.65 and 0.64 respectively; p 0.03) and represents an independent predictive factor of LNM with both tracers, in particular [18F]-fluciclovine (OR = 8.70, p 0.002, vs OR = 3.98, p = 0.03).

Conclusion

In high-risk primary PCa, [18F]-fluciclovine demonstrates some advantages compared with [11C]choline but sensitivity for metastatic LN detection is still inadequate compared to PLND. Visual (combined morphological and functional), compared to semi-quantitative assessment, is promising but relies mainly on readers’ experience rather than on unquestionable LN avidity.

Trial registration

EudraCT number: 2014–003,165-15

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Acknowledgements

Blue Earth Diagnostics (BED) kindly provided pre-loaded cassettes for [18F]-fluciclovine synthesis, thanks to an agreement without any financial relationship.

Funding

This research was funded by “programma di Ricerca Regione-Università Area 1 Bando Giovani Ricercatori “Alessandro Liberati 2013,” grant number PRUA1GR-2013–00000171.

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Authors and Affiliations

  1. Nuclear Medicine, Istituto Di Ricovero E Cure a Carattere Scientifico (IRCCS), Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy

    Lucia Zanoni, Cristina Nanni, Filippo Lodi & Stefano Fanti

  2. Division of Urology, Istituto Di Ricovero E Cure a Carattere Scientifico (IRCCS), Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy

    Lorenzo Bianchi, Cristian Pultrone, Riccardo Schiavina & Eugenio Brunocilla

  3. Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Cardio-Nephro-Thoracic Sciences Doctorate, University of Bologna, Bologna, Italy

    Lorenzo Bianchi, Riccardo Schiavina & Eugenio Brunocilla

  4. Pathology, Istituto Di Ricovero E Cure a Carattere Scientifico (IRCCS), Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy

    Francesca Giunchi & Antonietta D’Errico

  5. Nuclear Medicine, Istituti Clinici Scientifici Maugeri, Pavia, Italy

    Irene Bossert

  6. Nuclear Medicine, IRCCS Ospedale Sacro Cuore - Don Calabria, Negrar Di Valpolicella, (VR), Italy

    Antonella Matti

  7. Department of Specialistic Diagnostic and Experimental Medicine, University of Bologna, Bologna, Italy

    Michelangelo Fiorentino

  8. Urology Unit, Abano Terme Hospital, Padova, Italy

    Daniele Romagnoli

  9. Istituto Di Ricovero E Cure a Carattere Scientifico (IRCCS), Istituto Delle Scienze Neurologiche Di Bologna, Bologna, Italy

    Cristina Fonti

  10. Oncological Urology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy

    Angelo Porreca

  11. DIMES, University of Bologna, Bologna, Italy

    Stefano Fanti

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  1. Lucia Zanoni
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Conceptualization: ZL, NC, FS, SR, FM, and DEA; methodology: ZL, FS, and FC; formal analysis: ZL, BL, and FC; investigation: ZL, BI, MA, PC, GF, FM, SR, BL, NC, PA, and RD; resources: LF; data curation: ZL, BI, MA, GF, PC, BL, FC, and RD; writing—original draft preparation: ZL and BL; writing—review and editing: all authors; visualization: ZL and BL; supervision: ZL, NC, FS, SR, BE, MF, PA, and DEA; project administration: ZL and FS; funding acquisition: ZL, FS, FC, and NC. All authors have read and agreed to the published version of the manuscript and contributed substantially to the work reported. In particular, in order to qualify for authorship of a manuscript, the following criteria were observed: Substantial contributions to the conception or design of the work, or the acquisition, analysis, or interpretation of data for the work; AND Drafting the work or revising it critically for important intellectual content; AND Final approval of the version to be published; AND Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Lucia Zanoni.

Ethics declarations

Ethics 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. The study was approved by the Local Bioethics Committee (EudraCT number 2014–003165-15; Local Ethical Committee code: 139/2014/O/Sper).

Consent to participate and consent for publication

All patients included in the study signed informed consent to participate and publication. Informed consent to participate and for publication was obtained from all individual participants included in the study.

Competing interests

Lucia Zanoni had a scientific-only relationship with the company “Blue Earth Diagnostics Ltd.” as Medical Staff of the Sponsored Study BED001 (118/2014/O/Oss) (no financial relationship, no compensation received). She was Principal Investigator of the project entitled “18F-FACBC PET/CT for staging high risk prostate cancer” funded by “Programma di ricercar Regione-Università 2013-Area 1 “Ricerca Innovativa,” Bando “Alessandro Liberati-Giovani Ricercatori.” In the context of this project, Lucia Zanoni received a granted 1-year SSN contract as nuclear medicine project manager (both scientific and financial relationship; 2016). Cristina Nanni provided consultancy for Blue Earth Diagnostics Ltd. 2018–1019. She was Principal Investigator of the project entitled ANTI-3-18F-FACBC (anti1-amino-3-18F-fluorocyclobutane-1-carboxylic acid) in comparison to [11C]choline PET/CT in the evaluation of patients with prostate cancer radically treated and with rising PSA, “Programma di ricerca Regione-Università 2010–2012-Area 1” “Ricerca Innovativa,” Bando “Alessandro Liberati-Giovani Ricercatori.” Irene Bossert, Cristina Fonti, Cristian Pultrone, and Francesca Giunchi received granted universitary contracts as Staff of the project entitled “18F-FACBC PET/CT for staging high risk prostate cancer” funded by “Programma di ricerca Regione-Università 2013-Area 1” “Ricerca Innovativa,” Bando “Alessandro Liberati-Giovani Ricercatori.” Stefano Fanti, with respect to the mentioned paper, declares that he attended an advisory board of Blue Earth Diagnostics in 2014 and in 2015. The other authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

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Zanoni, L., Bianchi, L., Nanni, C. et al. [18F]-Fluciclovine PET/CT for preoperative nodal staging in high-risk primary prostate cancer: final results of a prospective trial. Eur J Nucl Med Mol Imaging 49, 390–409 (2021). https://doi.org/10.1007/s00259-021-05429-6

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