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Combined use of 177Lu-DOTATATE and metronomic capecitabine (Lu-X) in FDG-positive gastro-entero-pancreatic neuroendocrine tumors

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Abstract

Purpose

FDG-positive neuroendocrine tumors (NETs) have a poorer prognosis and exhibit shorter response duration to peptide receptor radionuclide therapy (PRRT). The aim of this prospective phase II study was to evaluate the efficacy and toxicity of PRRT with 177Lu-DOTATATE associated with metronomic capecitabine as a radiosensitizer agent in patients with advanced progressive FDG-positive gastro-entero-pancreatic (GEP) NETs.

Patients and methods

Patients with advanced somatostatin receptor- and FDG-positive G1-G3 GEP-NETs (Ki67 < 55%) were treated with a cumulative activity of 27.5 GBq of 177Lu-DOTATATE divided in five cycles of 5.5 GBq each every 8 weeks. Capecitabine (1000–1500 mg daily) was administered orally in the inter-cycle period between 177Lu-DOTATATE treatments. Prior to commencing capecitabine, all patients were triaged with the dihydropyrimidine dehydrogenase (DPD) test. Only DPD-proficient individuals were enrolled. The primary objectives were disease control rate (DCR) and safety. Secondary aims included progression-free (PFS) and overall survival (OS). Treatment response was assessed per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). Toxicity was assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Results

From August 2015 to December 2016, 37 subjects were consecutively enrolled. A total of 25 (68%) were affected by pancreatic neuroendocrine tumors (P-NETs), and 12 (32%) had gastrointestinal neuroendocrine tumors (GI-NETs). By grading (WHO 2010 classification), 12 patients (32%) had G1 (Ki67 ≤ 2%), 22 (59%) had G2 (3% < Ki67 ≤ 20%), and 3 patients (9%) had G3 (Ki67 > 20%) NETs. Grade 3 (G3) or 4 (G4) hematological toxicity occurred in 16.2% of patients. Other G3-G4 adverse events were diarrhea in 5.4% of cases and asthenia in 5.4%. No renal toxicity was observed for the duration of follow-up. In 37 patients, 33 were evaluable for response. Objective responses included partial response (PR) in 10 patients (30%) and stable disease (SD) in 18 patients (55%), with a DCR of 85%. The median follow-up was 38 months (range 4.6–51.1 months). The median PFS was 31.4 months (17.6–45.4), and mOS was not reached.

Conclusions

This study demonstrated that the combination of PRRT with 177Lu-DOTATATE and metronomic capecitabine is active and well tolerated in patients with aggressive FDG-positive G1-G3 GEP-NETs. These data constitute the basis for a randomized study of PPRT alone vs. PRRT plus metronomic capecitabine.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgments

The authors thank Gráinne Tierney for editorial assistance.

Funding

This work is partially supported by Fondazione AIRC per la Ricerca sul Cancro and Italian Ministry of Health.

Author information

Author notes

  1. Silvia Nicolini and Lisa Bodei contributed equally to this work.

Authors and Affiliations

  1. Nuclear Medicine and Radiometabolic Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, 47014, Meldola, Italy

    Silvia Nicolini, Maddalena Sansovini, Ilaria Grassi, Paola Caroli, Stefano Severi & Giovanni Paganelli

  2. Department of Nuclear Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Lisa Bodei

  3. Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

    Alberto Bongiovanni & Toni Ibrahim

  4. Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

    Manuela Monti

  5. Medical Physics Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

    Anna Sarnelli

  6. Radiology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

    Danila Diano

  7. Oncology Pharmacy, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

    Valentina Di Iorio

  8. Division of Nuclear Medicine, Istituto Europeo di Oncologia, Milan, Italy

    Chiara Maria Grana

  9. Nuclear Medicine Unit, University of Ferrara, Ferrara, Italy

    Corrado Cittanti

  10. Pathology Unit, Morgagni-Pierantoni Hospital, Forlì, Italy

    Federica Pieri

Authors
  1. Silvia Nicolini
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  2. Lisa Bodei
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  3. Alberto Bongiovanni
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Contributions

Study concept and design, Giovanni Paganelli and Lisa Bodei; provision of study materials or patients, Silvia Nicolini, Alberto Bongiovanni, Maddalena Sansovini, Stefano Severi, Ilaria Grassi, Toni Ibrahim, Chiara Maria Grana, Valentina Di Iorio, and Corrado Cittanti; diagnostic and therapeutic imaging, Paola Caroli and Danila Diano; pathology review, Federica Pieri; quality control and gamma camera calibration, Anna Sarnelli; data management, Manuela Monti; analysis and interpretation of data, Giovanni Paganelli and Silvia Nicolini; drafting of the manuscript, Silvia Nicolini, Lisa Bodei, and Giovanni Paganelli; critical revision of the manuscript for important intellectual content, Giovanni Paganelli and Lisa Bodei. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Giovanni Paganelli.

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Conflict of interests

The authors declare that they have no conflict of interest.

Ethics approval

The study was approved by the Ethics Committee of the Area Vasta Romagna-IRST (Approval No. 6929/2014 of December 17, 2014) and by the competent authorities and was conducted in full conformity with the current revision of the Declaration of Helsinki, the current ICH Guidelines for Good Clinical Practice, the Directive 2001/20/EEC, and other relevant current local legislation.

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All patients gave written informed consent.

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Nicolini, S., Bodei, L., Bongiovanni, A. et al. Combined use of 177Lu-DOTATATE and metronomic capecitabine (Lu-X) in FDG-positive gastro-entero-pancreatic neuroendocrine tumors. Eur J Nucl Med Mol Imaging 48, 3260–3267 (2021). https://doi.org/10.1007/s00259-021-05236-z

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  • DOI: https://doi.org/10.1007/s00259-021-05236-z

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