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Investigation of receptor radionuclide therapy with 177Lu-DOTATATE in patients with GEP-NEN and a high Ki-67 proliferation index

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Abstract

Purpose

In the 2010 WHO classification, a Ki-67 proliferation index of 20% is the cut-off between intermediate-grade and high-grade gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN). However, in clinical practice, tumours with a Ki-67 index of >15% are often considered high grade and treated with chemotherapy. In 40–70% of high-grade NENs, somatostatin receptors are overexpressed, enabling peptide receptor radionuclide therapy (PRRT) to be performed. We investigated the role of PRRT with 177Lu-DOTATATE in patients with GEP-NEN and a high Ki-67 proliferation index.

Methods

A total of 33 patients with advanced GEP-NENs, positive somatostatin receptor imaging (SRI+) and a Ki-67 proliferation index ranging from 15% to 70% were treated with Lu-PRRT. A cumulative activity of 18.5 GBq or 27.8 GBq of 177Lu-DOTATATE was administered in four or five cycles. Receiver operating characteristic (ROC) curve analysis was used to determine the best threshold of Ki-67 expression to predict disease progression.

Results

All patients completed the intended treatment. The median follow-up was 43 months (range 3–69 months). Two patients (6%) achieved a partial response and 21 (64%) showed stable disease, giving a disease control rate (DCR) of 70%. The median progression-free survival (PFS) was 23 months (95% CI 14.9–31.0 months) and the median overall survival was 52.9 months (95% CI 17.1–68.9 months). ROC curve analysis at 23 months revealed that the best Ki-67 index cut-off was 35%. In 23 patients (70%) the Ki-67 index was ≤35% and in 10 patients (30%) the Ki-67 index was in the range 36–70%. The DCR in the former group was 87% and 30% in the latter. The median PFS was 26.3 months (95% CI 18.4–37.7 months) and 6.8 months (95% CI 2.1–27 months), respectively (p = 0.005).

Conclusions

Lu-PRRT showed antitumour activity in SRI+ GEP-NENs of intermediate and high-grade. DCR and PFS were significantly better in patients with a Ki-67 index of ≤35% than in those with a Ki-67 index of >35%. On the basis of these results, PRRT should be considered as a therapeutic option in patients with high-grade SRI+ GEP-NENs, in particular those with a Ki-67 proliferation index of ≤35%.

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Acknowledgements

The authors thank Gráinne Tierney for editorial assistance. They also thank Monica Golinucci and the other members of the Nuclear Medicine and Radiometabolic Medicine Unit team for support and assistance.

Funding

This study was partially supported by AIRC (Associazione Italiana per la Ricerca sul Cancro; grant number: G10679).

Author information

Authors and Affiliations

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

    Silvia Nicolini, Stefano Severi, Annarita Ianniello, Maddalena Sansovini, Federica Matteucci & Giovanni Paganelli

  2. Nuclear Medicine Unit, Bufalini Hospital, Cesena, Italy

    Alice Ambrosetti

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

    Alberto Bongiovanni

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

    Emanuela Scarpi

  5. Nuclear Medicine Unit, University of Messina, Messina, Italy

    Francesca Di Mauro

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

    Alice Rossi

Authors
  1. Silvia Nicolini
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  2. Stefano Severi
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  3. Annarita Ianniello
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  4. Maddalena Sansovini
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  5. Alice Ambrosetti
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  6. Alberto Bongiovanni
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  7. Emanuela Scarpi
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  8. Francesca Di Mauro
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  9. Alice Rossi
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  10. Federica Matteucci
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  11. Giovanni Paganelli
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Contributions

Study concept and design: Giovanni Paganelli, Severi Stefano.

Provision of study materials or patients: Silvia Nicolini, Stefano Severi, Annarita Ianniello, Maddalena Sansovini, Alberto Bongiovanni, Giovanni Paganelli.

Collection and assembly of data: July 2011 to April 2016.

Diagnostic and therapeutic imaging: Federica Matteucci and Alice Rossi.

Analysis and interpretation of data: Giovanni Paganelli, Emanuela Scarpi, Silvia Nicolini.

Drafting of the manuscript: Silvia Nicolini.

Critical revision of the manuscript for important intellectual content: Giovanni Paganelli.

All authors read and approved the final manuscript.

Corresponding author

Correspondence to Giovanni Paganelli.

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None.

Ethical approval

The protocol was approved by the Ethics Committee of Area Vasta Romagna and by the competent Italian regulatory authorities. The study was performed in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki.

Informed consent

All patients gave their written informed consent.

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Nicolini, S., Severi, S., Ianniello, A. et al. Investigation of receptor radionuclide therapy with 177Lu-DOTATATE in patients with GEP-NEN and a high Ki-67 proliferation index. Eur J Nucl Med Mol Imaging 45, 923–930 (2018). https://doi.org/10.1007/s00259-017-3925-8

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  • DOI: https://doi.org/10.1007/s00259-017-3925-8

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