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

Silvia Nicolini, Stefano Severi, Annarita Ianniello, Maddalena Sansovini, Alice Ambrosetti, Alberto Bongiovanni, Emanuela Scarpi, Francesca Di Mauro, Alice Rossi, Federica Matteucci, Giovanni Paganelli

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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%.

Original languageEnglish
Pages (from-to)923-930
Number of pages8
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Volume45
Issue number6
DOIs
Publication statusPublished - Jun 1 2018

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Radioisotopes
Peptide Receptors
Neoplasms
Disease-Free Survival
Somatostatin Receptors
Therapeutics
ROC Curve
(177lutetium-DOTA(O)Tyr3)octreotate
Disease Progression
Drug Therapy
Survival

Keywords

  • Lu-DOTATATE
  • GEP-NEC
  • GEP-NEN
  • Ki-67
  • Neuroendocrine tumours
  • PRRT
  • WHO classification

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

@article{45e66fd53f4b4fec9e055f822be7b07c,
title = "Investigation of receptor radionuclide therapy with 177Lu-DOTATATE in patients with GEP-NEN and a high Ki-67 proliferation index",
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{\%}.",
keywords = "Lu-DOTATATE, GEP-NEC, GEP-NEN, Ki-67, Neuroendocrine tumours, PRRT, WHO classification",
author = "Silvia Nicolini and Stefano Severi and Annarita Ianniello and Maddalena Sansovini and Alice Ambrosetti and Alberto Bongiovanni and Emanuela Scarpi and {Di Mauro}, Francesca and Alice Rossi and Federica Matteucci and Giovanni Paganelli",
year = "2018",
month = "6",
day = "1",
doi = "10.1007/s00259-017-3925-8",
language = "English",
volume = "45",
pages = "923--930",
journal = "European Journal of Pediatrics",
issn = "0340-6199",
publisher = "Springer Berlin Heidelberg",
number = "6",

}

TY - JOUR

T1 - Investigation of receptor radionuclide therapy with 177Lu-DOTATATE in patients with GEP-NEN and a high Ki-67 proliferation index

AU - Nicolini, Silvia

AU - Severi, Stefano

AU - Ianniello, Annarita

AU - Sansovini, Maddalena

AU - Ambrosetti, Alice

AU - Bongiovanni, Alberto

AU - Scarpi, Emanuela

AU - Di Mauro, Francesca

AU - Rossi, Alice

AU - Matteucci, Federica

AU - Paganelli, Giovanni

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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%.

AB - 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%.

KW - Lu-DOTATATE

KW - GEP-NEC

KW - GEP-NEN

KW - Ki-67

KW - Neuroendocrine tumours

KW - PRRT

KW - WHO classification

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U2 - 10.1007/s00259-017-3925-8

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JF - European Journal of Pediatrics

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