Somatostatin Analogs for Pancreatic Neuroendocrine Tumors: Any Benefit When Ki-67 Is ≥10%?

Elettra Merola; Teresa Alonso Gordoa; Panpan Zhang; Taymeyah Al-Toubah; Eleonora Pellè; Agnieszka Kolasińska-Ćwikła; Wouter Zandee; Faidon Laskaratos; Louis de Mestier; Angela Lamarca; Jorge Hernando; Jaroslaw Cwikla; Jonathan Strosberg; Wouter de Herder; Martin Caplin; Mauro Cives; Rachel van Leeuwaarde

doi:10.1002/onco.13633

Somatostatin Analogs for Pancreatic Neuroendocrine Tumors: Any Benefit When Ki-67 Is ≥10%?

Elettra Merola
, Teresa Alonso Gordoa
, Panpan Zhang
, Taymeyah Al-Toubah
, Eleonora Pellè
, Agnieszka Kolasińska-Ćwikła
, Wouter Zandee
, Faidon Laskaratos
, Louis de Mestier
, Angela Lamarca
, Jorge Hernando
, Jaroslaw Cwikla
, Jonathan Strosberg
, Wouter de Herder
, Martin Caplin
, Mauro Cives^*
, Rachel van Leeuwaarde

^*Corresponding author for this work

Internal Medicine

Azienda Provinciale per i Servizi Sanitari
Ramón y Cajal Health Research Institute
Peking University
H. Lee Moffitt Cancer Center and Research Institute
Maria Sklodowska-Curie Institute of Oncology
Royal Free London NHS Foundation Trust
Beaujon Hospital
University of Manchester
Vall d'Hebron Institute of Oncology
University of Warmia and Mazury in Olsztyn
University of Bari Aldo Moro
University Medical Centre Utrecht

Research output: Contribution to journal › Article › Academic › peer-review

46 Citations (Scopus)

158 Downloads (Pure)

Abstract

Background: Long-acting somatostatin analogs (SSAs) are the primary first-line treatment of well-differentiated advanced gastroenteropancreatic neuroendocrine tumors (NETs), but data about their efficacy in pancreatic NETs (panNETs) with Ki-67 ≥10% are still limited. Materials and Methods: To assess the clinical outcomes of advanced, nonfunctioning, well-differentiated panNETs with Ki-67 ≥10% receiving first-line long-acting SSAs in a real-world setting, we carried out a retrospective, multicenter study including patients treated between 2014–2018 across 10 centers of the NET CONNECT Network. The primary endpoints were time to next treatment (TNT) and progression-free survival (PFS), whereas overall survival (OS) and treatment safety were secondary endpoints. Results: A total of 73 patients were included (68 grade [G]2, 5 G3), with liver metastases in 61 cases (84%). After a median follow-up of 36.4 months (range, 6–173), the median TNT and PFS were 14.2 months (95% confidence interval [CI], 11.6–16.2) and 11.9 months (95% CI, 8.6–14.1) respectively. No statistically significant difference was observed according to the somatostatin analog used (octreotide vs. lanreotide), whereas increased tumor grade (hazard ratio [HR], 4.4; 95% CI, 1.2–16.6; p =.04) and hepatic tumor load (HR, 2; 95% CI, 1–4; p =.03) were independently associated with shortened PFS. The median OS recorded was 86 months (95% CI, 56.8–86 months), with poor outcomes observed when the hepatic tumor burden was >25% (HR, 3.4; 95% CI, 1.2–10; p =.01). Treatment-related adverse events were reported in 14 patients, most frequently diarrhea. Conclusion: SSAs exert antiproliferative activity in panNETs with Ki-67 ≥10%, particularly in G2 tumors, as well as when hepatic tumor load is ≤25%. Implications for Practice: The results of the study call into question the antiproliferative activity of somatostatin analogs (SSAs) in pancreatic neuroendocrine tumors with Ki-67 ≥10%. Patients with grade 2 tumors and with hepatic tumor load ≤25% appear to derive higher benefit from SSAs. Prospective studies are needed to validate these results to optimize tailored therapeutic strategies for this specific patient population.

Original language	English
Pages (from-to)	294-301
Number of pages	8
Journal	Oncologist
Volume	26
Issue number	4
Early online date	29 Dec 2020
DOIs	https://doi.org/10.1002/onco.13633
Publication status	Published - Apr 2021

Bibliographical note

Funding Information:
The authors thank NET CONNECT for having made this study possible through logistical and organizational support provided by COR2ED. NET CONNECT is supported by an Independent Educational Grant from IPSEN. The program is therefore independent, and the content is not influenced by IPSEN and is under the sole responsibility of the experts. Elettra Merola, Teresa Alonso Gordoa, Panpan Zhang, Wouter Zandee, Faidon Laskaratos, Louis de Mestier, Angela Lamarca, Jorge Hernando, Wouter de Herder, Martin Caplin, Mauro Cives, and Rachel van Leeuwaarde are members of the NET CONNECT group. This research did not receive any specific grant from any funding agency in the public, commercial, or not‐for‐profit sector.

Funding Information:
ENETS excellence Academy fellowship 2017 (RF‐Grant awarded for another research project regarding neuroendocrine tumors); Ipsen, Novartis, Pfizer (C/A), Novartis (RF); Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan, Delcath (Other‐travel, educational support), Merck, Pfizer, Ipsen, Incyte, AAA (H‐Speaker), EISAI, Nutricia Ipsen, QED, Roche (H‐Advisory), Knowledge Network and NETConnect Initiatives funded by Ipsen (Other‐Member); Novartis (C/A), Ipsen, Lexicon (H); Ipsen (RF), AAA/Novartis (SAB); Novartis, AAA, Ipsen, Pfizer (H, SAB); AAA, Ipsen (SAB). The other authors indicate no financial relationships. Elettra Merola: Louis de Mestier: Angela Lamarca: Jonathan Strosberg: Wouter de Herder: Martin Caplin: Mauro Cives:

Publisher Copyright:
© 2020 AlphaMed Press

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10.1002/onco.13633

Somatostatin Analogs for Pancreatic Neuroendocrine TumorsFinal published version, 958 KBLicence: Unspecified

Cite this

Merola, E., Alonso Gordoa, T., Zhang, P., Al-Toubah, T., Pellè, E., Kolasińska-Ćwikła, A., Zandee, W., Laskaratos, F., de Mestier, L., Lamarca, A., Hernando, J., Cwikla, J., Strosberg, J., de Herder, W., Caplin, M., Cives, M., & van Leeuwaarde, R. (2021). Somatostatin Analogs for Pancreatic Neuroendocrine Tumors: Any Benefit When Ki-67 Is ≥10%? Oncologist, 26(4), 294-301. https://doi.org/10.1002/onco.13633

@article{9ef2ea7169a143349adc37e8022ad739,

title = "Somatostatin Analogs for Pancreatic Neuroendocrine Tumors: Any Benefit When Ki-67 Is ≥10\%?",

abstract = "Background: Long-acting somatostatin analogs (SSAs) are the primary first-line treatment of well-differentiated advanced gastroenteropancreatic neuroendocrine tumors (NETs), but data about their efficacy in pancreatic NETs (panNETs) with Ki-67 ≥10\% are still limited. Materials and Methods: To assess the clinical outcomes of advanced, nonfunctioning, well-differentiated panNETs with Ki-67 ≥10\% receiving first-line long-acting SSAs in a real-world setting, we carried out a retrospective, multicenter study including patients treated between 2014{\textendash}2018 across 10 centers of the NET CONNECT Network. The primary endpoints were time to next treatment (TNT) and progression-free survival (PFS), whereas overall survival (OS) and treatment safety were secondary endpoints. Results: A total of 73 patients were included (68 grade [G]2, 5 G3), with liver metastases in 61 cases (84\%). After a median follow-up of 36.4 months (range, 6{\textendash}173), the median TNT and PFS were 14.2 months (95\% confidence interval [CI], 11.6{\textendash}16.2) and 11.9 months (95\% CI, 8.6{\textendash}14.1) respectively. No statistically significant difference was observed according to the somatostatin analog used (octreotide vs. lanreotide), whereas increased tumor grade (hazard ratio [HR], 4.4; 95\% CI, 1.2{\textendash}16.6; p =.04) and hepatic tumor load (HR, 2; 95\% CI, 1{\textendash}4; p =.03) were independently associated with shortened PFS. The median OS recorded was 86 months (95\% CI, 56.8{\textendash}86 months), with poor outcomes observed when the hepatic tumor burden was >25\% (HR, 3.4; 95\% CI, 1.2{\textendash}10; p =.01). Treatment-related adverse events were reported in 14 patients, most frequently diarrhea. Conclusion: SSAs exert antiproliferative activity in panNETs with Ki-67 ≥10\%, particularly in G2 tumors, as well as when hepatic tumor load is ≤25\%. Implications for Practice: The results of the study call into question the antiproliferative activity of somatostatin analogs (SSAs) in pancreatic neuroendocrine tumors with Ki-67 ≥10\%. Patients with grade 2 tumors and with hepatic tumor load ≤25\% appear to derive higher benefit from SSAs. Prospective studies are needed to validate these results to optimize tailored therapeutic strategies for this specific patient population.",

author = "Elettra Merola and \{Alonso Gordoa\}, Teresa and Panpan Zhang and Taymeyah Al-Toubah and Eleonora Pell{\`e} and Agnieszka Kolasi{\'n}ska-{\'C}wik{\l}a and Wouter Zandee and Faidon Laskaratos and \{de Mestier\}, Louis and Angela Lamarca and Jorge Hernando and Jaroslaw Cwikla and Jonathan Strosberg and \{de Herder\}, Wouter and Martin Caplin and Mauro Cives and \{van Leeuwaarde\}, Rachel",

note = "Funding Information: The authors thank NET CONNECT for having made this study possible through logistical and organizational support provided by COR2ED. NET CONNECT is supported by an Independent Educational Grant from IPSEN. The program is therefore independent, and the content is not influenced by IPSEN and is under the sole responsibility of the experts. Elettra Merola, Teresa Alonso Gordoa, Panpan Zhang, Wouter Zandee, Faidon Laskaratos, Louis de Mestier, Angela Lamarca, Jorge Hernando, Wouter de Herder, Martin Caplin, Mauro Cives, and Rachel van Leeuwaarde are members of the NET CONNECT group. This research did not receive any specific grant from any funding agency in the public, commercial, or not‐for‐profit sector. Funding Information: ENETS excellence Academy fellowship 2017 (RF‐Grant awarded for another research project regarding neuroendocrine tumors); Ipsen, Novartis, Pfizer (C/A), Novartis (RF); Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan, Delcath (Other‐travel, educational support), Merck, Pfizer, Ipsen, Incyte, AAA (H‐Speaker), EISAI, Nutricia Ipsen, QED, Roche (H‐Advisory), Knowledge Network and NETConnect Initiatives funded by Ipsen (Other‐Member); Novartis (C/A), Ipsen, Lexicon (H); Ipsen (RF), AAA/Novartis (SAB); Novartis, AAA, Ipsen, Pfizer (H, SAB); AAA, Ipsen (SAB). The other authors indicate no financial relationships. Elettra Merola: Louis de Mestier: Angela Lamarca: Jonathan Strosberg: Wouter de Herder: Martin Caplin: Mauro Cives: Publisher Copyright: {\textcopyright} 2020 AlphaMed Press",

year = "2021",

month = apr,

doi = "10.1002/onco.13633",

language = "English",

volume = "26",

pages = "294--301",

journal = "Oncologist",

issn = "1083-7159",

publisher = "Oxford University Press",

number = "4",

}

Merola, E, Alonso Gordoa, T, Zhang, P, Al-Toubah, T, Pellè, E, Kolasińska-Ćwikła, A, Zandee, W, Laskaratos, F, de Mestier, L, Lamarca, A, Hernando, J, Cwikla, J, Strosberg, J, de Herder, W, Caplin, M, Cives, M & van Leeuwaarde, R 2021, 'Somatostatin Analogs for Pancreatic Neuroendocrine Tumors: Any Benefit When Ki-67 Is ≥10%?', Oncologist, vol. 26, no. 4, pp. 294-301. https://doi.org/10.1002/onco.13633

TY - JOUR

T1 - Somatostatin Analogs for Pancreatic Neuroendocrine Tumors

T2 - Any Benefit When Ki-67 Is ≥10%?

AU - Merola, Elettra

AU - Alonso Gordoa, Teresa

AU - Zhang, Panpan

AU - Al-Toubah, Taymeyah

AU - Pellè, Eleonora

AU - Kolasińska-Ćwikła, Agnieszka

AU - Zandee, Wouter

AU - Laskaratos, Faidon

AU - de Mestier, Louis

AU - Lamarca, Angela

AU - Hernando, Jorge

AU - Cwikla, Jaroslaw

AU - Strosberg, Jonathan

AU - de Herder, Wouter

AU - Caplin, Martin

AU - Cives, Mauro

AU - van Leeuwaarde, Rachel

N1 - Funding Information: The authors thank NET CONNECT for having made this study possible through logistical and organizational support provided by COR2ED. NET CONNECT is supported by an Independent Educational Grant from IPSEN. The program is therefore independent, and the content is not influenced by IPSEN and is under the sole responsibility of the experts. Elettra Merola, Teresa Alonso Gordoa, Panpan Zhang, Wouter Zandee, Faidon Laskaratos, Louis de Mestier, Angela Lamarca, Jorge Hernando, Wouter de Herder, Martin Caplin, Mauro Cives, and Rachel van Leeuwaarde are members of the NET CONNECT group. This research did not receive any specific grant from any funding agency in the public, commercial, or not‐for‐profit sector. Funding Information: ENETS excellence Academy fellowship 2017 (RF‐Grant awarded for another research project regarding neuroendocrine tumors); Ipsen, Novartis, Pfizer (C/A), Novartis (RF); Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan, Delcath (Other‐travel, educational support), Merck, Pfizer, Ipsen, Incyte, AAA (H‐Speaker), EISAI, Nutricia Ipsen, QED, Roche (H‐Advisory), Knowledge Network and NETConnect Initiatives funded by Ipsen (Other‐Member); Novartis (C/A), Ipsen, Lexicon (H); Ipsen (RF), AAA/Novartis (SAB); Novartis, AAA, Ipsen, Pfizer (H, SAB); AAA, Ipsen (SAB). The other authors indicate no financial relationships. Elettra Merola: Louis de Mestier: Angela Lamarca: Jonathan Strosberg: Wouter de Herder: Martin Caplin: Mauro Cives: Publisher Copyright: © 2020 AlphaMed Press

PY - 2021/4

Y1 - 2021/4

N2 - Background: Long-acting somatostatin analogs (SSAs) are the primary first-line treatment of well-differentiated advanced gastroenteropancreatic neuroendocrine tumors (NETs), but data about their efficacy in pancreatic NETs (panNETs) with Ki-67 ≥10% are still limited. Materials and Methods: To assess the clinical outcomes of advanced, nonfunctioning, well-differentiated panNETs with Ki-67 ≥10% receiving first-line long-acting SSAs in a real-world setting, we carried out a retrospective, multicenter study including patients treated between 2014–2018 across 10 centers of the NET CONNECT Network. The primary endpoints were time to next treatment (TNT) and progression-free survival (PFS), whereas overall survival (OS) and treatment safety were secondary endpoints. Results: A total of 73 patients were included (68 grade [G]2, 5 G3), with liver metastases in 61 cases (84%). After a median follow-up of 36.4 months (range, 6–173), the median TNT and PFS were 14.2 months (95% confidence interval [CI], 11.6–16.2) and 11.9 months (95% CI, 8.6–14.1) respectively. No statistically significant difference was observed according to the somatostatin analog used (octreotide vs. lanreotide), whereas increased tumor grade (hazard ratio [HR], 4.4; 95% CI, 1.2–16.6; p =.04) and hepatic tumor load (HR, 2; 95% CI, 1–4; p =.03) were independently associated with shortened PFS. The median OS recorded was 86 months (95% CI, 56.8–86 months), with poor outcomes observed when the hepatic tumor burden was >25% (HR, 3.4; 95% CI, 1.2–10; p =.01). Treatment-related adverse events were reported in 14 patients, most frequently diarrhea. Conclusion: SSAs exert antiproliferative activity in panNETs with Ki-67 ≥10%, particularly in G2 tumors, as well as when hepatic tumor load is ≤25%. Implications for Practice: The results of the study call into question the antiproliferative activity of somatostatin analogs (SSAs) in pancreatic neuroendocrine tumors with Ki-67 ≥10%. Patients with grade 2 tumors and with hepatic tumor load ≤25% appear to derive higher benefit from SSAs. Prospective studies are needed to validate these results to optimize tailored therapeutic strategies for this specific patient population.

AB - Background: Long-acting somatostatin analogs (SSAs) are the primary first-line treatment of well-differentiated advanced gastroenteropancreatic neuroendocrine tumors (NETs), but data about their efficacy in pancreatic NETs (panNETs) with Ki-67 ≥10% are still limited. Materials and Methods: To assess the clinical outcomes of advanced, nonfunctioning, well-differentiated panNETs with Ki-67 ≥10% receiving first-line long-acting SSAs in a real-world setting, we carried out a retrospective, multicenter study including patients treated between 2014–2018 across 10 centers of the NET CONNECT Network. The primary endpoints were time to next treatment (TNT) and progression-free survival (PFS), whereas overall survival (OS) and treatment safety were secondary endpoints. Results: A total of 73 patients were included (68 grade [G]2, 5 G3), with liver metastases in 61 cases (84%). After a median follow-up of 36.4 months (range, 6–173), the median TNT and PFS were 14.2 months (95% confidence interval [CI], 11.6–16.2) and 11.9 months (95% CI, 8.6–14.1) respectively. No statistically significant difference was observed according to the somatostatin analog used (octreotide vs. lanreotide), whereas increased tumor grade (hazard ratio [HR], 4.4; 95% CI, 1.2–16.6; p =.04) and hepatic tumor load (HR, 2; 95% CI, 1–4; p =.03) were independently associated with shortened PFS. The median OS recorded was 86 months (95% CI, 56.8–86 months), with poor outcomes observed when the hepatic tumor burden was >25% (HR, 3.4; 95% CI, 1.2–10; p =.01). Treatment-related adverse events were reported in 14 patients, most frequently diarrhea. Conclusion: SSAs exert antiproliferative activity in panNETs with Ki-67 ≥10%, particularly in G2 tumors, as well as when hepatic tumor load is ≤25%. Implications for Practice: The results of the study call into question the antiproliferative activity of somatostatin analogs (SSAs) in pancreatic neuroendocrine tumors with Ki-67 ≥10%. Patients with grade 2 tumors and with hepatic tumor load ≤25% appear to derive higher benefit from SSAs. Prospective studies are needed to validate these results to optimize tailored therapeutic strategies for this specific patient population.

UR - https://www.scopus.com/pages/publications/85098145034

U2 - 10.1002/onco.13633

DO - 10.1002/onco.13633

M3 - Article

C2 - 33301235

AN - SCOPUS:85098145034

SN - 1083-7159

VL - 26

SP - 294

EP - 301

JO - Oncologist

JF - Oncologist

IS - 4

ER -

Somatostatin Analogs for Pancreatic Neuroendocrine Tumors: Any Benefit When Ki-67 Is ≥10%?

Abstract

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