Characteristics and treatment outcome in a prospective cohort of 639 advanced high-grade digestive neuroendocrine neoplasms (NET G3 and NEC). The NORDIC NEC 2 study: Clinical Studies

Halfdan Sorbye; Geir Olav Hjortland; Lene Weber Vestermark; Morten Ladekarl; Johanna Svensson; Anna Sundlöv; Eva Tiensuu Janson; Herish Garresori; Eva Hofsli; Christian Kersten; Hege Elvebakken; Per Pfeiffer; Siren Morken; Jorg Assmus; Inger Marie Bowitz Lothe; Elizaveta Tabaksblat; Ulrich Knigge; Anne Couvelard; Aurel Perren; Seppo W Langer

doi:10.1038/s41416-025-03054-w

Characteristics and treatment outcome in a prospective cohort of 639 advanced high-grade digestive neuroendocrine neoplasms (NET G3 and NEC). The NORDIC NEC 2 study: Clinical Studies

Halfdan Sorbye^*, Geir Olav Hjortland, Lene Weber Vestermark, Morten Ladekarl, Johanna Svensson, Anna Sundlöv, Eva Tiensuu Janson, Herish Garresori, Eva Hofsli, Christian Kersten, Hege Elvebakken, Per Pfeiffer, Siren Morken, Jorg Assmus, Inger Marie Bowitz Lothe, Elizaveta Tabaksblat, Ulrich Knigge, Anne Couvelard, Aurel Perren, Seppo W Langer

^*Corresponding author for this work

21 Citations (Scopus)

Abstract

BACKGROUND: Digestive high-grade neuroendocrine neoplasms (HG-NEN) are rare and classified as neuroendocrine carcinomas (NEC) or neuroendocrine tumours G3 (NET G3), and differ in clinical and molecular characteristics, response to treatment and prognosis.

METHODS: Prospective multicenter study registering clinical data on patients with digestive HG-NEN. Treatment outcome in patients with advanced disease was compared after centralized pathological re-evaluation.

RESULTS: 427 NEC and 117 NET G3 received palliative chemotherapy. Immediate progression rate was 41% and 24%, progression-free survival (PFS) 3.4 m and 7.4 m, overall survival (OS) 7.4 m and 21.8 m for NEC and NET G3, respectively. Significant factors for OS in NEC were performance status (PS), Ki-67 > 55%, alkaline phosphatase (ALP), age, sex and for PFS colorectal primary and PS. NEC Ki-67 < 55% had similar OS comparing treatment. Significant factors for OS in NET G3 were platinum-based treatment, PS, age and ALP, and for PFS platinum-based treatment.

CONCLUSIONS: Survival was shorter than expected in this unique population-based cohort of advanced digestive HG-NEN, likely due to inclusion of elderly and patients with poor PS. Several novel prognostic factors were identified for NEC and NET G3. An initial sub-effective platinum-based treatment for NET G3 could not be compensated by later-line treatment.

Original language	English
Journal	British Journal of Cancer
Volume	133
Issue number	3
Pages (from-to)	316-324
Number of pages	9
ISSN	0007-0920
DOIs	https://doi.org/10.1038/s41416-025-03054-w https://doi.org/10.1038/s41416-025-03095-1
Publication status	Published - Aug 2025

Keywords

Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols/therapeutic use
Digestive System Neoplasms/pathology
Female
Humans
Male
Middle Aged
Neoplasm Grading
Neuroendocrine Tumors/pathology
Prognosis
Prospective Studies
Treatment Outcome

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10.1038/s41416-025-03095-1Licence: CC BY

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Sorbye, H., Hjortland, G. O., Vestermark, L. W., Ladekarl, M., Svensson, J., Sundlöv, A., Janson, E. T., Garresori, H., Hofsli, E., Kersten, C., Elvebakken, H., Pfeiffer, P., Morken, S., Assmus, J., Lothe, I. M. B., Tabaksblat, E., Knigge, U., Couvelard, A., Perren, A., & Langer, S. W. (2025). Characteristics and treatment outcome in a prospective cohort of 639 advanced high-grade digestive neuroendocrine neoplasms (NET G3 and NEC). The NORDIC NEC 2 study: Clinical Studies. British Journal of Cancer, 133(3), 316-324. https://doi.org/10.1038/s41416-025-03054-w, https://doi.org/10.1038/s41416-025-03095-1

Characteristics and treatment outcome in a prospective cohort of 639 advanced high-grade digestive neuroendocrine neoplasms (NET G3 and NEC). The NORDIC NEC 2 study: Clinical Studies. / Sorbye, Halfdan; Hjortland, Geir Olav; Vestermark, Lene Weber et al.
In: British Journal of Cancer, Vol. 133, No. 3, 08.2025, p. 316-324.

Research output: Contribution to journal › Journal article › Research › peer-review

Sorbye, H, Hjortland, GO, Vestermark, LW, Ladekarl, M, Svensson, J, Sundlöv, A, Janson, ET, Garresori, H, Hofsli, E, Kersten, C, Elvebakken, H, Pfeiffer, P, Morken, S, Assmus, J, Lothe, IMB, Tabaksblat, E, Knigge, U, Couvelard, A, Perren, A & Langer, SW 2025, 'Characteristics and treatment outcome in a prospective cohort of 639 advanced high-grade digestive neuroendocrine neoplasms (NET G3 and NEC). The NORDIC NEC 2 study: Clinical Studies', British Journal of Cancer, vol. 133, no. 3, pp. 316-324. https://doi.org/10.1038/s41416-025-03054-w, https://doi.org/10.1038/s41416-025-03095-1

Sorbye H, Hjortland GO, Vestermark LW, Ladekarl M, Svensson J, Sundlöv A et al. Characteristics and treatment outcome in a prospective cohort of 639 advanced high-grade digestive neuroendocrine neoplasms (NET G3 and NEC). The NORDIC NEC 2 study: Clinical Studies. British Journal of Cancer. 2025 Aug;133(3):316-324. Epub 2025 May 17. doi: 10.1038/s41416-025-03054-w, 10.1038/s41416-025-03095-1

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title = "Characteristics and treatment outcome in a prospective cohort of 639 advanced high-grade digestive neuroendocrine neoplasms (NET G3 and NEC). The NORDIC NEC 2 study: Clinical Studies",

abstract = "BACKGROUND: Digestive high-grade neuroendocrine neoplasms (HG-NEN) are rare and classified as neuroendocrine carcinomas (NEC) or neuroendocrine tumours G3 (NET G3), and differ in clinical and molecular characteristics, response to treatment and prognosis.METHODS: Prospective multicenter study registering clinical data on patients with digestive HG-NEN. Treatment outcome in patients with advanced disease was compared after centralized pathological re-evaluation.RESULTS: 427 NEC and 117 NET G3 received palliative chemotherapy. Immediate progression rate was 41\% and 24\%, progression-free survival (PFS) 3.4 m and 7.4 m, overall survival (OS) 7.4 m and 21.8 m for NEC and NET G3, respectively. Significant factors for OS in NEC were performance status (PS), Ki-67 > 55\%, alkaline phosphatase (ALP), age, sex and for PFS colorectal primary and PS. NEC Ki-67 < 55\% had similar OS comparing treatment. Significant factors for OS in NET G3 were platinum-based treatment, PS, age and ALP, and for PFS platinum-based treatment.CONCLUSIONS: Survival was shorter than expected in this unique population-based cohort of advanced digestive HG-NEN, likely due to inclusion of elderly and patients with poor PS. Several novel prognostic factors were identified for NEC and NET G3. An initial sub-effective platinum-based treatment for NET G3 could not be compensated by later-line treatment.",

keywords = "Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Digestive System Neoplasms/pathology, Female, Humans, Male, Middle Aged, Neoplasm Grading, Neuroendocrine Tumors/pathology, Prognosis, Prospective Studies, Treatment Outcome",

author = "Halfdan Sorbye and Hjortland, \{Geir Olav\} and Vestermark, \{Lene Weber\} and Morten Ladekarl and Johanna Svensson and Anna Sundl{\"o}v and Janson, \{Eva Tiensuu\} and Herish Garresori and Eva Hofsli and Christian Kersten and Hege Elvebakken and Per Pfeiffer and Siren Morken and Jorg Assmus and Lothe, \{Inger Marie Bowitz\} and Elizaveta Tabaksblat and Ulrich Knigge and Anne Couvelard and Aurel Perren and Langer, \{Seppo W\}",

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year = "2025",

month = aug,

doi = "10.1038/s41416-025-03054-w",

language = "English",

volume = "133",

pages = "316--324",

journal = "British Journal of Cancer",

issn = "0007-0920",

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number = "3",

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TY - JOUR

T1 - Characteristics and treatment outcome in a prospective cohort of 639 advanced high-grade digestive neuroendocrine neoplasms (NET G3 and NEC). The NORDIC NEC 2 study

T2 - Clinical Studies

AU - Sorbye, Halfdan

AU - Hjortland, Geir Olav

AU - Vestermark, Lene Weber

AU - Ladekarl, Morten

AU - Svensson, Johanna

AU - Sundlöv, Anna

AU - Janson, Eva Tiensuu

AU - Garresori, Herish

AU - Hofsli, Eva

AU - Kersten, Christian

AU - Elvebakken, Hege

AU - Pfeiffer, Per

AU - Morken, Siren

AU - Assmus, Jorg

AU - Lothe, Inger Marie Bowitz

AU - Tabaksblat, Elizaveta

AU - Knigge, Ulrich

AU - Couvelard, Anne

AU - Perren, Aurel

AU - Langer, Seppo W

PY - 2025/8

Y1 - 2025/8

N2 - BACKGROUND: Digestive high-grade neuroendocrine neoplasms (HG-NEN) are rare and classified as neuroendocrine carcinomas (NEC) or neuroendocrine tumours G3 (NET G3), and differ in clinical and molecular characteristics, response to treatment and prognosis.METHODS: Prospective multicenter study registering clinical data on patients with digestive HG-NEN. Treatment outcome in patients with advanced disease was compared after centralized pathological re-evaluation.RESULTS: 427 NEC and 117 NET G3 received palliative chemotherapy. Immediate progression rate was 41% and 24%, progression-free survival (PFS) 3.4 m and 7.4 m, overall survival (OS) 7.4 m and 21.8 m for NEC and NET G3, respectively. Significant factors for OS in NEC were performance status (PS), Ki-67 > 55%, alkaline phosphatase (ALP), age, sex and for PFS colorectal primary and PS. NEC Ki-67 < 55% had similar OS comparing treatment. Significant factors for OS in NET G3 were platinum-based treatment, PS, age and ALP, and for PFS platinum-based treatment.CONCLUSIONS: Survival was shorter than expected in this unique population-based cohort of advanced digestive HG-NEN, likely due to inclusion of elderly and patients with poor PS. Several novel prognostic factors were identified for NEC and NET G3. An initial sub-effective platinum-based treatment for NET G3 could not be compensated by later-line treatment.

AB - BACKGROUND: Digestive high-grade neuroendocrine neoplasms (HG-NEN) are rare and classified as neuroendocrine carcinomas (NEC) or neuroendocrine tumours G3 (NET G3), and differ in clinical and molecular characteristics, response to treatment and prognosis.METHODS: Prospective multicenter study registering clinical data on patients with digestive HG-NEN. Treatment outcome in patients with advanced disease was compared after centralized pathological re-evaluation.RESULTS: 427 NEC and 117 NET G3 received palliative chemotherapy. Immediate progression rate was 41% and 24%, progression-free survival (PFS) 3.4 m and 7.4 m, overall survival (OS) 7.4 m and 21.8 m for NEC and NET G3, respectively. Significant factors for OS in NEC were performance status (PS), Ki-67 > 55%, alkaline phosphatase (ALP), age, sex and for PFS colorectal primary and PS. NEC Ki-67 < 55% had similar OS comparing treatment. Significant factors for OS in NET G3 were platinum-based treatment, PS, age and ALP, and for PFS platinum-based treatment.CONCLUSIONS: Survival was shorter than expected in this unique population-based cohort of advanced digestive HG-NEN, likely due to inclusion of elderly and patients with poor PS. Several novel prognostic factors were identified for NEC and NET G3. An initial sub-effective platinum-based treatment for NET G3 could not be compensated by later-line treatment.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use

KW - Digestive System Neoplasms/pathology

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Neoplasm Grading

KW - Neuroendocrine Tumors/pathology

KW - Prognosis

KW - Prospective Studies

KW - Treatment Outcome

UR - https://www.scopus.com/pages/publications/105005119839

UR - https://www.nature.com/articles/s41416-025-03095-1

U2 - 10.1038/s41416-025-03054-w

DO - 10.1038/s41416-025-03054-w

M3 - Journal article

C2 - 40382522

SN - 0007-0920

VL - 133

SP - 316

EP - 324

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 3

ER -

Characteristics and treatment outcome in a prospective cohort of 639 advanced high-grade digestive neuroendocrine neoplasms (NET G3 and NEC). The NORDIC NEC 2 study: Clinical Studies

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