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Current Status of Neuroendocrine Tumors with a Special Focus on Diagnosis and Novel Treatments—2nd Edition

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (30 June 2025) | Viewed by 13372

Special Issue Editor

Dr. Dan Granberg

E-Mail Website
Guest Editor
1. Department of Molecular Medicine and Surgery, Karolinska Institute, Karolinska University Hospital, Solna, Stockholm, Sweden
2. Department of Endocrine Tumors and Sarcomas, Karolinska University Hospital, Solna, Stockholm, Sweden
Interests: neuroendocrine tumors; bronchial carcinoids; peptide receptor radionuclide therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the second edition of a previous issue on the topic of “Current Status of Neuroendocrine Tumors with a Special Focus on Diagnosis and Novel Treatments” (https://www.mdpi.com/journal/cancers/special_issues/neuroendocrine_tumors_diagnosis_novel_treatments).

Neuroendocrine tumors are a growing group of tumors, the majority of which malignant, with local or distant metastases at diagnosis. Tumors are divided according to their proliferative rate into grade 1, grade 2, and grade 3 (G1, G2, and G3, respectively). Most tumors are G1 and G2 and hence slow-growing, and patients suffering from such tumors may live for several years. Some tumors, however, are highly proliferative, and patients affected by them have a short survival and poor prognosis. Most G1 and G2 tumors, and some G3 tumors, express somatostatin receptors and may be detected by somatostatin receptor imaging. Diagnostic sensitivity has improved with the introduction of 68Gallium-DOTATOC PET CT. Somatostatin analogues are the main treatment for patients with low proliferative tumors. Other treatments include chemotherapy, PRRT with 177Lutetium-DOTATATE, and targeted therapies, such as Everolimus and Sunitinib, which have led to an improvement in prognosis. The need for newer therapeutic agents is, however, urgent.

This Special Issue will address current knowledge at the epidemiologic, diagnostic, molecular, and therapeutic level, focusing on new diagnostic and therapeutic measures.

Dr. Dan Granberg
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neuroendocrine tumors
  • somatostatin analogues
  • PRRT
  • chemotherapy
  • 68Gallium-DOTATOC
  • PET
  • CT
  • targeted therapies
  • mTOR
  • inhibitors
  • angiogenesis

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Related Special Issue

Published Papers (5 papers)

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Research

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16 pages, 2368 KB  
Article
Peptide Receptor Radionuclide Therapy (PRRT) Using Actinium-225- and Ac-225/Lutetium-177-Labeled (TANDEM) Somatostatin Receptor Antagonist DOTA-LM3 in Patients with Neuroendocrine Neoplasm: A Retrospective Study Concerning Safety and Survival
by Elisabetta Perrone, Maria Lucia Calcagni, Lucia Leccisotti, Roberto Moretti, Kriti Ghai, Aleksandr Eismant, Tanay Parkar, Lukas Greifenstein and Richard Paul Baum
Cancers 2025, 17(18), 3070; https://doi.org/10.3390/cancers17183070 - 19 Sep 2025
Viewed by 887
Abstract
Peptide Receptor Radionuclide Therapy (PRRT) offers radiomolecular precision medicine for somatostatin receptor (SSTR)-positive advanced neuroendocrine neoplasms (NEN). In cases resistant to Lutetium-177-labeled DOTATATE or DOTATOC PRRT, alpha-therapy with Actinium-225 labeled with SSTR antagonists like DOTA-LM3 can be a notable therapeutic option. This retrospective [...] Read more.
Peptide Receptor Radionuclide Therapy (PRRT) offers radiomolecular precision medicine for somatostatin receptor (SSTR)-positive advanced neuroendocrine neoplasms (NEN). In cases resistant to Lutetium-177-labeled DOTATATE or DOTATOC PRRT, alpha-therapy with Actinium-225 labeled with SSTR antagonists like DOTA-LM3 can be a notable therapeutic option. This retrospective study aimed to assess [225Ac]Ac-DOTA-LM3 safety in advanced NEN patients (as monotherapy and with Lutetium-177 as TANDEM), survival, and follow-up duration. Thirty-five patients received a total of 57 [225Ac]Ac-DOTA-LM3 cycles (March 2022–September 2024): 24 monotherapies and 33 TANDEM therapies. The pancreas was the most common primary site (n = 19). PRRT-related toxicity was assessed, focusing on hematological, renal, and hepatic toxicity (Common Terminology Criteria for Adverse Events—CTCAE v5.0). Therapy was generally well tolerated, with mostly mild acute adverse events (primarily nausea, n = 8). Some new grade 3/4 long-term adverse events were reported after treatment: anemia grade 3 (n = 2), leukocytopenia grade 4 (n = 1), absolute neutrophil count reduction grade 3 (n = 1), thrombocytopenia grade 3 (n = 7), acute myeloid leukemia (n = 1), nephrotoxicity grade 3 (n = 2), and hepatotoxicity grade 3 (n = 2). During follow-up, 13 patients died (survival range 5–30 months); 22 patients were alive (follow-up range 1–18 months). Our retrospective analysis shows that [225Ac]Ac-DOTA-LM3 PRRT is relatively safe concerning acute and long-term toxicity and bears promising survival outcomes in patients progressing after [177Lu]Lu-DOTATATE or [177Lu]Lu-DOTATOC PRRT. Full article
(This article belongs to the Special Issue Current Status of Neuroendocrine Tumors with a Special Focus on Diagnosis and Novel Treatments—2nd Edition)
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15 pages, 979 KB  
Article
Prognostic Factors in Neuroendocrine Neoplasms of the Rectum
by Frederike Butz, Charlotte Friederike Müller-Debus, Flora Georgina Ecseri, Gianna Sophia Mani, Elif Akgündüz, Agata Dukaczewska, Peter Richard Steinhagen, Uli Fehrenbach, Catarina A. Kunze, Henning Jann, Johann Pratschke, Eva Maria Dobrindt and Martina T. Mogl
Cancers 2025, 17(17), 2841; https://doi.org/10.3390/cancers17172841 - 29 Aug 2025
Viewed by 661
Abstract
Background/Objectives: Neuroendocrine neoplasms (NENs) of the rectum (rNEN) are a rare and heterogeneous group of tumors that can vary greatly in their biological behavior, from benign to highly aggressive. While small and well-differentiated tumors can often be handled endoscopically and still face a [...] Read more.
Background/Objectives: Neuroendocrine neoplasms (NENs) of the rectum (rNEN) are a rare and heterogeneous group of tumors that can vary greatly in their biological behavior, from benign to highly aggressive. While small and well-differentiated tumors can often be handled endoscopically and still face a very good prognosis, tumor size, and grade, as well as lymph node and distant metastasis, are known risk factors for impaired prognosis. This study aimed at the identification of further prognostic factors in rNEN. Methods: A retrospective analysis of patients treated for rNEN at the ENTES Center of Excellence at Charité—Universitätsmedizin, including n = 121 patients, was performed to identify risk factors for recurrence, progression, and impaired outcome. Results: Progression-free survival (PFS) and overall survival (OS) differed significantly according to tumor grade (p < 0.001). In rNET patients undergoing surgery, the Ki-67 index and distant metastases were independent risk factors for shorter PFS. Among stage I rNETs, 10 patients developed disease recurrence, associated with lymphatic invasion (1.9% vs. 30.0%, p = 0.008) and higher Ki-67 values (2 (1–6) vs. 2 (1–16), p = 0.054). Conclusions: Tumor grade and presence of metastases represent important predictive factors in rNEN. Notably, even small, early-stage rNETs can harbor a risk of recurrence when unfavorable pathological features are present, highlighting the importance of tailored, risk-adapted surveillance strategies to optimize patient outcomes. Full article
(This article belongs to the Special Issue Current Status of Neuroendocrine Tumors with a Special Focus on Diagnosis and Novel Treatments—2nd Edition)
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10 pages, 395 KB  
Article
Pathological Features Associated with Lymph Node Disease in Patients with Appendiceal Neuroendocrine Tumors
by Salvador Rodriguez Franco, Sumaya Abdul Ghaffar, Ying Jin, Reed Weiss, Mona Hamermesh, Andrii Khomiak, Toshitaka Sugawara, Oskar Franklin, Alexis D. Leal, Christopher H. Lieu, Richard D. Schulick, Marco Del Chiaro, Steven Ahrendt, Martin D. McCarter and Ana L. Gleisner
Cancers 2024, 16(16), 2922; https://doi.org/10.3390/cancers16162922 - 22 Aug 2024
Cited by 1 | Viewed by 2009
Abstract
This study aimed to evaluate the role of pathological features beyond tumor size in the risk of lymph node metastasis in appendiceal neuroendocrine tumors. Analyzing data from the national cancer database, we found that among 5353 cases, 18.8% had lymph node metastasis. Focusing [...] Read more.
This study aimed to evaluate the role of pathological features beyond tumor size in the risk of lymph node metastasis in appendiceal neuroendocrine tumors. Analyzing data from the national cancer database, we found that among 5353 cases, 18.8% had lymph node metastasis. Focusing on tumors smaller than 2 cm, a subject of considerable debate in treatment strategies, we identified lymphovascular invasion as one of the strongest predictors of lymph node disease. Interestingly, extension into the subserosa and beyond, a current factor in the staging system, was not a strong predictor. These findings suggest that careful interpretation of pathological features is needed when selecting therapeutic approaches using current staging systems. Full article
(This article belongs to the Special Issue Current Status of Neuroendocrine Tumors with a Special Focus on Diagnosis and Novel Treatments—2nd Edition)
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16 pages, 2071 KB  
Article
Metronomic Temozolomide (mTMZ) and Bevacizumab—The Safe and Effective Frontier for Treating Metastatic Neuroendocrine Tumors (NETs): A Single-Center Experience
by Çağlar Ünal and Sezer Sağlam
Cancers 2023, 15(23), 5688; https://doi.org/10.3390/cancers15235688 - 1 Dec 2023
Viewed by 1972
Abstract
Addressing the persistent challenges in treating metastatic neuroendocrine tumors (NETs) demands ongoing refinement and innovation in therapeutic strategies. This study investigates the potential advantages of combining metronomic temozolomide (mTMZ) with bevacizumab for patients diagnosed with metastatic NETs, particularly focusing on those with a [...] Read more.
Addressing the persistent challenges in treating metastatic neuroendocrine tumors (NETs) demands ongoing refinement and innovation in therapeutic strategies. This study investigates the potential advantages of combining metronomic temozolomide (mTMZ) with bevacizumab for patients diagnosed with metastatic NETs, particularly focusing on those with a Ki-67 index under 55%. Data from 30 patients were analyzed, using key performance indicators such as progression-free survival (PFS), overall survival (OS), and response rates to therapy, to gauge the treatment’s efficacy. The results were encouraging: the median PFS recorded was 16.3 months, and the OS was 25.9 months. The disease control rate (DCR) reached an impressive 86.7%, and the objective response rate (ORR) stood at 63.3%. The treatment regimen was well-tolerated, with no reported instances of grade 4 toxicities. Such a safety profile indicates that this regimen may be particularly advantageous for older, fragile patients who might struggle with conventional dosage levels. These initial findings suggest that the mTMZ and bevacizumab combination could potentially rival the conventional temozolomide–capecitabine therapy in managing metastatic NETs. We aimed to meticulously assess the efficacy of the mTMZ and bevacizumab combination in treating metastatic NETs. Given the initial promising results, a more conclusive understanding of its efficacy will require further research through larger, multicenter prospective clinical trials. Full article
(This article belongs to the Special Issue Current Status of Neuroendocrine Tumors with a Special Focus on Diagnosis and Novel Treatments—2nd Edition)
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Review

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18 pages, 2590 KB  
Review
Lung Carcinoids: A Comprehensive Review for Clinicians
by Dan Granberg, Carl Christofer Juhlin, Henrik Falhammar and Elham Hedayati
Cancers 2023, 15(22), 5440; https://doi.org/10.3390/cancers15225440 - 16 Nov 2023
Cited by 24 | Viewed by 6865
Abstract
Lung carcinoids are neuroendocrine tumors, categorized as typical or atypical carcinoids based on their histological appearance. While most of these tumors are slow-growing neoplasms, they still possess malignant potential. Many patients are diagnosed incidentally on chest X-rays or CT scans. Presenting symptoms include [...] Read more.
Lung carcinoids are neuroendocrine tumors, categorized as typical or atypical carcinoids based on their histological appearance. While most of these tumors are slow-growing neoplasms, they still possess malignant potential. Many patients are diagnosed incidentally on chest X-rays or CT scans. Presenting symptoms include cough, hemoptysis, wheezing, dyspnea, and recurrent pneumonia. Endocrine symptoms, such as carcinoid syndrome or ectopic Cushing’s syndrome, are rare. Surgery is the primary treatment and should be considered in all patients with localized disease, even when thoracic lymph node metastases are present. Patients with distant metastases may be treated with somatostatin analogues, chemotherapy, preferably temozolomide-based, mTOR inhibitors, or peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE. Most patients have an excellent prognosis. Poor prognostic factors include atypical histology and lymph node metastases at diagnosis. Long-term follow-up is mandatory since metastases may occur late. Full article
(This article belongs to the Special Issue Current Status of Neuroendocrine Tumors with a Special Focus on Diagnosis and Novel Treatments—2nd Edition)
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