Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Oct 26;14(21):5248.
doi: 10.3390/cancers14215248.

Treatment Sequencing Strategies in Advanced Neuroendocrine Tumors: A Review

Aman Chauhan  1 , Jaydira Del Rivero  2 , Robert A Ramirez  3 , Heloisa P Soares  4 , Daneng Li  5
Affiliations
Review

Treatment Sequencing Strategies in Advanced Neuroendocrine Tumors: A Review

Aman Chauhan et al. Cancers (Basel). .

Abstract

Neuroendocrine tumor (NET) incidence has grown. The treatment landscape for advanced NETs is rapidly evolving, but there are limited head-to-head data to guide treatment sequencing decisions. We assessed the available clinical data to aid practicing clinicians in their routine clinical decision-making. Clinical trials have demonstrated efficacy benefits for new therapies in advanced NETs. Emerging long-term data from these trials have enabled clinicians to make more accurate risk-benefit assessments, particularly for patients receiving multiple lines of therapy. However, clinical data specifically regarding treatment sequencing are limited. In lieu of definitive data, treatment sequencing should be based on disease-related factors (e.g., site of tumor origin, volume of disease) and patient-related characteristics (e.g., comorbidities, patient preferences). Clinical decision-making in advanced NETs remains highly individualized and complex; important evidence gaps regarding treatment sequencing remain. Given this, advanced NET management should be a joint effort of multidisciplinary teams at referring and high-volume centers. Additional clinical trial and real-world evidence are needed to meet the challenge of understanding how to sequence available NET therapies. Until these trials are conducted, the best practices provided in this review may serve as a guide for clinicians making treatment sequencing decisions based on the available data.

Keywords: clinical trials; efficacy; neuroendocrine tumors (NET); peptide receptor radionuclide therapy (PRRT); safety; treatment sequencing.

PubMed Disclaimer

Conflict of interest statement

Chauhan reported receiving grants from TerSera, Lexicon, Bristol Myers Squibb (BMS), Clovis Oncology, EMD Serono, Nanotherapeutics, and ECS Prograstin; and consulting fees from Novartis/Advanced Accelerator Applications, Ipsen, Lexicon, Entrensic Health Solutions, TerSera, and Seneca Therapeutics. Del Rivero declares no conflicts of interest. Li has received honoraria and advisory/consultancy fees from Lexicon, Ipsen, Eisai, Exelixis, Novartis/Advanced Accelerator Applications, Coherus, Sun Pharma, Genentech, QED, Merck, Adagene, Mina Therapeutics, Servier, Delcath, and TerSera; and received institutional research funding from Brooklyn Immunotherapeutics and AstraZeneca. Ramirez reported receiving research funding (to institution) from Merck and Aadi Bioscience; consulting fees from Amgen, Ipsen, Novartis, Advanced Accelerator Applications, Curium, EMD Serono, and AstraZeneca; and speaking fees from Ipsen and AstraZeneca. Soares has received honoraria and advisory/consultancy fees from Lexicon, Ipsen, Exelixis, Novartis/Advanced Accelerator Applications, AstraZeneca, Helsinn, Incyte, and TerSera.

Figures

Figure 1
Figure 1
Timeline of therapies approved for the treatment of NETs. 177Lu, lutetium-177; NET, neuroendocrine tumor; pNET, pancreatic neuroendocrine tumor.
Figure 2
Figure 2
Randomized, controlled clinical trials conducted in the advanced NET setting. PROMID and CLARINET were the only trials involving primarily treatment-naïve populations; all other trials were beyond first-line therapy. a Patients could receive SSAs at the investigator’s discretion. b After the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in PFS favoring sunitinib. c Due to slow accrual. d Based on number of deaths. e Median. f Including IM octreotide LAR administered at a dose of 30 mg. g Including open-label extension phase. BID, twice daily; CLARINET, Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors; ECOG, Eastern Cooperative Oncology Group; GEP, gastroenteropancreatic; IM, intramuscular; LAR, long-acting repeatable; NETs, neuroendocrine tumors; NETTER-1, Neuroendocrine Tumors Therapy; PFS, progression-free survival; pNET, pancreatic NET; PROMID, placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine MID gut tumors; QD, once daily; RADIANT-3, RAD001 in Advanced Neuroendocrine Tumors, third trial; RECIST, Response Evaluation Criteria in Solid Tumors; SPINET, Efficacy and safety of lanreotide autogel/depot 120 mg vs. placebo in subjects with lung neuroendocrine tumors; SSAs, somatostatin analogs; SSTR, somatostatin receptor; SUNNET, Study of Sunitinib Compared to Placebo for Patients with Advanced Pancreatic Islet Cell Tumors; WHO PS, World Health Organization performance status.
Figure 3
Figure 3
Novel therapy development in NETs as illustrated by select trials focusing on novel combinations and new agents or classes of drugs. Most of the agents listed are not commercially available in the United States for NETs. 177Lu, lutetium-177; NET, neuroendocrine tumor; RLT, radioligand therapy.
See this image and copyright information in PMC

References

    1. Dasari A., Shen C., Halperin D., Zhao B., Zhou S., Xu Y., Shih T., Yao J.C. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3:1335–1342. doi: 10.1001/jamaoncol.2017.0589. - DOI - PMC - PubMed
    1. Xu Z., Wang L., Dai S., Chen M., Li F., Sun J., Luo F. Epidemiologic trends of and factors associated with overall survival for patients with gastroenteropancreatic neuroendocrine tumors in the United States. JAMA Netw. Open. 2021;4:e2124750. doi: 10.1001/jamanetworkopen.2021.24750. - DOI - PMC - PubMed
    1. Chauhan A., Kohn E., Del Rivero J. Neuroendocrine tumors-less well known, often misunderstood, and rapidly growing in incidence. JAMA Oncol. 2020;6:21–22. doi: 10.1001/jamaoncol.2019.4568. - DOI - PMC - PubMed
    1. La Salvia A., Espinosa-Olarte P., Riesco-Martinez M.D.C., Anton-Pascual B., Garcia-Carbonero R. Targeted cancer therapy: What’s new in the field of neuroendocrine neoplasms? Cancers. 2021;13:1701. doi: 10.3390/cancers13071701. - DOI - PMC - PubMed
    1. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Neuroendocrine and Adrenal Tumors. 2021. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Neuroendocrine and adrenal tumors 4.2021. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed April 22, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. [(accessed on 22 April 2022)]. Available online: https://www.NCCN.org.

LinkOut - more resources