Transarterial embolization combined with octreotide long-acting release in treating rectal neuroendocrine tumor liver metastases: a single-institutional experience

Introduction

Neuroendocrine tumors (NETs) are still rare tumors although their incidence is on the rise (1). Most of them derive from the gastroenteropancreatic tract or the lung (2). They are the second most common malignant tumor of the digestive tract, second only to rectal cancer. Up to 90% of patients with NETs are presented with or will develop liver metastases during the course of disease (3). Hepatic metastasis is the most important independent prognostic factor contributing to the fastest tumor progression (4,5).

Transarterial embolization (TAE) for neuroendocrine tumor liver metastases (NETLMs) has been proved to be efficacious in tumor reduction and symptomatic relief (6). However, previous studies almost all investigated patients with NETLMs of various origin, thus it was impossible to avoid the impact produced by the distinction of biological characteristics of tumors from different primary sites. So far as we know, there have been no studies that are powered for the specific subgroup analyses of rectal NETLMs. Octreotide long-acting release (LAR) is a well-established therapy in patients with NETs, which is able to not only promote apoptosis but also inhibit proliferation (7-9).

The purpose of this study was to evaluate the efficacy and factors of hepatic progression-free survival (HPFS) and treatment response in patients with rectal NETLMs receiving TAE plus octreotide LAR therapy. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0055/rc).

Methods

Patient selection

This was a retrospective study approved by the Institutional Review Board of Fudan University Shanghai Cancer Center (No. 1612167-18) and the informed consent was exempted because of the retrospective nature of this study. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. A total of 84 patients with rectal NETLMs receiving the treatments of TAE plus octreotide LAR from January 2022 to December 2024 at one single institution were enrolled. Figure 1 shows the flow chart of patient enrollment. All cases were histologically confirmed rectal NETLMs by liver biopsy. All patients had extensive hepatic metastases or complex liver metastases that are difficult to resect surgically due to their anatomical location and are not suitable for ablation due to the limitation of tumor number or size. Exclusion criteria included: received prior systemic therapies and liver-directed therapies within 3 months; administrated with other antitumoral medication in parallel with TAE. Patients who had previously received somatostatin analogs (SSAs) but experienced disease progression in liver metastases were not excluded.

Figure 1 Flow chart of the study population selection. LAR, long-acting release; NETLM, neuroendocrine tumor liver metastasis; TAE, transarterial embolization.

Tumor characteristics

Tumor grade was designated by the World Health Organization (WHO) 2022 classification. The hepatic tumor burden (HTB) was estimated from 4 to 6 slices of a CT/magnetic resonance (MR) scan by a semiquantitative 3-dimensional approach and categorized as ≤10%, 10–25%, 25–50%, and >50% (10). Extrahepatic metastases were determined on review of pretreatment imaging.

Treatment

The therapeutic regimen of TAE plus octreotide LAR for all cases were made in the opinion of a multidisciplinary team (MDT). Short-acting octreotide was administered to the patients with hormonal syndromes half an hour before the beginning of TAE procedure. During the operation, celiac and superior mesenteric arteriography were performed with a 5-F catheter. Then, a 1.7-F microcatheter was superselectively advanced into the tumor-involved lobar or segmental hepatic arterial branches, depending on tumor distribution and hepatic functional reserve. Embolic agents including 45–150 µm polyvinyl alcohol (PVA; Merit Medical, City, Country) and 40–120 µm Embosphere (Merit Medical) were injected into the microcatheter under fluoroscopy. The endpoint of embolization was angiographic stasis of the embolized artery and devascularization of tumors. For the patients with very high liver tumor burden, TAE treatments were performed in multiple sessions (approximately 1 month between two sessions) to safely treat the entire liver. During the intervals, octreotide LAR (Sandostatin-LAR; Novartis, City, Country) was administered to inhibit the growth of untreated lesions. Immunohistochemical tests and ⁶⁸Ga-DOTATATE positron emission tomography-computed tomography (⁶⁸Ga-DOTATATE PET-CT) were performed pre-administration to confirm positive expression of somatostatin receptor (SSTR) on the tumors. The dosage of Octreotide LAR was determined by the MDT based on the tumor classification, patients’ hormone-related symptoms and treatment response.

Patient evaluation and follow-up protocol

Contrast enhanced CT/magnetic resonance imaging (MRI), ¹⁸F-fluorodeoxyglucose-positron emission tomography-computed tomography (¹⁸F-FDG PET-CT), and ⁶⁸Ga-DOTATATE PET-CT were performed at baseline. Follow-up imaging (contrast enhanced CT/MRI), lab tests and clinical evaluation were performed 1 month after TAE sessions. Then, contrast enhanced CT/MRI was carried out with 3-month interval for the first year, and at least every 6 months thereafter. The radiological outcome was assessed independently by a third-party group in accordance with the Response Evaluation Criteria in Solid Tumor (version 1.1) (RECIST 1.1). If all liver tumors were not treated in a single TAE session, only the treated tumors were evaluated. Tumor enhancement was defined as a significant hyperattenuation of the tumor comparing to the adjacent liver parenchyma by a visual assessment on the arterial phase images (11). Tumor border was assessed by a visual assessment on the arterial and portal phase images. Adverse events were assessed and recorded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Grade 3 or higher events were considered to be severe.

Outcomes

In this study, HPFS was defined as the time period from the date of initial TAE treatment to the first presence of progressive disease (PD) in the liver or all-cause mortality. Objective response rate (ORR) was defined as the proportion of patients achieving partial response (PR) and complete response (CR) according to the RECIST 1.1 (12).

Statistical analysis

Statistical analysis was performed using SPSS software (Version 31.0; IBM Corp.). Continuous variables were described by median and range. Categoric variables were described by frequency and percentage. Kaplan-Meier method was employed to analyze survival data. Cox regression models were applied to analyze factors affecting HPFS. Logistic regression models were applied to analyze factors affecting treatment response. In the logistic regression model, treatment response was classified into two categories: PR and non-PR. Non-PR included stable disease (SD) and PD. Factors with P<0.1 in univariate analysis were included in the multivariate model. P<0.05 was considered statistically significant.

Results

Baseline characteristics

Baseline characteristics of the 84 analyzed patients are shown in Table 1. A total of 230 sessions of TAE treatment were performed (2.7 per patient on average). Patients with G2 tumors accounted for 85%. The primary tumors were resected in 35 patients (41.7%). Extrahepatic metastases were found in 18 patients (21.4%).

Outcomes

In our study, the median follow-up time was 14 months (range, 1–40 months). HPFS was reached in 52 patients owing to progression. There was no death observed during the follow-up period. The median HPFS was 11.1 months (Figure 2). In terms of treatment response, PR was achieved in 71 patients (84.5%), SD in 9 patients (10.7%), and PD in 4 patients (4.8%) (Figure 3). The ORR was 84.5% (Table 2).

Figure 2 Kaplan-Meier curve of hepatic progression-free survival.

Figure 3 (A) A 71-year-old female patient with liver metastases of a WHO grade 2 rectal neuroendocrine tumor. The lesions showed mild enhancement on the baseline contrast-enhanced MR images with clear border. (B) No significant radioactive uptake was observed in the lesions on the baseline 18F-FDG PET-CT images. (C) The lesions showed heterogeneous radiotracer uptake on the baseline 68Ga-DOTATATE PET-CT images. (D) After two procedures of TAE treatment, the enhanced tumor region had significantly reduced or disappeared on the contrast-enhanced MR images after 3 months. Treatment response assessment for this patient was partial response using the RECIST 1.1. FDG, fluorodeoxyglucose; MR, magnetic resonance; PET-CT, positron emission tomography-computed tomography; RECIST, Response Evaluation Criteria in Solid Tumor; TAE, transarterial embolization; WHO, World Health Organization.

Factors affecting HPFS

In the univariate Cox regression analyses, Eastern Cooperative Oncology Group (ECOG) score, HTB and tumor border were significant factors. The multivariate Cox regression analyses revealed that HTB ≤25% [hazard ratio (HR) =4.188, P=0.02] might have an independent influence on HPFS (Table 3). The median PFS of patients with HTB ≤25% and >25% was 12.3 and 9.5 months, respectively. The median HPFS of patients with Ki-67 ≤10% and >10% was 11.7 and 9.7 months, respectively. The median HPFS of patients with negative and positive FDG status was 7 and 11.3 months, respectively.

Factors affecting treatment response

In the univariate logistic regression analyses, ECOG score, ¹⁸F-FDG PET-CT, Ki-67 >10% and tumor border were significant factors. In the multivariate logistic regression model, ¹⁸F-FDG PET-CT [odds ratio (OR) =11.919, P=0.003] and Ki-67 (OR =6.469, P=0.01) might have a negative influence on treatment response, whereas tumor border (OR =0.069, P=0.01) might have a positive influence (Table 4).

Adverse events

Adverse events were shown in Table 5. Postembolization syndrome was the most common adverse event after TAE, including abdominal pain (61.9%), fever (58.3%), nausea and vomiting (22.6%), and transiently impaired liver function (20.2%). Liver abscess was found in 2 patients (2.4%). Transient hypertension was found in 5 patients (5.9%). The adverse events caused by octreotide LAR were rare and mild.

Discussion

Prior studies showed that large HTB was associated with poor drug treatment outcomes and a significantly shortened PFS (13). However, those who have undergone successful intrahepatic tumor reduction treatment can also achieve better therapeutic effect with drug treatment (13-15). Numerous studies have demonstrated the efficacy and safety of TA(C)E on tumor reduction in patients with NETLMs (16-18). However, the optimal strategy of embolotherapy, such as the selection of variety and size of embolic agents, for NETLMs remains controversial, intensified by the inherent complexity of NET biological characteristics. In previous studies, results showed that there was no statistically significant difference in efficacy between TAE and TACE treatment, but TAE has a higher ORR and may avoid the adverse events due to chemotherapy drugs used in the TACE procedure (3,19). In terms of the particles size, Zener et al. demonstrated that NETLMs patients treated with TAE using particles <100 µm had more favorable initial response comparing to those using particles ≥100 µm (20).

To the best of our knowledge, there was no study on the analysis of TAE in treating the specific subgroup of rectal NETLMs before. In our study, the rectal NETLMs patients were all treated with TAE using the smallest particles available (40–120 µm Embosphere and 45–150 µm PVA) in combination with octreotide LAR. The therapeutic regimen aims to rapidly reduce HTB by TAE at the beginning of treatment, so as to decrease the dose and strengthen the therapeutic effect of octreotide LAR in a condition of relatively low HTB.

In this study, from the multivariate proportional hazards Cox regression models for HPFS, HTB ≤25% was a significant prognostic factor for prolonged HPFS. Previous studies showed that PFS ranged from 6.6 to 16.2 months in patients with NETLMs receiving TAE/TACE treatment, probably due to the difference in study population, such as the variety of primary tumor sites, tumor characteristics and embolotherapy modality (20-22). The HPFS outcome in our study was 11.1months, which was within the range of previously reported results. But our study population included more aggressive patients, 84.5% of whom had a HTB >25%. Larger HTB was supposed to be associated with poorer survival, with proposed thresholds at 25% (23,24). In this study, we observed that patients with HTB >25% had shorter HPFS, which was in accordance with previous study. Besides, the population in our study is composed of patients with NETLM deriving from the sole primary site of rectum.

The ORR in our study was 84.5%, which was superior to previous reports (ranging from 37% to 78.4%) (18,20,25), demonstrating the favorable efficacy that we have achieved by TAE combined with octreotide LAR in treating patients with rectal NETLMs. In the multivariate logistic regression analyses, Ki-67, ¹⁸F-FDG PET-CT, and hepatic tumor border were independent predictive factors of treatment response. Ki-67 has been supposed as a significant factor of stratifying prognosis in patients with NETs, for it directly reflected the proliferative ability and invasiveness of tumor cells (14,19). Ki-67 cutoff value of 10% had been demonstrated that could impact the prognosis of patients with G2 NETs (26). Therefore, in our study, a 10% cutoff for Ki-67 was pre-specified based on prior literature and was confirmed to be consistent with prior study.

¹⁸F-FDG PET-CT is widely acknowledged to be a functional imaging modality for tumor staging and determining the metabolic response to anticancer therapy (27). In previous study, ¹⁸F-FDG uptake showed a moderate positive correlation with tumor cell proliferation (28). de Mestier et al. reported that ¹⁸F-FDG PET-CT could supplement pathological evaluation of tumor biological aggressiveness (29). ¹⁸F-FDG PET-CT has also been demonstrated to be a useful tool for risk stratification of all NETs grades and an independent predictor of overall survival (30). Prior study reported that poorly defined radiologic tumor border was associated with significantly worse overall survival and recurrence-free survival in patients with pancreatic NETs (31). In this study, we observed that clear tumor border was related to better treatment response of TAE.

As to adverse events, the most common adverse event after TAE procedure was postembolization syndrome. In our study, the symptoms of relevance could relieve within 1 week in most cases. Hepatic abscess occurred in two patients, which was the most serious complication and disappeared after timely application of antibiotics and percutaneous drainage. Thus, our results revealed that the therapeutic plans of TAE combined with octreotide LAR are effective and well tolerated in patients with rectal NETLMs.

Up to now, this is the first study evaluating the efficacy and treatment response of the therapeutic strategy of combining TAE with octreotide LAR for patients with NETLMs deriving from the sole primary site of rectum. But there are several limitations in this study. Firstly, it is a retrospective study without comparison with monotherapy arms and the sample size is relatively small, so prospective randomized controlled trials with large sample size are needed to validate the results. Secondly, the follow-up time is not long enough to observe the overall survival outcome. Thirdly, in evaluating the treatment response of each TAE session, the approach that only treated tumors were evaluated according to RECIST 1.1 might potentially overestimate the response rates.

Conclusions

The combination therapy of TAE and octreotide LAR is safe and effective in managing patients with rectal NETLMs. HTB ≤25% was a significant prognostic factors for prolonged HPFS. Patients with Ki-67 ≤10%, negative ¹⁸F-FDG PET-CT and clear hepatic tumor border could derive prognostic advantage from the combination therapy.

Acknowledgments

The abstract of the article has been presented for poster exhibition at the 23rd Annual ENETS Conference.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0055/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0055/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0055/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0055/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the Institutional Review Board of Fudan University Shanghai Cancer Center (No. 1612167-18) and the informed consent was exempted because of the retrospective nature of this study. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Dasari A, Shen C, Halperin D, et al. Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States. JAMA Oncol 2017;3:1335-42. [Crossref] [PubMed]
2. Hallet J, Law CH, Cukier M, et al. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer 2015;121:589-97. [Crossref] [PubMed]
3. Tai E, Kennedy S, Farrell A, et al. Comparison of transarterial bland and chemoembolization for neuroendocrine tumours: a systematic review and meta-analysis. Curr Oncol 2020;27:e537-46. [Crossref] [PubMed]
4. Pavel M, Baudin E, Couvelard A, et al. ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 2012;95:157-76. [Crossref] [PubMed]
5. Partelli S, Inama M, Rinke A, et al. Long-Term Outcomes of Surgical Management of Pancreatic Neuroendocrine Tumors with Synchronous Liver Metastases. Neuroendocrinology 2015;102:68-76. [Crossref] [PubMed]
6. Fiore F, Del Prete M, Franco R, et al. Transarterial embolization (TAE) is equally effective and slightly safer than transarterial chemoembolization (TACE) to manage liver metastases in neuroendocrine tumors. Endocrine 2014;47:177-82. [Crossref] [PubMed]
7. Wolin EM, Benson Iii AB. Systemic Treatment Options for Carcinoid Syndrome: A Systematic Review. Oncology 2019;96:273-89. [Crossref] [PubMed]
8. Caplin ME, Pavel M, Ćwikła JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 2014;371:224-33. [Crossref] [PubMed]
9. Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009;27:4656-63. [Crossref] [PubMed]
10. Luo Y, Ameli S, Pandey A, et al. Semi-quantitative visual assessment of hepatic tumor burden can reliably predict survival in neuroendocrine liver metastases treated with transarterial chemoembolization. Eur Radiol 2019;29:5804-12. [Crossref] [PubMed]
11. Marrache F, Vullierme MP, Roy C, et al. Arterial phase enhancement and body mass index are predictors of response to chemoembolisation for liver metastases of endocrine tumours. Br J Cancer 2007;96:49-55. [Crossref] [PubMed]
12. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. [Crossref] [PubMed]
13. Liu Y, Liu H, Chen W, et al. Prolonged progression-free survival achieved by octreotide LAR plus transarterial embolization in low-to-intermediate grade neuroendocrine tumor liver metastases with high hepatic tumor burden. Cancer Med 2022;11:2588-600. [Crossref] [PubMed]
14. Carmona-Bayonas A, Jiménez-Fonseca P, Lamarca Á, et al. Prediction of Progression-Free Survival in Patients With Advanced, Well-Differentiated, Neuroendocrine Tumors Being Treated With a Somatostatin Analog: The GETNE-TRASGU Study. J Clin Oncol 2019;37:2571-80. [Crossref] [PubMed]
15. Caplin ME, Pavel M, Phan AT, et al. Lanreotide autogel/depot in advanced enteropancreatic neuroendocrine tumours: final results of the CLARINET open-label extension study. Endocrine 2021;71:502-13. [Crossref] [PubMed]
16. Libicher M, Bovenschulte H. Arterial embolization of hepatic metastases from neuroendocrine tumors. Radiologe 2009;49:233-41. [Crossref] [PubMed]
17. Fairweather M, Swanson R, Wang J, et al. Management of Neuroendocrine Tumor Liver Metastases: Long-Term Outcomes and Prognostic Factors from a Large Prospective Database. Ann Surg Oncol 2017;24:2319-25. [Crossref] [PubMed]
18. Okuyama H, Ikeda M, Takahashi H, et al. Transarterial (Chemo)Embolization for Liver Metastases in Patients with Neuroendocrine Tumors. Oncology 2017;92:353-9. [Crossref] [PubMed]
19. Chen JX, Rose S, White SB, et al. Embolotherapy for Neuroendocrine Tumor Liver Metastases: Prognostic Factors for Hepatic Progression-Free Survival and Overall Survival. Cardiovasc Intervent Radiol 2017;40:69-80. [Crossref] [PubMed]
20. Zener R, Yoon H, Ziv E, et al. Outcomes After Transarterial Embolization of Neuroendocrine Tumor Liver Metastases Using Spherical Particles of Different Sizes. Cardiovasc Intervent Radiol 2019;42:569-76. [Crossref] [PubMed]
21. Hur S, Chung JW, Kim HC, et al. Survival outcomes and prognostic factors of transcatheter arterial chemoembolization for hepatic neuroendocrine metastases. J Vasc Interv Radiol 2013;24:947-56; quiz 957. [Crossref] [PubMed]
22. Ziv E, Rice SL, Filtes J, et al. DAXX Mutation Status of Embolization-Treated Neuroendocrine Tumors Predicts Shorter Time to Hepatic Progression. J Vasc Interv Radiol 2018;29:1519-26. [Crossref] [PubMed]
23. Memon K, Lewandowski RJ, Riaz A, et al. Chemoembolization and radioembolization for metastatic disease to the liver: available data and future studies. Curr Treat Options Oncol 2012;13:403-15. [Crossref] [PubMed]
24. Sofocleous CT, Petre EN, Gonen M, et al. Factors affecting periprocedural morbidity and mortality and long-term patient survival after arterial embolization of hepatic neuroendocrine metastases. J Vasc Interv Radiol 2014;25:22-30; quiz 31. [Crossref] [PubMed]
25. Pelage JP, Fohlen A, Mitry E, et al. Chemoembolization of Neuroendocrine Liver Metastases Using Streptozocin and Tris-acryl Microspheres: Embozar (EMBOsphere + ZAnosaR) Study. Cardiovasc Intervent Radiol 2017;40:394-400. [Crossref] [PubMed]
26. Nuñez-Valdovinos B, Carmona-Bayonas A, Jimenez-Fonseca P, et al. Neuroendocrine Tumor Heterogeneity Adds Uncertainty to the World Health Organization 2010 Classification: Real-World Data from the Spanish Tumor Registry (R-GETNE). Oncologist 2018;23:422-32. [Crossref] [PubMed]
27. Hutchings M, Kostakoglu L, Zaucha JM, et al. In vivo treatment sensitivity testing with positron emission tomography/computed tomography after one cycle of chemotherapy for Hodgkin lymphoma. J Clin Oncol 2014;32:2705-11. [Crossref] [PubMed]
28. Deng SM, Zhang W, Zhang B, et al. Correlation between the Uptake of 18F-Fluorodeoxyglucose (18F-FDG) and the Expression of Proliferation-Associated Antigen Ki-67 in Cancer Patients: A Meta-Analysis. PLoS One 2015;10:e0129028. [Crossref] [PubMed]
29. de Mestier L, Armani M, Cros J, et al. Lesion-by-lesion correlation between uptake at FDG PET and the Ki67 proliferation index in resected pancreatic neuroendocrine tumors. Dig Liver Dis 2019;51:1720-4. [Crossref] [PubMed]
30. Binderup T, Knigge U, Johnbeck CB, et al. (18)F-FDG PET is Superior to WHO Grading as a Prognostic Tool in Neuroendocrine Neoplasms and Useful in Guiding PRRT: A Prospective 10-Year Follow-up Study. J Nucl Med 2021;62:808-15. [Crossref] [PubMed]
31. Ahn B, Park HJ, Kim HJ, et al. Radiologic tumor border can further stratify prognosis in patients with pancreatic neuroendocrine tumor. Pancreatology 2024;24:753-63. [Crossref] [PubMed]