Peptide receptor radionuclide therapy for recurrent neuroendocrine tumors after liver transplantation

Abstract

BACKGROUND

Liver transplantation (LT) is a curative intervention for neuroendocrine tumor liver metastasis (NETLM) patients with tumor burden and rapid progression, yet tumor recurrence is a bottleneck restricting survival. Long-term immunosuppression impairs tolerance to antitumor therapies and increases risk, leaving options for patients with recurrence. Peptide receptor radionuclide therapy (PRRT) is a therapy for somatostatin receptor-positive (SSTR+) neuroendocrine tumors; its efficacy and safety in liver transplant recipients with recurrent NETLM under everolimus immunosuppression remain unvalidated due to lack of comparative studies.

AIM

To evaluate the efficacy and safety of lutetium Lu 177 dotatate (¹⁷⁷Lu-DOTATATE) PRRT in patients with recurrent SSTR+ G2 NETLM after LT under immunosuppression.

METHODS

In this retrospective comparative cohort study at Tianjin First Central Hospital (2019-2025), 15 patients (7 PRRT and 8 controls) received everolimus immunosuppression plus conventional antitumor therapy; the PRRT group also received ¹⁷⁷Lu-DOTATATE. Group assignment was based on multidisciplinary decisions, patient preference and drug availability, not randomization. Toxicities and tumor responses graded per Common Terminology Criteria for Adverse Events version 5.0 and Response Evaluation Criteria in Solid Tumors version 1.1, respectively. Prognostic indicators were progression-free survival (PFS) and overall survival (OS). Survival curves were plotted by Kaplan-Meier method and compared using log-rank test.

RESULTS

Baseline characteristics were comparable between groups, with the exception of age (P = 0.019). The median follow-up period was 33 months (range: 6-72 months). In the PRRT group, the primary toxicities observed were grade I-III bone marrow suppression (7/7, 100%) and grade I-II proteinuria (4/7, 57.1%). All of these adverse events resolved with symptomatic management, except for one patient who discontinued PRRT due to persistent thrombocytopenia. In terms of efficacy, the PRRT group achieved an objective response rate of 14.3% and a disease control rate of 85.7%, compared with 0% and 37.5% in the control group (not significant). Kaplan-Meier analysis demonstrated superior PFS in the PRRT group (P = 0.028), whereas no significant difference was observed in OS between the two groups.

CONCLUSION

For patients with SSTR+ G2 NETLM, PRRT with standard-of-care treatment demonstrates improved PFS, suggesting promising therapeutic option for patient population. However, these findings require validation in larger, multicenter studies with follow-up.

Key Words: Liver transplantation; Neuroendocrine tumors; Liver metastasis; Peptide receptor radionuclide therapy; Recurrence; Progression-free survival

Core Tip: This retrospective comparative cohort study evaluates lutetium Lu 177 dotatate (¹⁷⁷Lu-DOTATATE) peptide receptor radionuclide therapy (PRRT) combined with everolimus in somatostatin receptor-positive G2 neuroendocrine tumor liver metastases after liver transplantation. In 7 PRRT-treated patients vs 8 controls, PRRT achieved a disease control rate of 85.7% and significantly improved progression-free survival (log-rank P = 0.028), with manageable hematologic toxicity (grade III in 28.6%) and no graft rejection. These hypothesis-generating findings suggest PRRT as a promising option for this rare cohort.

INTRODUCTION

Neuroendocrine tumors (NETs) are a class of highly heterogeneous malignancies derived from the diffuse neuroendocrine system, with the liver being the most frequent site of distant metastasis[1]. The extent of NET liver metastasis (NETLM) is a key determinant of patient prognosis. For NETLM patients with a tumor burden exceeding 50% of the liver volume and rapid progression, liver transplantation (LT) is a potential curative intervention[1]. However, the persistently high post-transplant tumor recurrence rate has become a major bottleneck restricting long-term survival in this cohort. Moreover, long-term post-transplant immunosuppression markedly impairs tolerance to conventional antitumor therapies (e.g., cytotoxic chemotherapy), while elevating toxicity-related risks. This leaves patients with extremely limited treatment options and highlights the urgent clinical demand for safe and effective therapeutic strategies.

Peptide receptor radionuclide therapy (PRRT), a typical example of which is lutetium Lu 177 dotatate (¹⁷⁷Lu-DOTATATE), combines a radionuclide with a somatostatin analog to specifically target and bind to somatostatin receptor-positive (SSTR+) tumor cells, thereby achieving selective internal radiation. As a standard therapy for advanced, progressive SSTR+ NETs, its efficacy and safety have been fully validated in multiple phase III clinical trials[2-4], including the pivotal NETTER-1 trial, which led to regulatory approval by the United States Food and Drug Administration and European Medicines Agency for gastroenteropancreatic NETs (GEP-NETs)[4]. ¹⁷⁷Lu-DOTATATE PRRT has been approved in clinical practice and confirmed to be well-tolerated for advanced GEP-NETs[5]. However, LT recipients represent a special clinical cohort, and the application of PRRT in this population remains highly uncertain. Long-term administration of immunosuppressants [e.g., calcineurin inhibitors (CNIs)] may compromise bone marrow reserve function and elevate infection risk, thus reducing tolerance to PRRT[6]. The potential effects of PRRT on graft liver function and rejection reactions remain unclear. To date, no prospective or retrospective comparative studies have been conducted on PRRT for patients with recurrent NETLM after LT, either domestically or internationally, leaving its efficacy and safety without high-quality evidence-based support.

Despite the significant survival benefits of PRRT in metastatic GEP-NETs confirmed by NETTER-1[4], its application in recurrent NETs after LT has not been systematically reported. Currently, second-line treatment options for post-transplant recurrent NETLM are scarce. Although targeted agents such as everolimus and sunitinib are used clinically, they are plagued by marked interindividual efficacy variability, the requirement for long-term adverse reaction monitoring, and inadequate safety data in immunosuppressed patients[7,8]. Notably, everolimus is the most commonly used third-line treatment for well-differentiated small bowel NETs (Wd-SBNETs), with the Ki-67 index serving as the main basis for third-line treatment selection[9]. This provides a strong clinical rationale for everolimus-based immunosuppression in this study, owing to its dual immunosuppressive and antitumor activities. Given the rarity of post-transplant recurrent NETLM and stringent treatment eligibility criteria, this study adopted a small-sample retrospective comparative cohort design to preliminarily validate PRRT efficacy and safety in a feasible manner.

We retrospectively collected clinical data from seven patients with recurrent NETLM after LT (who received PRRT) and eight baseline-comparable controls to compare the prognostic differences between PRRT and conventional therapies. This study fills the gap in preliminary evidence for PRRT in this specific population, with the objectives of hypothesis-generating exploration of PRRT safety, tolerability, and antitumor activity and providing preliminary data on whether PRRT yields a superior prognosis to conventional therapies, to in turn provide evidence-based references for clinical decision-making.

MATERIALS AND METHODS

Study population

From November 2019 to November 2025, our center conducted 996 LT procedures. Of these, 27 patients with GEP-NETLM exceeded the NET-Milan criteria. Referring to the criteria, all patients had a pathological grade of G1/2, and the primary tumors originated from the portal vein-drained gastroenteropancreatic system. Preoperative disease stability was achieved through multidisciplinary treatment before transplantation, despite the tumor burden exceeding 50% of the total liver volume. The inclusion criteria required that the primary tumor be deemed resectable during preoperative evaluation. Resection of the primary tumor was performed either during the transplant procedure or within 3 months post-transplant in high-risk individuals. Patients aged ≤ 55 years or > 55 years with preserved organ function were eligible for the study. This retrospective comparative cohort study included 15 of the 27 patients (55.6%) who had tumor recurrence or metastasis. These included two cases of intrahepatic recurrence (at 57 months and 43 months post-transplant), two cases of intracranial metastasis (at 24 months and 36 months), and one case of left renal metastasis (at 3 months). The remaining recurrences involved the peritoneal lymph nodes and osteoblastic metastases. Three patients (11.1%) died: One from sepsis following radiofrequency ablation of peritoneal lymph nodes 67 months after transplantation, one from intestinal obstruction and cachexia due to widespread peritoneal metastasis 19 months post-surgery, and one from infection combined with liver failure 6 months after transplantation. All patients received an immunosuppressive regimen based on everolimus along with SSTR inhibitors for the secondary prevention of tumor recurrence. For those who developed recurrence or metastasis, comprehensive antitumor therapy was administered; seven patients who had received PRRT were assigned to the PRRT group, and another eight patients who had not received PRRT were selected as the control group (Figure 1).

Figure 1 Flowchart of patient selection, grouping, and follow-up outcomes in this study. LT: Liver transplantation; NET: Neuroendocrine tumor; NETLM: Neuroendocrine tumor liver metastasis; GEP: Gastroenteropancreatic; MDT: Multidisciplinary team; IS: Immunosuppression; PRRT: Peptide receptor radionuclide therapy; NYHA: New York Heart Association; eGFR: Estimated glomerular filtration rate; WHO: World Health Organization; IHC: Immunohistochemistry; ⁶⁸Ga-DOTATATE: Gallium-68 dotatate; SSTR: Somatostatin receptor; PET/CT: Positron emission tomography/computed tomography.

Patients were not randomly assigned to the PRRT group or the control group; instead, group allocation reflected real-world clinical decisions made by a multidisciplinary team consisting of transplant surgeons, medical oncologists, and nuclear medicine physicians, based on comprehensive considerations including clinical judgment, patient preference, economic factors, drug availability, bone marrow reserve (absolute neutrophil count ≥ 1.5 × 10⁹/L, platelet count ≥ 100 × 10⁹/L), renal function [estimated glomerular filtration rate (eGFR) ≥ 60 mL/minute/1.73 m²], and treatment eligibility. The control group comprised consecutively enrolled patients who met the same inclusion criteria but either declined PRRT or were unable to receive it within the therapeutic window, primarily due to patient refusal or unavailability of ¹⁷⁷Lu-DOTATATE during the treatment period.

The inclusion criteria were as follows for the PRRT group: (1) Age ≥ 18 years; (2) Pathologically confirmed as well-differentiated G1/2 NETs per the 2019 World Health Organization classification of gastrointestinal tumors; (3) Post-LT tumor recurrence verified by imaging [contrast-enhanced computed tomography/magnetic resonance imaging (CT/MRI)] or percutaneous biopsy pathology; (4) SSTR positivity confirmed by immunohistochemistry (IHC) or gallium-68 dotatate (⁶⁸Ga-DOTATATE) positron emission tomography/computed tomography (PET/CT)[10] (tumor tissue radioactive uptake higher than hepatic parenchyma); (5) Stable tumor status for ≥ 6 months before LT; (6) Postoperative maintenance of an everolimus-based immunosuppressive regimen; and (7) Complete clinical medical records and follow-up data available, with patients having provided written informed consent prior to treatment.

The inclusion criteria for the control group were as follows: (1) Baseline characteristics (including age, sex, primary tumor site, Ki-67 proliferation index, SSTR expression status, pre-transplant liver tumor volume ratio, post-LT recurrence time and site, and everolimus-based immunosuppressive regimen) statistically balanced and comparable with the PRRT group (all intergroup comparisons except age, P > 0.05); (2) No PRRT or other radionuclide antitumor therapy received throughout the follow-up period; (3) Baseline treatment regimen consistent with the PRRT group, including symptomatic supportive care and on-demand use of long-acting somatostatin analogs such as octreotide; and (4) Complete clinical data and follow-up information available. Controls were selected consecutively from among eligible patients during the same period to minimize selection bias.

Exclusion criteria common to both groups included: (1) Severe cardiac, hepatic (graft liver), or renal dysfunction (New York Heart Association functional class ≥ III; Child-Pugh hepatic grade ≥ B; eGFR < 60 mL/minute/1.73 m²); (2) Uncontrolled active infection or ongoing hemorrhage; and (3) Severe psychiatric disorders or cognitive deficits that precluded adherence to treatment and follow-up procedures. Patients in the PRRT group were additionally excluded if they had a history of prior radionuclide therapy.

All organ donation and transplantation procedures were performed in strict accordance with the regulations of the China Organ Donation Committee and the Organ Transplantation Committee, and complied with the 2013 revised version of the Declaration of Helsinki. All donor livers were obtained from deceased citizen donors, and no organs from executed prisoners were used in this study. The study protocol was approved by the Ethics Committee of Tianjin First Central Hospital (approval No. KELUNSHEN 2026-51). Given the retrospective design, the requirement for additional written informed consent for this study was waived by the Ethics Committee.

Clinical data collection

Comprehensive collection and systematic organization of clinical data were conducted for both patient cohorts, including the following aspects: (1) Baseline demographic characteristics (age and gender); (2) Tumor-related features (primary tumor location, Ki-67 proliferation index, SSTR expression intensity measured by IHC or ⁶⁸Ga-DOTATATE PET/CT, pre-transplant intrahepatic tumor volume ratio, time to tumor recurrence after LT, and recurrence site); and (3) Treatment-related information: The PRRT cohort required documentation of immunosuppressive regimen details (drugs, doses, and adjustments), number of PRRT cycles, single and cumulative radiation doses, treatment efficacy [evaluated per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)], and treatment-emergent adverse events (AEs) [graded per Common Terminology Criteria for AEs version 5.0 (CTCAE 5.0)], while the control cohort needed documentation of immunosuppressive regimen specifics, baseline antitumor therapy, and supportive care protocols, along with efficacy outcomes (per RECIST 1.1) and AEs (graded per CTCAE 5.0). The primary study endpoint was progression-free survival (PFS), defined as the interval from the date of confirmed post-LT tumor recurrence to the first occurrence of RECIST 1.1-assessed disease progression or death from any cause, with patients alive and progression-free at the follow-up cutoff censored at their last follow-up visit. The secondary study endpoint was overall survival (OS), defined as the interval from the date of confirmed post-LT tumor recurrence to death from any cause. Patients who were still alive at the follow-up cutoff were censored at their last follow-up date.

Treatment plans

In the PRRT group, upon confirmation of post-LT tumor recurrence, all patients were switched to an everolimus-based immunosuppressive regimen with an initial oral dose of 1.0 mg/day. The dose was adjusted per the therapeutic drug monitoring results (adjustment step = 0.5 mg/day) to maintain a stable plasma concentration of 3-8 ng/mL. Everolimus was selected as the core immunosuppressant because of its dual role in immunosuppression and antitumor activity, as well as its wide application in the multi-line treatment of NETs[6,7,9]. ¹⁷⁷Lu-DOTATATE PRRT was administered intravenously at a standard dose of 7.4 gigabecquerel (GBq) [200 millicurie (mCi)] (1 mCi = 0.037 GBq) every 6-12 weeks. The number of treatment cycles was dynamically tailored to individual tolerance and treatment response, with a median of two cycles (range: 1-4) and a median cumulative dose of 12.099 GBq (327 mCi; range: 6.475-26.233 GBq/175-709 mCi). As a renal protective strategy, intravenous infusions of amino acid solutions (L-lysine 50 g + L-arginine 50 g) were administered 30 minutes before PRRT and continued for 4 hours after treatment, combined with maintenance of adequate hydration (daily fluid intake ≥ 2000 mL). During PRRT, the everolimus trough concentration, complete blood count (CBC), liver and kidney function, and 24-hour urine protein were monitored every 2 weeks. All patients received monthly intramuscular injections of 30 mg of long-acting octreotide (a standard adjuvant therapy for PRRT in patients with NET)[5].

In the control group, all patients received the same everolimus immunosuppression regimen as the PRRT group, with plasma concentrations maintained within stable ranges. Neither PRRT nor other radionuclide therapies were administered throughout the study period. Baseline treatment for both groups included symptomatic supportive care (such as analgesia and nutritional support) and long-term octreotide therapy (30 mg intramuscularly monthly).

Safety and efficacy assessment

For the PRRT group, patients underwent regular monitoring of CBC, liver and renal function, everolimus trough plasma concentration, and 24-hour urine protein quantification during treatment and throughout the follow-up period; treatment-related AEs were graded per the CTCAE 5.0, while efficacy assessment adhered to RECIST 1.1, with evaluations performed every 3 months starting at treatment initiation (encompassing both on-treatment and post-PRRT phases) via combined CT/MRI and ⁶⁸Ga-DOTATATE PET/CT[11,12]. Tumor responses were classified into four categories: Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). The objective response rate (ORR) refers to the proportion of patients who achieved a CR or PR after treatment. CR was defined as the disappearance of all target and non-target lesions, with no new lesions appearing, maintained for at least 4 weeks; PR was defined as a reduction of ≥ 30% in the sum of the longest diameters of target lesions, maintained for at least 4 weeks, with no new lesions and no progression of non-target lesions. The disease control rate (DCR) refers to the proportion of patients who achieved a CR, PR, or SD after treatment. SD was defined as neither sufficient shrinkage to qualify for PR nor a sufficient increase to qualify for PD, maintained for at least 4 weeks; PD was defined as an increase of ≥ 20% in the sum of the longest diameters of target lesions, the appearance of new lesions, or progression of non-target lesions. To minimize assessment bias, PET/CT-only detected lesions (e.g., small lymph nodes not seen on CT) were excluded from the RECIST 1.1 evaluation. The control group underwent an identical panel of laboratory parameter assessments at regular intervals, with systematic documentation of baseline treatment-related AEs. Efficacy evaluations were conducted every 3 months during follow-up in strict accordance with RECIST 1.1, utilizing only CT/MRI for imaging assessment. This asymmetry in imaging modalities (CT/MRI alone in controls vs CT/MRI plus PET/CT in the PRRT group) is a major limitation, as the higher sensitivity of PET/CT may lead to differential detection of progression or SD. To minimize assessment bias, the imaging findings for both groups were independently reviewed in a double-blind manner by two senior radiologists and two oncologists. Disagreements were resolved through group discussion to reach a consensus.

Statistical analysis

All statistical analyses were performed using SPSS 27.0, and graphical representations were created using GraphPad Prism 9.0.0. Quantitative data were first assessed for normality using the Shapiro-Wilk test. Data meeting the normality criteria were expressed as mean ± SD, and intergroup comparisons were performed using the independent samples t-test. Data not meeting the normality criteria were expressed as median [interquartile range (IQR)], and intergroup comparisons were performed using the Mann-Whitney U test. Count data were expressed as n (%), and intergroup comparisons were primarily performed using Fisher’s exact test (due to the total sample size < 40 and some theoretical frequencies < 5).χ² tests were used as supplementary tests when conditions permitted. Due to the small sample size, statistical power was limited, making it impossible to conduct multivariate Cox regression analysis or propensity score matching. Therefore, the findings of this study should be considered preliminary and intended to inform future research. Survival curves were plotted using the Kaplan-Meier method, and intergroup comparisons were performed using the log-rank test. All statistical tests were two-sided, with P < 0.05 indicating statistical significance.

RESULTS

Baseline characteristics

Fifteen patients were enrolled in this study, with 7 in the PRRT group and 8 in the control group. Only age showed a statistically significant difference between the two groups (P = 0.019), with the PRRT group being significantly younger (43.43 ± 10.24 years vs 57.38 ± 9.93 years). This age difference is a key confounding factor that may have affected treatment tolerance and outcomes, a limitation that cannot be adjusted for due to the small sample size. The younger age of the PRRT group might have led to an underestimation of toxicity compared to an older real-world population. All other key prognostic baseline characteristics, including sex, Ki-67 proliferation index, SSTR expression intensity, pre-transplant tumor volume fraction, and time and site of post-transplant recurrence, were well-balanced and comparable between the groups (Table 1).

Table 1 Comparison of baseline characteristics between the peptide receptor radionuclide therapy group and control group, mean ± SD/n (%).

	PRRT group (n = 7)	Control group (n = 8)	P value
Gender			1.000
Male	4 (57.1)	5 (62.5)
Female	3 (42.9)	3 (37.5)
Age at LT (years)	43.43 ± 10.24	57.38 ± 9.93	0.019a
Primary tumor			1.000
Lung	0 (0.00)	1 (12.5)
Pancreas	3 (42.9)	4 (50.0)
Rectum	4 (57.1)	3 (37.5)
Ki-67 index (%)	9.43 ± 5.29	14.13 ± 8.56	0.232
SSTR positive	7 (100.0)	8 (100.0)	1.000
Pre-LT liver tumor volume (%)	76.43 ± 15.20	80.00 ± 9.26	0.586
Time to recurrence after LT (months), median (IQR)	3 (3-6.5)	9 (3-12)	0.220
Recurrent site			0.806
Lymph nodes	7 (100.0)	7 (87.5)
Bone	7 (100.0)	8 (100.0)
Intracranial	1 (14.3)	1 (12.5)
Kidney	1 (14.3)	0 (0.0)
Liver	2 (28.6)	0 (0.0)
Combined long-acting octreotide	7 (100.0)	8 (100.0)	1.000
Treatment efficacy			0.110
Complete response	0 (0.0)	0 (0.0)
Partial response	1 (14.3)	0 (0.0)
Stable disease	5 (71.4)	3 (37.5)
Progressive disease	1 (14.3)	5 (62.5)
Overall response rate (%)	14.3	0.0	0.467
Disease control rate (%)	85.7	37.5	0.119

^aP < 0.05.

Group comparisons: Age was compared using the independent-samples t test; Ki-67 index and pre-transplant liver tumor volume percentage were compared using the t-test; Time to recurrence was compared using the Mann-Whitney U test; Categorical variables were compared using Fisher’s exact test (due to small sample size). LT: Liver transplantation; PRRT: Peptide receptor radionuclide therapy; SSTR: Somatostatin receptor; IQR: Interquartile range.

The detailed baseline data were as follows: In the PRRT group, there were four males (57.1%) and three females (42.9%), the primary tumor sites were the pancreas in three cases (42.9%) and the rectum in four cases (57.1%), the mean ± SD pre-transplant tumor volume percentage in the liver was 76.43 ± 15.20 and the median time to recurrence after transplantation was 3 months (IQR: 3-6.5). All patients had combined lymph node and bone metastases, with additional single-site metastases in some patients, including one case of intracranial metastasis, one case of kidney metastasis, and two cases of liver metastasis. In the control group, there were five males (62.5%) and three females (37.5%); the primary tumor sites were the pancreas in four cases (50.0%), the rectum in three cases (37.5%), and the lung in one case (12.5%). The mean ± SD pre-transplant liver tumor volume was 80.00% ± 9.26%; and the median time to recurrence post-transplantation was 9 months (IQR: 3-12). All patients had bone metastases; seven (87.5%) also had lymph node metastases, and one patient had intracranial metastasis. Notably, patients in both groups received concurrent long-acting octreotide combination therapy during treatment. Detailed individual baseline, treatment, and prognostic data for each patient are presented in Supplementary Table 1.

Safety outcomes (PRRT group)

PRRT was initiated at a median of 12 months (range: 6-42 months) from the date of LT surgery in the PRRT group. During PRRT treatment, the mean ± SD serum everolimus concentration in seven patients was 5.8 ± 1.3 ng/mL, consistently maintained within the target therapeutic window (3-8 ng/mL). There were no graft rejection episodes throughout the treatment course (Table 2).

Table 2 Individual patient characteristics and treatment outcomes in the peptide receptor radionuclide therapy group (n = 7).

Case	Tumor recurrence time after LT (month)	Everolimus level (ng/mL)	Time from LT to PRRT (month)	PRRT with 177Lu-DOTATATE cycles	PRRT with 177Lu-DOTATATE cumulative dose (mCi)	Myelosuppression (grade)	Proteinuria (grade)
1	7	6.8	42	2	327	III	II
2	3	7.5	6	4	709	II	None
3	3	5.2	14	3	502	II	None
4	9	7.2	9	1	175	III	I
5	6	4.5	22	2	327	II	None
6	3	5.8	12	3	502	II	I
7	3	3.8	12	2	327	I	I

Adverse events were graded according to Common Terminology Criteria for Adverse Events version 5.0. “None” indicates no proteinuria detected. GBq: Gigabecquerel (1 mCi = 0.037 GBq); mCi: Millicurie; LT: Liver transplantation; PRRT: Peptide receptor radionuclide therapy; ¹⁷⁷Lu-DOTATATE: Lutetium Lu 177 dotatate.

Treatment-related toxicities were primarily hematologic myelosuppression (Table 2): Grade III myelosuppression occurred in two patients (2/7, 28.6%), with one patient discontinuing PRRT after cycle 1 due to persistent thrombocytopenia (this patient was included in all efficacy analyses on an intention-to-treat basis); Grade II myelosuppression occurred in four patients (4/7, 57.1%), all of whom recovered with supportive care [e.g., granulocyte colony-stimulating factor (G-CSF), thrombopoietin]; Grade I myelosuppression occurred in one patient (1/7, 14.3%), who recovered spontaneously. The 100% incidence of hematologic toxicity, including a 28.6% rate of grade III events, is clinically meaningful and underscores that myelosuppression is the primary dose-limiting toxicity (DLT). Four patients (57.1%) developed grade I-II proteinuria, which was considered to be a synergistic nephrotoxic effect of everolimus and PRRT. Mechanistically, everolimus may impair hematopoietic stem cell proliferation and renal tubular repair, thereby potentiating PRRT-induced bone marrow and kidney injury. Laboratory evidence showed that the proteinuria was mainly mild glomerular proteinuria, with no significant changes in serum creatinine and the eGFR during follow-up. Following supportive management with fluid replacement, maintenance of adequate hydration, and discontinuation of other nephrotoxic medications, proteinuria did not progress further in any patient. No grade III or higher serious AEs (including severe graft liver/renal dysfunction, infection, or bleeding) were observed in the entire PRRT cohort. The toxicity profile was manageable and consistent with the anticipated safety characteristics of everolimus in combination with PRRT.

Treatment outcomes

Efficacy response: The efficacy evaluation results showed that the PRRT group had an ORR of 14.3% (PR, n = 1) and a DCR of 85.7% (PR, n = 1 + SD, n = 5), with one patient (14.3%) experiencing PD. The control group had an ORR of 0% (no PR or CR cases) and a DCR of 37.5% (three SD cases), with five patients (62.5%) experiencing PD. The differences in ORR and DCR between the two groups were not statistically significant [ORR: Fisher’s exact test, P = 0.467, 95% confidence interval (CI): 0.06-18.97; DCR: Fisher’s exact test, P = 0.119, 95%CI: 0.92-123.54]. The lack of statistical significance is likely attributable to the small sample size. The high odds ratio for DCR (10.67) suggests a clinically meaningful trend, but this should be interpreted only as a hypothesis-generating finding due to the wide CI and limited power.

Survival analysis: The median follow-up duration for all patients was 33 months (range: 6-72 months). The progression and mortality rates within the follow-up period were 14.3% (1/7) and 14.3% (1/7) in the PRRT group, respectively, compared to 62.5% (5/8) and 25.0% (2/8) in the control group. Kaplan-Meier survival curves demonstrated that the PRRT group had significantly superior PFS compared to the control group, with a markedly reduced progression risk (χ² = 4.829, P = 0.028; median PFS: Not reached vs 15 months, 95%CI: 6.2-23.8 months) (Figure 2A). However, given the significant age imbalance between the two groups (P = 0.019), this PFS difference should be interpreted with caution. Additionally, although the PRRT group showed a trend toward improved OS compared with the control group (median OS: Not reached vs 28 months, 95%CI: 11.5-44.5 months), this difference did not reach statistical significance (χ² = 0.408, P = 0.523) (Figure 2B), which is potentially attributable to the small sample size, limited follow-up duration, and relatively low mortality rate in both groups during the follow-up period.

Figure 2 Kaplan-Meier survival curves for the peptide receptor radionuclide therapy group and control group. A: Progression-free survival; B: Overall survival. PRRT: Peptide receptor radionuclide therapy.

DISCUSSION

As the first retrospective comparative cohort study on PRRT for recurrent SSTR+ G2 NETLM after LT, this study provides preliminary, hypothesis-generating evidence of the safety and efficacy of PRRT combined with everolimus. The results suggest that PRRT exhibits a manageable safety profile and potential antitumor activity when administered alongside an everolimus-based immunosuppressive regimen. Notably, no graft rejection events were observed during treatment, suggesting favorable compatibility between PRRT and everolimus. These findings provide hypothesis-generating clinical evidence for the management of this specific patient cohort. The safety profile of ¹⁷⁷Lu-DOTATATE radiopharmaceutical therapy in this study aligns with the findings of the NETTER-1 trial[4] and the evidence supporting its clinical approval in Spain[5], confirming its favorable tolerability in advanced NETs.

The core design of this therapeutic strategy lies in switching from traditional CNIs to the mechanistic target of rapamycin (mTOR) inhibitor everolimus, which has intrinsic antitumor potential. Everolimus not only exerts immunosuppressive effects by inhibiting the mTOR signaling pathway but also directly suppresses tumor cell proliferation[13,14] and may exert a synergistic effect with the targeted radiotherapy of PRRT to augment antitumor activity[15], although caution is warranted regarding the potential additive nephrotoxicity risk posed by the two agents. Notably, everolimus is the most commonly used third-line treatment for Wd-SBNETs[9], which further supports its rational use in combination with PRRT for recurrent NETs after LT, leveraging its dual mechanism of action. In this study, only four cases of grade I-II proteinuria were observed, with no severe nephrotoxicity reported, suggesting that the risk of nephrotoxicity can be effectively mitigated by strictly implementing amino acid-based nephroprotective measures, maintaining adequate hydration (daily fluid intake ≥ 2000 mL), avoiding concurrent use of other nephrotoxic agents (e.g., CNIs), and closely monitoring renal function every 2 weeks[16].

Everolimus may impair hematopoietic stem cell proliferation and exacerbate PRRT-induced bone marrow damage, leading to synergistic myelosuppression[17]. As the primary DLT of PRRT, myelosuppression can trigger potentially fatal long-term hematologic AEs, including treatment-related myeloid neoplasms (t-MNs)[18]. In patients with pancreatic NETs, grade III myelosuppression is closely correlated with cumulative PRRT dose, requiring rigorous dose management[19]. Given the significant hematologic toxicity of PRRT and the current lack of effective predictive biomarkers, individualized dose adjustment is critical[20]. In this study, the incidence of Grade III myelosuppression in the PRRT group was 28.57%, with one patient requiring treatment discontinuation due to persistent severe myelosuppression. This finding is indicative of substantial interindividual variability in bone marrow tolerance, and the younger age of the PRRT group (potentially with better bone marrow reserve) suggests that even patients with relatively good baseline bone marrow function may have poor tolerance to standard PRRT doses; thus, patients with poor bone marrow reserve may require dose reduction (e.g., 6.0 GBq per cycle) or prolonged treatment intervals (e.g., 8-12 weeks) to optimize treatment safety. Conversely, the age difference between the groups may also imply that the PRRT group’s better tolerance could have led to an underestimation of toxicity in an older, real-world population. Previous studies have established a cumulative dose threshold of 29 GBq for ¹⁷⁷Lu-DOTATATE[19], offering crucial guidance for clinical dose optimization. The median cumulative dose in this study was only 12.099 GBq (327 mCi), which is far lower than the reported threshold, but the incidence of grade III myelosuppression was still relatively high. This may be attributed to the synergistic myelosuppressive effect of everolimus and PRRT, as mTOR inhibitors can impair hematopoietic stem cell proliferation, potentially exacerbating PRRT-induced bone marrow damage. Further in-depth research is warranted to refine the dose strategies for this specific population. The overall incidence of hematologic toxicity in this study is consistent with previous reports, with grade I-II myelosuppression being the most common, while grade III toxicity is relatively rare[5]. Notably, although PRRT markedly improves prognosis in NETs patients, its rare yet potentially fatal long-term hematologic toxicities (e.g., t-MNs and myelodysplastic syndrome) have been increasingly documented in the literature[21], providing a theoretical rationale for prompt treatment discontinuation upon the onset of severe bone marrow suppression. Future studies with extended follow-up are needed to assess the long-term risk of t-MNs in this population. Mechanistically, PRRT exerts cytotoxic effects by inducing radionuclide-mediated DNA damage in tumor cells. Bone marrow tissue, characterized by high proliferative activity, exhibits heightened sensitivity to radiation, a biological property that underpins the mechanism of PRRT-induced hematologic toxicity[22]. Furthermore, Blakkisrud et al[23] conducted dynamic analyses of peripheral blood samples collected during treatment and follow-up periods (3 and 6 months) and revealed a statistically significant correlation between hematologic toxicity markers (such as relative reduction in platelet count) and bone marrow absorption dose[23]. This association aids in guiding individualized dose adjustments to manage toxicity in clinical practice.

High SSTR expression is an essential prerequisite for favorable PRRT efficacy. In this study, the PRRT group yielded a DCR of 85.7%, a value comparable to that reported in prior PRRT investigations for metastatic NETs[24], thus suggesting the potential applicability of this therapy in patients with post-transplant tumor recurrence. One patient achieved sustained disease stability for over 9 months following the completion of four treatment cycles, suggesting that a subset of patients may attain durable disease control via PRRT. It is noteworthy that PRRT not only demonstrates efficacy in advanced and recurrent NETs but also exhibits encouraging neoadjuvant therapeutic value in initially unresectable pancreatic NETs. This approach enables tumor downstaging, thereby creating conditions conducive to subsequent curative resection[25]. Notably, all patients included in this study presented with a high tumor burden (liver tumor volume > 50%) prior to transplantation and exhibited aggressive disease progression post-recurrence. Despite this unfavorable clinical context, PRRT still induced partial remission or disease stabilization in certain cases, thereby further corroborating the therapeutic merits of this regimen. Additionally, for patients receiving PRRT combined with long-acting octreotide therapy, efficacy may be further enhanced because octreotide induces the upregulation of SSTR expression on tumor cell surfaces. Long-acting octreotide is the standard adjuvant treatment regimen for PRRT and is applicable across all NET treatment stages[5,9]. However, the inherent sample size limitations of this study necessitate large-scale clinical trials with sufficient statistical power to validate the hypothesis.

Compared with the non-PRRT control group, the PRRT cohort in this study showed a significant improvement in PFS and a trend toward a higher DCR (OR = 10.67), suggesting that PRRT may serve as an effective therapeutic strategy to enhance disease control in this specific patient population. Navalkissoor and Grossman[26] reported that PRRT, as a well-tolerated and efficacious treatment modality, improves PFS and may also extend OS, especially among patients with unresectable metastatic NETs. This is consistent with our study results, where PRRT significantly improved PFS and showed a trend toward OS benefit. Notably, the landmark NETTER-1 trial, the first randomized phase III clinical trial evaluating PRRT, further confirmed that this therapy markedly prolonged PFS in patients with midgut NETs[27]. These findings collectively suggest that PRRT holds significant potential as a multimodal treatment strategy for recurrent NETs following LT. Zhang et al[28] investigated the safety and efficacy of intra-arterial PRRT (IA-PRRT) in SSTR+ NETs. The results demonstrated that administering radiopharmaceuticals via an intra-arterial route using specialized infusion devices significantly enhances the precision of targeted therapy for hepatic lesions. Moreover, it delivers clear clinical benefits for patients with PD, including those unresponsive to somatostatin analog therapy, providing robust support for personalized clinical application of IA-PRRT. Furthermore, Hoogenkamp et al[29] confirmed the therapeutic value of PRRT in advanced NETs through a systematic review. They proposed strategies that combined PRRT with locoregional therapies (e.g., transarterial radioembolization) and systemic anticancer drugs, providing an additional evidence-based rationale for integrating PRRT into multimodal treatment regimens. However, as an emerging therapeutic modality, the optimal sequential strategy for combining PRRT with other agents (e.g., interferon-α, everolimus, or sunitinib) remains unclear[30]. This research gap underscores the urgent need for further studies to establish standardized treatment protocols.

This study has several limitations that need to be acknowledged. First, as a single-center, retrospective study with a small sample size (15 cases), it carries potential selection bias, limited statistical power (increasing the risk of type II error), and possible unmeasured confounding variables. The absence of randomization and prespecified selection of controls further limit causal inference. Therefore, these findings require further validation in multicenter, large-sample prospective cohort studies. Second, the median follow-up period was relatively short (33 months), limiting the assessment of long-term OS benefits and toxicities (e.g., t-MNs), which may affect the stability of the results, and extended follow-up is needed to evaluate the long-term efficacy and safety of the combination regimen. Third, the statistically significant difference in age between the two groups (P = 0.019) represents a major confounding factor that may potentially influence treatment tolerance and survival outcomes. Due to the small sample size, we could not perform multivariable adjustment or propensity score matching. Therefore, the observed PFS benefit should be interpreted with caution, and the results are best considered hypothesis-generating. Subsequent studies could adopt stricter matching criteria or conduct subgroup analyses to eliminate the impact of age. Additionally, the use of PET/CT in the PRRT group but not in the control group is a methodological limitation. This asymmetry may have led to earlier detection of progression (stage migration) or, conversely, more sensitive detection of SD, thereby potentially biasing the DCR and PFS estimates in favor of the PRRT group. Although we excluded PET/CT-only detected micro-metastases from the RECIST 1.1 assessment to reduce bias, the higher sensitivity of PET/CT may still have affected the consistency of the treatment response evaluation. Future studies should unify the efficacy assessment imaging modalities (e.g., CT/MRI alone or PET/CT for both arms). Furthermore, this study did not systematically analyze the correlation between tumor markers such as serum chromogranin A and treatment efficacy, lacking multidimensional validation indicators, and subsequent studies could incorporate multiple tumor markers to comprehensively evaluate treatment efficacy. Finally, the predictive value of indicators such as SSTR expression levels and the Ki-67 proliferation index for PRRT efficacy remains unclear in this specific population, and further research is needed to explore predictive biomarkers to guide individualized PRRT treatment. Nevertheless, this study minimized selection bias during patient enrollment, with all patients receiving standardized treatment and follow-up protocols, ensuring high internal validity. Considering the limited effective treatment options for recurrent NETLM after LT and the conventional DCR of only 37.5%, PRRT demonstrated an 85.7% DCR and favorable PFS prolongation. These hypothesis-generating findings suggest a novel therapeutic option for this specific patient population, particularly for SSTR-positive patients intolerant to chemotherapy. Future research should also explore the value of PRRT as neoadjuvant therapy for patients with unresectable NETLM prior to LT[24] and further optimize the sequential strategy of PRRT combined with everolimus in multi-line treatment. Multicenter, large-sample prospective cohort studies are needed to further optimize PRRT treatment parameters (e.g., individualized dose adjustment based on bone marrow radionuclide uptake) and treatment intervals. Concurrently, exploring predictive biomarkers (e.g., SSTR expression intensity and circulating tumor cells) will enhance the precision and individualization of PRRT therapy.

CONCLUSION

This study provides preliminary, hypothesis-generating evidence that in carefully selected patients with recurrent SSTR+ G2 NETLM after LT, the combination of everolimus-based immunosuppression and ¹⁷⁷Lu-DOTATATE PRRT demonstrates manageable safety with no PRRT-related graft rejection, severe nephrotoxicity, or other grade III or higher serious AEs observed and significantly improves PFS, while also showing a favorable DCR and potential antitumor activity. These findings suggest this approach may be a viable and promising treatment option for this specific patient population. Myelosuppression has emerged as the primary DLT, occurring in all PRRT-treated patients (grade III in 28.6%), which necessitates rigorous hematologic monitoring during treatment and timely symptomatic intervention with G-CSF, thrombopoietin, and other supportive agents. However, given the study’s limitations, particularly the small sample size, short follow-up, potential age-related confounding, and asymmetric imaging assessment, the long-term efficacy and safety profile of this combination regimen requires further validation through large-scale, multicenter prospective clinical trials with extended follow-up. The optimal PRRT dose and treatment strategy for this population needs to be further refined.

ACKNOWLEDGEMENTS

The authors thank the staff and colleagues of the First Central Hospital of Tianjin Medical University for their valuable support and contributions to the development of this manuscript.