This systematic review and meta-analysis evaluated the efficacy and safety of 177 Lu-labelled peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors (NETs).
This systematic review and meta-analysis conducted a search of the PubMed/MEDLINE, Embase, and Web of Science databases. Included studies assessed treatment outcomes using Response Evaluation Criteria in Solid Tumors (RECIST) or World Health Organization (WHO) criteria. A random-effects model was used to calculate pooled proportions.
A total of 14 studies with 1844 patients were included. The pooled disease control rate (DCR) was 87.6% (95% Confidence Interval (CI), 82.5%-92%), and the objective response rate (ORR) was 32.2% (95% CI, 25.4%-39.3%). Median progression-free survival (PFS) was 30.87 months (95% CI, 22.71–39.04), and median overall survival (OS) was 51.85 months (95% CI, 39.99–63.71). Subgroup analysis revealed a significantly higher DCR in grade 1–2 NETs 97.7% (95% CI, 91.4%-100%) compared to grade 3 NETs 90.8% (95% CI, 85.1%-94.4%), and a higher ORR in grade 1–2 tumors 45.4% (95% CI, 35.3%-55.6%) compared to grade 3 tumors 27.1% (95% CI, 21.2%-33.4%). PFS was longer in pancreatic NETs 93.9 months (95% CI, 39.45–148.35) than in gastrointestinal NETs 66.32 months (95% CI, 41.78–90.87). The overall incidence of adverse events was 4.1%, with grade ≥3 toxicities in 4.3%. 177 Lu-PRRT demonstrates high efficacy and a favorable safety profile in treating NETs.
177 Lu-DOTA-Tyr3-octreotate (177 Lu-DOTATATE) demonstrates high efficacy and a favorable safety profile in treating NETs.
identifier CRD420251047030.
Neuroendocrine tumors (NETs) are malignant neoplasms arising from neuroendocrine cells, most commonly occurring in the digestive system. Their incidence has increased significantly, from 1.09 per 100,000 in 1973 to 6.98 per 100,000 in 2012, with current rates ranging from 5.25 to 7 per 100,000, according to Surveillance, Epidemiology, and End Results data.
First-line treatment strategies for metastatic or unresectable NETs typically include chemotherapy and somatostatin analogs. However, conventional therapies have limitations in managing disease progression. Recent advancements in peptide receptor radionuclide therapy (PRRT) have proven effective, particularly for well-differentiated G1–G2 gastroenteropancreatic NETs (GEP-NETs).PRRT, using radionuclide-coupled analogs like 177 Lu-DOTA-Tyr3-octreotate (177 Lu-DOTATATE) and 90 Y-DOTA-Tyr³-octreotide (90 Y-DOTATOC), targets tumor cells. 177 Lu-DOTATATE, with fewer adverse effects, has Food and Drug Administration and European Medicines Agency approval for receptor-positive GEP-NETs in adults. The recommended regimen is four cycles of 7.4 GBq (200 mCi). The NETTER-1 trial demonstrated superior progression-free survival (PFS) and objective response rate (ORR) in the 177 Lu-DOTATATE group compared to the control. Despite these promising clinical outcomes, safety considerations remain paramount and comprehensive efficacy data across heterogeneous NET subgroups require further elucidation.
Safety concerns primarily involve reversible hematologic toxicity and nephrotoxicity, with common adverse effects including anemia, leukopenia, and thrombocytopenia. Few meta-analysis have assessed the efficacy of 177 Lu-DOTATATE in different NET subgroups. This meta-analysis retrospectively evaluated the efficacy and safety of 177 Lu-DOTATATE across various NET grades and patient subgroups.
This meta-analysis was conducted in strict accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We systematically searched the PubMed/MEDLINE, Embase, and Web of Science databases for relevant literature up to April 8, 2025. Search terms included “neuroendocrine tumor”, “pancreatic neuroendocrine tumor”, “gastroenteropancreatic neuroendocrine tumor”, “PRRT”, and “177 Lu-DOTATATE”, along with related variants of these terms. Additionally, we manually searched the reference lists of relevant articles to identify any further relevant studies.
Inclusion Criteria:
Exclusion Criteria:
The risk of bias (RoB) assessment was performed using the latest Cochrane Collaboration’s RoB tool for randomized controlled trials (RCTs). This tool evaluates six domains: randomization process, deviations from intended interventions, missing outcome data, outcome measurement, selective reporting, and overall RoB, providing an overall judgment. For cohort studies and case-control studies, the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool was used for analysis. The overall risk of bias for each study was classified as low, moderate, serious, or critical.
Two researchers independently extracted data from the included studies, collecting the following information: first author, year of publication, study design, number of patients, tumor type, average therapeutic dose of radiopharmaceuticals, treatment duration, and follow-up period. The primary outcomes were efficacy and adverse events. Efficacy outcomes included disease control rate (DCR), ORR, pooled PFS, and overall survival (OS). DCR was defined as the percentage of patients achieving complete response, partial response, or stable disease, and ORR as the percentage achieving complete response or partial response. PFS was defined as the time from treatment initiation to tumor progression (e.g., enlargement or metastasis) or death, and OS as the time from treatment initiation to death from any cause. Imaging responses were assessed according to RECIST and mRECIST criteria. Adverse events were recorded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0, with an emphasis on hematologic and renal toxicities.
A meta-analysis was performed using Stata version 18.0 (StataCorp LLC, College Station, TX, USA) and R version 3.5.2 (R Foundation for Statistical Computing, Vienna, Austria). The efficacy of 177 Lu-DOTATATE treatment was assessed by calculating the DCR, ORR, PFS, and OS, each reported with 95% confidence intervals (CI). Treatment-related adverse events were also evaluated and reported with 95% CI. Statistical heterogeneity among studies was assessed using Cochran’s Q test and the Higgins I² statistic. Heterogeneity was considered significant if the Cochran’s Q test P-value was < 0.10 and I² was > 50%; in this case, a random-effects model was applied. Otherwise, a fixed-effects model was used. Sensitivity analyses were conducted by sequentially excluding each study (leave-one-out analysis) to test the robustness of the results. Statistical significance was defined as P< 0.05.
Systematic searches of electronic databases identified 1507 records. After removing 383 duplicate records, we screened the titles and abstracts of the remaining 1124 articles. During the title/abstract screening, 1,027 records were excluded due to being irrelevant to survival rates, meta-analyses and review articles, case reports, and non-English publications. A total of 97 articles were retained for full-text review. Full-text assessment led to the exclusion of 83 articles, primarily due to inappropriate publication type or failure to report DCR or ORR. Ultimately, 14 studies met all inclusion criteria and were included in the meta-analysis.
The 14 included studies comprised 5 retrospective and 9 prospective investigations; 12 employed a cohort design, and 2 were RCTs. Cohort studies were assessed using the ROBINS-I, and RCTs were evaluated with the Cochrane Collaboration’s RoB tool. All included studies were judged to have a low overall RoB, and the three RCTs were considered to be of high methodological quality. We enrolled a total of 1844 patients. The baseline characteristics of the study participants are presented in Table 2.
Methodological quality or risk of bias assessment of the included studies.
