Immune-checkpoint inhibitors (ICIs) have widened the therapeutic scenario of different cancer types. Phase I/II trials have been designed to evaluate the role of ICIs both as single agents and in combination in neuroendocrine neoplasms (NENs), but as yet no randomized controlled phase III trials have been carried out. A systematic review and meta-analysis of studies published could help to reduce the biases of single-phase II trials. Efficacy data were obtained on 636 patients. Pooled percentages of the overall response rate (ORR) and disease control rate (DCR) were 10% (95% CI: 6–15%, I² = 67%, p < 0.1) and 42% (95% CI: 28–56%, I² = 93%, p < 0.1), respectively. Median progression-free survival (mPFS) was 4.1 months (95% CI 2.6–5.4; I² = 96%, p < 0.1) and median overall survival (mOS) was 11 months (95% CI 4.8–21.1; I² = 98%, p < 0.1). Among the ICIs used as single agents, the anti-PD1 toripalimab achieved the highest ORR. Combination regimens were superior to monotherapy, e.g., the ICI combination nivolumab + ipilimumab, and the ICI + anti-angiogenetic combination atezolizumab + bevacizumab, both of which warrant further investigation. Promising efficacy and a good safety profile of ICIs represent a valid opportunity for expanding the therapeutic landscape of NENs. Predictive biomarkers are needed to identify the most suitable candidates for these regimens.

Introduction: Neuroendocrine tumors (NETs) are rare malignancies with different prognoses. At least 25% of metastatic patients have functioning neuroendocrine tumors (F-NETs) that secrete bioactive peptides, causing specific debilitating and occasionally life-threatening symptoms such as diarrhea and flushing. Somatostatin analogs (SSAs) are usually effective but beyond them few treatment options are available. We evaluated the clinical efficacy of 177 Lu-DOTATATE in patients with progressive metastatic F-NETs and SSA-refractory syndrome. Patients and Methods: A non-pre-planned joint analysis was conducted in patients enrolled in phase II clinical trials on metastatic NETs. We extrapolated data from F-NET patients with ≥1 refractory sign/symptom to octreotide, and ≥1 measurable lesion. Syndrome response (SR), overall survival (OS), progression-free survival (PFS), tolerance and disease response were analyzed. Results: Sixty-eight patients were enrolled, the majority (88.1%) with a SR. According to RECIST criteria, 1 (1.5%) patient showed a CR, 21 (32.3%) had a PR and 40 (61.5%) SD. At a median follow-up of 28.9 months (range 2.2–63.2) median PFS was 33.0 months (95%CI: 27.1–48.2). Median OS (mOS) had not been reached at the time of the analysis; the 2-year OS was 87.8% (95%CI: 76.1–94.1). Syndromic responders showed better survival than non-responders, with a 2-year OS of 93.9% (95%CI: 92.2–98.0) vs. 40.0% (95%CI: 6.6–73.4), respectively. A total of 233 adverse events were recorded. Grade 1–2 hematological toxicity was the most frequent. Conclusion: The 177 Lu-DOTATATE improved symptoms and disease control in patients with F-NETs. Treatment was well tolerated. The syndrome had an impact on both quality of life and OS.

Introduction: Lu-PRRT in neuroendocrine tumors is usually delivered with a total cumulative activity (TCA) of 29.6 GBq, divided into 4 cycles and with fixed interval between cycles (IBCs) of 8 weeks. Based on previous radiobiological studies, reducing IBC could improve efficacy without increasing toxicity. The purpose of this study was to evaluate safety of Lu-PRRT with two different IBC: intensive (every 5 weeks) or standard (every 8–10 weeks). Methods: From May 2016 to July 2018, patients with advanced and progressive GEP and bronchial NENs were enrolled in a prospective randomized phase II study. Patients with risk factors for toxicity (RF) were planned for a TCA of 18.5 GBq, patients without RF of 27.8 GBq, divided into 5 cycles. Patients were then randomly assigned to be treated according to the intensive or to the standard IBC. Toxicity was monitored according to CTCAE. Results: One hundred and twenty patients (61 in the intensive group and 59 in the standard one) were evaluable for overall toxicity. Five patients (4.1%) had major (G3) hematological toxicity, 2 in the intensive group and 3 in the standard one. Other G3 toxicities related to creatinine, alanine aminotransferase, nausea, and asthenia were observed in the intensive group. 112 patients (54 in the intensive group and 58 in the standard one) performed at least 2 cycles and were also evaluable for cycle-by-cycle toxicity, resulting similar between the two groups. Conclusion: According to our preliminary results, Lu-PRRT administered intensively could be considered as safe as the standard schedule, when TCA is chosen according to the RF. Further data are needed to confirm these results.

Purpose Metastatic castration-resistant prostate cancer (mCRPC) remains a therapeutic challenge. Radioligand therapy (RLT) with ¹⁷⁷Lu-PSMA-617 has shown promising efficacy. This study reports the first Italian prospective trial evaluating efficacy and safety at 5.5 GBq per cycle in mCRPC. Methods This prospective, single arm, monocentre, Phase-II study enrolled PSMA-avid mCRPC patients (April 2017–October 2022). Patients received 5.5 GBq of ¹⁷⁷Lu-PSMA-617 per cycle for four cycles at 8 ± 2 weeks; up to two additional cycles were allowed. Mannitol and polyglutamate tablets were given to limit renal and salivary uptake. Primary endpoint was PSA response, assessed as best response; secondary endpoints were safety, progression-free survival (PFS) according to PCWG3 criteria, and overall survival (OS). Adverse events were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results Forty-eight patients were assessed for safety; 44 were evaluable for efficacy. A ≥ 50% PSA decline occurred in 22 patients (50%). At 12 months, PFS was 22.7% (95% CI: 11.8–35.9) and OS 87.9% (95% CI: 73.4–94.8); median OS was 18.8 months. Treatment was generally well tolerated, with mostly Grade 1–2 events. Grade 3 toxicities were rare (6.3%), and no Grade 4 events occurred. One Grade 3 hyponatraemia led to discontinuation. Conclusions ¹⁷⁷Lu-PSMA-617 at 5.5 GBq per cycle was safe and effective, achieving survival comparable to studies using 7.4 GBq with fewer severe toxicities. Tailored regimens may benefit patients at higher toxicity risk. These data support further studies to optimize dosage, timing, sequencing and combinations of RLT.

The original research articles included in this Research Topic provide two different examples of how radionuclide therapy may continue to evolve in clinical practice. Innovation does not necessarily require a new target or radiopharmaceutical; it may also emerge from refining the way established treatments are delivered. Wang et al. investigated the administration of Lugol's solution following radioiodine therapy for remnant ablation in differentiated thyroid cancer. In this preliminary randomized study, structural ablation rates were comparable between groups, while some biochemical outcomes favored Lugol's solution and no clear increase in long-term toxicity was observed. Although the single-center design and limited sample size call for confirmation in larger multicenter studies, these findings illustrate how even long-established radionuclide treatments may still offer opportunities for optimization.A different therapeutic setting is represented by epidermal therapy with rhenium-188 for nonmelanoma skin cancer. Castellucci et al. describe an approach combining high local radiation delivery with limited penetration into deeper tissues. Available clinical experience indicates high response rates, generally favorable cosmetic outcomes and predominantly mild toxicity in appropriately selected patients. At the same time, the current evidence remains largely based on observational and single-center experience. Standardization of dosimetry, optimization of administered dose according to lesion characteristics and prospective comparisons with established treatment options will therefore be important to better define the role of this approach in clinical practice.Alongside these original contributions, the reviews collected in this Research Topic offer a broader perspective on the evolution of RLT, moving from expanding indications and established radionuclide treatments toward rapidly developing therapeutic strategies and emerging radionuclides.In our review, Grassi et al. explored RLT for primary brain tumors, including 30 studies on meningiomas and gliomas. Evidence is currently more substantial for meningiomas, whereas RLT in gliomas remains largely experimental. Nevertheless, these experiences are of particular interest because they illustrate the potential of target-based patient selection in diseases for which therapeutic alternatives may be limited. They also expose some of the challenges encountered when RLT moves beyond its best-established indications, including heterogeneous study designs, small patient populations and the need for standardized response criteria and well-designed multicenter trials.Real-world evidence becomes particularly valuable once radionuclide therapies enter broader clinical use, where patient populations are inevitably more heterogeneous than those enrolled in controlled trials. Song et al. addressed this issue in their meta-analysis of radium-223 in metastatic castrationresistant prostate cancer (mCRPC). Based on 25 observational studies including 8.795 patients, the authors identified several clinical and biochemical variables associated with overall survival and highlighted the relationship between treatment completion and outcome. Their findings emphasize how the effectiveness of radionuclide therapy in everyday practice is closely intertwined with patient selection, disease burden, hematologic reserve, previous treatments and the feasibility of completing the intended therapeutic course.PSMA-targeted RLT provides perhaps one of the clearest examples of how rapidly a theranostic strategy can evolve. Noamen et al. review the current evidence for PSMA-targeted beta-emitting RLT in prostate cancer and place it within a therapeutic landscape that continues to expand. The field is progressively moving beyond the concept of RLT predominantly as a late-line treatment, with increasing interest in earlier disease settings, therapeutic sequencing and combinations with systemic and local treatments. In this evolving scenario, molecular imaging becomes more than a diagnostic companion: it increasingly contributes to patient selection, assessment of target expression, and characterization of tumor heterogeneity over time. The challenge may therefore be less about identifying a universally superior radiopharmaceutical and increasingly about choosing the most appropriate therapeutic strategy for each biological and clinical context.At the most innovative end of this continuum, we were particularly pleased to include the contribution by Albano et al. exploring terbium-161-labelled PSMA ligands in mCRPC. Their systematic review and meta-analysis included six studies and 80 patients and reported encouraging disease control and an acceptable safety profile, although the available evidence remains limited and heterogeneous. The additional emission of low-energy electrons by terbium-161 provides an attractive rationale, particularly for microscopic disease. Whether this physical and dosimetric advantage will translate into superior clinically meaningful outcomes remains to be established. Comparative studies, longer follow-up and the incorporation of patient-reported outcomes will be essential before the precise therapeutic positioning of ^161Tb-labelled compounds can be defined.Taken together, the contributions to this Research Topic reflect a field in transition. From the refinement of established treatments to the exploration of new indications, from real-world experience with consolidated radionuclides to emerging radiopharmaceuticals, they suggest that innovation in RLT should not be understood exclusively as the introduction of a new agent. It may also lie in selecting treatments more intelligently, optimizing their delivery, identifying the patients most likely to benefit and integrating molecular imaging, dosimetry, biological characterization, and clinical information into therapeutic decision-making.Real-world evidence, systematic reviews, prospective...