Introduction
Neuroendocrine tumours represent a diverse and complex group of neoplasms originating from neuroendocrine cells found throughout the body, predominantly in the GI tract, pancreas, and lungs (1). These tumours are unique in their ability to produce hormones and other bioactive substances, which can lead to various clinical syndromes depending on the type and quantity of hormones secreted (2). Despite being relatively rare, the incidence of NETs has steadily risen over the past few decades, partly due to advancements in diagnostic techniques and heightened clinical awareness (3).
NETs are heterogeneous, both in terms of their biological behaviour and clinical presentation. The overall incidence is estimated to be around 5.86 per 100,000 individuals annually, and it has been increasing over the years (4). This rise in incidence can be attributed to improved imaging techniques, more widespread use of endoscopy, and increased screening practices that lead to the detection of asymptomatic cases (5).
The World Health Organization classifies NETs based on their histopathological characteristics (6). NETs are generally categorized into well-differentiated and poorly differentiated tumours, further classified into grades 1, 2, and 3 based on the Ki-67 index (6). Well-differentiated NETs typically have a low behaviour, whereas poorly differentiated neuroendocrine carcinomas (NECs) are more aggressive and have poorer prognoses (7).
The pathophysiology of NETs is closely linked to their neuroendocrine origin, which endows them with the ability to secrete a variety of peptides and amines. This leads to distinct clinical syndromes (8). For instance, carcinoid syndrome, often associated with gastrointestinal NETs, results from the secretion of serotonin and other vasoactive substances (9). The genetic underpinnings of NETs are also diverse, with common mutations identified in genes such as MEN1, DAXX, and ATRX, particularly in pNETs (10,11). Mutations in the MEN1 gene, which encodes the protein menin, are frequently observed in familial cases of NETs and are also present in sporadic cases (12). The loss of function of menin leads to unchecked cellular proliferation and tumour formation. Similarly, mutations in DAXX and ATRX, which are involved in chromatin remodelling, have been associated with more aggressive forms of NETs and are considered poor prognostic markers (13).
The clinical presentation of NETs can vary widely depending on the tumour's location, its size, the grade of the tumour, and its functional status. For example, insulinomas, which secrete insulin, can cause recurrent hypoglycaemia, while gastrinomas, which secrete gastrin, lead to Zollinger-Ellison syndrome, characterized by severe peptic ulcers (14). In contrast, non-functional NETs, which do not secrete hormones, may remain asymptomatic for a long time and are often discovered incidentally during imaging studies performed for other reasons (15). When symptoms do occur in these tumours, they are typically related to the tumour's mass effect or metastasis. The liver is the most common site of metastatic spread, particularly in gastrointestinal and pNETs (16).
Therapeutic strategies for neuroendocrine tumours have evolved rapidly alongside advances in pathway-targeted treatments. A significant milestone was reached on 26 March 2025, when the U.S. Food and Drug Administration authorized cabozantinib for patients with unresectable or metastatic pancreatic and extra pancreatic NETs who had progressed after prior systemic therapy (17). In addition, belzutifan, a selective hypoxia-inducible factor-2α inhibitor, was approved for the management of malignant pheochromocytoma and paraganglioma, representing a new metabolism-oriented therapeutic paradigm in neuroendocrine oncology (18).
At the same time, peptide receptor radionuclide therapy continues to advance beyond conventional 177Lu-DOTATATE, with ongoing development of somatostatin receptor antagonists and alpha-particle-emitting radionuclides aimed at improving tumour targeting and cytotoxic efficacy (19). Beyond radionuclide-based approaches, novel immunotherapeutic strategies are emerging as promising avenues that may substantially reshape systemic treatment options for NETs in the near future.
The diagnosis of NETs involves a combination of clinical evaluation, biochemical testing of markers (17,18) and imaging studies, such as CT, MDI and DORATATE PET/CT (19,20). When it comes to histopathological confirmation, the assessment of the Ki-67 index is important in determining the tumour grade and guiding treatment decisions (21,22).
The management of NETs is complex and requires a multidisciplinary approach. Surgical resection remains the cornerstone of treatment for localized NETs and offers the best chance for cure (23). Many patients are admitted to the hospital with advanced or metastatic disease at diagnosis, for which systemic therapies are the core of treatment (24). SSAs such as octreotide and lanreotide are used to control symptoms and slow tumour progression in patients with functional NETs (25). Targeted therapies such as the mammalian target of rapamycin (mTOR) inhibitor everolimus have demonstrated efficacy in treating advanced pNETs, providing both antiproliferative and symptom control effects (26). Similarly, the tyrosine kinase inhibitor sunitinib is approved for treating advanced pNETs and has been shown to improve progression-free survival in this patient population (27).
Despite advances in the understanding and treatment of NETs, several challenges remain. The heterogeneous nature of these tumours poses significant challenges in diagnosis, treatment, and prognosis (28). The rarity of NETs has also limited the ability to conduct large-scale clinical trials, resulting in a reliance on retrospective studies and small, prospective cohorts for much of the available evidence (29). Moreover, while new therapies have improved outcomes for some patients, others continue to experience poor prognosis, particularly those with high-grade or poorly differentiated NETs (30).
Accordingly, this systematic review aimed to evaluate contemporary therapeutic strategies for adult patients with neuroendocrine tumours. Using the PICO framework, the population included adult patients with NETs; interventions comprised surgery, systemic therapies, targeted agents, immunotherapy, and peptide receptor radionuclide therapy; comparators included alternative treatment strategies or standard of care where applicable; and outcomes of interest were progression-free survival, overall survival, and treatment-related outcomes.
Discussion
This systematic review provides an integrated evaluation of therapeutic strategies across neuroendocrine tumours and selected related malignancies, highlighting the diversity of available treatments and their variable impact on survival outcomes.
Across the included studies, immunotherapy emerged as a central area of investigation. Dual checkpoint blockade with nivolumab plus ipilimumab demonstrated durable benefits in several cohorts, with overall survival exceeding 55 months in certain populations, as shown by Larkin et al (45) and Motzer et al (49). These results confirm the potential of immune-based regimens to extend long-term survival, even though toxicity profiles and treatment costs remain limiting factors (68,69). This finding is also stated by Pánczél et al (70) who concluded that dual checkpoint blockade with ipilimumab and nivolumab achieved higher response and disease control rates, albeit with increased toxicity, suggesting a potential benefit for selected patients. In contrast, pembrolizumab monotherapy and combination regimens yielded more heterogeneous outcomes. For example, Eggermont et al (52) reported OS under 10 months in small-cell lung cancer, whereas Marabelle et al (42) observed more favourable responses in mismatch repair-deficient tumours. Similar to this, Hektoen et al (71) noticed a doubling in patients surviving more than 2 years when comparing improvement in survival with pembrolizumab relative to previous platinum-based chemotherapy. It continues to be used in the management of high-grade or poorly differentiated NETs and related carcinomas. The trial by Morizane et al (47) compared etoposide-cisplatin with irinotecan-cisplatin in advanced digestive neuroendocrine carcinoma, showing no significant difference in survival but confirming both regimens as standard first-line options. Choucair et al (72) investigated Irinotecan in combination with cisplatin for treating advanced poorly differentiated GEP-NETs, and in phase II of his trial, the researchers found that the objective response rate was comparable between IP and EP in small-cell NETs.
Targeted therapies also demonstrated clinically relevant benefits. Nintedanib in non-pancreatic gastroenteropancreatic NETs was associated with PFS of 11 months and OS approaching 33 months. Similarly, rovalpituzumab tesirine, directed at DLL3 in neuroendocrine prostate cancer, showed promising efficacy.
Another notable therapeutic avenue is radiolabelled peptide receptor therapy and other radiolabelled approaches. The trial by Reidy-Lagunes et al (59) demonstrated that Lu-satoreotide tetraxetan achieved a median PFS of 21 months and favourable long-term OS rates in somatostatin receptor-positive NETs. This is similar to what Wild et al (73) found. In their phase I/II study, Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three cycles, has an acceptable safety profile with a promising clinical response in patients with progressive, SSTR-positive NETs.
From a clinical practice perspective, the findings summarized support an individualized approach to neuroendocrine tumour management. Peptide receptor radionuclide therapy demonstrated the most durable disease control, with 177Lu-DOTATATE and Lu-satoreotide tetraxetan achieving the longest PFS in somatostatin receptor-positive tumours (59,62). In addition, dual immune checkpoint blockade with nivolumab and ipilimumab was associated with the longest OS in their selected cohorts (45,49). From a policy and future research perspective, the heterogeneity of outcomes highlights the need for equitable access to advanced therapies such as PRRT and combination immunotherapy (59,62). Healthcare policies should facilitate referral to specialized centres and support reimbursement for these treatments. Future research should prioritize NET-specific randomized trials and biomarker-driven approaches, building on existing evidence for PRRT and immunotherapy (45,49,62), to optimize patient selection, treatment sequencing, and long-term outcomes.
Despite encouraging results, the variability of outcomes across treatment modalities reflects the challenges of managing NETs. Some regimens, such as checkpoint inhibitors, may provide long-lasting benefit in a subset of patients but limited responses in others. Moreover, the included studies varied substantially in sample size, design, and endpoints. Thus, the analysis indicates that immunotherapy, targeted agents, and radiolabelled therapies offer meaningful clinical benefits for selected patients with NETs outside the pancreas.
The overall certainty of evidence for the main outcomes was considered moderate for PFS and OS in treatment modalities supported by randomized controlled trials, particularly for dual immune checkpoint inhibition and peptide receptor radionuclide therapy. In contrast, the certainty of evidence was low for outcomes derived primarily from single-arm phase II studies, retrospective analyses, and exploratory trials, due to limited sample sizes, lack of randomization, and heterogeneity in tumour types and treatment regimens.
This study presents some limitations. First of all, it includes a mix of RCTs, single-arm studies, and retrospective analyses. This variability in study design introduces heterogeneity that can affect the comparability of outcomes across studies. Including studies with different methodologies, sample sizes, and bias levels may have influenced the overall results. We included in the analysis various cancer types, stages, and patient demographics. While providing a broad overview of treatment effects, this diversity also limits the ability to draw specific conclusions about individual treatments' efficacy for particular cancer subtypes. Differences in tumour biology, patient characteristics, and previous treatments contribute to the variability in survival outcomes. We also found many small sample sizes and single-arm study designs, limiting the robustness and generalizability of the results.
To sum up, immunotherapy, particularly dual checkpoint blockade with nivolumab and ipilimumab, demonstrated the most durable effects, with progression-free survival around 11 months and overall survival extending to 55-60 months in advanced settings. Single-agent checkpoint inhibitors showed variable results: pembrolizumab achieved PFS between 2 and 5 months, with OS ranging from 9.6 months in small-cell lung cancer to 23.5 months in mismatch repair-deficient tumours. Chemotherapy remained a mainstay for high-grade carcinomas, with etoposide-cisplatin or irinotecan-cisplatin achieving OS of approximately 11-12.5 months. Targeted therapies, such as nintedanib, improved survival outcomes (PFS 11 months; OS 32.7 months), indicating benefit in selected cases. Radiolabelled therapies like Lu-satoreotide tetraxetan further extended PFS to 21 months, with long-term survival rates of 85% at two years and 63% at three years. Collectively, results emphasize tailored, multimodal strategies.