Pancreatic neuroendocrine tumor treatment in Germany may include surgery, organ-preserving approaches and active surveillance for localized tumors. Advanced disease may require hormone control, systemic medicines, chemotherapy or PRRT, while selected liver metastases can be treated with surgery, ablation or liver-directed therapies. The article also covers treatment after progression, long-term follow-up and multidisciplinary NET care in Germany.

Pancreatic Neuroendocrine Tumor Treatment in Germany: Surgery, Medicines and Advanced Options

Two people can receive the same diagnosis of a pancreatic neuroendocrine tumor (pNET) and still require very different treatment plans. One may be advised to undergo surgery, while another with a small, low-grade, non-functioning tumor may be monitored with regular imaging. This difference reflects the biology and extent of the disease rather than inconsistency in care. Treatment decisions carefully weigh the tumor grade, size, location, hormone production, receptor status, and disease extent.

Personalized Treatment Planning for Pancreatic NET

Before choosing treatment, a specialist team assesses how the tumor is likely to behave. Tumor grade and the Ki-67 proliferation index are particularly important: a grade 1 tumor with a Ki-67 below 3% and a grade 3 tumor above 20% can look similar on a scan yet require very different treatment However, grade is not determined by Ki-67 alone; mitotic count also contributes. More importantly, a pancreatic NET G3 is not synonymous with a poorly differentiated neuroendocrine carcinoma (NEC). Size, pancreatic location and proximity to the main pancreatic duct or major vessels influence what surgery can achieve, while somatostatin receptor expression helps determine whether receptor-directed options such as PRRT are suitable.

Alongside tumour biology, several practical factors shape the plan:

• Whether disease is localized, locally advanced or metastatic, and how quickly it has changed across previous scans.
• Hormone-related problems such as hypoglycemia, severe reflux, or persistent diarrhea, which sometimes require control before initiating other therapies and  alongside tumour-directed therapy.
• Previous surgery, chemotherapy or radioligand therapy, and how the tumour responded to each.
• General fitness, pancreatic function, existing diabetes, or other comorbidities, operative risk, expected recovery and the patient's treatment preferences.
• The goal being agreed: cure, long-term tumour control, hormone control, or symptom relief and quality of life.

The plan is not fixed. It may be revisited when new imaging, pathology or clinical information becomes available, usually through a multidisciplinary NET team.

Treatment Options for Localized Pancreatic NETs

When a pNET is confined to the pancreas, pancreatic cancer surgery can potentially provide long-term disease control or cure in selected patients. However, surgery is not automatically required for every localized tumor. The harder question is how much surgery is justified, because pancreatic surgery can reduce functioning pancreatic tissue. In the prospective ASPEN study of 500 patients with small, asymptomatic, non-functioning tumors of 2 cm or less, aggressive features were found in 19 of the 94 tumors resected, and 17 of these measured more than 10 mm on imaging. The findings show why tumor size should not be considered in isolation and are analyzed with  other features, including tumour growth, pathological characteristics and dilatation of the main pancreatic duct, rather than using size alone to determine management [1].

Surgical and Organ-Preserving Approaches

Which operation is offered depends on where the tumour sits and how it behaves:

• Enucleation removes the tumor while preserving surrounding pancreatic tissue and may suit selected small, low-grade lesions sufficiently distant from the main pancreatic duct.
• Distal pancreatectomy removes the body and tail, for tumours on the left side of the gland.
• Pancreaticoduodenectomy (Whipple procedure) is generally used for tumors in the pancreatic head when a less extensive operation is not appropriate.
• Lymph-node assessment may be added when nodal spread is a concern, including with larger or higher-grade tumors or suspicious nodes on imaging.

A single-centre series of 62 enucleations reported a grade B pancreatic fistula in 10 patients (16%); after a median follow-up of 153 months, none had exocrine insufficiency and 7 (11%) had developed diabetes. More extensive resections may provide greater oncological clearance but can also have a greater impact on pancreatic function. The choice should therefore be individualized rather than based on tumor size alone [2].

Active Surveillance for Selected Pancreatic NETs

Not every small tumor requires immediate surgery. Where a non-functioning tumour is 2 cm or smaller, low-grade and symptom-free, structured monitoring is a legitimate strategy rather than a compromise. In ASPEN, 406 of 500 patients were managed this way, and after a median of 25 months only 9 (2%) went on to surgery [1]. Surveillance means scheduled imaging, review and blood tests where relevant, not being left alone. Certain findings move the conversation back towards treatment:

• Meaningful tumor growth or other features suggesting a higher risk of progression.
• Dilatation of the main pancreatic duct, which correlates strongly with aggressive features.
• New or worsening hormone-related symptoms.
• Suspicious lymph nodes or new lesions on follow-up imaging.
• The patient's own preference for definitive treatment after an informed discussion.

Treatment for Advanced and Metastatic Pancreatic NETs

When disease cannot be completely removed surgically, treatment often focuses on controlling tumor growth, hormone-related symptoms and maintaining quality of life. Surgery or liver-directed and other local treatments may still be considered in carefully selected patients with limited metastatic disease, particularly when the distribution of disease and tumour biology make meaningful disease control feasible. Someone with a few stable liver lesions and a Ki-67 of 4% may do well on a somatostatin analogue for years; someone with rapidly enlarging deposits and a Ki-67 of 25% needs something that shrinks tumour quickly. Treatment selection and sequencing take into account tumour burden, growth rate, histologic grade and differentiation, somatostatin-receptor status, symptoms, prior treatment and the patient's overall condition; there is no single sequence that is appropriate for every patient. Hormone Control in Functional Pancreatic NETs

Some pNETs produce hormones that can cause significant clinical symptoms. In these cases, controlling hormone excess may become an immediate priority alongside treatment of the tumor itself. Hormone control and tumor control are related but are not always achieved by the same treatment.

• Insulinoma causes hypoglycaemia, managed with frequent carbohydrate intake and diazoxide; somatostatin analogues are used cautiously, as they can occasionally deepen hypoglycaemia.
• Gastrinoma drives severe ulceration and peptic ulcer disease, gastro-oesophageal reflux and diarrhoea; acid suppression with proton-pump inhibitors is the mainstay of treatment for the acid-hypersecretion syndrome.
• VIPoma causes profuse watery diarrhoea and potassium loss; somatostatin analogues such as octreotide and lanreotide are the mainstay, alongside fluid replacement.
• Glucagonoma produces a characteristic rash, weight loss and diabetes, usually responsive to somatostatin analogues.
• Somatostatinoma is rare, presenting with gallstones, diabetes and fatty stools.

Hormone control and tumor control may require different treatments, so both are assessed separately during follow-up.

Medical Treatment for Advanced Pancreatic NETs

Systemic treatment is selected according to tumor grade, growth rate, receptor status, disease burden, symptoms and previous treatment. Somatostatin analogues can control receptor-positive, well-differentiated disease and hormone symptoms. Everolimus and sunitinib are options for progressive well-differentiated tumors, while chemotherapy such as CAPTEM may be considered when substantial tumor shrinkage is needed or disease is progressing rapidly.

Real-world data provide context on clinical outcomes. Among 59 patients with metastatic pNETs treated after progression on earlier therapy, median progression-free survival was 21.9 months with PRRT and 20.0 months with CAPTEM, with response rates of 34.8% and 40.9%, respectively. Responses occurred sooner with CAPTEM in this retrospective cohort, showing a median time to response of 6.0 months versus 11.2 months with PRRT. Because this study was small and retrospective, non-randomized study, the findings are subject to selection and other confounding biases and should not be interpreted as establishing PRRT or CAPTEM as universally superior. Treatment selection is tailored individually for patients according to tumour biology, somatostatin-receptor expression, disease burden, rate of progression, symptoms, previous therapies and treatment goals [4].

Median progression-free survival by treatment and grade in a retrospective series of 59 patients with metastatic pancreatic NETs. Subgroups are small and were not randomised, so these figures describe one cohort rather than proving superiority [4].

Receptor-Directed Treatment and PRRT for Pancreatic NETs

PRRT is available through specialised nuclear medicine departments, including experienced centres in Germany that evaluate eligibility based on imaging findings, tumour biology and organ function: Lutetium-177-DOTATATE binds the receptor and delivers radiation from inside the tumour, reaching every receptor-positive deposit rather than one target area.

Receptor positivity alone does not determine PRRT eligibility. Uptake must be present across the disease rather than in one lesion, kidney and marrow function must be adequate, and rapidly growing disease with weak uptake may respond better to chemotherapy first. In a German retrospective cohort of 166 patients with metastatic pNET, median overall survival was 97 months for grade 1–2 disease versus 74.5 months for grade 3. These figures describe a selected study population and should not be interpreted as expected survival for every patient receiving PRRT [5].

Median overall survival by subgroup at a German centre, where most patients received four or more PRRT cycles. These subgroups reflect tumour biology and are not randomised comparisons [5].

Pancreatic NETs With Liver Metastases

The liver is a common site of metastatic spread from pNETs and may be the only site of distant disease in some patients. When disease is confined there, treating it aggressively can be worthwhile even at an advanced stage particularly when tumour biology is relatively indolent, the disease burden is technically treatable and the patient is fit enough to undergo treatment. The decision rests on lesion number, distribution between the lobes, how much healthy liver would remain, and tumour behaviour over time. Approaches include:

• Cytoreductive surgery and parenchyma-sparing resection, where enough of the burden can be removed safely.
• Thermal ablation, frequently combined with resection in a single session for scattered smaller lesions.
• Catheter-based liver-directed therapies for multifocal disease not suited to resection.

These approaches are usually considered alongside systemic treatment rather than as replacements, with the decision depending on disease distribution and overall tumour behaviour. In a population-based analysis of 1,270 patients with liver-only metastatic pNET, the 283 (22.3%) who had cancer-directed surgery of the primary showed a median overall survival of 95 months against 22 months in those who did not. However, patients selected for surgery had more favorable characteristics, so the survival difference cannot be attributed to surgery alone. The findings support considering surgery in carefully selected patients [6].

Treatment After Recurrence or Disease Progression

Recurrence or progression can occur during the course of pNETs, but it does not necessarily mean treatment options have been exhausted. Instead, it provides new information about tumor behavior and may prompt reassessment. Recurrence after surgery is usually distant rather than local in one surgical series, 12 of 86 patients recurred at a median of 36.3 months, most often in liver and lung. Reassessment may include updated cross-sectional and receptor imaging and, in selected cases, a repeat biopsy when clinical behavior or pathology raises concern about a change in tumor biology [3].

That reassessment drives the next step switching drug class, adding a local treatment to a systemic one, repeating PRRT in selected patients who responded well before, or entering a trial. In the series above, the second treatment generally gave a shorter progression-free interval than the first [4].

Monitoring Treatment Response and Long-Term Follow-Up

Follow-up serves two important purposes: checking whether the current treatment is working and watching for the cancer if it returns later. Since pNETs can recur even after five years, follow-up needs to continue for the long term.

• CT or MRI at intervals set by grade and previous behaviour, compared against the last scan rather than only the baseline.
• Hormone and biochemical monitoring in functional tumours, matched to the specific syndrome
• Blood counts, kidney and liver function during PRRT, chemotherapy or targeted treatment.
• Pancreatic exocrine function, blood glucose and nutrition after resection, since enzyme replacement is often needed.
• Weight, nutritional status and digestive symptoms should also be reviewed because pancreatic insufficiency and treatment effects may become clinically important.

Specialist Pancreatic NET Care and Emerging Treatments in Germany

Because pNETs are uncommon and treatment can involve several specialties, care is often coordinated at experienced NET centers. In Germany, ENETS-recognized centers and university hospitals provide multidisciplinary care involving surgery, oncology, endocrinology, nuclear medicine, radiology and pathology. For complex or borderline cases, multidisciplinary review can help clarify the most appropriate treatment strategy. International patients may also seek a specialist second opinion when considering treatment in Germany.

Research into pNET treatment includes new radioligand therapies, combinations of radioligand therapy with systemic treatments, alpha-emitting radionuclides and molecularly targeted approaches. Many remain investigational and should not be presented as established treatment options.

References

1. Partelli S, Massironi S, Zerbi A, Niccoli P, Kwon W, Landoni L, et al. Management of asymptomatic sporadic non-functioning pancreatic neuroendocrine neoplasms no larger than 2 cm: interim analysis of prospective ASPEN trial. British Journal of Surgery. 2022;109(12):1186–1190.

2. Bergamo F, Nardi M, Sperti C, Blandamura S, Vianello F, Merigliano S, et al. Enucleation for pancreatic neuroendocrine tumors: short- and long-term outcomes in a forty-year single-center experience. Endocrine Oncology. 2025;5(1):e250035.

3. Fouad M, Almahari SA, Zaitoun AM, Sonoo P, Malek S, Sourial K, Gomez D. Outcomes Following Surgery for Pancreatic Neuro-Endocrine Tumours: A Single-Centre Experience. Clinics and Practice. 2025;15(11):202.

4. Gujarathi R, Tobias J, Abou Azar S, Keutgen XM, Liao CY. Peptide Receptor Radionuclide Therapy versus Capecitabine/Temozolomide for the Treatment of Metastatic Pancreatic Neuroendocrine Tumors. Cancers. 2024;16(17):2993.

5. Mathew A, Kersting D, Fendler WP, Braegelmann J, Fuhrer D, Lahner H. Impact of functionality and grading on survival in pancreatic neuroendocrine tumor patients receiving peptide receptor radionuclide therapy. Frontiers in Endocrinology. 2025;16:1526470.

6. Yang Z, Liang J, Leng K, Shi G. Survival Benefit of Surgical Resection for Pancreatic Neuroendocrine Tumors With Oligometastatic Liver Metastasis: A Retrospective and Propensity Score-Matching Analysis. Frontiers in Oncology. 2022;12:903560.

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