Neuroendocrine Neoplasms: Pancreatic NEN, gastrointestinal NEN and neuroendocrine tumors of the lung

Pancreatic NENs account for approximately 5-10% of all neuroendocrine neoplasms. The incidence of pancreatic NETs is currently about 0.8-1.2 per 100,000 inhabitants per year, while pancreatic NECs occur much less frequently, at about 0.05-0.1 per 100,000 inhabitants per year [4, 5].

Gastrointestinal NENs constitute the largest group of neuroendocrine neoplasms, with approximately 4,000 cases per year in Germany. Small bowel NETs have an incidence of approximately 1.0-1.3 per 100,000 inhabitants per year and are among the most common gastroenteropancreatic NETs. Gastrointestinal NECs are significantly rarer, with an incidence of approximately 0.2-0.3 per 100,000 inhabitants per year [4, 7].

Pulmonary NETs (typical and atypical carcinoids) have an incidence of approximately 0.7–1.0 per 100,000 inhabitants per year. In Germany, just under 1,200 pulmonary NETs were diagnosed in 2023. In contrast, pulmonary NECs (small-cell and large-cell neuroendocrine carcinomas) represent the most common neuroendocrine neoplasms of the lung; these are not discussed in detail in this Onkopedia guideline [7]. Due to lung cancer screening, which has been established as a reimbursed service in Germany since April 2026, a significant increase in the incidence of bronchopulmonary carcinoids is expected for the coming years.

The prognosis for NENs is largely determined by the degree of differentiation, tumor stage, and primary tumor location. Overall, GEP-NETs have a 5-year and 10-year survival rate of 83% and 76%, respectively [5].

Well-differentiated NETs generally have a favorable long-term prognosis. In population-based analyses, median overall survival (OS) is often >10 years. The 10-year OS rate for NETs is approximately 80% for non-metastatic cases and 40% for NETs with distant metastases, depending on the primary tumor and tumor stage [4, 5]. Some entities, such as localized type I appendix, rectal and gastric NETs, have an excellent long-term prognosis with virtually no restrictions.

NEC, on the other hand, are associated with a significantly poorer prognosis. The median OS for metastatic disease is usually 6-12 months, while the 5-year OS rate is less than 10-20% [7]. Accordingly, disease-specific mortality is significantly higher for NEC than for NETs.

The prognosis for pulmonary NETs is largely determined by the histological subtype and the tumor stage. Typical carcinoids have an excellent prognosis; the 5-year OS rate is >95% for localized disease and remains around 50-60% even for metastatic disease. Atypical carcinoids, on the other hand, exhibit more aggressive biological behavior, with a 5-year OS rate of 80-90% in the localized stage and 20-35% in cases of distant metastasis [4, 8]. Long-term data also confirm a 10-year OS rate of 82-95% for typical carcinoids and 31-67% for atypical carcinoids [4, 8].

Pancreatic NETs are predominantly sporadic; approximately 10-20% occur in the context of hereditary tumor syndromes, particularly MEN1 syndrome. Characteristic features include alterations in chromatin remodeling and telomere stability due to mutations in MEN1, DAXX, and ATRX, as well as changes in the mTOR signaling pathway, which contribute significantly to tumor initiation and progression. In contrast, pancreatic NECs typically exhibit inactivations of TP53 and RB1, as well as high genomic instability, suggesting a tumorigenesis independent of NETs [9, 10, 11].

The pathogenesis of gastrointestinal NETs varies depending on the primary tumor site. Small intestine NETs are characterized by a low mutation burden; recurrent chromosomal aberrations and epigenetic alterations appear to play a greater role than classic driver mutations. In contrast, gastrointestinal NECs frequently exhibit alterations in TP53, RB1, KRAS, and BRAF and often share a mutation profile similar to that of classic adenocarcinomas of the same location [12, 13, 14, 15].

The pathogenesis of pulmonary NETs differs fundamentally from that of poorly differentiated, high-grade pulmonary NECs. Recurrent genetic alterations primarily involve MEN1 as well as genes involved in chromatin remodeling (e.g., ARID1A, EIF1AX and members of the SWI/SNF complex), while mutations in classic oncogenic drivers such as KRAS, EGFR or ALK alterations are rarely detected [16, 17].

Compared to typical carcinoids (Ki-67 < 5%), atypical carcinoids exhibit a higher proliferation rate, greater chromosomal instability, and more frequent mutations in cell cycle regulation genes. However, molecular evidence does not support a transition to high-grade NECs. Rather, small-cell and large-cell NECs are considered biologically distinct entities characterized by near-universal inactivation of TP53 and RB1, a high tumor mutation burden (TMB), and pronounced genomic instability. These fundamental molecular differences are also reflected in the significantly more aggressive clinical course of pulmonary NECs compared to well-differentiated carcinoids [16, 17, 18].

Chromogranin A (CgA) is the most commonly measured circulating biomarker in well-differentiated NETs. It may correlate with the tumor mass, particularly in cases of metastasis or high tumor burden, and can be used in the individual patient’s course to supplement the assessment of treatment response [29, 30].

Interpreting increased CgA levels is complicated by numerous confounding factors. The most common causes of false-positive results include:

• Treatment with proton pump inhibitors (PPIs) (most common cause; discontinue treatment at least ≥2 weeks before testing)

• Chronic renal insufficiency

• Atrophic gastritis or pernicious anemia

• Hypergastrinemia

• Chronic liver disease

• Chronic inflammatory diseases

• Heart failure

• Other malignant diseases

An isolated increase in CgA levels should therefore never lead to a diagnosis of a NEN, but should always be interpreted within the clinical context.

Neuron-specific enolase (NSE) has only low sensitivity and specificity in well-differentiated NETs and is therefore not routinely recommended. Increased levels are more commonly found in highly proliferative NECs, particularly in SCLC and extrapulmonary NECs, but can also be influenced by numerous non-neoplastic causes. These include, in particular, hemolysis, neurological disorders, and other neuroendocrine or neuroectodermal tumors. The value of NSE therefore lies primarily in the supplementary assessment of disease progression in selected NECs and not in primary diagnosis [31].

Measurement of 5-hydroxyindoleacetic acid (5-HIAA) in a 24-hour urine collection is the established laboratory marker for suspected carcinoid syndrome and should be performed, in particular, in patients with flushing, secretory diarrhea, or suspected serotonin-producing small intestinal NETs. A one-time 5-HIAA test should also be performed in all patients with metastatic small intestinal NETs. Increased 5-HIAA levels correlate with serotonin production and are associated with the risk of carcinoid-related heart disease [32].

Potential confounding factors should be taken into account prior to the test. Serotonin-rich foods should be avoided for at least 48-72 hours before and during the collection period, including in particular:

• Bananas

• Pineapples

• Kiwis

• Avocados

• Plums

• Tomatoes

• Eggplants

• Walnuts

Various medications can also influence test results and should be taken into account - provided it is clinically justifiable. These include, among others, acetaminophen, levodopa, methyldopa, amphetamines, and serotonin-modulating medications. In addition, malabsorption syndromes, chronic diarrhea, or impaired kidney function can complicate the interpretation of results.

Alternatively, the measurement of 5-HIAA in plasma is becoming increasingly important, as it offers comparable diagnostic value and eliminates the need for a 24-hour urine collection. However, its availability is currently still limited, and the method has not yet been widely established [33].

Somatostatin analogs are an established antiproliferative therapy for metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Due to their good tolerability and favorable safety profile, they are the preferred first-line therapy for SSTR-positive G1 NETs as well as low-proliferative G2 NETs (up to 10% Ki-67) with low to moderate tumor burden and slow tumor growth. The objective tumor response rate is low at <5%; the therapeutic goal is primarily long-term disease control and delaying disease progression.

The antiproliferative efficacy of octreotide LAR was demonstrated in the PROMID study in treatment-naive patients with metastatic midgut NETs. This resulted in an extension of the median time to tumor progression from 6.0 to 14.3 months [60]. For lanreotide autogel, the CLARINET study demonstrated a significant prolongation of progression-free survival (PFS) compared with placebo in patients with SSTR-positive, non-functional enteropancreatic NETs with Ki-67 ≤10% [61]. In both studies, documented tumor progression at the time of treatment initiation was not a formal inclusion criterion, meaning that antiproliferative therapy can be initiated regardless of the progression status.

For patients with slow tumor progression on a standard dose of an SSA, dose escalation by shortening the administration interval may be considered. The CLARINET-FORTE study showed that intensifying treatment to lanreotide autogel 120 mg every 14 days following progression on the standard dose can lead to further disease control. The median PFS was 8.3 months for small intestinal NETs and 5.6 months for pancreatic NETs; the benefit was particularly pronounced in tumors with Ki-67 ≤10% [62]. Similar data on high-dose therapy were observed in the NETTER-1 study with octreotide LAR 60 mg every 4 weeks following disease progression while on the standard SSA dose, with a median PFS of 8.4 months in this group [59]. The NETTER-1 study primarily enrolled patients with small intestinal NETs. High-dose SSA therapy may therefore be considered as a bridging or sequential therapy for patients with low tumor activity or who are not suitable for PRRT or other systemic therapies.

Peptide receptor radionuclide therapy is an established systemic therapy for patients with progressive, well-differentiated, SSTR-positive NETs. A prerequisite is sufficient and, as far as possible, homogeneous SSTR expression across all tumor manifestations as demonstrated by functional imaging. Today, ¹⁷⁷Lu-DOTATATE or ¹⁷⁷Lu-edotreotide are used almost exclusively, as ¹⁷⁷Lu has a more favorable safety profile than ⁹⁰Y-labeled radiopharmaceuticals, particularly with regard to nephrotoxicity.

The phase III NETTER-1 trial established PRRT as the standard of care for progressive midgut NETs following pretreatment with SSA. Compared with high-dose octreotide LAR, ¹⁷⁷Lu-DOTATATE resulted in a significant prolongation of PFS (28.4 vs. 8.5 months; HR 0.21), a higher objective response rate (18% vs. 3%), and an improvement in health-related quality of life and hormone-related symptoms [57, 59].

The NETTER-2 study investigated the role of PRRT in first-line therapy. In patients with SSTR-positive GEP-NETs G2 and G3 (Ki-67 10–55%), ¹⁷⁷ Lu-DOTATATE plus octreotide LAR, compared with high-dose octreotide LAR, resulted in a significant prolongation of PFS and a higher objective response rate (mPFS 22.8 months; ORR 43%). In the updated analysis, 35% of the enrolled patients had a G3 NET; the median Ki-67 was 30%. The ORR was 51.2% for pan-NETs and 33.3% for gastrointestinal NETs. These data support the early use of PRRT in more proliferative, SSTR-positive GEP-NETs. In the EU, there is still no specific approval for first-line use; therefore, treatment should be administered following a multidisciplinary benefit-risk assessment. In contrast, the U.S. approval of ¹⁷⁷Lu-DOTATATE for SSTR-positive GEP-NET is not tied to a specific line of therapy [63].

The evidence for PRRT has also expanded significantly in pancreatic NETs. In the randomized phase II OCLURANDOM trial^{, (177)}Lu-DOTATATE achieved a 12-month PFS rate of approximately 80% in patients with progressive, SSTR-positive pancreatic NETs, thereby meeting the primary endpoint of the study. The median PFS was 20.7 months with PRRT and 11.0 months with sunitinib; however, due to the limited number of cases and the study design, the trial was not powered to demonstrate formal superiority of PRRT over sunitinib. Nearly 60% of patients had received prior chemotherapy, and approximately 50% had already received at least two lines of therapy [64].

The phase III COMPETE trial was the first to prospectively compare PRRT directly with targeted therapy. In patients with progressive G1/G2 GEP-NET, 177Lu-edotreotide resulted in a significant prolongation of progression-free survival compared with everolimus (23.9 vs. 14.1 months; HR 0.67) while exhibiting a more favorable safety profile. The study confirms the high efficacy of PRRT beyond midgut NETs (40% small bowel NETs, 60% pancreatic NETs) and supports its early use prior to targeted therapies, including in pancreatic NETs [65].

Treatment with ¹⁷⁷Lu-DOTATATE is generally well tolerated. Transient hematologic side effects and mild impairments in renal function frequently occur. Severe long-term complications, such as myelodysplastic syndrome or treatment-associated leukemia, are rare and have been observed in approximately 1-4% of patients in larger series; the risk may be higher following intensive alkylating pretreatment [66].

Several ongoing randomized trials will further define the role of PRRT in the coming years. The phase III COMPOSE trial (NCT04919226) is evaluating ¹⁷⁷lu-edotreotide in aggressive SSTR-positive G2 and G3 GEP-NETs (Ki-67 15-55%) compared with investigator-selected systemic therapy (CAPTEM, FOLFOX [see below], or everolimus). Since no uniform therapy has been established for this setting, one should not speak of a “best possible standard of care.” The results will contribute in particular to determining the treatment sequence for more proliferative GEP-NETs.

Everolimus is an oral inhibitor of the mammalian target of rapamycin (mTOR) and represents an established treatment option for progressive, well-differentiated G1/G2 GEP-NETs. Its antiproliferative effect is primarily based on disease stabilization; objective tumor remissions are rare and are observed in fewer than 10% of patients.

The efficacy of everolimus in pan-NETs has been demonstrated in several prospective studies. In the randomized phase III RADIANT-3 trial, everolimus resulted in a significant prolongation of PFS compared with placebo in patients with progressive, metastatic pan-NETs (11.0 vs. 4.6 months; HR 0.35 [67]). A large proportion of study participants had already received prior systemic therapy, particularly with SSA and/or chemotherapy. Everolimus is therefore an established treatment option for progressive pan-NET; the choice of treatment line depends on tumor dynamics, the need for remission, and prior treatments.

In the phase III RADIANT-4 trial, a significant PFS prolongation was also demonstrated in patients with non-functional gastrointestinal NETs (11.0 vs. 3.9 months; HR 0.48 [68]). Efficacy was consistent across gastrointestinal, pulmonary and other NETs.

In the COOPERATE-2 study, the combination of everolimus and pasireotide in pan-NET resulted in a higher objective response rate but did not lead to a significant prolongation of PFS (the primary endpoint); in addition, significant additional adverse effects occurred [69]. Routine use of this combination is therefore not recommended. However, more recent data, including those from the Japanese STARTER-NET study with everolimus plus lanreotide, suggest that the role of combination therapy with SSA has not yet been definitively established.

The optimal place of everolimus within the treatment sequence has changed based on recent randomized trials. The phase III COMPETE trial demonstrated significantly longer PFS in patients with progressive SSTR-positive GEP-NETs treated with ¹⁷⁷Lu-edotreotide compared to everolimus (23.9 vs. 14.1 months; HR 0.67 [65]).

The randomized SEQTOR trial compared, in patients with progressive pan-NET, the sequence of everolimus followed by STZ/5-FU (see below) with the reverse sequence of STZ/5-FU followed by everolimus. Chemotherapy was not shown to be superior to everolimus in terms of PFS; nor did either sequence demonstrate an advantage in terms of OS. The median PFS in the first-line setting was 19.4 months with everolimus and 22.7 months with STZ/5-FU. However, STZ/5-FU achieved a higher objective response rate (30.3% vs. 11.6%). Interpretation is limited by the fact that a significant proportion of the included patients, despite the requirement for disease progression, did not show progression and had previously received systemic antitumor therapy (40% received SSA). Therefore, chemotherapy is often preferred in cases of high tumor burden or when tumor remission is necessary, while everolimus can be used to stabilize the disease, particularly in cases of slowly progressive disease [70].

For functionally active NETs, everolimus is not approved for the treatment of hormonal syndromes. A clinical benefit may be observed in individual cases, particularly in metastatic insulinoma or in treatment-refractory hormonal syndromes.

The most common side effects include stomatitis, diarrhea, fatigue, infections, hyperglycemia, and non-infectious pneumonitis. Most side effects can be managed by reducing the dose or interrupting therapy. Due to the risk of severe infections, metabolic complications, and rare but serious pulmonary side effects, careful patient education and regular clinical and laboratory monitoring are required.

For selected G3 NETs, everolimus may be considered on a case-by-case basis; however, robust prospective data are not yet available.

Sunitinib is an oral multi-tyrosine kinase inhibitor (TKI) that inhibits, among others, VEGFR, PDGFR, KIT, FLT3, and RET signaling pathways and represents an established treatment option for progressive, well-differentiated pancreatic NETs (G1/G2). The antiproliferative effect is primarily due to inhibition of tumor angiogenesis and stabilization of tumor growth; objective tumor remissions are rarely observed. Approval is based on a randomized, placebo-controlled phase III trial in patients with advanced, unresectable or metastatic pancreatic NETs. With sunitinib (37.5 mg once daily as a continuous infusion), median PFS was significantly prolonged compared with placebo (11.4 vs. 5.5 months; HR 0.42). In addition, a higher objective response rate (9.3% vs. 0%) was observed, as well as a trend toward improved OS [71, 72, 73]. Sunitinib is therefore a standard treatment for progressive G1/G2 pancreatic NETs and can be used both before and after chemotherapy or everolimus. Outside the setting of pancreatic NETs, there are insufficient data to justify treatment with sunitinib. The most common side effects include diarrhea, nausea, fatigue, hypertension, hand-foot syndrome, mucositis, hypothyroidism, cytopenias and hair discoloration. Blood pressure, thyroid function, and laboratory parameters should be monitored regularly. Dose reductions or treatment interruptions are necessary in some patients but usually allow treatment to continue.

Cabozantinib is an oral multi-TKI with activity against MET, VEGFR2, AXL, RET, KIT, ROS1, and other signaling pathways. By simultaneously inhibiting multiple proangiogenic and tumor-specific signaling pathways, cabozantinib exhibits pronounced antiproliferative and antiangiogenic effects and represents an important treatment option for previously treated NETs. The approval is based on the randomized phase III CABINET trial, which enrolled patients with progressive, previously treated pancreatic and extrapancreatic NETs (50% GI-NET, 20% lung-NET, 16% CUP-NET). Both groups had received prior treatment, with a median of 2 prior therapies in the extrapancreatic NET cohort and 3 prior therapies in the pancreatic NET cohort.

In both independent study cohorts, cabozantinib resulted in a significant prolongation of PFS compared with placebo. For pancreatic NETs, the median PFS was 13.8 vs. 4.4 months (HR 0.23); for extrapancreatic NETs, it was 8.4 vs. 3.9 months (HR 0.40). In addition, higher objective response rates and sustained disease control were achieved [74]. A recent predefined subgroup analysis of the CABINET study examined for the first time the role of cabozantinib in well-differentiated G3 NETs (Ki-67 >20%). A total of 24 patients with pancreatic and extrapancreatic G3 NETs were evaluated. Cabozantinib prolonged median PFS compared with placebo from 3.0 to 7.9 months (HR 0.15; 95% CI 0.04–0.57). The objective response rate was 25% with cabozantinib compared with 0% with placebo [70]; the safety profile was consistent with the results of the overall study. Although the number of patients was limited, this analysis provides the first randomized evidence of the efficacy of a TKI in well-differentiated G3 NETs and supports the use of cabozantinib in this patient group as well [75]. Cabozantinib thus represents an important treatment option for progressive pancreatic and extrapancreatic NETs following at least one prior systemic therapy (excluding SSA). The most common side effects include diarrhea, fatigue, hypertension, mucositis, palmar-plantar erythrodysesthesia (hand-foot syndrome), weight loss, loss of appetite, proteinuria and laboratory abnormalities in liver function tests. Rare but potentially serious side effects include gastrointestinal perforations, fistula formation, bleeding and thromboembolic events. Close clinical and laboratory monitoring, as well as consistent management of side effects, are therefore required.

Systemic chemotherapy plays an important role, particularly in advanced pancreatic NETs and in GEP-NET G3. In contrast, response rates are low for well-differentiated non-pancreatic gastrointestinal NETs (G1/G2); routine chemotherapy is therefore not recommended. It may be considered on a case-by-case basis for cases with high tumor activity, high tumor burden, a Ki-67 score in the upper G2 range, or when rapid tumor reduction is required.

SSAs are the first-line therapy for controlling hormone-related symptoms in functionally active pulmonary NETs. Antiproliferative therapy with octreotide LAR or lanreotide may also be used in SSTR-positive, slowly progressive pulmonary NETs with low to moderate tumor burden. The evidence is based primarily on retrospective series, small prospective studies, and extrapolated data from GEP-NET studies [83]. In the SPINET study of pulmonary NETs, a median PFS of 16.6 months was observed with SSA therapy (21.9 months in typical carcinoids and 13.8 months in atypical carcinoids). In cases of significant tumor progression, high tumor burden, or when tumor reduction is required, SSA therapy alone is generally insufficient. Formally, there is no approval for SSA therapy in patients with pulmonary NETs for antiproliferative purposes. If hormonal symptoms such as carcinoid syndrome worsen, shortening the administration interval or administering additional short-acting octreotide may be considered, even if the disease is radiologically stable. Radiological progression while on standard-dose SSA, however, should prompt consideration of a more effective antiproliferative therapy.

Everolimus is an established therapy approved in the European Union for progressive, non-functioning, well-differentiated pulmonary NETs. This approval is based in particular on the phase III RADIANT-4 trial, in which everolimus significantly prolonged PFS compared with placebo in patients with non-functioning gastrointestinal and pulmonary NETs [68]. In the prespecified pulmonary NET subgroup, a significant reduction in the risk of progression was also observed. Everolimus is particularly suitable for radiologically progressive disease, cases without high remission pressure, and cases with insufficient or heterogeneous SSTR expression. The objective response rate is low (less than 5%); the primary treatment goal is disease stabilization. The randomized phase II LUNA trial demonstrated antiproliferative activity of everolimus in advanced pulmonary and thymic carcinoids. However, the combination with pasireotide did not result in a sufficiently demonstrated added benefit; therefore, routine combination of targeted agents with SSA outside of clinical trials is not recommended [84].

PRRT with ¹⁷⁷Lu-DOTATATE may be considered for progressive pulmonary NETs with high and homogeneous SSTR expression. Before starting therapy, an SSTR-PET/CT should be performed to ensure that all clinically relevant tumor manifestations exhibit sufficient receptor expression. In cases of higher tumor dynamics or discordant imaging, a supplementary FDG-PET/CT scan may be useful for detecting SSTR-negative, biologically aggressive tumor components. However, atypical carcinoids exhibit sufficient SSTR expression in only about 50% of cases. To date, no completed randomized phase III data are available for pulmonary NETs. Retrospective studies and prospective cohorts, however, demonstrate significant disease control and response rates, as well as frequently prolonged progression-free intervals [85, 86]. PRRT is therefore an important treatment option, particularly for progressive, SSTR-positive disease following SSA, everolimus, or chemotherapy. The ongoing randomized phase III LEVEL study ¹⁷⁷compares Lu-edotreotide directly with everolimus in advanced pulmonary and thymic NETs and aims to further define the role and optimal sequence of PRRT [87]. Until these data become available, the indication should be determined on a case-by-case basis by the NEN tumor board.

Temozolomide-based chemotherapy can be used for progressive pulmonary NETs, either as temozolomide monotherapy or in combination with capecitabine (CAPTEM). It is particularly indicated for atypical carcinoids, higher proliferation activity, rapid tumor progression, high tumor burden, or when objective tumor reduction is required. Prospective data are available, among other sources, from the phase II ATLANT study on the combination of lanreotide and temozolomide; in addition, there are smaller prospective and retrospective series. CAPTEM demonstrates relevant disease control and response rates [48, 82, 88].

Oxaliplatin-based combinations, primarily FOLFOX and, less commonly, GemOX, are also used for pulmonary NETs, with an ORR of 20% and a median PFS of 15 months [89]. Therapy with platinum plus etoposide is generally not used for pulmonary NETs. For patients with atypical carcinoid tumors, very rapid progression, high proliferative activity, or particularly aggressive morphological behavior, this therapy may be considered on a case-by-case basis; however, a repeat pathological differentiation from NEC should be performed beforehand.

Antiangiogenic TKIs have been shown to have antiproliferative effects in extrapancreatic NETs. However, the evidence specifically for pulmonary NETs is limited. Their use should be guided by approval status, prior therapies, and an individual benefit-risk assessment. In the CABINET study, cabozantinib prolonged PFS in previously treated patients with extrapancreatic NETs. Since this cohort also included patients with pulmonary NETs (median PFS 8.2 months), cabozantinib is an approved treatment option following prior systemic therapy [74].

For SSTR-positive, slowly progressive disease, treatment with SSA is an initial option. In the event of significant progression, everolimus, PRRT, chemotherapy, and, in later lines, cabozantinib may be considered. Everolimus and cabozantinib are approved therapies; PRRT is off-label for pulmonary NETs. Whether PRRT is preferable to everolimus remains unclear and is being investigated in the LEVEL study. Therefore, a rigid treatment sequence has not been validated: PRRT can be initiated early in cases of high, homogeneous SSTR expression, whereas everolimus is particularly suitable for cases with low or heterogeneous receptor expression. In cases of high tumor burden, rapid progression, or when tumor reduction is required, temozolomide- or oxaliplatin-based chemotherapy should be considered at an early stage. The choice should be based on tumor growth, SSTR and, if applicable, FDG-PET findings, histology, proliferation activity, the need for remission, organ function, comorbidities and patient preference.

The standard first-line therapy is a combination of carboplatin and etoposide or, alternatively, cisplatin and etoposide, regardless of the primary gastroenteropancreatic tumor location or whether the morphology is small-cell or large-cell. A clear efficacy advantage of cisplatin over carboplatin has not been demonstrated; however, carboplatin is often preferred due to its generally better tolerability. Objective response rates are approximately 30-50%, and median OS is predominantly between 7 and 12 months [37].

In a randomized phase III trial, cisplatin plus irinotecan was not superior to cisplatin plus etoposide and is not the preferred standard of care in Europe. There is also currently insufficient evidence to support the use of CAPTEM or FOLFIRINOX as standard first-line therapy for GEP-NEC. Unlike in SCLC, the initial combination of platinum-based chemotherapy with an immune checkpoint inhibitor (ICI) cannot currently be recommended for GEP-NEC outside of clinical trials.

If there is a response and adequate tolerability, four to six cycles (often six cycles) are typically administered. Due to the significant proportion of primarily refractory cases, an initial follow-up imaging examination should be performed as early as 8-12 weeks.

Following progression on platinum-based first-line therapy, there is no established standard of care based on phase III trials. In the absence of a molecularly stratified treatment option, FOLFIRI represents the most extensively studied second-line chemotherapy. In the randomized phase II PRODIGE 41-BEVANEC trial, the addition of bevacizumab did not result in an improvement in OS. With FOLFIRI alone, an objective response rate of 18%, a median PFS of 3.5 months, and a median OS of 8.9 months were achieved. FOLFIRI can therefore be used as the preferred second-line option in patients with adequate general condition [90].

Alternatives include FOLFOX or CAPOX. The evidence is more limited and is based primarily on retrospective analyses. Temozolomide-based therapy, particularly CAPTEM, may be considered in selected cases; however, for morphologically confirmed NEC, the evidence base is significantly less robust than for well-differentiated G3 NETs.

In the randomized phase II NET-02 trial, the combination of nanoliposomal irinotecan, 5-FU, and folinic acid met the prespecified endpoint of the 6-month PFS rate and represents another possible subsequent-line option. Docetaxel did not meet this endpoint. A clear efficacy advantage over conventional FOLFIRI has not been demonstrated [91].

For patients who respond well to first-line therapy and have had a sufficiently long platinum-free interval of 6 months, a re-challenge with carboplatin or cisplatin plus etoposide may be considered. In retrospective series, objective remissions and disease stabilization were again observed; the decision should be based on the duration and depth of the initial response, general condition and cumulative toxicity.

Non-biomarker-selected monotherapy with PD-1 or PD-L1 inhibitors shows only low overall response rates in GEP-NEC and does not represent a general standard of care. The routine combination of immunotherapy with platinum/etoposide is also currently not sufficiently supported by evidence.

However, if dMMR/MSI-H or a high tumor mutation burden is detected, tumor-agnostic immunotherapy may be used. dMMR/MSI-H is found in approximately 5% of GEP-NEC cases, and a TMB ≥10 mutations/megabase in about 7%. For such molecularly defined tumors, PD-1 inhibitors such as pembrolizumab or, in the case of dMMR, dostarlimab are particularly suitable, depending on approval status, prior therapy, and primary tumor location. Use is guided by the respective tumor-agnostic approval or may require individual cost coverage. The decision should be made by the molecular tumor board.

Due to the limited efficacy of conventional follow-up therapies, broad DNA-based, and, if applicable, RNA-based, molecular profiling should be performed as early as possible in cases of advanced GEP-NEC. The results should be evaluated by the molecular tumor board.

BRAF mutations are observed in approximately 7-20% of GEP-NEC cases; in colorectal NEC, they are significantly more common in some series. BRAF V600E is of particular clinical relevance. For non-colorectal BRAF V600E-mutated NEC, combined BRAF/MEK inhibition, for example, with dabrafenib and trametinib, may be considered. In cases with a primary colorectal location, due to EGFR-mediated resistance, a combination of encorafenib and cetuximab is preferred, in accordance with the treatment strategies for BRAF V600E-mutated colorectal carcinoma. To date, the evidence specifically for NEC is based primarily on case series and molecularly stratified cohorts.

Depending on the primary tumor site, KRAS mutations are found in approximately 8-30% of GEP-NEC cases. KRAS status should therefore be determined as part of a comprehensive molecular profiling panel. For the majority of KRAS variants, there is currently no established NEC-specific therapy. For the very rare, theoretically treatable alterations seen in NEC, such as KRAS G12C, treatment should be considered based on recommendations from the molecular tumor board and, preferably, within clinical trials. Regarding the newer pan-RAS or specific selective KRAS inhibitors, there are currently no reliable data outside of pancreatic cancer and, in particular, for NEC.

The panel should also include rare but potentially relevant alterations such as NTRK, RET or ALK fusions; HER2 amplification; BRCA1/2 or other homologous recombination defects; and other tumor-specific alterations that can be targeted. The clinical relevance of broad genomic and transcriptomic profiling in advanced NENs is supported by the current analysis from the NCT/DKTK-MASTER program [92]. Treatment is guided by evidence, approval status and expected clinical benefit.

DLL3 is expressed in a high proportion of NECs and represents a promising therapeutic target. Detection is performed immunohistochemically; a uniform, generally validated definition of the required expression level for GEP-NEC does not yet exist. DLL3 immunohistochemistry should be considered, particularly in cases of advanced, previously treated GEP-NEC, if enrollment in a DLL3-targeted clinical trial is possible.

The DLL3/CD3 bispecific T-cell engager obrixtamig (BI 764532) demonstrated clinical activity in previous studies in DLL3-expressing NEC. In a preselected cohort of extrapulmonary NEC cases with high DLL3 expression, preliminary results reported an objective response rate of approximately 40%, a disease control rate of 67%, and a median duration of response of 7.9 months [93]. The published phase I data thus confirm the clinical activity of obrixtamig in DLL3-expressing NEC; there is currently no regular approval for GEP-NEC.

Tarlatamab is also a DLL3/CD3 bispecific T-cell engager and is approved in Germany for previously treated SCLC [94]. There is currently no approval or sufficiently robust evidence for GEP-NEC. Its use in DLL3-positive GEP-NEC should therefore be limited to clinical trials [95]. Adverse effects such as cytokine release syndrome and neurological toxicity require treatment at centers with appropriate expertise.

Malnutrition is common in patients with advanced NETs and can be caused by reduced food intake, chronic diarrhea, maldigestion, malabsorption, or tumor-induced hypermetabolism. Regular weight monitoring and standardized screening for malnutrition should be part of every follow-up visit. The goal of nutritional therapy is to maintain body weight, muscle mass, and quality of life. Restrictive diets without established evidence, including ketogenic or so-called “cancer diets”, are not recommended.

In general, a personalized, balanced mixed diet is recommended. Several smaller meals spread throughout the day are often better tolerated than a few large meals. If symptoms persist, a food diary can be helpful in identifying foods that an individual cannot tolerate. A general elimination diet, on the other hand, is not advisable.

In addition to inhibiting hormonal secretion, SSA also suppress exocrine pancreatic function and gallbladder motility. This can lead to steatorrhea, bloating, abdominal discomfort and deficiencies in fat-soluble vitamins. Therefore, when diarrhea develops for the first time while on SSA, the diagnosis should not be limited to tumor progression but should also consider exocrine pancreatic insufficiency.

If maldigestion is clinically suspected, fecal elastase levels should be measured, and, if appropriate, a trial of pancreatic enzyme replacement therapy should be initiated. The enzymes should be taken with all main meals and snacks and dosed according to the fat content of the meal. If steatorrhea persists despite adequate enzyme therapy, the dosage, timing of administration, and, if necessary, additional acid suppression should be reviewed. In addition, lipid-soluble vitamins (A, D, E, and K) should be monitored regularly and supplemented as needed.

Following partial or total pancreatectomy, many patients develop exocrine pancreatic insufficiency, and following total pancreatectomy, they additionally develop insulin-dependent diabetes mellitus. Lifelong enzyme replacement therapy is indicated in cases of clinical or laboratory-confirmed exocrine insufficiency.

The diet should be rich in energy and protein. Fat restriction is generally not necessary with sufficient enzyme replacement. Rather, the enzyme dose should be adjusted to the fat content of the meal. In addition, vitamin B12 (following duodenopancreatectomy), iron, folic acid, calcium, vitamin D and other micronutrients should be monitored regularly.

Patients who have undergone ileal or extensive small bowel resections often develop bile acid malabsorption, accelerated intestinal transit, and malabsorption of vitamin B12 and lipid-soluble vitamins. In cases of major ileal resections, short bowel syndrome may also develop.

The diet should be tailored to the individual. Smaller, more frequent meals are usually better tolerated. In cases of bile acid loss syndrome, treatment with bile acid binders (such as colestyramine) may be beneficial. Vitamin B12 levels should be monitored regularly, and in cases of terminal ileal resection, parenteral supplementation is usually required. Foods rich in oxalate should be consumed only in moderate amounts, particularly following extensive ileal resections, due to the increased risk of enteric hyperoxaluria and nephrolithiasis.

In carcinoid syndrome, diarrhea, accelerated intestinal transit, and hormone-mediated metabolic changes can contribute to weight loss and malnutrition. Adequate control of carcinoid syndrome through SSA is the most important supportive measure.

Some patients report an increase in symptoms after consuming foods rich in histamine or biogenic amines. These include, among others, aged cheeses, smoked or fermented meats and sausages, alcohol (especially red wine), sauerkraut and certain fish products. Since individual differences exist, a general list of prohibited foods should be avoided. Instead, it is recommended to identify personal triggers using a food diary and to avoid them specifically.

In cases of pronounced serotonin excess, increased tryptophan consumption can lead to a niacin (vitamin B3) deficiency, potentially progressing to pellagra. If a deficiency is clinically suspected or confirmed, appropriate supplementation should be provided. Regular monitoring of nutritional status and micronutrient levels is particularly advisable for patients with chronic diarrhea or weight loss. Those affected can also find further important information on nutrition in the patient brochure from the patient advocate network (https://www.netzwerk-net.de/wp-content/uploads/2024/06/net_ernaehrungsbroschuere-2024).

In patients with chronic diarrhea, exocrine pancreatic insufficiency, or following gastrointestinal resections, levels of vitamin B12, vitamin D, lipid-soluble vitamins (A, E, K), iron, folic acid, zinc, selenium, and, if necessary, magnesium should be measured regularly. Supplementation should be administered only in cases of proven or clinically probable deficiency. Routine administration of high-dose vitamins or trace elements in the absence of a confirmed deficiency is not recommended.

Bone metastases are not uncommon in advanced neuroendocrine neoplasms and are being diagnosed more frequently due to the increasing use of sensitive functional imaging, particularly SSTR-PET/CT. In a meta-analysis, their prevalence was approximately 18%; in a recent large SSTR-PET/CT series of patients with small intestinal and pancreatic NETs, bone metastases were detected in 18.4% of cases and were significantly more common in small intestinal NETs than in pancreatic NETs. In a German single-center series, bone metastases were found in 12.6% of all PNET patients; approximately 42% of the affected patients had bone pain and 12% had pathological fractures. Bone metastases predominantly affect the axial skeleton and are often multifocal [96, 97].

Treatment should be guided by symptoms, the number and location of the metastases, the risk of fracture or compression and the systemic tumor status. In the case of an asymptomatic, isolated bone metastasis without a risk of fracture or impending neurological complications, particularly in slowly proliferating NETs, active surveillance (“watch and wait”) with follow-up imaging is justifiable. This is also in line with the recommendation of the German AWMF NET guidelines.

In cases of multiple bone metastases, particularly osteolytic ones, bisphosphonates, especially zoledronic acid, or denosumab may be used to prevent skeletal-related events. However, there are no NET-specific randomized trials on the benefits of these agents; therefore, the indication and duration of therapy should be determined on an individual basis. Before and during antiresorptive therapy, particular attention should be paid to renal function, calcium and vitamin D status, and the risk of osteonecrosis of the jaw. Even in the absence of bone metastases, attention should be paid to bone health in NET patients. A recent study revealed frequent vitamin D deficiency, osteopenia, and impaired trabecular bone structure [98].

In cases of painful bone metastases, impending fracture, or local compression, local radiotherapy is an effective treatment option and should be initiated early. In cases of SSTR-positive multifocal bone metastases, PRRT may also be part of the systemic treatment plan; however, for isolated painful lesions that are amenable to radiation, local radiotherapy should be preferred [99].

Surgical management should be considered in cases of impending or manifest pathological fractures, instability of weight-bearing skeletal segments, vertebral metastases with instability or neurological compromise, as well as in selected solitary or oligometastatic lesions. Unlike many aggressive metastatic tumors, patients with well-differentiated NETs can live for many years despite distant metastases. Therefore, in cases of mechanically significant bone metastases, the approach should not be exclusively palliative; in suitable patients, long-term stable surgical reconstruction or stabilization may be appropriate. The decision should be made on a multidisciplinary basis, involving orthopedics/trauma surgery or spinal surgery and radiotherapy. The current references underscore the clinical relevance of bone manifestations even in lung NETs [100].

Even after R0 resection, there remains a long-term risk of recurrence in GEP-NET. Late recurrences can occur even more than 10 years later, particularly in pancreatic and small intestinal NETs as well as in typical bronchial carcinoids. Follow-up should therefore be long-term and frequently extend beyond 10 years if there is a significant risk of recurrence. In young patients, those with lymph node-positive disease, higher tumor grading, or other risk factors, lifelong clinical follow-up may be warranted.

Following R0 resection, follow-up should be tailored to the primary tumor and risk profile. For G1 pan-NETs without additional risk factors, the first imaging follow-up can be performed after approximately 6 months. For G2 pan-NETs, particularly higher-grade G2 tumors, lymph node-positive disease, or initial liver metastases following complete resection, postoperative staging should be performed as early as approximately 3 months. For G3 NETs, initial follow-up every 3 months is appropriate. If no evidence of tumor is found over time, the intervals can be extended as the patient progresses.

For pan-NETs, due to the higher and biologically more heterogeneous risk of recurrence compared to small intestinal NETs, more frequent risk-adapted follow-up is recommended: for G2 or the presence of additional risk factors, initial imaging after approximately 3 months; for low risk/G1, after approximately 6 months; followed by imaging every 6 months for the first 2-3 years and annually thereafter. Small-intestinal NETs often exhibit a different, generally more indolent biology; following a postoperative baseline examination after approximately 6 months, intervals of 6-12 months may be selected for low-risk patients. Follow-up should be long-term.

Following local or endoscopic resection of small gastric, duodenal, or rectal NETs, organ-specific follow-up protocols apply. For very small, completely resected tumors without risk factors, follow-up can be reduced. For example, no tumor-specific follow-up is required for an R0-resected appendix NET smaller than 1 cm without risk factors.

GEP-NEC carries a high risk of early relapses and distant metastases. After completion of curative therapy, clinical and imaging follow-up should be performed approximately every 3 months for the first two years. In the third year, intervals of 3-6 months may be chosen; thereafter, if the patient remains tumor-free, follow-up should be conducted every 6-12 months. Follow-up should continue for at least five years; it may be extended based on individual risk.

The standard procedure is a contrast-enhanced CT scan of the thorax, abdomen, and pelvis. A liver MRI is indicated in cases of unclear or liver-dominant findings. An SSTR-PET/CT does not have routine diagnostic value in poorly differentiated NEC due to frequently low or heterogeneous receptor expression. An FDG-PET/CT may be used as a supplementary tool in cases of curative treatment, unclear CT findings, or suspicion of an undetected relapse. However, FDG-PET/CT should not be performed for routine follow-up. For highly proliferative PNETs, the German AWMF guideline [26] recommends initial imaging follow-up at least every three months.

During systemic therapy, the first radiological follow-up should take place after two to three treatment cycles, typically after 6-9 weeks. Subsequent follow-ups should be performed approximately every 2-3 months. Previous imaging is required in cases of clinical deterioration or suspected primary refractoriness.

Follow-up monitoring is primarily performed using CT scans of the thorax, abdomen, and pelvis. MRI may be used as a supplement in cases of liver, CNS, or bone manifestations. FDG-PET/CT may be helpful in cases of discrepant findings or prior to a potentially local- ablative or curative intervention; however, it is not required for every routine follow-up.

Typical and atypical pulmonary carcinoids can recur even after long disease-free intervals. Follow-up should therefore be long-term and, particularly in cases of atypical carcinoid, lymph node-positive disease, high mitotic activity, or necrosis, should be continued for at least ten years, and often for life.

Following curative resection, baseline imaging should be performed postoperatively depending on histology, TNM classification, and R-status (see Figure 6).

For typical carcinoids without risk factors, longer intervals - often annual - may be sufficient following the initial postoperative follow-up. For atypical carcinoids, particularly in cases of lymph node-positive disease or other risk factors, follow-up should be more frequent; in the first few years, check-ups approximately every 3-6 months are generally appropriate. The intervals should subsequently be extended depending on histology, TNM stage and the course of the disease to date.

Due to the need for long-term follow-up, radiation-sparing approaches should be considered for pulmonary NETs, such as MRI of the mediastinum and abdomen in combination with a low-dose chest CT. An SSTR-PET/CT is not routinely required for all patients after one year. It should be used in particular if the tumor was already SSTR-positive preoperatively, in cases of unclear conventional findings, suspected clinical recurrence, or if the result influences a treatment decision. For atypical carcinoids that were SSTR-negative preoperatively, routine SSTR-PET/CT during follow-up is not recommended.

Routine bronchoscopy is not required after peripheral R0 resection. It may be appropriate on a case-by-case basis following bronchoplastic procedures (e.g., after endobronchial ablation of an endobronchial lesion in typical carcinoid tumors), in cases of a central tumor location, or when endobronchial relapse is suspected.

For metastatic pulmonary NETs, the first radiological follow-up should generally be performed approximately 8-12 weeks after initiation of a new active systemic therapy. This applies not only to chemotherapy but also to everolimus, cabozantinib, and other antiproliferative therapies. In cases of stable, slow-growing disease, the intervals can subsequently be extended to 3-6 months; intervals of 6-12 months are only considered for disease that has been stable for many years under minimally active therapy or observation. For atypical carcinoids with a higher growth rate, more frequent follow-up is required.

The baseline examination consists of a CT scan of the thorax including the upper abdomen or a CT scan of the thorax, abdomen, and pelvis. In cases of liver-dominant disease, a liver MRI should be used as a supplement or alternative. SSTR-PET/CT is relevant for SSTR-positive pulmonary NETs, particularly in cases of suspected progression, unclear findings, and prior to PRRT. In cases of high proliferation, rapid progression, or discordant SSTR imaging, an additional FDG-PET/CT may be useful for detecting aggressive tumor components.