What we have learnt from the past – would treament decicions for GEP- NET patients differ between 2012 to 2016 by the new recommendations in 2022?

doi:10.21203/rs.3.rs-1758790/v1

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Research Article

What we have learnt from the past – would treament decicions for GEP- NET patients differ between 2012 to 2016 by the new recommendations in 2022?

https://doi.org/10.21203/rs.3.rs-1758790/v1

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Journal Publication

published 13 Feb, 2023

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Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of tumors with a broad range of local and systemic treatment options. Still a lack of data regarding treatment sequences exists. The aim of this study was to analyze outcomes in GEP-NETs depending on stage and treatment steps and compare our treatment decisions to the latest treatment recommendations of ESMO 2020 for GEP-NETs.

Methods: Patients were included in this retrospective single-center analysis from 2012 - 2016. Patient outcomes and treatment lines were analyzed by uni- and multivariable analysis.

Results: Overall, we identified 256 GEP-NETs , mostly staged at advaced stage (62%) and located in small intestine tract and pancreatic gland. Survial depended on stage, grade, primary site and duration of response for the early systemic treatment. On average patients underwent 2.6 different treatment modalities, mostly depending on stage and higher tumor grade. Surgery was performed either early but as well in advanced stages, ususally followed by Somatostatine-Antagonist modalities. According to these findings, we formed a suggested treatment algorithm for advanced GEP-NETs, which does not differ from the latest treatment recommendation by ESMO guidelines for GEP-NETs.

Conclusion: The results of this project may define GEP-NET patients’ selection for upcoming clinical prosepctive studies.

GEP-NET

treatment sequences

SSA

overall survival

progression free survival

real-life population

Neuroendocrine tumors (NETs) represent a rare and heterogeneous spectrum of tumors, originating from the embryonal neural crest. Gastroenteropancreatic (GEP)-NETs represent about 60–70% of all NETs and occur at an age-adjusted incidence of 5.25 cases per 100'000 people.^{1, 2, 3} The annual report by SwissNET showed an increase by 26% between 2014 and 2015 and a stable increase of new NETs in Switzerland around 20% in 2020.^{4, 5} Although not fully understood, the raising incidence may also reflect better diagnostic tools or earlier detection, e.g. during appendectomy.⁶ Apart from the primary tumor site, histological characteristics define and predict biological behaviour and prognosis of GEP-NETs.^{7, 8, 9, 10}

According to the European Neuroendocrine Tumor Society (ENETS)/ World Health Organization (WHO) grading system, NET were until 2017 grouped into three grades according to tumor proliferation markers, including the Ki67 index and mitotic count (10 per high- power field [HPF]). This classification has moved forward in 2017, where the WHO grading system was updated and the group of NECs was subdivided into well-differentiated G3 NET (Ki-67 < 55%) and poorly differentiated NEC (Ki-67 index ≥ 55%).^{8, 11, 12} Recently, another update of the WHO classification in 2019, highlighted a new terminology of mixed neuroendocrine-non-neuroendocrine tumors (MiNEN), formally classified as MANEC as well more detailled classifications of NET G3 and a terminology of appendiceal goblet cell carcinoma/carcinoid.¹³

A precise staging is critical as over 50% of GEP-NETs initially manifest as advanced or metastatic stages. In addition to metastasis in lymph nodes, NET spreads predominantly into liver, peritoneum, bone and lung.¹⁴ Different staging systems include the TNM staging systems of ENETS (mostly used in Europe) or American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC, mostly used in the United States of America [USA]).^{15, 16}

Treatment decisions for localized and advanced stages are made by a consensus of experts among a NET dedicated MTB based on guidelines such as ENETS or ESMO for GEP-NETs.^{11, 17, 18, 19, 20, 21, 22, 23}

Curative treatment of GEP-NETs is only possible by surgical or endoscopic resection. This also refers to patients with limited disease or with limited regional disease or oligometastatic situation, whereas palliative surgery or ablation for symptom relief may also be considered in selected cases.^{24, 25, 26} Over the last decades, treatment of metastatic NET has dramatically evolved, providing novel strategies. For example targeting the somatostatin-receptor by somatostatin analogues (SSA) is one of the best evaluated options.³ Nowadays, long-acting Octreotide, Lanreotide are used to either control carcinoid symptoms by decreasing hormone and peptide secretion or control tumor growth and progression. ^{27, 28} These agents are mostly used for functional GEP-NETs or for management of well-differentiated proliferative tumors with expression of somatostatin receptors (SSTR).²⁹ Other essential systemic therapies include chemotherapy combinations (streptozotocin (STZ) and 5-fluorouracil (5-FU) or temozolomide and capecitabine in G2, or platin combination with etoposide in G3 NETs. Recently peptide receptor radionucleotide therapy (PRRT), using radiolabeled somatostatin analogues for targeting SSTR enriched the treatment modlity in second or further line.³⁰ Plus, targeting the Mechanistic Target of Rapamycin (mTOR, [Everolimus]) pathway or tyrosine kinase inhibitors (TKIs, [Sunitinib]) in advanced pancreas-NETs (p-NETs) as well bevacizumab or interferon-alpha as back-up options has put more variety in the further line treatment. ³

All these options are presented in the current guidelines of ENETS, ESMO or NCCN.^{11, 17, 18, 19, 20, 21, 22, 23, 31} According to grading, staging and the origin of GEP-NET, these guidelines reflect a clear recommendation for first line treatment. But no preference as well sequence recommendation is clearly stated for GEP-NETs. Of note, a head-to-head comparisions of active treatments are lacking and current treatment options have been approved by placebo controlled trials.^{30, 32, 33, 34, 35, 36} Therein real-world data are highly valuable to contribute survival and treatment data especially for a rare disease.^{37, 17, 20}

Due to this wide range of systemic treatment possibilities, it is eminently important to discuss a GEP-NETs situation among an interdisciplinary setting (if available at an certified ENETS Center of Excellence [CoE].^{17, 38} Therein, combined or sequential treatment options should be taken into consideration and is of utmost interest to improve survival. ^{3, 11}

In this project we aimed to analyse differences in treatment and survival outcome of GEP-NET patients in accordance to their course of treatments.

Between 2012 and 2016, GEP-NET pateint’s diagnosis were screened, treated or evaluated at the ENETS Center Zurich, Switzerland, including a follow-up until December 2018. {Appendix A1} All patients’ data was retrospectively extracted from routinely documented medical history. At the USZ the patient data including diagnostics and therapies were completely documented by electronic health record (EHR) and managed by a vendor EHR system (KISIM, CISTEC AG, Zurich, Switzerland). Missing medical reports of patients with lacking medical history files in our EHR system were requested at last attending physician. Patients’ and disease characteristics, such as kind of tumor and metastases, stages, histologic grades and dates of progression; diagnostics, dates and kinds of different treatment lines, as well as dates of follow-up and death were documented in chart review. Date of progression, including locoregional and distant metastatic progression, was reviewed in radiologists reports or physician notes. Date of death was matched with Swiss registry of deaths.

Disease Characteristics: GEP-NETs were classified according to TNM staging system of ENETS. Stage I and II were combined in localized disease, Stage III named as regional and Stage IV as distant disease or both of them combined in advanced disease.¹¹ We used ENETS/WHO 2010 grading system for classification into different grades according to proliferation index Ki-67 and mitotic count (10 HPF). {Appendix A2}

Treatment characteristics and follow-up data can be found in the supplementary material of this manuscript. {Appendix A3}
Primary endpoint and outcome: For final analysis, we calculated PFS for each treatment as primary endpoint and for secondary endpoints we analysed overall survival (OS) and time to progression (TTP), all of them in months. {Appendix A4} Patients who had received at least one therapy line were included in statistical analysis of treatment characteristics and PFS. PFS was calculated for implemented treatments and their sequences.

{Appendix A5}

Statistics: All analyses were performed in IBM SPSS Statistics, version 24 (IBM Corp., Armonk, NY, USA). Descriptive statistics were used to calculate proportions and frequencies for categorical variables, means, medians and 95% confidence intervals (CI’s) for continuous variables. We used Kaplan Meier curves to evaluate OS, TTP and PFS rates. We compared these by log-rank test and used Kaplan Meier estimator as well as Cox regression to compare survival rates between different sites of localization, grades or stages at first diagnosis and treatment patterns.³² {Appendix A6} The level of significance was set at p < 0.05. No multiple testing correction was adjusted to the p-values.

Ethics: An application for this study was submitted to Swiss Ethics for human research and was adopted by Swiss Ethics Committees in 2016. {Appendix A7}

Table 1 highlights the characteristic of our patient population including patients’, disease characteristics, diagnostics and treatment characteristics.

3.1. Patients’ Characteristics

328 NET patients between the age of 8 and 86 years (at first diagnosis) were screened, 256 patients had a GEP-NET and were included in analysis. Only 26% were cancer care patients and underwent diagnostics, therapy and follow-up at USZ. 24% went through specific therapy at our institution, 41% were sent for a specific diagnostic and 9% were just presented at the multidisciplinary cancer conference for second opinion. The average follow-up time was 77 months (range, 0.5–291 months). {Appendix A8} 14 patients suffered from a secondary malignancy during time of observation. An overview of the patient’s characteristics is summarized in Fig. 1.

3.2. Disease Characteristics

A detailed overview of subgroups by origin and grading of our GEP-NET/NEC population is depicted in Fig. 1. 55% patients presented with NET-associated symptoms. Interestingly, the majority (58%) were symptomatic only at first diagnosis, while in 3% of cases, the symptoms were exclusively caused by metastases. We detected 10% of NEC G3 and G1 and G2 were equally presented with 29–31% in our population. The majority of primary was detected at the pancreas (35%) and small intestine (36%), whereas one fourth of our GEP-NETs have been detected at a localized stage and 40% at metastatic stage. Within metastatic stage liver involvement (46%) and bone (18%) as well peritoneal metastasis (11%) were the most common detected regions.

Patients with p-NET, NET of small intestine and of unknown primary site were commonly diagnosed in advanced stage and suffered significantly more from distant metastases than patients with NET of other localizations (p < 0.001). {Appendix A9}

3.3. Treatment Characteristics

244 patients underwent at least one therapy line and all patients had been discussed at least once at our multidisciplinary tumor board (MTB). In our study population a patient received averagely 2.6 different treatment sequences (range 1 to maximum of 13 therapies). The amount of therapy sequences increased significantly with higher stages (p < 0.001) and higher grades ( p = 0.004) at first diagnosis. A Sankey diagram (Fig. 3) showes different treatment sequences.

{Appendix A10}

Surgery was in general the most abundant therapy with a total of 233 surgical operations in 172 (67%) patients and by far the most performed first-line therapy. 53% of all surgeries were reported as R0 resected. Advanced GEP-NETs underwent a higher amount of surgical operations than patients with locoregional disease, while these underwent surgery more frequently as a solitary treatment.

30% of GEP-NETs underwent therapy with SSA, mostly received during first-line setting. {Appendix A11}

Relatively few patients received targeted therapies like mTOR (everolimus [9%]) or tyrosine kinase inhibitors (sunitinib,[3%]). These treatments were only used in advanced disease, higher grading of G2 and mostly as third-line or subsequent therapy.

PRRT for GEP-NETs has been commonly used in our population. 22% patients were treated at least once with PRRT. 44 (77%) of them suffered from distant disease at time of first diagnosis. {Appendix A12}

16% of patients were treated with chemotherapy and p-NET as well NET of unknown origin received more often classical chemotherapy than well-differentiated extra-pancreatic NETs in their medical history. 18 patients were treated more than once with at least one of these agents (either CAPTEM, Carboplatin/Cisplatin + Etoposid or STZ + 5FU), whereas 22% resulted in first or second line treatment. CAPTEM was mostly used in G2 NETs. The combination of carbo- or cisplatin with etoposide was mostly used in G3 NETs/NEC or as a subsequent treatment in G2 NETs. Chemotherapy with streptozotocin/5-FU was only implemented in G2 NETs.

3.4 Secondary Endpoints and Outcome

Median OS of all patients was 181 months (95% CI, 106–256 months).

The OS curves differed significantly between different sites of GEP-NET p < 0.001). The longest median OS was observed in p-NET patients (251 months; 95% CI, 104–399 months), the shortest median OS in patients with NET of unknown primary site (78.5 months; 95% CI, 1–156 months), (HR = 0.40; 95% CI, 0.20–0.80; p = 0.009).

The OS distributions also differed between stages (p < 0.001) and different grades (p = 0.001) at first diagnosis (Figs. 1 and 2).

While in localized disease (Stage II) the median OS was 144 months (95% CI, 116–172 months), in distant disease (Stage IV) we observed a median OS of 109 months (95% CI, 77–142 months), (HR = 0.31; 95% CI, 0.12–0.79; p = 0.01).

In G1 GEP-NETs, median OS was 139 months (95% CI, 126–152 months), in moderately differentiated disease (G2) we observed a median OS of 114 months (95% CI, 77–153 months), while in G3 GEP-NETs or -NECs median OS was with 40 months (95% CI, 7–73 months) shorter (G1 versus G3; HR = 0.27; 95% CI, 0.13–0.54; p < 0.001; G2 versus G3; HR = 0.45; 95% CI, 0.23–0.88; p = 0.02). {Appendix A13}

Median TTP of all patients was 84 months (95% CI, 52–116 months). TTP curves differed also between different sites of GEP-NET (log-rank test, p < 0.001), with an extended median TTP from p-NETs of 107 months (95% CI, 64–150 months), while for a NET of unknown primary site resulted in the shortest median TTP of 34 months (95% CI, 0–73 months) was observed (HR = 0.33; 95% CI, 0.19–0.59; p < 0.001).

TTP differed between different grades and stages at time of first diagnosis (both, log-rank test, p < 0.001). We observed a significantly longer median TTP for Stage III-GEP-NETs with 109 months (95% CI, 72–146 months) than for Stage IV-GEP-NETs of 23 months (95% CI, 14–31 months; HR = 0.27; 95% CI, 0.17–0.44; p < 0.001). {Appendix A14}

3.5 Influence of Treatments and their Sequences to Progression free Survival

Patients who underwent systemic treatment or were treated with SSA showed negative outcome (shorter PFS) after a following operative intervention (systemic treatment; HR = 3.44; 95% CI, 1.85–6.38; p < 0.001; SSA; HR = 3.41; 95% CI, 2.09–5.56; p < 0.001).

SSA-related PFS was shorter if patients were additionally treated with systemic treatment (HR = 2.05; 95% CI, 1.12–3.78; p = 0.02). PFS of PRRT was shorter if patients underwent systemic treatment during time of disease (HR = 2.02; 95% CI, 1.02–4.01; p = 0.04).

Patients undergoing non-surgical interventions like radio-frequency ablation (RFA), selective internal radiotherapy (SIRT), radiotherapy or transarterial(chemo)-embolization (TA(C)E) had a shorter PFS after systemic treatments (HR = 3.35; 95% CI, 1.27–8.84; p = 0.02).

In stage IV, we found a positive effect of PFS after treatment with SSA (HR = 0.45; 95% CI, 0.21–0.97; p = 0.04) and systemic treatment (HR, 0.51; 95% CI, 0.26–0.99; p = 0.047) if patients underwent prior surgery or endoscopic resection.

In G2 NETs, treatment with SSA showed a longer PFS if patients were also treated with a non-surgical intervention (RFA, SIRT, radiotherapy or TA(C)E), (HR, 0.33; 95% CI, 0.12–0.97; p = 0.04). On the other hand, in G1 NETs we found shorter PFS of patients undergoing this treatment sequence (HR, 3.52; 95% CI, 1.05–11.8; p = 0.04).

In patients with G1 and G2 NETs, shorter PFS after operative interventions was shown, if patients were treated with prior PRRT (G1 NETs; HR = 3.06; 95% CI, 1.19–7.87; p = 0.02; G2 NETs; HR = 3.12; 95% CI, 1.17–8.29; p = 0.02).

In this real-life study at an ENETS CoE, we succeeded in evaluating efficacy of treatment (PFS) according to primary site, stage and grade of tumor.^{3, 43} To the best of our knowledge, this is the first analysis in this field with focus on long treatment sequences of GEP-NETs as well as on subanalyses of different types of GEP-NETs and multi-sequence treatments. There have been other studies that also focused on treatment patterns in GEP-NETs, but focused on fewer treatments and did not differ between various stages, grades or sites of neoplasm, which is relevant for daily clinical practice.^{39, 44}

Most studies exploring this rare and heterogeneous tumors are placebo-controlled intervention studies exploring a single treatment. The comparison of different treatment options in this real-life population study therefore is a valuable addition and helps clinical decision making.^{45, 46, 27}

In our center there is not only a single team responsible for GEP-NETs but rather these are separated into several departments with a dedicated ENETS responsible specialist (e.g. oncologist, gastroenterologist, surgeon, nuclear medicine, endocrinologist). Due to this, screening of patients, choice of diagnostics and also treatment lines may differ between departments. Thus, up to now, only limited and heterogeneous data of GEP-NETs for ENETS CoEs exist.

In our data collection, frequency and survival rates of different primary sites differed remarkably compared to well-known prevalence and outcome of GEP-NETs.⁶ In our cohort, rectal NETs (4%) and NETs of colon (3%) are underrepresented in comparison to generally known epidemiological data in US population (26–34% rectum, 16–18% colon), whereas pancreatic NETs with 35% are overrepresented (12% in US population).^{8, 37, 47} One of the reasons might be, that our data was collected in a ENETS CoE, respectively a tertiary hospital. Localized colorectal NETs, which were diagnosed and resected entirely by endoscopy, are rarely treated at our center. On the contrary, if colorectal NETs were notified at our center, they were refered due advanced stage for treatment making decisions. On the contrary, p-NETs even in early stages are referred to ENETS CoE in Switzerland as a multidisciplinary team with an experienced surgeon is mandatorily needed.

Against expectations, the longest median OS of our population was seen in p-NET patients, despite the fact that p-NET patients were overrepresented in the reported NET-related deaths. It is not completely clear, why p-NETs in our study achieved a much better outcome than other primary sites, in comparison to other literature. ⁶

One possible explanation is related to a relatively higher presentation of localized disease (Stage I and II, 31%) in p-NET within our cohort in comparison to other primary sites (16% in small intestine NET, 18% in rectal NET, 0% in NET of unknown primary site, Table 2).

Table 2

Different treatments (all subsequent lines) according to initial stage (ENETS) of disease.
Kind of treatment	Stage I	Stage II	Stage III	Stage IV	Unknown	Total
Surgery	19	29	52	61	11	172
SSA (Octreotide, Lanreotide, Pasireotide)	0	4	16	54	3	77
PRRT	1	2	9	44	1	57
Chemotherapy	1	2	6	31	0	40
Endoscopic resection	11	2	4	1	11	29
SIRT	0	2	3	19	1	25
Everolimus	0	1	2	20	0	23
Watch and wait	4	2	1	4	7	18
Radiotherapy	1	0	1	11	0	13
Sunitinib	0	1	0	6	0	7
RFA	1	1	0	5	0	7
TACE	1	0	0	6	0	7
Notes: 12 patients without any documented treatment were excluded. Multiple treatment options per patient are possible.
Abbreviations: ENETS, European Neuroendocrine Tumor Society; PRRT, peptide receptor radionucleotide therapy; RFA, radiofrequency ablation; SIRT, selective internal radiation therapy; SSA, somatostatin analogues; TA(C)E, transarterial (chemo-) embolization.
Abbreviations: CI, confidence interval; ENETS, European Neuroendocrine Tumor Society; OS, overall survival.
Abbreviations: CI, confidence interval; GEP, gastroenteropancreatic; NET, neuroendocrine tumor; OS, overall survival.

Furthermore, p-NETs and small intestine NET (s-NET) were most frequently encountered as cancer care patients who underwent diagnostic, treatment and periodic follow-ups at our center, which led to more complete data.

These two subgroups accounted for 81% of all cancer care patients in our study, while all other primary sites (appendix, stomach, rectum, colon/cecum, gallbladder and unknown primary site) made up the remaining 19% of cancer care patients.

These may be the main reasons why the results of our survival analysis could be biased.

We focused especially on well- (G1) and moderately differentiated (G2) p-NETs and s-NETs, since these represented the largest subgroup of our population (46%). Most of these patients underwent surgery as first treatment line, followed by consecutive surgical intervention or treatment with SSA as second-line therapy. As third therapy line, PRRT was the most used treatment, followed by sunitinib as the second most common used agent. We observed a widespread diversity of treatments in fourth-line. Against our expectation SSA was the most frequently used treatment in fourth-line, followed by PRRT and chemotherapy. Prior treatment with SSA or PRRT didn’t show any effect on PFS after systemic treatment in G2 p-NET or s-NET (log-rank test, p = 0.96 for SSA; log-rank test, p = 0.50 for PRRT) against recommendations in common literature.^{3, 11, 24, 40}

In the subgroup of G1 and G2 p-NETs (in total 21% of our population), we investigated also that surgery was the most abundant treatment as first-line therapy. Followed by other surgical intervention or treatment with SSA as second-line therapy. Sunitinib was most frequently used as a third-line therapy. As fourth-line, chemotherapy or PRRT were first choices of treatment.

In 2017, WHO classification got updated and therefore NECs are now divided into well-differentiated G3 NET with a Ki-67 index < 55% and in poorly differentiated NEC with a higher Ki-67 index of ≥ 55%.^{8, 11, 12} But we cannot make clear conclusion about subdivision in G3 NET and NEC of WHO classification system 2017, since pathologists at our center used at time of data collection the earlier WHO definition of 2010 to characterize these neoplasm.^{40, 40, 48} As well we could not translate our data to the updated WHO 2019 classification, wherein mixed types as MiNEN are also presented as an new entity (formerly classified as MANEC).¹³ And we did not have the pathologic features from different molecular profiles on high grade GEP-NEN and GEP-NEC, which have nowadays an impact for systemic treatment choices as platinum and etoposide based as well for capecitabine and temozolomide based regimens. ⁴⁹ Therein, recent updated guidelines as ESMO 2020 for GEP-NET differs categories of NET G3 (Ki.67 < 50%)and NEC G3 as well G1 or G1 GEP-NETs including recommendations of first line as well subsequent systemic treatment lines with multiple or equal options in second lines.¹⁷ Even for these recent guidelines we have to underline, that the updated pathologic WHO classification have been indirectly translated to the treatment recommendation of G1-G2 GEP-NETs as well for the subsequent treatment recommendation for NET G3. Especially the multiple options, depicted in 2nd line treatment recommendation by ESMO 2020 GEP-NETs are highlighting that a head-to-head comparison of the active agents is lacking including a lack of biomarker driven recommendation except SSTR2 positivity and the grading of the neuroendocrine neoplasia. Again, only limited data exist for real-world evidence in terms of benefits for subsequent treatment lines and this limitation is even scarce for local treatments as surgery, RFA or SIRT in the metastatic setting. This fact also reflects the low evidence level of recommendation within the latest guidelines for GEP-NETs.^{17, 31} On the contrary, in highly selected cases the choice for the right timing of liver surgery in oligometastatic GEP-NETs improves survival and the liver-directed strategy should be discussed among an expert team in NET and liver surgery, mostly placed at ENETS CoE.^{26, 41, 42}

Surgical intervention is generally mentioned and investigated in loco-regional disease for treatment option or only for NETs of advanced stage if more than 70–90% of tumor burden can be resected.^{2, 11, 25, 19, 35} Our study showed more surgical interventions in advanced setting than in localized disease in contrary to our expectation. The overrepresentation of surgical interventions in this subgroup is most probably based on metastatic resection, liver surgery combined with liver directed therapy (SIRT, RFA, TA(C)E) or urgent surgery, due to the fact that advanced disease commonly makes local complications like intestinal obstruction or bleeding. During collection of data, we did not distinguish between different types of surgical intervention; this may bias the results. As well, that with our position of an ENETS CoE a majority of surgical candidates in the advanced setting were transmitted by regional hospital for this indication.

However, we were able to demonstrate a benefit of treatment-adjusted PFS (especially for SSA and systemic therapies) in stage IV if patients underwent prior surgical intervention, against expectations and in contrast to other literature.⁴⁰ These results are very encouraging for the role of surgery in advanced GEP-NET and should be evaluated in future clinical trials.

Patients who were treated with SSA, surgery or PRRT suffered from a shorter PFS, if they underwent prior systemic treatment. An explanation for this observation may be that patients, who were treated with systemic therapies in an early therapy phase mostly suffered from an aggressive disease, which was spread at time of diagnosis. For these patients, treatment strategies are difficult and consist in efforts to delay progression of disease instead of cure.

Outcome (PFS) of patients who underwent systemic therapy or treatment with SSA was shorter after a following operative intervention. One hypothesis of the reduced survival of surgery followed by systemic treatment may be the fact that these patients suffered from distant disease and underwent surgery to resect metastases or to solve complications as ileus within the metastatic setting. Since no distinction was made between different types of surgery when collecting this retrospective data, this assumption cannot be statistically confirmed and must be examined in future prospective studies.

In advanced disease, we investigated a benefit of PFS after treatment with SSA and systemic treatment, if patients underwent prior surgery or endoscopic resection. Patients with initial operative treatment in distant disease underwent probably a cytoreductive treatment or were generally in a high performance status before undergoing surgical interventions. This concludes in longer PFS after subsequent treatments.

In G2 NETs, treatment with SSA showed longer PFS if patients were also treated with a non-surgical intervention (RFA, SIRT, Radiotherapy or TA(C)E). Whereas in G1 NETs a shorter PFS was shown, when they underwent this treatment sequence. One can assume that patients with the initial diagnosis of a well-differentiated (G1) GEP-NET, who underwent non-surgical intervention during time of their disease, suffered of a more aggressive progression with a generally worse outcome.

In our study, G1 and G2 NETs showed shorter PFS after surgical interventions if they were treated with prior PRRT. But independently from surgical interventions, PRRT may affect outcome in a positive way if using it in an early phase of treatment sequence. This is currently investigated in clinical trials.^{41, 42}

Given the character of this retrospective study with multiple potential biases, care must be taken to apply these results for clinical practice.⁵⁰

4.1 Suggested Treatment Algorithm and comparison to recent updates international guidelines of GEP-NETs

The present study with supplied data of the ENETS CoE at USZ consists of one of the largest collection of real-life patients’ information in Switzerland, even though only limited and heterogeneous data of GEP-NET patients (esp. outpatients) exist.⁵¹

We demonstrated that it is eminently important to choose individualized treatment with a multimodal therapeutic approach in patients suffering from a GEP-NET, based on stage and grade of disease, symptoms and performance status.¹¹

According to the findings based on our results, we suggest following treatment algorithm (Fig. 4) for advanced GEP-NETs.^{3, 11, 24, 35, 40} Interestingly, our recommendation in Fig. 4 for our patient collective of a period from 2012–2016 is in line with the recent recommendation by ESMO and NCCN for GEP-NETs.^{17, 31} Again, predictive biomarkers for GEP-NETs are quite limited and remain still to origin of the primary, grading and SSTR2 positivity. For sure, whole genome sequencing, as the study by Scarpa et al. revealed highly interesting data for pancreatic NET for diagnosis and mostly for prediction. Some analysis even directed to the prediction of mTOR pathway or MGMT status in favor for CAPTEM. But this has to be proven within clinical trial and these biomarkers have been again highly discussed among the annual ENETS conference in 2022.^{43, 44} Thus, even for a retrospective analysis 5 to 7 years ago. These treatment recommendation are in line with the latest guideline recommendation and patients in 2022 won’t have been treated differently. Another fact to this treatment scenarios compared to the latest guidelines still is the lack of new treatment options within the last years. Promising results of the DUNE trial for G3 NET and NEC reflected a trend in survival for the checkpoint blockade combination durvalumab and tremilimumab and new TKI as surufatinib in the SANET and SANET-p trial demonstrated significant improvements in GEP-NETs with advanced staged. But these therapies did not receive an EMA or SwissMedic approvement so far.^{45, 46, 47}

Surgical intervention is, regarding to survival rates (PFS) in our population, a favourable initial treatment in any stage of disease and should be considered as cytoreductive treatment also in advanced disease to reduce symptoms and to improve better effect of following systemic therapies.²⁵ In patients with advanced GEP-NET, resection as first-line treatment should only be considered, if over 80% of tumor burden can be safely resected. ^{11, 35} Well- or moderately differentiated GEP-NETs show a higher expression of SSTR, which is used for both diagnostic and therapy options.³ For this reason SSA is primary choice of first-line treatment but only in well-differentiated GEP-NET, favourable due to its less toxic profile and high tolerance.^{11, 39} If disease relapses, PRRT is considered as second-line treatment, which also makes use of a high expression of SSTR.³ mTOR or tyrosine kinase inhibitors (in our cohort Everolimus or Sunitinib) alone or in combination with SSA are considered the best third-line treatment. Fourth-line treatment consists of a chemotherapeutic approach with temozolomide in combination with capecitabine. Patients suffering from a G2 GEP-NET can be treated with chemotherapy with Streptozotocin and 5-FU alone or in combination with PRRT as second-line, if first-line treatment with mTOR or tyrosine kinase inhibitors alone, or in combination with SSA or PRRT has failed.³ As third-line therapy, another chemotherapeutic approach with temozolomide and capecitabine is considered. As fourth-line treatment, we recommend a platinum-based chemotherapy like carbo- or cisplatin in combination with etoposide.

In high-grade GEP-NETs (G3 or -NECs), the only suggested treatment with evidence of efficacy is chemotherapy. Subdivided into well-differentiated G3 NETs and poorly differentiated NECs according to WHO classification 2017, different chemotherapeutic agents are preferred. G3 GEP-NETs preferably are treated with temozolomide in combination with capecitabine as first choice and carbo- or cisplatin in combination with etoposide as second choice, while in NECs first choice consists in the latter. The only potential alternative treatment of NECs consists of a systemic chemotherapy based on oxaliplatin, irinotecan or 5-FU.^{3, 40} Interestingly, our suggestion are in line with most recent treatment recommendation for personalized treatment approaches in G3 NEN and G3 NEC.⁵²

4.2 Strength and Limitation of the Study

Although USZ was at the time of study analysis the only certified ENETS CoE in Switzerland, the cohort of this study contains of a relatively small study population that induces limited explanatory power in statistical analyses. Nevertheless, in the present study a great overview of all patients’ disease and treatment characteristics, as well as survival rates at our center over the last years was shown. Due to this, it is now possible to compare this data collection of GEP-NETs at USZ with those of other international ENETS CoE within the planned registry of the ENETS group in the future.

The main limitation of this study is the retrospective nature, especially regarding the comparison of PFS after deferent treatments.⁵⁰ Further, data of our patients was collected within clinical routine, which may cause additional biases and delimitates the explanatory power of our results.

Thus, we lack of information for all completed treatment lines or transformation into higher grade in progression of disease, which resulted in an incomplete statement about treatment-decisions in our population.^{39, 44}

A detailed statement of further minor limitation are placed at the appendix of study. {Appendix A15}

Based on our data, the best survival for a specific treatment sequence cannot be defined, since an insufficient number of patients received identical treatment sequences in this relatively small cohort. Above-noted treatment algorithm has been matched with recommendations of other studies.^{3, 11, 24, 35, 40}

We identified a unique real-life cohort of patients with GEP-NETs at our ENETS CoE. To the best of our knowledge, this is the first analysis in this field with focus on long treatment sequences of GEP-NET patients as well as on subanalysis by different types of GEP-NET and multi-sequence treatments. In this analysis we illustrated survival (PFS) depending on implemented therapies.

We demonstrated that surgery, as initial and only curative treatment, is favourable regarding to survival rates. Cytoreductive surgery should be also considered for patients with advanced disease to reduce symptoms and to improve the effect of following systemic therapies.^{11, 25} However, tumor burden should be > 80% resectable.^{11, 35}

Treatment with SSA is still the primary choice of first-line therapy in well-differentiated GEP-NETs (G1). PRRT gained importance as an alternative or combination option to other treatments in low (G1) or intermediate grade (G2) GEP-NETs and may affect outcome in a positive way if using it in an early phase of treatment sequence.^{41, 42} Inhibitors of mTOR or tyrosine kinase (in this cohort everolimus or sunitinib) alone or in combination with SSA are considered the best third-line treatment in G1 NETs or in first-line therapy in G2 NETs, also in combination with PRRT. Despite all these emerging treatments, we are still reliant upon systemic and cytostatic chemotherapy for treating high-grade GEP-NETs (G3 or -NECs).

With this study we expect to build a foundation for future investigation and for developing future prospective and randomized studies of treatment sequences in a large GEP-NET cohort to finally define guidelines to ensure these patients the best therapy and outcome.

Ethics approval and consent to participate: This retrospective study involving data from human participants was conducted in accordance with the ethical standards of the national research committee and with the 1964 Declaration of Helsinki or comparable ethical standards. The study design was approved by the Cantonal Ethics Committeeof Zurich (BASEC-Nr.2016-01575).

Informed consent was obtained from all patients involved in the study.

Consent for publication: not applicable

Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests: The authors declare no conflict of interest.

Funding: This IIT study was granted by IPSEN (unrestricted IIT grant). Funding did not have an impact to study results or outcome.

Authors contributions: Conceptualization, Dr. med. A. R. Siebenhüner and PD Dr. med. Th. Winder; methodology, Dr. med. R. Stiefel and Dr. med. A. R. Siebenhüner; software, Dr. med. R.Stiefel; validation, Dr. med. A. R. Siebenhüner, Prof. Dr. med. K. Lehmann and PD Dr. med. Th. Winder; formal analysis, Dr. med. R. Stiefel; investigation, Dr. med. R. Stiefel; resources, Dr. med. R. Stiefel and Dr. med. A. R. Siebenhüner; data curation, Dr. med. R. Stiefel; writing—original draft preparation, Dr. med. R.Stiefel; writing—review and editing, Dr. med. A. R. Siebenhüner, Prof. Dr. med. K. Lehmann and PD Dr. med. Th. Winder; visualization, Dr. med. R. Stiefel, Dr. med. Alexander Siebenhüner, Prof. Dr. med. K. Lehmann and PD Dr. med. Th. Winder; supervision, Dr. med. Alexander Siebenhüner, Prof. Dr. med. K. Lehmann; project administration, Dr. med. A.R. Siebenhüner. All authors have read and agreed to the published version of the manuscript.

Review and Editing: This article was reviewed by all Co-Authors.

Acknowledgments: I would like to express my gratitude to the following people: Alexander R. Siebenhüner, my supervisor and mentor, for his support and patience during time of investigation and writing. Thomas Winder for the helpful adjustments. The team of the Comprehensive Cancer Center, especially Aleksandra Aleksandrowicz, for helping me to collect patients’ data. Ramona Wechsler for statistical advices and support. Matthias Storz, Oliver Büchi, Timo Hegnauer and Marcel Jaggy for the adjustments, helping with Excel charts, SPSS calculations and drawing of diagrams.

Finally, I wish to thank all patients included in this study for providing their data for study research. This work was supported by University Hospital of Zurich, specifically the Clinic of Oncology and Haematology.

Rossi RE, Ciafardini C, Sciola V, Conte D, Massironi S. Chromogranin A in the Follow-up of Gastroenteropancreatic Neuroendocrine Neoplasms. Pancreas. 2018;47(10):1249–1255. doi:10.1097/MPA.0000000000001184
Kos-Kudła B, Čwikła J, Ruchała M, et al. Current treatment options for gastroenteropancreatic neuroendocrine tumors with a focus on the role of lanreotide. Wspolczesna Onkol. 2017;21(2):115–122. doi:10.5114/wo.2017.68619
Öberg K. Neuroendocrine tumors of the digestive tract: Impact of new classifications and new agents on therapeutic approaches. Curr Opin Oncol. 2012;24(4):433–440. doi:10.1097/CCO.0b013e328353d7ba
Oncology P. Database Report 2015. 2016.
Kollar A, Bütikofer L, Ochsenbein A, Stettler C, Trepp R. Treatment sequence in patients with neuroendocrine tumours: a nationwide multicentre, observational analysis of the Swiss neuroendocrine tumour registry. Swiss Med Wkly. 2020;150(January):w20176. doi:10.4414/smw.2020.20176
Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3(10):1335–1342. doi:10.1001/jamaoncol.2017.0589
Huguet I, Grossman AB, O’Toole D. Changes in the Epidemiology of Neuroendocrine Tumours. Neuroendocrinology. 2016;104(2):105–111. doi:10.1159/000441897
Kim JY, Hong SM. Recent updates on neuroendocrine tumors from the gastrointestinal and pancreatobiliary tracts. Arch Pathol Lab Med. 2016;140(5):437–448. doi:10.5858/arpa.2015-0314-RA
Pape UF, Jann H, Müller-Nordhorn J, et al. Prognostic relevance of a novel TNM classification system for upper gastroenteropancreatic neuroendocrine tumors. Cancer. 2008;113(2):256–265. doi:10.1002/cncr.23549
Hochwald SN, Zee S, Conlon KC, et al. Prognostic factors in pancreatic endocrine neoplasms: An analysis of 136 cases with a proposal for low-grade and intermediate-grade groups. J Clin Oncol. 2002;20(11):2633–2642. doi:10.1200/JCO.2002.10.030
Öberg K, Knigge U, Kwekkeboom D, Perren A. Neuroendocrine gastro-entero-pancreatic tumors: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23(SUPPL. 7). doi:10.1093/annonc/mds295
Kim JY, Hong SM, Ro JY. Recent updates on grading and classification of neuroendocrine tumors. Ann Diagn Pathol. 2017;29:11–16. doi:10.1016/j.anndiagpath.2017.04.005
Assarzadegan N, Montgomery E. What is new in the 2019 world health organization (WHO) classification of tumors of the digestive system: Review of selected updates on neuroendocrine neoplasms, appendiceal tumors, and molecular testing. Arch Pathol Lab Med. 2021;145(6):664–677. doi:10.5858/arpa.2019-0665-RA
Kung CH, Ou JL, Chen BC, Lin JC. Gastrointestinal neuroendocrine tumors. J Intern Med Taiwan. 2018;29(4):217–229. doi:10.1093/annonc/mdq290
Öberg K. Medical Therapy of Gastrointestinal Neuroendocrine Tumors. Visc Med. 2017;33(5):352–356. doi:10.1159/000475831
Cavalcanti MS, Gönen M, Klimstra DS. The ENETS/WHO grading system for neuroendocrine neoplasms of the gastroenteropancreatic system: a review of the current state, limitations and proposals for modifications. Int J Endocr Oncol. 2016;3(3):203–219. doi:10.2217/ije-2016-0006
Pavel M, Öberg K, Falconi M, et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(7):844–860. doi:10.1016/j.annonc.2020.03.304
Kaltsas G, Caplin M, Davies P, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Pre- A nd Perioperative Therapy in Patients with Neuroendocrine Tumors. Neuroendocrinology. 2017;105(3):245–254. doi:10.1159/000461583
Partelli S, Maurizi A, Tamburrino D, et al. GEP-NETS update: A review on surgery of gastro-entero-pancreatic neuroendocrine tumors. Eur J Endocrinol. 2014;171(4):R153-R162. doi:10.1530/EJE-14-0173
Pavel M, Valle JW, Eriksson B, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasms: Systemic Therapy-Biotherapy and Novel Targeted Agents. Neuroendocrinology. 2017;105(3):266–280. doi:10.1159/000471880
Garcia-Carbonero R, Rinke A, Valle JW, Fazio N, Caplin M, Gorbounova V, O Connor J, Eriksson B, Sorbye H, Kulke M, Chen J, Falkerby J, Costa F, de Herder W, Lombard-Bohas C PMACC participants. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasms. Systemic Therapy 2: Chemotherapy. Neuroendocrinology. 2017;105(3):281. doi:10.1159/000473892
Hicks RJ, Kwekkeboom DJ, Krenning E, Bodei L, Grozinsky-Glasberg S, Arnold R, Borbath I, Cwikla J, Toumpanakis C, Kaltsas G, Davies P, Hörsch D, Tiensuu Janson E RJACC participants. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasia: Peptide Receptor Radionuclide Therapy with Radiolabeled Somatostatin Analogues. Neuroendocrinology. 2017;105(3):295. doi:10.1159/000475526
Knigge U, Capdevila J, Bartsch DK, Baudin E, Falkerby J, Kianmanesh R, Kos-Kudla B, Niederle B, Nieveen van Dijkum E, O’Toole D, Pascher A, Reed N, Sundin A VMACCPACC participants. E. NETS Consensus Recommendations for the Standards of Care in Neuroendocrine Neoplasms: Follow-Up and Documentation. Neuroendocrinology. 2017;105(3):310. doi:10.1159/000458155
Uri I, Avniel-Polak S, Gross DJ, Grozinsky-Glasberg S. Update in the Therapy of Advanced Neuroendocrine Tumors. Curr Treat Options Oncol. 2017;18(12). doi:10.1007/s11864-017-0514-9
Knigge U, Hansen CP. Surgery for GEP-NETs. Best Pract Res Clin Gastroenterol. 2012;26(6):819–831. doi:10.1016/j.bpg.2012.12.005
Siebenhüner AR, Langheinrich M, Friemel J, Schaefer N, Eshmuminov D, Lehmann K. Orchestrating Treatment Modalities in Metastatic Pancreatic Neuroendocrine Tumors — Need for a Conductor. 2022:1–17.
Caplin ME, Pavel M, Ćwikła JB, et al. Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: The CLARINET open-label extension study. Endocr Relat Cancer. 2016;23(3):191–199. doi:10.1530/ERC-15-0490
Stueven AK, Kayser A, Wetz C, et al. Somatostatin analogues in the treatment of neuroendocrine tumors: Past, present and future. Int J Mol Sci. 2019;20(12). doi:10.3390/ijms20123049
Castaño JP, Sundin A, Maecke HR, et al. Gastrointestinal neuroendocrine tumors (NETs): New diagnostic and therapeutic challenges. Cancer Metastasis Rev. 2014;33(1):353–359. doi:10.1007/s10555-013-9465-1
Strosberg JR, Caplin ME, Kunz PL, et al. 177Lu-Dotatate plus long-acting octreotide versus high–dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021;22(12):1752–1763. doi:10.1016/S1470-2045(21)00572-6
NCCN Guidelines for Neuroendocrine and Adrenal Tumors. 2021.
Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): A randomised, placebo-controlled, phase 3 study. Lancet. 2011;378(9808):2005–2012. doi:10.1016/S0140-6736(11)61742-X
Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, Tomasek J, Raderer M, Lahner H, Voi M, Pacaud LB, Rouyrre N, Sachs C, Valle JW, Fave GD, Van Cutsem E, Tesselaar M, Shimada Y, Oh DY, Strosberg J, Kulke MH PM. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016;387(10022). doi:10.1016/S0140-6736(15)00817-X
Fine RL, Gulati AP, Krantz BA, et al. Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: The Pancreas Center at Columbia University experience. Cancer Chemother Pharmacol. 2013;71(3):663–670. doi:10.1007/s00280-012-2055-z
Eric Raymond, M.D., Ph.D., Laetitia Dahan, M.D., Ph.D., Jean-Luc Raoul, M.D., Ph.D., Yung-Jue Bang, M.D., Ivan Borbath, M.D., Ph.D., Catherine Lombard-Bohas, M.D., Juan Valle, M.D., Peter Metrakos, M.D., C.M., Denis Smith, M.D., Aaron Vinik, M.D., Ph.D., MD, Pascal Hammel, M.D., Ph.D., Bertram Wiedenmann, M.D., Ph.D., Eric Van Cutsem, M.D., Ph.D., Shem Patyna, Ph.D., Dongrui Ray Lu, M.Sc., Carolyn Blanckmeister, Ph.D., Richard Chao, M.D., and Philippe Ruszniewski MD. Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors. N Engl J Med. 2011;365:687–696.
Clewemar Antonodimitrakis P, Sundin A, Wassberg C, Granberg D, Skogseid B, Eriksson B. Streptozocin and 5-Fluorouracil for the Treatment of Pancreatic Neuroendocrine Tumors: Efficacy, Prognostic Factors and Toxicity. Neuroendocrinology. 2016;103(3–4):345–353. doi:10.1159/000439086
Shah MH, Goldner WS, Halfdanarson TR, et al. Neuroendocrine and adrenal tumors, version 2.2018 featured updates to the nccn guidelines. JNCCN J Natl Compr Cancer Netw. 2018;16(6):693–702. doi:10.6004/jnccn.2018.0056
Krug S, Damm M, Garbe J, et al. Finding the appropriate therapeutic strategy in patients with neuroendocrine tumors of the pancreas: Guideline recommendations meet the clinical reality. J Clin Med. 2021;10(14). doi:10.3390/jcm10143023
Lurie RH, Cancer C, Group A, et al. Real-World Treatment Patterns and Clinical Outcomes in Advanced Gastrointestinal Neuroendocrine Tumors (GI NET): A Multicenter Retrospective Chart Review Study. 2019:1–10. doi:10.1634/theoncologist.2018-0519
Heetfeld M, Chougnet CN, Olsen IH, et al. Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasm. Endocr Relat Cancer. 2015;22:657–664. doi:10.1530/ERC-15-0119
Clift AK, Kidd M, Bodei L, Toumpanakis C, Baum RP, Oberg K, Modlin IM FA. Neuroendocrine Neoplasms of the Small Bowel and Pancreas. Neuroendocrinology. 2020;110(6):444. doi:10.1159/000503721
Frilling A, Modlin IM, Kidd M, Russell C, Breitenstein S, Salem R, Kwekkeboom D, Lau WY, Klersy C, Vilgrain V, Davidson B, Siegler M, Caplin M, Solcia E SRWG on NLM. Recommendations for management of patients with neuroendocrine liver metastases. Lancet Oncol. 2014;15(1):e8-2. doi:10.1016/S1470-2045(13)70362-0
Scarpa A, Chang DK, Nones K, et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature. 2017;543(7643):65–71. doi:10.1038/nature21063
ENETS Conference Programme 2022. 2022.
Hernando J, Manzano JL, Teule A, et al. DUNE trial. Ann Oncol. 2021;(32 (suppl_5)). doi:S906-S920. 10.1016
Xu J, Shen L, Zhou Z, Li J, Bai C, Chi Y, Li Z, Xu N, Li E, Liu T, Bai Y, Yuan Y, Li X, Wang X, Chen J, Ying J, Yu X, Qin S, Yuan X, Zhang T, Deng Y, Xiu D, Cheng Y, Tao M, Jia R, Wang W, Li J, Fan S, Peng M SW. Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(11):150. doi:10.1016/S1470-2045(20)30496-4.
Xu J, Shen L, Bai C, Wang W, Li J, Yu X, Li Z, Li E, Yuan X, Chi Y, Yin Y, Lou W, Xu N, Bai Y, Zhang T, Xiu D, Wang X, Yuan Y, Chen J, Qin S, Jia R, Lu M, Cheng Y, Zhou Z, Li J, He J SW. Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;1489–1499. doi:10.1016/S1470-2045(20)30493-9

Tables 1 and 2 are available in the Supplementary Files section.

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What we have learnt from the past – would treament decicions for GEP- NET patients differ between 2012 to 2016 by the new recommendations in 2022?

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1. Introduction

2. Materials And Methods

3. Results

3.1. Patients’ Characteristics

3.2. Disease Characteristics

3.3. Treatment Characteristics

3.4 Secondary Endpoints and Outcome

3.5 Influence of Treatments and their Sequences to Progression free Survival

4. Discussion

4.1 Suggested Treatment Algorithm and comparison to recent updates international guidelines of GEP-NETs

4.2 Strength and Limitation of the Study

5. Conclusions

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Supplementary Files

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