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. 2022 May 31;14(11):2718.
doi: 10.3390/cancers14112718.

Treatment Approaches and Outcome of Patients with Neuroendocrine Neoplasia Grade 3 in German Real-World Clinical Practice

Simone Luecke  1 , Christian Fottner  2 , Harald Lahner  3 , Henning Jann  4 , Dominik Zolnowski  5 , Detlef Quietzsch  6 , Patricia Grabowski  7 , Birgit Cremer  8 , Sebastian Maasberg  9 , Ulrich-Frank Pape  9 , Hans-Helge Mueller  10 , Thomas Matthias Gress  1 , Anja Rinke  1 , The Members Of The German Net Registry  11
Affiliations

Treatment Approaches and Outcome of Patients with Neuroendocrine Neoplasia Grade 3 in German Real-World Clinical Practice

Simone Luecke et al. Cancers (Basel). .

Abstract

Background: Neuroendocrine neoplasia grade 3 (NEN G3) represents a rare and heterogeneous cancer type with a poor prognosis. The aim of our study was to analyze real-world data from the German NET Registry with a focus on therapeutic and prognostic aspects.

Methods: NEN G3 patients were identified within the German NET Registry. Demographic data and data on treatments and outcomes were retrieved. Univariate analyses were performed using the Kaplan-Meier-method. Multivariate analysis was performed using a Cox proportional hazard model.

Results: Of 445 included patients, 318 (71.5%) were diagnosed at stage IV. Well-differentiated morphology (NET G3) was described in 31.7%, 60% of cases were classified as neuroendocrine carcinoma (NEC), and the median Ki67 value was 50%. First-line treatment comprised chemotherapy in 43.8%, with differences in the choice of regimen with regard to NET or NEC, and surgery in 41.6% of patients. Median overall survival for the entire cohort was 31 months. Stage, performance status and Ki67 were significant prognostic factors in multivariate analysis.

Conclusions: The survival data of our national registry compare favorably to population-based data, probably mainly because of a relatively low median Ki67 of 50%. Nevertheless, the best first- and second-line approaches for specific subgroups remain unclear, and an international effort to fill these gaps is needed.

Keywords: Ki67; chemotherapy; neuroendocrine carcinoma; neuroendocrine neoplasia; neuroendocrine tumor G3; prognosis.

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Conflict of interest statement

The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Patient selection for this trial. GEP: gastroenteropancreatic; MANEC: mixed adeno-neuroendocrine carcinoma; MiNEN: mixed neuroendocrine/non-neuroendocrine neoplasms.
Figure 2
Figure 2
Distribution of first-line treatments in patients classified as NEC or NET. (a) First-line NEC, all treatments. (b) First-line NET G3, all treatments. (c) First-line chemotherapeutic protocols in NEC. (d) First-line chemotherapeutic protocols in NET G3. Ablative: local ablative treatment such as radiofrequency ablation or microwave ablation; carbo mono: monotherapy with carboplatin; carbo/tax: carboplatin + paclitaxel; chemo: chemotherapy; DTIC: dacarbazine; drugs nd: chemotherapy protocol not documented; EP: platinum + etoposide; FOLFOX: oxaliplatin + 5-fluorouracil; OP: operative treatment; others: sum of other regimens used in less than 1% of patients; PRRT: peptide receptor radionuclide treatment; SSA: somatostatin analog; STZ/FU: streptozocin+ 5-fluorouracil; Tem/Cap: temozolomide + capecitabine.
Figure 2
Figure 2
Distribution of first-line treatments in patients classified as NEC or NET. (a) First-line NEC, all treatments. (b) First-line NET G3, all treatments. (c) First-line chemotherapeutic protocols in NEC. (d) First-line chemotherapeutic protocols in NET G3. Ablative: local ablative treatment such as radiofrequency ablation or microwave ablation; carbo mono: monotherapy with carboplatin; carbo/tax: carboplatin + paclitaxel; chemo: chemotherapy; DTIC: dacarbazine; drugs nd: chemotherapy protocol not documented; EP: platinum + etoposide; FOLFOX: oxaliplatin + 5-fluorouracil; OP: operative treatment; others: sum of other regimens used in less than 1% of patients; PRRT: peptide receptor radionuclide treatment; SSA: somatostatin analog; STZ/FU: streptozocin+ 5-fluorouracil; Tem/Cap: temozolomide + capecitabine.
Figure 2
Figure 2
Distribution of first-line treatments in patients classified as NEC or NET. (a) First-line NEC, all treatments. (b) First-line NET G3, all treatments. (c) First-line chemotherapeutic protocols in NEC. (d) First-line chemotherapeutic protocols in NET G3. Ablative: local ablative treatment such as radiofrequency ablation or microwave ablation; carbo mono: monotherapy with carboplatin; carbo/tax: carboplatin + paclitaxel; chemo: chemotherapy; DTIC: dacarbazine; drugs nd: chemotherapy protocol not documented; EP: platinum + etoposide; FOLFOX: oxaliplatin + 5-fluorouracil; OP: operative treatment; others: sum of other regimens used in less than 1% of patients; PRRT: peptide receptor radionuclide treatment; SSA: somatostatin analog; STZ/FU: streptozocin+ 5-fluorouracil; Tem/Cap: temozolomide + capecitabine.
Figure 2
Figure 2
Distribution of first-line treatments in patients classified as NEC or NET. (a) First-line NEC, all treatments. (b) First-line NET G3, all treatments. (c) First-line chemotherapeutic protocols in NEC. (d) First-line chemotherapeutic protocols in NET G3. Ablative: local ablative treatment such as radiofrequency ablation or microwave ablation; carbo mono: monotherapy with carboplatin; carbo/tax: carboplatin + paclitaxel; chemo: chemotherapy; DTIC: dacarbazine; drugs nd: chemotherapy protocol not documented; EP: platinum + etoposide; FOLFOX: oxaliplatin + 5-fluorouracil; OP: operative treatment; others: sum of other regimens used in less than 1% of patients; PRRT: peptide receptor radionuclide treatment; SSA: somatostatin analog; STZ/FU: streptozocin+ 5-fluorouracil; Tem/Cap: temozolomide + capecitabine.
Figure 3
Figure 3
Kaplan–Meier plots of putative prognostic factors. (a) Overall survival in patients with ECOG performance statuses of 0, 1 and 2 or worse. ECOG: Eastern Co-operative Oncology Group Performance Status. (b): Overall survival depending on stage. (c) Overall survival depending on the primary tumor localization in metastatic disease. GI, gastrointestinal; CUP, cancer of unknown primary. (d) Overall survival depending on morphology: NEC versus NET. (e) Overall survival by proliferation rate: Ki67 ≥ 55% versus Ki67 < 55%. (f) Overall survival by proliferation rate: Ki67 ≥ 50% versus Ki67 < 50%. (g) Overall survival by serum level of LDH (lactate dehydrogenase). (h) Overall survival by plasma level of chromogranin A (CgA).
Figure 3
Figure 3
Kaplan–Meier plots of putative prognostic factors. (a) Overall survival in patients with ECOG performance statuses of 0, 1 and 2 or worse. ECOG: Eastern Co-operative Oncology Group Performance Status. (b): Overall survival depending on stage. (c) Overall survival depending on the primary tumor localization in metastatic disease. GI, gastrointestinal; CUP, cancer of unknown primary. (d) Overall survival depending on morphology: NEC versus NET. (e) Overall survival by proliferation rate: Ki67 ≥ 55% versus Ki67 < 55%. (f) Overall survival by proliferation rate: Ki67 ≥ 50% versus Ki67 < 50%. (g) Overall survival by serum level of LDH (lactate dehydrogenase). (h) Overall survival by plasma level of chromogranin A (CgA).
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