Sicherheit und Effektivität der kombinierten Behandlung mittels lokal - ablativer Therapie und Peptid - Rezeptor vermittelter Radionuklidtherapie bei Patienten mit neuroendokrinen Neoplasien und hoher funktioneller Aktivität oder Remissionsdruck

Background and Aim NEN are rare malignant tumors having their origin in the diverse neuroendocrine system. An increasing incidence has been observed in recent years due to scientific and technical advances of diagnosis. NEN are usually slow-growing and some produce bioactive amines and hormones. The diagnosis of neuroendocrine neoplasia is frequently made only at an advanced stage of disease and after hepatic metastasis. A novel systemic therapeutic approach based on the expression of SSTR, is peptide receptor radionuclide therapy (PRRT). In hepatic metastases, local ablative procedures such as transarterial percutaneous chemoembolization (TACE) can be useful to reduce the tumor load. The aim of this study was to investigate the efficacy of local ablative and systemic treatment with 90Y- [DOTA0, Tyr3] octreotide (90Y- DOTATOC) and / or 177Lu- [DOTA0, Tyr3, Thr8] -octreotide (177Lu-DOTATATE) in NEN with liver metastases and high functional activity. Material and Methods The tumor register of the Zentralklinik Bad Berka was analyzed. Survival in 50 patients (37 males, 13 females) with liver metastases of neuroendocrine neoplasms, which received a combination therapy of PRRT and TACE, was investigated. The start of the analysis was the first TACE with a maximum interval of 6 months to PRRT. Survival probabilities (OS and PFS) were assessed according to the log rank test (Mantel Cox) when proportional, and in the absence of proportionality, according to the Breslow test (generalized Wilcoxon test). It was tested for significance (significance level = 5 %) and the results in Kaplan - Meier curves were graphically compared with the current literature. Laboratory changes of transaminases (AST, ALT), alkaline phosphatase, total bilirubin, creatinine and changes in blood counts (hemoglobin, leukocytes, thrombocytes) were assessed according to the Common Terminology Criteria for Adverse Events v3.0 (CTCAE). 107 Results Combined therapy of PRRT and TACE is a therapeutic alternative for NEN metastasized to the liver. Median overall survival (OS) was 16 months and median time to progression was 5 months. The 1-year survival rate under therapy was 56 %. Statistically significant differences were found regarding tumor localization, Karnofsky index, tumor grading, cumulative total irradiation, number of interventions, pre-interventional chemotherapy, and site of metastasis. Mean survival for pancreatic primary tumor was significantly shorter as compared to the localization in other organs (p = 0.012). PFS also showed a significant difference and was shorter with pancreatic localization (p = 0.02). A Karnofsky index ≤ 70 was associated with shorter overall survival than an index > 70 (p = 0.02). Regarding proliferation-based grading, significant differences were found between G2 and G3 tumors concerning the overall survival (p = 0.026). A significantly longer median survival was observed as the cumulative administered total radioactivity increased, (p = 0.042). The disease progression was also delayed with increasing number of TACE interventions (p = 0.009). Overall and progression-free survival were not affected by the radionuclide used for PRRT (p > 0.05). However, disease progression was delayed when TACE was initially applied in the combination therapy (p = 0.033). Median overall survival was significantly longer in primary TACE as first intervention than in primary PRRT at 41 months vs 13 months, respectively (p = 0.062). When chemotherapy was administered prior to intervention, the PFS (p = 0.015) and the OS (p = 0.036) were shorter than without previous chemotherapy. The tumor response under therapy was determined according to morphological (RECIST) and molecular (PERCIST) response criteria. A partial remission (PR) of the disease was achieved in 28 % of patients and a stable disease (SD) in 24 %. A complete remission (CR) of the neuroendocrine tumor metastases was not observed. In 26 % of the patient population, disease progression could not be delayed. Both therapeutic methods have been described in literature as having been generally well tolerated with rare occurrence of side effects. There was an 108 increase (≥ grade 3 according to CTCAE) of transaminases in 58%, of alkaline phosphatase in 30 % and of bilirubin in 18 % of the patients. An increase in creatinine level of ≥ grade 3 was noted in only 8 % of the patients. Leukocytopenia and thrombocytopenia were only very rarely detectable. A decline in hemoglobin (≥ grade 3) was observed in 36 % of the patients receiving the combination therapy. Conclusion Combination therapy of NEN metastasized to the liver by using PRRT and local ablative TACE results in response of the tumor masses, delay of the tumor progression and thus prolonging the overall survival. Combination therapy is currently a promising therapeutic option. Standardized therapy protocols for the sequence of therapies are currently not available. A combination of therapeutic modalities and sequential intervention should be considered within the framework of an interdisciplinary tumor board. Further studies for standardizing the treatment regimens are warranted.