Prognostic Significance of Somatostatin Receptor Heterogeneity in Progressive Neuroendocrine Tumor Treated with Lu-177 DOTATOC or Lu-177 DOTATATE
One of the primary prerequisites for peptide receptor radionuclide therapy (PRRT) in patients with neuroendocrine tumors (NET) is the presence of somatostatin receptors (SSTR) on NET cells. NET are highly heterogeneous and an individual patient as well as separate metastases can harbor cells with different clones, which influence the SSTR expression on NET cells. With this background we looked into our institutional database to assess the prognostic significance of quality of SSTR expression on SSTR PET/CT imaging in patients treated with at least two cycles of Lu-177 DOTATOC or Lu-177 DOTATATE.
Clinical reports and images from 65 (25 females, 40 males; 65 ± 11 years old) patients with progressive grade 1 or grade 2 NET with 2–5 therapy cycles of PRRT with an average administered dose of 6.6 ± 0.97 GBq Lu-177 DOTATOC or Lu-177 DOTATATE were analyzed. All patients were examined with baseline Ga-68 DOTATATE or Ga-68 DOTATOC PET/CT (PET). Quality of SSTR expression as a measure of heterogeneity on indexed lesions was assessed visually. Patients were followed for a median duration of 25 months after the first PRRT (range 5–77 months).
A total of 70% of the patients received three or more therapy cycles. Twenty-six patients (40%) were treated with PRRT as first or second line while 39 (60%) as third line or more. SSTR expression was heterogeneous in 28 (44.4%) and homogeneous in 35 (55.6%) patients. Disease stabilization could be achieved in 23 patients (35.4%), whereas 17 (26.1%) showed partial remission and 25 patients (38.5%) had disease progression. Median OS was not reached. The 24-month survival rate of the whole study cohort was 83%. In univariate analyses, factors influencing OS were carcinoid heart disease, carcinoid syndrome and quality of SSTR expression (p < 0.05). Patients with heterogeneous SSTR expression on target lesions had a significantly lower OS (p = 0.01). Median time to progression in total patient population was found to be 40 months. Patients with heterogeneous SSTR expression on target lesions had significantly lower TTP (26 months vs 54 months log Rank p = 0.013). By multivariate analyses, quality of SSTR was found to be the only prognostic factor for OS (p = 0.04; HR = 3.68) and also for TTP (p = 0.03; HR = 3.09).
Visual assessment of SSTR heterogeneity has both predictive and prognostic value in progressive grade 1 or grade 2 NET patients undergoing PRRT.
KeywordsPRRT NET Heterogeneity SSTR PET
European neuroendocrine tumor society
Multidisciplinary tumor board
National comprehensive cancer network
Progression free survival
Peptide receptor radionuclide therapy
Time to progression
We would like to acknowledge Prof. Bertram Wiedenmann, Senior Professor and Head, NET Research, ENETS-Center of Excellence, Charite and Prof. Richard P Baum, Chairman and Clinical Director THERANOSTICS Center for Molecular Radiotherapy and Precision Oncology ENETS Center of Excellence, Zentralklinik Bad Berka, Germany, Prof. Rodney Hicks, Director Centre for Cancer Imaging, Peter MacCallum Cancer Center, Melbourne, Prof Lisa Bodei, Director of Targeted Radionuclide Therapy, Molecular Imaging and Therapy Service, Department of Radiology and Prof. Eric P Krennig from Erasmus, Rotterdam for their useful discussion which helped us in the manuscript drafting.
JG was involved in application for ethical clearance, study design, performed data collection, PET/CT image interpretation, performed statistical analyses and wrote the manuscript. UP, HJ, TD, RA, WB, MP were involved in patent management and interdisciplinary tumor board, and VP was involved in application for ethical clearance, study design, interdisciplinary tumor board, and also wrote the manuscript. All authors read and approved the final manuscript.
Compliance with ethical standards
Ethics approval and consent to participate
Charité’s Ethics Committee, which is our institutional review board, approved this study.
Consent for publication
All patients consented to the publication of their anonymised data and our institutional review board allowed the publication of the manuscript.
The authors declare that they have no competing interests.
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