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Prognostic Significance of Somatostatin Receptor Heterogeneity in Progressive Neuroendocrine Tumor Treated with Lu-177 DOTATOC or Lu-177 DOTATATE

  • Josephine Graf
  • Ulrich-Frank Pape
  • Henning Jann
  • Timm Denecke
  • Ruza Arsenic
  • Winfried Brenner
  • Marianne Pavel
  • Vikas PrasadEmail author
Original Article
Part of the following topical collections:
  1. Oncology – General

Abstract

Aim

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.

Method

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).

Results

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).

Conclusion

Visual assessment of SSTR heterogeneity has both predictive and prognostic value in progressive grade 1 or grade 2 NET patients undergoing PRRT.

Keywords

PRRT NET Heterogeneity SSTR PET 

Abbreviations

ENETS

European neuroendocrine tumor society

MDTB

Multidisciplinary tumor board

NCCN

National comprehensive cancer network

NEC

Neuroendocrine carcinomas

NEN

Neuroendocrine neoplasms

NET

Neuroendocrine tumor

PFS

Progression free survival

PRRT

Peptide receptor radionuclide therapy

OS

Overall survival

SD

Standard deviation

SSA

Somatostatin analog

SSTR

Somatostatin receptor

TTP

Time to progression

Notes

Acknowledgements

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.

Authors’ contributions

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.

Competing interests

The authors declare that they have no competing interests.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Nuclear MedicineCharité Universitätsmedizin BerlinBerlinGermany
  2. 2.Department of Hepatology and Gastroenterology, Campus Charité Mitte and Virchow ClinicCharité Universitätsmedizin BerlinBerlinGermany
  3. 3.Department of Diagnostic and Interventional RadiologyCharité Universitätsmedizin BerlinBerlinGermany
  4. 4.Institute of PathologyCharité Universitätsmedizin BerlinBerlinGermany
  5. 5.Division of Endocrinology, Department of Internal Medicine, EndocrinologyFriedrich-Alexander Universität ErlangenErlangenGermany
  6. 6.Department of Nuclear MedicineUniversitätsklinikum UlmUlmGermany

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