Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Molecular Imaging and Biology
Published in: Molecular Imaging and Biology 3/2019

Open Access 01-06-2019 | Research Article

Pre-therapy Somatostatin Receptor-Based Heterogeneity Predicts Overall Survival in Pancreatic Neuroendocrine Tumor Patients Undergoing Peptide Receptor Radionuclide Therapy

Authors: Rudolf A. Werner, Harun Ilhan, Sebastian Lehner, László Papp, Norbert Zsótér, Imke Schatka, Dirk O. Muegge, Mehrbod S. Javadi, Takahiro Higuchi, Andreas K. Buck, Peter Bartenstein, Frank Bengel, Markus Essler, Constantin Lapa, Ralph A. Bundschuh

Published in: Molecular Imaging and Biology | Issue 3/2019

Login to get access

Abstract

Purpose

Early identification of aggressive disease could improve decision support in pancreatic neuroendocrine tumor (pNET) patients prior to peptide receptor radionuclide therapy (PRRT). The prognostic value of intratumoral textural features (TF) determined by baseline somatostatin receptor (SSTR)-positron emission tomography (PET) before PRRT was analyzed.

Procedures

Thirty-one patients with G1/G2 pNET were enrolled (G2, n = 23/31). Prior to PRRT with [177Lu]DOTATATE (mean, 3.6 cycles), baseline SSTR-PET computed tomography was performed. By segmentation of 162 (median per patient, 5) metastases, intratumoral TF were computed. The impact of conventional PET parameters (SUVmean/max), imaging-based TF, and clinical parameters (Ki67, CgA) for prediction of both progression-free survival (PFS) and overall survival (OS) after PRRT were evaluated.

Results

Within a median follow-up of 3.7 years, tumor progression was detected in 21 patients (median, 1.5 years) and 13/31 deceased (median, 1.9 years). In ROC analysis, the TF entropy, reflecting derangement on a voxel-by-voxel level, demonstrated predictive capability for OS (cutoff = 6.7, AUC = 0.71, p = 0.02). Of note, increasing entropy could predict a longer survival (> 6.7, OS = 2.5 years, 17/31), whereas less voxel-based derangement portended inferior outcome (< 6.7, OS = 1.9 years, 14/31). These findings were supported in a G2 subanalysis (> 6.9, OS = 2.8 years, 9/23 vs. < 6.9, OS = 1.9 years, 14/23). Kaplan–Meier analysis revealed a significant distinction between high- and low-risk groups using entropy (n = 31, p < 0.05). For those patients below the ROC-derived threshold, the relative risk of death after PRRT was 2.73 (n = 31, p = 0.04). Ki67 was negatively associated with PFS (p = 0.002); however, SUVmean/max failed in prognostication (n.s.).

Conclusions

In contrast to conventional PET parameters, assessment of intratumoral heterogeneity demonstrated superior prognostic performance in pNET patients undergoing PRRT. This novel PET-based strategy of outcome prediction prior to PRRT might be useful for patient risk stratification.
Appendix
Available only for authorised users
Literature
1.
Fraenkel M, Faggiano A, Valk GD (2015) Epidemiology of neuroendocrine tumors. Front Horm Res 44:1–23CrossRefPubMed
2.
Lawrence B, Gustafsson BI, Chan A et al (2011) The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin N Am 40:1–18 viiCrossRef
3.
Cauley CE, Pitt HA, Ziegler KM, Nakeeb A, Schmidt CM, Zyromski NJ, House MG, Lillemoe KD (2012) Pancreatic enucleation: improved outcomes compared to resection. J Gastrointest Surg 16:1347–1353CrossRefPubMed
4.
Panzuto F, Di Fonzo M, Iannicelli E et al (2006) Long-term clinical outcome of somatostatin analogues for treatment of progressive, metastatic, well-differentiated entero-pancreatic endocrine carcinoma. Ann Oncol 17:461–466CrossRefPubMed
5.
Rinke A, Muller HH, Schade-Brittinger C et al (2009) Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 27:4656–4663CrossRefPubMed
6.
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, Pavel ME (2016) 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 387:968–977CrossRefPubMed
7.
Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364:501–513CrossRefPubMed
8.
9.
Brabander T, van der Zwan WA, Teunissen JJM, Kam BLR, Feelders RA, de Herder WW, van Eijck CHJ, Franssen GJH, Krenning EP, Kwekkeboom DJ (2017) Long-term efficacy, survival, and safety of [177Lu-DOTA(0),Tyr(3)]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clin Cancer Res 23:4617–4624CrossRefPubMed
10.
Aerts HJ, Velazquez ER, Leijenaar RT et al (2014) Decoding tumour phenotype by noninvasive imaging using a quantitative radiomics approach. Nat Commun 5:4006CrossRefPubMed
11.
Marusyk A, Almendro V, Polyak K (2012) Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer 12:323–334CrossRefPubMed
12.
Oberg K, Krenning E, Sundin A, Bodei L, Kidd M, Tesselaar M, Ambrosini V, Baum RP, Kulke M, Pavel M, Cwikla J, Drozdov I, Falconi M, Fazio N, Frilling A, Jensen R, Koopmans K, Korse T, Kwekkeboom D, Maecke H, Paganelli G, Salazar R, Severi S, Strosberg J, Prasad V, Scarpa A, Grossman A, Walenkamp A, Cives M, Virgolini I, Kjaer A, Modlin IM (2016) A Delphic consensus assessment: imaging and biomarkers in gastroenteropancreatic neuroendocrine tumor disease management. Endocr Connect 5:174–187CrossRefPubMedPubMedCentral
13.
Werner RA, Lapa C, Ilhan H, Higuchi T, Buck AK, Lehner S, Bartenstein P, Bengel F, Schatka I, Muegge DO, Papp L, Zsótér N, Große-Ophoff T, Essler M, Bundschuh RA (2017) Survival prediction in patients undergoing radionuclide therapy based on intratumoral somatostatin-receptor heterogeneity. Oncotarget 8:7039–7049CrossRefPubMed
14.
Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, Kamiyama M, Hruban RH, Eshleman JR, Nowak MA, Velculescu VE, Kinzler KW, Vogelstein B, Iacobuzio-Donahue CA (2010) Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467:1114–1117CrossRefPubMedPubMedCentral
15.
Couvelard A, Deschamps L, Ravaud P, Baron G, Sauvanet A, Hentic O, Colnot N, Paradis V, Belghiti J, Bedossa P, Ruszniewski P (2009) Heterogeneity of tumor prognostic markers: a reproducibility study applied to liver metastases of pancreatic endocrine tumors. Mod Pathol 22:273–281CrossRefPubMed
16.
Ezziddin S, Khalaf F, Vanezi M, Haslerud T, Mayer K, al Zreiqat A, Willinek W, Biersack HJ, Sabet A (2014) Outcome of peptide receptor radionuclide therapy with 177Lu-octreotate in advanced grade 1/2 pancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging 41:925–933CrossRefPubMed
17.
Ezziddin S, Opitz M, Attassi M, Biermann K, Sabet A, Guhlke S, Brockmann H, Willinek W, Wardelmann E, Biersack HJ, Ahmadzadehfar H (2011) Impact of the Ki-67 proliferation index on response to peptide receptor radionuclide therapy. Eur J Nucl Med Mol Imaging 38:459–466CrossRefPubMed
18.
Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Hörsch D, O'Dorisio MS, O'Dorisio TM, Howe JR, Cremonesi M, Kwekkeboom DJ, Zaknun JJ (2013) The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging 40:800–816CrossRefPubMedPubMedCentral
19.
Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, Feelders RA, van Aken MO, Krenning EP (2008) Treatment with the radiolabeled somatostatin analog [177Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol 26:2124–2130CrossRefPubMed
20.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247CrossRefPubMed
21.
22.
Surti S, Kuhn A, Werner ME, Perkins AE, Kolthammer J, Karp JS (2007) Performance of Philips Gemini TF PET/CT scanner with special consideration for its time-of-flight imaging capabilities. J Nucl Med 48:471–480PubMed
23.
Marti-Climent JM, Prieto E, Dominguez-Prado I et al (2013) Contribution of time of flight and point spread function modeling to the performance characteristics of the PET/CT Biograph mCT scanner. Rev Esp Med Nucl Imagen Mol 32:13–21PubMed
24.
Prieto E, Marti-Climent JM, Arbizu J et al (2010) Evaluation of spatial resolution of a PET scanner through the simulation and experimental measurement of the recovery coefficient. Comput Biol Med 40:75–80CrossRefPubMed
25.
Bailly C, Bodet-Milin C, Couespel S, Necib H, Kraeber-Bodéré F, Ansquer C, Carlier T (2016) Revisiting the robustness of PET-based textural features in the context of multi-centric trials. PLoS One 11:e0159984CrossRefPubMedPubMedCentral
26.
Nakajo M, Jinguji M, Nakabeppu Y, Nakajo M, Higashi R, Fukukura Y, Sasaki K, Uchikado Y, Natsugoe S, Yoshiura T (2017) Texture analysis of 18F-FDG PET/CT to predict tumour response and prognosis of patients with esophageal cancer treated by chemoradiotherapy. Eur J Nucl Med Mol Imaging 44:206–214CrossRefPubMed
27.
Li X, Rowe SP, Leal JP, Gorin MA, Allaf ME, Ross AE, Pienta KJ, Lodge MA, Pomper MG (2017) Semiquantitative parameters in PSMA-targeted PET imaging with 18F-DCFPyL: variability in normal-organ uptake. J Nucl Med 58:942–946CrossRefPubMedPubMedCentral
28.
Hatt M, Majdoub M, Vallieres M, Tixier F, le Rest CC, Groheux D, Hindie E, Martineau A, Pradier O, Hustinx R, Perdrisot R, Guillevin R, el Naqa I, Visvikis D (2015) F-18-FDG PET uptake characterization through texture analysis: investigating the complementary nature of heterogeneity and functional tumor volume in a multi-cancer site patient cohort. J Nucl Med 56:38–44CrossRefPubMed
29.
30.
Hachamovitch R, Di Carli MF (2008) Methods and limitations of assessing new noninvasive tests: part II: outcomes-based validation and reliability assessment of noninvasive testing. Circulation 117:2793–2801CrossRefPubMed
31.
Komaki K, Sano N, Tangoku A (2006) Problems in histological grading of malignancy and its clinical significance in patients with operable breast cancer. Breast Cancer 13:249–253CrossRefPubMed
32.
Bundschuh RA, Dinges J, Neumann L, Seyfried M, Zsoter N, Papp L, Rosenberg R, Becker K, Astner ST, Henninger M, Herrmann K, Ziegler SI, Schwaiger M, Essler M (2014) Textural parameters of tumor heterogeneity in 18F-FDG PET/CT for therapy response assessment and prognosis in patients with locally advanced rectal cancer. J Nucl Med 55:891–897CrossRefPubMed
33.
Tixier F, Le Rest CC, Hatt M et al (2011) Intratumor heterogeneity characterized by textural features on baseline 18F-FDG PET images predicts response to concomitant radiochemotherapy in esophageal cancer. J Nucl Med 52:369–378CrossRefPubMed
34.
Hatt M, Visvikis D, Pradier O, Cheze-le Rest C (2011) Baseline 18F-FDG PET image-derived parameters for therapy response prediction in oesophageal cancer. Eur J Nucl Med Mol Imaging 38:1595–1606CrossRefPubMedPubMedCentral
35.
Hicks RJ, Kwekkeboom DJ, Krenning E, et al. (2017) ENETS consensus guidelines for the standards of care in neuroendocrine neoplasia: peptide receptor radionuclide therapy with radiolabeled somatostatin analogues. Neuroendocrinology 105(3):295-309
36.
Strosberg JR, Cives M, Hwang J, Weber T, Nickerson M, Atreya CE, Venook A, Kelley RK, Valone T, Morse B, Coppola D, Bergsland EK (2016) A phase II study of axitinib in advanced neuroendocrine tumors. Endocr Relat Cancer 23:411–418CrossRefPubMedPubMedCentral
37.
Kratochwil C, Stefanova M, Mavriopoulou E, Holland-Letz T, Dimitrakopoulou-Strauss A, Afshar-Oromieh A, Mier W, Haberkorn U, Giesel FL (2015) SUV of [68Ga]DOTATOC-PET/CT predicts response probability of PRRT in neuroendocrine tumors. Mol Imaging Biol 17:313–318CrossRefPubMed
38.
Bergsma H, Konijnenberg MW, van der Zwan WA, Kam BLR, Teunissen JJM, Kooij PP, Mauff KAL, Krenning EP, Kwekkeboom DJ (2016) Nephrotoxicity after PRRT with 177Lu-DOTA-octreotate. Eur J Nucl Med Mol Imaging 43:1802–1811CrossRefPubMedPubMedCentral
39.
Gabriel M, Oberauer A, Dobrozemsky G, Decristoforo C, Putzer D, Kendler D, Uprimny C, Kovacs P, Bale R, Virgolini IJ (2009) 68Ga-DOTA-Tyr3-octreotide PET for assessing response to somatostatin-receptor-mediated radionuclide therapy. J Nucl Med 50:1427–1434CrossRefPubMed
40.
Sansovini M, Severi S, Ianniello A, Nicolini S, Fantini L, Mezzenga E, Ferroni F, Scarpi E, Monti M, Bongiovanni A, Cingarlini S, Grana CM, Bodei L, Paganelli G (2017) Long-term follow-up and role of FDG PET in advanced pancreatic neuroendocrine patients treated with 177Lu-D OTATATE. Eur J Nucl Med Mol Imaging 44:490–499CrossRefPubMed
41.
Hyun SH, Kim HS, Choi SH, Choi DW, Lee JK, Lee KH, Park JO, Lee KH, Kim BT, Choi JY (2016) Intratumoral heterogeneity of 18F-FDG uptake predicts survival in patients with pancreatic ductal adenocarcinoma. Eur J Nucl Med Mol Imaging 43:1461–1468CrossRefPubMed
42.
Pyka T, Bundschuh RA, Andratschke N, Mayer B, Specht HM, Papp L, Zsótér N, Essler M (2015) Textural features in pre-treatment [F18]-FDG-PET/CT are correlated with risk of local recurrence and disease-specific survival in early stage NSCLC patients receiving primary stereotactic radiation therapy. Radiat Oncol 10:100CrossRefPubMedPubMedCentral
43.
Koukouraki S, Strauss LG, Georgoulias V, Schuhmacher J, Haberkorn U, Karkavitsas N, Dimitrakopoulou-Strauss A (2006) Evaluation of the pharmacokinetics of 68Ga-DOTATOC in patients with metastatic neuroendocrine tumours scheduled for 90Y-DOTATOC therapy. Eur J Nucl Med Mol Imaging 33:460–466CrossRefPubMed
44.
Wetz C, Apostolova I, Steffen IG, Hofheinz F, Furth C, Kupitz D, Ruf J, Venerito M, Klose S, Amthauer H (2017) Predictive value of asphericity in pretherapeutic [111In]DTPA-octreotide SPECT/CT for response to peptide receptor radionuclide therapy with [177Lu]DOTATATE. Mol Imaging Biol 19:437–445CrossRefPubMed
45.
Garcia-Carbonero R, Garcia-Figueiras R, Carmona-Bayonas A et al (2015) Imaging approaches to assess the therapeutic response of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): current perspectives and future trends of an exciting field in development. Cancer Metastasis Rev 34:823–842CrossRefPubMedPubMedCentral
46.
Apostolova I, Ego K, Steffen IG, Buchert R, Wertzel H, Achenbach HJ, Riedel S, Schreiber J, Schultz M, Furth C, Derlin T, Amthauer H, Hofheinz F, Kalinski T (2016) The asphericity of the metabolic tumour volume in NSCLC: correlation with histopathology and molecular markers. Eur J Nucl Med Mol Imaging 43:2360–2373CrossRefPubMed
47.
Cook GJ, O'Brien ME, Siddique M et al (2015) Non-small cell lung cancer treated with erlotinib: heterogeneity of 18F-FDG uptake at PET-association with treatment response and prognosis. Radiology 276:883–893CrossRefPubMed
48.
Ezziddin S, Attassi M, Yong-Hing CJ, Ahmadzadehfar H, Willinek W, Grunwald F, Guhlke S, Biersack HJ, Sabet A (2014) Predictors of long-term outcome in patients with well-differentiated gastroenteropancreatic neuroendocrine tumors after peptide receptor radionuclide therapy with 177Lu-octreotate. J Nucl Med 55:183–190CrossRefPubMed
49.
Sharma N, Naraev BG, Engelman EG, Zimmerman MB, Bushnell DL Jr, OʼDorisio TM, OʼDorisio MS, Menda Y, Müller-Brand J, Howe JR, Halfdanarson TR (2017) Peptide receptor radionuclide therapy outcomes in a North American cohort with metastatic well-differentiated neuroendocrine tumors. Pancreas 46:151–156CrossRefPubMedPubMedCentral
50.
Chalkidou A, O'Doherty MJ, Marsden PK (2015) False discovery rates in PET and CT studies with texture features: a systematic review. PLoS One 10:e0124165CrossRefPubMedPubMedCentral
Metadata
Title
Pre-therapy Somatostatin Receptor-Based Heterogeneity Predicts Overall Survival in Pancreatic Neuroendocrine Tumor Patients Undergoing Peptide Receptor Radionuclide Therapy
Authors
Rudolf A. Werner
Harun Ilhan
Sebastian Lehner
László Papp
Norbert Zsótér
Imke Schatka
Dirk O. Muegge
Mehrbod S. Javadi
Takahiro Higuchi
Andreas K. Buck
Peter Bartenstein
Frank Bengel
Markus Essler
Constantin Lapa
Ralph A. Bundschuh
Publication date
01-06-2019
Publisher
Springer International Publishing
Published in
Molecular Imaging and Biology / Issue 3/2019
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI
https://doi.org/10.1007/s11307-018-1252-5

Other articles of this Issue 3/2019

Molecular Imaging and Biology 3/2019 Go to the issue

Research Article

Spatial Inhomogeneity of Cardiac Norepinephrine Transport Protein and Meta-[123I]Iodobenzylguanidine Uptake in Swine Myocardial Tissue

Editorial

Commemorating Britton Chance

Research Article

Optical Redox Imaging of Lonidamine Treatment Response of Melanoma Cells and Xenografts

Research Article

Inconsistent Detection of Sites of Metastatic Non-Clear Cell Renal Cell Carcinoma with PSMA-Targeted [18F]DCFPyL PET/CT

Brief Article

Optical Redox Imaging Detects the Effects of DEK Oncogene Knockdown on the Redox State of MDA-MB-231 Breast Cancer Cells

Research Article

Combined Early and Late [68Ga]PSMA-HBED-CC PET Scans Improve Lesion Detectability in Biochemical Recurrence of Prostate Cancer with Low PSA Levels