Original Article
Effectiveness of radiolabelled somatostatin analogs (90Y-DOTATOC and 177Lu-DOTATATE) in patients with metastatic neuroendocrine tumors: A single center experience in MexicoEficacia de los análogos de somatostatina radiomarcados (90Y-DOTATOC y 177Lu-DOTATATE) en pacientes con tumores neuroendocrinos metastásicos, experiencia de centro único en México☆

https://doi.org/10.1016/j.remnie.2017.01.007Get rights and content

Abstract

Objective

To determine the effectiveness of therapy with the radiolabelled somatostatin analogs, 90Y-DOTATOC and 177Lu-DOTATATE, in the treatment of metastatic neuroendocrine tumors with progression to first-line treatment.

Material and methods

A study was conducted on 30 patients diagnosed with neuroendocrine tumors (gastroenteropancreatic, bronchopulmonary, MEN2A, MEN2B, phaeochromocytoma, and paraganglioma) with metastatic disease diagnosed by the pathology department, with progression to first-line treatment, and recruited from December 2014 to February 2016. Efficacy was analyzed using computed tomography (CT) according RECIST 1.1 criteria, and the molecular changes using the SUVmax of PET/CT with 68Ga-DOTATOC. Safety was carried out with a renal scan with 99mTc-MAG3.

Results

The 30 patients received a total of 49 cycles 90Y-DOTATOC (21 doses) and 177Lu-DOTATATE (28 doses), with a mean of 1.5 cycles per patient. Of these, 17 (56.7%) showed a partial morphological response, 22 (73.3%) molecular and biochemical response, and 23 (76.6%) clinical response. One patient died during the median follow-up of 13 months. The median overall survival from diagnosis was 54 months (95% CI; 31.18–76.81), and median progression-free survival was 32 months (95% CI; 15.00–48.99).

Conclusion

Therapy with 90Y-DOTATOC and 177Lu-DOTATATE is a promising therapy for patients with well and moderately differentiated neuroendocrine tumors. The efficacy is better the larger the number of cycles administered, inversely proportional to the number of metastases (<10), and is associated with the level of uptake according to the SUVmax by the metastases, regardless of metabolically active tumor volume.

Resumen

Objetivo

Determinar la eficacia de la terapia con análogos de somatostatina radiomarcados 90Y-DOTATOC y 177Lu-DOTATATE en el tratamiento de tumores neuroendocrinos metastásicos con progresión después de la primera línea de tratamiento.

Material y métodos

Se estudiaron 30 pacientes con el diagnóstico de tumor neuroendocrino (gastroenteropancreático, broncopulmonar, MEN2A, MEN2B, feocromocitoma y paraganglioma) con enfermedad metastásica diagnosticados por el departamento de patología, con progresión después de la primera línea de tratamiento, reclutados de diciembre del 2014 a febrero del 2016. La eficacia fue analizada usando la TC siguiendo los criterios RECIST 1.1 y los cambios moleculares en el SUVmáx de la PET/TC con 68Ga-DOTATOC. La seguridad fue valorada mediante el renograma con 99mTc-MAG3.

Resultados

Los 30 pacientes recibieron un total de 49 ciclos de 90Y-DOTATOC (21 dosis) y 177Lu-DOTATATE (28 dosis), con una media de 1,5 ciclos por paciente; 17 (56,7%) mostraron respuesta morfológica parcial; 22 (73,3%) respuesta molecular y bioquímica, y 23 (76,6%) respuesta clínica. Durante la mediana de seguimiento (13 meses) un paciente falleció (3,4%). La mediana de supervivencia global desde el diagnóstico fue de 54 meses (IC 95%, 31,18-76,81), y la mediana de supervivencia libre de progresión fue de 32 meses (IC 95%, 15,00-48,99).

Conclusión

El tratamiento con 90Y-DOTATOC y 177Lu-DOTATATE es una terapia prometedora para los pacientes con tumores neuroendocrinos bien y moderadamente diferenciados. La eficacia es proporcional al número de ciclos administrados, inversamente proporcional al número de metástasis (<10) y en relación con el grado de captación conforme al SUVmáx por parte de las metástasis, independientemente del volumen tumoral metabólicamente activo.

Introduction

Neuroendocrine tumors (NET) are a heterogeneous group of neoplasms originating from neuroendocrine cells in the neural crest, endocrine glands, islet cells or the diffuse endocrine system.1 The largest series of patients with NET was described by Yao et al.,2 using data from 35,618 cases reported from 1973 to 2004 in the Surveillance, Epidemiology and End Results (SEER) database. Well and moderately differentiated metastatic NET usually express several subtypes of somatostatin receptors (SSTR), particularly type 2 receptors (SSRT2). The expression of these receptors allows functional images to be obtained using SPECT/CT with 111In-pentetreotide (OctreoScan®), or PET/CT with the 68Ga-DOTATOC/DOTATATE radiotracer, providing essential informaton for the evaluation of SSTR status and for making the most adequate treatment decisions.3, 4

The grade of 18F-FDG uptake is associated with the grade of cellular differentiation and proliferation assessed by Ki-67 levels and provides additional prognostic value.5

The benchmark of treatment of localized NET is surgery. However, surgery has a limited role in metastatic disease.1, 2 The current recommendations indicate that somatostatin analogs (SSA) such as octreotide or lanreotide should be the first line treatment since they reduce not only hormone overproduction to control symptoms but also increase the overall survival (OS) and progression-free survival (PFS), particularly in patients with low Ki-67 levels.6, 7, 8

Other therapeutic options include chemotherapy, locoregional and directed therapies and therapy with radionuclides with peptide receptors or SSA (SSA-R) radiolabeled with 90Y-DOTATOC and 177Lu-DOTATATE.8, 9

90Y is a β-emitting radionuclide with a maximum tissue penetration of 12 mm, energy of 2.27 MeV and a half life of 2.7 days. Labeling can remain stable with the modified SSA [Tyr3] octreotide and a chelating agent (DOTA or DTPA).10

177Lu is a β-emitting radionuclide which has an energy of 0.5 MeV and a maximum tissue pentration of 2 mm. This radionuclide produces less renal toxicity and myelotoxicity compared with 90Y and has a half life of 6.7 days. In addition, 177Lu emits low energy γ-rays (208 and 113 keV, with 10 and 6% of abundance, respectively) thereby allowing scintigraphic images to be obtained after treatment or for dosimetric purposes. With the modified SSA [DOTA0Tyr3] octreotate allows stable labeling with greater affinitity for SSTR2 than with octreotide.11

The efficacy of therapy with SSA-R (90Y-DOTATOC and 177Lu-DOTATATE) has been studied for more than a decade, and the results of most clinical studies have shown that a tumoricide dose can be administered to neoplasms expressing SSTR2 (within the range of 10–340 Gy) leading to partial or total response in up to 30% of the patients. Gastroenteropancreatic NET show the best response (partial response from 9 to 29% and complete remission of 2 to 6%), with bronchopulmonary NET presenting similar rates.9, 12, 13, 14

The aim of the present study was to determine the effectiveness and safety of 90Y-DOTATOC and 177Lu-DOTATATE in patients with metastatic NET with progression following first line treatment as well as the OS, PFS and safety parameters, particularly regarding renal toxicity.

Section snippets

Material and methods

We performed a retrospective study with an in depth review of the histories of 30 patients with metastatic NET (17 patients from our institution and 13 from different centers in our country) admitted to the Department of Nuclear Medicine and Molecular Imaging of the National Institute of Cancer, Mexico City, Mexico from December 2014 to February 2016 for therapy with SSA-R and followed until May 2016.

Efficacy

Of the 30 patients studied, 14 presented metastatic gastroenteropancreatic NET and 8 had bronchopulmonary NET. Table 1 shows the characteristics of the remaining patients. On closing the database, 9 patients (30%) had received only one cycle of SSA-R. Of these, one patient died one month after the administration of the radiotracer with no data related to disease progression. One patient presented disease progression, 2 patients were lost to follow up for economic reasons (one patient presented

Discussion

The results of the present study show that therapy with SSA-R is useful in a large group of well selected NET with good radiotracer uptake in the PET/CT study with 68Ga-DOTATOC. With the modified renal protection method the therapy can be safely administered without adverse renal effects. Similar to previous studies elevated tumor load with multiple metastases and metastatic patterns involving the liver and bones is associated with a shorter survival. In contrast, elevated tumor uptake

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

We would like to thank Dr. Norma Yanet Hernández Pedro from the Department of Clinical Investigation of the National Cancer Institute for her invaluable contribution to the statistical analysis. We also thank Mario Esau Romero Piña from Nuclear Medicine for his help in the acquisition of the studies as well as Omar Balgañón for his availability and help in the administration of the treatments. Lastly, we thank all the physicians and residents of the Department of Nuclear Medicine of the

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    Please cite this article as: Medina-Ornelas SS, García-Pérez FO. Eficacia de los análogos de somatostatina radiomarcados (90Y-DOTATOC y 177Lu-DOTATATE) en pacientes con tumores neuroendocrinos metastásicos, experiencia de centro único en México. Rev Esp Med Nucl Imagen Mol. 2017;36:166–174.

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    These authors have contributed equally to this work.

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