TY - JOUR

T1 - Prospective Phase II Trial of [68Ga]Ga-NODAGA-E[c(RGDyK)]2 PET/CT Imaging of Integrin αvβ3 for Prognostication in Patients with Neuroendocrine Neoplasms

AU - Carlsen, Esben Andreas

AU - Loft, Mathias

AU - Loft, Annika

AU - Czyzewska, Dorota

AU - Andreassen, Mikkel

AU - Langer, Seppo Wang

AU - Knigge, Ulrich

AU - Kjaer, Andreas

N1 - Copyright © 2022 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

PY - 2023

Y1 - 2023

N2 - Integrin α vβ 3, a subtype of the arginine-glycine-aspartate (RGD) recognizing cell surface integrins, is upregulated on endothelial cells during angiogenesis and on tumor cells. Due to involvement in tumor growth, invasiveness/metastases, and angiogenesis, integrin α vβ 3 is an attractive target in cancers. In this study we applied 68Ga-NODAGA-E[c(RGDyK)] 2 for imaging of integrin α vβ 3 in patients with neuroendocrine neoplasms (NEN) and its potential use for prognostication. We hypothesized that 68Ga-NODAGA-E[c(RGDyK)] 2 PET/CT would show tumor lesion uptake and that higher tumor lesion uptake was associated with a poorer prognosis. Methods: Between December 2017-November 2020 we prospectively enrolled 113 patients with NEN of all grades (2019 World Health Organization classification) for 68Ga-NODAGA-E[c(RGDyK)] 2 PET/CT. The scan was acquired 45 minutes after injection of 200 MBq of 68Ga-NODAGA-E[c(RGDyK)] 2 Board certified specialists in nuclear medicine and radiology analyzed the PET/CT measuring SUV max in tumor lesions. Positive tumor lesions were defined as those with tumor-to-liver background ≥ 2. Maximal tumor SUV max for each patient was used as predictor of outcome. Patients were followed for at least one year to assess progression-free survival (PFS) and overall survival (OS). Results: Of 113 patients enrolled in the trial, 99 had a 68Ga-NODAGA-E[c(RGDyK)] 2 PET/CT performed, hereof 97 patients having evaluable lesions. The patients predominantly had small intestinal (64%) or pancreatic (20%) NEN and most had metastatic disease (93%). The majority of patients had low-grade tumors (78%), while (22%) had high-grade tumors. During follow-up of median 31 months (interquartile range: 26-38), 62 patients (64%) experienced disease progression and 26 (27%) patients died. In total, 76% of patients had positive tumor lesions, and of patients with high-grade tumors, 91% had positive tumor lesions. High integrin α vβ 3 expression, defined as SUV max at least 5.25 had a hazard ratio (95% confidence interval) of 2.11 (1.18-3.78) and 6.95 (1.64-29.51) for PFS and OS, respectively ( P = 0.01 for both). Conclusion: Tumor lesion uptake of 68Ga-NODAGA-E[c(RGDyK)] 2 was evident in patients with all grades of NEN. High uptake was associated with a poorer prognosis. Further studies are warranted to establish if 68Ga-NODAGA-E[c(RGDyK)] 2 PET/CT may become a prediction tool for identification of patients eligible for treatments targeting integrin α vβ 3.

AB - Integrin α vβ 3, a subtype of the arginine-glycine-aspartate (RGD) recognizing cell surface integrins, is upregulated on endothelial cells during angiogenesis and on tumor cells. Due to involvement in tumor growth, invasiveness/metastases, and angiogenesis, integrin α vβ 3 is an attractive target in cancers. In this study we applied 68Ga-NODAGA-E[c(RGDyK)] 2 for imaging of integrin α vβ 3 in patients with neuroendocrine neoplasms (NEN) and its potential use for prognostication. We hypothesized that 68Ga-NODAGA-E[c(RGDyK)] 2 PET/CT would show tumor lesion uptake and that higher tumor lesion uptake was associated with a poorer prognosis. Methods: Between December 2017-November 2020 we prospectively enrolled 113 patients with NEN of all grades (2019 World Health Organization classification) for 68Ga-NODAGA-E[c(RGDyK)] 2 PET/CT. The scan was acquired 45 minutes after injection of 200 MBq of 68Ga-NODAGA-E[c(RGDyK)] 2 Board certified specialists in nuclear medicine and radiology analyzed the PET/CT measuring SUV max in tumor lesions. Positive tumor lesions were defined as those with tumor-to-liver background ≥ 2. Maximal tumor SUV max for each patient was used as predictor of outcome. Patients were followed for at least one year to assess progression-free survival (PFS) and overall survival (OS). Results: Of 113 patients enrolled in the trial, 99 had a 68Ga-NODAGA-E[c(RGDyK)] 2 PET/CT performed, hereof 97 patients having evaluable lesions. The patients predominantly had small intestinal (64%) or pancreatic (20%) NEN and most had metastatic disease (93%). The majority of patients had low-grade tumors (78%), while (22%) had high-grade tumors. During follow-up of median 31 months (interquartile range: 26-38), 62 patients (64%) experienced disease progression and 26 (27%) patients died. In total, 76% of patients had positive tumor lesions, and of patients with high-grade tumors, 91% had positive tumor lesions. High integrin α vβ 3 expression, defined as SUV max at least 5.25 had a hazard ratio (95% confidence interval) of 2.11 (1.18-3.78) and 6.95 (1.64-29.51) for PFS and OS, respectively ( P = 0.01 for both). Conclusion: Tumor lesion uptake of 68Ga-NODAGA-E[c(RGDyK)] 2 was evident in patients with all grades of NEN. High uptake was associated with a poorer prognosis. Further studies are warranted to establish if 68Ga-NODAGA-E[c(RGDyK)] 2 PET/CT may become a prediction tool for identification of patients eligible for treatments targeting integrin α vβ 3.

U2 - 10.2967/jnumed.122.264383

DO - 10.2967/jnumed.122.264383

M3 - Journal article

C2 - 35981899

VL - 64

SP - 252

EP - 259

JO - The Journal of Nuclear Medicine

JF - The Journal of Nuclear Medicine

SN - 0161-5505

IS - 2

ER -