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Review
. 2021 Dec 28;14(1):129.
doi: 10.3390/cancers14010129.

Peptide Receptor Radionuclide Therapy Targeting the Somatostatin Receptor: Basic Principles, Clinical Applications and Optimization Strategies

Niloefar Ahmadi Bidakhvidi  1   2 , Karolien Goffin  1   2 , Jeroen Dekervel  3 , Kristof Baete  1   2 , Kristiaan Nackaerts  4 , Paul Clement  5 , Eric Van Cutsem  3 , Chris Verslype  3 , Christophe M Deroose  1   2
Affiliations
Review

Peptide Receptor Radionuclide Therapy Targeting the Somatostatin Receptor: Basic Principles, Clinical Applications and Optimization Strategies

Niloefar Ahmadi Bidakhvidi et al. Cancers (Basel). .

Abstract

Peptide receptor radionuclide therapy (PRRT) consists of the administration of a tumor-targeting radiopharmaceutical into the circulation of a patient. The radiopharmaceutical will bind to a specific peptide receptor leading to tumor-specific binding and retention. The only target that is currently used in clinical practice is the somatostatin receptor (SSTR), which is overexpressed on a range of tumor cells, including neuroendocrine tumors and neural-crest derived tumors. Academia played an important role in the development of PRRT, which has led to heterogeneous literature over the last two decades, as no standard radiopharmaceutical or regimen has been available for a long time. This review provides a summary of the treatment efficacy (e.g., response rates and symptom-relief), impact on patient outcome and toxicity profile of PRRT performed with different generations of SSTR-targeting radiopharmaceuticals, including the landmark randomized-controlled trial NETTER-1. In addition, multiple optimization strategies for PRRT are discussed, i.e., the dose-effect concept, dosimetry, combination therapies (i.e., tandem/duo PRRT, chemoPRRT, targeted molecular therapy, somatostatin analogues and radiosensitizers), new radiopharmaceuticals (i.e., SSTR-antagonists, Evans-blue containing vector molecules and alpha-emitters), administration route (intra-arterial versus intravenous) and response prediction via molecular testing or imaging. The evolution and continuous refinement of PRRT resulted in many lessons for the future development of radionuclide therapy aimed at other targets and tumor types.

Keywords: 177Lu-DOTATATE; 90Y-DOTATOC; NET; NETTER-1; PPRT; neuroendocrine tumor; peptide receptor chemoradionuclide therapy; peptide receptor radionuclide therapy.

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Conflict of interest statement

E.V.C. has received research grants from Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche and Servier, and he has received consulting fees from Abbvie, Array, Astellas, Astrazeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi, Halozyme, GSK, Helsinn, Incyte, Ipsen, Janssen Research, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Pierre Fabre, Roche, Seattle Genetics, Servier, Sirtex, Terumo, Taiho, TRIGR and Zymeworks, all outside this work. C.M.D. has received consulting fees from Sirtex, PSI CRO, Terumo, Ipsen and Advanced Accelerator Applications, all outside this work. C.V. has received research grants and consulting fees from Ipsen, Bayer and Roche, all outside this work. P.C. has received consulting fees from Bristol-Myers Squibb, Abbvie, Merck Serono, Merck Sharp & Dohme, Vifor Pharma, Daiichi Sankyo, LEO Pharma, AstraZeneca, Takeda, MSD Belgium BVBA, Rakuten Medical Inc., Bayer NV and Orbus, and he has received research grants from AstraZeneca, all outside this work. No other potential conflict of interest relevant to this article was reported.

Figures

Figure 1
Figure 1
Proposed standardized PRRT scheme. IV = intravenous; SSA = somatostatin analogue; LAR = long-acting release; mo = months; w = weeks; d = day; PRRT = peptide receptor radionuclide therapy; CR = complete response; PR = partial response; SD = stable disease; SSTR = somatostatin receptor; FDG = fluorodeoxyglucose.
Figure 2
Figure 2
Optimization of PRRT. LET = linear energy transfer; SSTR = somatostatin receptor; SSA = somatostatin analogue; PRRT = peptide receptor radionuclide therapy; PARP = Poly-[ADP-ribose]-polymerase; mTOR = mammalian target of rapamycin; 5-FU = 5-fluorouracil; PET = positron emission tomography.
Figure 3
Figure 3
Example of FDG positive disease and response after 2 cycles PRRT. Thirty-two-year-old patient with an advanced neuroendocrine tumor of the small intestine (Ki-67 index: 10%) that presented with disease progression after previous treatment with somatostatin analogues, everolimus and temozolomide-capecitabine. She was deemed eligible for peptide receptor radionuclide therapy (PRRT) after work-up. 68Ga-DOTATATE PET/CT scan prior to PRRT ((A) maximum intensity projection (MIP) image; (B) fusion PET/CT; (C) native PET) showed strongly increased somatostatin receptor-expression in the malignant bone, lymph nodes and liver metastases. 18F-FDG PET/CT prior to PRRT ((D) MIP image; (E) fusion PET/CT; (F) native PET) showed strong 18F-FDG-avidity in the liver metastases. 18F-FDG PET/CT after 2 cycles of PRRT revealed a complete metabolic response in the liver metastases ((G) MIP image; (H) fusion PET/CT; (I) native PET). SUV = standardized uptake value.
Figure 4
Figure 4
A patient with an extensive tumor burden in the left liver lobe and multiple lesions in the right lobe and disseminated bone marrow metastases predominantly in the spine and pelvis ((a) coronal and sagittal maximum-intensity projections 68Ga-DOTATOC PET). Liver metastases showed significant shrinkage after administration of 10.5 GBq of 213Bi-DOTATOC into the common hepatic artery (b). Additional systemic efficiency resulting from the 213Bi-DOTATOC reaching the systemic circulation after the first pass of the liver was noted after 6 months in that most of the bone marrow metastases had also diminished (b). This image nicely demonstrates the potential of alpha-emitters and the feasibility of intra-arterial administration of peptide receptor radionuclide therapy. This image was originally published by Kratochwil et al. [25] and it is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/, accessed on 20 October 2021). No adaptations to this image were made.
Figure 5
Figure 5
Ten lessons from PRRT. PRRT = peptide receptor radionuclide therapy.
See this image and copyright information in PMC

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