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Review
. 2024 Jan 1;14(3):940-953.
doi: 10.7150/thno.91268. eCollection 2024.

Peptide receptor radionuclide therapy combinations for neuroendocrine tumours in ongoing clinical trials: status 2023

Gianpaolo di Santo  1 , Giulia Santo  1   2 , Anna Sviridenko  1 , Irene Virgolini  1
Affiliations
Review

Peptide receptor radionuclide therapy combinations for neuroendocrine tumours in ongoing clinical trials: status 2023

Gianpaolo di Santo et al. Theranostics. .

Abstract

A growing body of literature reports on the combined use of peptide receptor radionuclide therapy (PRRT) with other anti-tumuor therapies in order to anticipate synergistic effects with perhaps increased safety issues. Combination treatments to enhance PRRT outcome are based on improved tumour perfusion, upregulation of somatostatin receptors (SSTR), radiosensitization with DNA damaging agents or targeted therapies. Several Phase 1 or 2 trials are currently recruiting patients in combined regimens. The combination of PRRT with cytotoxic chemotherapy, capecitabine and temozolomide (CAPTEM), seems to become clinically useful especially in pancreatic neuroendocrine tumours (pNETs) with acceptable safety profile. Neoadjuvant PRRT prior to surgery, PRRT combinations of intravenous and intraarterial routes of application, combinations of PRRT with differently radiolabelled (alpha, beta, Auger) SSTR-targeting agonists and antagonists, inhibitors of immune checkpoints (ICIs), poly (ADP-ribose) polymerase-1 (PARP1i), tyrosine kinase (TKI), DNA-dependent protein kinase, ribonucleotide reductase or DNA methyltransferase (DMNT) are tested in currently ongoing clinical trials. The combination with [131I]I-MIBG in rare NETs (such as paraganglioma, pheochromocytoma) and new non-SSTR-targeting radioligands are used in the personalization process of treatment. The present review will provide an overview of the current status of ongoing PRRT combination treatments.

Keywords: PRRT; SSTR; chemotherapy; combination treatments; neuroendocrine tumours.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Combination of PRRT with CAPTEM. The patient was diagnosed with pancreatic NET (Ki-67 15%, pT3N0M0R0) following partial pancreatectomy in 2012. Dual tracer PET/CT with (A) [68Ga]Ga-DOTATOC and (B) [18F]F-FDG indicated multiple liver metastases in 2020. The combination treatment with 1500 mg/m2 capecitabine (CAP) and 200 mg/m2 temozolomide (TEM) with 177Lu[Lu]Lu-DOTATATE (accumulated activity 29.54 GBq) resulted in partial response in (C) [68Ga]Ga-DOTATOC PET/CT (SUVmax decreased from 57.43 to 24.92) and (D) complete response in 18[F]F-FDG PET/CT (SUVmax decreased from 14.51 to 4.76).
Figure 2
Figure 2
Combination Treatment of PRRT with [131I]I-mIBG. [68Ga]Ga-DOTA-TOC, [18F]F-FDG, [131I]I-mIBG, and [18F]F-NaF imaging in a 30 year old male patient with metastatic pheochromocytoma (functional tumour). In such rare cases, the combination treatment of PRRT with [131I]I-mIBG can be considered based on tumour accumulation of both thera(g)nostics.
Figure 3
Figure 3
[68Ga]Ga-DOTATOC PET/CT Study Prior to (A) and 12 weeks after (B) Cytoreductive Surgery. The patient (64 y) was diagnosed with medullary thyroid cancer (MTC) at stage pT1a N1a R0 Mx in 2005. After complete thyroidectomy in July 2005 the disease was stable until 2014 when SSTR-positive liver metastases were diagnosed. PRRT with [177Lu]Lu-DOTATATE (accumulated activity 29.47 GBq) then resulted in disease stabilisation until January 2022. Appearance of increased size of liver metastases (A) were associated with increased episodes of watery diarrhea, not responsive to symptomatic therapy. In April 2023 the patient underwent cytoreductive surgery (B) and currently receives a postsurgery second period of [177Lu]Lu-DOTATATE PRRT. Symptoms are completely relieved and the patient has gained >10 kg body weight (September 2023).
Figure 4
Figure 4
[68Ga]Ga-DOTA-MGS5 (DOTA-DGlu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1-NaI-NH2) and [18F]F-DOPA PET/CT in a Patient with Medullary Thyroid Cancer (MTC). The patient was diagnosed with medullary thyroid cancer in 2014 (Ki-67 15%). Disease progression was evidenced after treatment with sorafenib, vandetanib, cabozantinib and long-acting octreotide. In 2023, disseminated metastases were seen in both examinations, [18F]F-DOPA and [68Ga]Ga-MGS5 PET/CT. The patient currently receives treatment with the CCK2-targeting [177Lu]Lu-labelled antagonist [177Lu]-Lu-PP-F11N (DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2) in Basel, Switzerland.
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