Theranostics for Neuroendocrine Cancer – A Find and Destroy Mission

Theranostics is a joining of the words therapeutics and diagnostics. You may also see it conveyed as ‘Theragnostics’ and these terms are interchangeable. The basic aim of theragnostics is to find and then destroy the ‘bad guys‘. With Neuroendocrine Cancer, finding the tumours (the bad guys) can often be a challenge – they can be small and/or difficult to find – they are sometimes expert at camouflage. Moreover, once found, they can then be difficult to treat (destroy), as they can often prove resistant to conventional cancer drugs and many are inoperable due to sheer quantity, spread and positioning. When they are found and identified, it’s also really helpful to know from the intelligence gathered, how successful the destroy (therapeutic) part of the mission might be.

Enter Somatostatin Receptor (SSTR) PET and Targeted SSTR Therapy e.g. Peptide Receptor Radionuclide Therapy (PRRT). All of this comes under the heading of Nuclear Medicine.

You may see this called Radioligand Therapy (RLT) or Targeted Radioligand Therapy (TRT) or Radiopharmaceutical Therapy (RPT) – I wish someone would set a standard! However, these terms can have a much broader much broader scope of targeting – (see summary below).

THERANOSTICS – the mission to FIND

Example

The nuclear scan uses the same targeting agent as the therapy, therefore if you cancer lights up on the nuclear scan, then the therapy will find its way to the cancer and hopefully work well. That is the beauty of what is called a theranostic pairing, i.e. the use of the same agent in the diagnostics – the ability to find, estimate likely success criteria and then hopefully destroy – or at least reduce the capability of the tumours and extend life. It’s worth pointing out that using the same agent is often known as “true theranostic pairing” but it’s become clear that scanning (finding) and treating (destroying) do not need to use the same agent.

A great example of an approved Theranostic Pair in Neuroendocrine Cancer, is the combination of the Somatostatin Receptor based PET scan using NETSPOT or SomaKit TOC™ (US/Europe respectively) and Peptide Receptor Radiotherapy (PRRT) using Lutathera which both target NETs expressing the same somatostatin receptor,(SSTR) with PRRT intended to kill tumour cells by emitting a different kind of low-energy, short-range radiation than that of the diagnostic version. As mentioned above, the Ga68 PET scan can give a reasonably indication of therapeutic success using PRRT based on measurements taken during the scan (too complex for this article).

permission given from AAA to list this graphic – company now subsumed into Novartis.

SSTR Nuclear Scans

Octreotide Scans – Somatostatin receptor scintigraphy (SRS) using radionuclides such as ¹¹¹In-DTPA-octreotide are slowly being discontinued. Octreoscans were not based on PET technology but utilised nuclear medicine imaging platforms specifically using gamma cameras, e.g. Planar Gamma Camera Imaging (2D) or SPECT (Single-Photon Emission Computed Tomography (3D). For NET, they are been replaced by newer ‘tech’ known as SSTR PET.

SSTR PET

Newer imaging agents targeting somatostatin receptors (SSTR) labelled with ⁶⁸ Ga have been developed, namely, DOTATATE, DOTATOC and less commonly DOTANOC. Today in 2026, there’s a whole bunch of new arrivals, mostly in clinical trials, some using more powerful agents introducing alpha-emitter techniques (currently approved PRRT is beta-emitter).

The full titles of the 3 types are:

⁶⁸Ga-DOTA-Phe¹-Tyr³-Octreotide (TOC),
⁶⁸Ga-DOTA-NaI³-Octreotide (NOC),
⁶⁸Ga-DOTA-Tyr³-Octreotate (TATE).

The main difference among these three tracers (DOTA-TOC, DOTA-NOC, and DOTA-TATE) is their variable affinity to SSTR subtypes. All of them can bind to SSTR2 and SSTR5, while only DOTA-NOC shows good affinity for SSTR3.

These agents have several benefits over In111-pentetreotide (Octreotide scan), including improved detection sensitivity, improved patient convenience due to the 2 hour length of the study (compared to 2 or 3 days with Octreoscan), decreased radiation dose, decreased biliary excretion due to earlier imaging after radiotracer administration, and the ability to quantify uptake. The quantification of the uptake can help decide whether a patient is suitable for PRRT. Eventually, all Octreotide scans should be replaced with SSTR PET. To confirm the advantages of SSTR PET over Octreotide scans, a study comprising 1,561 patients reported a change in tumour management occurred in over a third of patients after SSTR PET/CT even when performed after an Octreotide scan. Worth pointing out that SSTR PET is replacing the ageing Octreotide scan and not conventional imaging (CI). You can see the recommended scenarios for use of SSTR PET in this article published by the Journal of Nuclear Medicine

Ga68 PET scans have been in many locations for some time. Current excitement is focused on USA locations with Ga68 PET (NETSPOT) only recently approved (DOTATATE). Other countries/scan centres may use one of the other types of imaging agent. e.g. Europe uses SOMAkit???

Read much more about this scan in my detailed article on Ga68 PET here.

So SSTR PETs above have the ability to find and estimate likely success criteria for therapy. We are now in a position to move on to ‘THERApy’ – e.g. Peptide Receptor Radiotherapy or PRRT.

THERANOSTICS – the mission to hopefully DESTROY

Peptide Receptor Radionuclide Therapy (PPRT)

Definitions:

Europe Approval: LUTATHERA®(lutetium (177Lu) Oxodotreotide) is indicated for the treatment of unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours (GEPNETs) in adults.

USA Approval: LUTATHERA® (lutetium Lu 177 dotatate) is indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut and hindgut neuroendocrine tumors in adults.

PRRT with LUTATHERA^®

LUTATHERA^® solution for infusion is a ‘radiolabelled somatostatin analog (SSA)’ comprised of a radionuclide (Lutetium-177) and a peptide (differs between Europe and USA)

The relevant SSA binds with high affinity to the somatostatin receptors (SSTR) overexpressed in malignant neuroendocrine cells such as the ones found in GEP-NETs.
Lutetium-177 is a β particle emitting radionuclide, with a mean penetration range of 0.67 millimetres in tissue (maximum penetration range of 2.2 mm) which is sufficient to kill targeted tumour cells with a limited effect on neighbouring normal cells.
The affinity for SSTRs and the specificity of binding ensures a high level of specificity in the delivery of radiation to the tumour. Before starting treatment with LUTATHERA^®, imaging must confirm the presence of these receptors in tumour tissues.

Generic PRRT

Since Lutathera was approved, 2 generics have been approved in 2026, on two different approval pathways in USA.

1. Lanthaus BRAVNETSA is a bioequivalent and therapeutically equivalent to LUTATHERA and approved through the full ANDA route – click here to read more.

2, Curium’s BEXLUTRY is said to be a radioequivalent approved via the 505(b)(2) route. Click here to read more

Read what is happening in next generation PRRT in the world of alpha-emitter PRRT – click here

Summary and Further reading on Theranostics

Somatostatin Receptor Imaging and Theranostics: Current Practice and Future Prospects (2021). A particularly relevant review covering SSTR PET, PRRT selection and response assessment. Authors include Lisa Bodei, Thomas A. Hope and Erik Mittra. Read the paper via PubMed [pubmed.ncb…lm.nih.gov] Five years old now but some big nuclear med hitters in the list of authors.
SNMMI Procedure Standard/EANM Practice Guideline for SSTR PET: Imaging Neuroendocrine Tumors (2023). A more technical guide to SSTR PET imaging in NETs, with authors including Thomas A. Hope, Lisa Bodei, Erik Mittra, Ken Herrmann and Andreas Kjaer. Read the guideline via PubMed [pubmed.ncb…lm.nih.gov]
Radionuclide Theranostics in Neuroendocrine Neoplasms: An Update (2024). A useful recent overview of PET-guided PRRT, retreatment, combination strategies, disease heterogeneity and emerging theranostic pairs. Authors include nuclear-medicine specialists Stefano Fanti and Valentina Ambrosini. Read the open-access paper [link.springer.com]

Note: Many of the latest papers I wanted to list are behind paywalls.

There’s even Theranostics developing for non-SSTR targets including for Neuroendocrine Neoplasms, e.g. DLL-3 – click here to read.

Thanks for reading