Imaging and liquid biopsy in the prediction and evaluation of response to PRRT in neuroendocrine tumors: implications for patient management

Abstract

Purpose: The aim of this narrative review is to give an overview on current and emerging imaging methods and liquid biopsy for prediction and evaluation of response to PRRT. Current limitations and new perspectives, including artificial intelligence, are discussed.

Methods: A literature review of PubMed/Medline was performed with representative keywords. The search included articles published online through August 31, 2020. All searches were restricted to English language manuscripts.

Results: Peptide radio receptor therapy (PRRT) is a prospectively evaluated and approved therapy option in neuroendocrine tumors (NETs). Different ligands targeting the somatostatin receptor (SSTR) are used as theranostic pairs for imaging NET and for PRRT. Response assessment in prospective trials often relies on the morphological RECIST 1.1 criteria, based on lesion size in CT or MRI. The role of SSTR-PET and quantitative uptake parameters and volumetric data is still not defined. Monoanalyte tumor marker chromogranin A has a limited value for response assessment after PRRT. New emerging liquid biopsy techniques are offering prediction of response to PRRT and prognostic value.

Conclusions: New response criteria for NET patients undergoing PRRT will comprise multiparametric hybrid imaging and blood-based multianalyte markers. This represents tumor biology and heterogeneity.

Keywords: Liquid biopsy; NET; PRRT; SSTR-PET.

Fig. 1

An 80-year-old patient with liver and lymph node metastases of NET (G2; Ki-67: 19%) with unknown primary. Maximum intensity projection (MIP) of 68Ga-DOTATATE PET (a) shoes high level of SSTR expression, higher than uptake in liver and spleen, an advantage for PRRT. MRI (b, c) shows typical early arterial hyperenhancement (b) and low ADC values (d), consistent with malignant lesions, as shown in fused images (e). [18F]F-FDG-PET MIP (f) and transversal PET of the liver (g) did not show elevated uptake in NET metastases, being a favorable prognostic marker in highly proliferative NET. 177Lu-post-therapy whole-body scan after the first of four cycles of 177Lu-DOTATATE therapy proved high uptake metastases of NET (Krenning scale 4; higher than uptake in liver and spleen). Post-therapy staging by 68Ga-DOTATATE PET/MRI (h) revealed mixed response with partly constant (seg. II) and partly regressive liver metastasis (seg. V) (i, j) with continuously low ADC values (l). A situation difficult to assess by current response assessment criteria. Furthermore, fused images (k) and MIP (h) show reduced SSTR expression and reduced SSTR-positive volume compared to initial staging. As these parameters are not integrated into current response assessment criteria, its role for outcome prediction remains unclear

Fig. 2

Utility of the NETest and PPQ for stratification and monitoring of PRRT in a patient affected by a well-differentiated G2 neuroendocrine tumor of unknown primary metastatic to the liver, status post somatostatin analogues. The patient is selected for PRRT with a positive PPQ (predicted to respond) and receives ¹⁷⁷Lu-DOTATATE (26 GBq in 4 cycles). The pretreatment imaging (a, b, fused and pure ⁶⁸Ga-DOTATATE images) demonstrates bilobar liver metastases. The restaging exam performed 5 months later (c, d, fused and pure SSR PET images) demonstrates a decrease in size and avidity of the liver metastases, thus confirming the PPQ prediction. The NETest levels (e, activity 1–100%, positive >20) measured throughout the therapy are decreased during the treatment cycles