Correlation of dose with toxicity and tumour response to 90Y- and 177Lu-PRRT provides the basis for optimization through individualized treatment planning

Abstract

Purpose: Peptide receptor radionuclide therapy (PRRT) with ⁹⁰Y-labelled and ¹⁷⁷Lu-labelled peptides is an effective strategy for the treatment of metastatic/nonresectable neuroendocrine tumours (NETs). Dosimetry provides important information useful for optimizing PRRT with individualized regimens to reduce toxicity and increase tumour responses. However, this strategy is not applied in routine clinical practice, despite the fact that several dosimetric studies have demonstrated significant dose-effect correlations for normal organ toxicity and tumour response that can better guide therapy planning. The present study reviews the key relationships and the radiobiological models available in the literature with the aim of providing evidence that optimization of PRRT is feasible through the implementation of dosimetry.

Methods: The MEDLINE database was searched combining specific keywords. Original studies published in the English language reporting dose-effect outcomes in patients treated with PRRT were chosen.

Results: Nine of 126 studies were selected from PubMed, and a further five were added manually, reporting on 590 patients. The studies were analysed and are discussed in terms of weak and strong elements of correlations.

Conclusion: Several studies provided evidence of clinical benefit from the implementation of dosimetry in PRRT, indicating the potential contribution of this approach to reducing severe toxicity and/or reducing undertreatment that commonly occurs. Prospective trials, possibly multicentre, with larger numbers of patients undergoing quantitative dosimetry and with standardized methodologies should be carried out to definitively provide robust predictive paradigms to establish effective tailored PRRT.

Keywords: Absorbed dose correlations; Dose–effect; Dose–toxicity; Dosimetry; Peptide receptor radionuclide therapy (PRRT).

Fig. 1

Absorbed dose of ⁹⁰Y-DOTATOC per unit activity in the kidneys (a), red marrow (b), and tumour (c). The asterisks indicate older studies when no kidney protection was given, so a 30% to 60% absorbed dose reduction would be expected with administration of kidney protectors. Bars with full shading show mean values and standard deviations of absorbed doses per unit activity; bars with hatching show median values and ranges of variability

Fig. 2

Absorbed dose of ¹⁷⁷Lu-DOTATATE per unit activity in the kidneys (a), red marrow (b), and tumour (c). This therapy was always administered with kidney protection. Bars with full shading show mean values and standard deviations of absorbed doses per unit activity; bars with hatching show median values and ranges of variability

Fig. 3

Kidney toxicity rates reported in studies of PRRT with ⁹⁰Y-DOTATOC, ⁹⁰Y-DOTATATE, ¹⁷⁷Lu-DOTATATE, and the combination of ⁹⁰Y-DOTATOC and ¹⁷⁷Lu-DOTATATE (yellow bars grades I/II, orange bars grade II, red bars grades III–V). ⁹⁰Y alone and ⁹⁰Y + ¹⁷⁷Lu were associated with significantly higher nephrotoxicity, while severe nephrotoxicity was virtually absent after treatment with ¹⁷⁷Lu-labelled peptides. The data of Marincek [43] a, b and c correspond to three groups of patients receiving low, medium and high activities, with median values of 9.6, 12.6, and 13.3 GBq, respectively. Table 3 provides more detailed information on the studies considered in this figure

Fig. 4

Creatinine clearance loss as a function of cumulative absorbed dose to the kidneys for 2 to 4 cycles (diamonds) and 5 to 11 cycles (triangles). Patients receiving therapy in a higher number of cycles experienced creatinine clearance loss at higher absorbed doses. Data derived from the study by Bodei et al. [37]

Fig. 5

Tumour response in relation to tumour absorbed dose for all lesions evaluated with a diameter >2.2 cm (blue circles) and for lesions with a diameter >4.0 cm (red triangles). Adapted from Ilan et al. [31]