Long-term Nephrotoxicity After Peptide Receptor Radionuclide Therapy (PRRT): Myth or Reality?

Objectives: Kidneys are generally considered as the potential dose-limiting organ for peptide receptor radionuclide therapy (PRRT) and consequently are of primary concern. The aim of this study was to assess nephrotoxicity of peptide receptor radionuclide therapy (PRRT) in a large cohort of patients with neuroendocrine neoplasms (NEN) treated over the last 20 years in our institution.

Methods: A total of 1361 patients with NEN (male 767; mean age 60.0 ± 11.8y), treated with ¹⁷⁷Lu-DOTATATE/-TOC/-JR11, ⁹⁰Y-DOTATATE/-TOC/-JR11, DUO-PRRT (sequential administration of ⁹⁰Y- and ¹⁷⁷Lu-), or TANDEM-PRRT (in combination of ⁹⁰Y- and ¹⁷⁷Lu- on the same day concomitantly), were included with all parameters prospectively documented in a structured database (comprising over 250 items per patient) and retrospectively analyzed. Kidney function (serum creatinine, blood urea nitrogen, cGFR, electrolytes) was evaluated prior to each PRRT cycle and in follow up (restaging was performed regularly at 6-months intervals until death). Renal function was further quantified by measuring the tubular extraction rate (TER) using ^99mTc-MAG3 renal scintigraphy as well as by determination of the glomerular function (GFR) using ^99mTc-DTPA. Treatment-related adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE v.5.0).

Results: 5448 cycles of PRRT were administered; in addition, 4052 records were available for restaging. The median overall survival was 70.1 months with a median follow-up time of 91.8 months. Baseline creatinine was normal in 82.0% of subjects, grade 1 (G1) renal insufficiency (RI) was present prior to PRRT in 16.2%, G2 in 1.7%, and G3 in 0.1%, respectively. After treatment, renal function was normal in 78.2%, 18.9% had G1, and 1.9% had G2 RI. CTC grade 3 events were recorded in only four patients (0.3%), of which two had a history of recurrent urinary tract infections and two had already GTC-3 at baseline. No CTC-4 or 5 nephrotoxicity was observed. TER changed from 207.7 ± 56.6 to 186.3 ± 53.8 ml/min (p<0.05); 45.5% of patients had a clinically non-significant fall in renal function, whereas 32% showed an improvement of renal parameters after treatment. GFR changed from 83.9 ± 24.3 to 76.4 ± 25.7 ml/min/1.73 m2 (p<0.05), including a clinically not relevant decline of >10% in 46.2%, whereas 33.0% showed an improvement. Furthermore, there was no significant change in the difference between the standardized absolute GFR and the individual normal value before and after treatment (p>0.05). For those patients who received 1-4 and 5-10 cycles of PRRT, CTCAE at the end of PRRT were 78.5% vs 72.9% in G0 (normal), 18.8% vs 21.9% in G1, 2.4% vs 4.8% in G2, and 0.3% vs 0.2% in G3, respectively. For subgroup who received 8-10 cycles of PRRT, the annual loss of the mean value of TER between 2003 and 2017 were <5% in 47.1%, 5%-10% in 17.6%, with an improvement in 35.5%, none were >10%. Conclusion: This retrospective analysis with prospective documentation in a large cohort of 1361 NEN patients, receiving 5448 cycles of PRRT with optimal nephroprotection, treated at a single institution over 20 years (with a median follow-up time of 91.8 months) did not reveal any evidence of significant long-term nephrotoxicity after PRRT. Part of these, dedicated multidisciplinary term of experienced NET specialists took care of these patients.

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