Long-term effects of [177Lu]Lu-PSMA therapy on the kidneys based on cumulative absorbed dose

Abstract Background 177 Lu-PSMA radiopharmaceutical therapy shows favorable clinical responses for metastatic castration-resistant prostate cancer patients but may cause radiation-induced kidney damage due to specific and nonspecific activity accumulation. We evaluated the association between cumulative kidney absorbed doses and long-term kidney toxicity. Methods This retrospective analysis included 127 patients who underwent treatment of mCRPC using 177 Lu-based ligands (7.4 GBq at each cycle for [ 177 Lu]Lu-PSMA-617 [ n = 25] or 3.6–9.5 GBq throughout the treatment for [ 177 Lu]Lu-PSMA-I&T [ n = 102]). MIM Software (7.3.4) was used to calculate the absorbed dose (AD) to the kidney (CT-based segmentation) using one of three validated protocols based on data availability: multiple timepoint acquisition, Hänscheid approach at 48 h, or the prior information approach. [ 99m Tc]Tc-MAG3 scintigraphy scans were used to obtain tubular excretion rates, while serum-based sampling for glomerular filtration rate (eGFR) quantification was used. Up to 36 months post-treatment initiation CTCAE v5.0: Chronic Kidney Disease was determined. Results The AD of [ 177 Lu]Lu-PSMA-617 (0.26 ± 0.09 Gy/GBq) was significantly less than [ 177 Lu]Lu-PSMA-I&T (0.32 ± 0.13 Gy/GBq) [ p = 0.01] at cycle 1. Kidney AD per cycle did not significantly change across treatment cycles for either [ 177 Lu]Lu-PSMA-617 (median change: cycle 1–2, 1%; 2–3, 7%; 3–4, −5%; 4–5, 8%; 5–6, 26%) or [ 177 Lu]Lu-PSMA-I&T (cycle 1–2, 0%; 2–3, 0%; 3–4, 0%; 4–5, 3%; 5–6, 5%), although patient numbers decreased with increasing cycles. The percent change in AD from cycle 1 to cycle 6 was 0.6% ± 34.1% [n=3] and 12.2% ± 32.8% [n=9] for [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T, respectively. Cumulative AD exceeded 20 Gy in 5/127 (4%) patients, each who received at least 6 cycles of therapy. eGFR decrease was slightly greater in [ 177 Lu]Lu-PSMA-I&T than [ 177 Lu]Lu-PSMA-617; -13% [range: -76 – 40%] vs. -10% [range: -26 – 13%] at 24 months post-treatment. By 36 months post-treatment initiation of [ 177 Lu]Lu-PSMA-I&T, one patient reported CTCAE-3 and another CTCAE-4. 36 month follow-up of [ 177 Lu]Lu-PSMA-617 is unmatured. Conclusion Only 5/127 patients exceeded a kidney AD of 20 Gy, none developed CTCAE-3/4 nephrotoxicity. eGFR decrease was slightly greater in [ 177 Lu]Lu-PSMA-I&T than [ 177 Lu]Lu-PSMA-617, yet clinical repercussions is unknown. Radiation-induced nephrotoxicity remains rare within three-years.