The impact of 177Lu-octreotide therapy on 99mTc-MAG3 clearance is not predictive for late nephropathy

Abstract

Peptide Receptor Radionuclide Therapy (PRRT) for the treatment of neuroendocrine tumors may lead to kidney deterioration. This study aimed to evaluate the suitability of 99mTc-mercaptoacetyltriglycine (99mTc--MAG3) clearance for the early detection of PRRT-induced changes on tubular extraction (TE). TE rate (TER) was measured prior to 128 PRRT cycles (7.6±0.4 GBq 177Lu-octreotate/octreotide each) in 32 patients. TER reduction during PRRT was corrected for age-related decrease and analyzed for the potential to predict loss of glomerular filtration (GF). The GF rate (GFR) as measure for renal function was derived from serum creatinine. The mean TER was 234 ± 53 ml/min/1.73 m² before PRRT (baseline) and 221 ± 45 ml/min/1.73 m² after a median follow-up of 370 days. The age-corrected decrease (mean: -3%, range: -27% to +19%) did not reach significance (p=0.09) but significantly correlated with the baseline TER (Spearman p=-0.62, p<0.001). Patients with low baseline TER showed an improved TER after PRRT, high decreases were only observed in individuals with high baseline TER. Pre-therapeutic TER data were inferior to plasma creatinine-derived GFR estimates in predicting late nephropathy. TER assessed by 99mTc-MAG3-clearance prior to and during PRRT is not suitable as early predictor of renal injury and an increased risk for late nephropathy.

Keywords: 177Lu; MAG3; PRRT; neuroendocrine tumor; renal scintigraphy.

Figure 1. Relative change of the tubular extraction rate (TER) normalized to the lower normal limit TER_LoLi between the first and last clearance measurements as a function of a

the cumulated activity (Spearman ρ = −0.21; p = 0.25) and b. the ratio TER/TER_LoLi prior to Peptide Receptor Radionuclide Therapy (PRRT) (Spearman ρ = −0.62; p < 0.001) as well as c. relative change of estimated glomerular filtration rate (eGFR) during treatment as a function of the renal function prior to PRRT (Spearman ρ = −0.38; p = 0.03) and d. the change of eGFR in the follow-up of 27 patients as a function of the change of TER/TER_LoLi during PRRT (Spearman ρ = −0.16; p = 0.42). The lines indicating linear regressions were drawn to guide the eyes.

Figure 2. Dependence of the change of tubular extraction rate TER/TER_LoLi per administered activity in GBq as a function of TER/TER_LoLi prior to first therapy

Each data point with error bars represents the result of a regression analysis as illustrated in Figure 3 with the correspondent uncertainty of the regression parameters. Small error bars indicate a clear trend of TER/TER_LoLi with minor scatter of data. The result of a weighted linear regression to the data is shown by a straight line characterized by intercept 1.08% ± 0.27% and slope −0.89% ± 0.20%. Individuals with typical renal clearance TER-1.43 TER_LoLi are expected to have a relative loss of TER of 0.20% per GBq [¹⁷⁷Lu-DOTA(0),Tyr(3)]-octreotate/octreotide (¹⁷⁷Lu-DOTATATE/-TOC) or 1.4% per treatment cycle with a standard activity of 7.5 GBq ¹⁷⁷Lu-DOTATATE/-TOC. TER = tubular extraction rate, TER/TER_LoLi = TER normalized to the lower normal limit TER_LoLi, PRRT = Peptide Receptor Radionuclide Therapy.

Figure 3. Tubular extraction rate (TER) normalized to the lower normal limit (TER_LoLi) vs

the cumulated activity (A_cum) in a patient with improving renal function in the course of 4 cycles of Peptide Receptor Radionuclide Therapy (dots) and a patient with loss of function during 8 cycles (circles). The dashed lines show the results of linear regression: TER/TER_LoLi = ß₀+ß₁*A_cum [GBq] (ß₀: 90.1% ± 2.3% and 132.7% ± 2.7%; ß₁: 0.50% ± 0.12% and −0.51% ± 0.07% per GBq, respectively). TER/TER_LoLi is 1 or larger in patients with normal kidney function and < 1 in those with impaired TER.