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. 2016 Sep;43(10):1802-11.
doi: 10.1007/s00259-016-3382-9. Epub 2016 May 10.

Nephrotoxicity after PRRT with (177)Lu-DOTA-octreotate

Hendrik Bergsma  1 , Mark W Konijnenberg  2 , Wouter A van der Zwan  2 , Boen L R Kam  2 , Jaap J M Teunissen  2 , Peter P Kooij  2 , Katya A L Mauff  3 , Eric P Krenning  2 , Dik J Kwekkeboom  2
Affiliations

Nephrotoxicity after PRRT with (177)Lu-DOTA-octreotate

Hendrik Bergsma et al. Eur J Nucl Med Mol Imaging. 2016 Sep.

Abstract

Purpose: After peptide receptor radionuclide therapy (PRRT), renal toxicity may occur, particular in PRRT with (90)Y-labelled somatostatin analogues. Risk factors have been identified for increased probability of developing renal toxicity after PRRT, including hypertension, diabetes and age. We investigated the renal function over time, the incidence of nephrotoxicity and associated risk factors in patients treated with PRRT with [(177)Lu-DOTA(0),Tyr(3)]-Octreotate ((177)Lu-Octreotate). Also, radiation dose to the kidneys was evaluated and compared with the accepted dose limits in external beam radiotherapy and PRRT with (90)Y-radiolabelled somatostatin analogues.

Methods: The annual decrease in creatinine clearance (CLR) was determined in 209 Dutch patients and the incidence of grade 3 or 4 renal toxicity (according to CTCAE v4.03) was evaluated in 323 patients. Risk factors were analysed using a nonlinear mixed effects regression model. Also, radiation doses to the kidneys were calculated and their association with high annual decrease in renal function were analysed.

Results: Of the 323 patients, 3 (1 %) developed (subacute) renal toxicity grade 2 (increase in serum creatinine >1.5 - 3.0 times baseline or upper limit of normal). No subacute grade 3 or 4 nephrotoxicity was observed. The estimated average baseline CLR (± SD) was 108 ± 5 ml/min and the estimated average annual decrease in CLR (± SD) was 3.4 ± 0.4 %. None of the risk factors (hypertension, diabetes, high cumulative injected activity, radiation dose to the kidneys and CTCAE grade) at baseline had a significant effect on renal function over time. The mean absorbed kidney dose in 228 patients was 20.1 ± 4.9 Gy.

Conclusion: Nephrotoxicity in patients treated with (177)Lu-octreotate was low. No (sub)acute grade 3 or 4 renal toxicity occurred and none of the patients had an annual decrease in renal function of >20 %. No risk factors for renal toxicity could be identified. Our data support the idea that the radiation dose threshold, adopted from external beam radiotherapy and PRRT with (90)Y-labelled somatostatin analogues, does not seem valid for PRRT with (177)Lu-octreotate.

Keywords: 177Lu-Octreotate; Dosimetry; Kidneys; Nephrotoxicity; PRRT; Renal function; Toxicity.

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Figures

Fig. 1
Fig. 1
Baseline 24-h urine creatinine clearance (CLR) versus serum-based CLR according to the Cockcroft-Gault formula in 281 of 323 patients. The solid line is the linear regression line with a slope of 1 with 95 % confidence intervals (dotted lines)
Fig. 2
Fig. 2
Distribution of creatinine clearance in 323 patients according to Common Terminology Criteria for Adverse Events (CTCAE) classification at baseline, and at 1, 2 and 3 years after inclusion. Number (N) of patients with serum creatinine available / total number of patients in follow-up. No CTCAE grade 4 was observed
Fig. 3
Fig. 3
Nonlinear model of creatinine clearance (CLR) over time based on 208 patients. Solid line is the exponential function with 95 % confidence interval (dashed lines). The estimated average baseline CLR (± SD) is 108 ± 5 ml/min and the estimated average annual change in CLR (± SD) is 3.4 ± 0.4 %
Fig. 4
Fig. 4
Time-course of creatinine clearance (CLR) and fitted monoexponential decay (solid line) in a 71-year-old patient with a neuroendocrine tumour, hypertension and diabetes, who received 4 × 7.4 GBq 177Lu-Octreotate. The estimated decrease in CLR is 11.4 % per year
Fig. 5
Fig. 5
Distribution of the change in creatinine clearance per year in 208 patients with long-term follow-up. Note the log scale on the y-axis. Coloured bars represent annual loss of renal function < 10% (blue), 10-15% (yellow) and >15% (orange)
Fig. 6
Fig. 6
Distribution in 1-Gy increments of the radiation dose to the kidneys for 407 patients and in 228 patients with quantifiable kidney uptake: a actual distribution in 407 patients; b hypothetical distribution for 4 × 7.4 GBq of 177Lu-Octreotate; c actual distribution in 228 Dutch patients. Gaussian fits (dashed lines) are overlain on the histograms. The green arrow indicates the kidney threshold dose (18 Gy) according to current EBRT guidelines [10]. The orange arrow (24 Gy) and red arrow (28 Gy) correspond to the PRRT dose limits for kidney damage according to Wessels et al. [11] and Bodei et al. [2], respectively, for therapies given in four cycles
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References

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