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Peptide Receptor Radionuclide Therapy with 177Lu Labeled Somatostatin Analogs DOTATATE and DOTATOC: Contrasting Renal Dosimetry in the Same Patient

Conference paper
First Online:
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 194)

Abstract

Aim: The aim of this study is to correlate the uptake, residence time, and resulting mean absorbed dose in the kidneys with the posttherapy effect on renal function using the two most commonly used somatostatin analogs, 177Lu-DOTATATE and 177Lu-DOTATOC, during consecutive cycles of peptide receptor radionuclide therapy (PRRNT) in the same patient. Methods: 22 patients with metastatic neuroendocrine tumors underwent PRRNT with 177Lu-DOTATATE and 177Lu-DOTATOC. Dosimetry (MIRD scheme) was performed using OLINDA software. The patients were followed up for 6–12 months with serum creatinine, BUN, tubular extraction rate (TER) using 99mTc-MAG3, and glomerular filtration rate (GFR) using 99mTc-DTPA before and after therapy. Age, hypertension, and diabetes mellitus were the associated risk factors for renal toxicity, which were taken into account. Results: Uptake, residence time, and mean absorbed dose to the kidney were slightly, but significantly, higher for DOTATATE (actual absorbed dose 1.9–9.2 Gy) as compared with DOTATOC (dose 2.3–7.8 Gy) in 19 out of the 22 (86%) patients (p < 0.05). The tumor-to-kidney ratio was higher for DOTATOC in 23 out of 43 (53%) of the lesions analyzed; however, this difference was not statistically significant. There were no statistically significant changes in serum creatinine, BUN, TER or GFR pre and post-therapy with either DOTATATE or DOTATOC. Five of the 22 patients had mildly elevated serum creatinine after PRRNT, of whom 3 had history of hypertension, 1 had diabetes, and 1 was more than 65 years of age. Conclusions: 177Lu-DOTATATE and 177Lu-DOTATOC are safe radiopharmaceuticals concerning renal toxicity. 177Lu-DOTATOC delivers a slightly, but significantly, lower renal dose.

Keywords

Mean absorbed dose DOTATATE DOTATOC 
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1 Introduction

Treatment with radiolabeled somatostatin analogs is a valid therapeutic option for management of patients with inoperable or metastasized well-differentiated neuroendocrine tumors. Favorable results have been obtained with both 90Y- and 177Lu-labeled peptides in terms of tumor regression (De Jong et al. 2002; Kwekkeboom et al. 2005a, b; Otte et al. 1998).

All the radiopharmaceuticals used for peptide receptor radionuclide therapy (PRRNT) show high uptake in parenchyma of kidneys and hence pose the risk of nephrotoxicity. Renal uptake is not somatostatin receptor mediated, but related primarily to the very rapid clearance of the small radiopeptides that are filtered through the glomeruli and reabsorbed by the tubular cells (Pauwels et al. 2005; De Jong et al. 1998; Behr et al. 1998). Kidneys are therefore the dose-limiting organs for PRRNT, making accurate renal dosimetry absolutely essential to minimize radiation nephropathy (Pauwels et al. 2005; Valkema et al. 2005; Lambert et al. 2004).

The pattern of nephrotoxicity after PRRNT is that of progressive chronic renal disease (Valkema et al. 2005). Age greater than 65 years, hypertension, and diabetes are the risk factors contributing to decline in renal function after PRRNT, in addition to the per-cycle and cumulative renal dose (Valkema et al. 2005; Arora et al. 2012; National Chronic Kidney Disease Fact Sheet 2010; Bodei et al. 2008).

The two radiolabeled peptides commonly used in PRRNT are 177Lu-DOTATATE and 177Lu-DOTATOC. The aim of this study is to compare and correlate the renal uptake, residence time, per-cycle mean absorbed dose, and toxicity to the kidneys in a group of patients having undergone PRRNT with both peptides, taking the additional risk factors into account.

2 Patients and Methods

2.1 Patients

All patients enrolled in this study were suffering from metastasized NETs with liver, lymph node, bone, or other metastases. Intense somatostatin receptor (SSTR) expression of primary tumors and metastases had been verified before therapy by using 68Ga DOTA-somatostatin receptor (SSTR) analog positron emission computed tomography (PET/CT) using DOTANOC/DOTATOC or DOTATATE. Each patient was extensively informed about the therapeutic procedure and possible adverse effects. The study was performed according to guidelines, approved by the local ethics committee, and in accordance with German regulations concerning radiation safety.

Twenty-two patients with neuroendocrine tumors (12 male, 10 female; age 45.3–75.5 years) underwent treatment with 177Lu-DOTATATE (5.0–9.5 GBq) and 177Lu-DOTATOC (5.5–8.5 GBq) in consecutive cycles (Table 1). The time period between cycles was 10–14 months. Data obtained from this group were used to compare kinetics and mean absorbed doses to kidneys with therapy using 177Lu-DOTATATE and 177Lu-DOTATOC in the same patients. The risk factors of chronic renal disease considered in the patient group were age greater than 65 years, hypertension, and diabetes mellitus (Table 2).
Table 1

Characteristics of 22 patients (12 male, 10 female) treated with DOTATATE and DOTATOC included in the study

 

DOTATATE

DOTATOC

Age

60.2 ± 9.1 years

 

45.3−75.2 years

 

Activity per cycle (GBq)

6.5 ± 1.1

7.3 ± 0.7

5.0−9.5

5.5−8.5

Table 2

Risk factors present in the patient group

Risk factor

No. of patients

Hypertension

9

Diabetes

2

Age more than 65 years

4

2.2 Radiopharmaceuticals

The radiopharmaceuticals were prepared in our own radio pharmacy. 177Lu-labeling of DOTA-peptides was done according to the general procedure: A solution of 500 μg 2,5-dihydroxybenzoic acid and 50 μg of the corresponding DOTA peptide in 50 μL 0.4 M sodium acetate buffer (pH 5.5) was added to a solution of 1 GBq in 30 μL 0.05 M HCl. The mixture was heated to 90°C for 30 min and then diluted with 0.9% saline solution followed by sterile filtration. Quality control settings were the following: RP-18-HPLC, solvent A: water; solvent B: acetonitrile (both with 0.1% TFA); gradient: 0–2 min 100% A, 20 min 100% B; flow rate: 1.2 mL/min; column: LiChrospher 100RP 18EC-5 μm 250 × 4 mm. The radiochemical purity was greater than 99.5%.

2.3 Infusion and Renal Protection

For kidney protection, every patient was co-infused with 1,500 mL of a renoprotective amino acid mixture of 5% lysine HCL and 10% l-arginine HCL in 250 mL NaCl at pH 7.4 and osmolarity of 400 mosmol/l. This infusion was started 30 min prior to administration of the therapeutic dose and continued for 4 h. The radiopharmaceutical was co-administered over 10–15 min by using a second infusion pump system. This co-infusion of amino acids reduces renal exposure and allows for higher mean absorbed doses to reach tumors (Jamar et al. 2003).

The activity to administer was chosen based on the general status of the patient (e.g., Karnofsky scale), kidney function, hematologic reserve, tumor mass and SSTR expression, previous treatments, and also experience reported by other groups (Kwekkeboom et al. 2005).

2.4 Monitoring of Renal Function

In all patients undergoing PRRNT, follow-up of renal function was carried out after each cycle after a period of 6–12 months with serum creatinine and BUN. GFR was determined using 110–185 MBq 99mTc-DTPA before and every 3–4 months after therapy, and the tubular extraction rate (TER) determined using 99mTc-MAG3 was also documented.

2.5 Dosimetry

Dosimetric calculations were performed according to the MIRD scheme from 2D planar whole image sets (Bolch et al. 2009). The time-dependent activity was determined based on conjugated planar whole-body scans acquired 0.5, 3, 20–24, 44–48, and 68–72 h post injection. For estimation of mean absorbed doses, we used a well-established dosimetry protocol, as was used in a previous study (Wehrmann et al. 2007).

2.6 Comparison and Statistics

The dosimetric parameters determined for kidneys in addition to the mean absorbed dose were uptake, half life, residence time, and tumor-to-kidney ratio. Pre- and post-therapy serum creatinine, GFR, and TER were also compared. The effect of age, diabetes, hypertension, and total administered activity on renal function was determined. For evaluation of statistically significant differences, nonparametric signed-rank tests for paired samples were used. All statistical tests were performed using ORIGINPRO 8.1G; p-values ≤ 0.05 were considered to be significant.

3 Results

The dosimetric parameters for kidneys were determined in 22 patients for both DOTATATE and DOTATOC (Fig. 1). Renal uptake, residence time, and mean absorbed dose per unit administered activity showed higher values for DOTATATE in 19 of 22 patients (86%, p < 0.05). These results were statistically significant. Only half-life was found to be similar for both peptides, where 12 patients (55%) showed longer half-life for DOTATATE (p > 0.05).
Fig. 1

Comparison of renal dosimetry parameters for DOTATATE and DOTATOC

Tumor-to-kidney ratio was higher for DOTATOC in 23 of 43 (53%) lesions measured; however, this difference was not statistically significant (p > 0.05).

There were no statistically significant changes in GFR (Fig. 2a), TER (Fig. 2b), or serum creatinine (Fig. 2c) pre and post-therapy with either DOTATATE or DOTATOC (p > 0.1). Five of the 22 patients had mild elevation in serum creatinine, of whom 3 had history of hypertension, 1 had diabetes mellitus, and 1 was aged >65 years. In none of these five patients did any significant fall in serum creatinine occur post-therapy. Thus, no significant changes in renal function were observed in any of the patients irrespective of the amount of administered radioactivity and peptide used for PRRNT.
Fig. 2

Comparison of pre- and post-therapy renal parameters in patients treated with DOTATOC and DOTATATE: a GFR, b TER, and C serum creatinine

4 Discussion

Since kidneys are the dose-limiting organs in PRRNT, the safe therapeutic window in our opinion would be best determined by the tumor-to-kidney ratio for absorbed dose. In the present study, this ratio was comparable for DOTATATE and DOTATOC, when individual lesions were considered. However, Forrer et al. (2004), in a study of five patients comparing 111In-DOTATATE and 111In-DOTATOC as surrogates to study the biodistribution of 90Y-labeled peptides, found a significant difference between the mean values for the two peptides and concluded on this basis to continue using DOTATOC for PRRNT.

Esser et al. (2006) compared 177Lu-DOTATATE and 177Lu-DOTATOC in seven patients and found also longer residence time in kidneys with DOTATATE. They concluded, however, that DOTATATE would be the better peptide for PRRNT based on the finding that the ratio of residence times of DOTATATE to DOTATOC in tumor was higher than that for kidneys and hence DOTATATE gives a higher dose to the tumor. On the other hand, Forrer et al. (2004) found no significant difference in mean absorbed dose to kidneys. In our study, the mean absorbed kidney dose was significantly higher for DOTATATE than for DOTATOC due to significantly higher renal uptake and longer residence time in kidneys.

The high interpatient variability in the mean absorbed doses was due to patients’ heterogeneity, presenting with varying receptor density and tumor burden. The estimated mean dose to the kidney in this study was 1.9–9.2 Gy, which is comparable to that determined by Valkema et al. (2005), who reported a renal dose of 1.8–7.8 Gy. In addition, the results showed also significant intrapatient variability (i.e., in the same patient undergoing PRRNT with different peptides) with respect to renal pharmacokinetics and renal dose.

However, in comparison with 90Y-labeled peptides (DOTATATE or DOTATOC), the renal dose is significantly lower when using 177Lu, which translates into lower renal toxicity (Forrer et al. 2004; Bodei et al. 2003; Helisch et al. 2004). This corresponds to the clinical experience, where renal impairment occurred more frequently in patients treated with 90Y-peptide as compared with the sporadic incidence observed with 177Lu-DOTATATE PRRNT (despite mean cumulative kidney doses of up to 45 Gy) (Valkema et al. 2005). This can be explained on the basis of the particle range and the site of peptide accumulation. All radiolabeled peptides localize in the proximal tubules, where they are reabsorbed. Since tubular cells are relatively radioresistant and able to repair and regenerate, renal toxicity due to radiation to the renal tubules is quite unlikely, as confirmed by the fact that there was no significant fall in TER in our study (Cremonesi et al. 2006). However, glomerular cells are relatively radiosensitive and not able to regenerate, therefore bearing a high nephrotoxic potential. The long-range β-particles of the 90Y-peptides may increase the toxicity due to cross-fire irradiation of glomerular cells. On the other hand, since the β-particles of 177Lu-peptides are of short range, they irradiate tubular cells more selectively, sparing glomeruli as confirmed by the evidence that there was no significant short-term decline in GFR in our study (Cremonesi et al. 2006).

As previous studies have shown, other contributing risk factors for chronic renal disease must also be considered, the presence of which accelerates the onset of end-stage renal disease (ESRD), especially when using 90Y-labeled peptides (Valkema et al. 2005; Bodei et al. 2008). A dose of 28 Gy has been advocated as the threshold for the biologically effective dose (BED) for patients with risk factors (mainly hypertension and diabetes) to minimize the risk of ESRD following PRRNT (Bodei et al. 2008). In our study we considered age greater than 65 years, diabetes, and hypertension as the most relevant risk factors for chronic renal disease. In fact, all five patients with mild renal dysfunction after PRRNT had one of the risk factors present; however, PRRNT with 177Lu-labeled peptides could be safely administered to these patients without any short-term adverse effects.

5 Conclusions

177Lu-DOTATATE and 177Lu-DOTATOC are safe radiopharmaceuticals concerning renal toxicity. Both are equivalent with respect to tumor-to-kidney ratio. 177Lu-DOTATOC delivers a slightly, but significantly, lower renal mean absorbed dose. The mean absorbed dose to the kidney with 177Lu-labeled peptides is significantly lower than renal mean absorbed doses delivered when using 90Y-labeled DOTATATE or DOTATOC, corresponding to lower renal toxicity. Finally, this study underlines the importance of clinical screening for risk factors of chronic renal disease before PRRNT.

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© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of Nuclear Medicine and Center for PET/CTENETS Center of Excellence, Zentralklinik Bad BerkaBad BerkaGermany

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