ORIGINAL ARTICLE

Accurate assessment of long-term nephrotoxicity after peptidereceptor radionuclide therapy with 177Lu-octreotate

Amir Sabet & Khaled Ezziddin & Ulrich-Frank Pape & Karl Reichman &

Torjan Haslerud & Hojjat Ahmadzadehfar & Hans-Jürgen Biersack &

James Nagarajah & Samer Ezziddin

Received: 6 August 2013 /Accepted: 1 October 2013 /Published online: 6 November 2013# Springer-Verlag Berlin Heidelberg 2013

AbstractPurpose Renal radiation during peptide receptor radionuclidetherapy (PRRT) may result in glomerular damage, a potentialreduction of glomerular filtration rate (GFR) and ultimatelylead to renal failure. While reported PRRT nephrotoxicity islimited to data derived from serum creatinine—allowing onlyapproximate estimates of GFR—the aim of this study is toaccurately determine PRRT-induced long-term changes ofrenal function and associated risk factors according to state-of-the-art GFR measurement.Methods Nephrotoxicity was analysed using 99mTc-diethylenetriaminepentaacetic acid (DTPA) clearance data of74 consecutive patients with gastroenteropancreatic neuroen-docrine tumours (GEP NET) undergoing PRRT with 177Lu-octreotate. The mean follow-up period was 21 months (range12–50) with a median of five GFR measurements per patient.The change of GFR was analysed by linear curve fit. Potentialrisk factors including diabetes mellitus, arterial hypertension,previous chemotherapy, renal impairment at baseline andcumulative administered activity were analysed regardingpotential impact on renal function loss. In addition, CommonTerminology Criteria for Adverse Events (CTCAE) v3.0 were

used to compare nephrotoxicity determined by 99mTc-DTPAclearance versus serum creatinine.Results The alteration in GFR differed widely among thepatients (mean −2.1±13.1 ml/min/m2 per year, relative yearlyreduction −1.8±18.9 %). Fifteen patients (21 %) experienceda mild (2–10 ml/min/m2 per year) and 16 patients (22 %) asignificant (>10 ml/min/m2 per year) decline of GFR follow-ing PRRT. However, 11 patients (15 %) showed an increaseof >10ml/min/m2 per year. Relevant nephrotoxicity accordingto CTCAE (grade ≥3) was observed in one patient (1.3 %)with arterial hypertension and history of chemotherapy. Neph-rotoxicity according to serum creatinine was discordant to thatdefined by GFR in 15 % of the assessments and led tounderestimation in 12 % of patients. None of the investigatedfactors including cumulative administered activity contributedto the decline of renal function.Conclusion Serious nephrotoxicity after PRRT with 177Lu-octreotate is rare (1.3 %). However, slight renal impairment(GFR loss >2 ml/min/m2 per year) can frequently (43 %) bedetected by 99mTc-DTPA clearance assessments. Cumulativeadministered activity of 177Lu-octreotate is not a major deter-minant of renal impairment in our study.

Keywords Nephrotoxicity . PRRT . 177Lu-octreotate . NET

Introduction

Peptide receptor radionuclide therapy (PRRT) withradiolabelled somatostatin analogues is a highly effectivesys temic t rea tment in pa t ien t s wi th metas ta t i cgastroenteropancreatic neuroendocrine tumours (GEP NET)[1–9]. Kidneys are often the dose-limiting organs and therelatively high radiation dose during PRRT can lead to renalimpairment and even end-stage renal disease, particularly afterPRRTwith 90Y-labelled peptides [10–15].

A. Sabet :K. Ezziddin :K. Reichman : T. Haslerud :H. Ahmadzadehfar :H.<J. Biersack : S. Ezziddin (*)Department of Nuclear Medicine, University Hospital Bonn,Sigmund-Freud-Str. 25, 53105 Bonn, Germanye-mail: samer.ezziddin@ukb.uni-bonn.de

U.<F. PapeDepartment of Hepatology and Gastroenterology, Charité, UniversityMedicine Berlin, Campus Virchow Clinic, Berlin, Germany

J. NagarajahDepartment of Nuclear Medicine, University Hospital,Essen, Germany

Eur J Nucl Med Mol Imaging (2014) 41:505–510DOI 10.1007/s00259-013-2601-x

Renal irradiation arises from the proximal tubular reabsorp-tion of the radiopeptide and the resulting retention in thecortex. Radiation nephropathy after PRRT is mainly due toprominent changes in arteriolar–glomerular area, ratherthan the tubular epithelium, leading to glomerular sclerosis[16, 17]. PRRT delivers continuous radiation at a relatively lowdose rate. It is, therefore, important to observe renal functionover a long period of time after PRRTas renal impairment maybecome clinically evident months after the treatment [13, 16,18–20]. However, standard measurements such as serum cre-atinine and creatinine clearance allow only an approximateestimation of the glomerular filtration rate (GFR) and inchoatealterations can only be demonstrated with more sensitivemethods such as 99mTc-diethylenetriaminepentaacetic acid(DTPA) or 51Cr-ethylenediaminetetraacetic acid (EDTA) clear-ance tests [21].

Several strategies to reduce nephrotoxicity in PRRT havebeen investigated. The coinfusion of positively chargedamino acids such as L-lysine and/or L-arginine as competi-tive inhibitors of proximal tubular reabsorption is currentlythe established renoprotective regimen in clinical PRRTwhich may reduce the renal dose ranging from 9 to 53 %[10, 11, 20]. The characteristics of the therapeutic radionu-clide may also influence the risk of nephrotoxicity. Due tothe lower energy characteristics and the shorter tissue pen-etration of beta particles, PRRT with 177Lu-labelled peptidesmay result in a lower radiation dose to the radiosensitiveglomeruli and a lower nephrotoxicity compared to that of90Y-labelled peptides [2, 22–26].

There are only limited data regarding nephrotoxicity afterPRRTwith 177Lu-octreotate and contributing risk factors. Theaim of this study was an accurate assessment of long-termchanges in GFR after treatment with 177Lu-octreotate usingthe 99mTc-DTPA clearance. The impact of potential risk fac-tors, including diabetes mellitus (DM), arterial hypertension(HTN), previous chemotherapy, decreased renal function atbaseline, age and cumulative administered activity was ofparticular interest.

Materials and methods

This retrospective analysis included 74 consecutive patientstreated with 177Lu-octreotate at our institution (45 men, 29women; age range 36–88 years; mean age 61 years). A min-imum follow-up of 12 months was required for patient inclu-sion. Inclusion criteria for treatment with PRRT were histo-logically confirmed, unresectable, metastatic NET, sufficienttumour uptake, i.e. ≥ liver uptake on baseline receptor imag-ing, GFR of >30 ml/min/1.73 m2, WBC count ≥2,000/mm3,haemoglobin ≥8 g/dl and platelets ≥75,000/mm3. Twenty-sixpatients had pancreatic NET (PNET) and 48 patients non-pancreatic GEP NET. The study was performed in accordance

with the Declaration of Helsinki and with national regulations.Patients had provided informed consent for the scientificanalysis of their data. Approval by the Institutional ReviewBoard is not required for retrospective studies on non-experimental interventions at the authors’ institution. Howev-er, explicit approval from the local Ethics Committee wasobtained for the prospective and retrospective assessment ofoutcome of NET patients throughout follow-up in our institu-tion, including this retrospective investigation.

PRRT was performed with a mean of 7.9 GBq (213 mCi)[177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) per treat-ment cycle, aimed at four courses and standard intervals of3 months (10–14 weeks). The 177Lu (IDB Holland, Baarle-Nassau, The Netherlands) had a specific activity in the ap-proximate range of 100–160 GBq/μmol at the time of admin-istration. The peptide labelling [27, 28] was performed suchthat an apparent specific activity of about 54 GBq/μmol (ratioof activity to the total amount of peptide) was obtained.

GFR using 99mTc-DTPA clearance test as well as serumcreatinine were measured prior to each treatment course,8–12 weeks after the last course of PRRT and at 3-monthintervals in the further follow-up with a median of fivemeasurements per patient. 99mTc-DTPA clearance assess-ment was performed with a single injection technique afterstandardized oral hydration using a two-point samplingapproach at 1 and 3 h post-injection according to themethod of Russell et al. [29]. Toxicity was recorded usingthe Common Terminology Criteria for Adverse Eventsv3.0 (CTCAE).

The annual GFR change was analysed by a linear curve fitmodel. The impact of baseline characteristics of the studypopulation and cumulative administered activity on the renalfunction loss was examined applying non-parametric tests forindependent samples and regression analysis. In addition,multiple logistic regression analysis was performed to identifyrisk factors for a GFR decrease of >10 ml/min/m2 per year.The statistical software package SPSS (version 20.0, SPSSInc., Chicago, IL, USA) was used to analyse the data.

Results

The 74 patients underwent 268 PRRTcourses with cumulativeactivities of 177Lu-octreotate ranging between 14.8 and37.8 GBq. The baseline GFR (pretreatment) was 80±23 ml/min/1.73 m2. The median follow-up period was 21 months(95 % confidence interval 12–50). Significant (≥ grade 3)renal toxicity according to CTCAE was observed in onlyone patient (79 years old, CTCAE grade 3) with a baselineGFR of 40 ml/min/1.73 m2, history of chemotherapy andarterial HTN almost 13 months after the start of PRRT. Thepatient had received a total of 21.8 GBq (589 mCi). No grade4 or 5 renal toxicity was observed in our cohort.

506 Eur J Nucl Med Mol Imaging (2014) 41:505–510

The mean long-term change of the body surface-correctedGFR was −2.1±13.1 ml/min/m2 per year (median −1.0 ml/min/m2 per year), corresponding to a relative yearly GFRreduction of −1.8±18.9 %. Following PRRT, 15 patients(21 %) experienced a mild (2–10 ml/min/m2 per year) and16 patients (22 %) a moderate to significant (>10 ml/min/m2

per year) decline in GFR. However, 11 patients (15 %)showed an increase of >10 ml/min/m2 per year.

Of the entire cohort, 54 patients (73 %) and 13 of the 16patients (81 %) with significant yearly loss of GFR had atleast one risk factor for development of radiation-inducedkidney disease (Table 1). However, statistical analysis re-vealed no significant relationship between the decline ofGFR and the baseline characteristics (i.e. age ≥70 years,GFR <60 ml/min/1.73 m2, DM, HTN, previous chemothera-py) of the patients (Fig. 1). Also, none of these factors wereassociated with a GFR reduction of >10 ml/min/m2 per year,applying logistic regression analysis (p >0.1 for all includedvariables). Interestingly, even the administration of highercumulative activities of 177Lu-octreotate was not associatedwith more pronounced reductions of GFR (Fig. 2, p =0.1). Todetermine how balanced other risk factors were over the totalactivities given, Table 2 lists respective patient characteristicsaccording to the cumulative administered activities(<29.6 GBq vs >29.6 GBq).

Nephrotoxicity (CTCAE) graded according to serum cre-atinine was different from that based on accurate determina-tion by GFR in 49 of 326 assessments (15 %). Overall, it

resulted in underestimation of the maximum observed renaltoxicity grade by serum creatinine in nine patients (12 %).

Discussion

This retrospective study on 74 patients provides the firstaccurate long-term follow-up assessment of renal functionafter PRRT with 177Lu-octreotate and demonstrates the renalsafety of this treatment even after high cumulative activities.However, minor renal impairment (GFR loss >2 ml/min/m2

per year) could be detected in 43 % of patients. This prevalentslight reduction of GFR over time was captured by the accu-rate assessment applying serial 99mTc-DTPA clearance mea-surements revealing the general underestimation of kidneyfunction loss by classical serum creatinine-based approaches.

To the best of our knowledge, this is the first study assessingthe influence of cumulative activity on long-term renal func-tion. Although previous studies have described the degree ofkidney toxicity in patient cohorts receiving <27.0–29.6 GBq177Lu-octreotate [30, 31], there are no data available on renaltoxicity after higher cumulative activities or on potentialactivity-toxicity relations. The results of our study show thatthere is no significant correlation but only a trend towardsmorepronounced reductions of GFR over time (Fig. 2) after higheractivities. In those patients receiving >29.6 GBq of 177Lu-octreotate (n =37, 50 % of all patients), no significant increaseof renal toxicity or yearly reduction of GFR was observed

Table 1 Patient characteristicswith potential risk factors and as-sociated change of renal function

GFR glomerular filtration rate,DM diabetes mellitus, HTNhypertensiona Student’s t testb Fisher’s exact test

Patients Decline of GFR(ml/min/m2 per year)

Decline of GFR>10 ml/min/m2 per year

n (%) Mean±SD pa n (%) pb

Age (years)

≥70 16 (21.6) 3.63±15.2 0.58 5 (31) 0.29<70 58 (78.6) 1.56±12.7 10 (17)

Chemotherapy

Yes 13 (17.6) 0.23±13.9 0.59 3 (23) 0.71No 61 (72.4) 2.40±13.1 12 (19)

Cumulative activity

>29.6 GBq 37 (50.0) 0.16±14.1 0.22 8 (22) 1.0<29.6 GBq 37 (50.0) 3.92±12.0 7 (19)

DM

Yes 9 (12.2) −2.56±13.6 0.27 1 (11) 0.67No 65 (87.8) 2.66±13.1 14 (21)

Arterial HTN

Yes 22 (29.7) 4.09±15.2 0.37 7 (32) 0.12No 52 (70.3) 1.12±12.2 8 (15)

Low baseline GFR

<60 ml/min/1.73 m2 9 (12.2) 2.89±15.4 0.83 3 (33) 0.37≥60 ml/min/1.73 m2 65 (87.8) 1.89±13.0 12 (18)

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(Table 1, Fig. 1). This unexpected observation was probablynot due to patient selection alone as the presence of potentialrisk factors was relatively well balanced between the two total-dose subgroups (Table 2). This may provide an argumentagainst dose reduction protocols intended to avoid renal toxic-ity in 177Lu-based PRRT.

While for 90Y-based PRRT there is some evidence of theinfluence of potential risk factors such as arterial HTN, DMand age on developing renal toxicity [25, 32], no comparabledata are available for 177Lu-based regimens, probably due tothe long follow-up GFR assessments needed to trace theseslighter reductions of renal function. By implementing thestate-of-the-art blood clearance-based assessment of GFR,we were able to provide a first risk factor analysis for time-related renal function loss after 177Lu-based PRRT. In agree-ment with previous studies the majority of our patients withsignificant yearly loss of GFR (81 %) had at least one risk

factor for development of radiation-induced kidney disease[30]. Interestingly, however, none of the previously suggestedand commonly considered risk factors for PRRT-inducednephrotoxicity including age >70 years, DM and HTN wereassociated with a significant time-dependent GFR reduction(Table 1, Fig. 1); history of previous systemic chemotherapyand a baseline GFR of less than 60 ml/min/1.73 m2 were alsonot predictive of significant renal toxicity. However, thesefindings are not in contradiction to any reported data on177Lu-based PRRT as the above-mentioned risk factors arederived from 90Y-associated renal events [2, 30, 33]. Ourfindings support the widely practised approach of includingpatients with renal risk factors for 177Lu-based PRRT. Accord-ingly, there is no current recommendation regarding dosereduction or withholding treatment in such patients for177Lu-based PRRT [1]. Our institutional cut-off GFR forpatient inclusion is as low as ≥30 ml/min/1.73 m2 and none

Fig. 1 Yearly change of GFR(ml/min/m2 per year) according topotential risk factors

Fig. 2 Association of cumulative administered activity and yearlychange of GFR (ml/min/m2 per year)

Table 2 Number of patients with potential risk factors according to theadministered cumulative activity

Cumulative activity>29.6 GBq

Cumulative activity<29.6 GBq

p value

n (%) n (%)

Age ≥70 years 6 (16.2) 10 (27.0) 0.258

Arterial HTN 8 (21.6) 14 (37.8) 0.203

Previous CTx 9 (24.3) 4 (10.8) 0.221

Low baseline GFR 2 (5.4) 7 (18.9) 0.152

DM 6 (16.2) 3 (8.1) 0.479

HTN hypertension, CTx chemotherapy, GFR glomerular filtration rate,DM diabetes mellitus

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of the mentioned potential risk factors serves as a relativecontraindication for PRRTwith 177Lu-octreotate.

Reported overall renal toxicities (grade 3–4), observedwith90Y-labelled somatostatin analogues vary between 1.6 and9.2 % [6, 7, 13, 25, 32] and a recent paper on 1,109 patientsstates an incidence of 9.2 % for this significant renal impair-ment [34]. For 177Lu-labelled somatostatin analogues theserates are less than 3 % [23, 32, 33, 35], and accordingly in ourstudy only one patient (1.4 %) had significant renal impair-ment after PRRT, which was a CTCAE grade 3 event. Nograde 4 renal toxicities were observed. This confirms the renalsafety of 177Lu-based PRRT.

In the study by Gupta et al. [31] a significant decrease ofbaseline GFR from 86.8±15.4 to 66.1±14.5 ml/min/1.73 m2

was observed 6 weeks after PRRTwith 177Lu-octreotate. Thisvery short follow-up period of the study, however, hampers areliable estimation of radiation-induced nephrotoxicity. Ex-trapolation of long-term renal function loss from these datawould lead to high rates of anticipated renal insufficiencywhich contradicts cumulative experience, especially the larg-est reported series from the Rotterdam group (2 cases of renalinsufficiency in 504 patients) [2]. Also, the deduction of renalfunction alterations from only two GFR measurements perpatient (pretreatment and 6 weeks post-treatment) furtherweakens the accuracy of the quantified renal function loss.In our study, repeated time-point measurements modelled by alinear curve fit may add accuracy to the individual GFRcourse and will probably better reflect the true long-termreduction of glomerular function.

However, our study also suffers from inaccuracies regard-ing true long-term renal function loss. One major issue is theinherent limitation of GFR measurement by means of 99mTc-DTPA as it is an operator-dependent technique and also de-pends on height and weight of the patient. Second, GFRimpairment is a late event in the development of kidneydamage after PRRT, whereas the primary targets of the irradi-ation are the proximal tubule, which reabsorbs theradiopeptide, and the interstitium, which subsequently retainsthe radioactivity. Thus, measurement of renal function usingtracers with tubular extraction, like orthoiodohippurate (OIH)or mercaptoacetyltriglycine (MAG3), may provide more in-formation about radiation nephropathy in early stages. Fur-thermore, renal dosimetry data were, unfortunately, not avail-able to be included in this clinical observational study. Itwould be definitely interesting to compare absorbed renaldoses to observed loss of renal function, which might be thesubject of further studies.

Conclusion

This study implementing a state-of-the-art monitoring methodof long-term renal function surveillance supports renal safetyof 177Lu-octreotate, although a slight reduction of GFR over

time (> 2 ml/min/m2 per year) is frequently detected. The lackof a significant association between higher cumulative activ-ities and loss of GFR or other assumed renal risk factorsdisputes the need for dose reduction or strict patient selectionbased on kidney function in 177Lu-based PRRT.

Acknowledgments The authors are grateful to Professor EricKrenning, Professor Dik Kwekkeboom and Professor Wouter A. P.Breeman (Erasmus Medical Center, Rotterdam, Netherlands) for sharingtheir experience in the receptor targeting field and making somatostatinreceptor-mediated treatment in our institution possible. Also, we thankProfessor Richard P. Baum (Department of Nuclear Medicine and PETCenter, Zentralklinik Bad Berka, Germany) for his critical and construc-tive input in this field. The authors also are thankful to the personnel of theNuclear Medicine Department and especially the nursing staff of thetherapy ward.

Conflicts of interest None.

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