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Prace oryginalne/Original papers |
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Nephrotoxicity after PRRT — still a serious clinical problem? Renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATATE and 90Y/177Lu-DOTATATE
Czy nefrotoksyczność po PRRT jest nadal poważnym problemem klinicznym? Analiza stopnia uszkodzenia nerek po terapii znakowanymi izotopowo analogami somatostatyny z zastosowaniem 90Y-DOTATATE i 90Y/177Lu-DOTATATE
Jolanta Kunikowska1, Leszek Królicki1, Anna Sowa-Staszczak2, Dariusz Pawlak3, Alicja Hubalewska-Dydejczyk 2, Renata Mikołajczak3
1Nuclear Medicine Department, Medical University of Warsaw, Poland
2Chair and Department of Endocrinology and Nuclear Medicine, Jagiellonian University Collegium Medicum, Krakow, Poland
3National Centre for Nuclear Research, Radioisotope Centre POLATOM, Otwock-Świerk, Poland
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Jolanta Kunikowska M.D., Nuclear Medicine Department, Medical University of Warsaw, Banacha St. 1a, 02–097 Warsaw, Poland, tel.: +48 22 599 22 70, fax: +48 22 599 11 70, e-mail: jolanta.kunikowska@wum.edu.pl |
Abstract
Introduction: The kidneys play an essential role in PRRT. The infusion of amino acids could reduce uptake in the kidney of radiolabelled peptides.
The purpose of this study was to determine the extent of kidney damage post PRRT.
Material and methods: 53 patients, with disseminated neuroendocrine tumours (NET), received 3–5 cycles of up to a maximum 7.4 GBq/m2 calculated dose of 90Y-DOTATATE (n = 25) and 90Y/177Lu-DOTATATE (n = 28). Creatinine levels were measured and glomerular filtration rates (GFR) were calculated. A mixed amino acid infusion was used for nephroprotection.
Results: Patients treated with 90Y-DOTATATE had a mean creatinine level of 0.77 ± 0.19 mg/dL and a mean GFR (mL/min/1.73 m2) of 103.6 ± 30.8. Patients treated with 90Y/177Lu-DOTATATE had a mean creatinine level of 0.92 ± 0.33 mg/dL and a mean GFR of 84.7 ± 26.3.
In the follow up, among patients treated with 90Y-DOTATATE and 90Y/177Lu-DOTATATE, the mean GFR level at 12 months was 101.2 ± ± 31.3 v. 83.9 ± 25.2, at 24 months 80.2 ± 32.7 v. 77.2 ± 31.1, at 36 months 78.9 ± 42.1 v. 67.5 ± 9.7, and 48 months 59.7 ± 15.2 v. 72.6 ± 11.2. The mean yearly decrease in GFR was 4.5 mL in all treated patients; for patients treated with 90Y-DOTATATE and 90Y/177Lu-DOTATATE it was 6.8 v. 3.0, respectively.
Conclusions: 90Y/177Lu-DOTATATE treatment induced statistically significantly less change in kidney function compared to 90Y-DOTATATE. (Endokrynol Pol 2013; 64 (1): 13–20)
Key words: somatostatin receptors, peptide receptor radionuclide therapy, neuroendocrine tumours, nephrotoxicity, 90Y-DOTATATE, tandem 90Y/177Lu-DOTATATE
Streszczenie
Wstęp: Narządem krytycznym w leczeniu guzów neuroendokrynnych z zastosowaniem znakowanych radioizotopowo analogów somatostatyny (PRRT) są nerki. Działanie nefrotoksyczne można ograniczyć, podając roztwór aminokwasów w formie wlewu dożylnego.
Celem pracy była analiza stopnia uszkodzenia nerek po PRRT w ciągu pierwszych czterech lat po leczeniu.
Materiał i metody: Do badania włączono 53 chorych, z rozpoznanym rozsianym procesem neuroendokrynnym (NET). Chorzy otrzymali 7,4 GBq/m2 90Y-DOTATATE (n = 25) lub 90Y/177Lu-DOTATATE (n = 28) w 3–5 cyklach. Radiofarmaceutyk podawano w trakcie wlewu i.v. roztworu aminokwasów. Oceniano stężenie kreatyniny, na podstawie którego obliczano wartość filtracji kłębuszkowej (GFR).
Wyniki: Przed leczeniem w grupie chorych leczonych 90Y-DOTATATE stężenie kreatyniny wynosiło 0,77 ± 0,19 (mg/dl), natomiast GFR 103,6 ± 30,8 (ml/min/1,73 m2). W grupie leczonej 90Y/177Lu-DOTATATE stężenie kreatyniny wynosiło 0,92 ± 0,33 i GFR 84,7 ± 26,3. Nie stwierdzono statystycznie znamiennej różnicy w wartościach badanych parametrów między obydwiema grupami.
Po 12 miesiącach wartość GFR w grupie leczonej 90Y-DOTATATE i grupie leczonej 90Y/177Lu-DOTATATE wynosiła odpowiednio: 101 ± ± 31,3 oraz 83,9 ± 25,2. Po 24 miesiącach odpowiednio: 80,2 ± 32,7 i 77,2 ± 31,1. Po 36 miesiącach odpowiednio 78,9 ± 42,1 i 67,5 ± 9,7. Po 48 miesiącach odpowiednio: 59,7 ± 15,2 i 72,6 ± 11,2. Średni spadek GFR dla wszystkich chorych wynosił 4,5 ml/rok, dla chorych leczonych 90Y-DOTATATE – 6,8 ml/rok, natomiast dla chorych leczonych 90Y/177Lu-DOTATATE — 3,0 ml/rok
Wnioski: Leczenie z zastosowaniem 90Y/177Lu-DOTATATE jest związane z istotnie mniejszym statystycznie uszkodzeniem czynności nerek w porównaniu do leczenia z zastosowaniem 90Y-DOTATATE. (Endokrynol Pol 2013; 64 (1): 13–20)
Słowa kluczowe: receptory somatostatynowe, terapia znakowanymi izotopowo analogami somatostatyny, guzy neuroendokrynne, nefrotoksyczność, 90Y-DOTATATE, 90Y/177Lu-DOTATATE
Introduction
PRRT, using radiolabelled somatostatin analogues, has shown promising results in the treatment of patients with inoperable or metastatic NET. However, PRRT may adversely affect the kidneys due to the re-absorption of radiolabelled somatostatin analogues in the proximal tubules of nephrons [1, 2] and the expression of somatostatin receptors [3].
Clinically, renal failure and end-stage renal disease (ESRD) have been documented post PRRT with 90Y-DOTATOC [4, 5]. Furthermore, renal damage may occur during external beam radiation therapy when absorbed doses reach 23 Gy or higher [6]. This was confirmed by Milano: a group of patients (n = 47) treated with 90Y-DOTATOC received a cumulative kidney dose of 27 Gy during six courses [7].
Co-administration of amino acids L-lysine and/or L-arginine competitively inhibit the proximal tubular re-absorption of radiopeptides, reducing uptake by 40%, thus offering significant nephroprotection [8]. Moreover, succinylated gelatin plasma expander Gelofusine co-injected with lysine can reduce kidney radiopeptide uptake by 62–70% [9, 10].
Renal malfunction may appear several years post PRRT, potentially coinciding with chronic kidney diseases found more often in the elderly. The age-associated decline in GFR during the third decade of life, from a peak of about 120 mL/min/1.73 m2, is approximately 1 mL/min/y/1.73 m2, reaching a mean value of 70 mL//min/1.73 m2 at the age of 70 [11]. GFR also declines in patients with additional risk factors: hypertension 2.32–4.1 mL/min/1.73 m2 [12,13], diabetes 4.7–7.2 mL/min/1.73 m2 [14,15], and cisplatin chemotherapy ≤ 6 mL/min/1.73 m2 per year [16]. In addition, post PRRT renal failure may be insidious; stages 1–3 of kidney failure are for the most part clinically silent. Consequently, it is important to observe long term renal function following PRRT.
In our study, we analysed changes in renal function post PRRT with 90Y-DOTATATE and tandem 90Y/177Lu-DOTATATE.
Material and methods
This study was approved by the ethical committee of the Medical University of Warsaw. All patients gave written informed consent.
53 patients with diffuse NETs were enrolled in an uncontrolled study. The 90Y-DOTATATE treatment group consisted of 25 patients (11 males and 14 females) with a mean age of 57.4 ± 9.9 years, ranging from 37–75 years. The 90Y/177Lu-DOTATATE treatment group consisted of ten males and 18 females, totalling 28 patients, with a mean age of 55 ± 10.9 years, ranging from 39–78 years.
The patients in our study were not randomised, but were treated first using 90Y DOTATATE; patients who presented later were treated with 90Y/177Lu DOTATATE. Subsequently, Cox analysis was used to evaluate the effects of relevant prognostic factors on the survival times in each treatment group, as well as the independency of these variables.
GFR was calculated using creatinine-based approximations based on the modification of diet in renal disease (MDRD) [17]. Basal creatinine values ranged from 0.5 to 1.3 mg/dL in the 90Y-DOTATATE treatment group, and from 0.5 to 1.9 mg/dL in the 90Y/177Lu-DOTATATE treatment group. Basal calculated GFR ranges were 171 to 43 mL/min in the 90Y-DOTATATE group, and 137 to 40 mL/min in the 90Y/177Lu-DOTATATE group.
The progression of disease, in both groups, was confirmed by CT and by an increase of chromogranin A (CgA) concentration in blood. Response to treatment was observed by CT and stratified according to the Response Evaluation Criteria in Solid Tumours (RECIST). The following inclusion criteria for therapy were used:
- — Somatostatin receptor imaging (99mTc-HYNIC-TATE or 68Ga-DOTATATE) positive uptake by tumour and metastases at least three months prior to inclusion;
- — Histological confirmation of NET tumour, determined to be inoperable or metastatic;
- — Haemoglobin level (Hb) ≥ 10 g/dL; leukocytes (WBC) ≥ 2 × 109/L; thrombocytes (PLT) ≥ 90 × 109/L;
- — Calculated GFR > 40 mL/min;
- — Karnofsky Performance Status ≥ 60;
- — Life expectancy > 3 months;
- — No pregnancy or lactation;
- — Interval between chemotherapy and PRRT of at least three months.
Treatment
Therapy was performed on an outpatient basis. Treatment sessions were repeated with a total calculated maximum dose of 7.4 GBq /m2. The injected activity per course equaled 2.2–3.7 GBq. Four patients from the 90Y-DOTATATE treatment group and two from the 90Y/177Lu-DOTATATE treatment group received two additional cycles due to recurrence of disease.
With regards to 90Y/177Lu-DOTATATE, 50% of the activity was attributed to 90Y-DOTATATE and the other 50% to 177Lu-DOTATATE. The median period between the treatments was 40 and 49 days, respectively. A mixed amino-acid infusion, consisting of 11.3 g of arginine and 9.0 g lysine (1,000 mL Vamin 18, Fresenius Kabi) and Ringer’s solutions (500 mL), was infused over eight hours in addition to 200 ml prior to administration of the treatment [18, 19]. Ondansetron (8 mg, Zofran, Glaxo Wellcome, Atossa, Anpharm S. A.) was given intravenously to prevent nausea and vomiting prior to the administration of radiopharmaceuticals.
Evaluation of Results and Assessment of Clinical Benefit
Creatinine level was assessed prior to treatment and reassessed seven, and 21–30 days after each cycle of therapy, and then after three, six, 12, 24, 36, and 48 months. Renal toxicity was defined by the National Cancer Institute.
Statistical methods
Means, standard deviations, and frequencies were used to summarise patient characteristics. Linear multi-parameters regression models were used to analyse the influence of risk factors over time, depending on the changes of GFR. Overall survival (OS), event free survival (EFS), and time to progression (TTP) were calculated using the Kaplan-Meier estimator. They were then compared using the log-rank test. Calculations were done using Stata v.10.1 software (Stata Statistical Software: Release 10, College Station, TX, Stata Corporation LP 2007).
Results
Patient characteristics
The study included 53 Caucasian patients with metastatic NETs. Medical history revealed common risk factors for kidney disease: age > 60 years, diabetes, hypertension, and positive family history. Additionally, previous chemotherapy (etoposide + cisplatin or streptozocin + 5-fluourouracyl) was evaluated. Refer to Table I for detailed patient characteristics.
Table I. Patient characteristics
Tabela I. Charakterystyka pacjentów
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90Y-DOTATATEN = 25 |
90Y /177Lu -DOTATATEN = 28 |
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Age rangeMean ± SD |
37–7557.4 ± 9.9 |
39–7355 ± 10.9 |
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Sex: Female |
14 (56%) |
18 (64%) |
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Age > 40 |
22 (88%) |
25 (89%) |
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Age > 60 |
10 (40%) |
13 (46%) |
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Chemotherapy |
9 (36%) |
9 (32%) |
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Diabetes mellitus |
5 (20%) |
8 (29%) |
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Hypertension |
15 (60%) |
20 (71%) |
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Primary tumours |
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Foregut |
16 (64%) |
14 (50%) |
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Midgut |
6 (24%) |
9 (32%) |
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Hindgut |
2 (8%) |
1 (4%) |
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Unknown primary |
1 (4%) |
2 (7%) |
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Other |
0 |
2 (7%) |
Outcome of therapy
Median OS, of patients treated with 90Y-DOTATATE, was 34.2 months and 49.8 months for patients treated with 90Y/177Lu-DOTATATE (p > 0.05). The median EFS time in the 90Y-DOTATATE and the 90Y/177Lu-DOTATATE group was 19.3 v. 24.3 months, respectively, while the median TTP was 24.2 compared to 24.3 months for the 90Y-DOTATATE and the 90Y/177Lu-DOTATATE group respectively. The differences were not statistically significant.
Kidney function after treatment with 90Y-DOTATATE and 90Y/177Lu-DOTATATE
Treatment was well tolerated without severe adverse events. Baseline mean creatinine level was 0.77 ± 0.19 mg/dL and GFR (mL/min/1.73 m2) was 103.6 ± 30.8 in patients treated with 90Y-DOTATATE. In contrast, baseline mean creatinine level of 0.92 ± 0.33 mg/dL and GFR of 84.7 ± 26.3 were noted in patients treated with 90Y/177Lu-DOTATATE (Fig. 1).
Figure 1. Baseline GFR of persons in the two groups treated with 90Y-DOTATATE and 90Y/177Lu-DOTATATE before PRRT. Line is presented as median
Rycina 1. Wyjściowe (przed terapią) wartości GFR dla obu grup leczonych 90Y-DOTATATE lub 90Y/177Lu-DOTATATE. Linia prezentuje medianę
Upon follow up, patients in the 90Y-DOTATATE and 90Y/177Lu-DOTATATE group had, at six months, creatinine levels (mg/dL) of 0.77 ± 0.24 v. 0.86 ± 0.32, at 12 months 0.8 ± 0.25 v. 0.94 ± 0.43, at 24 months 0.97 ± 0.36 v. 1.07 ± 0.55, at 36 months 1.07 ± 0.55 v. 1.03 ± 0.22, and at 48 months 1.3 ± 0.5 v. 0.96 ± 0.16.
The mean GFR level (mL/min/1.73 m2) at six months was 105.6 ± 35.1 v. 92.6 ± 33.9, at 12 months 101.2 ± 31.3 v. 83.9 ± 25.2, at 24 months 80.2 ± 32.7 v. 77.2 ± 31.1, at 36 months 78.9 ± 42.1 v. 67.5 ± 9.7, and at 48 months 59.7 ± 15.2 v. 72.6 ± 11.2.
The median changes of GFR at 48 months are presented in Figure 2 and detailed changes in particular patients in both treatment groups in Tables II and III.
Figure 2. Box-plot of changes in GFR at six, 12, 24, 36 and 48 months follow up in group treated with 90Y-DOTATATE and 90Y/177Lu-DOTATATE. Line is presented as median changes
Rycina 2. Wykres zmian GFR w kontroli po 6, 12, 24 ,36 i 48 miesiącach w grupie leczonej 90Y-DOTATATE lub 90Y/177Lu-DOTATATE. Linia prezentuje medianę
Table II. Number of risk factors and GRF changes after PRRT in group treated with 90Y-DOTATATE
Tabela II. Występujące czynniki ryzyka i zmiany GFR po PRRT w grupie leczonej 90Y-DOTATATE
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Age |
Number of risk factors |
Age > 60 |
CHT |
HA |
DM |
Total administered activity[GBq] |
GFR baseline[mL/min/m2] |
GFR follow up[mL/min/m2] |
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1 |
37 |
1 |
+ |
3.7 |
161.1 |
Death in first year |
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2 |
59 |
1 |
+ |
14.8 |
109.9 |
Death last follow up 12 months 86.2 |
|||
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3 |
63 |
1 |
+ |
13.3 |
96.8 |
Death last follow up 12 months 117.2 |
|||
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4 |
36 |
1 |
+ |
15 |
86.3 |
Death last follow up 24 months 86.3 |
|||
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5 |
59 |
1 |
+ |
17.8 |
134.2 |
134.2(48 months) |
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6 |
70 |
2 |
+ |
+ |
7.4 |
90.9 |
Death in first year |
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|
7 |
50 |
2 |
+ |
+ |
13.3 |
76.3 |
70.4(48 months) |
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|
8 |
64 |
2 |
+ |
+ |
12.6 |
107.0 |
59.3(36 months) |
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|
9 |
58 |
2 |
+ |
+ |
22.6 |
109.1 |
Death last follow up 36 months 54.2 |
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10 |
56 |
1 |
+ |
22.9 |
81.2 |
Death last follow up 24 months 55.7 |
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11 |
68 |
3 |
+ |
+ |
+ |
14.8 |
101.7 |
69.7(36 months) |
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12 |
65 |
4 |
+ |
+ |
+ |
+ |
13.3 |
43.7 |
Death last follow up 12 months 55.5 |
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13 |
46 |
0 |
13.3 |
163.6 |
135.7(24 months) |
||||
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14 |
44 |
0 |
14.8 |
110.0 |
Death last follow up 12 months 120.2 |
||||
|
15 |
61 |
2 |
+ |
+ |
14.8 |
171.7 |
Death last follow up 24 months 145.6 |
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|
16 |
66 |
2 |
+ |
+ |
6.7 |
70.2 |
Death in first year |
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|
17 |
44 |
2 |
+ |
+ |
14.1 |
128.1 |
61(48 months) |
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|
18 |
55 |
1 |
+ |
13.3 |
79.2 |
Death last follow up 36 months 64.1 |
|||
|
19 |
55 |
1 |
+ |
13.3 |
111.5 |
Death last follow up 24 months 93.1 |
|||
|
20 |
56 |
2 |
+ |
+ |
3.7 |
92.8 |
Death in first year |
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|
21 |
47 |
0 |
19.2 |
71.3 |
64.7(48 months) |
||||
|
22 |
60 |
3 |
+ |
+ |
+ |
17.8 |
72.6 |
33.5(48 months) |
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|
23 |
70 |
3 |
+ |
+ |
+ |
14.1 |
101.6 |
68.9(48 months) |
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|
24 |
59 |
1 |
+ |
20.7 |
100.8 |
Death last follow up 24 months 69.7 |
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25 |
68 |
1 |
+ |
11.8 |
119.3 |
69.7(24 months) |
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CHT — chemotherapy; HA — hypertension; DM — diabetes mellitus |
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Table III. Number of risk factors and GRF changes after PRRT in group treated with 90Y /177Lu-DOTATATE
Tabela III. Występujące czynniki ryzyka i zmiany GFR po PRRT w grupie leczonej 90Y/177Lu-DOTATATE
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Age |
Number of risk factors |
Age > 60 |
CHT |
HA |
DM |
Total administered activity[GBq] |
GFR baseline[mL/min/m2] |
GFR follow up[mL/min/m2] |
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|
1 |
39 |
2 |
+ |
+ |
14.1 |
133.4 |
Death last follow up 24 months 64.2 |
||
|
2 |
57 |
2 |
+ |
+ |
23.3 |
70.4 |
64.5 (48 months) |
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|
3 |
62 |
2 |
+ |
+ |
21.5 |
98.2 |
67.4(48 months) |
||
|
4 |
58 |
2 |
+ |
+ |
13.3 |
76.1 |
60.5(48 months) |
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|
5 |
69 |
4 |
+ |
+ |
+ |
+ |
14.8 |
40.2 |
45.8(36 months) |
|
6 |
45 |
1 |
+ |
13 |
82.4 |
82.4(24 months) |
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|
7 |
72 |
3 |
+ |
+ |
+ |
13.3 |
79.5 |
67.1(48 months) |
|
|
8 |
62 |
2 |
+ |
+ |
13 |
67.4 |
77.2(48 months) |
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|
9 |
62 |
2 |
+ |
+ |
11.1 |
86.4 |
Death last follow up 24 months 85.4 |
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|
10 |
67 |
2 |
+ |
+ |
16.7 |
71.7 |
64.0(36 months) |
||
|
11 |
50 |
1 |
+ |
14.8 |
80.3 |
84.1(48 months) |
|||
|
12 |
40 |
0 |
17 |
89.6 |
69.2(48 months) |
||||
|
13 |
38 |
1 |
+ |
10.4 |
118.9 |
Death last follow up 24 months 118.9 |
|||
|
14 |
67 |
2 |
+ |
+ |
14.8 |
87.3 |
76.0(48 months) |
||
|
15 |
57 |
2 |
+ |
+ |
14.8 |
116.2 |
Death last follow up 12 months 118.6 |
||
|
16 |
40 |
0 |
11.1 |
58.5 |
58.5(48 months) |
||||
|
17 |
42 |
1 |
+ |
12.6 |
64.6 |
52.4(48 months) |
|||
|
18 |
47 |
0 |
14.8 |
137.4 |
95.3(36 months) |
||||
|
19 |
64 |
2 |
+ |
+ |
14.8 |
81.8 |
71.6(48 months) |
||
|
20 |
59 |
2 |
+ |
+ |
10.4 |
52.4 |
54.0(48 months) |
||
|
21 |
63 |
1 |
+ |
13 |
132.4 |
89.8(24 months) |
|||
|
22 |
63 |
4 |
+ |
+ |
+ |
+ |
14.8 |
58 |
Death last follow up 24 months 54.3 |
|
23 |
44 |
1 |
+ |
13 |
93.5 |
Death last follow up 12 months 86.6 |
|||
|
24 |
68 |
4 |
+ |
+ |
+ |
+ |
11.1 |
105.7 |
Death in first year |
|
25 |
69 |
3 |
+ |
+ |
+ |
9.6 |
50.5 |
Death last follow up 24 months 22.2 |
|
|
26 |
60 |
2 |
+ |
+ |
14.1 |
58.1 |
63.0(24 months) |
||
|
27 |
52 |
1 |
+ |
13 |
107.4 |
123.4(24 months) |
|||
|
28 |
53 |
1 |
+ |
14.1 |
74.4 |
Death in first year |
|||
|
CHT — chemotherapy; HA — hypertension; DM — diabetes mellitus |
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The yearly mean increase in creatinine level for the entire study group was 0.056 mg/dL. The yearly decrease in GFR, calculated by a linear regression model, was 4.5 mL/min/1.73 m2 in all treated patients. The decrease in GFR in patients treated with 90Y-DOTATATE and 90Y/177Lu-DOTATATE was 6.8 v. 3 mL/min/1.73 m2 per year (p < 0.05).
It was observed that patients from both groups with more than two risk factors demonstrated the largest statistically significant changes in GFR (Fig. 3). Multi-parameter regression models (including previous reported risk factors) revealed GFR statistically significant changes depending on the type of therapy, hypertension and previous chemotherapy (Table IV). GFR declination percent upon follow-up was significantly lower in the group treated with 90Y/177Lu-DOTATATE (Fig. 4).
Figure 3. Graph presenting changes per year in GFR (mL/min/m2) in patients with 1–2 risk factors and > 2 risk factors
Rycina 3. Wykres zmian GFR/rok(ml/min/m2) u pacjentów z 1–2 czynnikami ryzyka oraz > 2 czynników ryzyka
Figure 4. Proportional changes in GFR at 6, 12, 24, 36 and 48 months follow up in group treated with 90Y-DOTATATE and 90Y/177Lu-DOTATATE
Rycina 4. Proporcjonalne zmiany GFR w kontroli po 6, 12, 24, 36 i 48 miesiącach w grupie leczonej 90Y-DOTATATE lub 90Y/177Lu-DOTATATE
Table IV. Regression model — influence of risk factors on changes of GFR
Tabela IV. Model regresji — wpływ czynników ryzyka na zmiany GFR
|
GFR |
P |
|
Therapy |
0.008 |
|
Age |
0.09 |
|
Chemotherapy |
0.014 |
|
Hypertension |
0.001 |
|
Diabetes |
0.426 |
Grade 1 nephrotoxicity was seen in 2/25 patients treated with 90Y-DOTATATE and 2/28 in the group treated with 90Y/177Lu-DOTATATE. Grade 2 nephrotoxicity was seen in 3/25 patients and 1/28 patients, respectively. Grade 3 and 4 nephrotoxicity was not observed in both groups.
Mild nausea occurred at equal frequencies in both groups; it affected 38% of the entire population and was reported upon administration of radiopharmaceuticals and amino-acids infusion. All cases of nausea and vomiting responded to ondansetron. Hyperkalemia was not observed clinically nor in blood tests.
Discussion
177Lu and 90Y demonstrate different physical properties. These differences include half-life, path length, and type of energy emission. 90Y emits β-particles with longer path lengths and higher energies. 177Lu has a shorter β-particle range, and longer half-life, resulting in lower kidney re-absorption and reduction of renal toxicity [20]. In the literature, nephrotoxicity after PRRT with 90Y -DOTATOC has been recognised as an important clinical problem which limits therapy [21–25]. Cumulative experience with 90Y-DOTATOC was reported by the Basel group [26]. Four cases of early renal insufficiency and two additional cases of delayed renal failure in studies without infusion of amino acids for renal protection were observed. In later studies, only a single patient developed late grade 2 renal toxicity when nephroprotecting agents, such as amino acids, were added during therapy [27]. In Milan’s study, 256 patients received amino acids [28] and no acute renal toxicity was reported. One patient developed grade 2 toxicity, two patients developed grade 1 toxicity, and two patients developed transient grade 1 toxicity. Bodei at al. [29] observed patients treated with 90Y-DOTATOC: 7/23 developed grade 1 toxicity, 1/23 patients developed grade 2 toxicity, and 1/23 patients developed grade 3 toxicity. A large study conducted by Imhof et al., consisting of 1,109 patients, demonstrated 9.2% permanent renal toxicity with grades 4 to 5; initial renal uptake was predictive for severe renal toxicity [30]. In the 177Lu-DOTATATE treatment group, renal toxicity was not observed [31]. A 2.5% solution of arginine and lysine has been used for nephroprotection in published data. This solution was not available in Poland. Consequently, a commercially available mixed amino-acid solution was used. In our study, nephrotoxicity occurred at a similar rate compared to reported data. Grade 1 nephrotoxicity was observed in 2/25 patients treated with 90Y-DOTATATE and 2/28 in the group treated with 90Y/177Lu-DOTATATE. Grade 2 nephrotoxicity was seen in 3/25 patients and 1/28 patients, respectively. Grades 3 and 4 were not observed.
Despite nephroprotection, loss of renal function can occur post PRRT, with a creatinine clearance loss of about 3.8% per year for 177Lu-DOTATATE and 7.3% per year for 90Y-DOTATOC [30]. Grade 4 and 5 kidney toxicity has been reported in 9.2% of patients treated with 90Y-DOTATOC [32].
The influence of additional risk factors on nephrotoxicity presents another dilemma. The clinical observation of renal damage post PRRT, in the study by Valkema et al., revealed five risk factors: cumulative renal absorbed doses of more than 25 Gy, diabetes, hypertension, age > 60 years and a renal radiation dose > 14 Gy per cycle [32]. Similar negative influences of hypertension, diabetes mellitus and previous chemotherapy were observed by Barone et al. [33] and by Bodei et al. [29].
In our study, we observed significant influences of one type of radioisotope therapy, hypertension and previous chemotherapy. The influence of diabetes mellitus and an age > 60 years were not statistically significant. This could be connected to the proportion of older patients and good control of diabetes. The majority of patients in our study had one or more risk factors for renal disease. The significant GFR changes were observed among patients with two or more risk factors.
The reported biological effective dose threshold for renal toxicity in patients with risk factors was 28 Gy. In patients without risk factors, the threshold for toxicity was 40 Gy [29]. Clinical experience and earlier dosimetry studies have indicated that the renal dose threshold does not accurately correlate with the renal toxicity observed in patients undergoing PRRT [30].
The limitations of this study were the small number of patients and the lack of dosimetry. Dosimetry is still an open problem for yttrium and tandem therapy. For PRRT with yttrium-90, dosimetry cannot be reconstructed from the bremsstrahlung images. For PRRT with tandem isotopes, different physical properties of isotopes used are presented. However, in our study there was no observed grade 3 and 4 renal toxicity, using 200 mCi (7.4 GBq) doses per m2. Analysis of GFR decline demonstrated that the toxicity of PRRT is comparable to the influence of nephotoxicity as a consequence of other risk factors.
Reports of end-stage renal failure during PRRT treatment have appeared in the past, particularly in patients receiving doses > 200 mCi (7.4 GBq/m2) [4,5]. Currently, this is not observed due to inclusion of nephroprotective agents during therapy. Infusion of amino acid used for nephroprotection can cause nausea, vomiting and hyperkalemia. Few adverse reactions were reported during this study. Mild nausea was observed in 38% of patients and vomiting in 19%, with equal frequency in both groups. Hyperkalemia did not occur in our investigation. Nonetheless, it was reported in previous studies in which patients received a total dose of 75 g lysine [8].
The evolution of nephroprotection during PRRT includes novel combinations of agents that reduce renal retention of radiolabelled peptides or the development of new somatostatin analogues less susceptible to renal retention. There is a need for standardisation of therapy protocols and multicentre studies in order to enhance the clinical value of PRRT in the advent of various other new oncological treatments.
Conclusions
90Y/177Lu-DOTATATE treatment induced statistically significantly less change in kidney function than 90Y-DOTATATE. On the basis of published data regarding chronic kidney disease, the change of renal function in patients after PRRT is comparable to that of any other progressive chronic kidney disease.
Acknowledgments
This study was supported by Research Grants (6 P05 2004 C/6453 and 4/85195/1210/529) from the Ministry of Health and the Ministry of Education.
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