Long-Term Follow-Up of Renal Function After Peptide Receptor Radiation Therapy with ⁹⁰Y-DOTA⁰,Tyr³-Octreotide and ¹⁷⁷Lu-DOTA⁰, Tyr³-Octreotate

MATERIALS AND METHODS

RESULTS

Two patients developed delayed radiation nephropathy after PRRT with ⁹⁰Y-DOTATOC. One patient (patient 7, Table 2) received a total of 11.6 GBq, equally divided over 4 treatments. Her renal radiation exposure was 27.5 Gy, based on ⁸⁶Y-DOTATOC PET imaging. She experienced worsening of preexisting hypertension and mild proteinuria from 1 y onward, with concurrent increasing s-creat and urea levels. A renal biopsy was consistent with radiation nephropathy (14). At 4.5-y follow-up after the first treatment, s-creat and urea levels were consistent with National Cancer Institute (NCI) common toxicity criteria grade 3, indicating that she would soon require dialysis. A second patient (patient 1, Table 2) showed clinical signs of radiation nephropathy at 12 mo, with decreasing renal function (grade 3 s-creat) at 18 mo after his first treatment. He had received a cumulative activity of 22.9 GBq (first cycle, 13.7 GBq), with a renal radiation dose of 27.0 Gy based on ⁸⁶Y-DOTATOC PET imaing. In the other 26 patients we observed maximal grade 2 renal toxicity during the follow-up period. Hypertension or worsening of preexisting hypertension occurred in 6 patients, including the 2 described previously. Only mild proteinuria was observed. Among the patients treated with ¹⁷⁷Lu-DOTATATE, a single patient experienced early onset renal insufficiency. This patient had a baseline CLR of 41 mL per min and unexplained rises in s-creat levels in the year before PRRT. Because of the short follow-up period, this patient was not included in the current analysis.

The observed percentage change in CLR differed widely among individual patients, but in most there was a clear, sustained decline in CLR throughout the follow-up period. In patients with a high loss of CLR in the first year after the start of treatment, this loss continued at a similar rate thereafter. Conversely, patients with stable CLR during the first years remained stable later (Fig. 1). Several patients treated with ¹⁷⁷Lu-DOTATATE showed an apparent improvement in CLR, which was caused by their rapid weight gain rather than a decline in s-creat values. This gain in weight often was associated with a clear improvement in clinical condition as a result of a good response to treatment. However, we suspect that the true improvement in CLR is less than indicated by the Cockcroft–Gault formula, which was derived from a cross-sectional study in patients with a stable clinical condition (13). Therefore, we decided to use the baseline weight as a constant for weight in the follow-up of CLR calculations for all ¹⁷⁷Lu-DOTATATE patients. This may have slightly overestimated the average decline in CLR in this group. The median CLR loss per patient was higher in the ⁹⁰Y-DOTATOC patients than in ¹⁷⁷Lu-DOTATATE patients but was not statistically significant (Mann–Whitney test, Table 1). The distribution of CLR change values was abnormal, and the ⁹⁰Y-DOTATOC group contained a greater proportion of extreme values (P = 0.007; Moses extreme reactions test). There appeared to be a separate cluster of patients who had CLR losses of >15% per year (9 in the ⁹⁰Y-DOTATOC group and 2 in the ¹⁷⁷Lu-DOTATATE group) (Fig. 2, Table 2). From the data presented in Table 2, it is clear that most of these patients were at least 60 y old and that maximum renal radiation dose per cycle and hypertension may have been determining factors. In total, 2 patients had a combination of hypertension and diabetes and both had a very high rate of decline in CLR after PRRT. The univariate ANOVA showed significance for hypertension (n = 14; P = 0.005) and per-cycle radiation dose >14 Gy (n = 11, all ⁹⁰Y-DOTATOC; P < 0.0005) as separate factors but not for diabetes (n = 11; P = 0.43) or age >60 y (n = 27; P = 0.37). However, the combination of hypertension, age, and diabetes (n = 2; P = 0.046) was significant in this 4-factor model (adjusted R² = 0.45). Moreover, hypertension and age were related factors. The mean age was 62.8 ± 8.7 y in patients with hypertension (n = 14) and 55.6 ± 11.2 y in patients without hypertension (n = 51; P = 0.03, t test).

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FIGURE 1.

Time course of CLR and fitted monoexponential decay. (A) Patient was 75-y-old woman with insulinoma and hypertension who received 11.6 GBq of ⁹⁰Y-DOTATOC, with estimated renal dose of 27.5 Gy. CLR loss was 26%/y (95% CI, 24.4%–27.5%), with ESRD at 5 y after first treatment. (B) Patient was 52-y-old man with papillary thyroid carcinoma who received 25.9 GBq of ¹⁷⁷Lu-DOTATATE, with estimated renal dose of 23.3 Gy. CLR loss was 2.7%/y (95% CI, 0.2%–5.0%).

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FIGURE 2.

Comparison of decline in CLR in 28 patients treated with ⁹⁰Y-DOTATOC (A) and 37 patients treated with ¹⁷⁷Lu-DOTATATE (B). Especially with ¹⁷⁷Lu-DOTATATE, most patients have CLR loss <5%/y (normal age-related CLR loss is 1%/y). Only patients with CLR loss >25%/y are expected to develop ESRD within 5 y.

In patient 1 in the ¹⁷⁷Lu-DOTATATE group (Table 2), the high loss in CLR may be attributed in part to a hepatorenal syndrome in the presence of extensive liver metastases, in addition to the combination of age, hypertension, and diabetes mellitus.

The majority of patients showed a <15% yearly decline in CLR (19 of 28 patients in the ⁹⁰Y-DOTATOC group and 35 of 37 patients in the ¹⁷⁷Lu-DOTATATE group). Within this large combined subgroup, the distribution of CLR rates was within normal limits (P = 0.27, Kolmogorov–Smirnov test). There was no significant difference between the mean yearly decline in CLR between the ⁹⁰Y-DOTATOC (3.7%/y) and ¹⁷⁷Lu-DOTATATE subgroups (3.9%/y; P = 0.92), despite significant differences in cumulative renal radiation dose (26.9 ± 3.7 Gy and 19.7 ± 4.4 Gy, respectively; P < 0.0005) and per-cycle dose (10.5 ± 5.7 Gy and 4.7 ± 1.5 Gy, respectively; P < 0.0005).

The expected time to ESRD (defined as CLR <15 mL/min/1.73 m²) was calculated using the baseline CLR and the decline in CLR. Only in patients with a yearly loss in CLR >25% could ESRD be expected to occur within 5 y after the start of treatment (Table 2).

In Figure 3, another more straightforward and simplified approach is presented. For patients treated with ⁹⁰Y-DOTATOC, hypertension, age, diabetes, and renal radiation dose >14 Gy per cycle were taken as risk factors for a decline in CLR of >20% and an associated high risk of ESRD within 5 y (Fig. 3A). This approach was repeated for the combined ⁹⁰Y-DOTATOC and ¹⁷⁷Lu-DOTATATE groups, with a cumulative renal radiation dose >25 Gy as an additional risk factor (Fig. 3B). The prevalence of >20% decline in CLR increased sharply when the number of risk factors increased within the ⁹⁰Y-DOTATOC group (P = 0.021, Pearson χ²; Spearman rank correlation coefficient = 0.61) or when both groups were combined (P < 0.0005, Pearson χ²; Spearman rank correlation coefficient = 0.52).

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FIGURE 3.

(A) Yearly loss in CLR >20% (black bars) and <20% (white bars) in 28 patients treated with ⁹⁰Y-DOTATOC who had 0–4 risk factors from hypertension, diabetes, age >60 y, and maximal per-cycle renal radiation dose >14 Gy. (B) Yearly loss in CLR >20% and <20% in 65 patients treated with ⁹⁰Y-DOTATOC or ¹⁷⁷Lu-DOTATATE who had 0–5 risk factors from hypertension, diabetes, age >60 y, cumulative renal radiation dose, and maximal per cycle radiation dose.

DISCUSSION

Nephrotoxicity from PRRT with ⁹⁰Y-DOTATOC has been recognized as an important clinical problem that has been discussed in the literature (15–23). Cumulative experience with ⁹⁰Y-DOTATOC by the Basel group consists of a pilot study with 29 patients (1), 2 phase 2 clinical studies with 41 patients (24) and 39 patients (25), and a study in 20 patients with medullary thyroid cancer (26). They reported 4 cases of early renal insufficiency and 2 additional cases of delayed renal failure (1,2,27) from their initial study, without amino acids for renal protection. In their later studies, always performed with amino acids, only a single patient was reported with late grade 2 renal toxicity (25). The cumulative experience from Milan was reported in 3 studies, with a total of 128 patients who received different regimens of amino acids (28–30). In addition, many patients were treated outside protocols, reaching a total of 256 patients (29). None of the patients developed acute renal toxicity, although 1 had delayed grade 2 toxicity, 2 had delayed grade 1 toxicity, and 2 had transient grade 1 toxicity. We have previously reported preliminary results from a multicenter dose-escalating phase 1 and 2 study of 60 patients who all received amino acids for renal protection (10). At the time of analysis, one patient was reported with delayed grade 3 renal function loss. Together, these reports include more than 400 patients treated with ⁹⁰Y-DOTATOC, including 7 patients with severe and 6 patients with mild renal toxicity. These used different administered activities, renal dosimetry estimations, renal protection schemes, and follow-up periods.

In the current study, we analyzed the time course of the most relevant parameter of renal function, the GFR, at individual and group levels in patients with long follow-up after PRRT with ⁹⁰Y-DOTATOC or ¹⁷⁷Lu-DOTATATE. Because we had long-term follow-up with many measurements per patient, the time trends in CLR (as a substitute for GFR) could be reliably assessed on an individual basis. Our results demonstrated that after PRRT, individual rates of decline vary widely among patients. In those patients who have a decline in CLR, this decline is sustained during the entire follow-up period after the start of therapy. This suggests that treatment with radioactive peptides may trigger a process at the level of the glomerulus that continues long after the end of radiation exposure.

We encountered no clinically notable impairment of tubular function, such as excessive loss of electrolytes, changes in phosphate reabsorption, or failure to concentrate urine, either shortly after administration of PRRT or during long-term follow-up. This is entirely in agreement with the histopathologic findings of radiation nephropathy as reported previously (27). In biopsies of 3 patients with renal insufficiency after PRRT with ⁹⁰Y-DOTATOC, typical signs of thrombotic microangiopathy (TMA) involving glomeruli, arterioles, and small arteries were seen, as well as tubular atrophy and interstitial fibrosis. Comparing patient data with the earlier report of this group, we estimate that biopsies were taken between 1 and 2 y after the start of the therapy (1). A similar case was reported by Stoffel et al. (31), who also found prominent glomerular changes accompanied by tubular atrophy and compensatory interstitial fibrosis in a biopsy of a patient who developed renal insufficiency 1 y after PRRT with ⁹⁰Y-DOTATOC.

In our series, renal biopsies were performed in 3 patients. In 1 patient with declining renal function, the biopsy showed signs of TMA, consistent with radiation nephropathy (14). In 2 other patients, renal biopsies were performed after an extra cycle of PRRT. They showed no clinical or biochemical signs of renal failure, and their renal biopsies were normal. Declines in their CLRs were 2% per y (95% CI, 0.7%–3.3%/y) and 9.4% per y (95% CI, 6.3%–12.4%/y), respectively.

From histologic studies it is known that the major focus of changes after external-beam irradiation is in the arteriolar–glomerular area, rather than the tubular epithelium, leading to glomerular sclerosis, and that the common denominator linking radiation nephropathy and TMA is presumably endothelial cell injury (32,33). Such changes may be seen many years after the radiation exposure.

Clinical observation of steadily progressive loss of CLR, with wide variations among individual patients, and the type of histologic changes as seen after PRRT with ⁹⁰Y-DOTATOC or external-beam radiation are compatible with the clinical and histologic spectrum of chronic kidney disease. Chronic kidney disease is defined clinically as either kidney damage or GFR <60 mL/min/1.73 m² for more than 3 mo (34). The leading causes of chronic kidney disease are hypertension and diabetes mellitus, but many other causes are known (34,35). It is now becoming accepted that progressive renal disease cannot be attributed to a single aberration in glomerular physiology but is characterized by a progressive loss of the microvasculature (36,37). The pathophysiology of chronic renal failure is complex. Regardless of the primary cause of nephron loss, some glomeruli usually survive or are less severely damaged. Adaptation mechanisms involve hypertrophy of the remaining glomeruli, with a cascade of events that has been termed “the final common path,” in which the adaptation processes eventually cause further loss of nephrons, leading to progressive loss of function. Well documented intermediate agents for these deleterious processes are angiotensin II, endothelin, and transforming growth factor.

With renal microvascular injury and the central role of the renin–angiotensin system in this process, it is clear that hypertension and diabetes may accelerate renal function loss in chronic kidney disease. In clinical practice, drugs that interfere with the renin–angiotensin system, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II inhibitors, are becoming the drugs of choice in slowing down the progression of chronic renal failure (35). In radiation nephropathy, experimental studies have also demonstrated the pivotal role of the renin–angiotensin system and the efficacy of ACE-inhibitors and angiotensin II inhibitors in diminishing the incidence of renal failure (38,39). Angiotensin II blockade was also successful in a patient with late radiation nephropathy (40).

In our study, 11 of 65 patients had a >15% yearly loss of CLR (Table 2). We infer from our observations that hypertension, old age, and diabetes (particularly in combination with hypertension) may be relevant risk factors (Table 2, Fig. 3). Paganelli et al. (28) cited preexisting hypertension as a possible contributing factor in their single patient with grade 2 renal toxicity after PRRT with ⁹⁰Y-DOTATOC.

Despite the contributing role of hypertension, age, and diabetes, the most prominent cause of renal toxicity with PRRT is probably the radiation to the kidney. The significant differences in cumulative renal radiation dose and renal radiation dose per cycle may be the most important factors to account for the fact that 9 out of 28 patients treated with ⁹⁰Y-DOTATOC had high yearly losses of CLR, compared with 2 out of 37 ¹⁷⁷Lu-DOTATATE patients. The numbers of patients with hypertension, old age, and diabetes were comparable in the 2 treatment groups. Therefore, it is possible that these risk factors become relevant only in the presence of a high cumulative or per-cycle radiation dose to the kidneys. On the other hand, it is reassuring that the risk of severe renal function loss seems low after PRRT with either ⁹⁰Y-DOTATOC or ¹⁷⁷Lu-DOTATATE in the absence of additional factors. At present, subtle dependencies between the proposed risk factors or relative weight of such factors are uncertain.

Unfortunately, it is difficult to derive from available studies a clear relationship between cumulative or per-cycle radiation dose and renal damage. In the studies from the Basel group, no individual dosimetry is reported, whereas the Milan group reported only individual dosimetry in a limited number of patients (30). An extensive dosimetric study in 18 patients using ¹¹¹In-DOTATOC predicted variable absorbed renal doses (3.31 ± 2.22 mGy/MBq) during treatment with ⁹⁰Y-DOTATOC, but the outcome after therapy was not reported specifically for these 18 patients (41). In a recent review from the Milan group, 16 other patients were evaluated, with cumulative administered activities of 4.1–13.9 GBq of ⁹⁰Y-DOTATOC, renal radiation doses of 1.6–6.0 mGy/MBq, and cumulative renal radiation doses of 6.6–47.1 Gy (42). During a follow-up period of 6–50 mo, 4 of these 16 patients developed NCI grade 1 s-creat levels, apparently not clearly correlated to the cumulative or per-cycle renal radiation dose.

In our studies, there was a substantial variation in uptake of ⁸⁶Y-DOTATOC and in mean residence time in the kidneys between individual patients, leading to different cumulative activities of ⁹⁰Y-DOTATOC required to reach the targeted renal radiation dose of 27 Gy (7). These differences are clear from the patient data in Table 2. A similar variability in the relation between administered activity and estimated renal radiation dose was found in the ¹⁷⁷Lu-DOTATATE patients, despite the different method that was used. Renal dose calculations were based on the MIRDOSE3 model, which assumes a homogeneous distibution of activity in a standard-sized kidney volume. Alternative methods include individual renal volume and inhomogeneous activity distributions. The results of these new approaches, which lead to a better (radiation) dose–effect relationship, are discussed by Pauwels et al. (43) elsewhere in this supplement.

The average distance from the tubular uptake (source) and the glomerulus (being the relevant target) is probably important for the dosimetry of different radionuclides that may be coupled to the peptides. The range of β-particles from ⁹⁰Y is maximally 12 mm, long enough to reach the glomeruli, whereas the low-energy Auger electrons travel only 10 μm, not far enough to leave the tubular cell. The range of the ¹⁷⁷Lu electrons is maximally 2.1 mm, thus the sensitive glomeruli may be partially spared. This means that 1 Gy from ¹⁷⁷Lu may lead to a lower average glomerular dose than 1 Gy from ⁹⁰Y, which may be an additional explanation for the much lower average decline in CLR in the ¹⁷⁷Lu-DOTATATE patients than in the ⁹⁰Y-DOTATOC patients. This also provides an explanation for the low renal toxicity (5 patients with grade 1 s-creat) in 50 patients who were treated with high doses of ¹¹¹In-diethylenetriaminepentaacetic acid (DTPA) octreotide (¹¹¹In-pentetreotide; OctreoScan), despite high renal dose estimates up to 45 Gy in 2 patients who were treated with a cumulative activity of >100 GBq (44). In a study including 27 patients treated with ¹¹¹In-DTPA-octreotide, one patient developed grade 2 renal toxicity, but this may have been caused by bilateral ureter obstruction rather than radiation nephropathy (45). Apart from a better scientific understanding of renal radiation dosimetry with PRRT, it is of utmost importance to have simple and practical dosimetric methods to be used in daily practice. Dosimetry methods based on ¹¹¹In-DTPA-octreotide scans or in combination with simple clinical parameters have been developed (46). Other methods are probably more accurate, based on the use of the chemically identical ⁸⁶Y-DOTATOC or nearly identical ¹¹¹In-DOTATOC, but these radiopharmaceuticals are not readily available (7,41).

Prevention of radiation nephropathy from PRRT can be accomplished in different ways. The affinity of radiolabeled ¹⁷⁷Lu-DOTATATE for the type 2 somatostatin receptors is twice as high as the affinity of ⁹⁰Y-DOTATOC, which gives a greater tumor-to-kidney uptake ratio and a better therapeutic window (47). The uptake mechanism of radiolabeled peptides in the kidney is mainly tubular reabsorption, not receptor binding. Coinfusion of positively charged amino acids, in particular lysine and arginine, has been found to be useful in experimental and clinical studies to counteract the reabsorption of peptides (4). Hammond et al. (6) showed that a mixture of amino acids inhibited the uptake of radiolabeled octreotide. Typically, renal dose reductions of 25% can be reached with these mixed amino acids. Additional investigations revealed that solutions with a combination of 25 g of lysine and 25 g of arginine in 1 L were safe and more effective than mixed amino acids (Fig. 4) (8). We now routinely use this combination in all patients receiving ¹⁷⁷Lu-DOTATATE. Alternative amino acid regimens have been investigated in Milan, with an average reduction in kidney dose of 25% (30). Reductions in renal radiation dose of up to 65% can be reached when additional 4-h amino acid infusions are administed 1 and 2 d after therapy (42). New studies in rats have shown that 1 mg per kg of colchicine, which disrupts cellular microtubules, adds significantly to the renal-protecting effects of lysine, which may be promising for future clinical use (48). Further prevention of renal radiation damage may be achieved by treatment with ACE inhibitors or angiotensin II inhibitors, in parallel with the recommendations for treatment of chronic kidney disease and with emerging experimental and clinical results with these drugs in external-beam radiation nephropathy.

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FIGURE 4.

Coronal SPECT images 24 h after injection of 220 MBq ¹¹¹In-DTPA-octreotide in the same patient at separate occasions. (B) Study was performed with coinfusion of lysine 25 g + arginine 25 g in 1,000 mL, with 40% reduction of renal activity compared with the control investigation (8).

With the assessment of renal toxicity by the commonly used NCI grades 0–4 for s-creat and blood urea nitrogen, it is difficult to predict which patient will develop nephrotoxicity after PRRT. On the basis of the time trend in c-CLR, one may predict, within a certain margin of error, when a patient will develop ESRD, even at a time when the s-creat is still NCI grade 1 or 2. This agrees with the guidelines for the diagnosis and treatment of chronic kidney disease, in which serial monitoring of CLR is recommended in all patients with GFR <60 mL/min/1.73 m², to install treatment to slow down the rate of loss in GFR (34).

CONCLUSION

Our data demonstrate that PRRT with ⁹⁰Y-DOTATOC leads to a decline in CLR, which is sustained at the same rate during years of follow-up and may vary between patients from no measurable loss to a loss of more than 50% per year. Probable contributing factors are the cumulative and per cycle renal radiation dose, age, hypertension, and diabetes, but the number of patients in this study is too small to allow definitive conclusions. In the absence of additional contributing factors, the rate of decline in CLR is low, and ESRD is not expected to occur within 5 y after PRRT with ⁹⁰Y-DOTATOC. The average rate of decline in CLR is less in patients treated with ¹⁷⁷Lu-DOTATATE, who received a lower renal radiation dose. This is encouraging, because with the chosen administered activities, both treatments are effective in patients with neuroendocrine tumors as PRRT with ⁹⁰Y-DOTATOC, as described elsewhere in this issue (49). The pattern of CLR loss is compatible with that of chronic kidney disease from other causes; the histologic changes found in patients after ⁹⁰Y-DOTATOC therapy resemble closely the changes as reported after external-beam radiation therapy and resemble the glomerular/microvascular changes as reported in progressive renal failure. This suggests that the spectrum of radiation nephropathy after PRRT and external-beam radiation therapy fits within the multifactorial pathophysiology of chronic kidney disease with its final common pathway leading to ESRD. To prevent unnecessary risks of PRRT, we recommend that radiolabeled peptides with high specific receptor binding be used, that the administration of PRRT be accompanied by amino acids, and that hypertension, diabetes mellitus, and other known risk factors of chronic kidney disease be considered in the treatment of individual patients. The current treatment schedule of ⁹⁰Y-DOTATOC as used in phase 2 studies is a fixed cumulative activity of 13.3 GBq, divided in 3 equal cycles of 4.4 GBq. With this schedule the renal dose per cycle remains low; thus a high dose per cycle is no longer a practical risk factor. In addition, simplified dose estimation using ¹¹¹In-pentetreotide scans may be considered to identify patients with exceptionally high renal uptake of peptides and thus a risk of high cumulative renal radiation dose with PRRT.