Personalized ¹⁷⁷Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumors: initial dosimetry and safety results of the P-PRRT trial

Objectives: ¹⁷⁷Lu-octreotate PRRT is commonly administered at fixed injected activity (IA) per cycle despite highly variable absorbed doses to critical organs and submaximal treatment of most patients. With the aim to maximize tumor irradiation without increasing toxicity, we are prospectively evaluating a novel personalized PRRT (P-PRRT) approach in which renal absorbed dose is standardized. Here we report on initial dosimetry and short-term safety results of the ongoing P-PRRT trial (NCT02754297).

Methods: From April to December 2016, 27 patients underwent 55 personalized ¹⁷⁷Lu-octreotate cycles (48 induction and 7 consolidation/maintenance cycles) followed by quantitative SPECT dosimetry in all but two cycles. The renal absorbed dose per IA (Gy/GBq) was predicted by BSA and GFR for the first cycle, and by measured renal Gy/GBq for subsequent cycles. IA was personalized to deliver 23 Gy to the kidney over a 4-cycle induction course, or 6 Gy during consolidation/maintenance cycles offered to responders. Prescribed renal absorbed dose (thus IA) was reduced by 25% or 50%, respectively, in cases of baseline grade 2 or 3 cytopenias or renal dysfunction (using CTCAE definitions). Increase in IA at any subsequent cycle was limited to 50% above the highest IA ever administered to the patient. Using actual Gy/GBq data, we extrapolated absorbed doses for fixed IA of 7.4 GBq/cycle (25% or 50% reductions applied as above). Data is reported as median (interquartile range) and comparisons were made using Wilcoxon test. Acute (<72 hr.) and subacute (<8 wk.) side effects were recorded. Blood counts, renal and hepatic biochemistry were performed at 2, 4 and 6 weeks after each cycle.

Results: Per-cycle personalized IA was 8.6 (6.2 - 10.5) GBq and was significantly higher than fixed IA of 7.4 (5.6 - 7.4) GBq (P<0.0001). P-PRRT resulted in per-cycle absorbed doses of 5.0 (3.9 - 6.1) Gy to the kidney and a maximum of 32.1 (15.4 - 58.2) Gy to the tumor, which were significantly higher than those extrapolated for a fixed-AI regime, of 4.3 (2.4 - 5.1) Gy and 24.6 (13.5 - 45.6) Gy, respectively (P<0.0001). P-PRRT allowed a median 1.26 (1.03 - 1.50) fold, and up to a 3.54-fold increase in IA and absorbed doses compared to the fixed-IA regime. Renal Gy/GBq was highly variable between patients, ranging from 0.21 to 4.25 Gy/GBq, but P-PRRT limited the highest per-cycle renal absorbed dose to 9.0 Gy, vs. 23.6 Gy in the fixed-IA regime. Commonest acute side effects were nausea, vomiting and abdominal discomfort/pain in 18.2%, 5.5% and 5.5% of 55 cycles, or in 22.2%, 7.4% and 7.4% of 27 patients, respectively. Fatigue was reported as a subacute side effect following 15.2% of 33 cycles, or in 22.7% of 22 patients. Grade 3 or 4 subacute toxicity occurred as lymphocytopenia, altered liver function tests, anemia, leucopenia and thrombocytopenia in 24.4%, 4.4%, 2.2%, 2.2% and 2.2% of 45 cycles, or in 30.8%, 7.7%, 3.8%, 3.8% and 3.8% of 26 patients, respectively. Of these events, grade 4 toxicity accounted for only three (6.7%) episodes of pronounced lymphocytopenia in two (7.7%) patients, without clinical consequences. No renal toxicity was observed during the study period.

Conclusion: ¹⁷⁷Lu-octreotate P-PRRT allowed a significant increase of IA per cycle over typical fixed IA in the majority of patients, without exceeding the conservative threshold of 23 Gy to the kidney over a 4-cycle induction course. Maximized tumor irradiation in these patients is expected to translate into improved therapeutic efficacy. P-PRRT appears well tolerated, with a favorable side effect and subacute toxicity profile, which is comparable to that reported for fixed-IA PRRT. Furthermore, severe chronic renal toxicity may potentially be avoided in the few patients receiving extremely high Gy/GBq to the kidney, as compared as if they would be treated with fixed-IA PRRT. Research Support: Canadian Institutes of Health Research (MOP-142233); Scholarship from FRQ-S to JMB.

• Download figure
• Open in new tab
• Download powerpoint