Comparison of Somatostatin Receptor Agonist and Antagonist for Peptide Receptor Radionuclide Therapy: A Pilot Study

Patients

Four consecutive patients with progressive neuroendocrine tumors and limited treatment options due to chronic grade 2 or 3 kidney disease were prospectively recruited. Patient characteristics are summarized in Table 1. Exclusion criteria were concurrent antitumor treatment (octreotide [Sandostatin; Novartis Pharmaceuticals] depot less than 4 wk before test injection and treatment), preexisting grade 3 and 4 hematologic toxicity, and pregnancy or breastfeeding. The institutional review board approved this study, and all subjects gave written informed consent in accordance with the Declaration of Helsinki.

Radiochemistry

DOTA-JR11 was synthesized as previously described (5). DOTATATE was received from piChem (Austria). For the preparation of ¹⁷⁷Lu-DOTA-JR11 and ¹⁷⁷Lu-DOTATATE, the corresponding peptide conjugate was dissolved in 500 μL of ascorbate buffer, pH 5.0, and ¹⁷⁷LuCl₃ was added. The solution was incubated at 95°C for 30 min. Quality control was performed by analytic reverse-phase high-performance liquid chromatography on a Phenomenex Jupiter C18 4-μm, 250 × 4.6 mm column (eluents, A = 0.1% trifluoroacetic acid in water and B = acetonitrile; gradient, 0–25 min, 95%–50% A; flow, 0.75 mL/min). The labeling yield of ¹⁷⁷Lu-DOTATATE and ¹⁷⁷Lu-DOTA-JR11 was more than 99% and the radiochemical purity of ¹⁷⁷Lu-DOTA-JR11 was at least 93%. Sterile filtration of the final product was performed before application to the patient.

Test Injection: Pharmacokinetics and Dosimetry

Tumor and organ doses of ¹⁷⁷Lu-DOTA-JR11 and ¹⁷⁷Lu-DOTATATE were compared in the same patient using a cross-over design in an interval of 3 wk. Blood sampling, whole-body imaging studies, and SPECT/CT of the abdomen were used to generate pharmacokinetic data. All studies were done with the same SPECT/CT scanner (BrightView XCT; Philips) equipped with medium-energy, parallel-hole collimators. Whole-body scanning and low-dose SPECT/CT were performed at 1, 3, 24, and 72 h after injection of a mean dose (±SD) of 175 ± 15 μg (range, 160–200 μg) (1,060 ± 75 MBq [range, 990–1,130 MBq]) of ¹⁷⁷Lu-DOTATATE and 150 ± 20 μg (range, 130–165 μg) (975 ± 115 MBq [range, 850–1,085 MBq]) of ¹⁷⁷Lu-DOTA-JR11. One hour before injection of both radiopeptides, an infusion of 1,000 mL of physiologic NaCl solution containing 20.7 mg of arginine per milliliter and 20.0 mg of lysine per milliliter was started and continued for 5 h to inhibit tubular reabsorption of radiopeptides. The patient’s vital parameters such as blood pressure, pulse rate, oxygen saturation, and electrocardiogram were monitored for at least 50 min after injection of ¹⁷⁷Lu-DOTA-JR11.

To avoid organ- and tumor-activity overlap, a 3-dimensional quantification technique using SPECT/CT information was used for the calculation of tumor and kidney doses (IMALYTICS workstation and STRATOS software; Philips) (6). SPECT images were corrected for scatter and attenuation. A calibration factor was determined using a water-filled cylinder phantom with three ¹⁷⁷Lu-filled spheres. Voxelwise residence time maps were calculated by integrating the time–activity curves using a monoexponential tail-fitting, and the mean absorbed tumor and kidney doses were calculated (7). Bone marrow doses were determined by blood-based red-marrow dose methodology (4). Blood samples were taken at 13 time points up to 22.5 h after injection. Urine samples were collected at 1.5, 3, 5, 8, and 21 h after injection to study the stability of ¹⁷⁷Lu-DOTA-JR11. Two-dimensional dosimetry technique was used for the calculation of all remaining organs (OLINDA/EXAM 1.0 software; Microsoft) as described before (4).

Treatment: Response and Adverse Events

Patients received 2–3 cycles of ¹⁷⁷Lu-DOTA-JR11 (105 ± 35 μg [range, 55–160 μg] [4,120 ± 1,260 MBq (range, 1,870–5,890 MBq)] per treatment cycle) in an interval of 8 wk. The amount of activity and number of treatment cycles was chosen on the basis of kidney dosimetry calculations. None of the patients received a kidney dose of more than 23 Gy. Kidney protection was performed in the same way as described above. The imaging and blood-sampling protocol were the same as for the test injections, with the same imaging and blood-sampling time points. As for the test injections, 3-dimensional voxel-based technique was used for the calculation of tumor and kidney doses. The doses of the remaining organs were calculated with 2-dimensional dosimetry technique as described above (4).

Initial staging, eligibility, and follow-up measurements were based on ⁶⁸Ga-DOTATATE PET/CT imaging, ^99mTc-mercaptoacetyltriglycine renography, and laboratory and clinical results. Initial staging was performed less than 2 wk before the first test-injection. Blood tests were performed every 3 wk between treatment cycles and every 3–4 mo thereafter. Morphologic response and tubular kidney function were evaluated 3 and 12 mo after treatment by ⁶⁸Ga-DOTATATE PET/CT and ^99mTc-mercaptoacetyltriglycine renography using a standard protocol (8,9). The CT scans were performed without contrast medium to avoid further kidney toxicity. ⁶⁸Ga-DOTATATE PET/CT scans were assessed independently by 1 experienced nuclear medicine physician and 1 experienced radiologist unaware of the date of the scan and patients’ identity. Any discrepant readings were resolved by consensus.