Abstract
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Objectives: Besides PSMA prostate cancer cells also express gastrin-releasing peptide receptor (GRPr) which is therefore an attractive target for theranostic approaches. A high affinity GRPr antagonist (RM2) for use as diagnostic imaging agent was developed by Mansi et al. [1], whose DOTA-conjugation also offers the opportunity to label it with beta-emitting radiometals, like Lutetium-177 for therapeutic purposes. Aim of this study was to perform first dose calculations for tumors, metastases, and critical organs after application of [177Lu]RM2 for the treatment of metastasized castration resistant prostate cancer (mCRPC) to determine the optimal activity to achieve best therapeutic effect in combination with tolerable side effects.
Methods: 32 patients suffering from mCRPC, without adequate treatment options for approved therapies received [68Ga]RM2-PET/CT. 5 patients showed sufficient GRPr expression justifying [177Lu]RM2 therapy. As 2 of these patients died within the waiting for therapy, 3 patients (mean age of 65 y (range: 60-80ys)) were recruited. 2 of these patients also received a 2nd therapy cycle. All therapies were conducted in accordance with the German Medicines Law (AMG, §13[2b]). Mean administered activity was 4.2 ± 0.4 GBq. Antiemetic prophylaxis and 2000 ml electrolyte solution for kidney protection were infused starting 30 min before the infusion of [177Lu]RM2, which was slowly infused together with saline solution. For dosimetry, each patient underwent planar whole body (WB) scintigraphy and SPECT/CT imaging (Siemens Symbia T6) of the upper and lower abdomen at approximately 2h, 24h, 48h and 72h p. i. along with blood sample collection. Quantitative SPECT/CT reconstruction was performed with corrections for scatter, attenuation and detector blurring (Hermes Hybrid Recon). A calibration factor derived from phantom measurements was applied for WB- and SPECT-imaging. Organ absorbed doses for kidneys, pancreas, liver, spleen, gallbladder and 4 tumor lesions were calculated in each patient with OLINDA/EXM 2.0 using the implemented ICRP-89 based NURBS male phantom. Individual organ masses were extracted from CT. Absorbed dose to bone marrow was derived from planar images and blood samples according to the EANM guideline [2].
Results: The therapy was well-tolerated by all patients and no side effects were observed. The mean dose estimated for tumor lesions was 4.4 ± 3.8 Gy/GBq. A highly increased uptake in the pancreas was seen within the first 2 h with overlap to the right kidney, compromising kidney dosimetry based only on planar images. The mean organ doses were 1.6 ± 0.6 Gy/GBq in the pancreas, 0.4 Gy ± 0.3 Gy/GBq in the kidneys, 0.08 Gy ± 0.03 Gy/GBq in the liver, 0.04 Gy ± 0.02 Gy/GBq in the gallbladder wall, 0.07 ± 0.05 Gy/GBq in the spleen and 16.3 ± 6.4 mGy/GBq for the red bone marrow. No significant difference of the absorbed doses between the cycles has been observed.
Conclusions: The use of the GRPr antagonist [177Lu]RM2 is suitable for targeted radiotherapy of mCRPC. It shows high tumor uptake, a rapid clearance from normal organs and the absorbed doses in tumor lesions are therapeutically relevant. No side effects have been observed. The organ receiving the highest absorbed dose was the pancreas, corresponding well with results of a previous study using [177Lu]RM2 in mice [3]. However, the critical dose limit for the pancreas is 50 to 60 Gy, allowing the application of high activities. The energy dose in the kidneys is also far from limiting the administration of higher activities or the application of further treatment cycles. Our results suggest that the activity administered for each cycle could be increased to maximize absorbed dose of tumors and metastases. References [1] Mansi R et al. Eur J Nucl Med Mol Imaging. 2011 Jan;38(1):97-107 [2] Hindorf C et al. Eur J Nucl Med Mol Imaging. 2010 Jun; 37(6):1238-50 [3] Dumont R A et al. J Nucl Med May 1, 2013 vol. 54 no. 5 762-769