Abstract
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Objectives Dosimetry is essential to achieve the optimal therapeutic effect of radiopharmaceutical therapy with limited side effects. Prostate specific membrane antigen (PSMA) has attracted attention as a target for molecular imaging and for targeted radioligand therapy (RLT). Beside the high and specific uptake of PSMA-ligands in prostate cancer tissue, different normal organs (e.g. kidney, salivary glands, proximal intestine) exhibit tracer accumulation. The purpose of this study was to estimate the absorbed doses for the new PSMA ligand 177Lu-PSMA I&T in normal organs to evaluate potential toxicity and in tumor lesions in patients with metastatic castrate-resistant prostate cancer (mCRPC).
Methods A total of 13 cycles 177Lu-PSMA I&T therapy for mCPRC performed between January 2015 and July 2015 in nine patients were analyzed encompassing 6, 5, 1 and 1 patient(s) with the 1st, 2nd, 3rd and 4th cycle, respectively. Mean activity of 177Lu-PSMA I&T was 7.13 GBq (range: 6.47 to 7.70 GBq) per cycle. Whole-body scintigraphy was performed at least between 30-120min, 24 hours, and 7 days after administration. Regions of interest (ROIs) covering the whole body, kidneys, liver, lacrimal glands, parotid glands, submandibular glands, and up to 4 tumor lesions were delineated manually on the anterior and posterior whole-body images. The volume of each organs were taken from the CT-dataset of a 68Ga-PSMA HBED-CC PET/CT performed for staging before each cycle. The volume of tumor lesions was estimated by using integrated 68Ga-PSMA HBED-CC PET/CT. In total 37 tumor lesions (26 bone, 5 lymph node and 6 liver metastases) were analyzed. All organs and tumor doses for individual cycles were calculated using OLINDA/EXM.
Results Mean whole body absorbed dose for all therapies was 0.31±0.20 Gy (range: 0.11-0.80 Gy). Mean organ doses were 4.95±1.47 Gy (range: 2.75-8.79 Gy) for the kidneys, 0.97±0.49 Gy (range: 0.35-1.82 Gy) for liver, 4.01±1.03 Gy (range: 2.32-5.93 Gy) for parotid glands, 28.91±11.00 Gy (range: 11.79-54.11 Gy) for lacrimal glands, 4.01±2.26 Gy (range: 1.70-10.41 Gy) for submandibular glands. No considerable differences for organ doses were observed between the groups of patients with 1st, 2nd, 3rd and 4th cycle: E.g. Mean doses were 0.70 Gy/GBq, 0.70Gy/GBq, 0.60 Gy/GBq and 0.72 Gy/GBq, respectively for the kidneys, 0.62 Gy/GBq, 0.56 Gy/GBq, 0.51 Gy/GBq and 0.32 Gy/GBq, respectively for the parotid glands. Notably the highest absorbed dose for the kidneys was observed in a patient with a mildly impaired kidney function (creatinine level of 1.3 mg/dl) probably induced by longer retention. In one patient the maximum tolerated dose (MTD) for the lacrimal gland (40 Gy) was mathematically exceeded (54.1 Gy). However, the ROI on lacrimal glands overlapped with bone metastasis in the skull and no keratoconjunctivitis sicca was observed within 6 months. In total, tumors lesions received a mean dose per cycle of 22.92±20.04 Gy (range: 1.45-82.16 Gy). Mean absorbed doses for bone, lymph node and liver metastases were 25.44 Gy (range: 1.45-82.16 Gy), 8.26 Gy (3.43-18.18) and 24.20 Gy (10.39-62.01), respectively.
Conclusions Organs at risk with 177Lu-PSMA I&T RLT are kidneys and salivary glands showing the higher absorbed doses. Using established dose limits from radiation oncology up to 4 cycles with each 7.4 GBq of 177Lu PSMA I&T RLT are feasible with limited risk of radiation induced side-effects on normal organs. The reason for the high variability of effective doses on tumor lesions need to be investigated (e.g. due to variable PSMA-expression, methodological aspects).