Study design and patients
Five patients were enrolled in this study. This study was approved by the Institutional Review Board of the Affiliated Hospital of Southwest Medical University (KY2022114). All the patients showed evidence of bone metastasis on 99mTc-MDP bone scans. Patients received surgery, radiotherapy, chemotherapy, endocrine therapy, immunotherapy, targeted therapy, or diphosphonates as previous treatments and were on palliative treatment if no other treatment options were available. Adequate bone marrow function, including a hemoglobin level of more than 60 g/L, total leukocyte count greater than 2.5×109/L, and platelet count greater than 60×109/L, was required for eligibility. The estimated life expectancy had to be at least 3 months. The exclusion criteria were the following: 1) a superscan finding on 99mTc-MDP bone scan, 2) pathologic bone fractures or spinal cord compression, 3) age < 18 years, and 4) pregnancy. Written informed consent was obtained from all the patients.
For the enrolled patients, 68Ga-DOTA-IBA PET/CT was performed for comparative purposes within 3 days of 99mTc-MDP bone scan. Blood biomarkers (including routine blood examination, liver function, and kidney function) were evaluated within 3 days before 177Lu-DOTA-IBA treatment (baseline) and at 2, 4, and 8 weeks after injection (follow-up).
177 Lu-DOTA-IBA treatment protocol
The detailed labelling method for 177Lu-DOTA-IBA was described in a previous study by Wang et al. [15]. In this study, all enrolled patients were treated with radionuclide vascular therapy. Patients were advised to maintain good oral hydration before and after the infusion of 177Lu-DOTA-IBA. A total of 1,110 MBq of 177Lu-DOTA-IBA was administered over 6–10 s followed by a saline flush. Serial 177Lu-DOTA-IBA planar whole-body bone scans were performed at 0.5 h, 4 h, 1 day, 3 days, 5 days, and 7 days after 177Lu-DOTA-IBA administration. SPECT/CT images of the abdomen were performed at 1 day and 3 days.
SPECT imaging
All enrolled patients underwent whole-body imaging at five time points after drug administration: 0.5 h (before urination), 4 h, 1 day, 3 days, and 5 days after injection. Acquisitions were performed with a dual-head Symbia SPECT/CT system (Symbia T16, Siemens, Germany) in the supine position using high-energy parallel-hole collimator with a 20% energy window located at the center of the 208 keV photopeak. Continuous acquisition was performed at a scan rate of 10 cm/min and a 1024 × 256 matrix. Three-dimensional SPECT/CT imaging were acquired in one bed of the abdomen (including the liver and kidney) at a scan rate of 15 s per frame for 32 frames and a matrix of 128 × 128.
Blood and urine sampling
After injection, blood samples were drawn intravenously at 0.5, 1, 4, and 24 h and at various times over 3, 5 and 7 days. After centrifugation in heparinized tubes, two 1 mL aliquots of plasma were prepared from each blood sample for determination using an automated gamma counter.
Urine was collected immediately after infusion of 177Lu-DOTA-IBA until approximately 24 h after administration of the dose in all patients. All voids were collected in separate plastic bottles, and the volume of urine collected in each bottle was carefully measured. Samples (1 mL) were taken from each plastic bottle and diluted to a total volume of 5 mL before being counted in an automated gamma counter.
Dosimetric analysis
For dosimetric calculations, the following source organs were included: kidneys, red marrow, cortical bone mineral surface, trabecular bone mineral surface, urinary bladder content, and the remainder of the body. SPECT images at five time points were aligned using OLINDA/EXM version 2.0 (Hermes Medical Solutions, Stockholm, Sweden), and low-dose CT images were used as a reference to outline the volume of interest (VOI) for the calculation of the percentage injected activity (%IA), absorbed dose, and effective dose.
The %IA for each source organ was entered into OLINDA/EXM version 2.0 model and the parameters were fitted in MATLAB (MathWorks, USA) using a mono- or bi-exponential curve to obtain the best curve fitting for the residence time.
The activity in bone was determined from an ROI over the whole body if the activity is only present in bone or from ROIs drawn around single bones [18]. To estimate the number of disintegrations in the skeletal system due to the nonuniform uptake of 177Lu-DOTA-IBA in the skeleton, disintegrations from the femur regions and other skeletal regions containing bone lesions were used and scaled-up according to the percentage of dry bone weight given by ICRP 70 [19].
DOTA-ZOL is a bisphosphonate that accumulates on the bone mineral surface [20], assuming that DOTA-IBA is also distributed on the bone surface. Cumulative skeletal activity was distributed between the cortical bone mineral surface (80%) and trabecular bone mineral surface (20%) [19].
Red marrow activity uptake was estimated from venous blood samples, and time-activity curves for the red marrow were estimated from venous blood sampling as follows [18]:
$${A}_{redmarrow}\left(MBq\right)=\frac{{AC}_{blood}(MBq/mL)\times RMBLR\times 1}{1.05\frac{g}{mL}}$$
where, A is the activity, AC is the activity concentration, and RMBLR is the red marrow-to-blood activity concentration ratio.Standard values for red marrow mass (1,500 g) and density (1.05 g/mL) were used for this estimation. An RMBLR of 1.0 was used as suggested for 177Lu-therapy [21].
The attenuation correction activity (MBq) of the excreted urine was input into Hermes software to supplement the attenuation caused by biological excretion. The bladder voiding interval was 2 h, and the bladder voiding model was used for calculations. The ICRP-103 ED was used to calculate the absorbed and effective doses to the whole body and organs, and the results were divided by the injected activity to obtain the mean absorbed dose (mGy/MBq) and mean effective dose (mSv/MBq) of the patients.
Diagnostic PET/CT images were used to select tumor lesions of interest and to determine the lesion volume, using a threshold of 40% of the SUVmax in the PET images [22]. Tumor masses were individually considered and assumed to have the same mass density as cortical bone (1.92 g/mL) [23]. For the absorbed dose in the tumor, a sphere model available in the same software was used. (OLINDA/EXM version 2.0 (Hermes Medical Solutions, Stockholm, Sweden)) Maximum tolerated adsorbed doses of 2 Gy (red marrow) and 23 Gy (kidneys) were used to determine the dose-limiting organs [24, 25].
Evaluation of side effects and toxicity
General follow-up toxicity and adverse effects were assessed at 2, 4, and 8 weeks after 177Lu-DOTA-IBA injection using blood biomarkers, including routine blood examination, liver function, and kidney function. Follow-up results were compared with those at baseline. Toxicities were graded according to the Common Terminology Criteria for Adverse Events, version 5.0.
Statistical analysis
All clinical data at baseline and 8 weeks after injection were compared using the paired Wilcoxon test. Statistical analysis was performed using SPSS statistical software (version 22.0; SPSS Inc., Chicago, Illinois, USA). Statistical significance was set at p < 0.05.