Safety and Efficacy of 68Ga- or 177Lu-Labeled DOTA-IBA as a Novel Theranostic Radiopharmaceutical for Bone Metastases: A Phase 0/I Study : Clinical Nuclear Medicine

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Original Articles

Safety and Efficacy of 68Ga- or 177Lu-Labeled DOTA-IBA as a Novel Theranostic Radiopharmaceutical for Bone Metastases

A Phase 0/I Study

Qiu, Lin MD, PhD∗,†,‡; Wang, Yingwei MM∗,†,‡,§; Liu, Hanxiang MM∗,†,‡; Wang, Qixin MM∗,†,‡; Chen, Lin MM∗,†,‡; Liu, Lin MM∗,†,‡; Wang, Li MD, PhD∗,†,‡; Feng, Yue MM∗,†,‡; Chen, Yue MM∗,†,‡

Author Information
Clinical Nuclear Medicine 48(6):p 489-496, June 2023. | DOI: 10.1097/RLU.0000000000004634

Abstract

Bone is a common site of metastases from various malignancies, such as carcinoma of lung, prostate, breast, liver, colorectum, kidney, thyroid, and so on. Currently, incurable, skeletal metastases considerably contribute to an increased morbidity and mortality.1 Bone metastases have been managed by multidisciplinary approach. The intervention could be chemotherapy, hormone therapy, local radiotherapy, bisphosphonates, and/or analgesics. Nuclear medicine techniques also play a key role in the diagnosis, staging, and radionuclide targeted therapy of the skeletal metastases.

Bisphosphonates are a well-known group of drugs used for treatment of bone disease. Currently, radionuclide-labeled bisphosphonates had been studied extensively as an alternative and potent diagnosis and treatment modality for bone metastases. 99mTc-MDP and 99mTc-HMDP have been the most commonly used skeletal imaging agent in clinical SPECT imaging. For bone metastasis therapy, several studies investigated nuclide-labeled bisphosphonates, such as 188Re/186Re-1,1-hydroxyethylidenediphosphonate (HEDP),2153Sm-ethylenediaminetetramethylene phosphonic acid (EDMTP),3177Lu-EDTMP,4177Lu-(4-{[(bis(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid (BPAMD),5 and so on. Although these radiopharmaceuticals proved to have high potential for diagnosis or treatment for bone metastases, they were not suitable as theranostic pairs. In contrast, investigators reported that the DOTA-conjugate zoledronic acid (ZOL) showed favorable results when labeled with 68Ga or 177Lu, providing a set of potential theranostic radiopharmaceuticals that enable individualized patient management.6–8

Similar to ZOL, ibandronic acid (IBA) is a third-generation amino-bisphosphonate with antiresorptive and antihypercalcemic properties. We successfully synthesized chelate DOTA-containing ligand DOTA-IBA, and preclinical studies with 68Ga/177Lu-DOTA-IBA have shown high hydroxyapatite binding and good target-to-background ratio with fast renal clearance.9,10 Biodistribution and skeletal lesion uptake were found to be comparable for 68Ga-DOTA-ZOL.6 Thus, 68Ga/177Lu-DOTA-IBA provides another set of potential theranostic radiopharmaceutical.

In this prospective study, the dosimetry, safety, and efficacy of 68Ga- or 177Lu-Labeled DOTA-IBA as a theranostic radiopharmaceutical for bone metastases were evaluated in patients with malignancy based on 68Ga- and 177Lu-DOTA-IBA images, blood samples, and dosimetric analysis.

PATIENTS AND METHODS

Patients Selection and Trial Procedure

This single-center prospective clinical study was performed in the Affiliated Hospital of Southwest Medical University. Study approval was obtained from the hospital’s ethics committee and conducted between September 2021 and August 2022 (ethics committee approval no. KY2022114; clinical trial registration no. ChiCTR2200064487). Patients enrolled in this study had histologically proven malignant tumor and had been diagnosed with multiple or disseminated skeletal metastases by 99mTc-MDP bone scan. Patients had received surgery, radiotherapy, chemotherapy, endocrinotherapy, immunotherapy, targeted therapy, or diphosphonate as previous treatments and were on palliative treatment with no other treatment options available or unwilling to accept other treatments except for 177Lu-DOTA-IBA at the time of inclusion. Adequate bone marrow function, including a hemoglobin level of more than 60 g/L, total leukocyte counts greater than 2.5 × 109/L, and platelet counts greater than 60 × 109/L, was required for eligibility. Estimated life expectancy had to be at least 3 months. Exclusion criteria included a superscan finding on 99mTc-MDP bone scan, pathologic bone fractures or spinal cord compression, age younger than 18 years old, and pregnancy. Written informed consent was obtained from all patients.

For the enrolled patients, 68Ga-DOTA-IBA PET/CT was performed for comparative purposes within 3 days after 99mTc-MDP bone scan. Blood biomarkers (including blood routine examination, liver function, and kidney function), Karnofsky Performance Status (KPS), and pain score were evaluated within 7 days before 177Lu-DOTA-IBA treatment (baseline); 370–1110 MBq of 177Lu-DOTA-IBA was administered over 6–10 seconds followed by a saline flush. Serial 177Lu-DOTA-IBA SPECT bone scan was performed at 1 hour, 1 day, 3 days, 7 days, and 14 days after 177Lu-DOTA-IBA administration. Karnofsky Performance Status and pain score were evaluated at 3 days, 7 days, 4 weeks, and 8 weeks after 177Lu-DOTA-IBA injection (follow-up). Blood biomarkers including blood routine examination, liver function, and kidney function were evaluated at 2, 4, and 8 weeks after injection (follow-up), usually as outpatients. 68Ga-DOTA-IBA PET/CT was performed for response evaluation at 8 weeks after 177Lu-DOTA-IBA treatment. The clinical trial procedures were described in Figure 1.

F1
FIGURE 1:
The scheme of clinical trial procedures.

PET and SPECT Imaging

For 68Ga-DOTA-IBA PET/CT, no specific preparation was requested before examination. The intravenously injection dose for 68Ga-DOTA-IBA was 1.85 MBq/kg. The patients were instructed to urinate before PET/CT scan. PET/CT scan (uMI780; United Imaging Healthcare) was performed after 90 minutes of IV tracer administration. A low-dose CT scan was performed first for lesion location and PET attenuation correction. 68Ga-DOTA-IBA PET imaging was then performed in the same bed position as CT scan in 3.0 min/position. Imaging data were transferred to the postprocessing workstation (Version R002, uWS-MI; United Imaging Healthcare). PET data were reconstructed using the ordered subset expectation maximization algorithm (2 iterations and 20 subsets).

Anterior and posterior views of the whole-body 99mTc-MDP SPECT were obtained with dual-head Symbia SPECT/CT system (Symbia T16; Siemens, Germany) using a low-energy, high-resolution collimator, and the energy window is ±10% centered on 140 keV. For serial 177Lu-DOTA-IBA SPECT after administration, acquisition was performed in the supine position using high-energy, parallel hole collimator with 20% energy window centered at a photopeak of 208 keV. Continuous acquisition mode was used with a scanning ratio of 10 cm/min with a 1024 × 256 matrix.

Imaging Analysis

For the comparison of 68Ga-DOTA-IBA PET versus 99mTc-MDP SPECT for detecting bone metastases, the imaging was interpreted independently by 2 experienced board-certified nuclear medicine physicians. Any difference in opinion was resolved by consensus. Individual skeletal metastasis was classified into 3 regions, including trunk bones, skull bones, and bones of the extremities. We classified radioactive uptake of skeletal metastases by visual assessment into 3 grades according to the following semiquantitative system: grade 0 = no uptake, grade 1 = suspicious uptake, and grade 2 = definite uptake. All skeletal metastases were identified and carefully located combined with CT, MRI, fusion PET/CT findings, and so on.

177Lu-DOTA-IBA Blood Pharmacokinetics and Dosimetric Analysis

The intravenously injection dose for 177Lu-DOTA-IBA therapy was 370–1110 MBq as shown in Table 1. Time-activity curves in blood were derived from serial blood samples (approximately 1 mL at each interval) drawn at 30 minutes, 1 hour, 4 hours, 24 hours, 72 hours, and 168 hours after 177Lu-DOTA-IBA administration in 4 patients who received 1110 MBq 177Lu-DOTA-IBA. The samples were counted in duplicates. The blood samples were weighed and measured in a γ-counter along with standards to determine the %ID/g. The initial blood samples containing high levels of radioactivity were appropriately diluted.

TABLE 1 - The Basic Characteristics of 18 Patients
Patient No. Sex Age Diagnosis 177Lu-DOTA-IBA Activity (MBq) Pain Response Performance Status Response Evaluation
1 M 65 Lung cancer with intrapulmonary, pleural, brain, and bone metastases 555 Relief Improve SD
2 M 69 Lung cancer with bone metastases 370 Relief Improve SD
3 F 39 Lung cancer with bone and brain metastases 740; 1110 (twice) Relief Improve SD
4 F 29 Breast cancer with lung, liver, and bone metastases 1110; 1110 (twice) Relief Improve PR
5 M 66 Lung cancer with lymph node, intrapulmonary, adrenal, muscle, brain, and bone metastases 1110 Relief Improve PR
6 M 56 Prostate cancer with lymph node, pleural, and bone metastases 1110 Relief Improve SD
7 M 44 Lung cancer with lymph node, brain, liver, and bone metastases 666; 1110 (twice) Relief Improve SD
8 F 34 Breast cancer with lymph node and bone metastases 1110 Relief Improve PR
9 M 66 Prostate cancer with bone metastasis 370 Relief Improve SD
10 F 62 Renal cancer with bone metastasis 481 Stable Stable SD
11 M 58 Lung cancer with lymph node, liver, and bone metastases 1110 Stable Stable SD
12 F 73 Thyroid cancer with lymph node and bone metastases 370 Relief Improve SD
13 M 56 Pancreatic neuroendocrine neoplasm with bone metastasis 1110 Relief Improve SD
14 M 71 Lung cancer with lymph node, intrapulmonary, adrenal, brain, and bone metastases 740 Relief Improve SD
15 F 65 Lung cancer and breast cancer with bone metastasis 1110 Relief Improve SD
16 M 56 Lung cancer with liver and bone metastases 1110 Stable Stable PD
17 F 19 Pheochromocytoma with bone metastasis 1110 No pain SD
18 M 47 Rectal cancer with lymph node, liver, and bone metastases 1110 Relief Improve SD

For dosimetric analysis, planar 177Lu-DOTA-IBA SPECT whole-body scans were carried out at 1 hour, 24 hours, 72 hours, 168 hours, and 336 hours postinjection in 4 patients. 177Lu-DOTA-IBA SPECT/CT scan was carried out at 24 hours interval. Patients were not allowed to urinate before the first scan (1 hour) in order not to lose any activity incorporated. Liver, kidneys, lumbar vertebrae (L2–L4), and whole body were selected as sources organs. Three lesions for each patient were selected as target lesions. HERMES software (HERMES, Stockholm, Sweden) was used to draw regions of interest (ROIs) encompassing the entire source organ or lesion on CT image for calculating organ or lesion volume to calculate the percent of injected activity (%IA) and the normalized radiation-absorbed doses. The percent of injected activity in source organs and lesion was calculated to generate time-activity curves.

Evaluation of Adverse Effects and Toxicity

Standard vital parameters (eg, blood pressure, pulse, respiration, and body temperature) were checked by a nuclear medicine physician between 68Ga-DOTA-IBA or 177Lu-DOTA-IBA injection and up to 2 hours after completion of the PET/CT scan or radionuclide therapy. Patients were asked to report any abnormalities.

General follow-up toxicity and adverse effects were assessed at 2, 4, and 8 weeks after 177Lu-DOTA-IBA injection by blood biomarkers including blood routine examination, liver function, and kidney function. The follow-up results were compared with that of baseline. Toxicities were graded according to the Common Terminology Criteria for Adverse Events version 5.0.

Response Evaluation

To determine the efficacy of 177Lu-DOTA-IBA, strict criteria were defined. Bone pain score and quality of life were evaluated at baseline, 3 days, 7 days, and 4 weeks after 177Lu-DOTA-IBA treatment. Visual analog score (VAS) was used to evaluate the severity of bone pain subjectively by the patient. Briefly, score 0~10 indicates varying degrees of pain. A score of 0 indicates no bone pain, and a score of 10 indicates constant, severe bone pain. Quality of life was assessed using the KPS. Briefly, a score of 0 indicates death, and a score of 100 indicates no symptoms and signs. The higher the KPS score, the better the quality of life for the patient. 68Ga-DOTA-IBA PET/CT was performed at 8 weeks after 177Lu-DOTA-IBA treatment to evaluate response according to the Response Evaluation Criteria in Solid Tumor, version 1.1 (RECIST1.1), compared with baseline 68Ga-DOTA-IBA PET/CT. All skeletal metastases were identified and carefully located combined with CT, MRI, fusion PET/CT findings, and so on. Responses were defined as complete response (CR), partial response (PR), stable disease (SD), and disease progression (PD).

Statistical Analysis

The statistical analysis was performed using SPSS statistical software 22.0 (SPSS Inc, Chicago, IL), with P values of less than 0.05 indicating a statistically significant difference. Categorical data were expressed as number and percentage. Continuous variables were expressed as mean ± standard deviation. The comparison of the visual analyses of 99mTc-MDP SPECT and 68Ga-DOTA-IBA PET was analyzed using Pearson χ2 test (2 × 3 χ2 test). All clinical data between baseline and follow-up results after injection were compared using the paired Wilcoxon test.

RESULTS

Patients Characteristics

Eighteen patients (7 women and 11 men) with bone metastasis were included in this study, with a mean age of 54.1 ± 15.6 years (range, 19–73 years; Table 1). There were 8 patients with lung cancer, 2 with prostate cancer, 2 with breast cancer, 1 with lung and breast cancer, 1 with pancreatic neuroendocrine neoplasm, 1 with pheochromocytoma, 1 with thyroid carcinoma, 1 with rectal cancer, and 1 with kidney cancer. All patients had received prior surgery, systemic chemotherapy, radiotherapy, endocrinotherapy, immunotherapy, targeted therapy, peptide receptor radionuclide therapy, diphosphonate, or palliative analgesic therapy. Among the 18 patients, 15 patients underwent 177Lu-DOTA-IBA therapy once, and 3 patients twice. Follow-up 68Ga-DOTA-IBA PET/CT was performed for all 18 patients at 8 weeks after 177Lu-DOTA-IBA therapy. The length of follow-up was at least 2 months for all patients.

Comparison of Baseline 99mTc-MDP SPECT Versus 68Ga-DOTA-IBA PET for Detecting Bone Metastases

The 18 patients underwent 21 paired baseline 99mTc-MDP SPECT and 68Ga-DOTA-IBA PET/CT scans in total before 177Lu-DOTA-IBA therapy since 3 patients received therapy twice. For whole-body skeletal metastasis analysis, 68Ga-DOTA-IBA PET detected more bone metastases in 10 paired scans (Figs. 2, 3A and B), and less bone metastases in 2 paired scans compared 99mTc-MDP SPECT. In the remaining 9 paired scans, 99mTc-MDP SPECT and 68Ga-DOTA-IBA PET demonstrated consistent detection efficacy (Fig. 4 and Supplemental Figure S1A and SB, Supplemental Digital Content, https://links.lww.com/CNM/A419). Table 2 shows a summary of bone metastases in trunk bones, skull bones, and bones of the extremities detected by 99mTc-MDP SPECT and 68Ga-DOTA-IBA PET with the scoring system. A total of 243 bone metastases were identified in the final decisions, including 173 in trunk bones, 4 in skull bones, and 66 in bones of the extremities. The number of bone metastases detected by 68Ga-DOTA-IBA PET was far more than that detected by 99mTc-MDP SPECT as shown in Table 2. The differences of intensity of uptake between 99mTc-MDP SPECT and 68Ga-DOTA-IBA PET were significant in the visualization of bone metastases in trunk bones (χ2 = 45.466, P < 0.001) and bones of the extremities (χ2 = 12.243, P = 0.002). Because the number of metastases in skull bones was low (n = 4), the statistical analysis was not performed. The 68Ga-DOTA-IBA PET demonstrated a higher efficacy for detecting bone metastases compared with 99mTc-MDP SPECT.

F2
FIGURE 2:
A 44-year-old man (patient 7) had a history of right pulmonary adenocarcinoma with multiple metastases (including lymph node, brain, liver, and bone metastases) for more than 1 year. Baseline 99mTc-MDP SPECT (A, anterior and posterior) demonstrated multiple bone metastases in bilateral scapula, sternum, bilateral multiple ribs, multiple vertebrae of spine, and pelvic bones. MIP of baseline 68Ga-DOTA-IBA PET/CT (B) demonstrated more bone metastases in bilateral ribs and spinal vertebrae than 99mTc-MDP SPECT. The patient received approximately 666 MBq 177Lu-DOTA-IBA therapy. Serial 177Lu-DOTA-IBA SPECT bone scans were performed at 1 hour, 1 day, 3 days, 7 days, and 14 days after 177Lu-DOTA-IBA administration. The serial SPECT scans after therapy demonstrated targeted and long-time 177Lu-DOTA-IBA accumulation in the bone metastases (CF).
F3
FIGURE 3:
A 66-year-old man (patient 5) had a history of pulmonary carcinoma with multiple metastases (including lymph node, intrapulmonary, adrenal, muscle, brain, and bone metastases). Baseline 99mTc-MDP SPECT (A, anterior and posterior) demonstrated multiple bone metastases in right humerus, right clavicle, sternum bilateral multiple ribs, multiple vertebrae of spine, pelvic bones, and right femur. Baseline 68Ga-DOTA-IBA PET (B) demonstrated more bone metastases in bilateral ribs and spinal vertebrae, especially for some small lesions. The patient received approximately 1110 MBq 177Lu-DOTA-IBA therapy. The 8-week follow-up 68Ga-DOTA-IBA PET (C) revealed partial remission for the multiple bone metastases.
F4
FIGURE 4:
A 29-year-old woman (patient 4) had a history of right breast cancer with lung, liver, and bone metastases. Baseline 99mTc-MDP SPECT (A, anterior and posterior) and 68Ga-DOTA-IBA PET (B) demonstrated multiple bone metastases in left parietal bone, cervical, thoracic vertebra, sternum, sacrum, bilateral ilium, and right ischium. 99mTc-MDP SPECT and 68Ga-DOTA-IBA PET demonstrated comparative detection efficacy for bone metastases in this patient. The patient received approximately 1110 MBq 177Lu-DOTA-IBA therapy. Complete bone pain relief was achieved within 1 week after therapy. The 8-week follow-up 68Ga-DOTA-IBA PET (C) revealed partial remission for the multiple bone metastases.
TABLE 2 - Number of Bone Metastases Detected on 99mTc-MDP SPECT and 68Ga-DOTA-IBA PET With the Scoring System
Lesion Intensity Lesion Site and Imaging Modality
Trunk Bones (n = 173) Skull Bones (n = 4) Bones of the Extremities (n = 66)
99mTc-MDP 68Ga-DOTA-IBA 99mTc-MDP 68Ga-DOTA-IBA 99mTc-MDP 68Ga-DOTA-IBA
Definite uptake 111 158 0 4 48 61
Suspicious uptake 21 13 2 0 8 5
No uptake 41 2 2 0 10 0

177Lu-DOTA-IBA Blood Pharmacokinetics and Dosimetric Analysis

The 177Lu-DOTA-IBA in human blood showed a fast clearance curve after IV injection (Supplemental Fig. S2, Supplemental Digital Content, https://links.lww.com/CNM/A419). Representative whole-body SPECT images at each interval are presented in Figures 2C–G. 177Lu-DOTA-IBA was cleared mainly via the urinary system. The outline of kidneys and bladder was visible at 1 hour SPECT imaging. No uptake in nonskeletal tissues was observed after 1 day.

The time-activity curves were expressed as %IA and not corrected for physical decay of the radionuclide. As shown in Figure 5A, kidneys and red marrow time-activity curves revealed a fast clearance, with a mean %IA of respective 2.67 ± 0.59 and 2.14 ± 0.28 at 1 hour after injection decreasing to less than 1 %IA at following each time point. Liver time-activity curve showed that low uptake was observed in the liver, with a mean %IA of less than 1.20 at any interval. In contrast, fast uptake and high retention of 177Lu-DOTA-IBA were observed in bone metastases, with a peak uptake of 9.43 ± 2.75 %IA at 24 hours after injection. Even at 14 days after injection, the activity in the skeletal lesions was approximately 5.45 ± 2.52 %IA. However, the shape of the bone time-activity curves varied not only within patients but also within the same patient, depending on lesion characteristics. As a result, the mean SD for each time point was approximately 40%. Similarly, the normalized radiation-absorbed doses were found highest for bone metastasis lesions (6.40 ± 2.13 Gy/GBq; Fig. 5B), which was significantly higher than that in red marrow (0.47 ± 0.19 Gy/GBq), kidneys (0.56 ± 0.19 Gy/GBq), or the liver (0.28 ± 0.07 Gy/GBq), with all P’s < 0.001. The mean normalized total body dose was 0.57 ± 0.12 Gy/GBq. The injected activity of at most 1.11 GBq did not surpass any of the defined maximum tolerated doses for the organs at risk.

F5
FIGURE 5:
Time-activity curves for tumor lesion, red marrow, liver, and kidneys (A). The normalized radiation-absorbed doses for tumor lesion, red marrow, liver, kidneys, and total body (B).

Evaluation of Safety and Adverse Events

All patients tolerated the 68Ga-DOTA-IBA PET/CT and 177Lu-DOTA-IBA therapy well. There were no signs of any drug-related pharmacologic effects or physiological responses. All observed vital signs (including blood pressure, pulse, respiration, and body temperature) remained normal during injection and at a 2-hour follow-up. No patients reported any abnormal symptoms such as relevant xerostomia, fatigue, nausea, and loss of appetite.

The 177Lu-DOTA-IBA therapy had no statistically significant effect on bone marrow hematopoietic function (leukocyte, neutrophil, erythrocyte, hemoglobin, and platelet), liver (ALT and AST), and kidney function (GFR, creatinine, and uric acid) at any follow-up visit (Supplemental Fig. S3, Supplemental Digital Content, https://links.lww.com/CNM/A419). Compared with baseline levels, a slight reduction was observed for leukocyte and neutrophil after 2 weeks and for platelets after 2 and 4 weeks after 177Lu-DOTA-IBA injection. Nevertheless, the differences were not significantly different (P > 0.05). In addition, the initial effect on leukocyte, neutrophil, and platelet was transitory, and patients showed recovery from 8 weeks for platelet and from 4 weeks for leukocyte and neutrophil. We observed grade 1 leukopenia in 3 of 18 patients (2 already had grade 1 leukopenia previously; the remaining 1 patient presented with prostate cancer with diffuse bone metastases), grade 1 anemia in 1 patient, grade 2 anemia in 2 patient, and grade 3 anemia in 1 patient (all the 4 patients had same grade anemia previously). Further, no patient experienced new nephrotoxicity and/or hepatotoxicity during the 8-week follow-up after 177Lu-DOTA-IBA therapy. We observed mild, moderate, and severe renal insufficiency in 2, 1, and 1 patients, respectively. However, all the 4 patients had the same the same degree renal insufficiency before 177Lu-DOTA-IBA therapy. Interestingly, baseline biochemical examination demonstrated severe renal insufficiency (GFR, 20.3; creatinine, 273.5) in patient 9. The patient received 370 MBq 177Lu-DOTA-IBA therapy because of moderate pain resulted from bone metastasis, and tolerated the 177Lu-DOTA-IBA therapy well even with the very low baseline GFR level. The kidney function at 2-week (GFR, 21.3; creatinine, 243.2), 4-week (GFR, 24.8; creatinine, 224.4), and 8-week (GFR, 19.8; creatinine, 281.5) follow-up was not impaired further.

Treatment Response

When the 18 patients received first 177Lu-DOTA-IBA therapy, bone pain was initially present in all patients except for patient 17. During the study period, bone pain palliation was achieved in 82% (14/17) of patients. The mean VAS score of 2.53 ± 1.55 at baseline decreased to 0.76 ± 1.03 at 4 weeks for the 17 patients with bone pain. The difference between the mean scores at baseline and 4 weeks was statistically significant (t = 4.915, P < 0.001). In responders, pain relief occurred promptly (within 3 days for 12 patients and within 1 week for 2 patients) after treatment. Complete pain relief was achieved after 3 days in 4 patients, and after 7 days in 4 patients. The other 6 patients experienced partial bone pain relief during the study period. Two patients experienced pain relief for 1 month after treatment, and 12 patients experienced pain relief for more than 2 months after treatment. The observed relief in bone pain was paralleled by an improvement in the KPS score. The mean KPS score increased from 75.88 ± 12.11 at baseline to 90.00 ± 7.91 at 4 weeks. Table 2 and Supplemental Table S1, Supplemental Digital Content, https://links.lww.com/CNM/A419, detailed the KPS and VAS scores of patients at baseline and different time points after therapy. 68Ga-DOTA-IBA PET/CT was performed at 8 weeks after 177Lu-DOTA-IBA treatment to evaluate response of bone metastasis, and the follow-up imaging was compared with baseline 68Ga-DOTA-IBA PET/CT. The follow-up 68Ga-DOTA-IBA PET/CT demonstrated PR in 3 patients (Figs. 3 and 4B and C, and Supplemental Figure S1B and C, Supplemental Digital Content, https://links.lww.com/CNM/A419), PD in 1 patient, and SD in 14 patients.

DISCUSSION

Bone metastases often occur in the late stage of a variety of malignancies, especially for pulmonary carcinoma, prostate, and breast cancer. Over the last decade, many radiopharmaceuticals have been used for bone metastasis therapy that includes 32P, 89Sr, 223Ra, 188Re/186Re-HEDP, 153Sm-EDMTP, 177Lu-EDTMP, 177Lu-BPAMD, and so on.2–5 Although these therapeutic radiopharmaceuticals proved to have high potential for pain palliation, they were not suitable as a theranostic pairs because of the lack of their corresponding diagnostic analogs expect for 68Ga/177Lu-BPAMD.5 In our study, the 68Ga-DOTA-IBA PET demonstrated a higher efficacy for detecting bone metastases compared with 99mTc-MDP SPECT. 68Ga-DOTA-IBA PET/CT imaging could be used for diagnosis, staging, and response evaluation dynamically for bone metastasis, which makes visual and individualized 177Lu-DOTA-IBA therapy possible. 68Ga/177Lu-DOTA-IBA provides a set of potential theranostic radiopharmaceuticals and may have a good prospect for the management of bone metastasis.

177Lu-DOTA-IBA was cleared mainly via the urinary system and showed a fast clearance curve in blood. Similarly, the time-activity curve showed a fast clearance and low uptake in the liver and red bone marrow. In contrast, fast uptake and consistent retention of 177Lu-DOTA-IBA were observed in bone metastases, with a peak uptake of 9.43 ± 2.75 %IA at 24 hours after injection, then becoming fairly constant and was approximately 5.45 ± 2.52 %IA even at 14 days after injection. The high and constant 177Lu-DOTA-IBA uptake in bone metastases results in long-time targeted internal irradiation for skeletal lesions. We found that the radiation-absorbed dose was highest for bone metastasis lesions (6.40 ± 2.13 Gy/GBq), which was significantly higher than that in red marrow (0.47 ± 0.19 Gy/GBq), kidneys (0.56 ± 0.19 Gy/GBq), or liver (0.28 ± 0.07 Gy/GBq). For a bone-seeking radiopharmaceutical, the red marrow was the dose-limiting organ.11 Assuming a maximum tolerated dose of 2 Gy for the red marrow,8 the mean maximum safely injectable activity was 4.26 GBq (2/0.47 GBq).

Compared with similar published investigations,8,12 we used a low injection dose of at most 1.11 GBq. The reason that we chose the low dose was that the bone metastases demonstrated a high target-to-nontarget ratio (range, 9–32) in baseline 68Ga-DOTA-IBA PET/CT. At the low injection dose, bone pain palliation was achieved in 82% (14/17) of patients. Two patients experienced pain relief for 1 month, and 12 patients experienced pain relief for more than 2 months after treatment. The follow-up 68Ga-DOTA-IBA PET/CT demonstrated PR in 3/18 patients. Compared with baseline level, only one patient who presented with diffuse bone metastases developed grade 1 leukopenia (toxicity rate, 6%). The 177Lu-DOTA-IBA therapy had no statistically significant effect on bone marrow hematopoietic function, liver function, and kidney function at any follow-up visit. The low injection dose showed good efficacy and safety.

In Table 3, 177Lu-DOTA-IBA was compared with other therapeutic bisphosphonate radiopharmaceuticals for bone metastases. Although the comparison of multiple radiopharmaceuticals is challenging because of methodological difference, 177Lu-DOTA-IBA may have a more favorable therapeutic index than the other bisphosphonate radiopharmaceuticals. Generally, a higher injection dose often suggested better therapy efficiency. However, the therapeutic adverse effects increased simultaneously, especially for bone marrow suppression.13–18 In our study, a low injection dose was used, but a comparable pain relief rate was reached. Furthermore, 177Lu-DOTA-IBA shows a relatively low red marrow absorbed dose. Accordingly, 177Lu-DOTA-IBA lead to fewer bone-related adverse effects (6%) than comparable therapies.

TABLE 3 - Comparison of 177Lu-DOTA-IBA With Other Bisphosphonate Radiopharmaceuticals Used for Bone Metastasis
Radiopharmaceutical Author (Year) Injection Dose (MBq) Red Marrow Dose (Gy/GBq) Pain Relief Rate Toxicity Rate
177Lu-DOTA-IBA Present study 891.5 ± 301.3 (range, 370–1110) 0.47 ± 0.25 82.5% 6% (1/18)
177Lu-DOTA-ZOL Fernandez et al 8 5780 ± 329 (range, 5215–6380) 0.36 ± 0.12 33%
177Lu-EDTMP Sharma et al 12 1935.1 ± 559.4 (range, 1073–2627) 0.83 ± 0.21 80% 10% (1/10)
Yuan et al 13 Low-dose group: 1290.0 ± 85.2 (range, 1146–1406); high-dose group: 2626.4 ± 91.3 (range, 2506–2720) Low-dose group: 55%; high-dose group: 80% Low-dose group: 81%; high-dose group: 80%
Bal et al 11 Phase 0: 148–222; phase I: 692–5550 0.80 ± 0.15 86% 67%
Agarwal et al 14 Low-dose group: 1295; high-dose group: 2590 86% 79%
153Sm-EDTMP Sharma et al 12 2155.2 ± 419.6 (range, 1347–2857) 1.41 ± 0.60 80% 5% (1/20)
Turner et al 15 740 65% 42%
Collins et al 16 37–111 MBq/kg 88% 87%
188Re-HEDP Liepe et al 2 3120 ± 419 (range, 2700–3459) 0.61 ± 0.21 8% (1/13)
Palmedo et al 17 1300; 2600; 3300; 4400 33% at 1300 MBq, 60% at 2600 MBq, 66% at 3300 MBq, 75% at 4400 MBq 0% (0/3) at 1300 MBq, 20% (1/5) at 2600 MBq, 33% (2/6) at 3300 MBq, 75% (6/8) at 4400 MBq
Savio et al 18 1300; 2200 78% 10% (2/21)

Limitations

Our study had several limitations. First, our study sample included a relatively low number of patients (n = 18). In addition, the study was limited by the absence of a control group and lack of long-term follow-up. Thus, survival rates could not be assessed because of our short follow-up period. Further studies with higher injection dose, parallel comparison, longer duration, and a larger population group are needed to assess survival rates, safety, and efficacy of 177Lu-DOTA-IBA.

CONCLUSIONS

This preliminary clinical study showed that 68Ga-DOTA-IBA PET/CT imaging could be used for diagnosis, staging and response evaluation for bone metastasis. 177Lu-DOTA-IBA therapy was well tolerated and had no observable severe adverse events. 177Lu-DOTA-IBA was safe and has a favorable therapeutic index compared with other bisphosphonate radiopharmaceuticals used in the treatment of bone metastases. 68Ga/177Lu-DOTA-IBA provides a set of potential theranostic radiopharmaceuticals and may have a good prospect for the management of bone metastasis.

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Keywords:

bone metastasis; theranostics; 68Ga/177Lu-DOTA-IBA; dosimetry; bone pain palliation

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