The role of nonneoplastic cells within the tumor microenvironment (TME) has increasingly been a focus of interest due to their role in tumor progression and therapeutic response. Tumor microenvironment regulates the complex tumor ecosystem and is responsible for drug resistance by impairing drug delivery and activity.1 Cancer-associated fibroblasts (CAFs), a prominent component of the TME, can contribute up to 90% of the tumor mass and are a potential target for diagnostic and therapeutic agents. In this regard, fibroblast activation protein (FAP)–specific inhibitors were first developed as anticancer drugs, and recently, a novel group of PET radiotracers targeting FAP found on the surface of CAFs has been introduced. Emerging evidence of various FAP-specific small-molecule inhibitor (FAPI) tracers for widespread oncological applications has presented promising results.2–4 The preliminary data suggest that FAPI not only has low uptake in almost all normal tissues5 but high uptake in particular cancer types, which are the ideal qualities of a theranostic agent.
Encouraging results with 68Ga-labeled FAPI imaging have been reported; however, FAP-targeted radionuclide therapy has only been investigated in preclinical investigations,6,7 and patient applications are limited to case reports.8 This study investigated a group of patients with metastatic cancers who underwent 68Ga-FAPI04 PET/CT. All patients were advanced-stage cancers and had no further treatment options for approved therapies. The patients underwent 68Ga-FAPI04 PET/CT imaging to evaluate the possibility of FAP-targeted radionuclide therapy on compassionate grounds. A radionuclide treatment’s outcome depends on successful individualization of the procedure; thus, a dosimetry study is essential,9,10 particularly for novel theranostic radiopharmaceuticals such as radiolabeled FAP inhibitors. Therefore, we performed dosimetry using low-dose pretherapeutic 177Lu-FAPI04 to estimate the radiation-absorbed doses to normal organs and tumor tissue and to determine the safety of FAP-targeted radionuclide therapy.
PATIENTS AND METHODS
An interdisciplinary board, in the presence of both a nuclear medicine physician and a medical oncologist, confirmed dosimetry study for patients meeting the following criteria: (1) progressive metastatic advanced-stage cancer, (2) completed treatment options according to current clinical practice and guidelines, (3) ECOG performance score of 0 or 1, (4) no deterioration in renal or liver functions, (5) no myelosuppression, and (6) high uptake of 68Ga-FAPI04 in all tumoral lesions. Subsequently, 4 advanced-stage metastatic cancer patients with high FAP-expressing tumoral lesions underwent a dosimetry study. The institutional review board approved this retrospective study, and written informed consent was obtained from all patients.
Synthesis of 177Lu-FAPI04
All syntheses were performed in a fully automated, good manufacturing practice-compliant procedure using a GRP module (Scintomics GmbH, Germany) equipped with a disposable single-use cassette kit (ABX, Germany). The FAPI precursor (DOTA-FAPI-04) was purchased from Huayi Isotopes Co (China) for research and development purposes, and the 177Lu solution was purchased from IDB Holland (the Netherlands). For labeling, 370 MBq of 177LuCl3 (950 GBq/mg, 80 GBq/mL of 0.05 M HCl) solution was added to a mixture of 10 μg of FAPI and 2 mL of 1 M sodium acetate buffer (pH, 4.5). The mixture was heated at 95°C for 25 minutes. The reaction mixture was transferred on a preconditioned Sep-Pak C18 cartridge, washed with water, and the final product eluted with ethanol/water (50/50). The eluate was passed through a sterile filter (0.22 μm) and diluted with saline to a total volume of 10 mL. Radiochemical purity (>99%) was determined by gradient high-performance liquid chromatography and thin-layer chromatography. In addition, the products were tested for ethanol content, pH, radionuclide purity, sterility, and endotoxins.
177Lu-FAPI04 Imaging and Data Acquisition
A series of whole-body and 3D SPECT/CT imaging was performed for tumor and organ dosimetry using a dedicated SPECT/CT scanner (GE Discovery NM/CT 670) equipped with medium-energy general-purpose collimators. Whole-body (10 cm/min; matrix size, 512 × 1024 pixels; pixel size, 8 mm) and SPECT/CT images were acquired at 4 time points (4, 24, 48, and 96 hours). SPECT/CT images covered the upper and lower abdomen in all patients and, additionally, the thorax in 2 patients. SPECT/CT acquisition parameters were 40 seconds per projection image in step-and-shoot mode, with a matrix of 128 × 128 pixels (64 views, 32 camera stops). Simultaneous CT images were acquired for anatomic localization and attenuation correction. The γ-camera photopeak window was set at 208 keV with a 20% window (range, 187.2–228.8 keV). A scatter window of 10% resulted in a lower scatter window ranging between 166.4 and 187.2 keV and an upper scatter window ranging between 228.8 and 249.6 keV. The tomographic data were reconstructed using the Q.Volumetrix MI reconstruction software (Xeleris 4 DR Workstation, GE Healthcare, 2019). Q.Volumetrix MI uses the OSEM iterative reconstruction algorithm (8 subsets, 4 iterations) and performs resolution recovery (Evolution Toolkit), scatter correction, and CT-based attenuation correction automatically. No postreconstruction filtering was used for dosimetric calculations. Whole-body images of patients are demonstrated in Supplemental Digital Content 1 (http://links.lww.com/CNM/A318).
Organ and Tumor Dosimetry
A calibration factor was determined using a standard activity source to convert the counts acquired by the γ-camera into absolute activity, which is essential for calculating the dose rate in dosimetry. Standard activity sources of 177Lu with different water volumes and activity were prepared to simulate different organ sizes and activities. The 177Lu activity in the syringe was measured in the dose calibrator, and the empty syringe activity was subtracted to achieve the net activity. This process was repeated in different activity configurations (37 MBq, 35.7 MBq, and 95.4 MBq), and the activities were added to rectangular-shaped plastic containers with different volumes (0.5 L, 1 L, and 5 L). The standard activity source performed whole-body planar and 3D SPECT/CT imaging using the same acquisition parameters for the patients. The counts in all SPECT images were measured and divided by the net activity to generate counts per unit activity (counts/megabecquerel). Subsequently, the mean calibration factor was calculated and applied to SPECT data set for each patient.
Calculation of Organ Doses
All calculations were made using a voxel-based approach. The reconstructed SPECT/CT data were transferred in DICOM format to a dedicated dosimetry workstation. Volumes of interest (VOIs) of normal organs and tumoral lesions were drawn on CT images using Osirix MD software (version 5.9; Pixmeo SARL, Switzerland). The VOIs of the tumoral lesions and organs at risk (liver, spleen, and kidneys excluding the renal pelvis) were drawn using the CT images as a reference and transferred to the corresponding reconstructed SPECT images for dosimetry calculations. For tumoral lesions, particularly bone metastases, which were not possible to be delineated from the CT images, diagnostic 68Ga-FAPI04 PET/CT images were used to determine the VOIs using a threshold of 40% of the maximum SUV. The tumor VOIs drawn at the first time point were copied to the remaining SPECT/CT series and adjusted manually if necessary. For regions of interest that SPECT/CT did not cover, the uptake of 177Lu-FAPI04 was determined from anterior and posterior whole-body images by calculating the geometric mean. Subsequently, organ volumes derived from the VOIs drawn on the CT images were transferred to a dedicated dosimetry workstation and input to OLINDA/EXM software 1.1 to be used as reference organ masses for each patient. Tumor volumes were also derived from CT images and adapted to the sequential SPECT images similarly.
Bone Marrow Dosimetry
Thirty-seven megabecquerels of 177Lu was measured in the dose calibrator (Capintec CRC-15 BETA) to set a standard for count activity conversions and added to a plastic container filled with 1 L of water. After ensuring homogeneous distribution of the activity, a precisely 1-mL sample measured with a micropipette was counted for 1 minute in a well-type γ counter (Atomlab 960; Biodex, United States). Measurements were performed by placing them in uniform tubes and repeated 5 times to minimize statistical errors, and the results were saved as counts per minute. The same process was repeated for 37 MBq of 177Lu in 0.5 L of water and 98.8 MBq of 177Lu in 5 L of water to minimize the error margin. All measurements were corrected for decay and background activity. The count activity conversion factor (megabecquerel/counts per minute) was used for blood-based bone marrow dosimetry. After the administration of 177Lu-FAPI04, at 5, 15, 30, 60, 60, 120, and 180 minutes, and 24, 48, and 96 hours, 1 mL of blood was drawn (measured with a micropipette) for bone marrow dosimetry calculations. Blood samples were counted in a well-type counter for 1 minute, and the counts were corrected for background activity. Total blood activity was calculated by multiplying the counts per 1 mL of blood and total blood volume for each patient. Bone marrow activity was calculated using the formula proposed by Wessels et al.11 Standard values for the red marrow mass (1500 g) and density (1.05 g/mL) and an RMBLR of 1.0 were used as suggested for 177Lu for this estimation.12
ARM: red marrow activity
Abl: blood activity
RMECFF: red marrow extracellular fluid fraction
MRM-patient: bone marrow mass of the patient (kilogram)
Mbl-patient: blood mass of the patient (kilogram)
A 41-year-old woman diagnosed with triple-negative metastatic invasive ductal breast cancer had a first-line treatment with doxorubicin-cyclophosphamide. Because of progression on 18F-FDG PET/CT imaging after the sixth cycle of paclitaxel-carboplatin, the chemotherapy regimen was shifted to capecitabine. Immunohistochemical analysis of liver metastasis revealed weak PD-L1 expression in the tumor stroma and immune cells; therefore, immunotherapy was opted out.
A 50-year-old man diagnosed with thymic carcinoma had first-line treatment with 6 cycles of doxorubicin-cisplatin-vincristine-cyclophosphamide in the neoadjuvant setting and 5 cycles of cisplatin-docetaxel after surgery. During follow-up, metastatic new lesions on 18F-FDG PET/CT were surgically removed, and subsequent external beam radiation therapy was performed. After a 2-year disease-free period, new metastases were detected in the lung, liver, and lymph nodes. Because of treatment failure with tyrosine kinase inhibitor and immunotherapy, the patient received 12 cycles of gemcitabine-capecitabine combination, which also did not work. Radioembolization and 177Lu-DOTATATE therapy were opted out due to the extrahepatic tumor burden and low SSTR expression (Fig. 1).
A 72-year-old woman diagnosed with papillary thyroid cancer received 5.5 GBq of 131I after total thyroidectomy with left cervical lymph node dissection. Because of progressive metastatic disease, she had multiple surgeries and radioiodine therapies, reaching a cumulative dose of 24 GBq. FDG PET/CT detected multiple metastases, none of which were 131I-avid on the posttreatment scan. Treatment with tyrosine kinase inhibitor failed, and the patient was not eligible for 177Lu-DOTATATE therapy as determined by 68Ga-DOTATATE PET/CT.
A 73-year-old woman with metastatic ovarian carcinosarcoma received neoadjuvant chemotherapy with 4 cycles of doxorubicin-cyclophosphamide. Total abdominal hysterectomy with bilateral salpingo-oophorectomy and total peritonectomy was followed by paclitaxel-carboplatin. Six months later, multiple peritoneal metastases were detected on 18F-FDG PET/CT. The patient was inoperable and received capecitabine, which was discontinued due to progression during chemotherapy.
The mean administered activity of 177Lu-FAPI04 was 267.5 ± 8.6 MBq (range, 259–278 MBq). All patients were assessed for vital parameters throughout the time between the injection of 177Lu-FAPI04 and 1 week after the last imaging study was performed. The procedure was tolerated very well by all patients, and no adverse effects were observed. No deterioration was observed in hematologic and metabolic blood panels acquired on the morning of 177Lu-FAPI04 administration, 24 hours after injection, and the 10th day after injection.
Absorbed doses per megabecquerel for different organs at risk can be found in Table 1. The mean absorbed doses per MBq were 0.25 ± 0.16 mGy (range, 0.11–0.47 mGy) to the kidneys, 0.11 ± 0.08 mGy (range, 0.06–0.22 mGy) to the liver, and 0.04 ± 0.002 mGy (range, 0.04–0.046 mGy) to the bone marrow. For the spleen, urinary bladder, and total body, the mean absorbed doses were 0.077 ± 0.04 mGy, 0.32 ± 0.08 mGy, and 0.04 ± 0.01 mGy, respectively. The maximum estimated amount of radioactivity to reach radiation-absorbed dose limits were also calculated, which were 120.9 ± 68.6 GBq, 47.5 ± 2.8 GBq, 397.8 ± 217.1 GBq, and 52.4 ± 15.3 GBq for kidneys, bone marrow, liver, and total body, respectively (Table 2).
TABLE 1 -
Calculated Radiation-Absorbed Doses of Organs (mGy/MBq 177
|Mean ± SD
||0.25 ± 0.16
||0.04 ± 0.002
||0.11 ± 0.08
||0.077 ± 0.04
||0.32 ± 0.08
||0.04 ± 0.01
TABLE 2 -
The Maximum Amount of Radioactivity (GBq) to Reach Radiation-Absorbed Dose Limits
||Kidney (23 Gy)
||Bone Marrow (2 Gy)
||Liver (32 Gy)
||Total Body (2 Gy)
|Mean ± SD
||120.9 ± 68.6
||47.5 ± 2.8
||397.8 ± 217.1
||52.4 ± 15.3
Absorbed dose per megabecquerel was calculated for 7 bone metastases, 3 metastatic lymph nodes, 3 liver metastasis, and 3 soft tissue metastases. Local recurrence in the thyroid bed (patient 2) and multiple peritoneal metastases (patient 4) were grouped as soft tissue metastases. Patient 4 had extensive peritoneal metastases; therefore, the VOIs were drawn covering the peritoneal carcinomatosis as 2 large lesions. In accordance with 68Ga-FAPI04 PET/CT, initial tumor uptake was also evident on 177Lu-FAPI04 scintigraphy images. The mean absorbed dose per MBq was 0.62 ± 0.55 mGy for bone metastases, 0.38 ± 0.22 mGy in metastatic lymph nodes, 0.33 ± 0.21 mGy in liver metastases, and 0.37 ± 0.29 in metastatic soft tissue. Absorbed doses for all evaluated tumor lesions are shown in Table 3. The maximum absorbed dose in a tumor lesion was 1.67 mGy/MBq for bone, 0.6 mGy/MBq for lymph node, 0.62 mGy/MBq for liver, and 1 mGy/MBq for soft tissue.
TABLE 3 -
Absorbed Doses to Tumor Lesions of Different Localizations
||No. Disintegrations, MBq-h/MBq
||Dose Rate, mGy/MBq
|Mean ± SD
||0.62 ± 0.55
|Mean ± SD
||0.38 ± 0.22
|Mean ± SD
||0.33 ± 0.21
|Mean ± SD
||0.37 ± 0.29
Recently, preclinical evaluations13 of FAPs have demonstrated an opportunity as a diagnostic target. Consequently, recent clinical PET imaging studies in 50 patients by Giesel et al,14 in 80 patients by Kratochwil et al,15 and 54 patients by Chen et al3 have demonstrated high expression of FAP across a wide range of cancer types, including ones with low FDG avidity. Although FAP expression has been evaluated as a therapeutic target in preclinical16 and phase 1 clinical studies,17 the therapeutic efficacy remains unclear; however, the theranostic possibility is appealing.
Radionuclide treatment using FAP targeting tracers has recently been studied in mice with human pancreatic cancer xenografts by Watabe et al.18 In that preclinical study, they proposed 225Ac-FAPI04 as an effective treatment strategy for FAP-expressing pancreatic cancer. In the clinical setting, a review by Lindner et al7 proposed that FAPI-04 is the most suitable as a potential theranostic tracer and presented a metastatic breast cancer patient treated with 2.9 GBq of 90Y-FAPI04 in a proof-of-principle approach. The significant reduction in pain medication and the absence of hematotoxicity were encouraging; however, the authors emphasized the need for dosimetric calculations and dose escalation studies to increase the dose and obtain a tumoricidal effect. Balal et al8 labeled another FAP inhibitor agent called DOTA.SA.FAPi with 177Lu and administered 3.2 GBq of 177Lu-DOTA.SA.FAPi to a breast cancer patient with brain metastasis. The patient experienced a decrease in headaches, and no adverse effects were observed. The authors suggested further dosimetric analysis for different types of cancers. To best our knowledge, only 2 metastatic breast cancer patients in the literature received this treatment. In our cohort, all patients have different cancer types, and only 1 is breast cancer. Another difference is that we used 177Lu-FAPI04, unlike the patients presented above treated with 177Lu-DOTA.SA.FAPi and 90Y-FAPI04. Although the preliminary results indicated that the treatment was safe, different radiopharmaceuticals will have different biodistribution or radiation energy levels.
In agreement with 68Ga-FAPI04 PET/CT images, nontarget organs showed very low tracer uptake on 177Lu-FAPI04 whole-body images, reducing the radiation burden. However, renal clearance of radioactivity from the bloodstream resulted in the visualization of the kidneys and the urinary bladder. Radionuclide therapies may cause a relatively high radiation dose19 to kidneys either via renal retention or excretion. Consequently, the potential toxicity may prevent the use of high radiation doses and render the treatment ineffective. Therefore, the kidneys are considered dose-limiting organs.20 In this study, the mean absorbed dose to the kidneys is 0.25 ± 0.16 Gy/GBq. Published data on the absorbed dose of kidneys for FAP-targeted radionuclide therapies are lacking; however, our results are lower than that of clinically established radionuclide therapies such as PSMA and DOTATATE.21 In similar studies, calculated radiation-absorbed doses per megabecquerel for 177Lu-PSMA by Delker et al22 and Kabasakal et al23 were reported 0.6 mGy and 0.88 ± 0.40 mGy, respectively. The 23-Gy dose limit derived from external beam radiation therapy practice for peptide-based radionuclide therapies is still controversial that it may be too conservative24,25 due to differences in the type of radiation, dose rate, and heterogeneity in dose delivery. Nevertheless, in our cohort, a mean activity of 120.9 ± 68.6 GBq radioactivity is required to reach the 23-Gy dose limit, which is above the average cumulative activity given to patients for peptide receptor radionuclide therapies. However, an individualized approach is mandatory because conditions that affect renal function can alter the radiation-absorbed doses.
Bone marrow is the most radiosensitive tissue, and a marrow-absorbed dose of 2 Gy has long been considered the safety threshold in radioiodine therapies.26 Clinically established peptide-based radionuclide therapies have also adopted 2 Gy as a threshold. In this study, the mean bone marrow–absorbed dose is 0.04 mGy/MBq. Transferring these results to 177Lu-FAPI04 treatment means that bone marrow toxicity is not expected below a mean cumulative activity of 47.5 ± 2.8 GBq. Our results are similar to 177Lu-PSMA-61722,27 and 177Lu-DOTATATE,12,28 which have been reported to range from 0.01 to 0.05 mGy/MBq and 0.03 to 0.07 mg/MBq, respectively. However, our cohort is small, and these results should be interpreted cautiously. Besides, factors such as extensive bone metastasis and delayed clearance of radioactivity from the blood pool due to renal impairment may increase the dose delivered to the bone marrow, and vigorous chemoradiotherapy in advanced stage cancers may increase the risk for hematotoxicity. On the other hand, the estimated mean absorbed doses for the liver and spleen (0.11 and 0.07 mGy/MBq, respectively) are far from limiting the administered radioactivity.
The tumor uptake pattern on 177Lu-FAPI04 images is expectedly analogous to 68Ga-FAPI04 PET/CT. Measured absorbed doses were highest for bone lesions, followed by lymph nodes, liver, and metastatic soft tissue. However, on average, the dose rates were significantly less than those achieved with 177Lu-PSMA therapies. Delker et al22 reported a mean absorbed dose rate of 5.3 ± 3.7 Gy/GBq to bone lesions, 4.2 ± 5.3 Gy/GBq to lymph nodes, and 2.1 ± 0.8 Gy/GBq, which are higher than our cohort. Similarly, mean absorbed dose for bone, lymph node, and liver metastases were significantly lower in our cohort than those reported by Okamoto et al,29 which were 3.4 Gy/GBq, 3.2 Gy/GBq, and 1.28 Gy/GBq, respectively. Interpatient variability of the mean absorbed doses to lesions should also be noted. This result may be explained by the fact that all patients in our cohort had different cancer types, which is a limitation of this study; thus, different tumor biology, variable receptor densities between individuals, and different types of metastases may be responsible. Also, considering the history of radioiodine theranostics, diagnostic low-dose scans have a much-reduced sensitivity compared with posttherapy imaging with higher therapeutic activities.30 Therefore, it is possible for low-dose 177Lu-FAPI04 imaging to underestimate the activity of the metastatic lesions. Accordingly, low-dose predicted dose rates might be underestimated compared with therapy-delivered absorbed doses. However, relatively low measured absorbed dose rates to dose-limiting organs compared with DOTA and PSMA allow antitumor effect compensation by administering higher activities. Also, assuming FAPI04 labeled with different radioisotopes will resemble a similar biodistribution hence low radiation-absorbed doses to normal organs, it is possible that using higher-energy radioisotopes, particularly 90Y, may compensate for the lower absorbed tumor dose rates. Low FAP expression in normal tissues is also advantageous for targeted α-therapy; therefore, 225Ac-FAPI04 may be a new treatment option.18
In addition to previous comments, another limitation of the study is the small number of patients. However, the primary end point was to determine the safety of 177Lu-FAPI04 administration, and the results might still be applicable to help with patient-specific treatment options considering the lack of prior research on the subject. Further research, guided by dosimetry, is required to focus on dose escalation, adverse effects, tumor control, and utilization of different radioisotopes.
This study shows that the estimated absorbed radiation dose to critical organs is significantly low with 177Lu-FAPI04 compared with clinically established peptide-based radionuclide therapies. Up to 50 GBq of cumulative activity can be tolerated using bone marrow as the dose-limiting organ. However, tumor-absorbed dose is also low, which lays the groundwork for future research into optimizing therapeutic efficacy by administrating higher doses or utilizing different radioisotopes.
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