This study, conducted at Shonan Kamakura General Hospital, aims to optimize the SPECT imaging schedule, evaluate differences among simulation software programs, and develop a protocol suitable for epidemiological studies to define dose constraints for normal organs in Lu-177-DOTATATE therapy. Specifically, we will investigate whether the standard 4-time-point protocol could be reduced to 1-, 2-, or 3-scan protocols without compromising dosimetric accuracy. The purpose of this study is to explore practical time points for dosimetry within a single treatment cycle. Inter-cycle variability will be examined in subsequent studies after optimal time points are established in this study.

The primary endpoint is to evaluate the effect of scan reduction on the estimated absorbed dose to the kidneys, given that renal toxicity—particularly radiation-induced nephropathy—is the primary dose-limiting factor. Secondary endpoints include comparing tumor and normal organ dosimetry across imaging protocols and analyzing dose variations among software programs to assess consistency and reliability.

This open-label, single-institution exploratory observational study will recruit patients with neuroendocrine tumors undergoing Lu-177-DOTATATE therapy. Gamma emissions from normal organs and tumors will be measured using SPECT imaging at 4, 24, 96, and 168 hours following radiopharmaceutical administration. These images will serve as inputs for simulation software to calculate absorbed doses to normal organs and target tissues.

 This study adopts the 4-time-point SPECT protocol (4-point method) as the reference standard for each patient within each software program. Doses calculated after omitting 1‐3 time points (1-, 2-, and 3-point methods) will be compared with the 4-point dose within each program. The evaluation frameworks for each method are summarized below. Fifteen dose simulations will be conducted per patient. Data collection will span from March 2024 to February 2027.

For the 4-point method, dosimetry calculation will be performed using SPECT images taken at 4, 24, 96, and 168 hours. For the 3-point method, dosimetry calculation will be performed using SPECT images taken at 24, 96, and 168 hours; 4, 9, and 168 hours; 4, 24, and 168 hours; and 4, 24, and 96 hours. For the 2-point method, dosimetry calculation will be performed using SPECT images taken at 4 and 24 hours; 4 and 96 hours; 4 and 168 hours; 24 and 96 hours; 24 and 168 hours; and 96 and 168 hours. For the 1-point method, dosimetry calculation will be performed using SPECT images taken at 4 hours; 24 hours; 96 hours; and 168 hours post-injection

If dose discrepancies remain within acceptable limits, the simplified protocol will be considered for future trials. Additionally, absorbed doses calculated using each program will be compared across algorithms.

This exploratory observational study will evaluate various SPECT imaging time-point protocols and dosimetry software programs in patients undergoing Lu-177-DOTATATE therapy. Patient randomization is not applicable because the objective is to evaluate dosimetric methods against a reference standard in a real-world clinical setting rather than to compare treatment groups.

This is an open-label study. Blinding of participants or investigators will not be performed, as the primary focus is on technical comparisons of dosimetry methodologies and software programs. Blinding of imaging protocols or software analyses would be impractical and irrelevant for assessing dosimetric accuracy in this context.

This study is designed as an exploratory observational trial and primarily involves the acquisition of additional SPECT/computed tomography (CT) images as part of the standard clinical protocol for Lu-177-DOTATATE therapy. As such, the research interventions are integral to routine clinical care and introduce minimal to no additional risks to participants beyond that associated with standard Lu-177-DOTATATE therapy.

The potential for additional radiation exposure from the extra SPECT/CT scans is considered negligible and will be kept as low as reasonably achievable, in accordance with the recommendations of the International Commission on Radiological Protection [13]. Any adverse events related to Lu-177-DOTATATE therapy will be managed and reported by the treating physicians according to standard clinical practice and existing institutional guidelines [14], and not as part of this study protocol, as the focus of this study is solely on dosimetry methodology.

Given the non-interventional and low-risk nature of this observational study, an independent data monitoring committee will not be established.

All acquired SPECT/CT images that meet technical quality control standards will be included in the dosimetry analysis. Data points, including individual SPECT scans, may be excluded if deemed technically inadequate—owing to motion artifacts, hardware malfunction, or incomplete acquisition—after review by a medical physicist, as these issues could compromise dose calculation accuracy. All exclusions will be thoroughly documented and reported.

The data will be entered and stored using Microsoft Excel software, cross-checked in pairs, saved on an encrypted computer, and backed up.

This study implements a 5+5 design, also known as a rule-based design [15]. The primary endpoint is the dose error incidence for each calculation algorithm. Figure 1 presents the decision-making workflow. The assumed dose error incidence in this study is set to be ≤5%; based on this assumption, the required number of eligible patients will be modified using the 5+5 design [16]. If the incidence (dose error per patient ≤ threshold) is ≤5% within the workflow, false-negative results will be observed in ≤23% of trials. If the incidence is ≥30%, false-positive results will occur in ≤17%.

Dose error below the predefined threshold will be considered acceptable for each calculation algorithm. The primary threshold will be set at 5%, following the International Commission on Radiation Units and Measurements Report 83 guidelines [17], which recommend that overall dosimetric uncertainty should ideally be within ±5%. For regions with absorbed doses <5 Gy, where larger errors are generally observed, the threshold will be relaxed to 10% [18]. A simplified method will be deemed “acceptable” if, in all five cases, the absorbed dose estimated by each software program falls within the threshold (5% or 10%, depending on the regional dose) when compared with the reference 4-point method. If multiple algorithms meet the criteria, priority will be given to the algorithm requiring the fewest time points for the subsequent trial. For example, if both the 3-point and 1-point methods meet the criteria, the 1-point method will be selected as the primary candidate. Among algorithms requiring the same number of time points, those incorporating the 4-hour or 24-hour sampling points will be preferred.

In external beam radiotherapy treatment planning, the total kidney dose threshold is 23 Gy [19], indicating that a dose of 5.5 Gy per treatment cycle is considered clinically acceptable. Therefore, we will relax the absorbed dose threshold from 5% to 10% if kidney doses are <5 Gy.

If the threshold is exceeded in 1 of the 5 patients, an additional 5 cases will be evaluated. The simplified method will be considered “acceptable” if at least 9 of the 10 cases meet the threshold. Conversely, if the dose error exceeds the threshold in 2 or more of the 10 cases, the simplified method will be considered “unacceptable.”

The true absorbed dose cannot be directly measured, and 4-point estimates are derived using software-specific kinetic models and dose-calculation frameworks. Therefore, it cannot be conclusively stated that these estimates are equivalent across different software programs. Consequently, consistency among software systems will be evaluated by comparing the magnitude and distribution of relative dose deviations from the 4-point reference and from the 1- to 3-point estimates using descriptive statistical methods. Visualization of these distributions, such as using box-and-whisker plots, may facilitate assessment of the validity of dose reduction at each time point. As a reference analysis, one-way analysis of variance will be used to compare absorbed doses to each organ of interest across software systems and between patients. The level of statistical significance is set at 0.05. If the P value is less than .05, the validity of the candidate calculation algorithm will be re-evaluated.

The eligibility criteria are presented in Textbox 1 .

Lu-177-DOTATATE will be administered following the protocol previously approved by the Food and Drug Administration [20]. Based on this protocol, TRT will be administered in four treatment cycles per patient, with each cycle scheduled at 8-week intervals. In each cycle, Lu-177-DOTATATE (7.4 GBq) will be administered over 30 minutes. An amino acid solution containing 2.5% lysine and 2.5% arginine will be co-administered via intravenous infusion at approximately 1000 mL over 4 hours, beginning 30 minutes before TRT. This solution facilitates renal protection by promoting urinary excretion of Lu-177-DOTATATE, thereby reducing the dose absorbed by the kidneys. Prior to amino acid infusion, an appropriate antiemetic agent will be administered as an intravenous bolus to prevent nausea and vomiting.

Participants will be enrolled after being administered at least one TRT cycle to minimize the risk of allergic reactions to the administered agents. Patients will not be enrolled until they have completed at least one treatment cycle and their ability to attend follow-up visits at our hospital has been confirmed. Eligible individuals will be invited to participate and will be provided with detailed study information by their radiation oncologist to support informed decision-making.

Ethics approval and consent to participate were reviewed and granted by the Tokushukai Group Ethics Committee Institutional Review Board (Approval No. 2447; UMIN000057478). Written informed consent will be obtained from all participants prior to study enrollment. All data will be de-identified prior to analysis, and no personally identifiable information will be accessible to the research team outside the treating institution. The study data will be handled in accordance with applicable data protection regulations. Participants will not receive any financial compensation for participation in this study. All study procedures will be conducted in accordance with the principles of the Declaration of Helsinki and applicable regulatory requirements.