Patients

The prospective study included 30 patients who received [177Lu]Lu-DOTA-TATE treatment in the Department of Nuclear Medicine at Fudan University Shanghai Cancer Center (FUSCC) from May 2023 to March 2024. The inclusion criteria for patients were: (1) age ≥ 18 years; (2) histologically confirmed unresectable or metastatic, progressive, well-differentiated (G1 and G2), SSTR-positive GEP-NENs; (3) at least one measurable lesion on baseline imaging and all target lesions confirmed as SSTR-positive (lesion uptake greater than normal liver uptake) by 68 Ga-DOTA-TATE positron emission tomography/computed tomography (PET/CT); (4) ECOG performance status of 0 or 1; (5) premenopausal patients willing to use contraception during and after treatment (4 months for males, 7 months for females). Patients with any of the following conditions were excluded from the study: serum creatinine > 1.7 mg/dL, hemoglobin < 80 g/L, white blood cell < 2.0 × 109/L, platelets < 75 × 109/L, serum total bilirubin > 3 times the upper limit of normal (ULN), serum albumin < 30 g/L, alanine aminotransferase (ALT) or glutamic pyruvic transaminase (AST) > 2.5 × ULN, international normalized ratio (INR) > 1.5. This study was approved by the Ethics Committee of FUSCC (Approval No. 2210262-2), and all patients provided informed consent.

[177Lu]Lu-DOTA-TATE PRRT protocol

The dosage of [177Lu]Lu-DOTA-TATE was 7.4 GBq (200 mCi) ± 10% per cycle, with a total of 4 cycles administered every 8 ± 2 weeks. The interval between two cycles was at least 6 weeks and up to a maximum of 16 weeks. In case of drug-related adverse events during treatment, dosing might be temporarily paused, reduced, or discontinued based on the specific circumstances (Supplemental Table 1). On the day of [177Lu]Lu-DOTA-TATE treatment, patients were admitted to a nuclear medicine ward equipped with specialized radiation protection measures. Patients were first given ondansetron hydrochloride injection to prevent nausea, followed by intravenous infusion of amino acids (arginine hydrochloride and lysine hydrochloride) 30 min after antiemetic administration to reduce radiation damage to the kidneys caused by [177Lu]Lu-DOTA-TATE [20], with the total duration of amino acid administration exceeding 4 h. The injection of [177Lu]Lu-DOTA-TATE was carried out 30 min after the start of amino acid infusion using an automated infusion device with shielding protection, and the administration duration exceeds 30 min [21]. After receiving radiation safety education, each patient was discharged at least 4 h after receiving [177Lu]Lu-DOTA-TATE to protect others from unnecessary radiation exposure.

Table 1 Basic information of the patients (n = 30)

After each administration of [177Lu]Lu-DOTA-TATE at 4, 24, 96 and 144 h, we performed whole-body single photon emission computed tomography (SPECT) imaging and localized tomographic imaging of metastatic lesions. A clinical SPECT/CT scanner (Discovery NM/CT 670, GE, USA) equipped with low energy high resolution (LEHR) collimator and energy window of 113 ± 10% keV was used. The CT parameters were as follows: tube voltage = 120 kV, tube current = 20 mA, slice thickness = 3.75 mm. The ordered subset expectation maximization (OSEM) algorithm was applied for reconstruction. And for corrections, resolution recovery, scatter and attenuation corrections were used.

Measurement method of EDR

Following the initiation of [177Lu]Lu-DOTA-TATE infusion, a portable x/γ radiation dose (RD) detector (SG-16A) (Jiufu Technology Co., Ltd, China) was used to measure the EDR on the patient’s chest every 5 min until the completion of [177Lu]Lu-DOTA-TATE infusion. After the completion of [177Lu]Lu-DOTA-TATE infusion, at immediate post-infusion, 0.5, 1, 1.5, 2, 3 and 4 h, and/or pre-discharge time points, patients were instructed to measure the EDR-1 m value from the front surface of each patient’s body and at a height of 1.5 m above the floor, with each patient measurement exceeding 4 h. The EDR-1 m value measurement was performed using the TOFTEK TERM-35 environmental radiation monitor (Tongtou Optoelectronic Technology Co., Ltd, China).

EDR decay curve fitting method

The decay law of EDR over time in vitro was analyzed using MATLAB_R2018.a software (MathWorks Inc., USA), the EDR values measured at 1–5 h, which were relatively stable and have high discriminative power, were fitted using a double exponential parameter model. The mean EDR values of all populations undergoing [177Lu]Lu-DOTA-TATE therapy and different treatment frequencies were also fitted. By fitting a double exponential function model to the data and obtaining the corresponding equation, we calculated the effective half-life of [177Lu]Lu-DOTA-TATE. The quality of the model fit was evaluated using the R2 and root mean square error (RMSE) values, where a higher R2 value and lower RMSE value indicated a better fit of the double exponential curve model, aligning more closely with dosimetry and pharmacokinetic studies.

Estimation radiation dose of direct family members

To estimate the RD received by the public or family members, the Mountford method was employed [22], assuming exposure patterns to estimate the RD for the public. We assume the contact distance for direct family members and co-workers with the patient after administration is 1.0 m, with contact times of 6 h per 24 h and 8 h per 24 h, respectively. Based on the calculation method for public RD outlined by National Council on Radiation Protection and Measurements (NCRP) Report No. 155 [23], and considering different occupancy factors for various human activities, the formula for calculating the public RD for the [177Lu]Lu-DOTA-TATE patients under different activity patterns from the time post-administration to infinite time of exposure is as follows:

$$\text=1.44\times \text(_)\times \text(_)\times \underset}\sum_^___}^\left(2\right)t}__}}}dt$$

Here, the expression \(\sum_^___}^\left(2\right)t}__}}}\) represents the exponential function modeling the metabolism of [177Lu]Lu-DOTA-TATE in the human body using a compartmental model. \(_\) denotes the relative distribution fractions of [177Lu]Lu-DOTA-TATE in each compartment, \(__}\) represents the effective half-life of [177Lu]Lu-DOTA-TATE (h), \(\text(_)\) and \(\text(_)\) refer to the dose rate and occupancy factor at a distance of \(_\), and t signifies the time of intravenous administration of [177Lu]Lu-DOTA-TATE (h). According to the Chinese Requirements for Radiological Protection in Nuclear Medicine GBZ 120–2020, the RD limits for patients receiving radionuclide therapy are typically set at 1 mSv/year for general public, and for direct family members, the RD limits are set at 1 mSv/year for children aged 3–10, 3 mSv/year for children older than 10, and 5 mSv/year for adult family members. We calculated the recommended social contact times for different populations using the formula.

Radiation dose measurement to staff

During the patient’s hospitalization, a specialized nuclear medicine nurse administering the dose worn a portable RD detector (SG-16A) throughout the procedure to measure the cumulative RD received during radioactive operations. The cumulative environmental RD was measured using a portable RD detector (SG-16A) which was placed on a shelf approximately 2 m away from the patient in the ward.

Statistical analysis

Other collected data were analyzed using SPSS v22.0 statistical software (IBM, USA) with a two-way repeated measures analysis of variance (Two-way ANOVA) to assess the impact of different [177Lu]Lu-DOTA-TATE treatment frequencies on the temporal changes in patients’ EDR. The Shapiro–Wilk test was used for normality testing, where p > 0.05 indicated data followed a normal distribution. For sphericity testing, if p > 0.05, the assumption of sphericity was met, otherwise, the results were corrected using the Greenhouse–Geisser method. Data were presented as mean ± standard deviation, and differences with p < 0.05 were considered statistically significant.