Patients
In this retrospective study, 777 patients (333 females and 444 males) with metastatic somatostatin receptor-positive neuroendocrine tumors treated with 177Lu-DOTATATE were included, and all of them met previously described inclusion criteria [21]. Dosimetry on these patients was performed during the years 2006 to 2019. Both the left and the right kidneys were included in the analysis, with the exception of the right kidney in 12 patients and the left kidney in 11 patients, in whom the kidneys had been resected or had very impaired function.
177LuCl3 was purchased from IDB Radiopharmacy bv, Baarle-Nassau, The Netherlands, and DOTATATE was a generous gift from Erasmus Medical Centre, Rotterdam, The Netherlands.
Compliance with ethical standards
The study received no external funding, and all authors declare no conflict of interest.
Since September 2010, all patients were included into a prospective study (EudraCT no. 2009-012260-14) approved by the Regional Ethical Review Board in Uppsala. Before that, from 2005, the patients were admitted on a single-patient basis for compassionate use with individual permission from the Swedish Medical Products Agency. All patients gave their written informed consent before study inclusion.
Image acquisition
All 777 patients underwent SPECT/CT of the abdomen 1, 4, and 7 days after administration of the first cycle of 7.4 GBq 177Lu-DOTATATE. For the first 69 patients, imaging was performed on a Hawkeye Millennium VG (GE Healthcare) dual-head camera equipped with 5/8” NaI(Tl) crystals and MEGP (medium energy general purpose) collimators. A 20% energy window around the 2 dominant γ-ray energies of 177Lu, 113.0 and 208.4 keV, was applied. SPECT/CT, applying 60 frames with a 60-s exposure time per frame (total acquisition time for SPECT is then 30 min), was performed over the upper abdomen including organs at risk (kidneys, liver, and spleen). In the next 400 patients, imaging was performed on an Infinia (International General Electric, General Electric Medical Systems, Haifa, Israel) dual-headed gamma camera with 3/8” NaI(Tl)-crystals equipped with MEGP collimators. The measurements employed a 20% energy window around the dominant 208.4 keV gamma ray energy of 177Lu. SPECT/CT of the upper abdomen included the organs at risk (kidneys, liver, and spleen), applying 120 frames with a 30-s exposure time per frame. In the last 308 patients, SPECT/CT was performed on a Discovery 670 PRO (International General Electric, General Electric Medical Systems, Haifa, Israel) dual-headed gamma camera with 3/8” NaI(Tl)-crystals equipped with MEGP collimators with the same settings as for the Infinia. For reconstruction, the ordered subset expectation maximization (OSEM) algorithm included in the Xeleris 3.0 workstation (International General Electric, General Electric Medical Systems, Haifa, Israel) was used with previously determined default settings (iterative reconstruction with eight subsets and four iterations followed by a Hann filtering with a cutoff of 0.85). In all the systems above, the images were attenuation corrected with the concomitantly acquired CT-based attenuation map but were not corrected for scatter, collimator/response, or PVE. The small VOI method is sensitive to artefacts, and because of the Gibbs artefacts, no collimator response/resolution recovery was included. Scatter correction was also omitted since the only available methods for us are the triple or dual energy window methods, which for us have generated more problems than they have solved.
Absorbed dose calculations
All volumes of interests (VOIs) were defined using in-house-developed software within the Hermes platform on a Hermes HNAC workstation with the Gold 2.9 software (HERMES, Stockholm, Sweden).
In the SPECT images, small spherical volumes of interests (VOIs; 4 ml) were placed in both kidneys to include the renal cortex as described previously [21]. Activity concentrations were determined for each time point (1, 4, and 7 days after 177Lu-administration), and time-integrated activity concentration was calculated as the area under the curve of a single exponential fit (from infusion start to infinity) to the time-activity concentration curve (A(t)).
In the MIRD 21 pamphlet [24], the mean absorbed dose D(rT,TD) to a target structure rT in the time period from time 0 to time TD is defined as:
$$ D\left({r}_{\mathrm{T}},{T}_{\mathrm{D}}\right)=\sum \limits_{r_{\mathrm{s}}}{\int}_0^{T_{\mathrm{D}}}A\left({r}_{\mathrm{S}},t\right)S\left({r}_{\mathrm{T}}\leftarrow {r}_{\mathrm{S}},t\right) dt $$
(1)
where A(rS,t) is the activity of the radiopharmaceutical in source tissue rS at time t, and S(rT ← rS,t) is the radionuclide-specific quantity representing the mean absorbed dose rate to target tissue rT at time t after administration per unit activity present in source tissue rS.
It has been shown [25] that the absorbed dose from surrounding organs to kidneys in therapy with 177Lu-DOTATATE does not add much to the absorbed dose. This general formula can be rewritten to only include the absorbed dose originating from the target structure itself:
$$ D\left({r}_{\mathrm{T}},{T}_{\mathrm{D}}\right)={\int}_0^{T_{\mathrm{D}}}A\left({r}_{\mathrm{T}},t\right)S\left({r}_{\mathrm{T}}\leftarrow {r}_{\mathrm{T}},t\right) dt $$
(2)
To simplify further, Eq. 2 can be rewritten again to work with concentrations instead.
$$ D\left({r}_{\mathrm{T}},{T}_{\mathrm{D}}\right)={\int}_0^{T_{\mathrm{D}}}C\left({r}_{\mathrm{T}},t\right)\ast \mathrm{ACDF}\left({r}_{\mathrm{T}}\leftarrow {r}_{\mathrm{T}},t\right) dt $$
(3)
where C(rS,t) is the activity concentration of the radiopharmaceutical in target tissue rS at time t, and ACDF(rT ← rT,t) (activity concentration dose factor) is the radionuclide-specific quantity representing the mean absorbed dose rate to target tissue rT at time t after administration per unit activity concentration present in target tissue rT. ACDF is a multiplication of S-factor with the volume for the S-factor. The ACDF does not change much with the volume, and using dose factors (DF) from the spherical model in OLINDA [26] gives an ACDF of 86.0 mGy*g/MBq*h for a 100-g sphere and 86.7 mGy*g/MBq*h for a 300-g sphere leading to a difference of less than 1%.
Calculating the time-integrated activity concentration (\( \overset{\sim }{C} \)) from time of administration to infinity and assuming a density of 1 means that the final equation for calculation of the absorbed dose to the kidneys ends up with a simple multiplication:
$$ {D}_{\mathrm{Kidney}}=\overset{\sim }{C}\ast {\mathrm{ACDF}}_{\mathrm{Kidney}\leftarrow \mathrm{Kidney}} $$
(4)
This procedure has previously been described in more detail in the following references [21, 23].
Fractional contributions
For the absorbed dose to the kidneys, several fractional contributions (f) (Eq. 5) were calculated for each therapy cycle of 7.4 GBq.
$$ f=\left(\frac{\int_{t_1}^{t_2}C(t) dt}{\int_{t_s}^{t_e}C(t) dt}\right) $$
(5)
In this equation, the fractional contribution (f) is defined as the area under the curve of the expression (C(t)) between the time of the first measurement point (t1) and the time of the last measurement point (t2) divided by the total area under the curve from the start time (ts) to the end time (te). The expression (C(t)) is in this case the single exponential fit to the measurements of radioactivity concentration in the kidneys.
The following fractional contributions were calculated on the single exponential curve fit on days 1, 4, and 7 measurements for the right and left kidney: (fc0-24) the extrapolated portion of the curve from time = 0 (start of 177Lu-DOTATATE infusion) to the measurement at day 1, (fc168-∞) the portion of the curve after day 7 measurement (to infinity), (fc0-24+168-∞) the sum of fc0-24 and fc168-∞, (fc96-∞) the portion of the curve after day 4 measurement (to infinity), and (fc0-24+96-∞) the sum of fc0-24 and fc96-∞; each of these extrapolations were calculated as a fraction of the total area under the curve from time zero to infinity. In addition, in the light of the reports of Guerriero et al. [27] and Delker et al. [28], indicating that there is a short rapid washout phase with elimination of radioactivity from the kidneys, chiefly affecting the first hours of the time activity curve but with a small influence present after 8 h, we also calculated (fc0-8) the fractional contribution of the first 8 h to the total area under the curve. Examples of all these fractional contributions are shown on a typical curve for the kidney in Fig. 1.
Simplification of the measurements
As a standard, absorbed dose (AD147) and teff (teff147) are calculated using single exponential fit to data from 3 measurements 1, 4, and 7 days after start of the therapy. As a first attempt to simplify the dosimetry measurements, two calculations of the absorbed dose (AD14 and AD17) and teff (teff14 and teff17) were performed, using the single exponential functions crossing only two points (1 and 4 days, and 1 and 7 days, respectively). In addition, absorbed doses were calculated using a single measurement (at 4 days), assuming the median of our 777 patients teff 52 h (AD4/52) and using Eq. 7 (adapted to activity concentration) in the paper by Hänscheid et al. [29] (AD4/H). Since the standard method in the paper by Hänscheid et al. [29] is based on 2D measurements ending at day 4, we also performed a comparison between AD14 versus AD4/52 and AD4/H, based on the 3D measurements from our cohort of 777 patients.
Statistical methods
Bland-Altman analyses for absorbed dose and teff values were performed for the comparisons between the different simplified methods, detailed above, relative to those based on the three-point measurement. Bland-Altman analyses of absorbed dose values relative to those based on days 1 and 4 measurement were calculated for the one time point method. Median, minimum, and maximum of the results were also calculated.