The overall aim in this study was to elucidate whether it is possible to use a less demanding treatment strategy or dosimetry method in individualized 177Lu-dotatate therapy, as compared to that used in the ongoing clinical trial (Iluminet), while maintaining a similar degree of accuracy in renal AD estimates.
For the clinical trial protocol, a hybrid dosimetry method has been used. This choice was a compromise between the axial coverage offered by the whole-body planar images, and the superior accuracy of SPECT/CT. Moreover, at the time of the writing of the clinical trial protocol, performing serial SPECTs in each cycle, including the subsequent processing and analysis of 3D images, was deemed too time-consuming to be feasible.
For the evaluation of the AD per cycle for the alternative treatment strategies (Fig. 3), we conclude that the dosimetry methods in which SPECT/CT are included are superior to the purely planar-based methods and that including one SPECT/CT in each cycle improves the dosimetric accuracy considerably. Results based on the cumulative AD (Table 2) are consistent with results from the per-cycle analysis. Dosimetry method G, including one SPECT/CT in each cycle at 96 h, yields results that are equivalent with the protocol dosimetry method P but with much lower demands on resources. Methods E and F, which also use SPECT in every cycle, give similar but slightly less consistent results.
Method G was implemented following the original work by Hänscheid et al. [19], where an approximate method for estimation of the area under the time-activity curve based on one single image acquisition was developed. The approximation can be derived from the expression of the absorbed dose for a mono-exponential curve, following
$$ D=\kern0.5em \frac{R\left({t}_{\mathrm{ref}}\right)\cdotp \exp \left(\lambda\ {t}_{\mathrm{ref}}\right)}{\lambda }=\frac{R\left({t}_{\mathrm{ref}}\right)\cdotp {2}^{\kern0.5em \left(\frac{t_{\mathrm{ref}}}{T_{1/2}}\right)}\cdotp {T}_{1/2}}{\ln (2)}\approx \frac{R\left({t}_{\mathrm{ref}}\right)\cdotp 2\cdotp {t}_{\mathrm{ref}}}{\ln (2)} $$
(9)
where the last, approximate equality is exact when the imaging time is equal to the effective half-time (tref = T1/2) or two times the effective half-time (tref = 2 T1/2). Hänscheid et al. [19] noted that the right-hand expression yields valid approximations when 0.75 T1/2 < tref < 2.5 T1/2 and in particular when tref = 96 h. If we denote the right-hand term as \( \widehat{D}, \) the theoretical fractional error, E1, becomes
$$ {E}_1=\frac{\left(\widehat{D}-D\right)}{D}=2f\cdotp {2}^{-f}-1 $$
(10)
with f = tref/T1/2. Figure 4 shows the theoretical fractional error, E1, as a function of tref for an effective half-time 51.6 h, as obtained in a previous study [18]. It was considered of interest to evaluate the fractional error for patient data for different choices of tref. Moreover, since in practice the imaging time point cannot be tuned to the effective half-life for a specific patient and cycle, for a given choice of tref, the dispersion in effective half-times will translate into a variance in the fractional error. The data underlying results in Fig. 3 (method G) were thus reanalysed to a patient-based fractional error, E2 = (DG − DP)/DP , where DG and DP are the absorbed doses obtained from method G and P, respectively. Figure 4 shows the mean value of E2 obtained over all patients and cycles, the SD around the mean and the root-mean square deviation (RMSD) in E2, when the value of tref in Eq. 8 is varied between 24 and 144 h. It appears that the theoretical fractional error (E1) compares well with the fractional error obtained for patients (mean of E2) and that the overall deviation, as described by the RMSD, contains both systematic (mean of E2) and random components (SD of E2). When the dispersion in effective half-times is comparably modest, as for the kidney data analysed herein, the RMSD exhibits a valley when T1/2 < tref < 2T1/2 and is lowest near 96 h (tref ≈ 2T1/2). For an imaging time near 50 h (tref ≈ T1/2), the systematic component of the error is equally low as for 96 h, while the SD is higher, thus yielding a slightly higher RMSD. The RMSD is also more sensitive to the exact acquisition time at 50 h than at 96 h. Thus, acquisition at approximately 4 days appears to be a valid choice for this approximation. This is also confirmed by the uncertainty analysis based on SPECT/CT on day 4 (Additional file 1), where method G yields ADs that are equivalent to the protocol results. One drawback with our evaluation of method G is that the effective half-time estimated for the individual patient is included in the calculation of the absorbed-dose rate at 96 h since our SPECT/CTs were not acquired at 96 h. However, we still find it motivated to perform an independent evaluation of this new method, and the included implementation is deemed to be the fairest.
The comparably small deviations obtained using method F, i.e. one SPECT/CT for each cycle and a standard effective half-time for all patients, were unexpected and prompted further investigation. Figure 5 shows data derived from a larger patient material (80 subjects) than the one used for the analyses above. From this figure, we see that the shape of the time-activity curves after 24 h (A and B) as described by the effective half-time (C) is similar between patients, the median being 51.7 h. It is possible, however, that this uniformity in effective half-time is partly due to the uniformity of patient selection and procedures dictated by the clinical trial protocol. It would be of interest to perform a similar analysis in a real-life setting and in different PRRT centres. The vast spread in the first data point in the time-activity curve is a result of the imaging being performed at a time when there is a fast initial turnover and washout of 177Lu-dotatate via the kidneys [26]. This thus supports the choice of fitting function where the first data point, acquired at approximately 1 h, is decoupled from the fitting of the exponential tail and is thus not allowed to influence the assessment of the effective half-time. In spite of the vast spread observed, the AD using method F is in most cases consistent with the protocol dosimetry method P. This is explained by results in Fig. 5d where it is observed that the majority of the AD is delivered after the first 24 h (left kidney median 76% (interquartile range 73 and 79%), right kidney median 75% (interquartile range 72 and 79%)).
The conversion from activity to absorbed-dose rate is, according to the clinical protocol, performed using Monte Carlo-based radiation-transport calculation in a voxelized geometry. Since the range of the electrons emitted from 177Lu is shorter than the spatial resolution of the SPECT images, the radiation-transport calculation could possibly have been simplified to a multiplication by the assumption that the electron kinetic energy is absorbed locally in the voxel [24]. However, it was considered important not to neglect the photon contribution, since parts of the kidneys are located near organs with high uptake such as the spleen, and since in addition to gamma radiation, there are also low-energy X-rays emitted in the 177Lu decay that contribute to the self-absorbed dose. The Monte Carlo method was considered the best choice based on accuracy and availability. Notably, given that only one SPECT/CT is available, it is assumed that the fractional contribution from photons to the total absorbed energy in the kidneys is constant during the entire treatment cycle, whereas in reality, the photon contribution varies with time depending on the activity present in surrounding tissues.
When attempting a conclusion from these results, we can look at them from two different angles. From a methodological point of view, we want the most accurate method to be used, while from a clinical perspective, the question is how much accuracy is really needed in relation to the observed efficacy and toxicity. Of the methods compared in this analysis, dosimetry as per protocol is presumably the most accurate one (as the rest are simplifications of the same), but doing four SPECTs/CT in each cycle would probably yield even more accurate results although to the price of a more time-consuming procedure. Among the simplified methods analysed, we would choose the one with the smallest mean difference for each cycle and the narrowest LOAs.
The methods which best fit these criteria are E and G, both of which incorporate SPECT-based dosimetry in every cycle but are less resource-intense than the reference method P. The strategy that deviates the most is unequivocally method A, i.e. giving 4 cycles to all patients, followed by the planar-based dosimetry methods (B, C and I). This is consistent with what is already known about the drawbacks of planar dosimetry, namely the difficulties in taking into account individual variations in activity concentration, especially in tumours, the liver and intestines, which may then lead to over- or underestimation of the renal AD.
When choosing between methods E and G, one aspect to take into account is that for most PRRT centres, it would be more resource-consuming to perform a SPECT at 96 h since the patients would have to come back to the hospital. Whether or not to still go for method G then becomes a matter of whether or not the small difference seen in the Bland-Altman analyses (2SD of 11 and 17% for methods G and E, respectively) makes a relevant difference in real-life patient management.
From a clinical perspective, on the other hand, some would argue that to give 4 cycles to all patients is already a very effective treatment with a low degree of toxicity, so the need for further optimization is marginal. There are two objections to this: firstly, our obligation to know what we are doing when employing radiation for therapeutic purposes (analogous to the demands in other radiation therapy modalities), and secondly, when these patients progress months or years after their 4 cycles of PRRT, we would like to retreat them since the majority of the cases have not reached the limits for the organs at risk. Without initial dosimetric estimates, we have no grounds on which to plan further treatment.
Given the highly clinically and statistically significant effect of PRRT demonstrated in the NETTER-1 trial [1], together with the ample experience and long safety follow-up with the standard 4 cycles of treatment, perhaps the optimal treatment strategy is a mix between this and dosimetry-based treatment. This could be achieved by initially giving 4 cycles to all (or less if tolerance limits are reached before), but performing dosimetry as well. When the tumour later progresses, the patient can be re-treated to risk organ tolerance limits. In this manner, we get a good risk-benefit balance at each stage of the disease—early in the disease when the patient has a longer expected survival, we use a low-risk treatment, but once progression has been confirmed and the prognosis is another, it is more reasonable to assume the possible risks of higher ADs to risk organs associated with further treatment. Even with the relatively high renal BED limits used in the Iluminet trial, the toxicity has so far been limited (unpublished data), so it is still an open question which limits we should use in the future. Perhaps further retreatment beyond the limits used in this trial will be feasible for some patients under certain conditions. For this reason also, it will be of essence to incorporate dosimetry in PRRT planning, both in clinical routine and future clinical trials, and thereby progressively increase our understanding and body of knowledge.