Correlations between [68Ga]Ga-DOTA-TOC uptake and absorbed dose from [177Lu]Lu-DOTA-TATE

doi:10.21203/rs.3.rs-1964153/v1

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Correlations between [⁶⁸Ga]Ga-DOTA-TOC uptake and absorbed dose from [¹⁷⁷Lu]Lu-DOTA-TATE

https://doi.org/10.21203/rs.3.rs-1964153/v1

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Background: Peptide receptor radionuclide therapy (PRRT) with [¹⁷⁷Lu]Lu-DOTA-TATE is used to treat gastroenteropancreatic neuroendocrine tumours (GEP-NET), by targeting somatostatin receptors (SSTRs). High SSTR expression assessed on [⁶⁸Ga]Ga-DOTA-TOC PET/CT images decides patient eligibility for [¹⁷⁷Lu]Lu-DOTA-TATE PRRT. This study aimed to investigate potential correlations between therapeutic absorbed dose to tumours and the pre-treatment [⁶⁸Ga]Ga-DOTA-TOC uptake.

Methods: This retrospective study included 301 tumours from 54 patients with GEP-NET. The tumours were segmented on pre-therapeutic [⁶⁸Ga]Ga-DOTA-TOC PET/CT, and post-therapy [¹⁷⁷Lu]Lu-DOTA-TATE SPECT/CT acquired 24 and 168 hours post administration (also 4 hours for some patients). The SPECT/CT images were used for absorbed dose calculations.

Results: Mean SUV_mean and SUV_maxfrom [⁶⁸Ga]Ga-DOTA-TOC PET was 24.0 (3.6-84.4) and 41.0 (6.7-146.5), and the mean absorbed dose from [¹⁷⁷Lu]Lu-DOTA-TATE was 26.9 Gy (2.4-101.9). An absorbed dose prediction model was formed based on a weak, but significant (R² = 0.44, p<0.05), linear relationship between SUV_mean and [¹⁷⁷Lu]Lu-DOTA-TATE activity concentration at 24 hours, together with a population-averaged pharmacokinetics. The relative error between predicted and calculated absorbed dose was 0.31+/-0.90.

Conclusions: Depending on the required accuracy, [⁶⁸Ga]Ga-DOTA-TOC PET imaging may estimate the [¹⁷⁷Lu]Lu-DOTA-TATE absorbed dose. While a linear correlation was found, differences between [⁶⁸Ga]Ga-DOTA-TOC and [¹⁷⁷Lu]Lu-DOTA-TATE uptake gave especially high variance.

Peptide receptor radionuclide therapy

[68Ga]Ga-DOTA-TOC

PET/CT

[177Lu]Lu-DOTA-TATE

SPECT/CT

Dosimetry

Prediction model

Gastroenteropancreatic neuroendocrine tumours (GEP-NET) are heterogeneous malignancies, characterised by a variable expression of somatostatin receptors (SSTR) on the cell surface of the dispersed neuroendocrine system in the pancreas and other parts of the gastrointestinal tract^1–3. Peptide receptor radionuclide therapy (PRRT) is a molecular cancer treatment using SSTR to target GEP-NETs. A high uptake of a diagnostic somatostatin analogue (SSTA) in tumour lesions is a common measure of PRRT eligibility^4,5. ⁶⁸Ga-DOTA-labelled SSTAs are currently considered the preferred tool for patient evaluation of SSTR expression^6–9, and for example the PET tracer [⁶⁸Ga]Ga-DOTA-TOC has shown favourable performance and is commonly used¹⁰.

Several radiolabelled SSTA alternatives such as [¹¹¹In]In-DOTA-TOC, [¹¹¹In]In-octreotide, [⁹⁰Y]Y-DOTA-TOC, [¹⁷⁷Lu]Lu-DOTA-NOC, [¹⁷⁷Lu]Lu-DOTA-TATE and [¹⁷⁷Lu]Lu-DOTA-TOC have been applied for therapeutic use^8,11−15. PRRT with [¹⁷⁷Lu]Lu-DOTA-TATE delivers targeted radiation and has shown promising response and survival statistics^15,16, while additionally permitting post-treatment imaging and personalised dosimetry¹⁷. [¹⁷⁷Lu]Lu-DOTA-TATE is usually prescribed by multiple cycles of 7.4 GBq with intervals of 8 weeks between¹⁵. Based on post-therapy SPECT/CT measurements of activity concentration at various time points, absorbed dose calculations can be performed. Dosimetry is necessary to limit absorbed dose to organs at risk, and should ideally be performed for tumours as well as to monitor absorbed dose to target tissue. A high inter- and intra-patient variability in tumour absorbed dose from PRRT is commonly observed^18–20, emphasising the need for personalised treatment. Given a sufficiently correlated uptake, the absorbed dose from PRRT with [¹⁷⁷Lu]Lu-DOTA-TATE could potentially be predicted from measurements of [⁶⁸Ga]Ga-DOTA-TOC. While the two radiopharmaceuticals are based on similar peptides, differences in SSTR affinity between TOC and TATE have been observed in vitro, although the clinical consequences of these differences remain uncertain²¹. In comparisons of tumour uptake of [⁶⁸Ga]Ga-DOTA-TOC and [⁶⁸Ga]Ga-DOTA-TATE as a tool for staging and PRRT patient selection, only minor clinical implications were shown^10,22. [¹⁷⁷Lu]Lu-DOTA-TATE has been found to have a 2.1 longer residence time in tumours than [¹⁷⁷Lu]Lu-DOTA-TOC²³, indicating that, opposed to the uptake level, the pharmacokinetics vary. Still, these comparisons are not directly translatable to predict correlations between [⁶⁸Ga]Ga-DOTA-TOC and [¹⁷⁷Lu]Lu-DOTA-TATE, as the radionuclide can possibly also change the molecular behaviour. A few earlier studies have investigated the correlation between PET-derived [⁶⁸Ga]Ga-DOTA-TOC uptake and SPECT-derived [¹⁷⁷Lu]Lu-DOTA-TATE uptake²⁴, and one study also investigated and found potential for absorbed dose prediction²⁵.

The aim of this work was to explore the correlation between [⁶⁸Ga]Ga-DOTA-TOC SUV and [¹⁷⁷Lu]Lu-DOTA-TATE uptake parameters in the first of the standard 7.4 GBq treatment fractions for tumours, and to investigate an absorbed dose prediction model for the therapy based on pre-therapeutic [⁶⁸Ga]Ga-DOTA-TOC PET/CT scans.

Patient population

This study included consecutive patients diagnosed with metastatic and progressive or recurrent GEP-NET, treated with at least one fraction of [¹⁷⁷Lu]Lu-DOTA-TATE PRRT. Eligibility criteria for the treatment were radiologic, symptomatic or biochemical progression despite optimal conventional treatment, and a high expression of SSTR (grade 3–4) as assessed on [⁶⁸Ga]Ga-DOTA-TOC PET/CT scans. Histological sampling was performed prior to the treatment to establish tumour grade and Ki-67 index. Adequate hepatic, renal and hematologic function are also critical prerequisites for treatment. This study was approved by the local data protection officer at Oslo University Hospital, and informed consent was waived. Data was handled according to relevant regulations.

Image Acquisition

Pre-therapeutic PET/CT imaging (example in Fig. 1A and 1C) was performed on a GE Discovery MI, 78 minutes (range: 54–96 minutes) post administration a nominal activity dosage of 150 MBq [⁶⁸Ga]Ga-DOTA-TOC. The acquisition time was 100 s per bed with 50% overlap. The images were gated using the Varian trigger system and reconstructed in the expiratory phase (Q.Static). The images were reconstructed with a Bayesian penalised likelihood reconstruction (Q.Clear) with a beta factor of 500, on a 384x384 matrix of 1.82 mm pixels with a slice thickness of 2.79 mm. The CT scans were acquired at 120 kV and a dose modulation noise index of 34.5, and reconstructed with an iterative reconstruction (ASIR-V) with 40% filtering on 512x512 matrices. The pixel size was 0.84 mm with slice thickness 0.625 mm.

[¹⁷⁷Lu]Lu-DOTA-TATE SPECT/CT imaging (example in Fig. 1B, 1D and 1E) was on average performed 23.1 hours (range 21.0-26.8) and 167.0 hours (range 119.1-218.8 hours) post administration (t₂₄ and t₁₆₈, respectively) of the first treatment cycle for all patients. An additional image (t₄) on average 4.7 hours (range 3.4–6.5) was acquired for nine of the patients. The average administered activity was 7574 MBq (range 7247–7907 excl. one patient given 4195 MBq). The imaging was performed on a GE Discovery 670 scanner with a medium energy, general purpose collimator. The images were acquired with an energy window set at 208 keV +/- 10% with 120 projections of 30 seconds frame duration, and two adjacent scatter windows of +/- 5%. A scatter- and attenuation-corrected reconstruction with 4 iterations and 8 subsets without resolution recovery was performed with the vendor software (Xeleris, GE Healthcare). Matrix size was128x128 and isotropic voxels of 4.42 mm were reconstructed. The CT scans were acquired at 120 kV and a dose modulation noise index of 26, and reconstructed with an iterative reconstruction (ASIR) with 40% filtering on 512x512 matrices. The pixel size was 0.98 mm with slice thickness 2.5 mm.

[⁶⁸Ga]Ga-DOTA-TOC PET Measurements

Tumours which could be visually matched between all images (PET and SPECT at t₂₄ and t₁₆₈), with negligible overlap with adjacent activity sources, were included for analysis. A manual identification of tumours confirmed by a nuclear medicine specialist was followed by a fixed threshold method for measurements, using a threshold of 40%²⁴ of the SUV_max. Both SUV_max, SUV_mean, and the volume defined by the threshold; referred to as the somatostatin receptor expressing tumour volume (SRETV) from here on, were recorded.

[¹⁷⁷Lu]Lu-DOTA-TATE SPECT Measurements and Tumour Dosimetry

The tumours were delineated using 40% threshold determined by volume matching in a phantom study, from which recovery coefficients were also found (supplementary Fig. 1). The VOI-derived counts were converted to activity by a system specific calibration coefficient of 8.4 cps/MBq. Time-activity curves (TACs) were calculated by assuming a linear activity build-up from time of administration to the first measuring point (t₂₄), followed by a mono-exponential curve fit based on t₂₄ and t₁₆₈. The TAC was integrated to yield the time-integrated activity (Ã). Tumour mass, m, was estimated by assuming a tissue mass density of 1 g/ml. The absorbed dose was calculated by assuming local deposition and a dose factor DF = 0.083 Gy∙g/MBq∙h, including all non-penetrative radiation from ¹⁷⁷Lu.

$$AD= \frac{\tilde{A}}{m}DF$$

Prediction Analysis

A linear relation was assumed between [⁶⁸Ga]Ga-DOTA-TOC SUV_mean and [¹⁷⁷Lu]Lu-DOTA-TATE activity concentration per administered activity at t₂₄ (${A}_{conc,24}/{A}_{adm}$), as a measure of uptake correlation.

$${A}_{conc,24}/{A}_{adm}=SU{V}_{avg}\cdot \alpha +\beta$$

The absorbed dose prediction model (Eq. 4) was based on SUV measurements and administered activity.

$$A{D}_{pred}\left({SUV}_{avg}\right) = ({SUV}_{avg}\cdot \alpha +\beta )\cdot {A}_{adm}\cdot DF\cdot \tau$$

The fitting parameters α and β were derived from the linear relationship between ${A}_{conc,24}/{A}_{adm}$ and SUV_mean. $\tau$ is a constant that represents the shape of the TAC based on the patient population average of t_24.pop and t_eff.pop:

$$\tau =\frac{{t}_{24,pop}}{2}+\frac{{t}_{eff,pop}}{\text{ln}\left(2\right)}$$

Group analysis

An analysis to investigate differences in absorbed dose and differences between predicted and actual absorbed dose for multiple tumour groups was conducted. Tumours were grouped by anatomical site (hepatic, lymphatic and skeletal lesions were compared), SUV-parameters and tumour mass. Two approaches were explored; one where tumours were divided into groups of equal size, and one where equal range of the parameter were grouped.

Statistics

A Shapiro-Wilk normality test and visual inspection of the probability plots of the residues were performed to test for normality. Pearson correlation was performed to test linear correlation between parameters. The linear correlation was evaluated in terms of the coefficient of determination, R². A significance level of 0.05 was used. Relative error (${\varDelta }_{AD}$) was used to determine the accuracy of the prediction model, defined by the relative difference between predicted, AD_pred, and actual absorbed dose:

$${\varDelta }_{AD}=100\%\bullet ({AD}_{pred}-AD)/AD$$

The accuracy of the prediction model was further explored by testing the ability to predict if the tumour absorbed dose was higher or lower than the population median using receiver operating characteristics analysis.

The group differences of relative error between predicted and measured absorbed dose were tested with a one-way analysis of variance (ANOVA)-test and significance of individual group differences were conducted using the Tukey-test. The difference of absorbed dose between groups was also tested.

All statistical analyses were conducted with the SciPy Statistical functions module in Python 3.8 (Python Software Foundation). The probability plot of the residuals was created with the SciPy stats probplot function against the normal distribution.

Patient Characteristics and Tumour Parameters

This study included 54 patients (15 female, 39 male) with an average age of 65 years (range 38–82 years). A total of 301 tumours (1–15 per patient, 3 being most frequent) were analysed, the majority being hepatic (230/301) or lymphatic (35/301). The [⁶⁸Ga]Ga-DOTA-TOC and [¹⁷⁷Lu]Lu-DOTA-TATE parameters are included in Table 1 and Fig. 2.

Table 1

Average and range of parameters measured in all 301 tumours from [⁶⁸Ga]Ga-DOTA-TOC PET/CT and [¹⁷⁷Lu]Lu-DOTA-TATE SPECT/CT images.
		Range
PET parameters
SUV_mean	24	3.6–84.4
SUV_max	41	6.7–146.5
SRETV [ml]	29.4	0.4–418.9
SPECT parameters
Absorbed dose [Gy]	26.9	2.4–101.9
Absorbed dose/A_adm[Gy/GBq]	3.6	0.3–13.2
${A}_{conc, 4}$ [(kBq/ml)/GBq]*	224.8	52.4–527.2
${A}_{conc,24}$ [(kBq/ml)/ GBq]	262.3	28.9–905.1
${A}_{conc, 168}$ [(kBq/ml)/GBq]	99.0	8.1–360.9
Effective half-life after t₂₄ [hours]	105.7	37.7–159.5
Tumour mass [g]	46	8–844
*Not all patients underwent imaging at this time point, and only 57 tumours are represented by this number.

Correlation Between [⁶⁸Ga]Ga-DOTA-TOC and [¹⁷⁷Lu]Lu-DOTA-TATE Parameters

The absorbed dose had a strong linear correlation to ${A}_{conc,24}$ (R² = 0.82, p < 0.05) but not to the effective half-life after 24 h (R² = 0.03, p < 0.05) (Fig. 3.). SUV_mean and SUV_max were strongly correlated (R² = 0.98, p < 0.05). A linear correlation was found between SUV and ${A}_{conc,4}/{A}_{adm}$ (SUV_mean: R² = 0.57, p < 0.05, SUV_max: R² = 0.53, p < 0.05). A somewhat weaker correlation was observed between SUV and ${A}_{conc,24}/{A}_{adm}$ (SUV_mean: R² = 0.44, p < 0.05, SUV_max: R² = 0.42, p < 0.05). The linear correlation between SUV-parameters and absorbed dose was weak (SUV_mean: R² = 0.25, p < 0.05, SUV_max: R² = 0.23, p < 0.05). The distribution of residuals of the data was deemed normal by visual inspection of the probability plots (supplementary Fig. 2).

Absorbed Dose Prediction

A prediction model based on the linear correlation between SUV_mean and ${A}_{conc,24}/{A}_{adm}$ was made. Fitting parameters α and β was found to be 6.79∙10^− 6 ml^− 1 and 9.95∙10^− 5 ml^− 1. The relative error (${\varDelta }_{AD}$) between absorbed dose estimated by the prediction model (AD_pred) and the actual absorbed dose was used to evaluate model accuracy (Fig. 4). The average ${\varDelta }_{AD}$ was 31.2% with a standard deviation of 89.6% and a 95% interval at 175.6%.

Using the population median absorbed dose, 23.3 Gy, as the cut-off point of a binary classifier, the predictive ability of the model was further tested. The performances of SUV_mean and SUV_max were comparable according to the ROC analysis (Fig. 5).

Tumour Sub-Groups

None of the anatomical site groups showed significant differences. Grouping the tumours by SUV-values did reveal that a higher absorbed dose was observed in patients with higher SUV-values (Fig. 6A). There were no statistical differences between tumours grouped by tumour mass. The results of the group analysis where equal range of the parameters are used are found in supplementary Fig. 3.

This retrospective study of 54 patients with GEP-NET found a weak albeit significant correlation between tumour specific uptake of [⁶⁸Ga]Ga-DOTA-TOC and [¹⁷⁷Lu]Lu-DOTA-TATE and hence an absorbed dose prediction model based on SUV_mean was made. The results are in agreement with earlier observations²⁵ which proposed an association between diagnostic uptake and therapeutic absorbed dose. There was a high inter- and intrapatient variability in tumour measurements both for [⁶⁸Ga]Ga-DOTA-TOC and [¹⁷⁷Lu]Lu-DOTA-TATE.

Previous publications have reported median [⁶⁸Ga]Ga-DOTA-TOC SUV_mean ranging from approx. 10 to 25 and SUV_max ranging from approx. 20 to 40^24–27, which is partly lower than our measurements. Slight variations may be due to differences in scanner performance, imaging acquisition (e.g. use of respiratory gating) and reconstruction settings. While delineation techniques will also be important for SUV_mean, this should not affect the SUV_max measurements. The absorbed dose previously found for [¹⁷⁷Lu]Lu-DOTA-TATE ranges from a few to 170 Gy^{18–20,28−30} which is comparable to our measurements. It should be noted that some of the previous publications report on more or less heterogeneous groups of patients with regard to types of NET than those reported in the current work. Still, the overall result of our absorbed dose calculations is in agreement with the ones previously found in somatostatin-receptor expressing NETs.

As described in the introduction, a few studies have reported on attempts to correlate diagnostic and post therapeutic imaging of GEP-NETs. One group did a feasibility study on a small, mixed population and investigated SUV-parameters defined with a 40% threshold on both [⁶⁸Ga]Ga-DOTA-TOC images and 24 hours p.i. images of [¹⁷⁷Lu]Lu-DOTA-TATE²⁴. They still found a significant but, commented by the authors, imperfect correlation. Another group looked at the correlation between PET-images of [⁶⁸Ga]Ga-DOTA-TOC and [¹⁷⁷Lu]Lu-Octreotate absorbed doses calculated from planar scans²⁵ of 61 tumours in 21 patients. They similarly found a significant but somewhat variable relationship between SUV_mean and absorbed dose. They argue that a “high SUV” (meaning SUV_mean > 15 and SUV_max > 25) could indicate a resulting “high dose range” of > 10 Gy/GBq. The authors argued that caution had to be used as a considerable fraction of the “high” SUV tumours gave low absorbed doses. The group analysis in the current work shows the same tendencies, as a higher absorbed dose is associated with a higher SUV-value (Fig. 6), but the large overlap of absorbed dose between SUV-groups still encourages caution. A limitation of the current study is the potential selection bias of only including tumours that could be clearly separated from adjacent tissues. While this probably results in more reliable measurements, and a broader range of tumours than selection of a predetermined number, especially tumours of low uptake may still be subjected to exclusion.

While the prediction model provided an average ${\varDelta }_{AD}$ of approx. 30%, a systematic trend depending on absorbed dose was observed. Also, a large intra- and interpatient variation was demonstrated by the high relative error variance, most notably for tumours of low [¹⁷⁷Lu]Lu-DOTA-TATE uptake concentration (and corresponding absorbed dose) where the predicted absorbed dose is highly overestimated (Fig. 4). The cut-off at the population median absorbed dose was used as a starting point to explore prediction performance. While the optimal cut-off value would be the absorbed dose that would classify the treatment as successful, this value is not firmly established. The median was therefore selected as a robust parameter, so the results could be compared with other tumour populations; as variations in methodology between centres will probably not affect the median to a large degree. An alternative cut-off investigated was 37.5 Gy, as this would result in a tumour dose above 150 Gy for four planned treatments, and this absorbed dose has been found associated with a RECIST best response above 30%¹⁸. The predictive performance of the model for this threshold was comparable (AUC = 0.79 and 0.78 for the SUV_mean and SUV_max respectively) to the median.

The difference between predicted and calculated absorbed dose was probably primarily due to the poor linear correlation between SUV_mean of [⁶⁸Ga]Ga-DOTA-TOC and ${A}_{conc,24}/{A}_{adm}$ of [¹⁷⁷Lu]Lu-DOTA-TATE. The PRRT absorbed dose was highly correlated to the [¹⁷⁷Lu]Lu-DOTA-TATE activity concentration at 24 hours p.i., but not to the effective half-life after 24 hours (Fig. 3). Therefore, a population-averaged pharmacokinetic model was chosen for the prediction model. Although SUV_mean was used in the current analyses, an argument can be made for the use of SUV_max as, although being sensitive to image noise, this parameter is virtually independent of the segmentation technique and is simple to define. In the current work it was also shown to be highly correlated with SUV_mean (Fig. 3), and while SUV_mean’s similar interpretation to ${A}_{conc,24}/{A}_{adm}$ resulted in its use, the results would be highly similar for SUV_max. For a subpopulation of the patients a SPECT/CT at 4 hours were also obtained, and the ${A}_{conc,4}/{A}_{adm}$ had a better correlation with SUV_mean. This indicates that the delay between administration and image acquisition for [⁶⁸Ga]Ga-DOTA-TOC and [¹⁷⁷Lu]Lu-DOTA-TATE can possibly explain the poor linear correlation between SUV_mean of [⁶⁸Ga]Ga-DOTA-TOC and ${A}_{conc,24}/{A}_{adm}$ of [¹⁷⁷Lu]Lu-DOTA-TATE. Since the information obtained by a SPECT/CT at 4 hours p.i. [¹⁷⁷Lu]Lu-DOTA-TATE will likely not be sufficient to accurately determine tumour absorbed doses (indicated both by a ${r}^{2}$-value of 0.541 compared with 0.861 and 0.996 for ${A}_{conc,24}/{A}_{adm}$ and ${A}_{conc,168}/{A}_{adm}$ respectively), the correlation between ${A}_{conc,4}/{A}_{adm}$ and SUV_mean cannot be used to form a prediction model. Still, the possibility for delayed 24 hours imaging of a PET tracer (possibly using another radionuclide) can prove fruitful for continued investigations.

There was a high inter- and intrapatient variability in tumour measurements both for [⁶⁸Ga]Ga-DOTA-TOC and [¹⁷⁷Lu]Lu-DOTA-TATE. While a significant correlation between tumour specific uptake of [⁶⁸Ga]Ga-DOTA-TOC and [¹⁷⁷Lu]Lu-DOTA-TATE absorbed dose was found for individual tumours, the correlation was noisy, and the absorbed dose prediction model based on SUV_mean should be used with care depending on the purpose and required accuracy.

Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Author Contributions

CS, LM, JB conceived and designed the study. RB analysed the data, with contributions and supervision from JB. All authors interpreted the data. RB wrote the manuscript, with contributions from JB and CS. All authors read and approved the final manuscript.

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No competing interests reported.

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Correlations between [⁶⁸Ga]Ga-DOTA-TOC uptake and absorbed dose from [¹⁷⁷Lu]Lu-DOTA-TATE

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