Introduction
Prostate cancer is the second most common cancer worldwide, with over 1.3 million patients diagnosed every year [
1,
2]. While survival is good in patients diagnosed in an early stage eligible for curative surgery or external beam radiotherapy, the prognosis of patients in advanced disease is poor [
3,
4]. Prostate-specific membrane antigen (PSMA) is a transmembrane protein highly overexpressed in about 90% of prostate cancers, and is positively correlated with level of expression and aggressiveness of the disease [
5‐
8]. Therefore, PSMA is considered an ideal target for molecular imaging and therapy of prostate cancer [
9‐
13].
In recent years, [
177Lu]Lu-PSMA-617 radioligand ([
177Lu]Lu-PSMA) treatment is increasingly applied to end-stage metastatic castrate-resistant prostate cancer (mCRPC) patients with remarkable responses coupled with a favorable toxicity profile [
14‐
22]. While various radionuclides are available for therapeutic application,
177Lu is particularly useful as the beta emission delivers tumoricidal absorbed doses in a range of 1–2 mm, while its gamma component allows for imaging and quantification with SPECT/CT, providing input for absorbed dose calculations. These dosimetry studies performed in end-stage disease found high absorbed doses of [
177Lu]Lu-PSMA to tumors and marked the salivary glands, lacrimal glands, kidneys, and bone marrow as organs at risk [
16,
20,
23‐
26].
Currently, [
177Lu]Lu-PSMA is only applied in high-volume mCRPC, but it is anticipated that patients in earlier stages could also benefit from this therapy. To date, only one prospective clinical trial was carried out applying [
177Lu]Lu-PSMA in low-volume hormone-sensitive metastatic prostate cancer (mHSPC) patients and revealed it to be a feasible and safe treatment modality [
27]. Yet, in contrast to mCRPC patients, mHSPC patients have a longer survival with several good treatment options available. This warrants more careful assessment of treatment efficacy and toxicity, which could be assured by dosimetry. Moreover, in these low-volume disease patients, there are concerns regarding the tumor sink effect, hypothesizing that low tumor volume could lead to unfavorable radioligand distribution to the organs at risk [
28,
29]. To date, no elaborate dosimetry study was performed in this early-stage patient cohort, so the pharmacokinetics of [
177Lu]Lu-PSMA in mHSPC patients are still unknown. Also, it is still unclear what the efficacy is of [
177Lu]Lu-PSMA in small tumor metastases (< 1 cm) since it is challenging to perform dosimetry on such small lesions and the currently available software methods are mainly appropriate to reliably assess dose to larger lesions. Information from dosimetry studies in end-stage patients has been less elaborate, either using fewer time points, missing 3D data, or focusing on just one treatment cycle. Hence, this is the first study, embedded in the abovementioned prospective study [
27], presenting all dosimetry results including the smallest lesions detected by PET and organs at risk (salivary glands, kidney, liver, and bone marrow), using a state-of-the-art dosimetry protocol. Moreover, the tumor absorbed doses were compared between treatment cycles and correlated to the observed clinical responses.
Discussion
Absorbed dose of [
177Lu]Lu-PSMA in organs was comparable to what was reported for high-volume mCRPC patients [
16,
20,
23‐
26], indicating that organ kinetics for [
177Lu]Lu-PSMA are more or less equal in both low-volume and high-volume metastatic patients. This confirms the physiologically based pharmacokinetic (PKPB) model finding by Begum et al. [
41], indicating minimal influence of total lesion volume on the absorbed dose to kidneys and salivary glands by [
177Lu]Lu-PSMA. However, Violet and colleagues found a correlation between tumor volume and absorbed dose in salivary glands in mCRPC patients [
23]. This was also observed for [
68Ga]Ga-PSMA-11, which showed a decrease in the order of 60% in SUV of salivary glands and kidneys for patients with high tumor load [
29]. Thus, a more elaborative comparative study will be needed to elucidate the differential observations. Nonetheless, our data clearly showed that the sink effect in low-volume disease is of less concern than was expected and we were able to show a promising tumor-to-organ ratio of [
177Lu]Lu-PSMA in these early-stage patients. We furthermore showed that the absorbed dose (Gy/GBq) in organs appeared to be similar or lower in the second cycle, which suggests that the tumor sink effect does not increase in later treatment cycles. This finding was supported by the result that the organ time integrated activity was not significantly different between cycles 1 and 2, indicating similar tracer biokinetics. The absence of organ toxicity [
27] corresponded well with the absorbed dose found in all organs, which remained below any threshold dose for radiation-induced tissue effects [
42‐
45]. Taking into account the range of absorbed dose (Gy/MBq) for each organ, our data suggest that a total activity up to at least 38 GBq [
177Lu]Lu-PSMA is safe regarding the organs at risk (Online Resource Table
S3). Moreover, these tolerance doses are mostly determined and used in external beam radiotherapy, whereas it is known that tissues can tolerate higher doses at the low dose rates associated with radionuclide therapy. This indicates that additional treatment cycles and/or higher injected activity per cycle are feasible to achieve higher tumor dose without risking negative effects to organs. However, no significant acute organ toxicity was found so correlations with tissue absorbed dose are not informative, as it falls within the constant (background) level of the sigmoid dose–response curve. Additionally, to date, no information is available on late occurring effects in for example kidneys, which is relevant in mHSPC patients because of their relatively long survival.
For bone marrow dosimetry, no active uptake in bone and bone marrow was assumed. Although some patients had bone metastases, these did not involve significant sections of the bone marrow. However, the blood sampling method might not be suitable if larger osseous areas are affected by tracer uptake, such as in high-volume (bone) disease.
In this study, we performed SPECT dosimetry of lesions with < 1 cm in diameter after [
177Lu]Lu-PSMA therapy, which has not been described in literature to date. SPECT/CT dosimetry of smaller lesions is challenging because the assessment of tumor volume and cumulated activity is complicated. This introduces uncertainty to the absorbed dose, especially using protocolized software. Therefore, we optimized the methodology to determine absorbed dose in small lesions. Cumulated activity was not determined in commercially available software but using an in-house developed method which enabled the application of background correction and more freedom in the fitting method, leading to a more precise estimation. Lesion volume was manually assessed slice by slice on [
68Ga]Ga-PSMA-PET/CT, leading to a more reliable volume estimation than based on SPECT signal. We also compared our final tumor volumes to volumes determined by measuring the lesion diameter on CT and calculating the volume assuming a spherical or cubical model for lymph node or bone metastases, respectively. This resulted in a similar mean lesion volume (3.45 ml vs. 3.72 ml for our method), but the uncertainty increased from 10 to 30%. Lack of background correction and less precise methodology for volume determination lead to an uncertainty in absorbed dose of around 43%, as compared to 25% in the present study. Using commercially available MIRD software may therefore serve to roughly estimate the absorbed doses in small lesions, as was reported by Privé et al. [
27], but one needs to be aware of the significant increase in uncertainty when using these methods. This might be especially relevant when the absorbed tumor dose is used for clinical decision-making in terms of further treatment planning. Also, more reliable dose estimations could potentially help to correlate absorbed lesion dose to clinical outcomes.
While the five different time point whole-body SPECT/CT imaging enabled accurate dosimetry, the clinical translation of the present protocol is unlikely as it is time-consuming and requires considerable effort and resources from patients and the clinics. Therefore, there is a need to perform dosimetry using a simplified yet reliable protocol.
One such option for simplification was provided by assessing index lesions. In high-volume disease with numerous metastases, the absorbed dose of a single index lesion might not reflect the response accurately due to tumor heterogenicity, as was indeed found for mCRPC patients. In these patients, a significant correlation between total lesion volume absorbed dose and PSA response was observed, but not when considering index lesions only [
23]. However, in the present study with low-volume mHSPC patients, less cancer heterogenicity between metastases exists [
46‐
48]. This was confirmed by a significant correlation between index lesion absorbed dose and PSA response in our study. Thus, single index lesion dosimetry could serve as a good indicator of expected treatment outcome in low-volume disease and a one-bed position SPECT/CT (per time point) might suffice for future studies and clinical translation.
Additionally, we compared absorbed dose is organs and lesions between cycles and found that it might be feasible to limit an elaborate dose estimation to the first cycle. Additional cycles could then be evaluated by acquiring a SPECT/CT at one time point and use kinetical information from the first cycle to estimate the absorbed dose using a simplified approach according to Hänscheid and colleagues [
49] (Additional Resource Materials
S2). For example, for the salivary glands, the 24 or 48 h time point could be sufficient to get a reliable dose estimation for the second cycle. For the lesions however, the correlation was less evident and additional time points might be necessary. Further studies to develop such a protocol are warranted.
We observed that soft tissue lesions in this patient cohort responded significantly better to radioligand therapy than bone lesions, which was also reflected in the corresponding volume and PSA change. This is in line with what was found in mCRPC patients [
50]. In early-stage prostate cancer patients, treatment with
177Lu-PSMA is expected to be especially beneficial in patients that predominantly have soft tissue lesions.
Furthermore, it was confirmed that PSMA-PET SUV can be accurately used for patient selection, since both salivary glands and lesion SUV correlated with the absorbed dose, again similar to the findings in mCRPC patients [
23]. Moreover, we showed that even single lesion SUV
max (instead of total lesion volume) correlated with the absorbed dose in the corresponding lesion. This information could be useful for [
177Lu]Lu-PSMA patient selection.
While there is uncertainty in absorbed dose for organs at risk and lesions, the standard deviation between patients was larger than the intra-patient uncertainty. Especially in the lesions, we found individual differences in [
177Lu]Lu-PSMA kinetics (Fig.
2). This suggests that our patient-specific dosimetry calculations are reliable enough to use for a personalized approach in the dosing scheme in this early-stage patient cohort, just like is recommended for patients receiving
177Lu-octreotate peptide receptor therapy for neuroendocrine tumors [
51]. Of course, our results are based on a small number of patients and lesions, so further studies on larger patient numbers are warranted to confirm these findings. Based on the current results, our perspective is standardization of administered activity in the first cycle whereas the following cycles are based on the dosimetry results of the first cycle. This way, therapeutic efficacy can be verified while preventing healthy organ toxicity, and individuals showing low tumoricidal doses can be recommended for an alternative therapeutic strategy.
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