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Citation: Feuerecker, B.; Gafita, A.;
Langbein, T.; Tauber, R.; Seidl, C.;
Bruchertseifer, F.; Gschwendt, J.E.;
Weber, W.A.; D’Alessandria, C.;
Morgenstern, A.; et al. Comparative
Analysis of Morphological and
Functional Effects of 225Ac- and
177Lu-PSMA Radioligand Therapies
(RLTs) on Salivary Glands. Int. J. Mol.
Sci. 2023,24, 16845. https://doi.org/
10.3390/ijms242316845
Academic Editor: Kalevi Kairemo
Received: 31 August 2023
Revised: 24 October 2023
Accepted: 13 November 2023
Published: 28 November 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
International Journal of
Molecular Sciences
Article
Comparative Analysis of Morphological and Functional Effects
of 225Ac- and 177Lu-PSMA Radioligand Therapies (RLTs) on
Salivary Glands
Benedikt Feuerecker 1,2,3,4,*, Andrei Gafita 5, Thomas Langbein 1, Robert Tauber 6, Christof Seidl 1,
Frank Bruchertseifer 7, Jürgen E. Gschwendt 6, Wolfgang A. Weber 1,2, Calogero D’Alessandria 1 ,† ,
Alfred Morgenstern 7, † and Matthias Eiber 1, 2, †
1Department of Nuclear Medicine, School of Medicine, Technical University of Munich,
81675 München, Germany
2Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partnersite München,
69124 Heidelberg, Germany
3Department of Radiology, University Hospital, LMU Munich, 81377 München, Germany
4Department of Radiology, School of Medicine, Technical University of Munich, 81675 München, Germany
5
Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and
Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
6Department of Urology, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich,
81675 München, Germany
7European Commission, Joint Research Centre (JRC), 76344 Karlsruhe, Germany
*Correspondence: benedikt.feuerecker@tum.de
†These authors are joint senior authors.
Abstract:
Most Prostate Specific Membrane Antigens (PSMAs) targeting small molecules accumulate
in the salivary glands (SGs), raising concerns about SG toxicity, especially after repeated therapies
or therapy with
225
Ac-labeled ligands. SG toxicity is assessed clinically by the severity of patient-
reported xerostomia, but this parameter can be challenging to objectively quantify. Therefore, we
explored the feasibility of using SG volume as a biomarker for toxicity. In 21 patients with late-
stage metastatic resistant prostate cancer (mCRPC), the PSMA volume and ligand uptake of SG
were analyzed retrospectively before and after two cycles of
177
Lu-PSMA (LuPSMA; cohort A) and
before and after one cycle of
225
Ac-PSMA-617 (AcPSMA, cohort B). Mean Volume-SG in cohort
A was 59
±
13 vs. 54
±
16 mL (
−
10%, p = 0.4), and in cohort B, it was 50
±
13 vs. 40
±
11 mL
(
−
20%, p = 0.007), respectively. A statistically significant decrease in the activity concentration in
the SG was only observed in group B (SUV
mean
: 9.2
±
2.8 vs. 5.3
±
1.8, p < 0.0001; vs. A: SUV
mean
:
11.2
±
3.3 vs. 11.1
±
3.5, p = 0.8). SG volume and PSMA-ligand uptake are promising markers to
monitor the SG toxicity after a PSMA RLT.
Keywords:
xerostomia; PSMA; Actinium-225-PSMA-617; mCRPC; radioligand therapy; salivary
glands; tumor sink effect
1. Introduction
The treatment of metastatic castration-resistant prostate cancer (mCRPC) remains a
major challenge. A prolonged overall survival with the radiopharmaceutical
177
Lu-PSMA-
617 has been recently proven in a phase III clinical trial compared to the standard of care
(median OS 15.3 vs. 11.3 months) [
1
]. However, primary or secondary radioresistance
to
177
Lu-PSMA (LuPSMA) limits its effect [
2
]. It has been proposed that targeted alpha
therapy (TAT) has the potential to overcome the radioresistance of beta emitters through
its higher linear energy transfer [
3
,
4
]. TAT has been proven to be more effective than beta
emitters in preclinical studies as it induces DNA double-strand breaks [3].
Int. J. Mol. Sci. 2023,24, 16845. https://doi.org/10.3390/ijms242316845 https://www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2023,24, 16845 2 of 13
The alpha emitter Actinium-225 (
225
Ac) has been recently used for the PSMA-targeted
treatment of mCRPC, and promising results have been reported using
225
Ac-PSMA-617
(AcPSMA) [
3
–
5
]. However, xerostomia is a major limiting side effect for AcPSMA, which
can lead to the discontinuation of treatment [
4
,
6
]. Deterioration of salivary function is
a clinical problem described after an external beam radiation treatment [
7
,
8
] and after a
radioiodine treatment [
9
–
11
]. Its extent has been related to the absorbed dose based on the
data of external beam radiation therapy [
12
]. For alpha emitters, quantitative radiation
dosimetry is not trivial, given the lack of direct gamma emissions. Therefore, a quantitative
measurement of delivered dose to the salivary glands (SGs) is highly challenging. Dose
estimations can be made based on the dosimetry of LuPSMA treatment and serial PET
measurements. Salivary gland scintigraphy provides an objective measure to quantify SG
function and has been reported as a tool to assess SG function in patients with thyroid
diseases [
13
–
16
] and mCRPC [
17
]. Furthermore, an indirect measurement of the effects of
radiation on SG can be made, based on pre- and post-therapeutic staging scans such as
PSMA PET combined with morphological imaging.
Therefore, our aim of this retrospective analysis was to investigate the potential corre-
lates in the morphological and molecular PET imaging of clinically observed xerostomia.
Pre- and post-treatments hybrid PET imaging in patients who have undergone
225
Ac-
PSMA-617 radioligand treatment (RLT) and
177
Lu-PSMA-I&T RLT were compared. We
hypothesize that decreases in SG volumes and PSMA-ligand uptake (a) are dependent on
the type of radiation (alpha vs. beta) and (b) are related to xerostomia.
2. Results
2.1. Volumetric Changes in Salivary Glands before and after LuPSMA and AcPSMA RLTs
In cohort A (before vs. after LuPSMA RLT), no significant volumetric size changes
were observed: the mean Volume-SG of the SG was 59
±
13 vs. 54
±
16 mL (p = 0.4,
Figure 1A). Mean relative and absolute changes in Volume-SG were 10% and 5 mL.
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 2 of 14
The alpha emier Actinium-225 (225Ac) has been recently used for the PSMA-targeted
treatment of mCRPC, and promising results have been reported using 225Ac-PSMA-617
(AcPSMA) [3–5]. However, xerostomia is a major limiting side effect for AcPSMA, which
can lead to the discontinuation of treatment [4,6]. Deterioration of salivary function is a
clinical problem described after an external beam radiation treatment [7,8] and after a
radioiodine treatment [9–11]. Its extent has been related to the absorbed dose based on the
data of external beam radiation therapy [12]. For alpha emiers, quantitative radiation
dosimetry is not trivial, given the lack of direct gamma emissions. Therefore, a
quantitative measurement of delivered dose to the salivary glands (SGs) is highly
challenging. Dose estimations can be made based on the dosimetry of LuPSMA treatment
and serial PET measurements. Salivary gland scintigraphy provides an objective measure
to quantify SG function and has been reported as a tool to assess SG function in patients
with thyroid diseases [13–16] and mCRPC [17]. Furthermore, an indirect measurement of
the effects of radiation on SG can be made, based on pre- and post-therapeutic staging
scans such as PSMA PET combined with morphological imaging.
Therefore, our aim of this retrospective analysis was to investigate the potential
correlates in the morphological and molecular PET imaging of clinically observed
xerostomia. Pre- and post-treatments hybrid PET imaging in patients who have
undergone 225Ac-PSMA-617 radioligand treatment (RLT) and 177Lu-PSMA-I&T RLT were
compared. We hypothesize that decreases in SG volumes and PSMA-ligand uptake (a) are
dependent on the type of radiation (alpha vs. beta) and (b) are related to xerostomia.
2. Results
2.1. Volumetric Changes in Salivary Glands before and after LuPSMA and AcPSMA RLTs
In cohort A (before vs. after LuPSMA RLT), no significant volumetric size changes
were observed: the mean Volume-SG of the SG was 59 ± 13 vs. 54 ± 16 mL (p = 0.4, Figure
1A). Mean relative and absolute changes in Volume-SG were 10% and 5 ml.
(A) (B)
Figure 1. Morphological changes in SG volume based on CT/MRI quantification after 177Lu-PSMA
(A) and 225Ac-PSMA-617 (B).
In contrast, a highly significant decrease in volumes was observed in cohort B (before
vs. after AcPSMA RLT): the mean Volume-SG was 50 ± 13 mL vs. 40 ± 11 mL (p = 0.007,
Figure 1B). Mean relative and absolute changes in Volume-SG were 20% and 10 mL.
2.2. Functional Changes in PSMA-Ligand Uptake before and after LuPSMA and AcPSMA RLTs
In cohort A, no significant changes in PSMA-ligand uptake were observed: the mean
SUVmax and SUVmean were 23.8 ± 7.7 vs. 24.7 ± 8.7 (p = 0.8) and 11.0 ± 3.3 vs. 10.8 ± 3.4 (p =
Figure 1.
Morphological changes in SG volume based on CT/MRI quantification after
177
Lu-PSMA
(A) and 225Ac-PSMA-617 (B).
In contrast, a highly significant decrease in volumes was observed in cohort B (before
vs. after AcPSMA RLT): the mean Volume-SG was 50
±
13 mL vs. 40
±
11 mL (p= 0.007,
Figure 1B). Mean relative and absolute changes in Volume-SG were 20% and 10 mL.
2.2. Functional Changes in PSMA-Ligand Uptake before and after LuPSMA and AcPSMA RLTs
In cohort A, no significant changes in PSMA-ligand uptake were observed: the mean
SUV
max
and SUV
mean
were 23.8
±
7.7 vs. 24.7
±
8.7 (p= 0.8) and 11.0
±
3.3 vs. 10.8
±
3.4
(p= 0.8), respectively (Figure 2A,C). Mean relative changes in SUV
max
and SUV
mean
were
Int. J. Mol. Sci. 2023,24, 16845 3 of 13
+3.8% and
−
1.8%. The mean PSMA-SGU was 757
±
264 vs. 721
±
316 (p= 0.7, Figure 3A).
Mean relative and absolute changes for PSMA-SGU were −5% and −30 (Figure 3A).
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 3 of 14
0.8), respectively (Figure 2A,C). Mean relative changes in SUVmax and SUVmean were +3.8%
and −1.8%. The mean PSMA-SGU was 757 ± 264 vs. 721 ± 316 (p = 0.7, Figure 3A). Mean
relative and absolute changes for PSMA-SGU were −5% and −30 (Figure 3A).
(A) (B)
(C) (D)
Figure 2. Changes in SUVmax (the total of submandibular and parotid glands) after 177Lu-PSMA RLT
(A) and after 225Ac-PSMA-617 RLT (B), respectively, and change in SUVmean (the total of submandibular
and parotid glands) after 177Lu-PSMA RLT (C) and 225Ac-PSMA-617 RLT (D), respectively.
In contrast, a highly significant decrease in PSMA-ligand uptake was observed in cohort
B: the mean SUVmax and SUVmean were 20.1 ± 5.4 vs. 12.3 ± 3.6 (p < 0.0001) and 9.2 ± 2.8 vs. 5.3 ±
1.8 (p < 0.0001), respectively (Figure 2B,D). Mean relative changes in SUVmax and SUVmean were
−38.8% and −42.4%. The mean PSMA-SGU was 711 ± 268 vs. 276 ± 162 (p < 0.0001). Mean
relative and absolute changes for PSMA-SGU were −61% and −435 (Figure 3B).
Figure 2.
Changes in SUV
max
(the total of submandibular and parotid glands) after
177
Lu-PSMA RLT
(
A
) and after
225
Ac-PSMA-617 RLT (
B
), respectively, and change in SUV
mean
(the total of submandibu-
lar and parotid glands) after 177Lu-PSMA RLT (C) and 225Ac-PSMA-617 RLT (D), respectively.
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 4 of 14
(A) (B)
Figure 3. Changes in PSMA-SGU after
177
Lu-177-PSMA RLT (A) and after
225
Ac-PSMA-617 RLT (B),
respectively.
2.3. Salivary Glands and Tumor Burden
Based on the five quartiles of pre-therapeutic whole body tumor burden, changes in
the salivary gland SUV
mean
and SUV
max
pre- and post-AcPSMA were quantified. Statisti-
cally significant decreases in SUV
max
of the SG were measured in groups with very low,
moderate, high, and very high pre-therapeutic tumor burden (Table 1 and Figure 4). No
correlation between SUV
mean
of the SG and tumor burden was observed in the low and
very high groups (Table 1). In each of these five tumor burden groups, no statistically sig-
nificant changes in whole body tumor burden were observed post-AcPSMA. No signifi-
cant changes in SUV
max
and SUV
mean
were observed in groups with very low, low, high,
and very high tumor burden patients treated with LuPSMA.
Figure 3.
Changes in PSMA-SGU after
177
Lu-177-PSMA RLT (
A
) and after
225
Ac-PSMA-617 RLT (
B
),
respectively.
Int. J. Mol. Sci. 2023,24, 16845 4 of 13
In contrast, a highly significant decrease in PSMA-ligand uptake was observed in cohort
B: the mean SUV
max
and SUV
mean
were 20.1
±
5.4 vs. 12.3
±
3.6 (p< 0.0001) and 9.2
±
2.8
vs. 5.3
±
1.8 (p< 0.0001), respectively (Figure 2B,D). Mean relative changes in SUV
max
and
SUV
mean
were
−
38.8% and
−
42.4%. The mean PSMA-SGU was 711
±
268 vs. 276
±
162
(p< 0.0001). Mean relative and absolute changes for PSMA-SGU were
−
61% and
−
435
(Figure 3B).
2.3. Salivary Glands and Tumor Burden
Based on the five quartiles of pre-therapeutic whole body tumor burden, changes in the
salivary gland SUV
mean
and SUV
max
pre- and post-AcPSMA were quantified. Statistically
significant decreases in SUV
max
of the SG were measured in groups with very low, moderate,
high, and very high pre-therapeutic tumor burden (Table 1and Figure 4). No correlation
between SUV
mean
of the SG and tumor burden was observed in the low and very high
groups (Table 1). In each of these five tumor burden groups, no statistically significant
changes in whole body tumor burden were observed post-AcPSMA. No significant changes
in SUV
max
and SUV
mean
were observed in groups with very low, low, high, and very high
tumor burden patients treated with LuPSMA.
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 6 of 14
Figure 4. SUVmax of the SG stratified by tumor burden before (pre) and after (post) 225Ac-PSMA-617 RLT
and also stratified by tumor load (colors indicate groups). Group moderate, n = 3, all other groups, n = 4.
3. Discussion
In this retrospective analysis, a treatment with one cycle of AcPSMA resulted in a
significant decrease in morphological and functional surrogate parameters of salivary
glands, which were assessed with PSMA PET. In contrast, no substantial differences could
be observed after treatment with two cycles of LuPSMA in the same patients.
The deterioration of the salivary gland function is a clinically relevant side effect of
AcPSMA reported in the literature [3,6,18]. Our retrospective study is the first to present
quantitative data from imaging to potentially link it with objective measures. For the exter-
nal beam radiation treatment [7,19] of the neck, different reports on potential xerostomia
using imaging as a quantitative measure are available. In an MRI study including 52 patients
with squamous cell carcinoma of the neck, the volume of the parotid glands decreased by
an average of 26% at 30 Gy and approx. 40% at 70 Gy [20]. In another study with 15 head
and neck cancer patients, the median parotid volume loss was 28.1% (range: 5.9–53.6%) [21].
Furthermore, in a study with 18 patients irradiated with a radiation dose of 38.1 to 64.4 Gy,
a reduction of the parotid glands by approximately 35%, was observed [22].
The evaluation of delivered doses of Actinium-225 to the salivary gland remains chal-
lenging because radiation doses depend on the microscopic distribution of the radioactiv-
ity within the tissue, which is currently unknown. Based on a dose assumption, an admin-
istration of 10 kBq/kg of 225Ac-PSMA-617 would result in a mean salivary gland dose of
approximately 67 Gy [23]. For LuPSMA, data on the dosimetry of the salivary glands for
both LuPSMA-617 [24–26] and LuPSMA-I&T [27] exist, resulting in a dose of 8.1–21.9 Gy
to the salivary glands (after two i.v. injections of 7.4 GBq LuPSMA).
In our retrospective analysis, Volume-SG was reduced by 10% in cohort A but by 20%
in cohort B. Similarly, PSMA-SGU was reduced by −5% in cohort A but by −61% in cohort
B. These data indicate that LuPSMA has only minor effects on the salivary glands, but
AcPSMA induces profound physical and biological effects on the salivary glands. This is
in line with the clinical observation that patients treated with LuPSMA rarely report a
permanent xerostomia or request for a stop of treatment [28].
Based on the data presented here, both function (PSMA-SGU) and morphological size
(Volume-SG) of the salivary glands decreased significantly after AcPSMA RLT. Considering
the production of ca. 1 Liter/day of saliva (70% arising from the parotid, submandibular,
and sublingual glands [29]), a reduction of ca. −20% (Volume-SG) to −61% (PSMA-SG) could
hypothetically result in a daily production of ca. 390–800 mL of saliva. A range of 0.12–0.16
salivary glands
very low pre
very low post
low pre
low post
moderate pre
moderate post
high pre
high post
very high pre
very high post
0
10
20
30
40
SUV
max
p = 0.03
p = 0.13p = 0.03 p = 0.19p = 0.01
Figure 4.
SUV
max
of the SG stratified by tumor burden before (pre) and after (post)
225
Ac-PSMA-617
RLT and also stratified by tumor load (colors indicate groups). Group moderate, n= 3, all other
groups, n= 4.
Int. J. Mol. Sci. 2023,24, 16845 5 of 13
Table 1.
Uptake characteristics of salivary glands (SUV
mean
and SUV
max
) before and after Ac- and Lu-PSMA RLTs of patients from cohort B. Patients are stratified in
five groups based on their whole body tumor volume prior to 225Ac-PSMA RLT. Statistically significant changes are marked in bold (* p= 0.03, ** p= 0.02, *** p= 0.04,
#p= 0.01).
Whole Body
Tumor Volume Prior
to AcPSMA
Very Low Low Moderate High Very High
pre post pre post pre post pre post pre post
AcPSMA RLT
Whole body PSMA-TV (mL) 602 ±354 431 ±296 1393 ±217 1456 ±391 1848 ±156 2370 ±1076 3378 ±288 3216 ±693 4869 ±342 4296 ±1252
Salivary glands SUVmean 11.7 ±2.4 6.7 ±2.4 * 8.1 ±3.3 4.9 ±1.1 11.1 ±1.8 5.7 ±1.6 ** 9.1 ±2.9 4.5 ±2.3 *** 7.8 ±2.7 5.3 ±1.7
SUVmax 24.8 ±4.9 14.7 ±4.8 * 17.7 ±6.1 11.5 ±2.3 22.7 ±3.4 13.5 ±2.9 ** 20.9 ±5.4 8.6 ±1.9 #17.3 ±5.3 12.7 ±3.2
LuPSMA RLT
Salivary glands SUVmean 14.9 ±2.9 13.5 ±2.6 11.3 ±2.2 11.2 + 5.3 9.0 ±2.8 11.9 ±1.9 * 10.2 ±2.6 8.8 ±1.4 11.3 ±2.8 10.3 ±3.1
SUVmax 33.6 ±9.8 33.4 ±14.3 23.9 ±4.0 23.7 ±10.3 18.6 ±4.1 25.4 ±5.9 ** 21.5 ±5.3 18.8 ±2.9 24.5 ±5.6 26.1 ±12.1
Int. J. Mol. Sci. 2023,24, 16845 6 of 13
3. Discussion
In this retrospective analysis, a treatment with one cycle of AcPSMA resulted in a
significant decrease in morphological and functional surrogate parameters of salivary
glands, which were assessed with PSMA PET. In contrast, no substantial differences could
be observed after treatment with two cycles of LuPSMA in the same patients.
The deterioration of the salivary gland function is a clinically relevant side effect of
AcPSMA reported in the literature [
3
,
6
,
18
]. Our retrospective study is the first to present
quantitative data from imaging to potentially link it with objective measures. For the
external beam radiation treatment [
7
,
19
] of the neck, different reports on potential xeros-
tomia using imaging as a quantitative measure are available. In an MRI study including
52 patients with squamous cell carcinoma of the neck, the volume of the parotid glands
decreased by an average of 26% at 30 Gy and approx. 40% at 70 Gy [
20
]. In another study
with 15 head and neck cancer patients, the median parotid volume loss was 28.1% (range:
5.9–53.6%) [
21
]. Furthermore, in a study with 18 patients irradiated with a radiation dose of
38.1 to 64.4 Gy, a reduction of the parotid glands by approximately 35%, was observed [
22
].
The evaluation of delivered doses of Actinium-225 to the salivary gland remains chal-
lenging because radiation doses depend on the microscopic distribution of the radioactivity
within the tissue, which is currently unknown. Based on a dose assumption, an adminis-
tration of 10 kBq/kg of
225
Ac-PSMA-617 would result in a mean salivary gland dose of
approximately 67 Gy [
23
]. For LuPSMA, data on the dosimetry of the salivary glands for
both LuPSMA-617 [
24
–
26
] and LuPSMA-I&T [
27
] exist, resulting in a dose of 8.1–21.9 Gy
to the salivary glands (after two i.v. injections of 7.4 GBq LuPSMA).
In our retrospective analysis, Volume-SG was reduced by 10% in cohort A but by 20%
in cohort B. Similarly, PSMA-SGU was reduced by
−
5% in cohort A but by
−
61% in cohort
B. These data indicate that LuPSMA has only minor effects on the salivary glands, but
AcPSMA induces profound physical and biological effects on the salivary glands. This
is in line with the clinical observation that patients treated with LuPSMA rarely report a
permanent xerostomia or request for a stop of treatment [28].
Based on the data presented here, both function (PSMA-SGU) and morphological size
(Volume-SG) of the salivary glands decreased significantly after AcPSMA RLT. Considering
the production of ca. 1 Liter/day of saliva (70% arising from the parotid, submandibular,
and sublingual glands [
29
]), a reduction of ca.
−
20% (Volume-SG) to
−
61% (PSMA-SG)
could hypothetically result in a daily production of ca. 390–800 mL of saliva. A range of
0.12–0.16 mL/min for salivary flow rate has been described as a critical range for patients
and defines a clinically relevant hypofunction [
30
]. This would translate into a critical range
of daily salivary production of approximately 172–230 mL. PSMA-SGU reduction after
AcPSMA RLT reaches close to this critical range as shown by the above calculation. In fact,
the relative morphological changes after AcPSMA RLT of the salivary glands were almost
three times lower compared to the functional changes (Volume-SG
−
20% vs. PSMA-SGU
−
61%), and therefore, a reduction in Volume-SG may not fully explain the loss of salivary
function. In summary, PSMA-SGU seems to correlate more closely to clinically observed
xerostomia than Volume-SG and might be a more predictive parameter of salivary gland
(dys)function.
With respect to the tumor sink effect, controversial results have been reported after
LuPSMA RLT. In mCRPC patients that were visually classified based on
68
Ga-PSMA uptake,
a decline in the salivary glands of 36–43% was observed [
31
]. Gafita et al. report a decrease
in SUV
max
in patients with a very high PSMA-VOL by an average of
−
26.6% [
32
]. Werner
et al. report no correlation between salivary gland uptake and tumor volume in a study
with 50 patients using
18
F-DCFPyL PET [
33
]. Given the already relatively high tumor
burden in our cohort, the observation of no additional tumor sink effect in the very high
PSMA-TUB group compared to the low volume group might be explainable. In the study
by Gafita et al., the patient group with a very high tumor burden had a Volume-SG of
≥
1355 mL, which corresponds to the second quintile (1095–1610 mL) of our study (the very
Int. J. Mol. Sci. 2023,24, 16845 7 of 13
high tumor burden group of our study exhibited a Volume-SG of
≥
4039 mL). However, a
tendency towards a tumor sink was observed (Figure 4).
Xerostomia as a result of PSMA treatment is a known side effect, which is caused by a
physiological tracer uptake [
34
–
36
]. It has been reported that xerostomia is less pronounced
after the first cycles of
177
Lu-PSMA RLT and in patients with a higher tumor burden due to
the tumor sink effect [
31
,
37
,
38
]. Xerostomia was also described after a
131
I-labeled MIP-1095
PSMA therapy as the second most common side effect after hematological toxicity [
39
]
with ca. 25% of the patients demonstrating a dry mouth [
40
]. However, xerostomia
was also reported in patients treated with other PSMA ligands at a high variability of
frequency [
2
,
41
–
44
]. Initial studies with
177
Lu-PSMA-617 reported that 2/56 patients
showed xerostomia [
45
], while the frequency of grade 1 xerostomia reached up to 80%
as per a report of a prospective phase 2 trial [
34
]. In a recent study including 30 patients
using
177
Lu-PSMA-617, CTCAE grade 2 xerostomia occurred in 17% of the patients [
46
].
On the other hand, the frequency of transient dry mouth symptoms in 26 patients treated
with repetitive cycles of
177
Lu-PSMA was 46% [
28
]. In patients treated with
225
Ac-PSMA-
RLT, data indicate a higher frequency and a pronounced impact on quality of life of
xerostomia, leading to the request of treatment in up to 25% of patients [
6
]. Interestingly,
our morphological data show that, at the initiation of the AcPSMA treatment, the salivary
glands were already reduced compared to the beginning of the LuPSMA treatment (ca.
59 vs. 50 mL,
−
15%), pointing to the fact that LuPSMA treatment results in a slow decrease
in salivary gland sizes.
4. Materials and Methods
4.1. Patient Population
Data of mCRPC patients who underwent PSMA PET/CT or PET/MRI before and after
177
Lu-PSMA-I&T—(LuPSMA) and
225
Ac-PSMA-617—(AcPSMA) RLTs were retrospectively
analyzed. Only patients who had comparable imaging data (which used similar PSMA-ligand
pre- and post-treatments) with a sufficient coverage of the parotid gland were included.
First, 21 patients (cohort B), who were treated with AcPSMA as a salvage therapy after
previous treatments (e.g., chemotherapy and the use of novel androgen receptor-targeted
therapy) and who showed disease progression after LuPSMA RLT, were included. Tumor
response and adverse events of these patients have been recently reported [
6
]. Second, out
of these 21 patients, 15 patients (cohort A) were identified who underwent LuPSMA at our
institution and for whom appropriate pairs of PSMA PET/CT or PET/MRI data (2 patients)
were available.
Patients’ xerostomia was graded on a three-point Likert scale (no to only mild xerostomia:
grade 1; moderate symptoms with minor effects on daily life: grade 2; and severe xerostomia
with major impacts on daily life/food or drink intake: grade 3). In total, nine patients had
grade 1 xerostomia, six patients had grade 2, and six patients had grade 3 xerostomia.
Patient and treatment details for AcPSMA and LuPSMA are given in Table 2. All
patients signed an informed consent and were treated under compassionate use after a
discussion of an interdisciplinary tumor board. The present retrospective analysis was
approved by the local ethics committee under the reference number of 115/18S.
4.2. PSMA-Ligand PET Imaging
PET/CT and PET/MRI scans were acquired using the Siemens Biograph mCT and the
Siemens Biograph mMR (Siemens Healthineers, Erlangen, Germany) in accordance with
the EANM/SNMMI guideline for PSMA-ligand PET imaging.
18
F-rhPSMA7.3 was used in 13 and 7 patients before and after AcPSMA (mean:
305
±
47 MBq) and LuPSMA (mean: 310
±
49 MBq), respectively.
68
Ga-PSMA-11 was
used in 8 and 8 patients before and after AcPSMA (mean: 121
±
22 MBq) and LuPSMA
(mean: 106
±
20 MBq), respectively. Only patients with the pairs of imaging sets with
the same radiotracer (
18
F-rhPSMA7.3 or
68
Ga-PSMA-11) and imaging modality (PET/CT
or PET/MRI) were included.
Int. J. Mol. Sci. 2023,24, 16845 8 of 13
Table 2. Patient characteristics at the timepoint of initiation of 225 Ac-PSMA RLT.
No.
Number (Agents) of
Previous mCRPC Lines
Prior to 225Ac-RLT
Number (Agents) of
Previous mCRPC Lines
Prior to 225Ac-RLT
Number of
LuPSMA
Cycles
Activity LuPSMA RLT
(GBq)/Cycle ECOG Score Metastases
Activity of First
AcPSMA RLT
(MBq)
1 * 4 (E, A, D, Lu) 4 2 8/7.2 0 B, LN 8
2 8 (D, C, A, C, E, C, Ra, Lu) 8 2 5.7/5.7 0 B 8
3 4 (D, E, A, Lu) 4 8
7.4/7.4/7.3/7.3/7.1/7.1/7.1/7.3
1 B, LN 8
4 * 5 (A, E, Lu, D, Cis/Eto) 5 4 7.2/7.7/7.2/7.7 1 B, LN 8
5 * 6 (D, A, Lu, C, E, Cis/Eto) 6 2 7.6/7.4 1 B, LN, Liver, Lungs 8
6 * 6 (D, Ra, E, C, A, Lu) 6 4 6.9/7.3/7.4/7.5 2 B, LN 10
7 4 (D, Ra, A, Lu) 4 5 7.5/7.3/7.5/7.8/7.7 1 B, LN 8
8 * 8 (CureVac, A + CureVac,
D, Study, C, Lu, E, A) 8 2 7.3/7.5 1 B, LN, Lungs 8
9 * 4 (A, D, Lu, E) 4 6 7.2/7.4/7.3/7.4/7.3/6.7 1 B, LN, Peritoneal 10
10 * 3 (A, E, Lu) 3 6 7.3/7.6/7.7/7.0/7.5/ 7.4 1 B, LN 10
11 7 (A, E, D, A, D, C, Lu) 7 6 8.3/7.9/8.3/7.9/7.4/7.3 1 B 8
12 6 (A, E, D, C, Lu, Cis/Eto) 6 2 8.3/7.8 1 B, LN 13
13 * 5 (E, D, A, E, Lu) 5 6 5.1/7.4/7.3/7.6/7.4/6.7 1 B, LN, Liver, Lung 11
14 * 5 (A, E, D, C, Lu) 5 1 7.9 1 B, LN, Liver, Brain 6
15 *
8 (CureVac, A, Ra, Lu, E, D,
O, C) 8 6 7.3/7.3/7.3/7.6/7.4/ 7.0 1 B, LN 10
16 * 8 (D, C, A, D, E, A, C, Lu) 8 8
7.3/7.8/7.2/7.2/7.5/7.5/7.5/7.4
0 B, LN, Lungs 12
17 * 5 (D/C, A, D/C, Carbo,
Lu) 5 4 7.3/7.6/7.2/7.3 1 LN, B, Peritoneal 9
18 3 (A, Lu, D) 3 5 3.7/3.7/5.5/5.5/4.2 1 B, LN 10
19 * 6 (D, A, E, C, Lu, C) 6 4 6.8/7.6/7.3/9.0 1 B, LN, Liver 14
20 * 5 (E, D, A, Lu, C) 5 4 8.2/7.5/6.2/7.5 1 B, LN 8
21 * 6 (A, E, D, Lu, Ra, C) 6 4 3.3/3.3/3.4/3.5 1 B 8
Abbreviations: Gs = Gleason Score, AP = alkaline phosphatase, LDH = lactate dehydrogenase, AcPSMA = 225Ac-PSMA-617, LuPSMA = 177Lu-PSMA, RLT = radioligand therapy, E =
Enzalutamide, A = Abiraterone, D = Docetaxel, Lu = 177Lu-PSMA I&T, RTx = Radiatio, C = Cabazitaxel, Ra = Ra-223-Dichloride, Cis/Eto = Cisplatin/Etoposide, Carbo = Carboplatin; I
= immune therapy, O = Olaparib, CureVac = CureVac Study, B = bones, and LN = lymph nodes. * cohort A.
Int. J. Mol. Sci. 2023,24, 16845 9 of 13
4.3. Image Analysis
The following parameters of the SG were analyzed in all patients to determine the
morphological and molecular correlates of its function: a. the morphological volume
determined with cross-sectional imaging datasets (Volume-SG), b. the total PSMA-ligand
uptake of the SG (PSMA-SGU), which is similar to the total lesion glycolysis determined
with
18
F-FDG PET and represents the total PSMA activity from all tumor voxels [
47
], and c.
SUV
mean
and SUV
max
of the SG. d. in patients who underwent
225
Ac-PSMA-617 RLT, the
PSMA-avid tumor volume (PSMA-TV), which is similar to the metabolic tumor volume
from
18
F-FDG PET, was obtained as previously proposed in [
47
]. All segmentations were
performed by one nuclear medicine physician. For all PET-measurements, values were not
corrected for body surface or lean body mass.
a. Volume-SG was determined in the simultaneously acquired anatomical data (CT or
MRI) of the SG. Delineation of the submandibular and parotid glands was measured
of each gland separately and on the basis of all available slices (Figure 5).
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 10 of 14
4.2. PSMA-Ligand PET Imaging
PET/CT and PET/MRI scans were acquired using the Siemens Biograph mCT and the
Siemens Biograph mMR (Siemens Healthineers, Erlangen, Germany) in accordance with
the EANM/SNMMI guideline for PSMA-ligand PET imaging.
18
F-rhPSMA7.3 was used in 13 and 7 patients before and after AcPSMA (mean: 305 ± 47
MBq) and LuPSMA (mean: 310 ± 49 MBq), respectively.
68
Ga-PSMA-11 was used in 8 and 8
patients before and after AcPSMA (mean: 121 ± 22 MBq) and LuPSMA (mean: 106 ± 20 MBq),
respectively. Only patients with the pairs of imaging sets with the same radiotracer (
18
F-
rhPSMA7.3 or
68
Ga-PSMA-11) and imaging modality (PET/CT or PET/MRI) were included.
4.3. Image Analysis
The following parameters of the SG were analyzed in all patients to determine the
morphological and molecular correlates of its function: a. the morphological volume de-
termined with cross-sectional imaging datasets (Volume-SG), b. the total PSMA-ligand
uptake of the SG (PSMA-SGU), which is similar to the total lesion glycolysis determined
with
18
F-FDG PET and represents the total PSMA activity from all tumor voxels [47], and
c. SUV
mean
and SUV
max
of the SG. d. in patients who underwent
225
Ac-PSMA-617 RLT, the
PSMA-avid tumor volume (PSMA-TV), which is similar to the metabolic tumor volume
from
18
F-FDG PET, was obtained as previously proposed in [47]. All segmentations were
performed by one nuclear medicine physician. For all PET-measurements, values were
not corrected for body surface or lean body mass.
a. Volume-SG was determined in the simultaneously acquired anatomical data (CT or
MRI) of the SG. Delineation of the submandibular and parotid glands was measured
of each gland separately and on the basis of all available slices (Figure 5).
b. PSMA-SGU was quantified before the first and after the first two cycles of LuPSMA
(cohort A) treatment and before and after the first cycle of AcPSMA (cohort B). SG was
defined as the parotid and the submandibular glands. PSMA-SGU was determined us-
ing the in-house developed software qPSMA (with a threshold SUV of 4).
c. SUV
mean
and SUV
max
was determined using Syngo.Via (Siemens Healthineers, Erlangen,
Germany). For SUV
mean
, a 3D VOI using an isocontour of 20% of the SUV
max
was used.
d. PSMA-TV was measured using qPSMA [47]. Bone lesions and soft tissue lesions were
separately segmented, and obtained results were summed up. The PSMA-ligand uptake
in normal organs was neglected before the quantification of whole-body tumor burden.
Figure 5. CT based segmentation (left) of submandibular (upper row) and parotid glands (lower
row), and the illustration of its transfer to the respective PET images (right). Green colored areas
indicate the respective salivary glands.
Figure 5.
CT based segmentation (left) of submandibular (upper row) and parotid glands (lower
row), and the illustration of its transfer to the respective PET images (right). Green colored areas
indicate the respective salivary glands.
b.
PSMA-SGU was quantified before the first and after the first two cycles of LuPSMA
(cohort A) treatment and before and after the first cycle of AcPSMA (cohort B). SG was
defined as the parotid and the submandibular glands. PSMA-SGU was determined
using the in-house developed software qPSMA (with a threshold SUV of 4).
c.
SUV
mean
and SUV
max
was determined using Syngo.Via (Siemens Healthineers, Er-
langen, Germany). For SUV
mean
, a 3D VOI using an isocontour of 20% of the SUV
max
was used.
d.
PSMA-TV was measured using qPSMA [
47
]. Bone lesions and soft tissue lesions were
separately segmented, and obtained results were summed up. The PSMA-ligand
uptake in normal organs was neglected before the quantification of whole-body
tumor burden.
4.4. Statistical Analysis
To assess the alterations in morphological and functional parameters of the SG after
AcPSMA and LuPSMA RLTs, means, standard deviations, and 95% confidence intervals
(95%CI) of Volume-SG, PSMA-SG, and SUV
mean
and SUV
max
of the salivary glands, and
their relative and absolute changes were calculated for cohorts A and B.
To determine the impact of a PSMA positive tumor volume on SG changes in cohort
B, PSMA-TV was classified into five groups based on quintiles: very low (Q1:
≤
20th
percentile), low (Q2: 20th–40th percentile), moderate (Q3: 40th–60th percentile), high (Q4:
60th–80th percentile), and very high (Q5:
≥
80th percentile). These quintiles were compared
with functional changes in the salivary glands.
Int. J. Mol. Sci. 2023,24, 16845 10 of 13
T-tests using a two-sided unpaired T-Test with Welch correction were used to compare
means of Volume-SG, PSMA-SG, and SUV
mean
and SUV
max
of the SG in cohorts A and B
and PSMA-TV in cohort B. A p-value of <0.05 was considered statistically significant. All
calculations were performed using GraphPad Prism version 5.00 (GraphPad Software, San
Diego, CA, USA).
5. Conclusions
Salivary gland volume and tracer uptake as measured from routine PSMA PET studies
are potential biomarker for SG toxicity and should be further evaluated in clinical trials of
PSMA radioligand therapy.
6. Limitations
One limitation of this retrospective analysis is that it includes both patients with
68
Ga-PSMA11 and
18
F-rhPSMA7.3, and this could potentially have an effect on the uptake
characteristics of salivary glands. However, we only investigated patients who underwent
the same radiotracer pre- and post-treatments, and an additional analysis of our data did
not show statistically significant differences in the SUV
max
and SUV
mean
in a sub-group
analysis both before and after Lu- and Ac-PSMA-RLTs (refer to Supplementary Table S1
and Supplementary Figure S1). Notably, limiting the investigation to only one radiotracer
would have substantially reduced the number of suitable patients. Moreover, the direct
measurements of the salivary gland function, e.g., using salivary scintigraphy, were not
available for analysis in this retrospective analysis.
Supplementary Materials:
The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/ijms242316845/s1.
Author Contributions:
B.F., conceptualization, data curation, methodology, and writing—review
and editing. A.G., writing—original draft, data curation, and methodology. T.L., investigation and
review and editing. R.T., data curation, investigation, and review. C.S., data curation, and review
and editing. F.B. and. J.E.G., review and editing. W.A.W., review and editing. C.D., investigation
and review and editing. A.M., investigation and review and editing. M.E., writing—original draft,
investigation, and review and editing. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement:
All procedures performed in studies involving human
participants were in accordance with the ethical standards of the institutional and/or national
research committee and with the 1964 Helsinki declaration and its later amendments or comparable
ethical standards. The study was approved by the local ethics committee (115/18 S).
Informed Consent Statement:
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: Data are contained within the article.
Acknowledgments: 225
Ac was kindly provided by the Joint Research Centre, European Commission,
Directorate for Nuclear Safety and Security, Karlsruhe, Germany. PSMA-617 was kindly provided by
Endocyte Inc., a subsidiary of Advanced Accelerator Applications, Saint-Genis-Pouilly, France.
Conflicts of Interest:
ME reports fees from Blue Earth Diagnostics Ltd. (consultant, research funding),
Novartis/AAA (consultant, speaker), Telix (consultant), Bayer (consultant, research funding), Rayze-
Bio (consultant), Point Biopharma (consultant), Eckert-Ziegler (speaker), Janssen Pharmaceuticals
(consultant, speakers bureau), Parexel (image review), and Bioclinica (image review) outside the
submitted work and a patent application for rhPSMA. BF reports fees from Novartis (consultant). WW
reports that he is on advisory boards and receives compensation from Bayer, Blue Earth Diagnostics,
Endocyte, Reflexion, Rayzebio, Vida Ventures, ITM, and Pentixapharm. He has received research
support from Siemens, BMS, Ipsen, Imaginab, and Piramal. The remaining authors declare that the
research was conducted in the absence of any commercial or financial relationships that could be
construed as potential conflict of interest.
Int. J. Mol. Sci. 2023,24, 16845 11 of 13
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