Discussion
This work demonstrated that premedication with GPB did not significantly reduce the uptake of PSMA-ligands or radioiodine in the salivary glands, despite successful functional inhibition of the glands resulting in patients complaining of a dry mouth. A limitation of this work is the small number of patients, especially in the iodine cohort. However, it is unlikely that a larger number of patients would yield a reduction in uptake that is clinically relevant, given the trends exhibited.
PSMA-ligand therapies show great promise in treating metastatic prostate cancer. Reducing salivary gland toxicity, especially in the case of alpha emitters, is of paramount importance if the therapy is to transition to wider use in the clinic [
7,
8,
20]. The exact mechanism of non-specific PSMA uptake in the salivary glands remains to be elucidated, but its presence indicates that there are a few distinct approaches by which the uptake in the salivary glands could be reduced.
One is by inhibiting the PSMA receptors in the glands, reducing specific uptake. A couple of murine studies [
37,
38] evaluated the PSMA inhibitor, 2-(phosphonomethyl)pentanedioic acid (2-PMPA). They found that while its ability to displace renal and potentially salivary gland uptake was substantial, it also resulted in an inhibition of tumour uptake, sacrificing therapeutic efficacy. One study that orally administered polyglutamate folate tablets, a competitive substrate for the PSMA receptor, to patients receiving [
177Lu]Lu-PSMA therapy, estimated that a reduction in parotid absorbed dose of at least 45% was possible, when compared to other dosimetry studies that did not employ protective strategies [
39]. Another recent murine study demonstrated that administering ‘cold’ PSMA could also greatly reduce uptake of [
177Lu]Lu-PSMA in the salivary glands and kidneys while only marginally reducing tumour uptake [
40]. Whether this will translate to human models remains to be seen.
Another method is by reducing non-specific uptake in the glands. Many PSMA-ligands require the integration of a glutamate moiety in order to bind specifically to the PSMA receptor. Recently, a randomised, double blinded, placebo-controlled study attempted to minimise non-specific [
18F]DCFPyl uptake by orally administering monosodium glutamate, having found favourable results in a previous murine model [
41]. In humans however, they found that while the uptake in the salivary glands and kidneys was significantly decreased, so was the uptake in the tumour, once again hampering therapeutic effects [
42].
Yet another method is by reducing the perfusion or amount of PSMA delivered to the gland, thereby potentially lowering both specific and non-specific uptake. One study using [
68Ga]Ga-PSMA PET, tested the hypothesis that applying ice-packs externally, causing vasoconstriction, could reduce perfusion to the glands and thereby reduce PSMA uptake; however, this showed very limited success [
43]. This was repeated by another group in a therapeutic setting. Patients who received [
177Lu]Lu-PSMA therapy with externally applied ice-packs underwent post-therapy SPECT and planar scintigraphy scans, which confirmed that there was no protective effect [
44]. Another study investigated the effect of injection of botulinum toxin into the parotid gland and found a significant reduction in [
68Ga]Ga-PSMA uptake on PET/CT [
34]. The result was later attributed to a reduction in non-specific uptake [
18,
45].
GPB, however, appears to have no effect on the specific or non-specific uptake of PSMA in the salivary glands. The clinical effect of GPB was apparent, as patients reported feeling a dry mouth for an extended period of time. A possible explanation for the lack of effect on uptake is that GPB, while reducing secretion of saliva, does not affect the delivery of PSMA ligands to the glands. Apparently, the inhibition of salivation and vasodilation does not induce a reduction in resting state perfusion of the salivary glands. PSMA-ligands that are bound to the receptor are not excreted by the glands into the saliva, irrespective of salivation activity. Altogether, the reduction in salivary secretion caused by GPB has no effect on PSMA uptake. We speculate that this suggests the mechanism behind the reduction in PSMA uptake exhibited by the similarly anticholinergic-action of botulinum toxin, is largely specific in nature. The only tissue type that showed a statistically significant difference in uptake was the kidneys. The result was a 9% reduction in uptake on average, suggesting that any nephroprotective effect is quite limited.
Reducing the radiation dose of
131I to the salivary glands by using various interventions has been studied before; however these studies have yielded conflicting results [
4]. Amifostine, a cytoprotective agent initially thought to be effective in reducing salivary gland toxicity, failed to do so in randomised controlled trials [
46]. Pilocarpine, a parasympathomimetic that works preferentially on the salivary glands, also failed to show any protective effects [
47]. Various sialagogues, like lemon juice, have also been tested, under the hypothesis that increasing salivation may also increase the secretion of radioiodine, thereby reducing its retention time in the salivary glands. Some studies demonstrated that this resulted in a reduction in uptake [
24], while others found an unexpected increase, possibly due to a hypothesised increase in perfusion from stimulation [
48,
49]. Our iodine study was conducted after the PSMA study was concluded. Despite the negative findings of the PSMA study, it was decided to test the effects of GPB on iodine uptake, since this is taken up by a different mechanism. The NIS is an active transporter and GPB may downregulate its action.
In our iodine study, all but one patient exhibited a considerable increase in 123I accumulation in the salivary glands on the intervention scan. Unlike PSMA, iodine is excreted into the saliva by the glands. The reduction in saliva production caused by GPB, could lead to less of the accumulated 123I being excreted by the glands. If the perfusion of the glands and NIS transport are unaffected by GPB, the increase in 123I counts in the salivary glands after administration GPB could be explained by this reduced excretion by salivation. Since this effect would also result in more salivary gland toxicity during therapy, we therefore would strongly advise against attempting to use GPB to reduce salivary gland toxicity from 131I therapy.
The effect of GPB on the stomach and intestinal uptake of iodine was quantitatively insignificant (< 1%). Visually however, the activity on the intervention scans seemed to ‘leak’ out of the stomach and spread more to the intestines, explicable by a potential reduction in gastric tone which is influenced by cholinergic control [
32,
50].
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