The Effects of Monosodium Glutamate on PSMA Radiotracer Uptake in Men with Recurrent Prostate Cancer: A Prospective, Randomized, Double-Blind, Placebo-Controlled Intraindividual Imaging Study

Abstract

The prostate-specific membrane antigen (PSMA) is an excellent target for theranostic applications in prostate cancer (PCa). However, PSMA-targeted radioligand therapy can cause undesirable effects due to high accumulation of PSMA radiotracers in salivary glands and kidneys. This study assessed orally administered monosodium glutamate (MSG) as a potential means of reducing kidney and salivary gland radiation exposure using a PSMA targeting radiotracer. Methods: This prospective, double-blind, placebo-controlled study enrolled 10 biochemically recurrent PCa patients. Each subject served as his own control. [ 18 F]DCFPyl PET/CT imaging sessions were performed 3-7 days apart, following oral administration of either 12.7 g of MSG or placebo. Data from the two sets of images were analyzed by placing regions of interest on lacrimal, parotid and submandibular glands, left ventricle, liver, spleen, kidneys, bowel, urinary bladder, gluteus muscle and malignant lesions. The results from MSG and placebo scans were compared by paired analysis of the ROI data. Results: A total of 142 pathological lesions along with normal tissues were analyzed. As hypothesized a priori, there was a significant decrease in maximal standardized uptake values corrected for lean body mass (SULmax) on images obtained following MSG administration in the parotids (24 ± 14%, P=0.001), submandibular glands (35 ± 11%, P<0.001) and kidneys (23 ± 26%, P=0.014). Significant decreases were also observed in lacrimal glands (49 ± 13%, P<0.001), liver (15 ± 6%, P<0.001), spleen (28 ± 13%, P=0.001) and bowel (44 ± 13%, P<0.001). Mildly lower blood pool SULmean was observed after MSG administration (decrease of 11 ± 13%, P=0.021). However, significantly lower radiotracer uptake in terms of SULmean, SULpeak, and SULmax was observed in malignant lesions on scans performed after MSG administration compared to the placebo studies (SULmax median decrease 33%, range-1 to 75%, P<0.001). No significant adverse events occurred and vital signs were stable following placebo or MSG administration. Conclusion: Orally administered MSG significantly decreased salivary gland, kidney and other normal organ PSMA radiotracer uptake in human subjects, using [ 18 F]DCFPyL as an exemplar. However, MSG caused a corresponding reduction in tumor uptake, which may limit the benefits of this approach for diagnostic and therapeutic applications.

The increasing potential of nuclear medicine imaging for the evaluation and reduction of normal tissue toxicity from radiation treatments

“…Assessment aside, strategies to reduce kidney toxicity in PSMA therapy have also been developed and tested. Mannitol, an osmotic diuretic acting on the proximal tubules, was found to reduce 68 Ga-PSMA uptake on PET/CT in the kidneys by up to 24% without affecting tumour uptake. However, no significant change in absorbed dose to the kidneys could be calculated in a subsequent 177 Lu-PSMA therapy study that used planar images for dosimetry [64,65].…”

“…Loss of [ 18 F]FDG uptake after radiotherapy has also been reported and quantified with dose-response curves, and while it correlated with sialometry and observer-rated outcomes, it failed to do so with patient-reported ones [104,105]. Recently, salivary gland damage from EBRT dose fields was also visualised with high resolution using 68 Ga-PSMA PET, as a marker of specific loss of the secretory cells in the salivary glands ( Fig. 4) [106].…”

“…A couple of studies that evaluated the effect of 2-(phosphonomethyl)pentanedioic acid (2-PMPA), a PSMA inhibitor, in mice using 125 I-and 111 In-based PSMA ligands, found a near total reduction in PSMA uptake in the kidneys, but tumour uptake was still compromised [66,67]. Recently, monosodium glutamate (MSG), which competes with the administered radiopharmaceutical for the PSMA receptor, has been tested, and while a 23% reduction in kidney uptake was found, an undesirable 33% reduction in tumour uptake was also seen [68]. The niche of kidney toxicity evaluation with nuclear medicine is a large one with much interest.…”

“…Salivary gland toxicity occurs in 131 I therapy, due to the expression of the sodium iodide symporter in the gland cells. Toxicity from 131 I therapy has been measured in the past using [ 99m Tc]pertechnetate scintigraphy [107,108] and timeactivity curves from these scans, but was also recently demonstrated using 68 Ga-PSMA PET, exhibiting large intra/ interpatient variation (Fig. 5) [109].…”

“…Toxicity also occurs in the glands in PSMA therapy for metastatic prostate cancer (with 177 Lu or 225 Ac), since the salivary glands express the PSMA receptor [22,29]. Strategies to reduce uptake specifically in the glands have been screened using 68 Ga-PSMA and [ 18 F]DCFPyl (a radiofluorinated PSMA inhibitor) PET/CT. One study superficially cooled the salivary glands with ice packs to reduce perfusion.…”