The present study shows no significant differences in PSMA uptake comparing the patient group that was scanned with bilateral icepacks to the patient group that was scanned without icepacks. When comparing radiotracer uptake in the intervention group with the control group, however, significant differences were found with regard to radiotracer uptake in the left parotid gland. These findings were confirmed by the intra-patient analysis. Based on these results, external cooling of the salivary glands seems to have some impact. Clinical relevance of these findings, however, remains debatable.
The rationale of skin cooling in the attempt to induce vasoconstriction of the peripheral blood vessels was earlier described in the literature on chemotherapy-induced alopecia . Cooling is assumed to reduce skin perfusion, decrease concentration of chemotherapy in the scalp, and consequently diminish cellular uptake by the hair follicles (due to a decreased metabolic activity of the cells). In a recently published review of 10 studies comprising 654 patients, it was concluded that scalp hypothermia indeed represents an effective preventative measure . The same underlying mechanism is assumed to prevent the salivary glands for toxicity in patients undergoing 177Lu-PSMA therapy, hopefully reducing both specific as unspecific binding . To our knowledge however, the effect of external cooling on PSMA uptake in the salivary glands was not investigated.
This is the first study that aims to systematically determine impact of external cooling on PSMA uptake in salivary glands in patients referred for 68Ga-PSMA PET/CT imaging in the setting of prostate cancer (re)-staging. However, several conference abstracts did address this issue earlier [12, 13]. Gaertner et al. measured PSMA uptake (SUVmean and SUVmax) in the bilateral parotid and submandibular glands of an intervention group of 25 patients . In this group, bilateral salivary glands were cooled with icepacks. PSMA uptake in the salivary glands was compared to SUV values of a control group that consisted of 33 patients. As a result of external cooling, a 12 and 15% reduction of SUVmean in the parotid glands and submandibular glands was found, respectively (all p < 0.01). Mean SUVmax decreased significantly in both parotid glands and submandibular glands as well (all p < 0.01). Bohn et al. included 50 patients undergoing diagnostic 68Ga-PSMA PET/CT for prostate cancer. PSMA uptake in an intervention group of 25 patients, of whom the left parotid gland was cooled with icepacks, was compared with a control group of 25 patients that were scanned without icepacks . Intra-patient analysis revealed the cooled left parotid gland showing 12% less radiotracer uptake compared to the non-cooled side (range 0–42%; p = 0.01), a statistical significant difference that was, as expected, not found under “normal” (non-cooled) circumstances.
Several German studies assessed efficacy and toxicity of 177Lu-PSMA therapy in metastatic castration-resistant prostate cancer patients [14,15,16,17,18,19,20]. The included patients in the studies by Ahmadzadehfar et al., Heck et al., and Rahbar et al. all underwent external cooling of the salivary glands [14, 15, 17, 19]. These patients received bilateral icepacks covering the cheeks from 30 min prior to treatment, up to 4 h post-administration of 177Lu-PSMA. Xerostomia was reported in 4–37% of the patients, probably caused by the high uptake of PSMA ligands in the salivary glands.
In the aforementioned study by Ahmadzadehfar et al., patients received icepacks covering the parotid and submandibular glands from 30 min prior to and up to 4 h after administration of a single cycle 177Lu-PSMA . All patients in this study underwent dynamic salivary gland scintigraphy with Technetium-99m (99mTc)-pertechnetate combined with salivary gland stimulation by lemon juice 20 min post-injection on the treatment day and 8 weeks after 177Lu-PSMA therapy to investigate salivary gland function. Comparison of baseline with follow-up salivary gland scintigraphy did not show therapy-induced functional impairment (i.e., no change in the uptake and clearance of 99mTc-pertechnetate) of the salivary glands. It was concluded that it is unclear whether cooling of the salivary glands is effective to prevent the salivary glands from therapy-related damage. Furthermore, the need for a study addressing the change in uptake of 68Ga-PSMA with and without icepacks was underlined.
The other study groups that did not apply icepacks reported on xerostomia in 4–7% of the patients [16, 18]. Rahbar et al. investigated 56 metastatic castration-resistant prostate cancer patients that underwent 177Lu-PSMA-617 therapy. Whereas mean PSMA uptake in the salivary glands was found to be greater than the dose that was absorbed by the kidneys, only 2 patients (4%) experienced mild, transient, xerostomia after 3 and 4 cycles. In the study by Kratochwil et al., 30 patients underwent 1–3 cycles 177Lu-PSMA-617 therapy. Two out of 30 patients developed xerostomia after the third cycle, in which prescription of artificial saliva was required. Less than 10% of the patients experienced temporal xerostomia after the first and second cycles, not affecting quality of life. It must be noted that the absolute number of patients experiencing transient xerostomia after treatment was not reported. Evaluating the results of the abovementioned studies, remarkably less xerostomia was found in the patient groups that underwent therapy without cooling of the salivary glands, when compared to the patients that were supplied with icepacks during 177Lu-PSMA administration by other study groups. In this respect, it is important to note that the PSMA uptake in the salivary glands in the abovementioned studies was not objectified. Differences may have been caused by bias as a result of the subjective experience of therapy-related toxicity: patients undergoing 177Lu-PSMA therapy that were supplied with icepacks may have been more focused on xerostomia than patients that were not supplied with icepacks. Furthermore, since it concerned a retrospective study, results may have been reported less accurately.
The results of the present study are in line with those found in the abovementioned conference abstracts. Intra-patient analysis with regard to PSMA uptake in the parotid gland indeed revealed some significant findings. Comparison of radiotracer activity in the salivary glands of the entire intervention group versus the control group confirmed these findings: a significant reduction of SUVmax (p = 0.02) and SUVpeak (p = 0.04) was found in the left parotid gland. The absolute reduction was 14.52 and 13.45%, respectively.
A direct (inter-patient) comparison of the bilateral icepack group with the control group did not reveal significant differences concerning radiotracer uptake in the salivary glands. Having a closer look to these specific results, however, marginal non-significant differences in radiotracer uptake were found regarding the SUVmax in the bilateral parotid glands (right side p = 0.08; left side p = 0.07). Absolute SUVmax reduction in the right parotid gland was 14.3 and 15.1% on the left side. These findings suggest that our results would be significantly different in a larger patient sample. On the other hand, when determining the required sample size for this study, a 40% reduction of radiotracer uptake was considered clinically relevant.
The general, but not significant observed lower mean SUV values in the submandibular glands may be explained by the argument that cutaneous cooling is not equally affective for both the parotid and submandibular glands. The first explanation for this observation might be that the parotid glands are more susceptible to external cooling than submandibular glands, due to their more superficial anatomical localization. Secondly, the parotid glands may have been cooled more effectively than the submandibular glands, causing a greater difference between the cooled and the non-cooled side. Another, although less likely, potential factor may be that the parotid and submandibular glands respond differently to cooling: causing differences in vasoconstriction, blood flow, cellular metabolism, and radiotracer uptake. A vast analysis of the assumed relation between skin temperature, perfusion of the salivary glands, and radiotracer uptake in patients undergoing PRLT may offer some clarification to the assumed underlying mechanism.
The general value of external cooling of the salivary glands to prevent of xerostomia in patients undergoing 177Lu-PSMA therapy remains debatable. Firstly, it is suggested that external cutaneous cooling of the skin induces reactive vasodilatation, undoing the intended vasoconstrictive effect that is assumed to prevent radiotracer uptake in the salivary glands . Furthermore, the presented 68Ga-PSMA accumulation data are meant to predict the behavior of 177Lu-PSMA. However, compartment modeling of radiotracer kinetics showed the presence of a relatively rapid blood clearance and a relatively slow early elimination phase of 68Ga-PSMA, while the effect of external cooling on these rates is not well determined . In the case of a relatively slow uptake of 177Lu-PSMA from interstitial or intracellular space into the salivary glands, in combination with the long half-life time of 177Lu, the reduction of PSMA uptake in salivary glands by cooling during a relatively short period of time can be anticipated to be even less effective.
Limitations comprise the measurements executed by one unblinded investigator, potentially affecting their accuracy. However, an experienced nuclear medicine physician randomly checked measurements. Secondly, baseline temperature of the icepacks was not standardized or systematically measured prior to application, making inter-patient differences possible, leading to potential differences in the effect of cooling and subsequent radiotracer uptake. However, the icepacks were cooled in the same fridge, in which the standard temperature of the freezer unit was approximately − 18 °Celsius. Strong points of the present study include the prospective design allowing for both inter-patient and intra-patient analysis.
Diagnostics and therapy using PSMA directing radioligands are gaining popularity. The first experiences with 177Lu-PSMA therapy show little side effects and with favorable toxicity profiles. However, xerostomia represents an undesirable side effect that needs to be reduced. Since the clinical relevance of our results is debatable, we suggest that long-term application of icepacks during the therapeutic procedure could be considered, but most likely does not contribute to reduction of xerostomia. Extension of knowledge on the mechanisms of non-specific uptake of PSMA ligands in the salivary glands may lead to new preventive strategies while improved treatments of salivary gland dysfunction, if these can be identified, are also important. We await the results of ongoing gene therapy trials with interest. Promising strategies encompassing intraglandular injection of several compounds (e.g., botulinum toxine), but also gene- and stem cell therapy, have been suggested to prevent xerostomia and might offer a solution to in the future . Prospective studies, investigating efficacy and toxicity including oncological outcomes regarding overall survival, are warranted to direct future 177Lu-PSMA therapy.