Part2: Renal And Salivary Gland Functions After Three Cycles Of PSMA-617 Therapy Every Four Weeks in Patients With Metastatic Castration-Resistant Prostate Cancer

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3. Results

3.1. Study Population

A total of 27 patients who underwent a proper [68Ga]Ga-PSMA PET scan as well as salivary and kidney scintigraphy prior to the first cycle and 4 weeks after the third cycle of PSMA-RLT were included in this study. The mean age of the patients was 71±7 years. Prior to therapy, the median and range of creatinine levels for all patients was 0.95 （0.71-1.16 mg/dL）， respectively and serum PSA level was 81.03 （5.91-3305 μg/L）， respectively. The characteristics of the studied patients are summarized in Table 1. Of these patients, a subset of 24 patients underwent additional salivary and renal scintigraphy immediately before each PSMA-RLT cycle.

3.2.Salioary Gland Scintigraphy

In total, 98 salivary scintigraphy were performed. In all patients (n: 27), and as demonstrated in Table2, there was no significant difference for the EF prior to as well as between each therapy cycle and four weeks after the 3rd PSMA-RLT cycle for the right and left parotid gland as well as for the right and left submandibular gland and for all glands together. Concerning the peak time in salivary scintigraphy prior to as well as between the three therapy cycles and one month after the last therapy cycle, there was no significant difference for the right and left parotid gland, or for the right and left submandibular gland. However, for all salivary glands combined, an ANOVA test yielded significant differences in the values of peak time before the start of therapy compared to the values four weeks after the last third treatment (p=0.03), with the Scheffe test as a post-hoc test then revealing no significant differences in mean values between cycles, as shown in Table 2. In addition, there was no significant difference between the values of RA after 5 min for the left and right parotid glands as well as for the left and right submandibular glands, and for all glands together prior to the initiation of PSMA-RLT and four weeks after the last third cycle, all depicted in Table 2 and Figure 2a.

3.3. Kidney Function and Scintigraphy

There was no significant difference in mean creatinine levels between the 3 cycles of therapy and 4 weeks after the last cycle:(last cycle 0.98±0.28;2nd cycle: 0.94± 0.27;3rd cycle: 0.95±0.28; four weeks after 3rd cycle: 1.02±0.35;p=0.58), as shown in Table3. Furthermore, parameters of relative renal function acquired from renal scintigraphy such as the slopes of the right and left Patlak did not reveal significant differences between the first three therapy cycles and one month after the third cycle in all studied patients: Patlak right 1st cycle:47.3±11.9; 2nd cvcle:48.9±13.1;3rd cycle:51.6±8.0; four weeks after 3rd cycle:45.4±11.1;p=0.28)and (Patlak left:1st cycle:52.7 ±11.9;2nd cycle:51.1±13.1;3rd cycle:48.4±8.0 four weeks after 3rd cycle: 54.6±11.1;p=0.28). There was also no significant difference for the integral of 0.7 to 2 min over the renogram curves normalized to the injected activity as a measure of clearance, as well as there being no significant difference between the values before the three cycles of therapy and the values four weeks after the third-to-last cycle:(both kidneys combined:1st cycle: 94.5± 46.7;2nd cycle:94.3±40.5;3rd cycle: 101.5±36.5; four weeks after 3rd cycle:83.1±32.7;p=0.16), (right kidney:1st cycle: 88.7±42.3; 2nd cycle: 89.1± 38.8;3rd cycle: 100.8±31.7; four weeks after3rd cycle:77.0±34.2;p=0.20)and (left kidney:1st cycle: 100.4±50.5;2nd cycle:99.7±43.0;3rd cycle: 102.2±41.8; four weeks after 3rd cycle:89.2±30.6;p=0.67), see Table 3 and Figure 2b.

3.4. 168Ga]Ga-PSMA PET Imaging

Quantification of the [6Ga]Ga-PSMA PET images demonstrated a significant difference in the SUVmax values for whole submandibular glands of both sides (20.2±5.5 vs.16.6±4.8;p= 0.001)before the first cycle and 4 weeks after the third therapy cycle. Furthermore, SUVmaxvalues of the left（20.5主 5.7vs.16.6±4.8; p=0.014） and the right （19.9 土 5.4 vs. 16.6主 4.9;p= 0.03） submandibular glands significantly decreased four weeks after the third therapy cycle as compared to the SUVmax values before the therapy start, Table 4.

Concerning metabolic volume, on the other hand, results indicated no significant difference between the PSMA scan before and 4 weeks after the last therapy cycle, neither for the right nor for the left side, nor for the whole submandibular gland, see Table 4 and Figure 2c.

3.5. Questionnaire

Of the 27 patients, 21 completed a questionnaire concerning dry mouth prior to obtaining the first cycle,20 prior to the second cycle, 14 prior to the third cycle, and 19 one month after the third cycle. Of these, four patients answered"yes"(19%) and seventeen (81%) answered"no" to the question about a dry mouth before receiving PSMA-RLT. Before the second cycle, three men (15%) answered"yes" and seventeen (85%) answered"no". Before the third cycle, two patients (14%)answered"yes" and twelve (86%) answered"no". Four weeks after the third cycle, seven patients(37%)gave a"yes" response and twelve (63%) gave a"no" response. The results of the Cochran's O test indicated no significant differences on the question of dry mouth (yes or no)before obtaining each cycle and four weeks after the last third cycle, p = 0.19.

4. Discussion

Salivary glands feature a high expression of PSMA receptors and are, consequently, the organ with the highest absorbed radiation dose(1.0±0.6 Gy/GBq) after PSMA-RLT [43]. This study is the first to utilize both salivary gland scintigraphy and [68Ga]Ga-PSMA PET images to assess the effect of an intensive PSMA-RLT regimen of three cycles of 7400 PSMA-RLT every four weeks on salivary gland function. Besides the fact that the values of salivary scintigraphy parameters such as EF, RA after 5 min, and peak time did not change significantly before and after treatment with this therapeutic regimen, there was only a small but statistically non-significant increase from 19% to 37% of patients reporting dry mouth. This is in good agreement with the mild and transient impairment of salivary glands previously noted in other studies under various PSMA-RLT regimens. Ahmadzarfar et al. reported dry lips in merely 20% of patients 2 weeks after receiving a cycle of 4.1-6.1 GBq[/Lu]Lu-PSMA-617 [31]. Other studies have either reported temporary xerostomia or only a slight percentage of xerostomia (about 8.7%) in men who acquired 1-2 cycles of 4.1-7.1 GBq PSMA-RLT[44,45]. In addition, Scarpa et al.recorded xerostomia in three out of ten patients, which was transient in two patients and permanent in only one patient [46], and Kratochwil and colleagues described relevant xerostomia after three PSMA-RLT cycles in two out of thirty patients [27]. Although it was only mild (i.e., grade 1)or transient functional impairment, other earlier studies detected xerostomia in a large proportion of patients (87%) after up to four cycles of 7.5 GBq PSMA-RLT[43,47]. Hence, for the patients we studied, the mean peak time increased by approximately one minute when we compared values before and four weeks after the third cycle, indicating a slight impairment of salivary gland function after three cycles of therapy.

Furthermore, the results of the quantified [6Ga]Ga-PSMA PET scan displayed a significant decrease in SUVmax for the right and left submandibular glands and for both submandibular glands combined. This is in accordance with the findings of a previous study [46] in which a significant decrease in SUVmax was also evident for the submandibular glands after 2-3 cycles of 6.1±0.3 GBq PSMA-RLT. Indeed, PSMA is known to be expressed on the epithelium of acinar gland cells and not on duct cells [48]. The decline in SUVmax can, thus, probably be explained by cell death resulting from salivary toxicity, which is accompanied by a loss of function. In contrast to Scarpa et al. who found a significant decrease in the volume of the submandibular glands from 7.5 mL to 6.2 mL, we did not find a meaningful change in the metabolic volume, which would have to be associated with an appreciable cell loss. This is also supported by the consideration that assuming an absorbed dose to the salivary glands of 0.8 to 2.5 Gy/GBq [49], the maximum cumulative dose under our therapy regimen of 3 cycles of7.4 GBq only slightly exceeds the critical dose to the salivary glands of 26-50 Gy[43]. As mentioned in the introduction, PSMA-RLT can also be conducted with alpha emitters, in particular with [225Ac]Actinium. Here, salivary gland toxicity is also an important limiting factor of this therapy [50,51. Thus, studies comparable to ours with salivary gland scintigraphy would be beneficial to assess the precise impact of such therapies on salivary gland function.

Regarding renal function, there was no significant change in mean creatinine levels during the entire duration of therapy and four weeks after the last cycle. This corresponds well with outcomes of several other studies that used other therapeutic regimens, in which no significant changes in renal function were also reported after PSMA-RLT. Among them is the recent work of Rosar et al. who demonstrated an increase in GFR determined by the MDRD formula after six cycles of PSMA-RLT with a median activity of 6.5 GBq [52]. Some studies described a dose-dependent mild renal function impairment of approximately 4.5% after 2-5 five cycles of PSMA-RLT with a mean cumulative [//Lu]Lutetium dose of 18.8± 6.7 GBq at 6-10 week intervals [53,54]. In other earlier studies, such as the study by Yadav et al., no nephrotoxicity was detected in 31 patients after 1.11-5.55 GBq [177LulLu-PSMA-617 [55]. The proportion of patients with elevated cystatin C who had a higher diagnostic sensitivity than serum creatinine and could detect even moderate GFR limitation, increased from 25% at baseline to 58% after treatment in a study by Yordanova et al. [23], which might further indicate a slight reduction of only about 30% from baseline and the low burden of therapy on the renal function of mCRPC patients. Nevertheless, Rahbar et al. found no significant alteration in the median creatinine and median tubular extraction rate in male patients who experienced up to two doses of PSMA-RLT with a mean activity of 5.9± 0.5 GBq [56].

Essentially, even under our stricter therapy interval of only 4 weeks, there was no relevant nephrotoxicity, which was also confirmed by the results of renal scintigraphy.

Specifically, the finding that the integral (0.7-2.0min)/activity, as a surrogate parameter of renal function, did not change significantly suggests that no clinically relevant restriction of renal function occurs after PSMA-RLT. Likewise, the implication of [51Cr]Cr-EDTA GFR in the study of Hofman et al.to evaluate renal toxicity under the effect of PSMA-RLT revealed no renal toxic effects of this therapy on mCRPC patients after obtaining up to 4 cycles with a median activity of 7.5 GBq and a median time between treatment cycles of 6.1 weeks [47].

Despite the use of scintigraphy as a dependable investigation to assess salivary and renal function in a cohort of patients who all obtained a homogeneous therapy protocol with equal activity dose and the interval between the cycles, the retrospective design of the study and the small sample size of patients analyzed might limit the findings of this research. Therefore, differences in the patient population concerning their pre-PSMA-RLT treatments including chemotherapy, which might negatively affect renal function, and tumor stages could have influenced the incidence of treatment toxicity observed in patients included in this study. In addition, the short follow-up period of only 4 weeks after the last cycle of therapy is another issue that may hinder the conclusions of this present study.

5. Conclusions

Altogether, we concluded that the salivary gland and renal function of mCRPC patients were only slightly affected under the more restrictive treatment regimen of 7.4 GBq per cycle and an interval of only 4 weeks between cycles. This further supports the good tolerability and innocuity of PSMA-RLT in male patients with mCRPC, even though longitudinal studies of salivary gland function after PSMA-RLT might provide a better assessment of the long-term effects of this therapy.

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