Part1: Renal And Salivary Gland Functions After Three Cycles Of PSMA-617 Therapy Every Four Weeks in Patients With Metastatic Castration-Resistant Prostate Cancer
May 06, 2022
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Abstract: Background:[1LulLu-PSMA-617 radioligand therapy (PSMA-RLT)could affect kidney and salivary gland functions in metastatic castration-resistant prostate cancer (mCRPC) patients. Methods: We retrospectively analyzed clinical, renal, and salivary scintigraphy data and salivary [68Ga]Ga-PSMA-11 ligand PET scan measures such as metabolic volume and SUVmax values of 27 McCracken (mean age 71±7 years) before and 4 weeks after receiving three cycles of PSMA-RLT every 4 weeks. Twenty-two patients additionally obtained renal and salivary scintigraphy prior to each cycle. A one-way ANOVA, post-hoc Scheffé test, and Cochran's Q test were applied to assess organ toxicity. Results: In total, 54 PSMA PET scans,98 kidneys, and 98 salivary scintigraphy results were evaluated. There were no significant differences in the ejection fraction, peak time, and residual activity after 5 min for both parotid and submandibular glands prior to each cycle and 4 weeks after the last cycle. Similarly, no significant differences in serum creatinine and renal scintigraphy parameters were observed prior to each cycle and 4 weeks after the last treatment. Despite there being no changes in the metabolic volume of both submandibular glands, SUVmax values dropped significantly (p<0.05). Conclusion: Results evidenced no alterations in renal function and only minimal impairment of the salivary function of mCRPCpatients who acquired an intense PSMA-RLT regimen every 4 weeks.
Keywords: PSMA; prostate cancer;mCRPC; renal scintigraphy; salivary scintigraphy
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1. Introduction
Prostate cancer is one of the most commonly diagnosed cancers and the second leading cause of tumor-related death in men []. Prostate-specific membrane antigen (PSMA)is a
class II transmembrane glycoprotein is expressed in all types of prostate tissues. Nevertheless, overexpression of PSMA has been found in prostate tumors including its metastatic cells, and in metastatic castration-resistant prostate cancer (mCRPC), making it an ideal target for prostate cancer diagnosis and therapy [2-6]. Therefore, various small molecule PSMA ligands have been developed, labeled with either gamma or positron emitters for positron emission tomography (PET) diagnosis or with beta or alpha particles for radionuclide therapy [7-11]. While the initial growth of prostate cancer is still androgen-dependent and can be effectively treated with luteinizing hormone-releasing hormone (LHRH)agonists and antagonists or anti-androgen receptors (ARs), almost all patients eventually advance to mCRPCwhere these therapies are no longer effective [12-14]. Consequently, [17Lu]Lu-PSMA-617 targeted radionuclide therapy (PSMA-RLT)has shown in numerous studies, including TheraP and Vision studies [15,16], promising results in terms of good tolerability, a favorable response rate, and the fewest adverse effects and organ toxicities in treated mCRPC patients [17-20].
However, PSMA is not prostate-specific and several other organs such as the kidneys, salivary glands, lacrimal glands, or small intestine also express PSMA [21]. Therefore, proximal renal tubules and salivary glands, among others, are considered critical organs in patients receiving PSMA-RLT [22-25]. In this context, it has been shown that a highly standardized therapy regimen of 4-6 therapy cycles at 8-10-week intervals did not exceed the International Commission on Radiological Protection critical dose for critical organs such as kidneys and salivary glands, and no significant nephrotoxicity occurred in 10 patients treated with PSMA-RLT [26]. Indeed, the results of previous studies on the effects of PSMA-RLT on the kidney and salivary gland were largely based on the results of clinical centers offering this treatment to mCRPC patients with different inhomogeneous therapeutic regimens consisting of 1-8 cycles of 2-8 GBq activity per cycle and with an inter-cycle interval of 6-12 weeks [17,27,28]. Previously, we have shown that a more intensive, highly standardized PSMA-RLT protocol applied at our clinical institution with a shorter interval of only four weeks between the cycles has good tolerability and favorable response rates, progression-free survival, and survival rates for patients with mCRPC[29,30]. Therefore, the purpose of this study was to evaluate the renal and salivary glands (parotid and sub-mandibular) toxicity under this unique intensive treatment regimen using clinical and scintigraphy parameters in mCRPC patients who all equally received three cycles of highly standardized PSMA-RLT every 4 weeks.
2. Methods
2.1.Study Population
In this study, patients (n: 61)referred to the Department of Nuclear Medicine, Medical University of Vienna, Vienna General Hospital, between September 2015 and December 2020 to receive PSMA-RLT due to mCRPC were retrospectively evaluated. The therapy was performed on all patients with the recommendation of an interdisciplinary tumor board. The treatments were performed according to S8 of the Austrian Medicines Act (AMG). However, this analysis included only patients with properly and fully performed PSMA PET scans as well as salivary and renal scintigraphy(Figure 1). None of the patients studied underwent radiotherapy to the neck region. The studied patients had acquired a salivary and kidney scintigraphy directly before the first cycle and one month after the last (3rd) cycle of PSMA-RLT. Among them, a subgroup of patients additionally underwent salivary and kidney scintigraphy prior to each of the 3 therapy cycles. In addition, all patients underwent [6Ga]Ga-PSMA-11 ligand ([68Ga]Ga-PSMA)PET scans before the first cycle and 4 weeks after the last (3rd)therapy cycle. Clinical laboratory parameters including serum creatinine levels were measured in all patients before the start of each cycle and 4 weeks after the third cycle of therapy, and patients were requested to answer a questionnaire asking whether they suffer from dry mouth.
2.2. [17Lu]Lu-PSMA-617 Radioligand Therapy
The PSMA-617 precursor was obtained from ABX GmbH(Radeberg, Germany) and was labeled with [177Lu]Lutetium following procedures described previously [31]. In all patients, the therapy protocol consisted of 3 cycles of 7361±293 MBq of PSMA-RLT administered intravenously every 4 weeks [30,32]. Prior to and after the slow intravenous administration of PSMA-RLT, each patient received 1000 mL of normal 0.9%saline infusion at 300 mL/h over 30 min. To protect the salivary glands, each patient received cold packs on the salivary glands 30 min before and up to 6 h after the therapy injection (p.i.), which were changed regularly.
2.3. Salivary Gland Scintigraphy
The salivary gland scintigraphy was performed on a double-headed gamma camera (Axis, Philips Medical Systems, Amsterdam, The Netherlands) equipped with a low energy all-purpose parallel hole collimator. The energy window around the 140 keV photopeak of [9mTe]Technetium was 15%. Dynamic imaging was performed over 30 min after an intravenous administration of 102± 13 MBg 99mTc-pertechnetate in a 64×64-pixel matrix with 30s per frame. Twenty minutes of p.i., p.i.=after the therapy injection, each patient received 5 mL lemon juice diluted with water(1:1). Patients were encouraged not to swallow the juice immediately but to hold it in their mouth for as long as possible and then swallow it without moving the head.
The data were analyzed using Hermes Hybrid 3Dsoftware (Hermes Medical Solutions, Stockholm, Sweden). For image analysis, a region of interest (ROI)was drawn over each salivary gland (left and right parotid, submandibular gland, oral cavity, and background). Time-activity curves were generated for each region. From these time-activity curves, the ejection fraction(EF)was defined as the percentage of the difference between the maximum count and the minimum count after stimulation divided by the maximum count [33-35]. Peak time was defined as the time after injection when the maximum count was reached.
The residual activity (RA) at peak time plus 5 min was specified as the percentage of counts 5 min after the peak time divided by the maximum counts.
2.4.Kidney Scintigraphy
All kidney scintigraphy was also conducted on a double-headed gamma camera (Axis, Philips Medical Systems, Eindhoven, Nederland) equipped with a low energy all-purpose parallel hole collimator. The energy window around the 140 keV photopeak of [mTe]Technetium was 15%. After injection of 95±11 MBq[99mTc]-Mercaptoacetyltriglycine3(MAG3), dynamic planar images from the dorsal were acquired over 20 min (120 frames, 10 s per frame) in a 128× 128 matrix. As for salivary gland scintigraphy, the data were analyzed using Hermes Hybrid 3D software (Hermes Medical Solutions, Stockholm, Sweden). For this, ROIs were drawn around each kidney. The background ROIs were then automatically drawn by the software.
From the generated time-activity curves, the relative function of the kidney was determined from the slopes of the right and left Patlak plots [36-38]. Since no blood samples were taken during the renal scintigraphy, the clearance parameters were determined using a camera-based method without blood or urine sampling. Therefore, we determined a measure of clearance similar to the methods that have been previously published [39,40]. Because the counts of the injected activity were not available, we could not express the clearance in terms of the percent of uptake. Thus, we normalized the integral from 0.7 to 2 min over the renogram curves to the amount of the injected activity, which should be proportional to the injected counts using the same camera system for every patient.
2.5.PSMA-PET Imaging
Following our therapy protocol, all patients underwent [68Ga]Ga-PSMA PET examination prior to the initiation of the therapy and four weeks after the third treatment cycle. The scan was carried out 60 min after the application of 173.5±16.3 MBg [68Ga]Ga-PSMA. Imaging was performed with four-bed positions at 5 min scan time, thoroughly described in [41]. Accordingly, the parotid gland was not fully imaged in PET scans and, thus, a volume of interest (VOI) was generated only for the submandibular gland. To estimate the metabolic volume and the maximum standardized uptake value (SUVmax) of the submandibular glands, a cubic VOI was placed around the submandibular glands and then a threshold value of 10% of the maximum pixel value within the VOI was used for the delineation of the corresponding submandibular gland, as described previously in van Kalmhout et al. study [42].
2.6. Statistical Analysis
Descriptive statistical analysis was conducted with the software IBM SPSS Statistics version 24.0. The Kolmogorov-Smirnov test was applied to check the distribution of the values. Non-normally distributed data were presented as medians and ranges while normally distributed data were expressed as mean + standard deviation. Other mentioned statistical analysis was performed using MedCalc v19.1(Ostend, Belgium). One-way analysis of variance (one-way ANOVA)was used to test for statistically significant differences between the means of three or more groups. As a post-hoc test, the Scheffe test was conducted to find out which pairs of means were significant. Cochran's Q test was used for the evaluation of the results of the questionnaire concerning mouth dryness. A p-value lower than 0.05 was considered statistically significant.
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