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Background. PET/CT with radiolabeled PSMA inhibitors gained clinical relevance in the imaging and therapy of mCRPC patients. Different PSMA radioligands are currently available for PET imaging but few data exist on comparative rate of detection, degree of uptake, correlation with RLT effectiveness, levels of PSA and disease symptoms. Methods. Fifteen mCRPC patients underwent to [68Ga]Ga-PSMA-11/[18F]PSMA-1007 PET/CT imaging, and to 4 up to 6 [177Lu]Lu-PSMA-617 RLT cycles (n. 6). The detection rate and the uptake in target lesions or in normal organs were compared to highlight similarities and differences. Results. [68Ga]/[18F]-PSMA-radioligands show similar rates of detection with overlapping levels of uptake in PCa sites, that is different in normal organs. In the six patients who completed RLT, [177Lu]Lu-PSMA-617 targeted the same lesions causing a drastic reduction in SUVmax after the second dose. Conclusions. These three PSMA radioligands concentrated in the same foci of PCa disease. Thus, the choice for PET imaging may be defined adopting the following parameters: local availability, costs of production/purchasing, number of studies and clinical demands for PET/CT per session. The use of PET radioligands did not influence a proper selection of patients to treat by RLT.

The role of internal dosimetry is usually proposed for investigational purposes in patients treated by RLT; while the application in clinical practice is still very restricted. The limited application is partially justified by the use of fixed doses, the lack of well established methods to calculate absorbed doses to organ at risk and tumours, the time consuming needed for imaging and calculations, the lack of trained, highly-specialized personal, and the discomfort to the patients for the numerous and prolonged sessions of imaging. Methods: In our series thirty patients with NENs, candidate to RLT with Lutathera®, dosimetry was performed after each of the four cycles and used as reference method (M0). Data were then used to assess the feasibility of simplified, lighter, protocols: defining the dosimetry after the first cycle only (M1) and after the first and last cycles (M2). Results: The mean difference, comparing the cumulative absorbed dose (cAD) obtained with M1 and M0, was: -10% for kidneys, -5% for spleen, +34% for liver, +13% for red marrow and +37% for tumour lesions. Such differences decreased comparing cAD obtained with M2 and M0: -3% for kidneys, -0,3% for spleen, +6% for liver, +3% for red marrow and 6% for tumour lesions. Conclusions: The dosimetry established by M2 protocol was not statistically different from that calculated by M0; while M1 overestimates for all OARs but spleen.

The aim of this work is to compare [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 to highlight advantages and drawbacks, analyzing processes of synthesis, imaging properties related to the different pharmacokinetics features, and the consequent impact on patient eligibility for radioligand therapy (RLT). At least, economical aspects were also evaluated. For the production of [68Ga]Ga-PSMA-11, two ranges of starting activity of [68Ga]Gallium chloride and their impact on final radiochemical yeld (RCY), were considered: for the lower (X), with an average activity value of 596.55±37.97 MBq, the RCY was of 80.98±0.051 %, while for the higher range (Y), with an average starting activity value of1436.27±68.68 MBq, the RCY was 71.48±0.038 %. This demonstrated that the increasing starting activity of [68Ga]Gallium chloride negatively affects the RCY. Furthermore, economical evaluations suggested better advantages of [18F]PSMA-1007 vs [68Ga]Ga-PSMA-11..From our clinical experience, comparing all diagnostic and therapeutic PSMA-inhibitors used,there are no significant differences in their binding within tumor lesions but a different uptake in normal organs. Data resulting from this study allow us to search a new and promising approach to overcome the limitations observed in the routinary clinical activity for [68Ga]Ga-PSMA-11.

Additional file 1. Supplementary table 1. Description of genes expressed either with cetirizine administration or without cetirizine in the overall population.

Research Report, 11, 2022

Key Points Question Does sequential scheduling of bevacizumab administration in combination with chemotherapy improve treatment efficacy in patients with metastatic colorectal cancer in keeping with the tumor vascular normalization hypothesis? Findings In this phase 3 randomized clinical trial of 230 patients, the primary end point objective response rate did not significantly differ between the sequential and the concomitant schedule of bevacizumab administration in combination with standard oxaliplatin-based regimens. However, the sequential schedule of bevacizumab administration was associated with longer overall survival, fewer adverse effects, and better health-related quality of life. Meaning Sequential bevacizumab scheduling plus chemotherapy might be relevant to optimize therapeutic efficacy and to explore antiangiogenic combination treatments with innovative perspectives., This randomized clinical trial compares outcomes of concomitant and sequential administration of bevacizumab in combination with standard oxaliplatin-based regimens in untreated or single line–treated patients with metastatic colorectal cancer., Importance Although bevacizumab is a standard of care in combination treatments for metastatic colorectal cancer (mCRC), its clinical benefit has been limited. Objective To determine whether sequential scheduling of bevacizumab administration in combination with chemotherapy improves treatment efficacy in patients with mCRC, in keeping with the tumor vascular normalization hypothesis. Design, Setting, and Participants This open-label, randomized clinical phase 3 trial was conducted from May 8, 2012, to December 9, 2015, at 3 Italian centers. Patients aged 18 to 75 years with unresectable, previously untreated, or single line–treated mCRC were recruited. Follow-up was completed December 31, 2019, and data were analyzed from February 26 to July 24, 2020. Interventions Patients received 12 biweekly cycles of standard oxaliplatin-based regimens (modified FOLFOX-6 [levo–folinic acid, fluorouracil, and oxaliplatin]/modified CAPOX [capecitabine and oxaliplatin]) plus bevacizumab administered either on the same day as chemotherapy (standard arm) or 4 days before chemotherapy (experimental arm). Main Outcomes and Measures The primary end point was the objective response rate (ORR) measured with Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included progression-free survival, overall survival, safety, and quality of life (QOL). Results Overall, 230 patients (136 men [59.1%]; median age, 62.3 [interquartile range, 53.3-67.6] years) were randomly assigned to the standard arm (n = 115) or the experimental arm (n = 115). The median duration of follow-up was 68.3 (95% CI, 61.0-70.0) months. No difference in ORR (57.4% [95% CI, 47.8%-66.6%] in the standard arm and 56.5% [95% CI, 47.0-65.7] in the experimental arm; P = .89) or progression-free survival (10.5 [95% CI, 9.1-12.3] months in the standard arm and 11.7 [95% CI, 9.9-12.9] months in the experimental arm; P = .15) was observed. However, the median overall survival was 29.8 (95% CI, 22.5-41.1) months in the experimental arm compared with 24.1 (95% CI, 18.6-29.8) months in the standard arm (adjusted hazard ratio, 0.73; 95% CI, 0.54-0.99; P = .04). Moreover, the experimental arm was associated with a significant reduction in the rate of severe diarrhea (6 [5.3%] vs 19 [16.5%]; P = .006) and nausea (2 [1.8%] vs 8 [7.0%]; P = .05) and improved physical functioning (mean [SD] change from baseline, 0.65 [1.96] vs −7.41 [2.95] at 24 weeks; P = .02), and constipation scores (mean [SD] change from baseline, −17.2 [3.73] vs −0.62 [4.44]; P = .003). Conclusions and Relevance In this randomized clinical trial, sequential administration of bevacizumab plus chemotherapy did not improve ORR, the primary end point. However, the overall survival advantage, fewer adverse effects, and better health-related QOL associated with sequential bevacizumab administration might provide the basis for exploring antiangiogenic combination treatments with innovative perspectives. Trial Registration EudraCT Identifier: 2011-004997-27; ClinicalTrials.gov Identifier: NCT01718873