Papers by Valentina Di Iorio
Therapy with 177Lu-PSMA-617 in advanced mCRPC patients: Results of the phase 2 prospective trial IRST-185.03 (EUDRACT: 2016-002732-32)
European Urology Open Science
EJNMMI Radiopharmacy and Chemistry, 2016
Background: The arginine-glycine-aspartic (RGD) peptide sequence serves as a high-affinity antago... more Background: The arginine-glycine-aspartic (RGD) peptide sequence serves as a high-affinity antagonist of the integrin α v β 3 receptor that plays an important role in tumor angiogenesis. Recently we reported [ 68 Ga]FSC(succ-RGD) 3 , a trimeric RGD peptide, exhibited excellent targeting properties for α v β 3 integrin expression and significant improved tumor uptake compared to monomeric [ 68 Ga]NODAGA-RGD.(1) Here we report the PET imaging properties of [ 68 Ga]FSC(succ-RGD) 3 in different xenograft tumor model and compared them with [ 68 Ga]NODAGA-RGD. Materials and methods: The PET imaging properties of [ 68 Ga]FSC(succ-RGD) 3 were studied in nude mice bearing M21 human melanoma xenografts and human glioblastoma U87MG xenograft tumor. A parallel PET imaging of 68 GaNODAGA-RGD in same mouse bearing U87MG xenograft tumor was performed as a comparison. Results: The static PET image of [ 68 Ga]FSC(succ-RGD) 3 in nude mice showed highly visualized tumors of M21 (positive) whereas nonvisualized tumor of M21-L (negative) tumor xenografts 1 h post injection confirming receptor-specific activity accumulation. The dynamic PET images of [ 68 Ga]FSC(succ-RGD) 3 showed rapid clearance of [ 68 Ga]FSC(succ-RGD) 3 from the circulation while the tumor remained clearly visible. A direct comparison of [ 68 Ga]FSC(succ-RGD) 3 with [ 68 Ga]NODAGA-RGD in nude mice bearing U87MG xenograft tumor using PET/CT resulted comparable target/background ratio (tumor/kidneys ratio = 1.3 and 1.6, tumor/ muscle ratio = 4.9, 5, respectively, 90 min post injection). The time activity curves from dynamic PET data showed an increase of the activity concentration of [ 68 Ga]FSC(succ-RGD) 3 in tumor firstly, then remained almost constant whereas that of [ 68 Ga]NO-DAGA-RGD decreased quickly. The significant enhanced tumor uptake (3.8 vs. 1.6 % ID/g) in addition to the slower washout rate from tumor for [ 68 Ga]FSC(succ-RGD) 3 not only allows the PET EJNMMI Radiopharmacy and Chemistry
European Journal of Nuclear Medicine and Molecular Imaging, Jun 26, 2020
Purpose To evaluate the clinical value of 68 Ga-PSMA PET/CT negativity in patients with biochemic... more Purpose To evaluate the clinical value of 68 Ga-PSMA PET/CT negativity in patients with biochemical recurrent prostate cancer (BCR). Methods One hundred three BCR patients (median age, 70 years; median PSA, 0.47 ng/mL) with negative 68 Ga-PSMA PET/ CT, followed up for at least 1 year, were retrospectively identified in a database of 1003 consecutive patients undergoing 68 Ga-PSMA PET/CT for BCR. Clinical recurrence (CR) was determined or excluded on follow-up imaging selected as per clinical practice. Clinical recurrence-free survival (CRFS) was computed from the date of negative 68 Ga-PSMA PET/CT to the date of evident disease; frequencies of CRFS were described as per ISUP patient subset (subset 1: ISUP grades 1 and 2; subset 2: ISUP grade 3; subset 3: ISUP grades 4 and 5) and other conventional variables. Results In 57 patients out of 103 (55.3%), CR was detected in the prostatic fossa (45.6%), nodes (38.6%), and bone (15.8%). The median CRFS was 15.4 months (range, 12.1-20.5), with a CRFS at 12 months in 61.4% of cases (range, 50.9-70.4) whereas the 24-month CRFS was 34.8% (range, 24-45.8). ISUP subset 1 benefited from significantly longer CRFS compared to subset 2 and subset 3 (median CRFS, 20.5 months, 12.6 months, and 12.1 months, respectively). ISUP subset 3 had significantly poorer 24month CRFS (9.3%) compared to subset 1 (47.8%) and subset 2 (33.5%). At the univariate and multivariate analyses, the ISUP subset was the only significant risk factor for clinical relapse; ISUP subset 3 and subset 2 patients held a higher risk of CR compared to subset 1 patients (HR of 2.75 [1.35-5.57] for subset 3 versus subset 1; HR of 2.08 [1.11-3.88] for subset 2 versus subset 1). Conclusion 68 Ga-PSMA PET/CT negativity in early BCR patients (PSA < 0.5 ng/mL) with low-grade primary prostate cancer (ISUP1 and 2) may support the exploration of a clinical surveillance approach in future prospective studies.
European Journal of Nuclear Medicine and Molecular Imaging, May 29, 2020
Purpose In March 2014, we reported the activity and safety of 177 Lu-DOTA-octreotate peptide rece... more Purpose In March 2014, we reported the activity and safety of 177 Lu-DOTA-octreotate peptide receptor radionuclide therapy (Lu-PRRT) at two different dosages (18.5 GBq and 27.5 GBq in 5 cycles) in patients with progressive metastatic gastrointestinal neuroendocrine tumors (GI-NETs). Disease control rate (DCR) and toxicity were addressed. Herein, we report the late toxicity, progression-free survival (PFS), and overall survival (OS) in the same cohort after a 10-year follow-up. Methods We conducted an open-label, disease-oriented prospective phase II trial. From March 2008 to June 2011, 43 patients received 3.7 GBq or 5.5 GBq of Lu-PRRT every 6 to 8 weeks, each cycle repeated 5 times. All patients showed 68 Gallium-DOTA-peptide PET/Octreoscan® positivity (score 3-4 Rotterdam scale) in known lesions. Tumor burden was estimated radiologically. Time-to-event data (PFS and OS) were described using Kaplan-Meier curves and compared with the log-rank test. Results Forty-three patients (28 males and 15 females) were evaluable and were monitored for a median period of 118 months (range 12.6-139.6). Median PFS in patients receiving 18.5 GBq was 59.8 months (95% confidence interval [95% CI] 14.3-79.6), identical to that of patients treated with 27.5 GBq (59.8 months, 95% CI 23.4-82.0). Median OS was 71.0 months (95% CI 46.1-107.3) in the group who received 18.5 GBq and 97.6 months (95% CI 64.3-not reached) in the group treated with 27.5 GBq (P = 0.22). Patients with progression limited to lymph nodes showed significantly longer median PFS and OS than those with hepatic lesions (P = 0.02 for PFS and P = 0.04 for OS). Age over 65 years at the time of PRRT was also significant for OS. Of note, no late hematological or renal toxicity was observed in either group. Conclusions The long-term follow-up of the IRST phase II study shows that Lu-PRRT is a safe and effective therapy for patients with advanced GI-NET, the most important prognostic factor being tumor burden, hepatic lesions, and age. We believe that Lu-PRRT should be offered to patients with early-stage disease. Keywords 177 Lu-DOTA-octreotate. GI-NET. PRRT. Long-term follow-up. Tumor burden. Overall survival This article is part of the Topical Collection on Oncology-Digestive tract
Frontiers in Medicine, 2022
Background: Academic research is important to face unmet medical needs. The Oncological community... more Background: Academic research is important to face unmet medical needs. The Oncological community encounters many hurdles in setting up multicenter investigator-driven trials mainly due to administrative complexity. The purpose of a network organization at a multinational level is to facilitate clinical trials through standardization, coordination, and education for drug development and regulatory approval.Methods: The application of an European grant foresees the creation of a consortium which aims at facilitating multi-center academic clinical trials.Results: The ERA-NET TRANSCAN Call 2011 on “Validation of biomarkers for personalized cancer medicine” was released on December 2011. This project included Italian, Spanish, French and German centers. The approval process included Consortium constitution, project submission, Clinical Trial Submission, and activation on a national level. The different timescales for submitting study documents in each Country and the misalignment of obj...
European Journal of Nuclear Medicine and Molecular Imaging, 2020
Purpose In March 2014, we reported the activity and safety of 177 Lu-DOTA-octreotate peptide rece... more Purpose In March 2014, we reported the activity and safety of 177 Lu-DOTA-octreotate peptide receptor radionuclide therapy (Lu-PRRT) at two different dosages (18.5 GBq and 27.5 GBq in 5 cycles) in patients with progressive metastatic gastrointestinal neuroendocrine tumors (GI-NETs). Disease control rate (DCR) and toxicity were addressed. Herein, we report the late toxicity, progression-free survival (PFS), and overall survival (OS) in the same cohort after a 10-year follow-up. Methods We conducted an open-label, disease-oriented prospective phase II trial. From March 2008 to June 2011, 43 patients received 3.7 GBq or 5.5 GBq of Lu-PRRT every 6 to 8 weeks, each cycle repeated 5 times. All patients showed 68 Gallium-DOTA-peptide PET/Octreoscan® positivity (score 3-4 Rotterdam scale) in known lesions. Tumor burden was estimated radiologically. Time-to-event data (PFS and OS) were described using Kaplan-Meier curves and compared with the log-rank test. Results Forty-three patients (28 males and 15 females) were evaluable and were monitored for a median period of 118 months (range 12.6-139.6). Median PFS in patients receiving 18.5 GBq was 59.8 months (95% confidence interval [95% CI] 14.3-79.6), identical to that of patients treated with 27.5 GBq (59.8 months, 95% CI 23.4-82.0). Median OS was 71.0 months (95% CI 46.1-107.3) in the group who received 18.5 GBq and 97.6 months (95% CI 64.3-not reached) in the group treated with 27.5 GBq (P = 0.22). Patients with progression limited to lymph nodes showed significantly longer median PFS and OS than those with hepatic lesions (P = 0.02 for PFS and P = 0.04 for OS). Age over 65 years at the time of PRRT was also significant for OS. Of note, no late hematological or renal toxicity was observed in either group. Conclusions The long-term follow-up of the IRST phase II study shows that Lu-PRRT is a safe and effective therapy for patients with advanced GI-NET, the most important prognostic factor being tumor burden, hepatic lesions, and age. We believe that Lu-PRRT should be offered to patients with early-stage disease. Keywords 177 Lu-DOTA-octreotate. GI-NET. PRRT. Long-term follow-up. Tumor burden. Overall survival This article is part of the Topical Collection on Oncology-Digestive tract
Targeted alpha PSMA-based therapy of metastatic castrate-resistant prostate-cancer patients (mCRPC): prediction dosimetry
Physica Medica, 2021
Circulating androgen receptor gene amplification and resistance to 177Lu-PSMA-617 in metastatic castration-resistant prostate cancer: results of a Phase 2 trial
British Journal of Cancer, 2021
BACKGROUND In a Phase 2 clinical trial, we aimed to determine the lutetium-177 [177Lu]-PSMA-617 a... more BACKGROUND In a Phase 2 clinical trial, we aimed to determine the lutetium-177 [177Lu]-PSMA-617 activity and the clinical utility of levels of plasma androgen receptor (AR) gene in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). METHODS We determined AR copy number in pretreatment plasma samples. We used logistic regression to estimate the odds ratio (OR) and 95% confidence intervals (95% CIs) in order to evaluate the independent relevance of AR status and to evaluate patients with early progressive disease (PD) defined as treatment interruption occurring within 4 months after the start of 177Lu-PSMA-617. RESULTS Twelve of the 15 (80%) with AR gene gain and 5 of the 25 (20%) patients with no gain of AR had early PD (p = 0.0002). The OR for patients without PSA response having AR gain was 3.69 (95% CI 0.83-16.36, p = 0.085). The OR for patients with early PD having AR gain was 16.00, (95% CI 3.23-79.27, p = 0.0007). Overall, median PFS and OS were 7.5 and 12.4 months, respectively. AR-gained had a significant shorter OS compared to AR-normal patients (7.4 vs 19.1 months, p = 0.020). No treatment interruptions due to adverse effects were reported. DISCUSSION Plasma AR status helped to indicate mCRPC with early resistance to 177Lu-PSMA-617. TRIAL REGISTRATION NCT03454750.
Theragnostic in neuroendocrine tumors
The Quarterly Journal of Nuclear Medicine and Molecular Imaging, 2022
In the last few decades incidence and prevalence of neuroendocrine tumours has been increasing. T... more In the last few decades incidence and prevalence of neuroendocrine tumours has been increasing. The theragnostic approach, that allows the diagnosis and treatment of different neoplasms with the same ligand, is a typical nuclear medicine tool. Applied for years, is also pivotal in Neuroendocrine Tumours (NETs) where has improved the diagnostic accuracy and therapeutic efficacy with impact on patient's survival. Theragnostic also allows the identification of important prognostic factors such as tumour location and burden, presence of liver metastases and intensity of Somatostatin Receptors (SSTR) expression to consider in new and possibly combined studies to ameliorate patient's outcome. Moreover, the possibility to evaluate receptor expression even in non-NET malignancies has "de facto" widened the possible indications for PRRT. We believe that this innovative therapeutic approach will be implemented in next years by radiomics and biological tumours characterization to better address PRRT applications.
![Research paper thumbnail of Production and Quality Control of [177Lu]Lu-PSMA-I&T: Development of an Investigational Medicinal Product Dossier for Clinical Trials](https://attachments.academia-assets.com/89522613/thumbnails/1.jpg)
Molecules
Since prostate cancer is the most commonly diagnosed malignancy in men, the theranostic approach ... more Since prostate cancer is the most commonly diagnosed malignancy in men, the theranostic approach has become very attractive since the discovery of urea-based PSMA inhibitors. Different molecules have been synthesized starting from the Glu-urea-Lys scaffold as the pharmacophore and then optimizing the linker and the chelate to improve functional characteristics. This article aimed to highlight the quality aspects, which could have an impact on clinical practice, describing the development of an Investigational Medicinal Product Dossier (IMPD) for clinical trials with [177Lu]Lu-PSMA-I&T in prostate cancer and other solid tumors expressing PSMA. The results highlighted some important quality issues of the final preparation: radiolabeling of PSMA-I&T with lutetium-177 needs a considerably longer time compared with the radiolabeling of the well-known [177Lu]Lu-PSMA-617. When the final product was formulated in saline, the stability of [177Lu]Lu-PSMA-I&T was reduced by radiolysis, showing...
Feasibility and utility of re-treatment with 177Lu-DOTATATE in GEP-NENs relapsed after treatment with 90Y-DOTATOC
European Journal of Nuclear Medicine and Molecular Imaging, 2015
Peptide receptor radionuclide therapy (PRRT) is a valid therapy for grade 1/2 gastroenteropancrea... more Peptide receptor radionuclide therapy (PRRT) is a valid therapy for grade 1/2 gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). Although a median progression-free survival (PFS) of more than 20 months is frequently observed, the majority of patients relapse after 2 - 3 years. In the present study, we investigated the use of low dosage re-treatment with (177)Lu-DOTATATE (Lu-PRRT) in patients with GEP-NENs who relapsed after treatment with (90)Y-DOTATOC (Y-PRRT). Upon tumour progression, 26 patients with a PFS of at least 12 months after Y-PRRT were consecutively enrolled in a phase II study of re-treatment with Lu-PRRT. All patients had preserved kidney and haematological parameters and received 14.8 - 18.5 GBq of Lu-PRRT in four or five cycles. The disease control rate (DCR), toxicity, PFS and prognostic factors were evaluated. Median total activity of Lu-PRRT was 16.5 GBq in five cycles. The DCR was 84.6 %, median PFS was 22 months (95 % CI 16 months - not reached) compared to 28 months (95 % CI 20 - 36 months) after Y-PRRT. Tumour burden and number of liver metastases were important prognostic factors. Toxicity was mild after Lu-PRRT re-treatment in the majority of patients, with only two patients with grade 2 and one with grade 3 bone marrow toxicity; one patient had grade 2 and one grade 3 renal toxicity. Patients with GEP-NEN who have previously responded to Y-PRRT are suitable candidates for Lu-PRRT re-treatment on progression. Although our sample size was limited, low-dosage Lu-PRRT was safe, and led to DCR and PFS rates comparable with those observed when Y-PRRT was used as primary treatment.
![Research paper thumbnail of [18F]F-PSMA-1007 Radiolabelling without an On-Site Cyclotron: A Quality Issue](https://attachments.academia-assets.com/78443641/thumbnails/1.jpg)
Pharmaceuticals, 2021
Radiopharmaceuticals targeting the prostate-specific membrane antigen (PSMA) has become the gold ... more Radiopharmaceuticals targeting the prostate-specific membrane antigen (PSMA) has become the gold standard for PET imaging of prostate cancer. [68Ga]Ga-PSMA-11 has been the forerunner but a [18F]F-PSMA ligand has been developed because of the intrinsic advantages of Fluorine-18. Fluorine-18 labelled compounds are usually prepared in centers with an on-site cyclotron. Since our center has not an on-site cyclotron, we decided to verify the feasibility of producing the experimental 18F-labelled radiopharmaceutical [18F]F-PSMA-1007 with [18F]F- from different external suppliers. A quality agreement has been signed with two different suppliers, and a well-established and correctly implemented quality assurance protocol has been followed. The [18F]F- was produced with cyclotrons, on Nb target, but with different beam energy and current. Extensive validation of the [18F]F-PSMA-1007 synthesis process has been performed. The aim of this paper was the description of all the quality documentati...
![Research paper thumbnail of [18F]F-PSMA-1007 Radiolabelling without an On-Site Cyclotron: A Quality Issue](https://attachments.academia-assets.com/77068213/thumbnails/1.jpg)
Pharmaceuticals
Radiopharmaceuticals targeting the prostate-specific membrane antigen (PSMA) has become the gold ... more Radiopharmaceuticals targeting the prostate-specific membrane antigen (PSMA) has become the gold standard for PET imaging of prostate cancer. [68Ga]Ga-PSMA-11 has been the forerunner but a [18F]F-PSMA ligand has been developed because of the intrinsic advantages of Fluorine-18. Fluorine-18 labelled compounds are usually prepared in centers with an on-site cyclotron. Since our center has not an on-site cyclotron, we decided to verify the feasibility of producing the experimental 18F-labelled radiopharmaceutical [18F]F-PSMA-1007 with [18F]F- from different external suppliers. A quality agreement has been signed with two different suppliers, and a well-established and correctly implemented quality assurance protocol has been followed. The [18F]F- was produced with cyclotrons, on Nb target, but with different beam energy and current. Extensive validation of the [18F]F-PSMA-1007 synthesis process has been performed. The aim of this paper was the description of all the quality documentati...
Methods for preparation and administration of lutetium-177 oxodotreotide 3.7 GBq: proceedings from an Italian advisory board
Clinical and Translational Imaging, 2021
Lutetium-177 (177Lu)-oxodotreotide (Lutathera®) is a targeted radiolabelled somatostatin analog a... more Lutetium-177 (177Lu)-oxodotreotide (Lutathera®) is a targeted radiolabelled somatostatin analog approved for metastatic or unresectable, well-differentiated (G1 and G2), progressive, somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) [1]. Oxodotreotide has high affinity for somatostatin subtype 2 receptors, which are overexpressed by most GEP-NET cells but have low expression in normal tissues [1, 2]. 177Lu-oxodotreotide binds to these receptors and is internalized, thus delivering ionizing radiation more specifically to tumor cells than surrounding cells. In the phase 3 NETTER-1 study, 177Lu-oxodotreotide plus long-acting octreotide low-dose (30 mg; for symptom control) significantly improved progression-free survival and response rates compared with long-acting octreotide high-dose (60 mg) alone [3]. 177Lu-oxodotreotide is supplied in a single-dose vial (370 MBq/mL; expected radioactivity at infusion: 7.4 GBq; total vial volume: 20 mL), which is...
Combined use of 177Lu-DOTATATE and metronomic capecitabine (Lu-X) in FDG-positive gastro-entero-pancreatic neuroendocrine tumors
European Journal of Nuclear Medicine and Molecular Imaging
FDG-positive neuroendocrine tumors (NETs) have a poorer prognosis and exhibit shorter response du... more FDG-positive neuroendocrine tumors (NETs) have a poorer prognosis and exhibit shorter response duration to peptide receptor radionuclide therapy (PRRT). The aim of this prospective phase II study was to evaluate the efficacy and toxicity of PRRT with 177Lu-DOTATATE associated with metronomic capecitabine as a radiosensitizer agent in patients with advanced progressive FDG-positive gastro-entero-pancreatic (GEP) NETs. Patients with advanced somatostatin receptor- and FDG-positive G1-G3 GEP-NETs (Ki67 < 55%) were treated with a cumulative activity of 27.5 GBq of 177Lu-DOTATATE divided in five cycles of 5.5 GBq each every 8 weeks. Capecitabine (1000–1500 mg daily) was administered orally in the inter-cycle period between 177Lu-DOTATATE treatments. Prior to commencing capecitabine, all patients were triaged with the dihydropyrimidine dehydrogenase (DPD) test. Only DPD-proficient individuals were enrolled. The primary objectives were disease control rate (DCR) and safety. Secondary aims included progression-free (PFS) and overall survival (OS). Treatment response was assessed per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). Toxicity was assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. From August 2015 to December 2016, 37 subjects were consecutively enrolled. A total of 25 (68%) were affected by pancreatic neuroendocrine tumors (P-NETs), and 12 (32%) had gastrointestinal neuroendocrine tumors (GI-NETs). By grading (WHO 2010 classification), 12 patients (32%) had G1 (Ki67 ≤ 2%), 22 (59%) had G2 (3% < Ki67 ≤ 20%), and 3 patients (9%) had G3 (Ki67 > 20%) NETs. Grade 3 (G3) or 4 (G4) hematological toxicity occurred in 16.2% of patients. Other G3-G4 adverse events were diarrhea in 5.4% of cases and asthenia in 5.4%. No renal toxicity was observed for the duration of follow-up. In 37 patients, 33 were evaluable for response. Objective responses included partial response (PR) in 10 patients (30%) and stable disease (SD) in 18 patients (55%), with a DCR of 85%. The median follow-up was 38 months (range 4.6–51.1 months). The median PFS was 31.4 months (17.6–45.4), and mOS was not reached. This study demonstrated that the combination of PRRT with 177Lu-DOTATATE and metronomic capecitabine is active and well tolerated in patients with aggressive FDG-positive G1-G3 GEP-NETs. These data constitute the basis for a randomized study of PPRT alone vs. PRRT plus metronomic capecitabine.
EJNMMI Radiopharmacy and Chemistry
Background The stability of precursors and reagents is of utmost importance for developing a robu... more Background The stability of precursors and reagents is of utmost importance for developing a robust radiolabelling method that provides high and constant radiochemical yield and radiochemical purity. While performing the QC of the [68Ga]Ga-PSMA-11 injectable solutions according to Ph. Eur. Monograph that has recently been published, a trend to the instability of the standard PSMA-11, the same used as a precursor for [68Ga]Ga-PSMA-11 radiosynthesis, has been observed. This instability led to the formation of a side product in a time-dependent manner. The formation of this compound, besides making the implementation of the Ph. Eur. analytical method more difficult, negatively influenced the radiochemical yield and the radiochemical purity by increasing gallium-68 in colloidal and ionic forms. Results The nature of the side product was investigated by adding chelators, such as EDTA, to PSMA-11 solutions and using the combination of UHPLC-HRMS. The results led to the definition of the s...
Biomedicines
To investigate the role of 68 Ga-PSMA-11 PET/CT in guiding retreatment stereotactic body radiatio... more To investigate the role of 68 Ga-PSMA-11 PET/CT in guiding retreatment stereotactic body radiation therapy (SBRT) in prostate cancer (PCa) patients in biochemical recurrence (BCR) after salvage radiotherapy (S-RT). (2) Methods: We retrospectively evaluated PCa patients previously treated with S-RT on the prostate bed and with proven serum prostate antigen (PSA) failure after S-RT. In all patients (pts), 68 Ga-PSMA-11 PET/CT was positive in the prostate bed only and guided retreatment SBRT. All retreatments were performed by applying the same radiotherapy protocol (median dose of 18 Gy/3 fractions; IQR 18-21 Gy). The median follow-up was 27 months (range 4-35 months). (3) Results: 38 consecutive patients were considered in this analysis. The overall median PSA level before RT was 1.10 ng/mL (IQR 0.82-2.59). PSA decreased at 3 and 6 months after treatment, with a median value of 0.60 ng/mL (IQR 0.31-0.96; p < 0.001) and 0.51 ng/mL (IQR 0.29-1.17; p < 0.001), respectively. Overall, biochemical recurrence-free survival (b-RFS) was 15.0 months (95% CI 13-23). Grade-1 toxicity was reported in 31.6% of patients (12/38). (4) Conclusion: These results confirm that 68 Ga-PSMA-11-PET/CT is able to identify the site of recurrence in patients who have failed S-RT, thus supporting the use of metastases-directed radiotherapy as a safe and effective treatment.
Targeted Alpha Therapy in mCRPC (Metastatic Castration-Resistant Prostate Cancer) Patients: Predictive Dosimetry and Toxicity Modeling of 225Ac-PSMA (Prostate-Specific Membrane Antigen)
Frontiers in Oncology
Radioligand therapy is a type of internal radiotherapy combining a short-range radioisotope label... more Radioligand therapy is a type of internal radiotherapy combining a short-range radioisotope labeled to a carrier with a high affinity for a specific receptor expressed on tumor cells. Targeted alpha therapy (TAT) combines a high-linear energy transfer (LET) emitter (225Ac) with a prostate-specific membrane antigen (PSMA) carrier, specifically binding tumor cells in patients with metastatic castration-resistant prostate cancer. Although the antitumor activity of 225Ac-PSMA is well-documented, this treatment is nowadays only used as salvage therapy because the high incidence of xerostomia limits the therapeutic window. Thus, methods to reduce salivary toxicity and models able to describe xerostomia incidence are needed. We recently studied the efficacy of salivary gland protectors administered in combination with 177Lu-PSMA therapy. Starting from these data, we performed a predictive dosimetric evaluation of 225Ac-PSMA to assess the impact of salivary gland protectors in TAT. 225Ac-PSMA predictive dosimetry was performed in 13 patients treated with 177Lu-PSMA. Sequential whole-body planar images were acquired 0.5–1, 16–24, 36–48, and 120 h post-injection. 177Lu time-activity curves were corrected for 225Ac physical decay and assumed in equilibrium for all daughters. The OLINDA/EXM spherical model was used for dose estimation of the parotid and submandibular glands. The dose for each daughter was calculated and summed for the total dose estimation. The biologically effective dose formalism was extended to high-LET emitters. For the total biologically effective dose formalism extended to high-LET emitters, including the contribution of all daughter isotopes, the brachytherapy formalism for a mixture of radionuclides was implemented. Equivalent doses in 2 Gy/fraction (EQD2) were then calculated and compared with the normal tissue complication probability model derived from external beam radiotherapy for grade ≥2 xerostomia induction. Median predictive doses were 0.86 BdRBE5/MBq for parotid glands and 1.05 BdRBE5/MBq for submandibular glands, with a 53% reduction compared with previously published data. The results show that the radiobiological model implemented is conservative, as it overestimates the complication rate with respect to the clinical data. Our data shows the possibility of reducing salivary gland uptake in TAT with the coadministration of organ protectors, but these results should be confirmed for TAT with 225Ac-PSMA by carrying out prospective trials with defined toxicity endpoints and dosimetry procedures.
SUV95th as a Reliable Alternative to SUVmax for Determining Renal Uptake in [68Ga] PSMA PET/CT
Molecular Imaging and Biology
Widely used in clinical practice, the maximum standardized uptake value (SUVmax) is a statistical... more Widely used in clinical practice, the maximum standardized uptake value (SUVmax) is a statistical index highly prone to physical and biological variations, which can lead to unpredictable errors. This study has a methodological aim: to identify a more robust SUV-based index representing the tracer accumulation. In particular, the new metric was tested to confirm the potential of mannitol to reduce renal uptake Ga-68 prostate-specific membrane antigen ([68Ga]PSMA). To this aim, our previously published work, proving the efficacy of mannitol, was considered as a background study. Renal SUVmax was calculated in nine patients undergoing [68Ga]PSMA positron emission tomography (PET)/X-ray computed tomography (CT) at baseline (b-PET/CT) and at follow-up after intravenous infusion of 500 ml of 10 % mannitol (m-PET/CT). SUV values of kidney volumes were extracted by a new 3D segmentation method. A new parameter, the median computed on the upper 10% of the SUV distribution (SUV95th), was introduced to better characterize the tracer accumulation. A comparison between SUVmax and SUV95th was also performed. Kruskal-Wallis test was used to assess the statistical significance of the differences in SUV95th between b-PET/CT and m-PET/CT. SUV95th not only confirmed the efficacy of mannitol as demonstrated in the previous study but improved the separability of b-PET/CT and m-PET/CT examinations, overturning SUVmax findings in two cases. The outcomes of the Kruskal-Wallis test computed for each kidney proved that differences between b-PET/CT and m-PET/CT SUV95th values were significant (p value < 0.001). Our findings indicate that SUV95th is a more robust index to assess high uptake level, representing a reliable alternative to SUVmax. Independently from the segmentation method, the superiority of SUV95th and its easy computation could make its clinical impact decisive. The results obtained with SUV95th, more representative of tracer uptake than those with SUVmax suggest, in our opinion, that mannitol infusion could be used to reduce the adsorbed dose to the kidneys during [68Ga]PSMA PET/CT and Lu-177 or Ac-225 therapy. Our future goal will be confirming this effect in a larger cohort of patients, also verifying the role of SUV95th in the evaluation of tumor response to therapy.
Pembrolizumab in a Patient With Heavily Pre-Treated Squamous Cell Thymic Carcinoma and Cardiac Impairment: A Case Report and Literature Review
Frontiers in Oncology
Immunotherapy directed at the programmed cell death-1 receptor (PD-1) or its ligand PD-L1 has pro... more Immunotherapy directed at the programmed cell death-1 receptor (PD-1) or its ligand PD-L1 has proven effective in solid malignancies such as melanoma, non-small cell lung cancer (NSCLC), urothelial cancer, renal cell carcinoma, and head and neck cancer. Compared with cytotoxic chemotherapy, radiotherapy, or molecular targeted agents, immunotherapy is an innovative strategy for treating malignancies, with durable clinical responses and manageable adverse events. Thymic carcinomas are extremely rare, constituting only 0.06% of all malignancies, are much more aggressive tumours than thymomas and have a worse prognosis. Nowadays, first line platinum-based chemotherapy for metastatic tumours are the cornerstone of treatment. However, the results of further therapeutic lines for metastatic or relapsed thymic carcinoma are unsatisfactory, with no regimen showing a consistent benefit. Moreover, the rarity of these tumours makes it difficult to carry out clinical trials. Herein we report a remarkable result of 1 year stable disease with good quality of life and no side effects obtained from the use of immunotherapy with pembrolizumab in a case of heavily pre-treated squamous cell thymic carcinoma and cardiac impairment. We also include a literature review of clinical trials on PD-1/PD-L1 inhibitors for the treatment of thymic epithelial cancers, taking a close look at cardiac toxicity.
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Papers by Valentina Di Iorio