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In the published publication [...].
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BACKGROUND: There are currently no standard first-line treatment options for patients with higher grade 2-3, well-differentiated, advanced, gastroenteropancreatic neuroendocrine tumours. We aimed to investigate the efficacy and safety of first-line [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) treatment. METHODS: NETTER-2 was an open-label, randomised, parallel-group, superiority, phase 3 trial. We enrolled patients (aged ≥15 years) with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced gastroenteropancreatic neuroendocrine tumours from 45 centres across nine countries in North America, Europe, and Asia. We used interactive response technologies to randomly assign (2:1) patients to receive four cycles (cycle interval was 8 weeks ± 1 week) of intravenous 177Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks (177Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 vs 3) and origin (pancreas vs other). Tumour assessments were done at baseline, week 16, and week 24, and then every 12 weeks until disease progression or death. The primary endpoint was progression-free survival by blinded, independent, central radiology assessment. We did the primary analysis at 101 progression-free survival events as the final progression-free survival analysis. NETTER-2 is registered with ClinicalTrials.gov, NCT03972488, and is active and not recruiting. FINDINGS: Between Jan 22, 2020, and Oct 13, 2022, we screened 261 patients, 35 (13%) of whom were excluded. We randomly assigned 226 (87%) patients (121 [54%] male and 105 [46%] female) to the 177Lu-Dotatate group (n=151 [67%]) and control group (n=75 [33%]). Median progression-free survival was 8·5 months (95% CI 7·7-13·8) in the control group and 22·8 months (19·4-not estimated) in the 177Lu-Dotatate group (stratified hazard ratio 0·276 [0·182-0·418]; p<0·0001). During the treatment period, adverse events (of any grade) occurred in 136 (93%) of 147 treated patients in the 177Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period. INTERPRETATION: First-line 177Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. 177Lu-Dotatate should be considered a new standard of care in first-line therapy in this population. FUNDING: Advanced Accelerator Applications, a Novartis Company.
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Neoplasias Intestinales , Tumores Neuroendocrinos , Octreótido , Compuestos Organometálicos , Neoplasias Pancreáticas , Neoplasias Gástricas , Humanos , Octreótido/uso terapéutico , Octreótido/administración & dosificación , Octreótido/análogos & derivados , Octreótido/efectos adversos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/mortalidad , Masculino , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/mortalidad , Femenino , Persona de Mediana Edad , Compuestos Organometálicos/uso terapéutico , Compuestos Organometálicos/administración & dosificación , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Neoplasias Gástricas/mortalidad , Anciano , Neoplasias Intestinales/tratamiento farmacológico , Neoplasias Intestinales/patología , Neoplasias Intestinales/radioterapia , Neoplasias Intestinales/mortalidad , Adulto , Radiofármacos/uso terapéutico , Resultado del Tratamiento , Clasificación del Tumor , Supervivencia sin ProgresiónRESUMEN
PURPOSE: Gastroenteropancreatic -neuroendocrine tumours (GEP-NETs) are commonly treated with surgical resection or long-term therapies for tumour growth control. Lutetium [177Lu]-DOTA-TATE was approved for the treatment of GEP-NETs after the phase III NETTER 1trial demonstrated improved progression free survival, objective response rates and health-related quality of life (HRQoL) compared to high-dose somatostatin analogues. No real-world data exist on prescribing habits and clinically significant endpoints for [177Lu]Lu-DOTA-TATE treatment in Italy. REAL-LU is a multicentre, long-term observational study in patients with unresectable/metastatic GEP-NETs progressing on standard therapies in Italian clinical practice. A pre-specified interim analysis was performed at the end of the enrolment period, data from which are described herein. METHODS: Overall duration of REAL-LU will be approximately 48 months, with 12- and 36-month recruitment and follow-up periods, respectively. The primary objective is to evaluate [177Lu]Lu-DOTA-TATE effectiveness in terms of progression-free survival. Secondary objectives include safety, impact on HRQoL, and identification of prognostic factors. This pre-specified interim analysis describes patient profiles, at the end of enrollment, of those prescribed [177Lu]Lu-DOTA-TATE for GEP-NETs in Italy. RESULTS: Among 161 evaluable patients, mean age was 64.7 ± 10.3 years at study entry, 83.8% presented with no clinical signs of disease at physical examination, and most had minor disease symptoms. All patients had metastatic disease, most commonly in the liver (83.9%) with a median of two metastatic sites. In 90.7% of patients, the disease was stage IV, and 68.3% had ≥ 1 target lesion. [177Lu]Lu-DOTA-TATE was prescribed mainly as second-line therapy (61.6%) and following surgery (58.4%). HRQoL assessments revealed high levels of functioning and low levels of symptoms at baseline; 50.0% of patients were symptom-free at study entry. CONCLUSION: The characteristics of patients who received [177Lu]Lu-DOTA-TATE in Italy are similar to those of the GEP-NET population of NETTER 1 with trial but with a higher proportion of patients with a grade 2 (71%). With regard to the tumor grade profile, our study cohort appears to be closer to that of NETTER-2 study population which included patients with G2 or G3 advanced GEP-NETs (i.e. Ki-67 ≥ 10% and ≤ 55%). Further analysis of effectiveness and safety can be anticipated as REAL-LU data mature. STUDY REGISTRATION: ClinicalTrials.gov, NCT04727723; Study Registration Date: 25 January, 2021; https://clinicaltrials.gov/study/NCT04727723?cond=NCT04727723&rank=1.
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Oral tongue squamous-cell carcinoma (OTSCC) is the most prevalent malignancy in the head and neck region. Lymphatic spread, particularly to cervical lymph nodes, significantly impacts 5-year survival rates, emphasizing the criticality of precise staging. Metastatic cervical lymph nodes can decrease survival rates by 50%. Yet, elective neck dissection (END) in T1-2 cN0 patients proves to be an overtreatment in around 80% of cases. To address this, sentinel lymph node biopsy (SLNB) was introduced, aiming to minimize postoperative morbidity. This study, conducted at the ENT and Maxillofacial Surgery department of the Istituto Nazionale Tumori in Naples, explores SLNB's efficacy in early-stage oral tongue squamous-cell carcinoma (OTSCC). From January 2020 to January 2022, 122 T1/T2 cN0 HNSCC patients were enrolled. Radioactive tracers and lymphoscintigraphy identified sentinel lymph nodes, aided by a gamma probe during surgery. Results revealed 24.6% SLN biopsy positivity, with 169 SLNs resected and a 21.9% positivity ratio. The study suggests SLNB's reliability for T1-2 cN0 OTSCC patient staging and early micrometastasis detection.
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Radioligand therapy (RLT) with lutetium (177Lu) oxodotreotide is an approved therapy in combination with somatostatin analogues (SSAs) for patients with advanced, well-differentiated G1-G2, gastro-entero-pancreatic neuroendocrine tumours (GEP-NETs) that progress on SSAs. We conducted a series of round table meetings throughout Italy to identify issues related to RLT delivery to patients with GEP-NETs. Four key issues were identified: (1) the proper definition of tumour progression prior to RLT initiation; (2) the impact of RLT in patients with bone metastases and/or high hepatic tumour burden; (3) the optimal follow-up protocol after RLT; and (4) organisational issues related to RLT use and managerial implications. This article reviews the literature relating to the aforementioned issues and makes recommendations based on available evidence and Italian NET experts' opinions. In particular, the group recommends the development of a diagnostic-therapeutic care pathway (DTCP) for patients undergoing RLT which provides systematic guidance but can still be individualised for each patient's clinical and psychosocial needs. A DTCP may clarify the diagnostic, therapeutic and post-treatment monitoring process, and improve communication and the coordination of care between hub and spoke centres. The DTCP may also contribute to changes in the care process related to the 2013/59/EURATOM Directive and to the definition of costs when planning for future or updated reimbursement of RLT in Italy.
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Neoplasias Hepáticas , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/tratamiento farmacológico , Tumores Neuroendocrinos/radioterapia , Testimonio de Experto , Somatostatina/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológicoRESUMEN
Pulmonary carcinoids (PCs) are part of a spectrum of well-differentiated neuroendocrine neoplasms (NENs) and are classified as typical carcinoid (TC) and atypical carcinoid (AC). TC differ from AC not only for its histopathological features but also for its "functional imaging pattern" and prognosis. ACs are more undifferentiated and characterized by higher aggressiveness. Positron emission tomography/computed tomography (PET/CT) with somatostatin analogs (SSA) labeled with Gallium-68 (68Ga-DOTA-TOC, 68Ga-DOTA-NOC, 68Ga-DOTA-TATE) has widely replaced conventional imaging with gamma camera using 111In- or 99mTc-labelled compounds and represents now the gold standard for diagnosis and management of NENs. In this setting, as already described for gastro-entero-pancreatic NENs, 18F-Fluorodeoxiglucose ([18F]FDG) in addition to 68Ga-SSA can play an important role in clinical practice, particularly for ACs that show a more aggressive behavior compared to TCs. The aim of this systematic review is to analyze all original studies collected from the PubMed and Scopus databases regarding PCs in which both 68Ga-SSA PET/CT and [18F]FDG PET/CT were performed in order to evaluate the clinical impact of each imaging modality. The following keywords were used for the research: "18F, 68Ga and (bronchial carcinoid or carcinoid lung)". A total of 57 papers were found, of which 17 were duplicates, 8 were reviews, 10 were case reports, and 1 was an editorial. Of the remaining 21 papers, 12 were ineligible because they did not focus on PC or did not compare 68Ga-SSA and [18F]FDG. We finally retrieved and analyzed nine papers (245 patients with TCs and 110 patients with ACs), and the results highlight the importance of the combined use of 68Ga-SSA and [18F]FDG PET/CT for the correct management of these neoplasms.
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INTRODUCTION: Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE and 90Y-DOTATOC showed efficacy in the metastatic setting of pheocromocytomas (PCCs) and paragangliomas (PGLs) where no standard therapies have been established. BACKGROUND: A search of peer-reviewed and English articles reporting on 177Lu-DOTATATE and 90Y-DOTATOC efficacy was performed through Medline and Scopus. A subsequent meta-analysis was performed to evaluate the pooled effect size on disease control rate (DCR) with PRRT. Secondary endpoints were description of patients' genetic characteristics, hematologic toxicity, and time-to-outcome. The pooled effect was estimated with both a mixed-effects model and a random-effects model. RESULTS: Twelve studies met the criteria for this meta-analysis: ten with 177Lu- and two with 90Y-PRRTs (213 patients). The largest one included 46 patients. Median ages ranged from 32.5 to 60.4 years. When reported, mutations of SDHB were the most frequent genetic alterations. The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for 177Lu- and 90Y-PRRT, respectively. The pooled DCR for PRRT was 0.81 (95% CI: 0.74-0.87). CONCLUSIONS: We report an updated and solid estimate of DCR achieved with 177Lu- and 90Y-PRRT in PCCs and PGLs, showing that these therapies can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy.
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The role of internal dosimetry is usually proposed for investigational purposes in patients treated by RLT, even if its application is not yet the standard method in clinical practice. This limited use is partially justified by several concomitant factors that make calculations a complex process. Therefore, simplified dosimetry protocols are required. METHODS: In our study, dosimetric evaluations were performed in thirty patients with NENs who underwent RLT with [177Lu]Lu-DOTATATE. The reference method (M0) calculated the cumulative absorbed dose performing dosimetry after each of the four cycles. Obtained data were employed to assess the feasibility of simplified protocols: defining the dosimetry only after the first cycle (M1) and after the first and last one (M2). RESULTS: The mean differences of the cumulative absorbed doses between M1 and M0 were - 10% for kidney, - 5% for spleen, + 34% for liver, + 13% for red marrow, and + 37% for tumor lesions. Conversely, differences lower than ± 10% were measured between M2 and M0. CONCLUSION: Cumulative absorbed doses obtained with the M2 protocol resembled the doses calculated by M0, while the M1 protocol overestimated the absorbed doses in all organs at risk, except for the spleen.
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Octreótido , Tomografía de Emisión de Positrones , Humanos , Octreótido/uso terapéutico , Cintigrafía , Radiometría/métodosRESUMEN
Cervical cancer (CC) is the second most commonly diagnosed cancer and the third leading cause of cancer death among females. The options of treatment for recurrent/advanced CC are limited and patients experiencing recurrence after first line platinum-based chemotherapy have a poor prognosis. In this context, immune checkpoint inhibitors (ICI)s antagonizing PD-1 and programmed death-ligand 1 (PD-L1) have profoundly changed the treatment scenario and outcomes in CC in the first or subsequent lines both as monotherapies or in combination with chemotherapy or other ICIs. Herein, we report the clinical case of a 74-year-old woman with metastatic CC with negative tumor PD-L1 expression who having disease progression after first-line of systemic treatment with platinum, thus undergoing to anti-PD-1 namely cemiplimab. The patient achieved a surprising, fast and complete metabolic response to cemiplimab immediately discontinued after only two cycles due to the onset of rare and severe immune-related adverse events (irAE)s such cardiovascular toxicity and hypertransaminasemia. Despite this, thirteen months later, the patient remains disease-free despite cemiplimab was withdrawn.
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Neoplasias del Cuello Uterino , Femenino , Humanos , Anciano , Neoplasias del Cuello Uterino/tratamiento farmacológico , Antígeno B7-H1 , Recurrencia Local de Neoplasia , Anticuerpos Monoclonales Humanizados/efectos adversosRESUMEN
BACKGROUND: The clinical observation showed a potential additive effect of anti-PD-1 agents and cetirizine in patients with advanced melanoma. METHODS: Clinical outcomes of concomitant cetirizine/anti-PD-1 treatment of patients with stage IIIb-IV melanoma were retrospectively collected, and a transcriptomic analysis was performed on blood samples obtained at baseline and after 3 months of treatment. RESULTS: Patients treated with cetirizine concomitantly with an anti-PD-1 agent had significantly longer progression-free survival (PFS; mean PFS: 28 vs 15 months, HR 0.46, 95% CI: 0.28-0.76; p = 0.0023) and OS (mean OS was 36 vs 23 months, HR 0.48, 95% CI: 0.29-0.78; p = 0.0032) in comparison with those not receiving cetirizine. The concomitant treatment was significantly associated with ORR and DCR (p < 0.05). The expression of FCGR1A/CD64, a specific marker of macrophages, was increased after the treatment in comparison with baseline in blood samples from patients receiving cetirizine, but not in those receiving only the anti-PD1, and positively correlated with the expression of genes linked to the interferon pathway such as CCL8 (rho = 0.32; p = 0.0111), IFIT1 (rho = 0.29; p = 0.0229), IFIT3 (rho = 0.57; p < 0.0001), IFI27 (rho = 0.42; p = 0.008), MX1 (rho = 0.26; p = 0.0383) and RSAD2 (rho = 0.43; p = 0.0005). CONCLUSIONS: This retrospective study suggests that M1 macrophage polarization may be induced by cetirizine through the interferon-gamma pathway. This effect may synergize with the immunotherapy of advanced melanoma with anti-PD-1 agents.
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Melanoma , Receptor de Muerte Celular Programada 1 , Cetirizina/farmacología , Cetirizina/uso terapéutico , Humanos , Interferón gamma/uso terapéutico , Macrófagos/metabolismo , Melanoma/genética , Estudios RetrospectivosRESUMEN
The aim of this work is to compare [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 PET/CT as imaging agents in patients with prostate cancer (PCa). Comparisons were made by evaluating times and costs of the radiolabeling process, imaging features including pharmacokinetics, and impact on patient management. The analysis of advantages and drawbacks of both radioligands might help to make a better choice based on firm data. For [68Ga]Ga-PSMA-11, the radiochemical yield (RCY) using a low starting activity (L, average activity of 596.55 ± 37.97 MBq) was of 80.98 ± 0.05%, while using a high one (H, average activity of 1436.27 ± 68.68 MBq), the RCY was 71.48 ± 0.04%. Thus, increased starting activities of [68Ga]-chloride negatively influenced the RCY. A similar scenario occurred for [18F]PSMA-1007. The rate of detection of PCa lesions by Positron Emission Tomography/Computed Tomography (PET/CT) was similar for both radioligands, while their distribution in normal organs significantly differed. Furthermore, similar patterns of biodistribution were found among [18F]PSMA-1007, [68Ga]Ga-PSMA-11, and [177Lu]Lu-PSMA-617, the most used agent for RLT. Moreover, the analysis of economical aspects for each single batch of production corrected for the number of allowed PET/CT examinations suggested major advantages of [18F]PSMA-1007 compared with [68Ga]Ga-PSMA-11. Data from this study should support the proper choice in the selection of the PSMA PET radioligand to use on the basis of the cases to study.
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Radioisótopos de Galio , Neoplasias de la Próstata , Ácido Edético , Isótopos de Galio , Humanos , Masculino , Niacinamida/análogos & derivados , Oligopéptidos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Radiofármacos/farmacocinética , Distribución TisularRESUMEN
Many treatment approaches are now available for neuroendocrine neoplasms (NENs). While several societies have issued guidelines for diagnosis and treatment of NENs, there are still areas of controversy for which there is limited guidance. Expert opinion can thus be of support where firm recommendations are lacking. A group of experts met to formulate 14 statements relative to diagnosis and treatment of NENs and presented herein. The nominal group and estimate-talk-estimate techniques were used. The statements covered a broad range of topics from tools for diagnosis to follow-up, evaluation of response, treatment efficacy, therapeutic sequence, and watchful waiting. Initial prognostic characterization should be based on clinical information as well as histopathological analysis and morphological and functional imaging. It is also crucial to optimize RLT for patients with a NEN starting from accurate characterization of the patient and disease. Follow-up should be patient/tumor tailored with a shared plan about timing and type of imaging procedures to use to avoid safety issues. It is also stressed that patient-reported outcomes should receive greater attention, and that a multidisciplinary approach should be mandatory. Due to the clinical heterogeneity and relative lack of definitive evidence for NENs, personalization of diagnostic-therapeutic work-up is crucial.
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Increasing evidence suggests that liquid biopsy might play a relevant role in the management of metastatic non-small cell lung cancer (NSCLC) patients. Here, we show how the Molecular Tumor Board (MTB) in our cancer center employed liquid biopsy to support therapeutic decisions in a patient with NSCLC carrying a rare EGFR mutation. A 44-year-old woman, never-smoker with an EGFR, ALK, and ROS1-negative lung adenocarcinoma and multiple brain metastases received systemic therapy and surgery before being referred to our Institute. The MTB suggested NGS testing of tumor biopsy that revealed a rare exon-20 EGFR insertion (p.His773dup; c.2315_2316insCCA) and EGFR amplification. The MTB recommended treatment with erlotinib and follow-up with liquid biopsy, by using both cell-free DNA (cfDNA) and circulating tumor cells (CTCs). An increase of EGFR mutation levels in cfDNA revealed resistance to treatment about 6 months before clinical progression. Extremely low levels of EGFR p.T790M were detected at progression. Based on preclinical data suggesting activity of osimertinib against EGFR exon-20 insertions, the MTB recommended treatment with brain and bone radiotherapy and osimertinib. A dramatic reduction of EGFR mutation levels in the cfDNA was observed after 4 weeks of treatment. The PET scan demonstrated a metabolic partial remission that was maintained for 9 months. This case supports the evidence that liquid biopsy can aid in the management of metastatic NSCLC. It also suggests that treatment with osimertinib might be a therapeutic option in patients with EGFR exon-20 insertions when a clinical trial is not available.
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Carcinoma de Pulmón de Células no Pequeñas , Ácidos Nucleicos Libres de Células , Neoplasias Pulmonares , Adulto , Compuestos de Anilina/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/genética , Receptores ErbB/uso terapéutico , Exones/genética , Femenino , Humanos , Biopsia Líquida , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genéticaRESUMEN
Importance: Data about the optimal timing for the initiation of peptide receptor radionuclide therapy (PRRT) for advanced, well-differentiated enteropancreatic neuroendocrine tumors are lacking. Objective: To evaluate the association of upfront PRRT vs upfront chemotherapy or targeted therapy with progression-free survival (PFS) among patients with advanced enteropancreatic neuroendocrine tumors who experienced disease progression after treatment with somatostatin analogues (SSAs). Design, Setting, and Participants: This retrospective, multicenter cohort study analyzed the clinical records from 25 Italian oncology centers for patients aged 18 years or older who had unresectable, locally advanced or metastatic, well-differentiated, grades 1 to 3 enteropancreatic neuroendocrine tumors and received either PRRT or chemotherapy or targeted therapy after experiencing disease progression after treatment with SSAs between January 24, 2000, and July 1, 2020. Propensity score matching was done to minimize the selection bias. Exposures: Upfront PRRT or upfront chemotherapy or targeted therapy. Main Outcomes and Measures: The main outcome was the difference in PFS among patients who received upfront PRRT vs among those who received upfront chemotherapy or targeted therapy. A secondary outcome was the difference in overall survival between these groups. Hazard ratios (HRs) were fitted in a multivariable Cox proportional hazards regression model to adjust for relevant factors associated with PFS and were corrected for interaction with these factors. Results: Of 508 evaluated patients (mean ([SD] age, 55.7 [0.5] years; 278 [54.7%] were male), 329 (64.8%) received upfront PRRT and 179 (35.2%) received upfront chemotherapy or targeted therapy. The matched group included 222 patients (124 [55.9%] male; mean [SD] age, 56.1 [0.8] years), with 111 in each treatment group. Median PFS was longer in the PRRT group than in the chemotherapy or targeted therapy group in the unmatched (2.5 years [95% CI, 2.3-3.0 years] vs 0.7 years [95% CI, 0.5-1.0 years]; HR, 0.35 [95% CI, 0.28-0.44; P < .001]) and matched (2.2 years [95% CI, 1.8-2.8 years] vs 0.6 years [95% CI, 0.4-1.0 years]; HR, 0.37 [95% CI, 0.27-0.51; P < .001]) populations. No significant differences were shown in median overall survival between the PRRT and chemotherapy or targeted therapy groups in the unmatched (12.0 years [95% CI, 10.7-14.1 years] vs 11.6 years [95% CI, 9.1-13.4 years]; HR, 0.81 [95% CI, 0.62-1.06; P = .11]) and matched (12.2 years [95% CI, 9.1-14.2 years] vs 11.5 years [95% CI, 9.2-17.9 years]; HR, 0.83 [95% CI, 0.56-1.24; P = .36]) populations. The use of upfront PRRT was independently associated with improved PFS (HR, 0.37; 95% CI, 0.26-0.51; P < .001) in multivariable analysis. After adjustment of values for interaction, upfront PRRT was associated with longer PFS regardless of tumor functional status (functioning: adjusted HR [aHR], 0.39 [95% CI, 0.27-0.57]; nonfunctioning: aHR, 0.29 [95% CI, 0.16-0.56]), grade of 1 to 2 (grade 1: aHR, 0.21 [95% CI, 0.12-0.34]; grade 2: aHR, 0.52 [95% CI, 0.29-0.73]), and site of tumor origin (pancreatic: aHR, 0.41 [95% CI, 0.24-0.61]; intestinal: aHR, 0.19 [95% CI, 0.11-0.43]) (P < .001 for all). Conversely, the advantage was not retained in grade 3 tumors (aHR, 0.31; 95% CI, 0.12-1.37; P = .13) or in tumors with a Ki-67 proliferation index greater than 10% (aHR, 0.73; 95% CI, 0.29-1.43; P = .31). Conclusions and Relevance: In this cohort study, treatment with upfront PRRT in patients with enteropancreatic neuroendocrine tumors who had experienced disease progression with SSA treatment was associated with significantly improved survival outcomes compared with upfront chemotherapy or targeted therapy. Further research is needed to investigate the correct strategy, timing, and optimal specific sequence of these therapeutic options.
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Tumores Neuroendocrinos , Neoplasias Pancreáticas , Radioterapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/epidemiología , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/radioterapia , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/radioterapia , Supervivencia sin Progresión , Radioterapia/efectos adversos , Radioterapia/métodos , Radioterapia/estadística & datos numéricos , Receptores de Péptidos , Estudios RetrospectivosRESUMEN
BACKGROUND: Prostate-specific membrane antigen is overexpressed in prostate cancer and it is considered a good target for positron emission tomography/computed tomography imaging of primary cancer and recurrent/metastatic disease, as well as for radioligand therapy. Different PSMA-analogues labeled with [68Ga]gallium have been investigated, showing excellent imaging properties; however, only small amounts can be produced for each radiolabeling. Recently, a [18F]fluoride labeled PSMA-inhibitor, [18F]PSMA-1007, has been introduced, and it has ensured large-scale productions, overcoming this limitation of [68Ga]PSMAs. In this study, PSMA-1007 has been labeled with low (A), medium (B) and high (C) starting activities of [18F]fluoride, in order to verify if radiochemical yield, radiochemical purity and stability of [18F]PSMA-1007 were affected. These parameters have been measured in sixty-five consecutive batches. In addition, the estimation of [18F]PSMA-1007 production costs is provided. RESULTS: The radiochemical yield for low and medium activities of [18F]fluoride was 52%, while for the high one it decreased to 40%. The radiochemical purity was 99% for all three activities. [18F]PSMA-1007 did not show radiolysis up to 8 h after the end of synthesis, confirming that the radiopharmaceutical is stable and suitable to perform diagnostic studies in humans for a long period of time after the end of radiolabeling. Furthermore, radiochemical stability was demonstrated in fetal bovine serum at 4 °C and 37 °C for 120'. CONCLUSIONS: A starting activity of [18F]fluoride of 90 GBq (B) seems to be the best option enabling a final amount of about of 50 GBq of [18F]PSMA-1007, which is promising as it allows to: (a) perform a large number of scans, and/or (b) supply the radiopharmaceutical to any peripheral diagnostic centers in need.
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BACKGROUND: Eighty percent of patients with pancreatic adenocarcinoma present a locally advanced or metastatic disease at diagnosis and are not eligible for surgery if not with palliative intent. In cases of locally advanced disease (LAPC), the combination of chemo and radiotherapy is the only therapeutic option and correlates with a median survival of 15 months (10 months without treatment), with partial remission of disease in 50% of cases. The feasibility and safety of Electrochemotherapy (ECT) have been demonstrated in the treatment of deep tumors. AIM: The aim of the study is to evaluate the efficacy of electrochemotherapy (ECT) followed by conventional systemic treatment compared to the only conventional systemic treatment in LAPC in terms of objective response and overall survival. PATIENTS AND METHODS: This study is a phase IIb prospective multicenter randomized controlled trial with two arms. The study will include 90 patients: 45 in the control group and 45 in the experimental group. Patients with LAPC in the control arm will receive conventional chemotherapy (FOLFOXIRI). Patients with LAPC in the experimental arm will be subjected to Electrochemotherapy and subsequently to FOLFOXIRI. The objective response at 30, 90, and 180 days from treatment will be based on the computed tomography (CT), magnetic resonance (MR), and positron emission tomography/CT response (PET/CT). The objective long-term treatment response will be evaluated with the modified response evaluation criteria in solid tumors (m-RECIST) criteria, which will take into account the difference in vascularization, determined by the images obtained by CT and MR of the tumor treated before and after ECT. CONCLUSIONS: Not resectable liver metastasis, pancreatic tumors, and locally advanced renal carcinomas can be treated with laparoscopic electrodes. ECT could represent an effective therapeutic option for patients not eligible for surgery susceptible to be managed only with palliative therapies.
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Oligometastatic prostate cancer is an intermediate state between localized disease and widespread metastasis. Its biological and clinical peculiarities are still to be elucidated. New imaging techniques contribute to the detection of patients with oligometastatic disease. PET/CT scanning with prostate-specific membrane antigen can improve the selection of men with true early, low-volume oligometastatic disease, who are candidates for metastasis-directed therapy. Clinical studies demonstrated that androgen deprivation therapy can be delayed in oligometastatic patients with a low tumor burden, although no survival benefit has been demonstrated at present. This article presents available evidence on the treatment strategies for oligometastatic prostate cancer.
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Neoplasias de la Próstata/terapia , Antagonistas de Andrógenos/uso terapéutico , Antígenos de Superficie , Glutamato Carboxipeptidasa II , Humanos , Masculino , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patologíaRESUMEN
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.
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Inhibidores de la Angiogénesis/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bevacizumab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Oxaliplatino/administración & dosificación , Adolescente , Adulto , Anciano , Inhibidores de la Angiogénesis/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Diarrea/inducido químicamente , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Metástasis de la Neoplasia , Oxaliplatino/efectos adversos , Supervivencia sin Progresión , Calidad de Vida , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: To assess local disease control rates (LDCR) and overall survival (OS) in locally advanced pancreatic cancer (LAPC) treated with electrochemotherapy (ECT). METHODS: Electrochemotherapy with bleomycin was performed in 25 LAPC patients who underwent baseline Magnetic Resonance Imaging (MRI) and/or Computed Tomography (CT) and Position Emission Tomography (PET) scans before ECT and 1 and 6 months post ECT. LDCR were assessed using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and Choi criteria. Needle electrodes with fixed linear (N-30-4B) or fixed hexagonal configurations (N-30-HG or I-40-HG or H-30-ST) or variable geometry (VGD1230 or VGD1240) (IGEA S.p.A., Carpi, Italy) were used to apply electric pulses. Pain evaluation was performed pre-ECT, after 1 month and after 6 months with ECT. Overall survival estimates were calculated by means of a Kaplan-Meier analysis. RESULTS: At 1 month after ECT, 76% of patients were in partial response (PR) and 20% in stable disease (SD). Six months after ECT, 44.0% patients were still in PR and 12.0% in SD. A LDCR of 56.0% was reached six months after ECT: 13 patients treated with fixed geometry had a LDCR of 46.1%, while for the 12 patients treated with variable geometry, the LDCR was 66.7%. The overall survival median value was 11.5 months: for patients treated with fixed geometry the OS was 6 months, while for patients treated with variable geometry it was 12 months. Electrochemotherapy was well-tolerated and abdominal pain was rapidly resolved. CONCLUSIONS: Electrochemotherapy obtained good results in terms of LDCR and OS in LAPC. Multiple needle insertion in a variable geometry configuration optimized by pre-treatment planning determined an increase in LDCR and OS compared to a fixed geometry configuration.
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The recently reported CXCR4 antagonist 3 (Ac-Arg-Ala-[DCys-Arg-2Nal-His-Pen]-CO2H) was investigated as a molecular scaffold for a CXCR4-targeted positron emission tomography (PET) tracer. Toward this end, 3 was functionalized with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 1,4,7-triazacyclononanetriacetic acid (NOTA). On the basis of convincing affinity data, both tracers, [68Ga]NOTA analogue ([68Ga]-5) and [68Ga]DOTA analogue ([68Ga]-4), were evaluated for PET imaging in "in vivo" models of CHO-hCXCR4 and Daudi lymphoma cells. PET imaging and biodistribution studies revealed higher CXCR4-specific tumor uptake and high tumor/background ratios for the [68Ga]NOTA analogue ([68Ga]-5) than for the [68Ga]DOTA analogue ([68Ga]-4) in both in vivo models. Moreover, [68Ga]-4 and [68Ga]-5 displayed rapid clearance and very low levels of accumulation in all nontarget tissues but the kidney. Although the high tumor/background ratios observed in the mouse xenograft model could partially derive from the hCXCR4 selectivity of [68Ga]-5, our results encourage its translation into a clinical context as a novel peptide-based tracer for imaging of CXCR4-overexpressing tumors.