RESUMEN
BACKGROUND: Neuroendocrine tumours (NETs) are a heterogeneous group of tumours, which is characterized by rich vascularization. The role of angiogenesis in NETs has been widely researched. Peptide receptor radionuclide therapy (PRRT) is an effective treatment method for patients with disease progression in NETs. Due to the heterogeneousness of NETs, the response to treatment varies. Currently, the finding of efficient markers helpful in assessing the response to treatment in NETs is crucial. The aim of this study was to assess chromogranin A (CgA) and angiogenic factors in gastro-entero-pancreatic (GEP) and broncho-pulmonary (BP) NET patients treated with PRRT. MATERIAL AND METHODS: The study group included 40 patients with GEP NETs and BP NETs who completed four cycles of PRRT. Serum levels of CgA and angiogenic factors such as vascular endothelial growth factor (VEGF), its receptors (VEGF-R1, VEGF-R2, VEGF-R3), were assessed before and after four cycles of PRRT. All tests were determined using ELISA. RESULTS: The concentration of CgA, VEGF-R1 and VEGF-R2 decreased significantly, whereas VEGF-R3 increased significantly after PRRT. PRRT did not affect VEGF, it was similar before and after the radioisotope treatment. Based on AUROC, only for VEGF-R1 AUC was a consequence of 0.7 which can be considered as a good response to PRRT treatment. CONCLUSIONS: VEGF-R1 may be a potential biomarker useful in assessing the effectiveness of PRRT in NET patients.
Asunto(s)
Cromogranina A , Tumores Neuroendocrinos , Humanos , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/sangre , Femenino , Masculino , Persona de Mediana Edad , Adulto , Anciano , Cromogranina A/sangre , Receptores de Péptidos/metabolismo , Biomarcadores de Tumor/sangre , Factor A de Crecimiento Endotelial Vascular/sangre , Neovascularización Patológica/radioterapia , Neovascularización Patológica/sangre , Octreótido/análogos & derivados , Octreótido/uso terapéutico , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/sangre , Resultado del TratamientoRESUMEN
BACKGROUND: Resection of non-functioning pancreatic neuroendocrine tumours (NF-PanNETs) is curative in most patients. The potential benefits of neoadjuvant treatments have, however, never been explored. The primary aim of this study was to evaluate the safety of neoadjuvant 177Lu-labelled DOTA0-octreotate (177Lu-DOTATATE) followed by surgery in patients with NF-PanNETs. METHODS: NEOLUPANET was a multicentre, single-arm, phase II trial of patients with sporadic, resectable or potentially resectable NF-PanNETs at high-risk of recurrence; those with positive 68Ga-labelled DOTA PET were eligible. All patients were candidates for neoadjuvant 177Lu-DOTATATE followed by surgery. A sample size of 30 patients was calculated to test postoperative complication rates against predefined cut-offs. The primary endpoint was safety, reflected by postoperative morbidity and mortality within 90 days. Secondary endpoints included rate of objective radiological response and quality of life. RESULTS: From March 2020 to February 2023, 31 patients were enrolled, of whom 26 completed 4 cycles of 177Lu-DOTATATE. A partial radiological response was observed in 18 of 31 patients, and 13 patients had stable disease. Disease progression was not observed. Twenty-four R0 resections and 4 R1 resections were performed in 29 patients who underwent surgery. One tumour was unresectable owing to vascular involvement. There was no postoperative death. Postoperative complications occurred in 21 of 29 patients. Severe complications were observed in seven patients. Quality of life remained stable after 177Lu-DOTATATE and decreased after surgery. CONCLUSION: Neoadjuvant treatment with 177Lu-DOTATATE is safe and effective for patients with NF-PanNETs.
Surgical removal of non-functioning pancreatic neuroendocrine tumours (NF-PanNETs) can often cure patients. However, it is not known whether treating patients before surgery provides additional benefits. The main aim of the study was to investigate safety of treatment called peptide receptor radionuclide therapy with 177Lu-labelled DOTA0-octreotate (177Lu-DOTATATE) before surgery in patients with NF-PanNETs. The NEOLUPANET study was conducted from March 2020 to February 2023 across multiple centres. Patients with NF-PanNETs that were at high risk of recurrence after surgery were included. All patients received 177Lu-DOTATATE before surgery. The main measure of success was safety, reflected by complications or death within 90 days after surgery. The study enrolled 31 patients and 26 completed four cycles of 177Lu-DOTATATE. Tumours shrank partially in 18 patients, and in 13 patients the tumour remained the same. No tumours increased in size. The entire tumour was removed in 28 of 29 patients. No patients died, but 72% had some complications (severe in 7 patients). The study found that using 177Lu-DOTATATE before surgery is safe and useful for treating patients with NF-PanNETs.
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Terapia Neoadyuvante , Octreótido , Compuestos Organometálicos , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Femenino , Masculino , Persona de Mediana Edad , Octreótido/uso terapéutico , Octreótido/análogos & derivados , Anciano , Compuestos Organometálicos/uso terapéutico , Adulto , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/cirugía , Tumores Neuroendocrinos/patología , Radiofármacos/uso terapéutico , Calidad de Vida , Pancreatectomía/métodosRESUMEN
Everolimus and peptide receptor radionuclide therapy (PRRT, 177Lu-DOTATATE) are 2 treatments recommended in guidelines for gastroenteropancreatic metastatic neuroendocrine tumors. However, the best treatment sequence remains unknown. Methods: We designed a retrospective multicenter study that included patients from the national prospective database of the Groupe d'Étude des Tumeurs Endocrines who had been treated using everolimus and PRRT between April 2004 and October 2022. The primary aim was to compare the 2 treatments (everolimus and PRRT) in terms of efficacy and safety, and the secondary aim was to evaluate the sequences (PRRT followed by everolimus or everolimus followed by PRRT) based on overall progression-free survival (PFS) (PFS during first treatment + PFS during second treatment) in patients with metastatic neuroendocrine tumors. Results: Both treatments were used for 84 patients. The objective response rate and median PFS were 5 (6.0%) and 16.1 mo (95% CI, 11.5-20.7 mo), respectively, under everolimus and 19 (22.6%) and 24.5 mo (95% CI, 17.7-31.3 mo), respectively, for PRRT. The safety profile was also better for PRRT. Median overall PFS was 43.2 mo (95% CI, 33.7-52.7 mo) for the everolimus-PRRT sequence and 30.6 mo (95% CI, 17.8-43.4 mo) for the PRRT-everolimus sequence (hazard ratio, 0.69; 95% CI, 0.39-1.24; P = 0.22). Conclusion: PRRT was more effective and less toxic than everolimus. Overall PFS was similar between the 2 sequences, suggesting case-by-case discussion if the patient is eligible for both treatments, but PRRT should be used first when an objective response is needed or in frail populations.
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Everolimus , Metástasis de la Neoplasia , Tumores Neuroendocrinos , Octreótido , Everolimus/uso terapéutico , Humanos , Masculino , Femenino , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/patología , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Octreótido/análogos & derivados , Octreótido/uso terapéutico , Octreótido/efectos adversos , Adulto , Receptores de Péptidos/metabolismo , Francia , Compuestos Organometálicos/uso terapéutico , Anciano de 80 o más Años , Resultado del TratamientoAsunto(s)
Terapia Neoadyuvante , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/terapia , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/terapia , Terapia Neoadyuvante/métodos , Octreótido/uso terapéutico , Octreótido/análogos & derivados , Receptores de Péptidos/metabolismo , Radiofármacos/uso terapéuticoRESUMEN
PURPOSE: Well-differentiated neuroendocrine neoplasms (NETs) overexpress the somatostatin receptor, which is the target for the peptide receptor radionuclide therapy (PRRT). NETs have a slow growth rate and can metastasize to liver, bone, and lungs. In NETs patients, liver metastasis is an important prognostic marker because liver failure is one of the most common causes of death in this population. In this regard, we aimed to describe the changes in laboratorial parameters in patients submitted to PRRT with 177 Lu-DOTATATE, focusing on hepatic parameters. PATIENTS AND METHODS: One hundred ten patients treated with 1 to 4 cycles of 7.4 GBq (200 mCi) of 177 Lu-DOTATATE from January 2011 to December 2021 were analyzed in this retrospective observational single-center study. Patients were submitted to blood tests before and after each cycle of PRRT. Laboratory measurements were collected to assess liver function, cholestasis, kidney, and bone marrow function. RESULTS: In the general population (n = 110), ALP ( P = 0.013) and GGT ( P < 0.001) showed a statistically significant reduction. Patients with high liver disease volume showed a statistically significant reduction in ALT ( P = 0.016), whereas patients with low liver disease volume showed a statistically significant reduction in GGT ( P = 0.013). All parameters for bone marrow function showed a statistically significant decrease in all population subsets. CONCLUSIONS: Patients treated with 177 Lu-DOTATATE showed a significant improvement in liver function and cholestasis parameters, and a consistent decrease in bone marrow function, even in the presence of advanced liver disease.
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Octreótido , Compuestos Organometálicos , Humanos , Octreótido/análogos & derivados , Octreótido/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Hígado/diagnóstico por imagen , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/diagnóstico por imagen , Estudios Retrospectivos , Adulto , Estudios de Cohortes , Anciano de 80 o más AñosRESUMEN
177Lu-DOTATATE is an effective second-line treatment for metastatic or nonresectable neuroendocrine tumors. This treatment can result in hematologic severe adverse reactions (SARs). Preemptive identification of patients at risk of SARs could mitigate this risk and improve treatment safety and outcomes. Methods: Demographic and oncologic history, pretreatment laboratory values, and SAR frequency were obtained for 126 sequential patients treated with 177Lu-DOTATATE. Univariable and multivariable logistic regression models identified factors correlating with SARs. Results: Relative pretreatment anemia, leukopenia, thrombocytopenia, and elevated mean corpuscular volume (MCV) were significantly correlated with SARs, with an odds ratio of 16 (95% CI, 5-65) in patients with an MCV greater than 95 fL. Conclusion: Pretreatment bone marrow dyscrasias, including an MCV greater than 95 fL, may predict patients at risk for SARs when treated with 177Lu-DOTATATE. Further study is needed to determine whether the risks of SARs outweigh the benefit in these patients.
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Índices de Eritrocitos , Tumores Neuroendocrinos , Octreótido , Compuestos Organometálicos , Humanos , Octreótido/análogos & derivados , Octreótido/uso terapéutico , Octreótido/efectos adversos , Compuestos Organometálicos/uso terapéutico , Compuestos Organometálicos/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/sangre , Adulto , Enfermedades Hematológicas/etiología , Anciano de 80 o más Años , Estudios RetrospectivosRESUMEN
ABSTRACT: A 76-year-old woman with liver and bone metastasis of a duodenal neuroendocrine tumor received peptide receptor radionuclide therapy with 177 Lu-DOTATATE. Scintigraphy with SPECT/CT performed 4 days after the treatment demonstrated 177 Lu-DOTATATE uptake as multifocal ground glass opacities in the bilateral lungs. This uptake was considered to be due to COVID-19 pneumonia because the patient was infected with the virus 7 days prior to the treatment. The lung opacities became smaller, showing a decreased uptake, 2 months later, after the second treatment. 177 Lu-DOTATATE may be taken up during the active phase of COVID-19 pneumonia.
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COVID-19 , Pulmón , Octreótido , Compuestos Organometálicos , Neumonía Viral , Humanos , COVID-19/diagnóstico por imagen , COVID-19/complicaciones , Anciano , Femenino , Pulmón/diagnóstico por imagen , Octreótido/análogos & derivados , Octreótido/uso terapéutico , Neumonía Viral/diagnóstico por imagen , Neumonía Viral/complicaciones , Pandemias , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único , Infecciones por Coronavirus/diagnóstico por imagen , Infecciones por Coronavirus/complicaciones , Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/radioterapiaRESUMEN
Purpose: This study aims to elucidate the role of quantitative SSTR-PET metrics and clinicopathological biomarkers in the progression-free survival (PFS) and overall survival (OS) of neuroendocrine tumors (NETs) treated with peptide receptor radionuclide therapy (PRRT). Methods: A retrospective analysis including 91 NET patients (M47/F44; age 66 years, range 34-90 years) who completed four cycles of standard 177Lu-DOTATATE was conducted. SSTR-avid tumors were segmented from pretherapy SSTR-PET images using a semiautomatic workflow with the tumors labeled based on the anatomical regions. Multiple image-based features including total and organ-specific tumor volume and SSTR density along with clinicopathological biomarkers including Ki-67, chromogranin A (CgA) and alkaline phosphatase (ALP) were analyzed with respect to the PRRT response. Results: The median OS was 39.4 months (95% CI: 33.1-NA months), while the median PFS was 23.9 months (95% CI: 19.3-32.4 months). Total SSTR-avid tumor volume (HR = 3.6; P = 0.07) and bone tumor volume (HR = 1.5; P = 0.003) were associated with shorter OS. Also, total tumor volume (HR = 4.3; P = 0.01), liver tumor volume (HR = 1.8; P = 0.05) and bone tumor volume (HR = 1.4; P = 0.01) were associated with shorter PFS. Furthermore, the presence of large lesion volume with low SSTR uptake was correlated with worse OS (HR = 1.4; P = 0.03) and PFS (HR = 1.5; P = 0.003). Among the biomarkers, elevated baseline CgA and ALP showed a negative association with both OS (CgA: HR = 4.9; P = 0.003, ALP: HR = 52.6; P = 0.004) and PFS (CgA: HR = 4.2; P = 0.002, ALP: HR = 9.4; P = 0.06). Similarly, number of prior systemic treatments was associated with shorter OS (HR = 1.4; P = 0.003) and PFS (HR = 1.2; P = 0.05). Additionally, tumors originating from the midgut primary site demonstrated longer PFS, compared to the pancreas (HR = 1.6; P = 0.16), and those categorized as unknown primary (HR = 3.0; P = 0.002). Conclusion: Image-based features such as SSTR-avid tumor volume, bone tumor involvement, and the presence of large tumors with low SSTR expression demonstrated significant predictive value for PFS, suggesting potential clinical utility in NETs management. Moreover, elevated CgA and ALP, along with an increased number of prior systemic treatments, emerged as significant factors associated with worse PRRT outcomes.
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Biomarcadores de Tumor , Tumores Neuroendocrinos , Octreótido , Compuestos Organometálicos , Humanos , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/metabolismo , Anciano , Persona de Mediana Edad , Compuestos Organometálicos/uso terapéutico , Masculino , Femenino , Octreótido/análogos & derivados , Octreótido/uso terapéutico , Adulto , Estudios Retrospectivos , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Tomografía de Emisión de Positrones/métodos , Receptores de Somatostatina/metabolismo , Radiofármacos , Resultado del Tratamiento , Cromogranina A/metabolismo , Fosfatasa Alcalina/metabolismo , Antígeno Ki-67/metabolismo , Supervivencia sin Progresión , Carga TumoralRESUMEN
Background: 177Lu-oxodotreotide peptide receptor therapy (LuPRRT) is an efficient treatment for midgut neuroendocrine tumors (NETs) of variable radiological response. Several clinical, biological, and imaging parameters may be used to establish a relative disease prognosis but none is able to predict early efficacy or toxicities. We investigated expression levels for mRNA and miRNA involved in radiosensitivity and tumor progression searching for correlations related to patient outcome during LuPRRT therapy. Methods: Thirty-five patients received LuPRRT for G1/G2 midgut NETs between May 2019 and September 2021. Peripheral blood samples were collected prior to irradiation, before and 48 h after the second and the fourth LuPRRT, and at 6-month follow-up. Multiple regression analyses and Pearson correlations were performed to identify the miRNA/mRNA signature that will best predict response to LuPRRT. Results: Focusing on four mRNAs and three miRNAs, we identified a miRNA/mRNA signature enabling the early identification of responders to LuPRRT with significant reduced miRNA/mRNA expression after the first LuPRRT administration for patients with progressive disease at 1 year (p < 0.001). The relevance of this signature was reinforced by studying its evolution up to 6 months post-LuPRRT. Moreover, nadir absolute lymphocyte count within the first 2 months after the first LuPRRT administration was significantly related to low miRNA/mRNA expression level (p < 0.05) for patients with progressive disease. Conclusion: We present a pilot study exploring a miRNA/mRNA signature that correlates with early hematologic toxicity and therapeutic response 12 months following LuPRRT. This signature will be tested prospectively in a larger series of patients.
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Neoplasias Intestinales , MicroARNs , Tumores Neuroendocrinos , ARN Mensajero , Humanos , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/sangre , Tumores Neuroendocrinos/terapia , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/patología , Masculino , Femenino , MicroARNs/sangre , MicroARNs/genética , Persona de Mediana Edad , Neoplasias Intestinales/sangre , Neoplasias Intestinales/patología , Neoplasias Intestinales/genética , Neoplasias Intestinales/tratamiento farmacológico , ARN Mensajero/genética , ARN Mensajero/sangre , Anciano , Estudios de Seguimiento , Adulto , Pronóstico , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Somatostatina/análogos & derivados , Somatostatina/uso terapéutico , Receptores de Péptidos/genética , Radiofármacos/uso terapéutico , Radiofármacos/administración & dosificación , Lutecio , RadioisótoposRESUMEN
OBJECTIVE: We investigated metabolic tumor volume (MTV) and total lesion glycolysis (TLG) on pre-treatment FDG-PET as prognostic markers for survival in patients with metastatic neuroendocrine neoplasms (NENs) receiving peptide receptor radionuclide therapy (PRRT). METHODS: A retrospective review of patients with metastatic NENs receiving PRRT was undertaken. Pre-treatment FDG-PET images were analyzed and variables collected included MTV and TLG (dichotomized by median into high vs low). Main Outcomes were overall survival (OS) and progression-free survival (PFS) by MTV and TLG (high vs low). RESULTS: One hundred five patients were included. Median age was 64 years (50% male). Main primary NEN sites were small bowel (43.8%) and pancreas (40.0%). Median MTV was 3.8 mL and median TLG was 19.9. Dichotomization formed identical cohorts regardless of whether MTV or TLG were used. Median OS was 72 months; OS did not differ based on MTV/TLG high versus low (47.4 months vs not reached; hazard ratio, 0.43; 95% confidence interval [CI], 0.18-1.04; P = 0.0594). Median PFS was 30.4 months; PFS differed based on MTV/TLG high versus low (21.6 months vs 45.7 months; hazard ratio, 0.35; 95% CI, 0.19-0.64; P = 0.007). CONCLUSIONS: Low MTV/TLG on pre-treatment FDG-PET was associated with longer PFS in metastatic NEN patients receiving PRRT.
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Fluorodesoxiglucosa F18 , Tumores Neuroendocrinos , Octreótido , Compuestos Organometálicos , Tomografía de Emisión de Positrones , Radiofármacos , Carga Tumoral , Humanos , Masculino , Persona de Mediana Edad , Femenino , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/mortalidad , Estudios Retrospectivos , Anciano , Octreótido/análogos & derivados , Octreótido/uso terapéutico , Tomografía de Emisión de Positrones/métodos , Pronóstico , Compuestos Organometálicos/uso terapéutico , Adulto , Receptores de Péptidos/metabolismo , Glucólisis , Anciano de 80 o más Años , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/mortalidad , Supervivencia sin Progresión , Resultado del TratamientoRESUMEN
177Lu-DOTATATE therapy is an effective treatment for advanced neuroendocrine tumors, despite its dose-limiting hematotoxicity. Herein, the significance of off-target splenic irradiation is unknown. Our study aims to identify predictive markers of peptide receptor radionuclide therapy-induced leukopenia. Methods: We retrospectively analyzed blood counts and imaging data of 88 patients with histologically confirmed, unresectable metastatic neuroendocrine tumors who received 177Lu-DOTATATE treatment at our institution from February 2009 to July 2021. Inclusion criterium was a tumor uptake equivalent to or greater than that in the liver on baseline receptor imaging. We excluded patients with less than 24 mo of follow-up and those patients who received fewer than 4 treatment cycles, additional therapies, or blood transfusions during follow-up. Results: Our study revealed absolute and relative white blood cell counts and relative spleen volume reduction as independent predictors of radiation-induced leukopenia at 24 mo. However, a 30% decline in spleen volume 12 mo after treatment most accurately predicted patients proceeding to leukopenia at 24 mo (receiver operating characteristic area under the curve of 0.91, sensitivity of 0.93, and specificity of 0.90), outperforming all other parameters by far. Conclusion: Automated splenic volume assessments demonstrated superior predictive capabilities for the development of leukopenia in patients undergoing 177Lu-DOTATATE treatment compared with conventional laboratory parameters. The reduction in spleen size proves to be a valuable, routinely available, and quantitative imaging-based biomarker for predicting radiation-induced leukopenia. This suggests potential clinical applications for risk assessment and management.
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Leucopenia , Tumores Neuroendocrinos , Octreótido , Compuestos Organometálicos , Receptores de Péptidos , Bazo , Humanos , Femenino , Leucopenia/etiología , Masculino , Bazo/diagnóstico por imagen , Bazo/efectos de la radiación , Persona de Mediana Edad , Octreótido/análogos & derivados , Octreótido/uso terapéutico , Octreótido/efectos adversos , Estudios Retrospectivos , Anciano , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/diagnóstico por imagen , Receptores de Péptidos/metabolismo , Compuestos Organometálicos/efectos adversos , Compuestos Organometálicos/uso terapéutico , Tamaño de los Órganos , Adulto , Biomarcadores , Anciano de 80 o más AñosRESUMEN
Purpose: In a prior, retrospective study, 76% of patients with advanced neuroendocrine tumors undergoing 177Lu-DOTATOC molecular radiotherapy (MRT) showed their best response within 8 months from the first MRT cycle. In 24% of patients, latency was much greater up to >22 months after the first cycle, and long after near-complete decay of 177Lu from the last cycle. An immune response induced by MRT seems a likely explanation. As a crude measure of immunocompetence, the authors investigated whether blood cell counts (BCCs) may have predictive value for MRT outcome with 177Lu-DOTATOC. Methods: 56 Patients with neuroendocrine tumors (NET) were administered 177Lu-DOTATOC (mean 2.1 cycles; range 1-4) with median radioactivity of 7.0 GBq/cycle at 3-month intervals. Patients' BCCs were evaluated for four responder categories: CR, PR, SD, and PD (RECIST 1.1). Furthermore, baseline BCCs were correlated with progression-free survival (PFS). Finally, BCCs of patients with (PMT+) and without prior medical therapy (PMT-) were compared. Results: Significant differences between responder categories were found for baseline hemoglobin (Hb), erythrocytes, neutrophils, lymphocytes, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and LEHN-score, integrating lymphocyte, erythrocyte, and neutrophil counts, and Hb level, but not for leukocytes and platelets. LEHN-score yielded an almost complete separation between CR and PD groups. In analogy, PFS times showed significant correlations with baseline Hb, erythrocytes, neutrophils, lymphocytes, NLR, PLR, and LEHN-score, the LEHN-score showing the strongest correlation, but not with leukocytes and platelets. For PMT- patients, median PFS was 34.5 months, compared with 20.8 months in PMT+ patients, with corresponding baseline lymphocyte (32.1 ± 9.6% vs. 24.5 ± 11.6%, p = 0.028) and neutrophil (54.9 ± 11.6% vs. 63.5 ± 13.7%, p = 0.039) counts. Conclusion: These findings emphasize the significance of an immune response to MRT for obtaining optimal therapy efficacy and support concepts to enhance the immune response of less immunocompetent patients before MRT. It seems advisable to avoid prior or concomitant immunosuppressant medical therapy.
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Tumores Neuroendocrinos , Octreótido , Humanos , Femenino , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/inmunología , Tumores Neuroendocrinos/sangre , Persona de Mediana Edad , Masculino , Octreótido/análogos & derivados , Octreótido/uso terapéutico , Anciano , Adulto , Estudios Retrospectivos , Recuento de Células Sanguíneas , Valor Predictivo de las Pruebas , Resultado del Tratamiento , Anciano de 80 o más Años , Lutecio/uso terapéutico , Supervivencia sin ProgresiónRESUMEN
Theragnostics represents one of the most innovative fields of precision medicine with a huge potential in the field of oncology in the next years. The use of a pair of selective radiopharmaceuticals for cellular receptors, used for diagnostic and therapeutic purposes (PRRT), finds applications in the Neuroendocrine tumors and metastatic Castration-Resistant prostate cancer (mCRPC) thanks, respectively, to somatostatin receptor agonists and PSMA-based peptides. Further evolutions of theragnostics will be possible to the radioimmunoconjugates used both in the diagnostic (Immuno-PET) and in the therapeutic fields (radioimmunotherapy). It is evident that in the "omics-era," theragnostics could become a necessary method, not only in order to improve our knowledge of tumor biology, but also, to find more and more targeted therapies in a multidisciplinary context and in a tailor-based approach.
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Medicina de Precisión , Humanos , Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/radioterapia , Medicina de Precisión/métodos , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico por imagen , Radiofármacos/uso terapéutico , MasculinoRESUMEN
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
The benefit of multicompartment dosimetry in the radioembolization of neuroendocrine neoplasms is not firmly established. We retrospectively assessed its potential with patient outcome. Methods: Forty-three patients were eligible. The association of mean absorbed dose (MAD) for tumors and treatment response was tested per lesion with a receiver operating characteristic curve analysis, and the association of MAD with progression-free survival (PFS) and overall survival was tested per patient using uni- and multivariate Cox regression analyses. Results: The area under the curve for treatment response based on MAD was 0.79 (cutoff, 196.6 Gy; P < 0.0001). For global PFS, grade (grade 2 vs. 1: hazard ratio [HR], 2.51; P = 0.042; grade 3 vs. 1: HR, 62.44; P < 0.001), tumor origin (HR, 6.58; P < 0.001), and MAD (HR, 0.998; P = 0.003) were significant. For overall survival, no prognostic parameters were significant. Conclusion: In line with prior publications, a MAD of more than 200 Gy seemed to favor treatment response. MAD was also associated with PFS and may be of interest for radioembolization planning for neuroendocrine neoplasm patients.
Asunto(s)
Relación Dosis-Respuesta en la Radiación , Embolización Terapéutica , Neoplasias Hepáticas , Microesferas , Tumores Neuroendocrinos , Radioisótopos de Itrio , Humanos , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/patología , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/secundario , Masculino , Femenino , Radioisótopos de Itrio/uso terapéutico , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Adulto , Vidrio/química , Resultado del Tratamiento , Anciano de 80 o más AñosRESUMEN
PURPOSE: The aim of this study was to assess the association among toxicity, dosimetry of organs-at-risk, and disease progression in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with 177 Lu-DOTATATE. PATIENTS AND METHODS: Thirty-seven patients with GEP-NETs underwent 177 Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in a single-arm, prospective, phase 2 study, where patients were followed up with blood tests, isotopic glomerular filtration rate (iGFR), and imaging examinations (CT/MRI and PET) every 6 months until disease progression. Adverse events (AEs) graded per CTCAEv4.03 and occurring during treatment were collected and followed up until resolution. Dosimetry, including biologically effective doses (BEDs) to kidneys, BED to bone marrow, and absorbed dose (AD) to spleen, was performed after each PRRT cycle. Statistical analyses explored associations among dosimetry, toxicity, and patient progression free-survival. RESULTS: The most common AEs were anemia and lymphopenia (65%), followed by thrombocytopenia and fatigue (each 51%), alopecia (46%), and nausea (41%). The most common grade ≥3 AE was lymphopenia (43%). There was no grade ≥3 nephrotoxicity. The median iGFR % decrease was 11% ( P < 0.001), at a median follow-up of 23 months. iGFR %decrease and renal BED did not correlate (Spearman ρ = -0.09). Similarly, no significant association was found between bone marrow BED or spleen AD and the grades of hematological toxicities. We observed no association between progression free-survival and either the decline of renal function or the occurrence of hematological toxicities during PRRT. CONCLUSIONS: This study confirms the safety profile of 177 Lu-DOTATATE PRRT in patients with GEP-NETs irrespective of the dosimetry of organs at risk. Kidney, bone marrow, and spleen dosimetry measures were not associated with renal or hematological toxicity.
Asunto(s)
Neoplasias Intestinales , Tumores Neuroendocrinos , Octreótido , Compuestos Organometálicos , Órganos en Riesgo , Neoplasias Pancreáticas , Radiometría , Neoplasias Gástricas , Humanos , Tumores Neuroendocrinos/radioterapia , Masculino , Femenino , Compuestos Organometálicos/efectos adversos , Octreótido/análogos & derivados , Octreótido/efectos adversos , Octreótido/uso terapéutico , Persona de Mediana Edad , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/diagnóstico por imagen , Estudios Prospectivos , Anciano , Neoplasias Gástricas/radioterapia , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Intestinales/radioterapia , Órganos en Riesgo/efectos de la radiación , Adulto , Seguridad , Receptores de Péptidos , Anciano de 80 o más AñosRESUMEN
In the evolving landscape of precision medicine, NET-targeted radiopharmaceuticals are emerging as pivotal tools for the diagnosis and treatment of a range of conditions, from heart failure and neurodegenerative disorders to neuroendocrine cancers. This review evaluates the advancements offered by 18F-labeled PET tracers and 211At alpha-particle therapy, juxtaposed with current 123I-MIBG SPECT and 131I-MIBG therapies. The enhanced spatial resolution and capability for quantitative analysis render 18F-labeled PET tracers potential candidates for improved detection and management of diseases. Alpha-particle therapy with 211At may offer increased specificity and tumoricidal efficacy, pointing towards a shift in therapeutic protocols. While preliminary data is promising, these innovative approaches require thorough validation against current modalities. Ongoing clinical trials are pivotal to confirm the expected clinical benefits and to address safety concerns. This review underscores the need for rigorous research to verify the clinical utility of NET-targeted radiopharmaceuticals, which may redefine precision medicine paradigms and significantly impact patient care.
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Tumores Neuroendocrinos , Medicina de Precisión , Radiofármacos , Humanos , Medicina de Precisión/métodos , Medicina de Precisión/tendencias , Radiofármacos/uso terapéutico , Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/radioterapia , Tomografía de Emisión de Positrones/métodos , AnimalesRESUMEN
PURPOSE: This study aimed to develop a user-friendly prediction formula for dose rate adjustment after initial 177Lu-Dotatate therapy from a prospective observational study of patients. MATERIALS AND METHODS: This study included consenting patients in a prospective observational study who underwent their first treatment in four cycles of 177Lu-Dotatate treatment at our hospital between January 2022 and February 2024. All patients received 7.4 GBq of 177Lu-Dotatate. The prediction formula was derived from the regression analysis of tumor-related factors and renal function. Creatinine clearance was estimated using the Cockcroft-Gault equation in this study for renal function. RESULTS: Among the 13 patients (seven males, six females, median age: 59 years), logarithmically transformed total tumor volume (cc) and maximum tumor diameter (mm) of primary tumors or metastases showed strong correlations (p < 0.001, R2 = 0.897). As such, the maximum tumor diameter was used as the tumor parameter in the prediction formula. Additionally, maximum tumor diameter and creatinine clearance showed strong (p < 0.001, R2 = 0.768) and moderate (p = 0.013, R2 = 445) correlations, respectively, with the ratio of the dose rate 5.5-h post-administration to the dose rate immediately post-administration (%) at 1 m from the body surface. The resulting formula, 51.4 + 0.360 × maximum tumor diameter (mm) - 0.212 × creatinine clearance (ml/min), demonstrated an extremely strong correlation (p < 0.001, R2 = 0.937). CONCLUSION: The present study showed that the maximum tumor diameter and renal function affected the declining the dose rate of patients surface after 177Lu-Dotatate, which can inform post-administration dose rate management and potentially facilitate outpatient treatment in Japan.
Asunto(s)
Octreótido , Compuestos Organometálicos , Humanos , Masculino , Femenino , Persona de Mediana Edad , Compuestos Organometálicos/uso terapéutico , Compuestos Organometálicos/administración & dosificación , Octreótido/análogos & derivados , Octreótido/uso terapéutico , Octreótido/administración & dosificación , Estudios Prospectivos , Anciano , Japón , Adulto , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/diagnóstico por imagen , Carga Tumoral , Radiofármacos/uso terapéutico , Riñón/diagnóstico por imagen , Riñón/patología , Pruebas de Función Renal/métodos , Dosificación RadioterapéuticaRESUMEN
PURPOSE: Somatostatin receptor (SSTR) imaging features are predictive of treatment outcome for neuroendocrine tumor (NET) patients receiving peptide receptor radionuclide therapy (PRRT). However, comprehensive (all metastatic lesions), longitudinal (temporal variation), and lesion-level measured features have never been explored. Such features allow for capturing the heterogeneity in disease response to treatment. Furthermore, models combining these features are lacking. In this work we evaluated the predictive power of comprehensive, longitudinal, lesion-level 68GA-SSTR-PET features combined with a multivariate linear regression (MLR) model. METHODS: This retrospective study enrolled NET patients treated with [177Lu]Lu-DOTA-TATE and imaged with [68Ga]Ga-DOTA-TATE at baseline and post-therapy. All lesions were segmented, anatomically labeled, and longitudinally matched. Lesion-level uptake and variation in uptake were measured. Patient-level features were engineered and selected for modeling of progression-free survival (PFS). The model was validated via concordance index, patient classification (ROC analysis), and survival analysis (Kaplan-Meier and Cox proportional hazards). The MLR was benchmarked against single feature predictions. RESULTS: Thirty-six NET patients were enrolled and stratified into poor and good responders (PFS ≥ 25 months). Four patient-level features were selected, the MLR concordance index was 0.826, and the AUC was 0.88 (0.85 specificity, 0.81 sensitivity). Survival analysis led to significant patient stratification (p<.001) and hazard ratio (3⨯10-5). Lastly, in a benchmark study, the MLR modeling approach outperformed all the single feature predictors. CONCLUSION: Comprehensive, lesion-level, longitudinal 68GA-SSTR-PET analysis, combined with MLR modeling, leads to excellent predictions of PRRT outcome in NET patients, outperforming non-comprehensive, patient-level, and single time-point feature predictions. MESSAGE: Neuroendocrine tumor, peptide receptor radionuclide therapy, Somatostatin Receptor Imaging, Outcome Prediction, Treatment Response Assessment.